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diff --git a/gn3/llms/pub_med.json b/gn3/llms/pub_med.json deleted file mode 100644 index 193be14..0000000 --- a/gn3/llms/pub_med.json +++ /dev/null @@ -1,29590 +0,0 @@ -{ - "5d9d5e09-f80b-496a-b6b2-dfc7d7cf7f2b": [ - { - "pub_id": "31185988", - "title": "Machine-learning to stratify diabetic patients using novel cardiac biomarkers and integrative genomics.", - "authors": "Quincy A Hathaway,Skyler M Roth,Mark V Pinti,Daniel C Sprando,Amina Kunovac,Andrya J Durr,Chris C Cook,Garrett K Fink,Tristen B Cheuvront,Jasmine H Grossman,Ghadah A Aljahli,Andrew D Taylor,Andrew P Giromini,Jessica L Allen,John M Hollander", - "abstract": "Diabetes mellitus is a chronic disease that impacts an increasing percentage of people each year. Among its comorbidities, diabetics are two to four times more likely to develop cardiovascular diseases. While HbA1c remains the primary diagnostic for diabetics, its ability to predict long-term, health outcomes across diverse demographics, ethnic groups, and at a personalized level are limited. The purpose of this study was to provide a model for precision medicine through the implementation of machine-learning algorithms using multiple cardiac biomarkers as a means for predicting diabetes mellitus development. Right atrial appendages from 50 patients, 30 non-diabetic and 20 type 2 diabetic, were procured from the WVU Ruby Memorial Hospital. Machine-learning was applied to physiological, biochemical, and sequencing data for each patient. Supervised learning implementing SHapley Additive exPlanations (SHAP) allowed binary (no diabetes or type 2 diabetes) and multiple classification (no diabetes, prediabetes, and type 2 diabetes) of the patient cohort with and without the inclusion of HbA1c levels. Findings were validated through Logistic Regression (LR), Linear Discriminant Analysis (LDA), Gaussian Na\u00efve Bayes (NB), Support Vector Machine (SVM), and Classification and Regression Tree (CART) models with tenfold cross validation. Total nuclear methylation and hydroxymethylation were highly correlated to diabetic status, with nuclear methylation and mitochondrial electron transport chain (ETC) activities achieving superior testing accuracies in the predictive model (~\u200984% testing, binary). Mitochondrial DNA SNPs found in the D-Loop region (SNP-73G, -16126C, and -16362C) were highly associated with diabetes mellitus. The CpG island of transcription factor A, mitochondrial (TFAM) revealed CpG24 (chr10:58385262, P\u2009=\u20090.003) and CpG29 (chr10:58385324, P\u2009=\u20090.001) as markers correlating with diabetic progression. When combining the most predictive factors from each set, total nuclear methylation and CpG24 methylation were the best diagnostic measures in both binary and multiple classification sets. Using machine-learning, we were able to identify novel as well as the most relevant biomarkers associated with type 2 diabetes mellitus by integrating physiological, biochemical, and sequencing datasets. Ultimately, this approach may be used as a guideline for future investigations into disease pathogenesis and novel biomarker discovery.", - "journal_title": "Cardiovascular diabetology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/31185988/" - } - ], - "733e85a8-8ba1-4aae-8ce0-8597faaeefc7": [ - { - "pub_id": "25660258", - "title": "The 6 year incidence of diabetes-associated autoantibodies in genetically at-risk children: the TEDDY study.", - "authors": "Jeffrey P Krischer,Kristian F Lynch,Desmond A Schatz,Jorma Ilonen,\u00c5ke Lernmark,William A Hagopian,Marian J Rewers,Jin-Xiong She,Olli G Simell,Jorma Toppari,Anette-G Ziegler,Beena Akolkar,Ezio Bonifacio, ", - "abstract": "Islet autoantibodies, in addition to elevated blood glucose, define type 1 diabetes. These autoantibodies are detectable for a variable period of time before diabetes onset. Thus, the occurrence of islet autoantibodies is associated with the beginning of the disease process. The age at, and order in, which autoantibodies appear may be associated with different genetic backgrounds or environmental exposures, or both. Infants with HLA-DR high-risk genotypes (DR3/4, DR4/4, DR4/8 and DR3/3) were enrolled and prospectively followed with standardised autoantibody assessments quarterly throughout the first 4\u00a0years of life and then semi-annually thereafter. Autoantibodies appeared in 549/8,503 (6.5%) children during 34,091 person-years of follow-up. Autoantibodies at 3 (0.1%) and 6 (0.2%) months of age were rare. Of the 549, 43.7% had islet autoantibodies to insulin (IAA) only, 37.7% had glutamic acid decarboxylase autoantibodies (GADA) only, 13.8% had both GADA and IAA only, 1.6% had insulinoma antigen-2 only and 3.1% had other combinations. The incidence of IAA only peaked within the first year of life and declined over the following 5\u00a0years, but GADA only increased until the second year and remained relatively constant. GADA only were more common than IAA only in HLA-DR3/3 children but less common in HLA-DR4/8 children. Islet autoantibodies can occur very early in life and the order of appearance was related to HLA-DR-DQ genotype.", - "journal_title": "Diabetologia", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/25660258/" - } - ], - "7d331e2e-0bed-4d06-880f-f882c6d07214": [ - { - "pub_id": "12750858", - "title": "A functional polymorphism in the promoter/enhancer region of the FOXP3/Scurfin gene associated with type 1 diabetes.", - "authors": "Wafaa M Bassuny,Kenji Ihara,Yuka Sasaki,Ryuichi Kuromaru,Hitoshi Kohno,Nobuo Matsuura,Toshiro Hara", - "abstract": "FOXP3/Scurfin, a member of forkhead/winged-helix proteins, is involved in the regulation of T-cell activation, and essential for normal immune homeostasis. The FOXP3/Scurfin gene is located on chromosome Xp11.23, which includes one of the type 1 diabetes susceptible loci. Therefore, we investigated whether the human FOXP3/Scurfin gene might be a new candidate gene for type 1 diabetes. We first screened the human FOXP3/Scurfin gene for microsatellite and single nucleotide polymorphisms. Next, we performed an association study between the FOXP3/Scurfin gene and type 1 diabetes. Then, the evaluation of promoter/enhancer activity of the intron with (GT)(n) polymorphism was performed by dual luciferase reporter assay. We demonstrated two regions contained microsatellite polymorphisms; one was (GT)(n), located on intron zero and the other (TC)(n) on intron 5, which were under linkage-disequilibrium. The (GT)(15) allele showed a significantly higher frequency in patients with type 1 diabetes than in controls (43.1% vs 32.6%, P=0.0027). The genotype frequencies of (GT)(15)/(GT)(15) in female patients and of (GT)(15) in male patients tended to be higher than those in female ( P=0.064) and male ( P=0.061) controls, respectively. A significant difference in the enhancer activity between (GT)(15) and (GT)(16) dinucleotide repeats was detected. In conclusion, the FOXP3/Scurfin gene appears to confer a significant susceptibility to type 1 diabetes in the Japanese population.", - "journal_title": "Immunogenetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/12750858/" - } - ], - "2ad3a7ba-8f21-4a1d-a92d-a3b3c9aa02e0": [ - { - "pub_id": "28918587", - "title": "Genome-wide association studies of albuminuria: towards genetic stratification in diabetes?", - "authors": "Cristian Pattaro", - "abstract": "Genome-wide association studies (GWAS) have been very successful in unraveling the polygenic structure of several complex diseases and traits. In the case of albuminuria, despite the large sample size achieved by some studies, results look sparse with a limited number of loci reported so far. This review searched for GWAS studies of albumin excretion, albuminuria, and proteinuria. The resulting picture sets elements of uniqueness for albuminuria GWAS with respect to other complex traits. So far, very few loci associated with albuminuria have been validated by means of genome-wide significant evidence or formal replication. With rare exceptions, the validated loci are ethnicity specific. Within a given ethnicity, variants are common and have relatively large effects, especially in the presence of diabetes. In most cases, the identified variants were functional and a biological involvement of the target genes in renal damage was established. Recently reported variants associated with albuminuria in diabetes may be potentially combined into a genetic risk score, making it possible to rank diabetic patients by increasing risk of albuminuria. Validation of this model is required. To expand the understanding of the biological basis of albumin excretion regulation, future initiatives should achieve larger sample sizes and favor a transethnic study design.", - "journal_title": "Journal of nephrology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/28918587/" - } - ], - "a644f3d8-5b62-4416-b787-66c0de198beb": [ - { - "pub_id": "32488059", - "title": "Fine-tuning of Genome-Wide Polygenic Risk Scores and Prediction of Gestational Diabetes in South Asian Women.", - "authors": "Amel Lamri,Shihong Mao,Dipika Desai,Milan Gupta,Guillaume Par\u00e9,Sonia S Anand", - "abstract": "Gestational diabetes Mellitus (GDM) affects 1 in 7 births and is associated with numerous adverse health outcomes for both mother and child. GDM is suspected to share a large common genetic background with type 2 diabetes (T2D). The aim of our study was to characterize different GDM polygenic risk scores (PRSs) and test their association with GDM using data from the South Asian Birth Cohort (START). PRSs were derived for 832 South Asian women from START using the pruning and thresholding (P\u2009+\u2009T), LDpred, and GraBLD methods. Weights were derived from a multi-ethnic and a white Caucasian study of the DIAGRAM consortium. GDM status was defined using South Asian-specific glucose values in response to an oral glucose tolerance test. Association with GDM was tested using logistic regression. Results were replicated in South Asian women from the UK Biobank (UKB) study. The top ranking\u00a0P\u2009+\u2009T, LDpred and GraBLD PRSs were all based on DIAGRAM's multi-ethnic study. The best PRS was highly associated with GDM in START (AUC\u2009=\u20090.62, OR\u2009=\u20091.60 [95% CI\u2009=\u20091.44-1.69]), and in South Asian women from UKB (AUC\u2009=\u20090.65, OR\u2009=\u20091.69 [95% CI\u2009=\u20091.28-2.24]). Our results highlight the importance of combining genome-wide genotypes and summary statistics from large multi-ethnic studies to optimize PRSs in South Asians.", - "journal_title": "Scientific reports", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/32488059/" - } - ], - "713ad3a2-efa9-44af-8639-f4e67efc7001": [ - { - "pub_id": "18368358", - "title": "Interoperability across neuroscience databases.", - "authors": "Luis Marenco,Prakash Nadkarni,Maryann Martone,Amarnath Gupta", - "abstract": "Data interoperability between well-defined domains is currently performed by leveraging Web services. In the biosciences, more specifically in neuroscience, robust data interoperability is more difficult to achieve due to data heterogeneity, continuous domain changes, and the constant creation of new semantic data models (Nadkarni et al., J Am Med Inform Assoc 6, 478-93, 1999; Miller et al., J Am Med Inform Assoc 8, 34-48, 2001; Gardner et al., J Am Med Inform Assoc 8, 17-33, 2001). Data heterogeneity in neurosciences is primarily due to its multidisciplinary nature. This results in a compelling need to integrate all available neuroscience information to improve our understanding of the brain. Researchers associated with neuroscience initiatives such as the human brain project (HBP) (Koslow and Huerta, Neuroinformatics: An Overview of the Human Brain Project, 1997), the Bioinformatics Research Network (BIRN), and the Neuroinformatics Information Framework (NIF) are exploring mechanisms to allow robust interoperability between these continuously evolving neuroscience databases. To accomplish this goal, it is crucial to orchestrate technologies such as database mediators, metadata repositories, semantic metadata annotations, and ontological services. This chapter introduces the importance of database interoperability in neurosciences. We also describe current data sharing and integration mechanisms in genera. We conclude with data integration in bioscience and present approaches on neuroscience data sharing.", - "journal_title": "Methods in molecular biology (Clifton, N.J.)", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/18368358/" - } - ], - "7f5fa726-75d1-47c9-a6d7-dae36b0cb211": [ - { - "pub_id": "34435740", - "title": "Deep intronic variant in the ARSB gene as the genetic cause for Maroteaux-Lamy syndrome (MPS VI).", - "authors": "Dina Marek-Yagel,Aviva Eliyahu,Alvit Veber,Nechama Shalva,Amit Mary Philosoph,Ortal Barel,Elisheva Javasky,Ben Pode-Shakked,Neta Loewenthal,Yair Anikster,Orna Staretz-Chacham", - "abstract": "Maroteaux-Lamy syndrome (MPS-VI) is a rare autosomal-recessive disorder with a wide spectrum of clinical manifestations, ranging from an attenuated to a rapidly progressive disease. It is caused by variants in ARSB, which encodes the lysosomal arylsulfatase B (ARSB) enzyme, part of the degradation process of glycosaminoglycans in lysosomes. Over 220 variants have been reported so far, with a majority of missense variants. We hereby report two siblings of Bedouin origin with a diagnosis of MPS-VI. Western blots in patient fibroblasts revealed total absence of ARSB protein production. Complete sequencing of the coding region of ARSB did not identify a candidate disease-associated variant. However, deep sequencing of the noncoding region of ARSB by whole genome sequencing (WGS) revealed a c.1142+581A to G variant. The variant is located within intron 5 and fully segregated with the disease in the family. Determination of the genetic cause for these patients enabled targeted treatment by enzyme replacement therapy, along with appropriate genetic counseling and prenatal diagnosis for the family. These results highlight the advantage of WGS as a powerful tool, for improving the diagnostic rate of rare disease-causing variants, and emphasize the importance of studying deep intronic sequence variation as a cause of monogenic disorders.", - "journal_title": "American journal of medical genetics. Part A", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/34435740/" - } - ], - "8b086e53-79f4-498a-91e0-48f6217388d7": [ - { - "pub_id": "31264924", - "title": "A genome-wide association study implicates that the <i>TTC39C</i> gene is associated with diabetic maculopathy with decreased visual acuity.", - "authors": "Weihua Meng,Brian W Chan,Chinenyenwa Ezeonwumelu,Harry L H\u00e9bert,Amy Campbell,Vencent Soler,Colin Na Palmer", - "abstract": "<b>Background</b>: Diabetic maculopathy is a form of diabetic retinopathy. The visual acuity of one third of patients with diabetic maculopathy will be affected. The purpose of this study was to identify genetic contributors of diabetic maculopathy with decreased visual acuity based on a genome-wide association approach using a well-defined Scottish diabetic cohort. <b>Methods</b>: We used linked e-health records of diabetic patients to define our cases and controls. The cases in this study were defined as type 2 diabetic patients who had ever been recorded in the linked e-health records as having maculopathy (observable or referable) in at least one eye and whose visual acuity of the eye was recorded to have decreased between the first and the last visual acuity record of that eye in the longitudinal e-health records. The controls were defined as a type 2 diabetic individual who had never been diagnosed with maculopathy or retinopathy in the linked e-health records. Anyone who had laser photocoagulation treatment was also excluded from the controls. A standard genome-wide association approach was applied. <b>Results</b>: Overall, we identified 469 cases and 1,374 controls within the Genetics of Diabetes Audit and Research in Tayside Scotland (GoDARTS) dataset. We found that the <i>P</i> value of rs9966620 in the <i>TTC39C</i> gene was 4.13x10<sup>-8</sup>, which reached genome-wide significance. <b>Conclusions</b>: We suggest that the <i>TTC39C</i> gene is associated with diabetic maculopathy with decreased visual acuity. This needs to be confirmed by further replication studies and functional studies.", - "journal_title": "Ophthalmic genetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/31264924/" - } - ], - "09218e05-177e-438a-9526-a7572ecfbf6a": [ - { - "pub_id": "23348805", - "title": "Mutations in the genes encoding the transcription factors hepatocyte nuclear factor 1 alpha and 4 alpha in maturity-onset diabetes of the young and hyperinsulinemic hypoglycemia.", - "authors": "Kevin Colclough,Christine Bellanne-Chantelot,Cecile Saint-Martin,Sarah E Flanagan,Sian Ellard", - "abstract": "Maturity-onset diabetes of the young (MODY) is a monogenic disorder characterized by autosomal dominant inheritance of young-onset (typically <25 years), noninsulin-dependent diabetes due to defective insulin secretion. MODY is both clinically and genetically heterogeneous with mutations in at least 10 genes. Mutations in the HNF1A gene encoding hepatocyte nuclear factor-1 alpha are the most common cause of MODY in most adult populations studied. The number of different pathogenic HNF1A mutations totals 414 in 1,247 families. Mutations in the HNF4A gene encoding hepatocyte nuclear factor-4 alpha are a rarer cause of MODY with 103 different mutations reported in 173 families to date. Sensitivity to treatment with sulfonylurea tablets is a feature of both HNF1A and HNF4A mutations. The HNF4A MODY phenotype has been expanded by the reports of macrosomia in \u223c50% of babies, and more rarely, neonatal hyperinsulinemic hypoglycemia. The identification of an HNF1A or HNF4A gene mutation has important implications for clinical management in diabetes and pregnancy, but MODY is significantly underdiagnosed. Current research is focused on identifying biomarkers and developing probability models to identify those patients most likely to have MODY, until next generation sequencing technology enables cost-effective gene analysis for all patients with young onset diabetes.", - "journal_title": "Human mutation", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/23348805/" - } - ], - "ccaaa580-3fb9-4b14-b048-42934a198adf": [ - { - "pub_id": "16415884", - "title": "Variant of transcription factor 7-like 2 (TCF7L2) gene confers risk of type 2 diabetes.", - "authors": "Struan F A Grant,Gudmar Thorleifsson,Inga Reynisdottir,Rafn Benediktsson,Andrei Manolescu,Jesus Sainz,Agnar Helgason,Hreinn Stefansson,Valur Emilsson,Anna Helgadottir,Unnur Styrkarsdottir,Kristinn P Magnusson,G Bragi Walters,Ebba Palsdottir,Thorbjorg Jonsdottir,Thorunn Gudmundsdottir,Arnaldur Gylfason,Jona Saemundsdottir,Robert L Wilensky,Muredach P Reilly,Daniel J Rader,Yu Bagger,Claus Christiansen,Vilmundur Gudnason,Gunnar Sigurdsson,Unnur Thorsteinsdottir,Jeffrey R Gulcher,Augustine Kong,Kari Stefansson", - "abstract": "We have previously reported suggestive linkage of type 2 diabetes mellitus to chromosome 10q. We genotyped 228 microsatellite markers in Icelandic individuals with type 2 diabetes and controls throughout a 10.5-Mb interval on 10q. A microsatellite, DG10S478, within intron 3 of the transcription factor 7-like 2 gene (TCF7L2; formerly TCF4) was associated with type 2 diabetes (P = 2.1 x 10(-9)). This was replicated in a Danish cohort (P = 4.8 x 10(-3)) and in a US cohort (P = 3.3 x 10(-9)). Compared with non-carriers, heterozygous and homozygous carriers of the at-risk alleles (38% and 7% of the population, respectively) have relative risks of 1.45 and 2.41. This corresponds to a population attributable risk of 21%. The TCF7L2 gene product is a high mobility group box-containing transcription factor previously implicated in blood glucose homeostasis. It is thought to act through regulation of proglucagon gene expression in enteroendocrine cells via the Wnt signaling pathway.", - "journal_title": "Nature genetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/16415884/" - } - ], - "9b0c38a0-79b3-4680-b47a-177dfe307957": [ - { - "pub_id": "20165882", - "title": "High-throughput assessment of CpG site methylation for distinguishing between HCV-cirrhosis and HCV-associated hepatocellular carcinoma.", - "authors": "Kellie J Archer,Valeria R Mas,Daniel G Maluf,Robert A Fisher", - "abstract": "Methylation of promoter CpG islands has been associated with gene silencing and demonstrated to lead to chromosomal instability. Therefore, some postulate that aberrantly methylated CpG regions may be important biomarkers indicative of cancer development. In this study we used the Illumina GoldenGate Methylation BeadArray Cancer Panel I for simultaneously profiling methylation of 1,505 CpG sites in order to identify methylation differences in 76 liver tissues ranging from normal to pre-neoplastic and neoplastic states. CpG sites for ESR1, GSTM2, and MME were significantly differentially methylated when comparing the pre-neoplastic tissues from patients with concomitant hepatocellular carcinoma (HCC) to the pre-neoplastic tissues from patients without HCC. When comparing paired HCC tissues to their corresponding pre-neoplastic non-tumorous tissues, eight CpG sites, including one CpG site that was hypermethylated (APC) and seven (NOTCH4, EMR3, HDAC9, DCL1, HLA-DOA, HLA-DPA1, and ERN1) that were hypomethylated in HCC, were identified. Our study demonstrates that high-throughput methylation technologies may be used to identify differentially methylated CpG sites that may prove to be important molecular events involved in carcinogenesis.", - "journal_title": "Molecular genetics and genomics : MGG", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/20165882/" - } - ], - "b16d3c53-cf17-44cd-b1ec-ffd293e92ec5": [ - { - "pub_id": "20140211", - "title": "Gut microbiota in human adults with type 2 diabetes differs from non-diabetic adults.", - "authors": "Nadja Larsen,Finn K Vogensen,Frans W J van den Berg,Dennis Sandris Nielsen,Anne Sofie Andreasen,Bente K Pedersen,Waleed Abu Al-Soud,S\u00f8ren J S\u00f8rensen,Lars H Hansen,Mogens Jakobsen", - "abstract": "Recent evidence suggests that there is a link between metabolic diseases and bacterial populations in the gut. The aim of this study was to assess the differences between the composition of the intestinal microbiota in humans with type 2 diabetes and non-diabetic persons as control. The study included 36 male adults with a broad range of age and body-mass indices (BMIs), among which 18 subjects were diagnosed with diabetes type 2. The fecal bacterial composition was investigated by real-time quantitative PCR (qPCR) and in a subgroup of subjects (N = 20) by tag-encoded amplicon pyrosequencing of the V4 region of the 16S rRNA gene. The proportions of phylum Firmicutes and class Clostridia were significantly reduced in the diabetic group compared to the control group (P = 0.03). Furthermore, the ratios of Bacteroidetes to Firmicutes as well as the ratios of Bacteroides-Prevotella group to C. coccoides-E. rectale group correlated positively and significantly with plasma glucose concentration (P = 0.04) but not with BMIs. Similarly, class Betaproteobacteria was highly enriched in diabetic compared to non-diabetic persons (P = 0.02) and positively correlated with plasma glucose (P = 0.04). The results of this study indicate that type 2 diabetes in humans is associated with compositional changes in intestinal microbiota. The level of glucose tolerance should be considered when linking microbiota with metabolic diseases such as obesity and developing strategies to control metabolic diseases by modifying the gut microbiota.", - "journal_title": "PloS one", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/20140211/" - } - ], - "92eb0c69-5e98-41aa-9084-506e7f223b1a": [ - { - "pub_id": "28138367", - "title": "Machine Learning and Data Mining Methods in Diabetes Research.", - "authors": "Ioannis Kavakiotis,Olga Tsave,Athanasios Salifoglou,Nicos Maglaveras,Ioannis Vlahavas,Ioanna Chouvarda", - "abstract": "The remarkable advances in biotechnology and health sciences have led to a significant production of data, such as high throughput genetic data and clinical information, generated from large Electronic Health Records (EHRs). To this end, application of machine learning and data mining methods in biosciences is presently, more than ever before, vital and indispensable in efforts to transform intelligently all available information into valuable knowledge. Diabetes mellitus (DM) is defined as a group of metabolic disorders exerting significant pressure on human health worldwide. Extensive research in all aspects of diabetes (diagnosis, etiopathophysiology, therapy, etc.) has led to the generation of huge amounts of data. The aim of the present study is to conduct a systematic review of the applications of machine learning, data mining techniques and tools in the field of diabetes research with respect to a) Prediction and Diagnosis, b) Diabetic Complications, c) Genetic Background and Environment, and e) Health Care and Management with the first category appearing to be the most popular. A wide range of machine learning algorithms were employed. In general, 85% of those used were characterized by supervised learning approaches and 15% by unsupervised ones, and more specifically, association rules. Support vector machines (SVM) arise as the most successful and widely used algorithm. Concerning the type of data, clinical datasets were mainly used. The title applications in the selected articles project the usefulness of extracting valuable knowledge leading to new hypotheses targeting deeper understanding and further investigation in DM.", - "journal_title": "Computational and structural biotechnology journal", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/28138367/" - } - ], - "09cad84f-bc56-430e-861a-b2cad49af9d9": [ - { - "pub_id": "36547967", - "title": "Association of Metformin With the Development of Age-Related Macular Degeneration.", - "authors": "Amitha Domalpally,Samuel A Whittier,Qing Pan,Dana M Dabelea,Christine H Darwin,William C Knowler,Christine G Lee,Jose A Luchsinger,Neil H White,Emily Y Chew, ", - "abstract": "Age-related macular degeneration (AMD) is a leading cause of blindness with no treatment available for early stages. Retrospective studies have shown an association between metformin and reduced risk of AMD. To investigate the association between metformin use and age-related macular degeneration (AMD). The Diabetes Prevention Program Outcomes Study is a cross-sectional follow-up phase of a large multicenter randomized clinical trial, Diabetes Prevention Program (1996-2001), to investigate the association of treatment with metformin or an intensive lifestyle modification vs placebo with preventing the onset of type 2 diabetes in a population at high risk for developing diabetes. Participants with retinal imaging at a follow-up visit 16 years posttrial (2017-2019) were included. Analysis took place between October 2019 and May 2022. Participants were randomly distributed between 3 interventional arms: lifestyle, metformin, and placebo. Prevalence of AMD in the treatment arms. Of 1592 participants, 514 (32.3%) were in the lifestyle arm, 549 (34.5%) were in the metformin arm, and 529 (33.2%) were in the placebo arm. All 3 arms were balanced for baseline characteristics including age (mean [SD] age at randomization, 49 [9] years), sex (1128 [71%] male), race and ethnicity (784 [49%] White), smoking habits, body mass index, and education level. AMD was identified in 479 participants (30.1%); 229 (14.4%) had early AMD, 218 (13.7%) had intermediate AMD, and 32 (2.0%) had advanced AMD. There was no significant difference in the presence of AMD between the 3 groups: 152 (29.6%) in the lifestyle arm, 165 (30.2%) in the metformin arm, and 162 (30.7%) in the placebo arm. There was also no difference in the distribution of early, intermediate, and advanced AMD between the intervention groups. Mean duration of metformin use was similar for those with and without AMD (mean [SD], 8.0 [9.3] vs 8.5 [9.3] years; P\u2009=\u2009.69). In the multivariate models, history of smoking was associated with increased risks of AMD (odds ratio, 1.30; 95% CI, 1.05-1.61; P\u2009=\u2009.02). These data suggest neither metformin nor lifestyle changes initiated for diabetes prevention were associated with the risk of any AMD, with similar results for AMD severity. Duration of metformin use was also not associated with AMD. This analysis does not address the association of metformin with incidence or progression of AMD.", - "journal_title": "JAMA ophthalmology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/36547967/" - } - ], - "2c6178fe-c05a-42e6-aafb-7408592dcc50": [ - { - "pub_id": "15043217", - "title": "WebQTL: web-based complex trait analysis.", - "authors": "Jintao Wang,Robert W Williams,Kenneth F Manly", - "abstract": "WebQTL is a website that combines databases of complex traits with fast software for mapping quantitative trait loci (QTLs) and for searching for correlations among traits. WebQTL also includes well-curated genotype data for five sets of mouse recombinant inbred (RI) lines. Thus, to identify QTLs, users need provide only quantitative trait data from one of the supported populations. The WebQTL databases include both biological traits--neuroanatomical, pharmacological, and behavioral traits--and microarray-based gene expression data from BXD RI lines. A search function finds correlations between RNA expression and biological traits, and mapping functions find QTLs for either type of trait. The WebQTL service is available at http://www.webqtl.org/.", - "journal_title": "Neuroinformatics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/15043217/" - } - ], - "4673d8d9-6b1e-46b9-b8b4-add9e1048b3e": [ - { - "pub_id": "31298643", - "title": "Clinical features of precursor-targeted immune-mediated anemia in dogs: 66 cases (2004-2013).", - "authors": "Tara D Assenmacher,L Ari Jutkowitz,Amy M Koenigshof,Cynthia de A Lucidi,Michael A Scott", - "abstract": "To characterize the clinical features of dogs with precursor-targeted immune-mediated anemia (PIMA). 66 dogs with PIMA. Electronic record databases of a teaching hospital were searched to identify dogs with a diagnosis of nonregenerative anemia between 2004 and 2013. Inclusion criteria included persistent nonregenerative anemia (Hct \u2264 30% and reticulocyte count < 76,000 reticulocytes/\u03bcL), cytologic findings supportive of ineffective bone marrow erythropoiesis, and absence of underlying disease. Information regarding clinical signs, clinicopathologic findings, treatment, and outcome was extracted from records of eligible dogs. A regenerative response was defined as a reticulocyte count > 76,000 reticulocytes/\u03bcL or sustained increase in Hct of > 5%. Remission was defined as a stable Hct \u2265 35%. The median Hct was 13%, and reticulocyte count was 17,900 reticulocytes/\u03bcL. Rubriphagocytosis was identified in bone marrow aspirate samples from 61 of 66 dogs. Collagen myelofibrosis was detected in bone marrow biopsy specimens obtained from 31 of 63 dogs. Immune-mediated targeting of mature erythrocytes was uncommon. All dogs received immunosuppressive therapy. Fifty-five dogs developed a regenerative response at a median of 29 days, and 40 of those dogs went into remission at a median of 59 days after PIMA diagnosis. Thromboembolic events were confirmed for 9 dogs and were associated with a decreased survival time. Median survival time was 913 days for all dogs. Results indicated that most dogs with PIMA responded to prolonged immunosuppressive therapy. Studies to determine optimal immunosuppressive and thromboprophylactic protocols for dogs with PIMA are warranted.", - "journal_title": "Journal of the American Veterinary Medical Association", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/31298643/" - } - ], - "cc715f3d-98fc-404b-9ade-ad6af24c2181": [ - { - "pub_id": "16288901", - "title": "Recombinant herpes vector-mediated analgesia in a primate model of hyperalgesia.", - "authors": "David C Yeomans,Ying Lu,Charles E Laurito,Michael C Peters,Gina Vota-Vellis,Steven P Wilson,George D Pappas", - "abstract": "Some chronic pain syndromes are characterized by episodes of intense burning and hyperalgesia in localized areas of skin. These sensations are thought to be mediated, at least in part, by the activity of damaged, unmyelinated C nociceptors. These phenomena were modeled by assaying responses of macaques to thermal and chemical stimuli that produced periodic activation and sensitization of C nociceptors. Upon validation of this method, a recombinant herpes simplex vector encoding human preproenkephalin was topically applied to the dorsal surface of the feet of the monkeys. Immunohistochemistry and radioimmunoassay revealed that enkephalin peptides were being produced in releasable pools in sensory neurons innervating the treated skin area. Behavioral responses evoked by periodic sensitization and activation of C nociceptors innervating the vector-treated skin area revealed a substantial and long-lasting (at least 20 weeks) antihyperalgesic and analgesic effect limited to the areas to which the virus was applied. This approach may be a viable means of treating localized cutaneous burning pain and hyperalgesia.", - "journal_title": "Molecular therapy : the journal of the American Society of Gene Therapy", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/16288901/" - } - ], - "83f8e645-1ebd-4b72-8f86-53abb2603246": [ - { - "pub_id": "27409075", - "title": "Proceedings of the 3rd IPLeiria's International Health Congress : Leiria, Portugal. 6-7 May 2016.", - "authors": "Catarina Cardoso Tom\u00e1s,Emanuel Oliveira,D. Sousa,M. Uba-Chupel,G. Furtado,C. Rocha,A. Teixeira,P. Ferreira,Celeste Alves,Stefan Gisin,Elisabete Catarino,Nelma Carvalho,Tiago Coucelo,Lu\u00eds Bonfim,Carina Silva,D\u00e9bora Franco,Jes\u00fas Alcoba Gonz\u00e1lez,Helena G. Jardim,Rita Silva,Cristina L. Baixinho,M\u00aa Helena Presado,M\u00aa F\u00e1tima Marques,M\u00e1rio E. Cardoso,Marina Cunha,Joana Mendes,Ana Xavier,Ana Galhardo,Margarida Couto,Jo\u00e3o G. Frade,Carla Nunes,Jo\u00e3o R. Mesquita,Maria S. Nascimento,Guilherme Gon\u00e7alves,Concei\u00e7\u00e3o Castro,Alice M\u00e1rtires,M\u00aa Jo\u00e3o Monteiro,Concei\u00e7\u00e3o Rainho,Francisco P. Caballero,Fatima M. Monago,Jose T. Guerrero,Rocio M. Monago,Africa P. Trigo,Milagros L. Gutierrez,Gemma M. Milan\u00e9s,Mercedes G. Reina,Ana G. Villanueva,Ana S. Pi\u00f1ero,Isabel R. Aliseda,Francisco B. Ramirez,Andrea Ribeiro,Ana Quelhas,Concei\u00e7\u00e3o Manso,Francisco P. Caballero,Jose T. Guerrero,Fatima M. Monago,Rafael B. Santos,Nuria R. Jimenez,Cristina G. Nu\u00f1ez,Inmaculada R. Gomez,M\u00aa Jose L. Fernandez,Laura A. Marquez,Ana L. Moreno,M\u00aa Jesus Tena Huertas,Francisco B. Ramirez,Daniel Seabra,M\u00aa C\u00e9u Salvador,Luciene Braga,Pedro Parreira,Anabela Salgueiro-Oliveira,Cristina Arreguy-Sena,Bibiana F. Oliveira,M\u00aa Adriana Henriques,Joana Santos,Sara Lebre,Alda Marques,Clarinda Festas,Sandra Rodrigues,Andrea Ribeiro,Jos\u00e9 Lumini,Ana G. Figueiredo,Francisco J. Hernandez-Martinez,Liliana Campi,M\u00aa Pino Quintana-Montesdeoca,Juan F. Jimenez-Diaz,Bienvenida C. Rodriguez-De-Vera,Alexandra Parente,M\u00aa Augusta Mata,Ana M\u00aa Pereira,Ad\u00edlia Fernandes,Manuel Br\u00e1s,M\u00aa Ros\u00e1rio Pinto,Pedro Parreira,Marta L. Basto,Ana C. Rei,Lisete M. M\u00f3nico,Gilberta Sousa,Clementina Morna,Ot\u00edlia Freitas,Greg\u00f3rio Freitas,Ana Jardim,Rita Vasconcelos,Lina G. Horta,Roger S. Rosa,Lu\u00eds F. Kranz,Rita C. Nugem,Mariana S. Siqueira,Ronaldo Bordin,Rosiane Kniess,Josimari T. Lacerda,Joana Guedes,Idalina Machado,Sidalina Almeida,Adriano Zilh\u00e3o,Helder Alves,\u00d3scar Ribeiro,Ana P. Amaral,Ana Santos,Joana Monteiro,M\u00aa Clara Rocha,Rui Cruz,Ana P. Amaral,Marina Louren\u00e7o,M\u00aa Clara Rocha,Rui Cruz,Sandra Antunes,Ver\u00f3nica Mendon\u00e7a,Isabel Andrade,N\u00e1dia Os\u00f3rio,Ana Valado,Armando Caseiro,Ant\u00f3nio Gabriel,Anabela C. Martins,Fernando Mendes,L\u00eddia Cabral,Manuela Ferreira,Amadeu Gon\u00e7alves,Tatiana D. Luz,Leonardo Luz,Raul Martins,Alice Morgado,Maria L. Vale-Dias,Rui Porta-Nova,T\u00e2nia C. Fleig,\u00c9boni M. Reuter,Miriam B. Froemming,Sabrina L. Guerreiro,Lisiane L. Carvalho,Daniel Guedelha,P. Coelho,A. Pereira,Ant\u00f3nio Calha,Raul Cordeiro,Ana Gon\u00e7alves,Ana Certo,Ana Galv\u00e3o,M\u00aa Augusta Mata,Aline Welter,Elayne Pereira,Sandra Ribeiro,Marcia Kretzer,Juan-Fernando Jim\u00e9nez-D\u00edaz,Carla Jim\u00e9nez-Rodr\u00edguez,Francisco-Jos\u00e9 Hern\u00e1ndez-Mart\u00ednez,Bienvenida-Del-Carmen Rodr\u00edguez-De-Vera,Alexandre Marques-Rodrigues,Patr\u00edcia Coelho,Tiago Bernardes,Alexandre Pereira,Patr\u00edcia Sousa,Jo\u00e3o G. Filho,Nazare Nazario,Marcia Kretzer,Odete Amaral,Ant\u00f3nio Garrido,N\u00e9lio Veiga,Carla Nunes,Ana R. Pedro,Carlos Pereira,Ant\u00f3nio Almeia,Helder M. Fernandes,Carlos Vasconcelos,Nelson Sousa,Victor M. Reis,M. Jo\u00e3o Monteiro,Romeu Mendes,Isabel C. Pinto,T\u00e2nia Pires,Jo\u00e3o Gama,Vera Preto,Norberto Silva,Carlos Magalh\u00e3es,Matilde Martins,Mafalda Duarte,Constan\u00e7a Pa\u00fal,Ign\u00e1cio Mart\u00edn,Arminda A. Pinheiro,Sandra Xavier,Julieta Azevedo,Elisabete Bento,Cristiana Marques,Mariana Marques,Ant\u00f3nio Macedo,Ana T. Pereira,Jos\u00e9 P. Almeida,Ant\u00f3nio Almeida,Josiane Alves,Nelson Sousa,Francisco Saavedra,Romeu Mendes,Ana S. Maia,Michelle T. Oliveira,Anderson R. Sousa,Paulo P. Ferreira,Luci S. Lopes,Eujcely C. Santiago,S\u00edlvia Monteiro,\u00c2ngelo Jesus,Armanda Cola\u00e7o,Ant\u00f3nio Carvalho,Rita P. Silva,Agostinho Cruz,Ana Ferreira,Catarina Marques,Jo\u00e3o P. Figueiredo,Susana Paix\u00e3o,Ana Ferreira,Carla Lopes,Fernando Moreira,Jo\u00e3o P. Figueiredo,Ana Ferreira,Diana Ribeiro,Fernando Moreira,Jo\u00e3o P. Figueiredo,Susana Paix\u00e3o,Telma Fernandes,Diogo Amado,J\u00e9ssica Leal,Marcelo Azevedo,S\u00f3nia Ramalho,Catarina Mangas,Jaime Ribeiro,Rita Gon\u00e7alves,Am\u00e9lia F Nunes,Ana R. Tuna,Carlos R. Martins,Henriqueta D. Forte,Cl\u00e1udia Costa,Jos\u00e9 A. Tened\u00f3rio,Paula Santana,J. A. Andrade,J. L. Pinto,C. Campofiorito,S. Nunes,A. Carmo,A. Kaliniczenco,B. Alves,F. Mendes,C. Jesus,F. Fonseca,F. Gehrke,Carlos Albuquerque,Rita Batista,Madalena Cunha,Ant\u00f3nio Madureira,Oliv\u00e9rio Ribeiro,Rosa Martins,Teresa Madeira,Catarina Peixoto-Pl\u00e1cido,Nuno Santos,Osvaldo Santos,Astrid Bergland,Asta Bye,Carla Lopes,Violeta Alarc\u00e3o,Beatriz Goul\u00e3o,Nuno Mendon\u00e7a,Paulo Nicola,Jo\u00e3o G. Clara,Jo\u00e3o Gomes,Ana Querido,Catarina Tom\u00e1s,Daniel Carvalho,Marina Cordeiro,Marlene C. Rosa,Alda Marques,Daniela Brand\u00e3o,\u00d3scar Ribeiro,Lia Ara\u00fajo,Constan\u00e7a Pa\u00fal,Beatriz Minghelli,Sylvina Richaud,Ana L. Mendes,Joana Marta-Sim\u00f5es,In\u00eas A. Trindade,Cl\u00e1udia Ferreira,Teresa Carvalho,Marina Cunha,Jos\u00e9 Pinto-Gouveia,Morgana C. Fernandes,Roger S. Rosa,Rita C. Nugem,Lu\u00eds F. Kranz,Mariana S. Siqueira,Ronaldo Bordin,Anabela C. Martins,Anabela Medeiros,Rafaela Pimentel,Andreia Fernandes,Carlos Mendon\u00e7a,Isabel Andrade,Susana Andrade,Ruth L. Menezes,Rafael Bravo,Marta Miranda,Lierni Ugartemendia,Jos\u00e9 M\u00aa Tena,Francisco L. P\u00e9rez-Caballero,Lorena Fuentes-Broto,Ana B. Rodr\u00edguez,Barriga Carmen,M. A. Carneiro,J. N. Domingues,S. Paix\u00e3o,J. Figueiredo,V. B. Nascimento,C. Jesus,F Mendes,F. Gehrke,B. Alves,L. Azzalis,F. Fonseca,Ana R. Martins,Am\u00e9lia Nunes,Arminda Jorge,N\u00e9lio Veiga,Ana Amorim,Andr\u00e9 Silva,Liliana Martinho,Lu\u00eds Monteiro,Rafael Silva,Carina Coelho,Odete Amaral,In\u00eas Coelho,Carlos Pereira,Andr\u00e9 Correia,Diana Rodrigues,N\u00eddia Marante,Pedro Silva,Sara Carvalho,Andr\u00e9 Rts Araujo,Maximiano Ribeiro,Paula Coutinho,Sandra Ventura,F\u00e1tima Roque,Cristina Calvo,Manoela Reses,Jorge Conde,Ana Ferreira,Jo\u00e3o Figueiredo,David Silva,Lu\u00eds Sei\u00e7a,Raquel Soares,Ricardo Mour\u00e3o,Teresa Kraus,Ana C. Abreu,Jos\u00e9 M. Padilha,J\u00falia M. Alves,Paulino Sousa,Manuel Oliveira,Joana Sousa,S\u00f3nia Novais,Felismina Mendes,Joana Pinto,Joana Cruz,Alda Marques,Hugo Duarte,Maria Dos Anjos Dixe,Pedro Sousa,In\u00eas Cruz,Fernanda Bastos,Filipe Pereira,Francisco L. Carvalho,Teresa T. Oliveira,V\u00edtor R. Raposo,Concei\u00e7\u00e3o Rainho,Jos\u00e9 C. Ribeiro,Isabel Barroso,V\u00edtor Rodrigues,Carmo Neves,Teresa C. Oliveira,B\u00e1rbara Oliveira,M\u00aa Carminda Morais,Pilar Baylina,Rog\u00e9rio Rodrigues,Zaida Azeredo,Cor\u00e1lia Vicente,H\u00e9lia Dias,Margarida Sim-Sim,Pedro Parreira,Anabela Salgueiro-Oliveira,Am\u00e9lia Castilho,Rosa Melo,Jo\u00e3o Graveto,Jos\u00e9 Gomes,Marina Vaquinhas,Carla Carvalho,Lisete M\u00f3nico,Nuno Brito,Cassilda Sarroeira,Jos\u00e9 Amendoeira,F\u00e1tima Cunha,Anabela C\u00e2ndido,Patr\u00edcia Fernandes,Helena R. Silva,Elsa Silva,Isabel Barroso,Leila Lapa,Cristina Antunes,Ana Gon\u00e7alves,Ana Galv\u00e3o,M\u00aa Jos\u00e9 Gomes,Susana R. Escanciano,Maria Freitas,Pedro Parreira,Jo\u00e3o Mar\u00f4co,Ana R. Fernandes,Cremilde Cabral,Samuel Alves,Pedro Sousa,Ant\u00f3nio Ferreira,Fernanda Pr\u00edncipe,Ulla-Maija Sepp\u00e4nen,Margarida Ferreira,Maribel Carvalhais,Marilene Silva,Manuela Ferreira,Joana Silva,J\u00e9ssica Neves,Diana Costa,Bruno Santos,Soraia Duarte,S\u00edlvia Marques,S\u00f3nia Ramalho,Isabel Mendes,Clarisse Louro,Eva Menino,Maria Dixe,Sara S. Dias,Marina Cordeiro,Catarina Tom\u00e1s,Ana Querido,Daniel Carvalho,Jo\u00e3o Gomes,Frederico C. Valim,Joyce O. Costa,L\u00facia G. Bernardes,Helena Prebianchi,Marlene Cristina Rosa,Narcisa Gon\u00e7alves,Maria M. Martins,Paulina Kurcgant,Andr\u00e9 Vieira,Sandrina Bento,S\u00e9rgio Deodato,Isabel Rabiais,Laura Reis,Ana Torres,S\u00e9rgio Soares,Margarida Ferreira,Pedro Gra\u00e7a,C\u00e9u Leit\u00e3o,Renato Abreu,Fernando Bell\u00e9m,Ana Almeida,Edna Ribeiro-Varandas,Ana Tavares,Jo\u00e3o G. Frade,Carolina Henriques,Eva Menino,Clarisse Louro,C\u00e9lia Jord\u00e3o,Sofia Neco,Carminda Morais,Pedro Ferreira,Carla R. Silva,Alice Brito,Ant\u00f3nia Silva,Hugo Duarte,Maria Dos Anjos Dixe,Pedro Sousa,Gabriela Postolache,Raul Oliveira,Isabel Moreira,Lu\u00edsa Pedro,S\u00f3nia Vicente,Samuel Domingos,Octavian Postolache,Darlen Silva,Jo\u00e3o G. Filho,Nazare Nazario,Marcia Kretzer,Dulcineia Schneider,F\u00e1tima M. Marques,Pedro Parreira,Carla Carvalho,Lisete M. M\u00f3nico,Carlos Pinto,Sara Vicente,S\u00e3o Jo\u00e3o Breda,Jos\u00e9 H. Gomes,Rosa Melo,Pedro Parreira,Anabela Salgueiro,Jo\u00e3o Graveto,Marina Vaquinhas,Am\u00e9lia Castilho,\u00c2ngelo Jesus,Nuno Duarte,Jos\u00e9 C. Lopes,H\u00e9lder Nunes,Agostinho Cruz,Anabela Salgueiro-Oliveira,Pedro Parreira,Marta L. Basto,Luciene M. Braga,Ant\u00f3nio Ferreira,Beatriz Ara\u00fajo,Jos\u00e9 M. Alves,Margarida Ferreira,Maribel Carvalhais,Marilene Silva,S\u00f3nia Novais,Ana S. Sousa,C\u00e2ndida Ferrito,Pedro L. Ferreira,Alexandre Rodrigues,Margarida Ferreira,Isabel Oliveira,Manuela Ferreira,J\u00e9ssica Neves,Diana Costa,Soraia Duarte,Joana Silva,Bruno Santos,Cristina Martins,Ana P. Macedo,Odete Ara\u00fajo,Cl\u00e1udia Augusto,F\u00e1tima Braga,Lisa Gomes,Maria A. Silva,Rafaela Ros\u00e1rio,Lu\u00eds Pimenta,Diana Carreira,Patr\u00edcia Teles,Teresa Barros,Catarina Tom\u00e1s,Ana Querido,Daniel Carvalho,Jo\u00e3o Gomes,Marina Cordeiro,Daniel Carvalho,Ana Querido,Catarina Tom\u00e1s,Jo\u00e3o Gomes,Marina Cordeiro,Cristina J\u00e1come,Alda Marques,Sylvie Capelas,Andreia Hall,Dina Alves,Marisa Lousada,M\u00aa Helena Loureiro,Ana Camarneiro,Margarida Silva,Aida Mendes,Ana Pedreiro,Anne G.Silva,Elza S. Coelho,Fl\u00e1vio Melo,Fernando Ribeiro,Rui Torres,Rui Costa,T\u00e2nia Pinho,Cristina J\u00e1come,Alda Marques,B\u00e1rbara Cruz,Daniel Seabra,Diogo Carreiras,Maria Ventura,x Cruz,Dina Brooks,Alda Marques,M Ros\u00e1rio Pinto,Pedro Parreira,Marta Lima-Basto,Miguel Neves,Lisete M. M\u00f3nico,Carla Bizarro,Marina Cunha,Ana Galhardo,Couto Margarida,Ana P. Amorim,Eduardo Silva,Susana Cruz,Jos\u00e9 M. Padilha,Jorge Valente,Jos\u00e9 T. Guerrero,Francisco P. Caballero,Rafael B. Santos,Estefania P. Gonzalez,F\u00e1tima M. Monago,Lierni U. Ugalde,Marta M. V\u00e9lez,Maria J. Tena,Jos\u00e9 T. Guerrero,Rafael Bravo,Francisco L. P\u00e9rez-Caballero,Isabel A. Becerra,M\u00aa Elizabeth Agudelo,Guadalupe Acedo,Roberto Bajo,Isabel Malheiro,Filomena Gaspar,Lu\u00edsa Barros,Guilherme Furtado,Mateus Uba-Chupel,Mariana Marques,Lu\u00eds Rama,Margarida Braga,Jos\u00e9 P. Ferreira,Ana M\u00aa Teixeira,Jo\u00e3o Cruz,Tiago Barbosa,\u00c2ngela Sim\u00f5es,Lu\u00eds Coelho,Alexandre Rodrigues,Juan-Fernando Jim\u00e9nez-D\u00edaz,Francisco Martinez-Hernandez,Bienvenida Rodriguez-De-Vera,Pedro Ferreira,Alexandrina Rodrigues,Andr\u00e9 Ramalho,Jo\u00e3o Petrica,Pedro Mendes,Jo\u00e3o Serrano,In\u00eas Santo,Ant\u00f3nio Rosado,Paula Mendon\u00e7a,K\u00e1tia Freitas,Dora Ferreira,Ant\u00f3nio Brito,Renato Fernandes,Sofia Gomes,Fernando Moreira,Cl\u00e1udia Pinho,Rita Oliveira,Ana I. Oliveira,Paula Mendon\u00e7a,Ana P. Casimiro,Patr\u00edcia Martins,Iryna Silva,Diana Evangelista,Catarina Leit\u00e3o,F\u00e1bia Velosa,N\u00e9lio Carecho,Lu\u00eds Coelho,Eva Menino,Anjos Dixe,Helena Catarino,F\u00e1tima Soares,Ester Gama,Clementina Gordo,Eliana Moreira,Cristiana Mid\u00f5es,Marlene Santos,Sara Machado,V\u00e2nia P. Oliveira,Marlene Santos,Ana Querido,Anjos Dixe,Rita Marques,Zaida Charepe,Ana Antunes,Sofia Santos,Marlene C. Rosa,Marlene C. Rosa,Silvana F. Marques,Beatriz Minghelli,Eul\u00e1lia CaroMinghelli,M\u00aa Jos\u00e9 Lu\u00eds,Teresa Brand\u00e3o,Pedro Mendes,Daniel Marinho,Jo\u00e3o Petrica,Diogo Monteiro,Rui Paulo,Jo\u00e3o Serrano,In\u00eas Santo,Lina Monteiro,F\u00e1tima Ramalho,Rita Santos-Rocha,S\u00f3nia Morgado,Teresa Bento,Gilberta Sousa,Ot\u00edlia Freitas,Isabel Silva,Greg\u00f3rio Freitas,Clementina Morna,Rita Vasconcelos,Tatiana Azevedo,Salete Soares,Jacinta Pisco,Paulo P. Ferreira,Efrain O. Olszewer,Michelle T. Oliveira,Anderson R. Sousa,Ana S. Maia,Sebasti\u00e3o T. Oliveira,Erica Santos,Ana I. Oliveira,Carla Maia,Fernando Moreira,Joana Santos,Maria F. Mendes,Rita F. Oliveira,Cl\u00e1udia Pinho,Eduarda Barreira,Ana Pereira,Josiana A. Vaz,Andr\u00e9 Novo,Lu\u00eds D. Silva,Bruno Maia,Eduardo Ferreira,Filipa Pires,Renato Andrade,Lu\u00eds Camarinha,Lu\u00eds D. Silva,Bruno Maia,Eduardo Ferreira,Filipa Pires,Renato Andrade,Lu\u00eds Camarinha,Ana F. C\u00e9sar,Mariana Po\u00e7o,David Ventura,Raquel Loura,Pedro Gomes,Catarina Gomes,Cl\u00e1udia Silva,Elsa Melo,Jo\u00e3o Lindo,Joana Domingos,Zaida Mendes,Susana Poeta,Tiago Carvalho,Catarina Tom\u00e1s,Helena Catarino,M\u00aa Anjos Dixe,Andr\u00e9 Ramalho,Ant\u00f3nio Rosado,Pedro Mendes,Rui Paulo,In\u00eas Garcia,Jo\u00e3o Petrica,Sandra Rodrigues,Rui Meneses,Carlos Afonso,Lu\u00eds Faria,Ad\u00e9rito Seixas,Marina Cordeiro,Paulo Granjo,Jos\u00e9 C. Gomes,Nelba R. Souza,Guilherme E. Furtado,Saulo V. Rocha,Paula Silva,Joana Carvalho,Marina Ana Morais,Sofia Santos,Paula Lebre,Ana Antunes,Ant\u00f3nio Calha,Ana Xavier,Marina Cunha,Jos\u00e9 Pinto-Gouveia,Liana Alencar,Madalena Cunha,Ant\u00f3nio Madureira,Ilda Cardoso,Ana Galhardo,Fernanda Daniel,V\u00edtor Rodrigues,Leonardo Luz,Tatiana Luz,Maur\u00edcio R. Ramos,Dayse C. Medeiros,Bruno M. Carmo,Andr\u00e9 Seabra,Cristina Padez,Manuel C. Silva,Ant\u00f3nio Rodrigues,Patr\u00edcia Coelho,Alexandre Coelho,Madson Caminha,Filipe Matheus,Elenice Mendes,Jony Correia,Marcia Kretzer,Francisco J. Hernandez-Martinez,Juan F. Jimenez-Diaz,Bienvendida C. Rodriguez-De-Vera,Carla Jimenez-Rodriguez,Yadira Armas-Gonzalez,C\u00e1tia Rodrigues,Rosa Pedroso,Jennifer Apolin\u00e1rio-Hagen,Viktor Vehreschild,Milene Veloso,Celina Magalh\u00e3es,Isabel Cabral,Maira Ferraz,Filipe Nave,Em\u00edlia Costa,Filomena Matos,Jos\u00e9 Pacheco,Ant\u00f3nio Dias,Carlos Pereira,Jo\u00e3o Duarte,Madalena Cunha,Daniel Silva,Lisete M. M\u00f3nico,Valentim R. Alferes,M\u00aa S\u00e3o Jo\u00e3o Br\u00eada,Carla Carvalho,Pedro M. Parreira,M\u00aa Carminda Morais,Pedro Ferreira,Rui Pimenta,Jos\u00e9 Boavida,Isabel C. Pinto,T\u00e2nia Pires,Catarina Silva,Maria Ribeiro,Maria Viega-Branco,Filomena Pereira,Ana M\u00aa Pereira,Fabr\u00edcia M. Almeida,Gustavo L. Estevez,Sandra Ribeiro,Marcia R. Kretzer,Paulo V. Jo\u00e3o,Paulo Nogueira,Sandra Novais,Ana Pereira,Lara Carneiro,Maria Mota,Rui Cruz,Luiz Santiago,Carlos Fontes-Ribeiro,Guilherme Furtado,Saulo V. Rocha,Andr\u00e9 P. Coutinho,Jo\u00e3o S. Neto,L\u00e9lia R. Vasconcelos,Nelba R. Souza,Est\u00e9lio Dantas,Alexandra Dinis,S\u00e9rgio Carvalho,Paula Castilho,Jos\u00e9 Pinto-Gouveia,Alexandra Sarreira-Santos,Am\u00e9lia Figueiredo,Lurdes Medeiros-Garcia,Paulo Seabra,Rosa Rodrigues,M\u00aa Carminda Morais,Paula O. Fernandes,Concei\u00e7\u00e3o Santiago,M\u00aa Henriqueta Figueiredo,Marta L. Basto,Teresa Guimar\u00e3es,Andr\u00e9 Coelho,Anabela Gra\u00e7a,Ana M. Silva,Ana R. Fonseca,Luz Vale-Dias,B\u00e1rbara Minas,Graciete Franco-Borges,Cristina Sim\u00f5es,Sofia Santos,Ana Serra,Maria Matos,Lu\u00eds Jesus,Ana S. Tavares,Ana Almeida,C\u00e9u Leit\u00e3o,Edna Varandas,Renato Abreu,Fernando Bell\u00e9m,In\u00eas A. Trindade,Cl\u00e1udia Ferreira,Jos\u00e9 Pinto-Gouveia,Joana Marta-Sim\u00f5es,Odete Amaral,Cristiana Miranda,Pedro Guimar\u00e3es,Rodrigo Gon\u00e7alves,N\u00e9lio Veiga,Carlos Pereira,T\u00e2nia C. Fleig,Elisabete A. San-Martin,C\u00e1ssia L. Goulart,Paloma B. Schneiders,Natacha F. Miranda,Lisiane L. Carvalho,Andrea G. Silva,Joana Topa,Concei\u00e7\u00e3o Nogueira,Sofia Neves,Rita Ventura,Cristina Nazar\u00e9,Daniela Brand\u00e3o,Alberto Freitas,\u00d3scar Ribeiro,Constan\u00e7a Pa\u00fal,Cristiana Merc\u00ea,Marco Branco,Pedro Almeida,Daniela Nascimento,Juliana Pereira,David Catela,Helga Rafael,Alcinda C. Reis,Ana Mendes,Ana R. Valente,Marisa Lousada,Diana Sousa,Ana L. Baltazar,M\u00aa Helena Loureiro,Ana Oliveira,Jos\u00e9 Apar\u00edcio,Alda Marques,Alda Marques,Ana Oliveira,Joana Neves,Rodrigo Ayoub,Lu\u00eds Sousa,Cristina Marques-Vieira,Sandy Severino,Helena Jos\u00e9,In\u00eas Cadorio,Marisa Lousada,Marina Cunha,Diogo Andrade,Ana Galhardo,Margarida Couto,Fernando Mendes,C\u00e1tia Domingues,Susann Schukg,Ana M. Abrantes,Ana C. Gon\u00e7alves,Tiago Sales,Ricardo Teixo,Rita Silva,J\u00e9ssica Estrela,Mafalda Laranjo,Jo\u00e3o Casalta-Lopes,Clara Rocha,Paulo C. Sim\u00f5es,Ana B. Sarmento-Ribeiro,M\u00aa Filomena Botelho,Manuel S. Rosa,Virg\u00ednia Fonseca,Diogo Cola\u00e7o,Vanessa Neves,Carlos Jesus,Camilla Hesse,Clara Rocha,N\u00e1dia Os\u00f3rio,Ana Valado,Armando Caseiro,Ant\u00f3nio Gabriel,Lola Svensson,Fernando Mendes,Wafa A. Siba,Cristina Pereira,Jorge Tomaz,Teresa Carvalho,Jos\u00e9 Pinto-Gouveia,Marina Cunha,Diana Duarte,Nuno V. Lopes,Rui Fonseca-Pinto,Diana Duarte,Nuno V. Lopes,Rui Fonseca-Pinto,Anabela C. Martins,Piedade Brand\u00e3o,Laura Martins,Margarida Cardoso,Nuno Morais,Joana Cruz,Nuno Alves,Paula Faria,Artur Mateus,Pedro Morou\u00e7o,Nuno Alves,Nelson Ferreira,Artur Mateus,Paula Faria,Pedro Morou\u00e7o,Isabel Malheiro,Filomena Gaspar,Lu\u00edsa Barros,Pedro Parreira,Andreia Cardoso,Lisete M\u00f3nico,Carla Carvalho,Albino Lopes,Anabela Salgueiro-Oliveira,Ad\u00e9rito Seixas,Valter Soares,Tiago Dias,Ricardo Vardasca,Joaquim Gabriel,Sandra Rodrigues,Hugo Paredes,Ars\u00e9nio Reis,Sara Marinho,V\u00edtor Filipe,Jorge Lains,Jo\u00e3o Barroso,Carolina Da Motta,C\u00e9lia B. Carvalho,Jos\u00e9 Pinto-Gouveia,Ermelindo Peixoto,Ana A. Gomes,Vanessa Costa,Diana Couto,Daniel R. Marques,Jos\u00e9 A. Leit\u00e3o,Jos\u00e9 Tavares,Maria H. Azevedo,Carlos F. Silva,Jo\u00e3o Freitas,Pedro Parreira,Jo\u00e3o Mar\u00f4co,Miguel A. Garcia-Gordillo,Daniel Collado-Mateo,Gang Chen,Angelo Iezzi,Jos\u00e9 A. Sala,Jos\u00e9 A. Parra\u00e7a,Narcis Gusi,Jani Sousa,Mariana Marques,Jacinto Jardim,Anabela Pereira,S\u00f3nia Sim\u00f5es,Marina Cunha,Pedro Sardo,Jenifer Guedes,Jo\u00e3o Lindo,Paulo Machado,Elsa Melo,C\u00e9lia B. Carvalho,Joana Benevides,Marina Sousa,Joana Cabral,Carolina Da Motta,Ana T. Pereira,Sandra Xavier,Julieta Azevedo,Elisabete Bento,Cristiana Marques,Rosa Carvalho,Mariana Marques,Ant\u00f3nio Macedo,Ana M. Silva,Juliana Alves,Ana A. Gomes,Daniel R. Marques,M\u00aa Helena Azevedo,Carlos Silva,Ana Mendes,Huei D. Lee,Newton Spola\u00f4r,Jefferson T. Oliva,Wu F. Chung,Rui Fonseca-Pinto,Keila Bairros,Cl\u00e1udia D. Silva,Cl\u00f3vis A. Souza,Silvana S. Schroeder,Elsa Ara\u00fajo,Helena Monteiro,Ricardo Costa,Sara S. Dias,Jorge Torgal,Carolina G. Henriques,Lu\u00edsa Santos,Elisa F. Caceiro,S\u00f3nia A. Ramalho,Rita Oliveira,Vera Afreixo,Jo\u00e3o Santos,Priscilla Mota,Agostinho Cruz,Francisco Pimentel,Rita Marques,M\u00aa Anjos Dixe,Ana Querido,Patr\u00edcia Sousa,Joana Benevides,Carolina Da Motta,Marina Sousa,Suzana N. Caldeira,C\u00e9lia B. Carvalho,Ana Querido,Catarina Tom\u00e1s,Daniel Carvalho,Jo\u00e3o Gomes,Marina Cordeiro,Joyce O. Costa,Frederico C. Valim,L\u00edgia C. Ribeiro,Zaida Charepe,Ana Querido,M\u00aa Henriqueta Figueiredo,Priscila S. Aquino,Samila G. Ribeiro,Ana B. Pinheiro,Paula A. Lessa,Mirna F. Oliveira,Lu\u00edsa S. Brito,\u00cdtalo N. Pinto,Alessandra S. Furtado,R\u00e9gia B. Castro,Caroline Q. Aquino,Eveliny S. Martins,Ana B Pinheiro,Priscila S. Aquino,Lara L. Oliveira,Patr\u00edcia C. Pinheiro,Caroline R. Sousa,V\u00edvien A. Freitas,Tatiane M. Silva,Adman S. Lima,Caroline Q. Aquino,Karizia V. Andrade,Camila A. Oliveira,Eglidia F. Vidal,Ana Ganho-\u00c1vila,Mariana Moura-Ramos,\u00d3scar Gon\u00e7alves,Jorge Almeida,Armando Silva,Irma Brito,Jo\u00e3o Amado,Ant\u00f3nio Rodrigo,Sofia Santos,Fernando Gomes,Marlene C. Rosa,Silvana F. Marques,Sara Lu\u00eds,Lu\u00eds Cavalheiro,Pedro Ferreira,Rui Gon\u00e7alves,Rui S. Lopes,Lu\u00eds Cavalheiro,Pedro Ferreira,Rui Gon\u00e7alves,Bruno H. Fiorin,Marina S. Santos,Edmar S. Oliveira,Rita L. Moreira,Elizabete A. Oliveira,Braulio L. Filho,Lara Palmeira,Teresa Garcia,Jos\u00e9 Pinto-Gouveia,Marina Cunha,Sara Cardoso,Lara Palmeira,Marina Cunha,Jos\u00e9 Pinto-Gouveia,Joana Marta-Sim\u00f5es,Ana L. Mendes,In\u00eas A. Trindade,Sara Oliveira,Cl\u00e1udia Ferreira,Ana L. Mendes,Joana Marta-Sim\u00f5es,In\u00eas A. Trindade,Cl\u00e1udia Ferreira,Filipe Nave,Mariana Campos,Iris Gaud\u00eancio,Fernando Martins,Lino Ferreira,Nuno Lopes,Rui Fonseca-Pinto,Rog\u00e9rio Rodrigues,Zaida Azeredo,Cor\u00e1lia Vicente,Joana Silva,Patr\u00edcia Sousa,Rita Marques,Isabel Mendes,Rog\u00e9rio Rodrigues,Zaida Azeredo,Cor\u00e1lia Vicente,Ricardo Vardasca,Ana R. Marques,Ad\u00e9rito Seixas,Rui Carvalho,Joaquim Gabriel,Paulo P. Ferreira,Michelle T. Oliveira,Anderson R. Sousa,Ana S. Maia,Sebasti\u00e3o T. Oliveira,Pablo O. Costa,Maiza M. Silva,Cristina Arreguy-Sena,Nath\u00e1lia Alvarenga-Martins,Paulo F. Pinto,Denize C. Oliveira,Pedro D. Parreira,Ant\u00f4nio T. Gomes,Luciene M. Braga,Odete Ara\u00fajo,Isabel Lage,Jos\u00e9 Cabrita,Laetitia Teixeira,Rita Marques,M\u00aa Anjos Dixe,Ana Querido,Patr\u00edcia Sousa,Sara Silva,Eug\u00e9nio Cordeiro,Jo\u00e3o Pimentel,Vera Ferro-Lebres,Juliana A. Souza,Mariline Tavares,M\u00aa Anjos Dixe,Pedro Sousa,Rui Passadouro,Teresa Peralta,Carlos Ferreira,Georgina Louren\u00e7o,Jo\u00e3o Serrano,Jo\u00e3o Petrica,Rui Paulo,Samuel Hon\u00f3rio,Pedro Mendes,Alexandra Sim\u00f5es,Lucinda Carvalho,Alexandre Pereira,Sara Silva,Paulino Sousa,Jos\u00e9 M. Padilha,Daniela Figueiredo,Carolina Valente,Alda Marques,Patr\u00edcia Ribas,Joana Sousa,Frederico Brand\u00e3o,Cesar Sousa,Matilde Martins,Patr\u00edcia Sousa,Rita Marques,Francisco Mendes,Rosina Fernandes,Em\u00edlia Martins,C\u00e1tia Magalh\u00e3es,Patr\u00edcia Ara\u00fajo,Carla Grande,M\u00aa Augusta Mata,Juan G. Vieitez,Bruna Bianchini,Nazare Nazario,Jo\u00e3o G. Filho,Marcia Kretzer,T\u00e2nia Costa,Armando Almeida,Gabriel Baffour,Armando Almeida,T\u00e2nia Costa,Gabriel Baffour,Zaida Azeredo,Carlos Laranjeira,Magda Guerra,Ana P. Barbeiro,Regina Ferreira,Sara Lopes,Liliana Nunes,Ana Mendes,Julian Martins,Dulcineia Schneider,Marcia Kretzer,Fl\u00e1vio Magajewski,C\u00e9lia Soares,Ant\u00f3nio Marques,Marco Batista,Ruth J. Castuera,Helena Mesquita,Ant\u00f3nio Faustino,Jorge Santos,Samuel Hon\u00f3rio,Betina P. Vizzotto,Leticia Frigo,Hedioneia F. Pivetta,Dolores Sardo,Cristina Martins,Wilson Abreu,M\u00aa C\u00e9u Figueiredo,Marco Batista,Ruth Jimenez-Castuera,Jo\u00e3o Petrica,Jo\u00e3o Serrano,Samuel Hon\u00f3rio,Rui Paulo,Pedro Mendes,Patr\u00edcia Sousa,Rita Marques,Ant\u00f3nio Faustino,Paulo Silveira,Jo\u00e3o Serrano,Rui Paulo,Pedro Mendes,Samuel Hon\u00f3rio,Catarina Oliveira,Fernanda Bastos,In\u00eas Cruz,Cl\u00e1udia K. Rodriguez,M\u00e1rcia R. Kretzer,Nazar\u00e9 O. Naz\u00e1rio,Pedro Cruz,Daniela C. Vaz,Rui B. Ruben,Francisco Avelelas,Susana Silva,M\u00aa Jorge Campos,Maria Almeida,Liliana Gon\u00e7alves,L\u00edgia Antunes,Pedro Sardo,Jenifer Guedes,Jo\u00e3o Sim\u00f5es,Paulo Machado,Elsa Melo,Susana Cardoso,Osvaldo Santos,Carla Nunes,Isabel Loureiro,Fl\u00e1via Santos,Gilberto Alves,Cl\u00e1udia Soar,Teresa O. Marsi,Ernestina Silva,Dora Pedrosa,Andrea Le\u00e7a,Daniel Silva,Ana Galv\u00e3o,Maria Gomes,Paula Fernandes,Ana Non\u00e9,Jaime Combad\u00e3o,C\u00e1tia Ramalhete,Paulo Figueiredo,Patr\u00edcia Caeiro,Karine C. Fontana,Josimari T. Lacerda,Patr\u00edcia O. Machado,Raphaelle Borges,Fl\u00e1vio Barbosa,Dayse S\u00e1,Germana Brunhoso,Gra\u00e7a Apar\u00edcio,Am\u00e2ncio Carvalho,Ana P. Garcia,Paula O. Fernandes,Adriana Santos,N\u00e9lio Veiga,Carina Br\u00e1s,In\u00eas Carvalho,Joana Batalha,Margarida Gl\u00f3ria,Filipa Bexiga,In\u00eas Coelho,Odete Amaral,Carlos Pereira,Cl\u00e1udia Pinho,Nilson Para\u00edso,Ana I. Oliveira,Crist\u00f3v\u00e3o F. Lima,Alberto P. Dias,Pedro Silva,M\u00e1rio Espada,M\u00e1rio Marques,Ana Pereira,Ana M\u00aa Pereira,M\u00aa Veiga-Branco,Filomena Pereira,Maria Ribeiro,Vera Lima,Ana I. Oliveira,Cl\u00e1udia Pinho,Gra\u00e7a Cruz,Rita F. Oliveira,Lu\u00edsa Barreiros,Fernando Moreira,Ana Camarneiro,M\u00aa Helena Loureiro,Margarida Silva,Catarina Duarte,\u00c2ngelo Jesus,Agostinho Cruz,Maria Mota,Sandra Novais,Paulo Nogueira,Ana Pereira,Lara Carneiro,Paulo V. Jo\u00e3o,Teresa Maneca Lima,Anabela Salgueiro-Oliveira,Marina Vaquinhas,Pedro Parreira,Rosa Melo,Jo\u00e3o Graveto,Am\u00e9lia Castilho,Jos\u00e9 H. Gomes,Mar\u00eda S. Medina,Valeriana G. Blanco,Osvaldo Santos,Elisa Lopes,Ana Virgolino,Alexandra Dinis,Sara Ambr\u00f3sio,In\u00eas Almeida,Tatiana Marques,M\u00aa Jo\u00e3o Heitor,Miguel A. Garcia-Gordillo,Daniel Collado-Mateo,Pedro R. Olivares,Jos\u00e9 A. Parra\u00e7a,Jos\u00e9 A. Sala,Am\u00e9lia Castilho,Jo\u00e3o Graveto,Pedro Parreira,Anabela Oliveira,Jos\u00e9 H. Gomes,Rosa Melo,Marina Vaquinhas,M\u00f3nica Cheio,Agostinho Cruz,Ol\u00edvia R. Pereira,Sara Pinto,Adriana Oliveira,M. Concei\u00e7\u00e3o Manso,Carla Sousa,Ana F. Vinha,M\u00aa Manuela Machado,Margarida Vieira,Beatriz Fernandes,Teresa Tom\u00e1s,Diogo Quirino,Gustavo Desouzart,Rui Matos,Magali Bordini,Pedro Mouro\u00e7o,Ana R. Matos,Mauro Serapioni,Teresa Guimar\u00e3es,Virg\u00ednia Fonseca,Andr\u00e9 Costa,Jo\u00e3o Ribeiro,Jo\u00e3o Lobato,Inmaculada Z. Martin,Anita Bj\u00f6rklund,Aida I. Tavares,Pedro Ferreira,Rui Passadouro,S\u00f3nia Morgado,Nuno Tavares,Jo\u00e3o Valente,Anabela C. Martins,Patr\u00edcia Ara\u00fajo,Rosina Fernandes,Francisco Mendes,C\u00e1tia Magalh\u00e3es,Em\u00edlia Martins,Pedro Mendes,Rui Paulo,Ant\u00f3nio Faustino,Helena Mesquita,Samuel Hon\u00f3rio,Marco Batista,Josimari T. Lacerda,Angela B. Ortiga,M\u00aa Cristina Calvo,S\u00f4nia Natal,Marta Pereira,Manuela Ferreira,Ana R. Prata,Paula Nelas,Jo\u00e3o Duarte,Juliana Carneiro,Ana I. Oliveira,Cl\u00e1udia Pinho,Cristina Couto,Rita F. Oliveira,Fernando Moreira,Ana S. Maia,Michelle T. Oliveira,Anderson R. Sousa,Paulo P. Ferreira,G\u00e9ssica M. Souza,L\u00edvia F. Almada,Milena A. Concei\u00e7\u00e3o,Eujcely C. Santiago,Sandra Rodrigues,Gabriela Domingues,Irina Ferreira,Lu\u00eds Faria,Ad\u00e9rito Seixas,Ana R. Costa,\u00c2ngelo Jesus,Am\u00e9rico Cardoso,Alexandra Meireles,Armanda Cola\u00e7o,Agostinho Cruz,Viviane L. Vieira,Kellem R. Vincha,Ana M\u00aa Cervato-Mancuso,Melissa Faria,Cl\u00e1udia Reis,Marco P. Cova,Rita T. Ascenso,Henrique A. Almeida,Eunice G. Oliveira,Miguel Santana,Rafael Pereira,Eunice G. Oliveira,Henrique A. Almeida,Rita T. Ascenso,Rita Jesus,Rodrigo Tapadas,Carolina Tim-Tim,Catarina Cezanne,Matilde Lagoa,Sara S. Dias,Jorge Torgal,Jo\u00e3o Lopes,Henrique Almeida,Sandra Amado,Lu\u00eds Carr\u00e3o,Madalena Cunha,Lu\u00eds Saboga-Nunes,Carlos Albuquerque,Oliv\u00e9rio Ribeiro,Suzete Oliveira,M\u00aa Carminda Morais,Em\u00edlia Martins,Francisco Mendes,Rosina Fernandes,C\u00e1tia Magalh\u00e3es,Patr\u00edcia Ara\u00fajo,Ana R. Pedro,Odete Amaral,Ana Escoval,Victor Assun\u00e7\u00e3o,Henrique Lu\u00eds,Lu\u00eds Lu\u00eds,Jennifer Apolin\u00e1rio-Hagen,Viktor Vehreschild,Ulrike Fotschl,Gerald Lirk,Anabela C. Martins,Isabel Andrade,Fernando Mendes,Ver\u00f3nica Mendon\u00e7a,Sandra Antunes,Isabel Andrade,N\u00e1dia Os\u00f3rio,Ana Valado,Armando Caseiro,Ant\u00f3nio Gabriel,Anabela C. Martins,Fernando Mendes,Paula A. Silva,Lisete M. M\u00f3nico,Pedro M. Parreira,Carla Carvalho,Carla Carvalho,Pedro M. Parreira,Lisete M. M\u00f3nico,Joana Ruivo,V\u00e2nia Silva,Paulino Sousa,Jos\u00e9 M. Padilha,Vera Ferraz,Gra\u00e7a Apar\u00edcio,Jo\u00e3o Duarte,Carlos Vasconcelos,Ant\u00f3nio Almeida,Joel Neves,Telma Correia,Helena Amorim,Romeu Mendes,Lu\u00eds Saboga-Nunes,Madalena Cunha,Carlos Albuquerque,Elsa S. Pereira,Leonino S. Santos,Ana S. Reis,Helena R. Silva,Jo\u00e3o Rombo,Jorge C. Fernandes,Patr\u00edcia Fernandes,Jaime Ribeiro,Catarina Mangas,Ana Freire,Sara Silva,Irene Francisco,Ana Oliveira,Helena Catarino,M\u00aa Anjos Dixe,M\u00aa Clarisse Louro,Saudade Lopes,Anjos Dixe,M\u00aa Anjos Dixe,Eva Menino,Helena Catarino,F\u00e1tima Soares,Ana P. Oliveira,Sara Gordo,Teresa Kraus,Catarina Tom\u00e1s,Paulo Queir\u00f3s,Teresa Rodrigues,Pedro Sousa,Jo\u00e3o G. Frade,Catarina Lob\u00e3o,Cynthia B. Moura,Laysa C. Dreyer,Vanize Meneghetti,Priscila P. Cabral,Francisca Pinto,Paulino Sousa,M\u00aa Raquel Esteves,Sofia Galv\u00e3o,Ite Tytgat,Isabel Andrade,N\u00e1dia Os\u00f3rio,Ana Valado,Armando Caseiro,Ant\u00f3nio Gabriel,Anabela C. Martins,Fernando Mendes,M\u00f3nica Casas-Novas,Helena Bernardo,Isabel Andrade,Gracinda Sousa,Ana P. Sousa,Clara Rocha,Pedro Belo,N\u00e1dia Os\u00f3rio,Ana Valado,Armando Caseiro,Ant\u00f3nio Gabriel,Anabela C. Martins,Fernando Mendes,F\u00e1tima Martins,Montserrat Pulido-Fuentes,Isabel Barroso,Gil Cabral,M. Jo\u00e3o Monteiro,Concei\u00e7\u00e3o Rainho,Alessandro Prado,Yara M. Carvalho,Maria Campos,Liliana Moreira,Jos\u00e9 Ferreira,Ana Teixeira,Lu\u00eds Rama,Maria Campos,Liliana Moreira,Jos\u00e9 Ferreira,Ana Teixeira,Lu\u00eds Rama", - "abstract": "S1 Health literacy and health education in adolescence Catarina Cardoso Tom\u00e1s S2 The effect of a walking program on the quality of life and well-being of people with schizophrenia Emanuel Oliveira, D. Sousa, M. Uba-Chupel, G. Furtado, C. Rocha, A. Teixeira, P. Ferreira S3 Diagnosis and innovative treatments - the way to a better medical practice Celeste Alves S4 Simulation-based learning and how it is a high contribution Stefan Gisin S5 Formative research about acceptability, utilization and promotion of a home fortification programme with micronutrient powders (MNP) in the Autonomous Region of Pr\u00edncipe, S\u00e3o Tom\u00e9 and Pr\u00edncipe Elisabete Catarino, Nelma Carvalho, Tiago Coucelo, Lu\u00eds Bonfim, Carina Silva S6 Safety culture of the patient: a reflexion about the therapeutic approach on the patient with vocal pathology D\u00e9bora Franco S7 About wine, fortune cookies and patient experience Jes\u00fas Alcoba Gonz\u00e1lez O1 The psychological impact on the emergency crews after the disaster event on February 20, 2010 Helena G. Jardim, Rita Silva O2 Musculoskeletal disorders in midwives Cristina L. Baixinho, M\u00aa Helena Presado, M\u00aa F\u00e1tima Marques, M\u00e1rio E. Cardoso O3 Negative childhood experiences and fears of compassion: Implications for psychological difficulties in adolescence Marina Cunha, Joana Mendes, Ana Xavier, Ana Galhardo, Margarida Couto O4 Optimal age to give the first dose of measles vaccine in Portugal Jo\u00e3o G. Frade, Carla Nunes, Jo\u00e3o R. Mesquita, Maria S. Nascimento, Guilherme Gon\u00e7alves O5 Functional assessment of elderly in primary care Concei\u00e7\u00e3o Castro, Alice M\u00e1rtires, M\u00aa Jo\u00e3o Monteiro, Concei\u00e7\u00e3o Rainho O6 Smoking and coronary events in a population of Spanish health-care centre: An observational study Francisco P. Caballero, Fatima M. Monago, Jose T. Guerrero, Rocio M. Monago, Africa P. Trigo, Milagros L. Gutierrez, Gemma M. Milan\u00e9s, Mercedes G. Reina, Ana G. Villanueva, Ana S. Pi\u00f1ero, Isabel R. Aliseda, Francisco B. Ramirez O7 Prevalence of musculoskeletal injuries in Portuguese musicians Andrea Ribeiro, Ana Quelhas, Concei\u00e7\u00e3o Manso O8 Hip fractures, psychotropic drug consumption and comorbidity in patients of a primary care practice in Spain Francisco P. Caballero, Jose T. Guerrero, Fatima M. Monago, Rafael B. Santos, Nuria R. Jimenez, Cristina G. Nu\u00f1ez, Inmaculada R. Gomez, M\u00aa Jose L. Fernandez, Laura A. Marquez, Ana L. Moreno, M\u00aa Jesus Tena Huertas, Francisco B. Ramirez O9 The role of self-criticism and shame in social anxiety in a clinical SAD sample Daniel Seabra, M\u00aa C\u00e9u Salvador O10 Obstruction and infiltration: a proposal of a quality indicator Luciene Braga, Pedro Parreira, Anabela Salgueiro-Oliveira, Cristina Arreguy-Sena, Bibiana F. Oliveira, M\u00aa Adriana Henriques O11 Balance and anxiety and depression symptoms in old age people Joana Santos, Sara Lebre, Alda Marques O12 Prevalence of postural changes and risk factors in school children and adolescents in a northern region (Porto) Clarinda Festas, Sandra Rodrigues, Andrea Ribeiro, Jos\u00e9 Lumini O13 Ischemic stroke vs. haemorrhagic stroke survival rate Ana G. Figueiredo O14 Chronobiological factors as responsible for the appearance of locomotor pathology in adolescents Francisco J. Hernandez-Martinez, Liliana Campi, M\u00aa Pino Quintana-Montesdeoca, Juan F. Jimenez-Diaz, Bienvenida C. Rodriguez-De-Vera O15 Risk of malnutrition in the elderly of Bragan\u00e7a Alexandra Parente, M\u00aa Augusta Mata, Ana M\u00aa Pereira, Ad\u00edlia Fernandes, Manuel Br\u00e1s O16 A Lifestyle Educational Programme for primary care diabetic patients: the design of a complex nursing intervention M\u00aa Ros\u00e1rio Pinto, Pedro Parreira, Marta L. Basto, Ana C. Rei, Lisete M. M\u00f3nico O17 Medication adherence in elderly people Gilberta Sousa, Clementina Morna, Ot\u00edlia Freitas, Greg\u00f3rio Freitas, Ana Jardim, Rita Vasconcelos O18 Hospitalization for cervical cancer of residents in the metropolitan region of Porto Alegre, Southern Brazil, 2012 to 2014 Lina G. Horta, Roger S. Rosa, Lu\u00eds F. Kranz, Rita C. Nugem, Mariana S. Siqueira, Ronaldo Bordin O19 Oncologic assistance of high complexity: evaluation of regulating accesses Rosiane Kniess, Josimari T. Lacerda O20 Perceived barriers for using health care services by the older population as seen by the social sector: findings from the Vila Nova de Gaia Gerontological Plan Joana Guedes, Idalina Machado, Sidalina Almeida, Adriano Zilh\u00e3o, Helder Alves, \u00d3scar Ribeiro O21 Sleep difficulties and depressive symptoms in college students Ana P. Amaral, Ana Santos, Joana Monteiro, M\u00aa Clara Rocha, Rui Cruz O22 Psychopathological symptoms and medication use in higher education Ana P. Amaral, Marina Louren\u00e7o, M\u00aa Clara Rocha, Rui Cruz O23 Sexually transmitted diseases in higher education institutions Sandra Antunes, Ver\u00f3nica Mendon\u00e7a, Isabel Andrade, N\u00e1dia Os\u00f3rio, Ana Valado, Armando Caseiro, Ant\u00f3nio Gabriel, Anabela C. Martins, Fernando Mendes O24 Alcohol consumption and suicide ideation in higher education students L\u00eddia Cabral, Manuela Ferreira, Amadeu Gon\u00e7alves O25 Quality of life in university students Tatiana D. Luz, Leonardo Luz, Raul Martins O26 Male and female adolescent antisocial behaviour: characterizing vulnerabilities in a Portuguese sample Alice Morgado, Maria L. Vale-Dias O27 Risk factors for mental health in higher education students of health sciences Rui Porta-Nova O28 International classification of functioning disability and health as reflexive reasoning in primary attention in health T\u00e2nia C. Fleig, \u00c9boni M. Reuter, Miriam B. Froemming, Sabrina L. Guerreiro, Lisiane L. Carvalho O29 Risk factors and cardiovascular disease in Portalegre Daniel Guedelha, P. Coelho, A. Pereira O30 Health status of the elderly population living in Portalegre historic city centre: A longitudinal study Ant\u00f3nio Calha, Raul Cordeiro O31 Student\u2019s sleep in higher education: sleep quality among students of the IPB Ana Gon\u00e7alves, Ana Certo, Ana Galv\u00e3o, M\u00aa Augusta Mata O32 Trend in mortality from cervical cancer in the metropolitan area of Florian\u00f3polis, state of Santa Catarina, Brazil, 2000 to 2013 Aline Welter, Elayne Pereira, Sandra Ribeiro, Marcia Kretzer O33 Adherence to treatment in the elderly in an urban environment in Spain Juan-Fernando Jim\u00e9nez-D\u00edaz, Carla Jim\u00e9nez-Rodr\u00edguez, Francisco-Jos\u00e9 Hern\u00e1ndez-Mart\u00ednez, Bienvenida-Del-Carmen Rodr\u00edguez-De-Vera, Alexandre Marques-Rodrigues O34 Beira Baixa Blood Pressure Study (Study PABB) Patr\u00edcia Coelho, Tiago Bernardes, Alexandre Pereira O35 Trends in cervical cancer mortality statistics in Santa Catarina State, Brazil, by age group and macro-region, from 2000 to 2013 Patr\u00edcia Sousa, Jo\u00e3o G. Filho, Nazare Nazario, Marcia Kretzer O36 Sleep problems among Portuguese adolescents: a public health issue Odete Amaral, Ant\u00f3nio Garrido, N\u00e9lio Veiga, Carla Nunes, Ana R. Pedro, Carlos Pereira O37 Association between body fat and health-related quality of life in patients with type 2 diabetes Ant\u00f3nio Almeia, Helder M. Fernandes, Carlos Vasconcelos, Nelson Sousa, Victor M. Reis, M. Jo\u00e3o Monteiro, Romeu Mendes O38 Therapy adherence and polypharmacy in non-institutionalized elderly from Amares county, Portugal Isabel C. Pinto, T\u00e2nia Pires, Jo\u00e3o Gama O39 Prevalence of surgical site infection in adults at a hospital unit in the North of Portugal Vera Preto, Norberto Silva, Carlos Magalh\u00e3es, Matilde Martins O40 Frailty phenotype in old age: implications to intervention Mafalda Duarte, Constan\u00e7a Pa\u00fal, Ign\u00e1cio Mart\u00edn O41 Portuguese women: sexual symptoms in perimenopause Arminda A. Pinheiro O42 Predictive ability of the Perinatal Depression Screening and Prevention Tool \u2013 preliminary results of the categorical approach Sandra Xavier, Julieta Azevedo, Elisabete Bento, Cristiana Marques, Mariana Marques, Ant\u00f3nio Macedo, Ana T. Pereira O43 Aging and muscle strength in patients with type 2 diabetes: cross sectional analysis Jos\u00e9 P. Almeida, Ant\u00f3nio Almeida, Josiane Alves, Nelson Sousa, Francisco Saavedra, Romeu Mendes O44 Accessibility of the elderly in the prevention of hypertension in a family health unit Ana S. Maia, Michelle T. Oliveira, Anderson R. Sousa, Paulo P. Ferreira, Luci S. Lopes, Eujcely C. Santiago O45 Community Health screenings and self-reported chronic diseases S\u00edlvia Monteiro, \u00c2ngelo Jesus, Armanda Cola\u00e7o, Ant\u00f3nio Carvalho, Rita P. Silva, Agostinho Cruz O46 Evaluation of indoor air quality in Kindergartens Ana Ferreira, Catarina Marques, Jo\u00e3o P. Figueiredo, Susana Paix\u00e3o O47 Atmospheric exposure to chemical agents under the occupational activity of pathology technicians Ana Ferreira, Carla Lopes, Fernando Moreira, Jo\u00e3o P. Figueiredo O48 Occupational exposure to air pollutants in night entertainment venues workers Ana Ferreira, Diana Ribeiro, Fernando Moreira, Jo\u00e3o P. Figueiredo, Susana Paix\u00e3o O49 Beliefs and attitudes of young people towards breastfeeding Telma Fernandes, Diogo Amado, J\u00e9ssica Leal, Marcelo Azevedo, S\u00f3nia Ramalho O50 Profiling informal caregivers: surveying needs in the care of the elderly Catarina Mangas, Jaime Ribeiro, Rita Gon\u00e7alves O51 Visual health in teenagers Am\u00e9lia F Nunes, Ana R. Tuna, Carlos R. Martins, Henriqueta D. Forte O52 Amenable mortality and the geographic accessibility to healthcare in Portugal Cl\u00e1udia Costa, Jos\u00e9 A. Tened\u00f3rio, Paula Santana O53 Bacterial contamination of door handles in a S\u00e3o Paulo See Metropolitan Cathedral public restrooms in Brazil J. A. Andrade, J. L. Pinto, C. Campofiorito, S. Nunes, A. Carmo, A. Kaliniczenco, B. Alves, F. Mendes, C. Jesus, F. Fonseca, F. Gehrke O54 Adherence of patients to rehabilitation programmes Carlos Albuquerque, Rita Batista, Madalena Cunha, Ant\u00f3nio Madureira, Oliv\u00e9rio Ribeiro, Rosa Martins O55 Prevalence of malnutrition among Portuguese elderly living in nursing homes: preliminary results of the PEN-3S project Teresa Madeira, Catarina Peixoto-Pl\u00e1cido, Nuno Santos, Osvaldo Santos, Astrid Bergland, Asta Bye, Carla Lopes, Violeta Alarc\u00e3o, Beatriz Goul\u00e3o, Nuno Mendon\u00e7a, Paulo Nicola, Jo\u00e3o G. Clara O56 Relation between emotional intelligence and mental illness in health students Jo\u00e3o Gomes, Ana Querido, Catarina Tom\u00e1s, Daniel Carvalho, Marina Cordeiro P1 Fall risk factors in people older than 50\u00a0years old \u2013 a pilot report Marlene C. Rosa, Alda Marques P2 What about the Portuguese oldest old? A global overview using census data Daniela Brand\u00e3o, \u00d3scar Ribeiro, Lia Ara\u00fajo, Constan\u00e7a Pa\u00fal P3 Prevalence of injuries in senior amateur volleyball athletes in Alentejo and Algarve clubs, Portugal: factors associated Beatriz Minghelli, Sylvina Richaud P4 Shame feelings and quality of life: the role of acceptance and decentring Ana L. Mendes, Joana Marta-Sim\u00f5es, In\u00eas A. Trindade, Cl\u00e1udia Ferreira P5 Assessment of social support during deployment in portuguese colonial war veterans Teresa Carvalho, Marina Cunha, Jos\u00e9 Pinto-Gouveia P6 Hospitalization for acute viral bronchiolitis of residents in the metropolitan region of Porto Alegre, Southern Brazil, 2012 to 2014 Morgana C. Fernandes, Roger S. Rosa, Rita C. Nugem, Lu\u00eds F. Kranz, Mariana S. Siqueira, Ronaldo Bordin P7 Falls-risk screening \u2013 an opportunity for preventing falls in the elderly from Nordeste Anabela C. Martins, Anabela Medeiros, Rafaela Pimentel, Andreia Fernandes, Carlos Mendon\u00e7a, Isabel Andrade, Susana Andrade, Ruth L. Menezes P8 Aging provokes chronodisruption in mature people in temperature circadian rhythm Rafael Bravo, Marta Miranda, Lierni Ugartemendia, Jos\u00e9 M\u00aa Tena, Francisco L. P\u00e9rez-Caballero, Lorena Fuentes-Broto, Ana B. Rodr\u00edguez, Barriga Carmen P9 The influence of climate and pollution factors in dengue cases of great ABC region, S\u00e3o Paulo M. A. Carneiro, J. N. Domingues, S. Paix\u00e3o, J. Figueiredo, V. B. Nascimento, C. Jesus, F Mendes, F. Gehrke, B. Alves, L. Azzalis, F. Fonseca P10 Visual function and impact of visual therapy in children with learning disabilities: a pilot study Ana R. Martins, Am\u00e9lia Nunes, Arminda Jorge P11 Edentulism and the need of oral rehabilitation among institutionalized elderly N\u00e9lio Veiga, Ana Amorim, Andr\u00e9 Silva, Liliana Martinho, Lu\u00eds Monteiro, Rafael Silva, Carina Coelho, Odete Amaral, In\u00eas Coelho, Carlos Pereira, Andr\u00e9 Correia P12 Therapy adherence of outpatients in the pharmacy services of a hospital unit Diana Rodrigues, N\u00eddia Marante, Pedro Silva, Sara Carvalho, Andr\u00e9 Rts Araujo, Maximiano Ribeiro, Paula Coutinho, Sandra Ventura, F\u00e1tima Roque P13 Universal access and comprehensive care of oral health: an availability study Cristina Calvo, Manoela Reses P14 Is the respiratory function of children a predictor of air quality? Coimbra as a case study Jorge Conde, Ana Ferreira, Jo\u00e3o Figueiredo P15 Meaning-in-life of college students David Silva, Lu\u00eds Sei\u00e7a, Raquel Soares, Ricardo Mour\u00e3o, Teresa Kraus O57 Training needs for nurses in palliative care Ana C. Abreu, Jos\u00e9 M. Padilha, J\u00falia M. Alves O58 Impact of computerized information systems in the global nurses\u2019 workload: nurses\u2019 perceptions and real-time Paulino Sousa, Manuel Oliveira, Joana Sousa O59 The perspective of health care professionals on self-care in hereditary neurodegenerative disease: a qualitative study S\u00f3nia Novais, Felismina Mendes O60 Contribution for health-related physical fitness reference values in healthy adolescents Joana Pinto, Joana Cruz, Alda Marques School of Health Sciences, University of Aveiro, 3810-193 Aveiro, Portugal O61 Perception of learning, satisfaction and self-efficacy of nursing students about High-Fidelity Simulation Hugo Duarte, Maria Dos Anjos Dixe, Pedro Sousa O62 Analysis of statements of diagnosis about health deviation in self-care requisites customized in a Nursing Practice Support System (SAPE\u00ae): Management of therapeutic regimen In\u00eas Cruz, Fernanda Bastos, Filipe Pereira O63 Hybrid management and hospital governance: doctors and nurses as managers Francisco L. Carvalho, Teresa T. Oliveira, V\u00edtor R. Raposo O64 Time management in health professionals Concei\u00e7\u00e3o Rainho, Jos\u00e9 C. Ribeiro, Isabel Barroso, V\u00edtor Rodrigues O65 Financial rewards and wellbeing in primary health care Carmo Neves, Teresa C. Oliveira O66 Patient safety promotion in the operating room B\u00e1rbara Oliveira, M\u00aa Carminda Morais, Pilar Baylina O67 Difficulties and needs of pre-graduate nursing students in the area of Geriatrics/Gerontology Rog\u00e9rio Rodrigues, Zaida Azeredo, Cor\u00e1lia Vicente O68 Teaching and learning sexuality in nursing education H\u00e9lia Dias, Margarida Sim-Sim O69 Entrepreneurial Motivations Questionnaire: AFC and CFA in academy Pedro Parreira, Anabela Salgueiro-Oliveira, Am\u00e9lia Castilho, Rosa Melo, Jo\u00e3o Graveto, Jos\u00e9 Gomes, Marina Vaquinhas, Carla Carvalho, Lisete M\u00f3nico, Nuno Brito O70 Nursing intervention to patient with Permanent Pacemakers and Implantable Cardioverter Defibrillators: a qualitative analysis Cassilda Sarroeira, Jos\u00e9 Amendoeira, F\u00e1tima Cunha, Anabela C\u00e2ndido, Patr\u00edcia Fernandes, Helena R. Silva, Elsa Silva O71 Alcohol consumption among nursing students: where does education fail? Isabel Barroso, Leila Lapa, Cristina Antunes O72 Labour stress in nursing Ana Gon\u00e7alves, Ana Galv\u00e3o, M\u00aa Jos\u00e9 Gomes, Susana R. Escanciano O73 The influence of safe staff nursing in patient satisfaction with nursing care Maria Freitas, Pedro Parreira, Jo\u00e3o Mar\u00f4co O74 Intention to use eHealth strategies with nursing students Ana R. Fernandes, Cremilde Cabral, Samuel Alves, Pedro Sousa O75 Community Based Mental Health: contributions of an interdisciplinary international program for students in higher health education Ant\u00f3nio Ferreira, Fernanda Pr\u00edncipe, Ulla-Maija Sepp\u00e4nen, Margarida Ferreira, Maribel Carvalhais, Marilene Silva O76 Study of satisfaction at work of graduates in nursing: 2002-2014 Manuela Ferreira, Joana Silva, J\u00e9ssica Neves, Diana Costa, Bruno Santos, Soraia Duarte O77 Health professionals\u2019 attitudes towards breastfeeding S\u00edlvia Marques, S\u00f3nia Ramalho, Isabel Mendes O78 Continuity of nursing care to person with type 2 diabetes Clarisse Louro, Eva Menino, Maria Dixe, Sara S. Dias O79 Stigma toward mental illness among future health professionals Marina Cordeiro, Catarina Tom\u00e1s, Ana Querido, Daniel Carvalho, Jo\u00e3o Gomes O80 Working with fears and anxieties of medical students in search of a humanized care Frederico C. Valim, Joyce O. Costa, L\u00facia G. Bernardes P16 Surgical paediatrics patients\u2019 psycho prophylaxis at a teaching hospital Helena Prebianchi P17 Patient-perceived outcomes in physiotherapy \u2013 a pilot study Marlene Cristina Rosa P18 Building competencies for managers in nursing Narcisa Gon\u00e7alves, Maria M. Martins, Paulina Kurcgant P19 Theoretical basis underlying physiotherapy practice in stroke rehabilitation Andr\u00e9 Vieira P20 When the life-cycle ends: the nurse\u2019s confrontation with death Sandrina Bento, S\u00e9rgio Deodato, Isabel Rabiais P21 Nursing students\u2019 opinion about the supervision relationship during their first clinical experience Laura Reis P22 Nursing Relational Laboratory: Pedagogical, dialogic and critical project Ana Torres, S\u00e9rgio Soares, Margarida Ferreira, Pedro Gra\u00e7a P23 Job satisfaction of bioscientists at a Lisbon hospital C\u00e9u Leit\u00e3o, Renato Abreu, Fernando Bell\u00e9m, Ana Almeida, Edna Ribeiro-Varandas, Ana Tavares P24 Sociodemographic and professional profile of nurses and its relation with the importance of family in nursing practices Jo\u00e3o G. Frade, Carolina Henriques, Eva Menino, Clarisse Louro, C\u00e9lia Jord\u00e3o P25 Professional satisfaction of rehabilitation nurses Sofia Neco, Carminda Morais, Pedro Ferreira P26 The person living with a stoma: the formalization of knowledge in nursing Carla R. Silva, Alice Brito, Ant\u00f3nia Silva P27 Validation of the Portuguese versions of the nursing students\u2019 perceptions of learning and learner satisfaction with simulation tool Hugo Duarte, Maria Dos Anjos Dixe, Pedro Sousa P28 Physiotherapists\u2019 perceived knowledge on technologies for electronic health records for physiotherapy Gabriela Postolache, Raul Oliveira, Isabel Moreira, Lu\u00edsa Pedro, S\u00f3nia Vicente, Samuel Domingos, Octavian Postolache P29 Quality of life and physical activity of medicine undergraduate students in the University of Southern Santa Catarina, Brazil Darlen Silva, Jo\u00e3o G. Filho, Nazare Nazario, Marcia Kretzer, Dulcineia Schneider P30 The curricular skills for decision making education in a Nursing Degree F\u00e1tima M. Marques P31 Effect of nurses\u2019 mobilization in satisfaction at work and turnover: An empirical study in the hospital setting Pedro Parreira, Carla Carvalho, Lisete M. M\u00f3nico, Carlos Pinto, Sara Vicente, S\u00e3o Jo\u00e3o Breda P32 Entrepreneurial skills of students of polytechnic higher education in Portugal: Business influences Jos\u00e9 H. Gomes, Rosa Melo, Pedro Parreira, Anabela Salgueiro, Jo\u00e3o Graveto, Marina Vaquinhas, Am\u00e9lia Castilho P33 Design and assessment of e-learning modules for Pharmacology \u00c2ngelo Jesus, Nuno Duarte, Jos\u00e9 C. Lopes, H\u00e9lder Nunes, Agostinho Cruz P34 Perspective of nurses involved in an action-research study on the changes observed in care provision: results from a focus group Anabela Salgueiro-Oliveira, Pedro Parreira, Marta L. Basto, Luciene M. Braga P35 Use of peer feedback by nursing students during clinical training: teacher\u2019s perception Ant\u00f3nio Ferreira, Beatriz Ara\u00fajo, Jos\u00e9 M. Alves, Margarida Ferreira, Maribel Carvalhais, Marilene Silva, S\u00f3nia Novais P36 What\u2019s new on endotracheal suctioning recommendations Ana S. Sousa, C\u00e2ndida Ferrito P37 Assessment of the nurses satisfaction on the Central Region of Portugal Pedro L. Ferreira, Alexandre Rodrigues, Margarida Ferreira, Isabel Oliveira P38 Study of graduate\u2019s satisfaction with the school of nursing Manuela Ferreira, J\u00e9ssica Neves, Diana Costa, Soraia Duarte, Joana Silva, Bruno Santos P39 Partnership between the school of nursing and the hospital: Supervisors\u00b4 perspectives Cristina Martins, Ana P. Macedo, Odete Ara\u00fajo, Cl\u00e1udia Augusto, F\u00e1tima Braga, Lisa Gomes, Maria A. Silva, Rafaela Ros\u00e1rio P40 Coping strategies of college students Lu\u00eds Pimenta, Diana Carreira, Patr\u00edcia Teles, Teresa Barros P41 Emotional intelligence and mental health stigma in health students Catarina Tom\u00e1s, Ana Querido, Daniel Carvalho, Jo\u00e3o Gomes, Marina Cordeiro P42 Stigma of mental health assessment: Comparison between health courses Daniel Carvalho, Ana Querido, Catarina Tom\u00e1s, Jo\u00e3o Gomes, Marina Cordeiro O81 Short- and long-term effects of pulmonary rehabilitation in mild COPD Cristina J\u00e1come, Alda Marques O82 Phonological awareness programme for preschool children Sylvie Capelas, Andreia Hall, Dina Alves, Marisa Lousada O83 REforma ATIVA: An efficient health promotion program to be implemented during retirement M\u00aa Helena Loureiro, Ana Camarneiro, Margarida Silva, Aida Mendes, Ana Pedreiro O84 Intervention for men who batter women, a case report Anne G.Silva, Elza S. Coelho O85 Immediate effects of Bowen Therapy on muscle tone and flexibility Fl\u00e1vio Melo, Fernando Ribeiro, Rui Torres, Rui Costa O86 Predictive equation for incremental shuttle walk test in adolescents T\u00e2nia Pinho, Cristina J\u00e1come, Alda Marques O87 Life satisfaction and psychopathology in institutionalized elderly people: The results of an adapted Mindfulness-Based Stress Reduction program B\u00e1rbara Cruz, Daniel Seabra, Diogo Carreira, Maria Ventura O88 Outcome changes in COPD rehabilitation: exploring the relationship between physical activity and health-related outcomes Joana Cruz, Dina Brooks, Alda Marques O89 Assessing the effectiveness of a Complex Nursing Intervention M Ros\u00e1rio Pinto, Pedro Parreira, Marta Lima-Basto, Miguel Neves, Lisete M. M\u00f3nico O90 Psychotherapeutic intervention in addiction disorders: Change in psychopathological symptoms and emotional states Carla Bizarro, Marina Cunha, Ana Galhardo, Couto Margarida, Ana P. Amorim, Eduardo Silva O91 Economic impact of a nursing intervention program to promote self-management in COPD Susana Cruz, Jos\u00e9 M. Padilha, Jorge Valente O92 Multimodal acute pain management during uterine artery embolization in treatment of uterine myomas Jos\u00e9 T. Guerrero, Francisco P. Caballero, Rafael B. Santos, Estefania P. Gonzalez, F\u00e1tima M. Monago, Lierni U. Ugalde, Marta M. V\u00e9lez, Maria J. Tena O93 Fluid administration strategies in major surgery: Goal-directed therapy Jos\u00e9 T. Guerrero, Rafael Bravo, Francisco L. P\u00e9rez-Caballero, Isabel A. Becerra, M\u00aa Elizabeth Agudelo, Guadalupe Acedo, Roberto Bajo O94 Development and implementation of a self-management educational programme using lay-led\u2019s in adolescents Spina Bifida: A pilot study Isabel Malheiro, Filomena Gaspar, Lu\u00edsa Barros O95 Influence of chair-based yoga exercises on salivary anti-microbial proteins in institutionalized frail-elderly women: a preliminary study Guilherme Furtado, Mateus Uba-Chupel, Mariana Marques, Lu\u00eds Rama, Margarida Braga, Jos\u00e9 P. Ferreira, Ana M\u00aa Teixeira O96 High intensity interval training vs moderate intensity continuous training impact on diabetes 2 Jo\u00e3o Cruz, Tiago Barbosa, \u00c2ngela Sim\u00f5es, Lu\u00eds Coelho O97 Family caregiver of people with pressure ulcer: Nursing intervention plan Alexandre Rodrigues, Juan-Fernando Jim\u00e9nez-D\u00edaz, Francisco Martinez-Hern\u00e1ndez, Bienvenida Rodriguez-De-Vera, Pedro Ferreira, Alexandrina Rodrigues O98 Chronic effects of exercise on motor memory consolidation in elderly people Andr\u00e9 Ramalho, Jo\u00e3o Petrica, Pedro Mendes, Jo\u00e3o Serrano, In\u00eas Santo, Ant\u00f3nio Rosado O99 Impression cytology of the ocular surface: Collection technique and sample processing Paula Mendon\u00e7a, K\u00e1tia Freitas O100 Does sport practice affect the reaction time in neuromuscular activity? Dora Ferreira, Ant\u00f3nio Brito, Renato Fernandes O101 Efficiency of the enteral administration of fibbers in the treatment of chronic obstipation Sofia Gomes, Fernando Moreira, Cl\u00e1udia Pinho, Rita Oliveira, Ana I. Oliveira O102 Fast decalcifier in compact bone and spongy bone Paula Mendon\u00e7a, Ana P. Casimiro, Patr\u00edcia Martins, Iryna Silva O103 Health promotion in the elderly \u2013 Intervention project in dementia Diana Evangelista O104 Prevention of musculoskeletal disorders through an exercise protocol held in labour context Catarina Leit\u00e3o, F\u00e1bia Velosa, N\u00e9lio Carecho, Lu\u00eds Coelho O105 Knowledge of teachers and other education agents on diabetes type 1: Effectiveness of an intervention program Eva Menino, Anjos Dixe, Helena Catarino, F\u00e1tima Soares, Ester Gama, Clementina Gordo O106 Treatment of diabetic peripheral neuropathic pain: a systematic review of clinical trials of phase II and III Eliana Moreira, Cristiana Mid\u00f5es, Marlene Santos O107 New drugs for osteoporosis treatment: Systematic review of clinical trials of phase II and III Sara Machado, V\u00e2nia P. Oliveira, Marlene Santos O108 Promoting hope at the end of life: Effectiveness of an Intervention Programme Ana Querido, Anjos Dixe, Rita Marques, Zaida Charepe P43 Psychomotor therapy effects on adaptive behaviour and motor proficiency of adults with intellectual disability Ana Antunes, Sofia Santos P44 The effect of exercise therapy in multiple sclerosis \u2013 a single study case Marlene C. Rosa P45 Physical condition and self-efficacy in people with fall risk \u2013 a preliminary study Marlene C. Rosa, Silvana F. Marques P46 Shock waves: their effectiveness in improving the symptoms of calcifying tendinitis of the shoulder Beatriz Minghelli, Eul\u00e1lia Caro P47 Pacifier \u2013 construction and pilot application of a parenting intervention for parents of babies until six months in primary health care M\u00aa Jos\u00e9 Lu\u00eds, Teresa Brand\u00e3o P48 The influence of Motor Imagery in fine motor skills of individuals with disabilities Pedro Mendes, Daniel Marinho, Jo\u00e3o Petrica, Diogo Monteiro, Rui Paulo, Jo\u00e3o Serrano, In\u00eas Santo P49 Evaluation of the effects of a walking programme on the fall risk factors in older people \u2013 a longitudinal pilot study Lina Monteiro, F\u00e1tima Ramalho, Rita Santos-Rocha, S\u00f3nia Morgado, Teresa Bento P50 Nursing intervention programme in lifestyles of adolescents Gilberta Sousa, Ot\u00edlia Freitas, Isabel Silva, Greg\u00f3rio Freitas, Clementina Morna, Rita Vasconcelos P51 The person submitted to hip replacement rehabilitation, at home Tatiana Azevedo, Salete Soares, Jacinta Pisco P52 Effects of Melatonin use in the treatment of neurovegetative diseases Paulo P. Ferreira, Efrain O. Olszewer, Michelle T. Oliveira, Anderson R. Sousa, Ana S. Maia, Sebasti\u00e3o T. Oliveira P53 Review of Phytotherapy and other natural substances in alcohol abuse and alcoholism Erica Santos, Ana I. Oliveira, Carla Maia, Fernando Moreira, Joana Santos, Maria F. Mendes, Rita F. Oliveira, Cl\u00e1udia Pinho P54 Dietary programme impact on biochemical markers in diabetics: systematic review Eduarda Barreira, Ana Pereira, Josiana A. Vaz, Andr\u00e9 Novo P55 Biological approaches to knee osteoarthritis: platelet-rich plasma and hyaluronic acid Lu\u00eds D. Silva, Bruno Maia, Eduardo Ferreira, Filipa Pires, Renato Andrade, Lu\u00eds Camarinha P56 Platelet-rich plasma and hyaluronic acid intra-articular injections for the treatment of ankle osteoarthritis Lu\u00eds D. Silva, Bruno Maia, Eduardo Ferreira, Filipa Pires, Renato Andrade, Lu\u00eds Camarinha P57 The impact of preventive measures in the incidence of diabetic foot ulcers: a systematic review Ana F. C\u00e9sar, Mariana Po\u00e7o, David Ventura, Raquel Loura, Pedro Gomes, Catarina Gomes, Cl\u00e1udia Silva, Elsa Melo, Jo\u00e3o Lindo P58 Dating violence among young adolescents Joana Domingos, Zaida Mendes, Susana Poeta, Tiago Carvalho, Catarina Tom\u00e1s, Helena Catarino, M\u00aa Anjos Dixe P59 Physical activity and motor memory in pedal dexterity Andr\u00e9 Ramalho, Ant\u00f3nio Rosado, Pedro Mendes, Rui Paulo, In\u00eas Garcia, Jo\u00e3o Petrica P60 The effects of whole body vibration on the electromyographic activity of thigh muscles Sandra Rodrigues, Rui Meneses, Carlos Afonso, Lu\u00eds Faria, Ad\u00e9rito Seixas P61 Mental health promotion in the workplace Marina Cordeiro, Paulo Granjo, Jos\u00e9 C. Gomes P62 Influence of physical exercise on the self-perception of body image in elderly women: A systematic review of qualitative studies Nelba R. Souza, Guilherme E. Furtado, Saulo V. Rocha, Paula Silva, Joana Carvalho O109 Psychometric properties of the Portuguese version of the \u00c9xamen Geronto-Psychomoteur (P-EGP) Marina Ana Morais, Sofia Santos, Paula Lebre, Ana Antunes O110 Symptoms of depression in the elderly population of Portugal, Spain and Italy Ant\u00f3nio Calha O111 Emotion regulation strategies and psychopathology symptoms: A comparison between adolescents with and without deliberate self-harm Ana Xavier, Marina Cunha, Jos\u00e9 Pinto-Gouveia O112 Prevalence of physical disability in people with leprosy Liana Alencar, Madalena Cunha, Ant\u00f3nio Madureira O113 Quality of life and self-esteem in type 1 and type 2 diabetes mellitus patients Ilda Cardoso, Ana Galhardo, Fernanda Daniel, V\u00edtor Rodrigues O114 Cross-cultural comparison of gross motor coordination in children from Brazil and Portugal Leonardo Luz, Tatiana Luz, Maur\u00edcio R. Ramos, Dayse C. Medeiros, Bruno M. Carmo, Andr\u00e9 Seabra, Cristina Padez, Manuel C. Silva O115 Electrocardiographic differences between African and Caucasian people Ant\u00f3nio Rodrigues, Patr\u00edcia Coelho, Alexandre Coelho O116 Factors associated with domestic, sexual and other types of violence in the city of Palho\u00e7a - Brazil Madson Caminha, Filipe Matheus, Elenice Mendes, Jony Correia, Marcia Kretzer O117 Tinnitus prevalence study of users of a hospital of public management - Spain Francisco J. Hernandez-Martinez, Juan F. Jimenez-Diaz, Bienvendida C. Rodriguez-De-Vera, Carla Jimenez-Rodriguez, Yadira Armas-Gonzalez O118 Difficulties experienced by parents of children with diabetes mellitus of preschool age in therapeutic and nutritional management C\u00e1tia Rodrigues, Rosa Pedroso O119 E-mental health - \u201cnice to have\u201d or \u201cmust have\u201d? Exploring the attitudes towards e-mental health in the general population Jennifer Apolin\u00e1rio-Hagen, Viktor Vehreschild O120 Violence against children and adolescents and the role of health professionals: Knowing how to identify and care Milene Veloso, Celina Magalh\u00e3es, Isabel Cabral, Maira Ferraz O121 Marital violence. A study in the Algarve population Filipe Nave, Em\u00edlia Costa, Filomena Matos, Jos\u00e9 Pacheco O122 Clinical factors and adherence to treatment in ischemic heart disease Ant\u00f3nio Dias, Carlos Pereira, Jo\u00e3o Duarte, Madalena Cunha, Daniel Silva O123 Can religiosity improve optimism in participants in states of illness, when controlling for life satisfaction? Lisete M. M\u00f3nico, Valentim R. Alferes, M\u00aa S\u00e3o Jo\u00e3o Br\u00eada, Carla Carvalho, Pedro M. Parreira O124 Empowerment, knowledge and quality of life of people with diabetes type 2 in the Alto Minho Health Local Unit M\u00aa Carminda Morais, Pedro Ferreira, Rui Pimenta, Jos\u00e9 Boavida O125 Antihypertensive therapy adherence among hypertensive patients from Bragan\u00e7a county, Portugal Isabel C. Pinto, T\u00e2nia Pires, Catarina Silva O126 Subjective perception of sexual achievement - An exploratory study on people with overweight Maria Ribeiro, Maria Viega-Branco, Filomena Pereira, Ana M\u00aa Pereira O127 Physical activity level and associated factors in hypertensive individuals registered in the family health strategy of a basic health unit from the city of Palho\u00e7a, Santa Catarina, Brazil Fabr\u00edcia M. Almeida, Gustavo L. Estevez, Sandra Ribeiro, Marcia R. Kretzer O128 Perception of functional fitness and health in non-institutionalised elderly from rural areas Paulo V. Jo\u00e3o, Paulo Nogueira, Sandra Novais, Ana Pereira, Lara Carneiro, Maria Mota O129 Medication adherence in patients with type 2 diabetes mellitus treated at primary health care in Coimbra Rui Cruz, Luiz Santiago, Carlos Fontes-Ribeiro O130 Multivariate association between body mass index and multi-comorbidities in elderly people living in low socio-economic status context Guilherme Furtado, Saulo V. Rocha, Andr\u00e9 P. Coutinho, Jo\u00e3o S. Neto, L\u00e9lia R. Vasconcelos, Nelba R. Souza, Est\u00e9lio Dantas O131 Metacognition, rumination and experiential avoidance in Borderline Personality Disorder Alexandra Dinis, S\u00e9rgio Carvalho, Paula Castilho, Jos\u00e9 Pinto-Gouveia O132 Health issues in a vulnerable population: nursing consultation in a public bathhouse in Lisbon Alexandra Sarreira-Santos, Am\u00e9lia Figueiredo, Lurdes Medeiros-Garcia, Paulo Seabra O133 The perception of quality of life in people with multiple sclerosis accompanied in External Consultation of the Local Health Unit of Alto Minho Rosa Rodrigues, M\u00aa Carminda Morais, Paula O. Fernandes O134 Representation of interaction established between immigrant women and nurse during pregnancy to postpartum, from the perspective of immigrant women Concei\u00e7\u00e3o Santiago, M\u00aa Henriqueta Figueiredo, Marta L. Basto O135 Illness perceptions and medication adherence in hypertension Teresa Guimar\u00e3es, Andr\u00e9 Coelho, Anabela Gra\u00e7a, Ana M. Silva, Ana R. Fonseca O136 A Portuguese study on adults\u2019 intimate partner violence, interpersonal trust and hope Luz Vale-Dias, B\u00e1rbara Minas, Graciete Franco-Borges P63 QOL\u2019 predictors of people with intellectual disability and general population Cristina Sim\u00f5es, Sofia Santos P64 Content validation of the Communication Disability Profile (CDP) - Portuguese Version Ana Serra, Maria Matos, Lu\u00eds Jesus P65 Study of biochemical and haematological changes in football players Ana S. Tavares, Ana Almeida, C\u00e9u Leit\u00e3o, Edna Varandas, Renato Abreu, Fernando Bell\u00e9m P66 Body image dissatisfaction in inflammatory bowel disease: exploring the role of chronic illness-related shame In\u00eas A. Trindade, Cl\u00e1udia Ferreira, Jos\u00e9 Pinto-Gouveia, Joana Marta-Sim\u00f5es P67 Obesity and sleep in the adult population - a systematic review Odete Amaral, Cristiana Miranda, Pedro Guimar\u00e3es, Rodrigo Gon\u00e7alves, N\u00e9lio Veiga, Carlos Pereira P68 Frequency of daytime sleepiness and obstructive sleep apnea risk in COPD patients T\u00e2nia C. Fleig, Elisabete A. San-Martin, C\u00e1ssia L. Goulart, Paloma B. Schneiders, Natacha F. Miranda, Lisiane L. Carvalho, Andrea G. Silva P69 Working with immigrant-origin clients: discourses and practices of health professionals Joana Topa, Concei\u00e7\u00e3o Nogueira, Sofia Neves P70 Systemic Lupus Erythematosus \u2013 what are audiovestibular changes? Rita Ventura, Cristina Nazar\u00e9 P71 Mental disorders in the oldest old: findings from the Portuguese national hospitalization database Daniela Brand\u00e3o, Alberto Freitas, \u00d3scar Ribeiro, Constan\u00e7a Pa\u00fal P72 Recurrence analysis in postural control in children with cerebral palsy Cristiana Merc\u00ea, Marco Branco, Pedro Almeida, Daniela Nascimento, Juliana Pereira, David Catela P73 The experience of self-care in the elderly with COPD: contributions to reflect proximity care Helga Rafael P74 Culturally competent nurses: managing unpredictability in clinical practice with immigrants Alcinda C. Reis O137 Paediatric speech and language screening: An instrument for health professionals Ana Mendes, Ana R. Valente, Marisa Lousada O138 Anthropometric and nutritional assessment in bodybuilders Diana Sousa, Ana L. Baltazar, M\u00aa Helena Loureiro O139 Computerized adventitious respiratory sounds in children with lower respiratory tract infections Ana Oliveira, Jos\u00e9 Apar\u00edcio, Alda Marques O140 Role of computerized respiratory sounds as a marker in LRTI Alda Marques, Ana Oliveira, Joana Neves, Rodrigo Ayoub O141 Confirmatory factor analysis of the Personal Wellbeing Index in people with chronic kidney disease Lu\u00eds Sousa, Cristina Marques-Vieira, Sandy Severino, Helena Jos\u00e9 O142 Phonological awareness skills in school aged children In\u00eas Cadorio, Marisa Lousada O143 Assessment of early memories of warmth and safeness in interaction with peers: its relationship with psychopathology in adolescence Marina Cunha, Diogo Andrade, Ana Galhardo, Margarida Couto O144 The molecular effects induced by single shot irradiation on a diffuse large B cell lymphoma cell line Fernando Mendes, C\u00e1tia Domingues, Susann Schukg, Ana M. Abrantes, Ana C. Gon\u00e7alves, Tiago Sales, Ricardo Teixo, Rita Silva, J\u00e9ssica Estrela, Mafalda Laranjo, Jo\u00e3o Casalta-Lopes, Clara Rocha, Paulo C. Sim\u00f5es, Ana B. Sarmento-Ribeiro, M\u00aa Filomena Botelho, Manuel S. Rosa O145 Morpho-functional characterization of cardiac chambers by Transthoracic Echocardiography, in young athletes of gymnastics competition Virg\u00ednia Fonseca, Diogo Cola\u00e7o, Vanessa Neves O146 Prevalence of the antibodies of the new histo-blood system \u2013 FORS system Carlos Jesus, Camilla Hesse, Clara Rocha, N\u00e1dia Os\u00f3rio, Ana Valado, Armando Caseiro, Ant\u00f3nio Gabriel, Lola Svensson, Fernando Mendes, Wafa A. Siba, Cristina Pereira, Jorge Tomaz O147 Assessment of the war-related perceived threat in Portuguese Colonial War Veterans Teresa Carvalho, Jos\u00e9 Pinto-Gouveia, Marina Cunha O148 Pulse transit time estimation for continuous blood pressure measurement: A comparative study Diana Duarte, Nuno V. Lopes, Rui Fonseca-Pinto O149 Blood pressure assessment during standard clinical manoeuvres: A non-invasive PPT based approach Diana Duarte, Nuno V. Lopes, Rui Fonseca-Pinto O150 Development and initial validation of the Activities and Participation Profile related to Mobility (APPM) Anabela C. Martins O151 MEASYCare-2010 Standard\u2013A geriatric evaluation system in primary health care: Reliability and validity of the latest version in Portugal Piedade Brand\u00e3o, Laura Martins, Margarida Cardoso O152 Interrater and intrarater reliability and agreement of the range of shoulder flexion in the standing upright position through photographic assessment Nuno Morais, Joana Cruz O153 Three-dimensional biofabrication techniques for tissue regeneration Nuno Alves, Paula Faria, Artur Mateus, Pedro Morou\u00e7o O154 A new computer tool for biofabrication applied to tissue engineering Nuno Alves, Nelson Ferreira, Artur Mateus, Paula Faria, Pedro Morou\u00e7o O155 Development and psychometric qualities of a scale to measure the functional independence of adolescents with motor impairment Isabel Malheiro, Filomena Gaspar, Lu\u00edsa Barros O156 Organizational Trust in Health services: Exploratory and Confirmatory factor analysis of the Organizational Trust Inventory- Short Form (OTI-SF) Pedro Parreira, Andreia Cardoso, Lisete M\u00f3nico, Carla Carvalho, Albino Lopes, Anabela Salgueiro-Oliveira O157 Thermal symmetry: An indicator of occupational task asymmetries in physiotherapy Ad\u00e9rito Seixas, Valter Soares, Tiago Dias, Ricardo Vardasca, Joaquim Gabriel, Sandra Rodrigues O158 A study of ICT active monitoring adoption in stroke rehabilitation Hugo Paredes, Ars\u00e9nio Reis, Sara Marinho, V\u00edtor Filipe, Jo\u00e3o Barroso O159 Paranoia Checklist (Portuguese Version): Preliminary studies in a mixed sample of patients and healthy controls Carolina Da Motta, C\u00e9lia B. Carvalho, Jos\u00e9 Pinto-Gouveia, Ermelindo Peixoto O160 Reliability and validity of the Composite Scale on Morningness: European Portuguese version, in adolescents and young adults Ana A. Gomes, Vanessa Costa, Diana Couto, Daniel R. Marques, Jos\u00e9 A. Leit\u00e3o, Jos\u00e9 Tavares, Maria H. Azevedo, Carlos F. Silva O161 Evaluation scale of patient satisfaction with nursing care: Psychometric properties evaluation Jo\u00e3o Freitas, Pedro Parreira, Jo\u00e3o Mar\u00f4co O162 Impact of fibromyalgia on quality of life: Comparing results from generic instruments and FIQR Miguel A. Garcia-Gordillo, Daniel Collado-Mateo, Gang Chen, Angelo Iezzi, Jos\u00e9 A. Sala, Jos\u00e9 A. Parra\u00e7a, Narcis Gusi O163 Preliminary study of the adaptation and validation of the Rating Scale of Resilient Self: Resilience, self-harm and suicidal ideation in adolescents Jani Sousa, Mariana Marques, Jacinto Jardim, Anabela Pereira, S\u00f3nia Sim\u00f5es, Marina Cunha O164 Development of the first pressure ulcer in inpatient setting: Focus on length of stay Pedro Sardo, Jenifer Guedes, Jo\u00e3o Lindo, Paulo Machado, Elsa Melo O165 Forms of Self-Criticizing and Self-Reassuring Scale: Adaptation and early findings in a sample of Portuguese children C\u00e9lia B. Carvalho, Joana Benevides, Marina Sousa, Joana Cabral, Carolina Da Motta O166 Predictive ability of the Perinatal Depression Screening and Prevention Tool \u2013 Preliminary results of the dimensional approach Ana T. Pereira, Sandra Xavier, Julieta Azevedo, Elisabete Bento, Cristiana Marques, Rosa Carvalho, Mariana Marques, Ant\u00f3nio Macedo O167 Psychometric properties of the BaSIQS-Basic Scale on insomnia symptoms and quality of sleep, in adults and in the elderly Ana M. Silva, Juliana Alves, Ana A. Gomes, Daniel R. Marques, M\u00aa Helena Azevedo, Carlos Silva O168 Enlightening the human decision in health: The skin melanocytic classification challenge Ana Mendes, Huei D. Lee, Newton Spola\u00f4r, Jefferson T. Oliva, Wu F. Chung, Rui Fonseca-Pinto O169 Test-retest reliability household life study and health questionnaire Pomerode (SHIP-BRAZIL) Keila Bairros, Cl\u00e1udia D. Silva, Cl\u00f3vis A. Souza, Silvana S. Schroeder O170 Characterization of sun exposure behaviours among medical students from Nova Medical School Elsa Ara\u00fajo, Helena Monteiro, Ricardo Costa, Sara S. Dias, Jorge Torgal O171 Spirituality in pregnant women Carolina G. Henriques, Lu\u00edsa Santos, Elisa F. Caceiro, S\u00f3nia A. Ramalho O172 Polypharmacy in older patients with cancer Rita Oliveira, Vera Afreixo, Jo\u00e3o Santos, Priscilla Mota, Agostinho Cruz, Francisco Pimentel O173 Quality of life of caregivers of people with advanced chronic disease: Translation and validation of the quality of life in life threatening illness - family carer version (QOLLTI-C-PT) Rita Marques, M\u00aa Anjos Dixe, Ana Querido, Patr\u00edcia Sousa O174 The psychometric properties of the brief Other as Shamer Scale for Children (OAS-C): preliminary validation studies in a sample of Portuguese children Joana Benevides, Carolina Da Motta, Marina Sousa, Suzana N. Caldeira, C\u00e9lia B. Carvalho O175 Measuring emotional intelligence in health care students \u2013 Revalidation of WLEIS-P Ana Querido, Catarina Tom\u00e1s, Daniel Carvalho, Jo\u00e3o Gomes, Marina Cordeiro O176 Health indicators in prenatal assistance: The impact of computerization and of under-production in basic health centres Joyce O. Costa, Frederico C. Valim, L\u00edgia C. Ribeiro O177 Hope genogram: Assessment of resources and interaction patterns in the family of the child with cerebral palsy Zaida Charepe, Ana Querido, M\u00aa Henriqueta Figueiredo O178 The influence of childbirth type in postpartum quality of life Priscila S. Aquino, Samila G. Ribeiro, Ana B. Pinheiro, Paula A. Lessa, Mirna F. Oliveira, Lu\u00edsa S. Brito, \u00cdtalo N. Pinto, Alessandra S. Furtado, R\u00e9gia B. Castro, Caroline Q. Aquino, Eveliny S. Martins O179 Women\u2019s beliefs about pap smear test and cervical cancer: influence of social determinants Ana B Pinheiro, Priscila S. Aquino, Lara L. Oliveira, Patr\u00edcia C. Pinheiro, Caroline R. Sousa, V\u00edvien A. Freitas, Tatiane M. Silva, Adman S. Lima, Caroline Q. Aquino, Karizia V. Andrade, Camila A. Oliveira, Eglidia F. Vidal O180 Validity of the Portuguese version of the ASI-3: Is anxiety sensitivity a unidimensional or multidimensional construct? Ana Ganho-\u00c1vila, Mariana Moura-Ramos, \u00d3scar Gon\u00e7alves, Jorge Almeida O181 Lifestyles of higher education students: the influence of self-esteem and psychological well-being Armando Silva, Irma Brito, Jo\u00e3o Amado P75 Assessing the quality of life of persons with significant intellectual disability: Portuguese version of Escala de San Mart\u00edn Ant\u00f3nio Rodrigo, Sofia Santos, Fernando Gomes P76 Childhood obesity and breastfeeding - A systematic review Marlene C. Rosa, Silvana F. Marques P77 Cross-cultural adaptation of the Foot and Ankle Ability Measure (FAAM) for the Portuguese population Sara Lu\u00eds, Lu\u00eds Cavalheiro, Pedro Ferreira, Rui Gon\u00e7alves P78 Cross-cultural adaptation of the Patient-Rated Wrist Evaluation score (PRWE) for the Portuguese population Rui S. Lopes, Lu\u00eds Cavalheiro, Pedro Ferreira, Rui Gon\u00e7alves P79 Cross-cultural adaptation of the Myocardial Infraction Dimensional Assessment Scale (MIDAS) for Brazilian Portuguese language Bruno H. Fiorin, Marina S. Santos, Edmar S. Oliveira, Rita L. Moreira, Elizabete A. Oliveira, Braulio L. Filho P80 The revised Portuguese version of the Three-Factor Eating Questionnaire: A confirmatory factor analysis Lara Palmeira, Teresa Garcia, Jos\u00e9 Pinto-Gouveia, Marina Cunha P81 Assessing weight-related psychological inflexibility: An exploratory factor analysis of the AAQW\u2019s Portuguese version Sara Cardoso, Lara Palmeira, Marina Cunha; Jos\u00e9 Pinto-Gouveia P82 Validation of the Body Appreciation Scale-2 for Portuguese women Joana Marta-Sim\u00f5es, Ana L. Mendes, In\u00eas A. Trindade, Sara Oliveira, Cl\u00e1udia Ferreira P83 The Portuguese validation of the Dietary Intent Scale Ana L. Mendes, Joana Marta-Sim\u00f5es, In\u00eas A. Trindade, Cl\u00e1udia Ferreira P84 Construction and validation of the Inventory of Marital Violence (IVC) Filipe Nave P85 Portable continuous blood pressure monitor system Mariana Campos, Iris Gaud\u00eancio, Fernando Martins, Lino Ferreira, Nuno Lopes, Rui Fonseca-Pinto P86 Construction and validation of the Scale of Perception of the Difficulties in Caring for the Elderly (SPDCE) Rog\u00e9rio Rodrigues, Zaida Azeredo, Cor\u00e1lia Vicente P87 Development and validation of a comfort rating scale for the elderly hospitalized with chronic illness Joana Silva, Patr\u00edcia Sousa, Rita Marques P88 Construction and validation of the Postpartum Paternal Quality of Life Questionnaire (PP-QOL) Isabel Mendes, Rog\u00e9rio Rodrigues, Zaida Azeredo, Cor\u00e1lia Vicente P89 Infrared thermal imaging: A tool for assessing diabetic foot ulcers Ricardo Vardasca, Ana R. Marques, Ad\u00e9rito Seixas, Rui Carvalho, Joaquim Gabriel P90 Pressure ulcers in an intensive care unit: An experience report Paulo P. Ferreira, Michelle T. Oliveira, Anderson R. Sousa, Ana S. Maia, Sebasti\u00e3o T. Oliveira, Pablo O. Costa, Maiza M. Silva P91 Validation of figures used in evocations: instrument to capture representations Cristina Arreguy-Sena, Nath\u00e1lia Alvarenga-Martins, Paulo F. Pinto, Denize C. Oliveira, Pedro D. Parreira, Ant\u00f4nio T. Gomes, Luciene M. Braga P92 Telephone assistance to decrease burden in informal caregivers of stroke older people: Monitoring and diagnostic evaluation Odete Ara\u00fajo, Isabel Lage, Jos\u00e9 Cabrita, Laetitia Teixeira P93 Hope of informal caregivers of people with chronic and advanced disease Rita Marques, M\u00aa Anjos Dixe, Ana Querido, Patr\u00edcia Sousa P94 Functionality and quality information from the Portuguese National Epidemiological Surveillance System Sara Silva, Eug\u00e9nio Cordeiro, Jo\u00e3o Pimentel P95 Resting metabolic rate objectively measured vs. Harris and Benedict formula Vera Ferro-Lebres, Juliana A. Souza, Mariline Tavares O182 Characteristics of non-urgent patients: Cross-sectional study of an emergency department M\u00aa Anjos Dixe, Pedro Sousa, Rui Passadouro, Teresa Peralta, Carlos Ferreira, Georgina Louren\u00e7o O183 Physical fitness and health in children of the 1st Cycle of Education Jo\u00e3o Serrano, Jo\u00e3o Petrica, Rui Paulo, Samuel Hon\u00f3rio, Pedro Mendes O184 The impact of physical activity on sleep quality, in children Alexandra Sim\u00f5es, Lucinda Carvalho, Alexandre Pereira O185 What is the potential for using Information and Communication Technologies in Arterial Hypertension self-management? Sara Silva, Paulino Sousa, Jos\u00e9 M. Padilha O186 Exploring psychosocial factors associated with risk of falling in older patients undergoing haemodialysis Daniela Figueiredo, Carolina Valente, Alda Marques O187 Development of pressure ulcers on the face in patients undergoing non-invasive ventilation Patr\u00edcia Ribas, Joana Sousa, Frederico Brand\u00e3o, Cesar Sousa, Matilde Martins O188 The elder hospitalized: Limiting factors of comfort Patr\u00edcia Sousa, Rita Marques O189 Physical activity and health state self-perception by Portuguese adults Francisco Mendes, Rosina Fernandes, Em\u00edlia Martins, C\u00e1tia Magalh\u00e3es, Patr\u00edcia Ara\u00fajo O190 Satisfaction with social support in the elderly of the district of Bragan\u00e7a Carla Grande, M\u00aa Augusta Mata, Juan G. Vieitez O191 Prevalence of death by traumatic brain injury and associated factors in intensive care unit of a general hospital, Brazil Bruna Bianchini, Nazare Nazario, Jo\u00e3o G. Filho, Marcia Kretzer O192 Relation between family caregivers burden and health status of elderly dependents T\u00e2nia Costa, Armando Almeida, Gabriel Baffour O193 Phenomena sensitive to nursing care in day centre Armando Almeida, T\u00e2nia Costa, Gabriel Baffour O194 Frailty: what do the elderly think? Zaida Azeredo, Carlos Laranjeira, Magda Guerra, Ana P. Barbeiro O195 The therapeutic self-care as a nursing-sensitive outcome: A correlational study Regina Ferreira O196 Phonetic-phonological acquisition for the European Portuguese from 18\u00a0months to 6\u00a0years and 12\u00a0months Sara Lopes, Liliana Nunes, Ana Mendes O197 Quality of life of patients undergoing liver transplant surgery Julian Martins, Dulcineia Schneider, Marcia Kretzer, Fl\u00e1vio Magajewski O198 Professional competences in health: views of older people from different European Countries C\u00e9lia Soares, Ant\u00f3nio Marques O199 Life satisfaction of working adults due to the number of hours of weekly exercise Marco Batista, Ruth J. Castuera, Helena Mesquita, Ant\u00f3nio Faustino, Jorge Santos, Samuel Hon\u00f3rio O200 Therapeutic itinerary of women with breast cancer in Santa Maria City/RS Betina P. Vizzotto, Leticia Frigo, Hedioneia F. Pivetta O201 The breastfeeding prevalence at 4\u00a0months: Maternal experience as a determining factor Dolores Sardo O202 The impact of the transition to parenthood in health and well-being Cristina Martins, Wilson Abreu, M\u00aa C\u00e9u Figueiredo P96 Self-determined motivation and well-being in Portuguese active adults of both genders Marco Batista, Ruth Jimenez-Castuera, Jo\u00e3o Petrica, Jo\u00e3o Serrano, Samuel Hon\u00f3rio, Rui Paulo, Pedro Mendes P97 The geriatric care: ways and means of comforting Patr\u00edcia Sousa, Rita Marques P98 The influence of relative age, subcutaneous adiposity and physical growth on Castelo Branco under-15 soccer players 2015 Ant\u00f3nio Faustino, Paulo Silveira, Jo\u00e3o Serrano, Rui Paulo, Pedro Mendes, Samuel Hon\u00f3rio P99 Data for the diagnostic process focused on self-care \u2013 managing medication regime: An integrative literature review Catarina Oliveira, Fernanda Bastos, In\u00eas Cruz P100 Art therapy as mental health promotion for children Cl\u00e1udia K. Rodriguez, M\u00e1rcia R. Kretzer, Nazar\u00e9 O. Naz\u00e1rio P101 Chemical characterization of fungal chitosan for industrial applications Pedro Cruz, Daniela C. Vaz, Rui B. Ruben, Francisco Avelelas, Susana Silva, M\u00aa Jorge Campos P102 The impact of caring older people at home Maria Almeida, Liliana Gon\u00e7alves, L\u00edgia Antunes P103 Development of the first pressure ulcer in an inpatient setting: Focus on patients\u2019 characteristics Pedro Sardo, Jenifer Guedes, Jo\u00e3o Sim\u00f5es, Paulo Machado, Elsa Melo P104 Association between General Self-efficacy and Physical Activity among Adolescents Susana Cardoso, Osvaldo Santos, Carla Nunes, Isabel Loureiro O203 Characterization of the habits of online acquisition of medicinal products in Portugal Fl\u00e1via Santos, Gilberto Alves O204 Waiting room \u2013 A space for health education Cl\u00e1udia Soar, Teresa O. Marsi O205 Safey culture evaluation in hospitalized children Ernestina Silva, Dora Pedrosa, Andrea Le\u00e7a, Daniel Silva O206 Sexual Self-awareness and Body Image Ana Galv\u00e3o, Maria Gomes, Paula Fernandes, Ana Non\u00e9 O207 Perception of a Portuguese population regarding the acquisition and consumption of functional foods Jaime Combad\u00e3o, C\u00e1tia Ramalhete, Paulo Figueiredo, Patr\u00edcia Caeiro O208 The work process in primary health care: evaluation in municipalities of southern Brazil Karine C. Fontana, Josimari T. Lacerda, Patr\u00edcia O. Machado O209 Exploration and evaluation of potential probiotic lactic acid bacteria isolated from Amazon buffalo milk Raphaelle Borges, Fl\u00e1vio Barbosa, Dayse S\u00e1 O210 Road safety for children: Using children\u2019s observation, as a passenger Germana Brunhoso, Gra\u00e7a Apar\u00edcio, Am\u00e2ncio Carvalho O211 Perception and application of quality-by-design by the Pharmaceutical industry in Portugal Ana P. Garcia, Paula O. Fernandes, Adriana Santos O212 Oral health among Portuguese children and adolescents: a public health issue N\u00e9lio Veiga, Carina Br\u00e1s, In\u00eas Carvalho, Joana Batalha, Margarida Gl\u00f3ria, Filipa Bexiga, In\u00eas Coelho, Odete Amaral, Carlos Pereira O213 Plant species as a medicinal resource in Igatu-Chapada Diamantina (Bahia, Brazil) Cl\u00e1udia Pinho, Nilson Para\u00edso, Ana I. Oliveira, Crist\u00f3v\u00e3o F. Lima, Alberto P. Dias O214 Characterization of cognitive and functional performance in everyday tasks: Implications for health in institutionalised older adults Pedro Silva, M\u00e1rio Espada, M\u00e1rio Marques, Ana Pereira O215 BMI and the perception of the importance given to sexuality in obese and overweight people Ana M\u00aa Pereira, M\u00aa Veiga-Branco, Filomena Pereira, Maria Ribeiro O216 Analysis and comparison of microbiological contaminations of two different composition pacifiers Vera Lima, Ana I. Oliveira, Cl\u00e1udia Pinho, Gra\u00e7a Cruz, Rita F. Oliveira, Lu\u00edsa Barreiros, Fernando Moreira O217 Experiences of couple relationships in the transition to retirement Ana Camarneiro, M\u00aa Helena Loureiro, Margarida Silva O218 Preventive and corrective treatment of drug-induced calcium deficiency: an analysis in a community pharmacy setting Catarina Duarte, \u00c2ngelo Jesus, Agostinho Cruz O219 Profile of mood states in physically active elderly subjects: Is there a relation with health perception? Maria Mota, Sandra Novais, Paulo Nogueira, Ana Pereira, Lara Carneiro, Paulo V. Jo\u00e3o O220 (Un)Safety behaviour at work: the role of education towards a health and safety culture Teresa Maneca Lima O221 Analysis of the entrepreneurial profile of students attending higher education in Portugal: the Carland Entrepreneurship Index application Anabela Salgueiro-Oliveira, Marina Vaquinhas, Pedro Parreira, Rosa Melo, Jo\u00e3o Graveto, Am\u00e9lia Castilho, Jos\u00e9 H. Gomes O222 Evaluation of welfare and quality of life of pregnant working women regarding the age of the pregnant Mar\u00eda S. Medina, Valeriana G. Blanco O223 Psychological wellbeing protection among unemployed and temporary workers: Uncovering effective community-based interventions with a Delphi panel Osvaldo Santos, Elisa Lopes, Ana Virgolino, Alexandra Dinis, Sara Ambr\u00f3sio, In\u00eas Almeida, Tatiana Marques, M\u00aa Jo\u00e3o Heitor O224 Chilean population norms derived from the Health-related quality of life SF-6D Miguel A. Garcia-Gordillo, Daniel Collado-Mateo, Pedro R. Olivares, Jos\u00e9 A. Parra\u00e7a, Jos\u00e9 A. Sala O225 Motivation of college students toward Entrepreneurship: The influence of social and economic instability Am\u00e9lia Castilho, Jo\u00e3o Graveto, Pedro Parreira, Anabela Oliveira, Jos\u00e9 H. Gomes, Rosa Melo, Marina Vaquinhas O226 Use of aromatic and medicinal plants, drugs and herbal products in Bragan\u00e7a city M\u00f3nia Cheio, Agostinho Cruz, Ol\u00edvia R. Pereira O227 Edible flowers as new novel foods concept for health promotion Sara Pinto, Adriana Oliveira, M. Concei\u00e7\u00e3o Manso, Carla Sousa, Ana F. Vinha O228 The influence of leisure activities on the health and welfare of older people living in nursing homes M\u00aa Manuela Machado, Margarida Vieira O229 Risk of falling, fear of falling and functionality in community-dwelling older adults Beatriz Fernandes, Teresa Tom\u00e1s, Diogo Quirino O230 Musculoskeletal pain and postural habits in children and teenage students Gustavo Desouzart, Rui Matos, Magali Bordini, Pedro Mouro\u00e7o O231 What's different in Southern Europe? The question of citizens\u2019 participation in health systems Ana R. Matos, Mauro Serapioni O232 Occupational stress in Portuguese police officers Teresa Guimar\u00e3es, Virg\u00ednia Fonseca, Andr\u00e9 Costa, Jo\u00e3o Ribeiro, Jo\u00e3o Lobato O233 Is occupational therapy culturally relevant to promote mental health in Burkina Faso? Inmaculada Z. Martin, Anita Bj\u00f6rklund P105 Pay-for-performance satisfaction and quality in primary care Aida I. Tavares, Pedro Ferreira, Rui Passadouro P106 Economic development through life expectancy lenses S\u00f3nia Morgado P107 What is the effectiveness of exercise on smoking cessation to prevent clinical complications of smoking? Nuno Tavares, Jo\u00e3o Valente, Anabela C. Martins P108 A systematic review of the effects of yoga on mental health Patr\u00edcia Ara\u00fajo, Rosina Fernandes, Francisco Mendes, C\u00e1tia Magalh\u00e3es, Em\u00edlia Martins P109 Healthy lifestyle: comparison between higher education students that lived until adult age in rural and urban environment Pedro Mendes, Rui Paulo, Ant\u00f3nio Faustino, Helena Mesquita, Samuel Hon\u00f3rio, Marco Batista P110 Evaluation of the Mobile Emergency Care Service (SAMU) in Brazil Josimari T. Lacerda, Angela B. Ortiga, M\u00aa Cristina Calvo, S\u00f4nia Natal P111 Bioactive compounds - antioxidant activity of tropical fruits Marta Pereira P112 Use of non-pharmacological methods to relieve pain in labour Manuela Ferreira, Ana R. Prata, Paula Nelas, Jo\u00e3o Duarte P113 Mechanical safety of pacifiers sold in Portuguese pharmacies and childcare stores Juliana Carneiro, Ana I. Oliveira, Cl\u00e1udia Pinho, Cristina Couto, Rita F. Oliveira, Fernando Moreira P114 The importance of prenatal consultation: Information to pregnant women given on a unit of primary care Ana S. Maia, Michelle T. Oliveira, Anderson R. Sousa, Paulo P. Ferreira, G\u00e9ssica M. Souza, L\u00edvia F. Almada, Milena A. Concei\u00e7\u00e3o, Eujcely C. Santiago P115 Influence of different backpack loading conditions on neck and lumbar muscles activity of elementary school children Sandra Rodrigues, Gabriela Domingues, Irina Ferreira, Lu\u00eds Faria, Ad\u00e9rito Seixas P116 Efficacy and safety of dry extract Hedera helix in the treatment of productive cough Ana R. Costa, \u00c2ngelo Jesus, Am\u00e9rico Cardoso, Alexandra Meireles, Armanda Cola\u00e7o, Agostinho Cruz P117 A portrait of the evaluation processes of education groups in primary health care Viviane L. Vieira, Kellem R. Vincha, Ana M\u00aa Cervato-Mancuso P118 Benefits of vitamins C and E in sensorineural hearing loss: a review Melissa Faria, Cl\u00e1udia Reis P119 BODY SNAPSHOT \u2013 a web-integrated anthropometric evaluation system Marco P. Cova, Rita T. Ascenso, Henrique A. Almeida, Eunice G. Oliveira P120 Anthropometric evaluation and variation during pregnancy Miguel Santana, Rafael Pereira, Eunice G. Oliveira, Henrique A. Almeida, Rita T. Ascenso P121 Knowledge of college students on the amendments of their eating habits and physical activity index in the transition to higher education Rita Jesus, Rodrigo Tapadas, Carolina Tim-Tim, Catarina Cezanne, Matilde Lagoa, Sara S. Dias, Jorge Torgal P122 Muscular activity of a rally race car driver Jo\u00e3o Lopes, Henrique Almeida, Sandra Amado, Lu\u00eds Carr\u00e3o O234 Literacy and results in health Madalena Cunha, Lu\u00eds Saboga-Nunes, Carlos Albuquerque, Oliv\u00e9rio Ribeiro O235 Literacy promotion and empowerment of type 2 diabetics elderly in four family health units of the group of health centers of D\u00e3o Laf\u00f5es Suzete Oliveira, M\u00aa Carminda Morais O236 Mediterranean diet, health and life quality among Portuguese children Em\u00edlia Martins, Francisco Mendes, Rosina Fernandes, C\u00e1tia Magalh\u00e3es, Patr\u00edcia Ara\u00fajo O237 Health literacy, from data to action - translation, validation and application of the European Health Literacy Survey in Portugal (HLS-EU-PT) Ana R. Pedro, Odete Amaral, Ana Escoval O238 Oral health literacy evaluation in a Portuguese military population Victor Assun\u00e7\u00e3o, Henrique Lu\u00eds, Lu\u00eds Lu\u00eds O239 Preferences to Internet-based cognitive behavioural therapy \u2013 do attachment orientations matter? Jennifer Apolin\u00e1rio-Hagen, Viktor Vehreschild O240 A comparative transnational study in health literacy between Austria and Portugal Ulrike Fotschl, Gerald Lirk, Anabela C. Martins, Isabel Andrade, Fernando Mendes O241 Health literacy and social behaviours: relationship with sexually transmitted diseases? Ver\u00f3nica Mendon\u00e7a, Sandra Antunes, Isabel Andrade, N\u00e1dia Os\u00f3rio, Ana Valado, Armando Caseiro, Ant\u00f3nio Gabriel, Anabela C. Martins, Fernando Mendes O242 Parenting styles and attachment to parents: what relationships? Paula A. Silva, Lisete M. M\u00f3nico, Pedro M. Parreira, Carla Carvalho O243 Work-life balance in health professionals and professors: comparative study of workers with shift work and fixed schedule Carla Carvalho, Pedro M. Parreira, Lisete M. M\u00f3nico, Joana Ruivo O244 Technology literacy in self-management of diabetes V\u00e2nia Silva, Paulino Sousa, Jos\u00e9 M. Padilha O245 Satisfaction with therapeutic education and its relationship with clinical variables in children with type 1 diabetes Vera Ferraz, Gra\u00e7a Apar\u00edcio, Jo\u00e3o Duarte O246 Nutrition-related knowledge in middle-age and older patients with type 2 diabetes Carlos Vasconcelos, Ant\u00f3nio Almeida, Joel Neves, Telma Correia, Helena Amorim, Romeu Mendes O247 Validating the HLS-EU-(PT) questionnaire to measure health literacy in adolescents (CrAdLiSa project: HLS-EU-PT) Lu\u00eds Saboga-Nunes, Madalena Cunha, Carlos Albuquerque O248 Health education in people with coronary heart disease: Experience of the cardiology department of a hospital on the outskirts of Lisbon Elsa S. Pereira, Leonino S. Santos, Ana S. Reis, Helena R. Silva, Jo\u00e3o Rombo, Jorge C. Fernandes, Patr\u00edcia Fernandes O249 Information and training needs of informal caregivers of individuals with stroke sequelae: a qualitative survey Jaime Ribeiro, Catarina Mangas, Ana Freire O250 Prevention of psychoactive substances consumption in students from 6th grade of Albergaria-a-Velha\u00b4s School Group Sara Silva, Irene Francisco, Ana Oliveira O251 Promoting healthy sexuality: shared responsibility for family, youth and educators Helena Catarino, M\u00aa Anjos Dixe, M\u00aa Clarisse Louro O252 Sexual risk behaviour in adolescents and young people Saudade Lopes, Anjos Dixe O253 Knowledge of school staff on type 1 diabetes M\u00aa Anjos Dixe, Eva Menino, Helena Catarino, F\u00e1tima Soares, Ana P. Oliveira, Sara Gordo, Teresa Kraus O254 Sexual health in adolescents: the impact of information search in literacy Catarina Tom\u00e1s, Paulo Queir\u00f3s, Teresa Rodrigues P123 Improving basic life support skills in adolescents through a training programme Pedro Sousa, Jo\u00e3o G. Frade, Catarina Lob\u00e3o P124 Difficulties in sexual education reported by basic education teachers in the city of Foz do Igua\u00e7u - Brazil Cynthia B. Moura, Laysa C. Dreyer, Vanize Meneghetti, Priscila P. Cabral P125 Breast cancer survivors: subjects and resources for information. A qualitative systematic review Francisca Pinto, Paulino Sousa, M\u00aa Raquel Esteves P126 Relationship between health literacy and prevalence of STI in Biomedical Laboratory Science students Sofia Galv\u00e3o, Ite Tytgat, Isabel Andrade, N\u00e1dia Os\u00f3rio, Ana Valado, Armando Caseiro, Ant\u00f3nio Gabriel, Anabela C. Martins, Fernando Mendes P127 Health literacy, risk behaviours and sexually transmitted diseases among blood donors M\u00f3nica Casas-Novas, Helena Bernardo, Isabel Andrade, Gracinda Sousa, Ana P. Sousa, Clara Rocha, Pedro Belo, N\u00e1dia Os\u00f3rio, Ana Valado, Armando Caseiro, Ant\u00f3nio Gabriel, Anabela C. Martins, Fernando Mendes P128 Promoting literacy in pregnancy health-care F\u00e1tima Martins, Montserrat Pulido-Fuentes P129 The lifestyles of the operating assistants of education Isabel Barroso, Gil Cabral, M. Jo\u00e3o Monteiro, Concei\u00e7\u00e3o Rainho P130 Experiences of service-learning health and the literary art: reflections about the health education Alessandro Prado, Yara M. Carvalho P131 Life long swimming \u2013 a European Erasmus\u2009+\u2009project Maria Campos, Liliana Moreira, Jos\u00e9 Ferreira, Ana Teixeira, Lu\u00eds Rama", - "journal_title": "BMC health services research", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/27409075/" - } - ], - "5f89ab63-e167-4d41-baec-50178d0e93d0": [ - { - "pub_id": "24693236", - "title": "Effect of fluorosis on liver cells of VC deficient and wild type mice.", - "authors": "Wei Wei,Yan Jiao,Yonghui Ma,John M Stuart,Xiudian Li,Fusheng Zhao,Lishi Wang,Dianjun Sun,Weikuan Gu", - "abstract": "For decades, mouse and other rodents have been used for the study of oxidative or related studies such as the effect of fluoride. It is known that rodents normally synthesize their own vitamin C (VC) due to the presence of a key enzyme in ascorbic acid synthesis, l-gulono-lactone-\u03b3-oxidase (Gulo), while humans do not have the capacity of VC synthesis due to the deletion of most parts of the GULO gene. The spontaneous fracture (sfx) mouse recently emerged as a model for study of VC deficiency. We investigated the effect of fluoride on liver cells from wild type Balb/c and sfx mice. We found that activities of SOD, GPx, and CAT were reduced in both wild type and sfx mice; however, the amount of reduction in the sfx cells is more than that in Balb/c cells. In addition, while both cells increased MDA, the increase in the sfx cells is greater than that in Balb/c cells. Gene networks of Sod, Gpx, and Cat in the liver of humans and mice are also different. Our study suggests that reaction to fluoride in vitamin C deficient mice might be different from that of wild type mice.", - "journal_title": "TheScientificWorldJournal", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/24693236/" - } - ], - "0e5c8923-7b94-43b0-9aa8-2b7d9736127d": [ - { - "pub_id": "34351703", - "title": "Proteome-Wide Profiling of Readers for DNA Modification.", - "authors": "Lin Bai,Guojian Yang,Zhaoyu Qin,Jiacheng Lyu,Yunzhi Wang,Jinwen Feng,Mingwei Liu,Tongqing Gong,Xianju Li,Zhengyang Li,Jixi Li,Jun Qin,Wenjun Yang,Chen Ding", - "abstract": "DNA modifications, represented by 5-methylcytosine (5mC), 5-hydroxymethylcytosine (5hmC), 5-formylcytosine (5fC), and 5-carboxylcytosine (5caC), play important roles in epigenetic regulation of biological processes. The specific recognition of DNA modifications by the transcriptional protein machinery is thought to be a potential mechanism for epigenetic-driven gene regulation, and many modified DNA-specific binding proteins have been uncovered. However, the panoramic view of the roles of DNA modification readers at the proteome level remains largely unclear. Here, a recently developed concatenated tandem array of consensus transcription factor (TF) response elements (catTFREs) approach is employed to profile the binding activity of TFs at DNA modifications. Modified DNA-binding activity is quantified for 1039 TFs, representing 70% of the TFs in the human genome. Additionally, the modified DNA-binding activity of 600 TFs is monitored during the mouse brain development from the embryo to the adult stages. Readers of these DNA modifications are predicted, and the hierarchical networks between the transcriptional protein machinery and modified DNA are described. It is further demonstrated that ZNF24 and ZSCAN21 are potential readers of 5fC-modified DNA. This study provides a landscape of TF-DNA modification interactions that can be used to elucidate the epigenetic-related transcriptional regulation mechanisms under physiological conditions.", - "journal_title": "Advanced science (Weinheim, Baden-Wurttemberg, Germany)", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/34351703/" - } - ], - "bbc7cd33-8707-43d8-9058-d68c5fee97f7": [ - { - "pub_id": "34385904", - "title": "Associations Among Parental Caregiving Quality, Cannabinoid Receptor 1 Expression-Based Polygenic Scores, and Infant-Parent Attachment: Evidence for Differential Genetic Susceptibility?", - "authors": "Amelia Potter-Dickey,Nicole Letourneau,Patricia P Silveira,Henry Ntanda,Gerald F Giesbrecht,Martha Hart,Sarah Dewell,A P Jason de Koning", - "abstract": "Attachment is a biological evolutionary system contributing to infant survival. When primary caregivers/parents are sensitive and responsive to their infants' needs, infants develop a sense of security. Secure infant attachment has been linked to healthy brain and organ-system development. Belsky and colleagues proposed the term differential susceptibility to describe context-dependent associations between genetic variations and behavioral outcomes as a function of parenting environments. Variations in the Cannabinoid Receptor Gene 1 (CNR1) are associated with memory, mood, and reward and connote differential susceptibility to more and less optimal parental caregiving quality in predicting children's behavioral problems. To determine if parental caregiving quality interacts with children's expression-based polygenic risk score (ePRS) for the CNR1 gene networks in the prefrontal cortex, striatum, and hippocampus in predicting the probability of attachment security and disorganized attachment. Prospective correlational methods examined maternal-infant pairs (<i>n</i> = 142) from which infants provided DNA samples at 3 months. Parental caregiving quality was assessed via the Child Adult Relationship Experiment (CARE)-index at 6 months, and attachment security via the Strange Situation Procedure at a mean age of 22 months. The CNR1 ePRSs include genes co-expressed with the CNR1 genes in the prefrontal cortex, striatum, or hippocampus, and were calculated using the effect size of the association between the individual single nucleotide polymorphisms from those genes and region-specific gene expression (GTEx). Logistic regression was employed (alpha < 0.05, two-tailed) to examine the main and interaction effects between parental caregiving quality and ePRSs in predicting attachment patterns. Interpretation of results was aided by analyses that distinguished between differential susceptibility and diathesis-stress. Significant interactions were observed between (1) maternal sensitivity and ePRS in the striatum in predicting attachment security, (2) maternal unresponsiveness with the ePRS in the hippocampus in predicting disorganization, and (3) maternal controlling with the ePRS in the hippocampus in predicting disorganization. These findings offer support for genetic differential susceptibility to the quality of maternal sensitivity in the context of the ePRS in the striatum. However, the significant interactions between hippocampal ePRS and maternal unresponsiveness and controlling in predicting the probability of disorganization were more suggestive of the diathesis-stress model.", - "journal_title": "Frontiers in neuroscience", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/34385904/" - } - ], - "443efea1-ffe7-446e-b2fb-37d8ec3cb74a": [ - { - "pub_id": "36293318", - "title": "Genomic Basis for Individual Differences in Susceptibility to the Neurotoxic Effects of Diesel Exhaust.", - "authors": "Alexandra No\u00ebl,David G Ashbrook,Fuyi Xu,Stephania A Cormier,Lu Lu,James P O'Callaghan,Shyam K Menon,Wenyuan Zhao,Arthur L Penn,Byron C Jones", - "abstract": "Air pollution is a known environmental health hazard. A major source of air pollution includes diesel exhaust (DE). Initially, research on DE focused on respiratory morbidities; however, more recently, exposures to DE have been associated with neurological developmental disorders and neurodegeneration. In this study, we investigated the effects of sub-chronic inhalation exposure to DE on neuroinflammatory markers in two inbred mouse strains and both sexes, including whole transcriptome examination of the medial prefrontal cortex. We exposed aged male and female C57BL/6J (B6) and DBA/2J (D2) mice to DE, which was cooled and diluted with HEPA-filtered compressed air for 2 h per day, 5 days a week, for 4 weeks. Control animals were exposed to HEPA-filtered air on the same schedule as DE-exposed animals. The prefrontal cortex was harvested and analyzed for proinflammatory cytokine gene expression (<i>Il1\u03b2</i>, <i>Il6</i>, <i>Tnf\u03b1</i>) and transcriptome-wide response by RNA-seq. We observed differential cytokine gene expression between strains and sexes in the DE-exposed vs. control-exposed groups for <i>Il1\u03b2</i>, <i>Tnf\u03b1</i>, and <i>Il6</i>. For RNA-seq, we identified 150 differentially expressed genes between air and DE treatment related to natural killer cell-mediated cytotoxicity per Kyoto Encyclopedia of Genes and Genomes pathways. Overall, our data show differential strain-related effects of DE on neuroinflammation and neurotoxicity and demonstrate that B6 are more susceptible than D2 to gene expression changes due to DE exposures than D2. These results are important because B6 mice are often used as the default mouse model for DE studies and strain-related effects of DE neurotoxicity warrant expanded studies.", - "journal_title": "International journal of molecular sciences", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/36293318/" - } - ], - "44fdea8f-75e7-4ffd-9b16-80a9aa66b511": [ - { - "pub_id": "36714272", - "title": "Behavioral phenotypes revealed during reversal learning are linked with novel genetic loci in diversity outbred mice.", - "authors": "Jared R Bagley,Lauren S Bailey,Leona H Gagnon,Hao He,Vivek M Philip,Laura G Reinholdt,Lisa M Tarantino,Elissa J Chesler,James D Jentsch", - "abstract": "Impulsive behavior and impulsivity are heritable phenotypes that are strongly associated with risk for substance use disorders. Identifying the neurogenetic mechanisms that influence impulsivity may also reveal novel biological insights into addiction vulnerability. Our past studies using the BXD and Collaborative Cross (CC) recombinant inbred mouse panels have revealed that behavioral indicators of impulsivity measured in a reversal-learning task are heritable and are genetically correlated with aspects of intravenous cocaine self-administration. Genome-wide linkage studies in the BXD panel revealed a quantitative trait locus (QTL) on chromosome 10, but we expect to identify additional QTL by testing in a population with more genetic diversity. To this end, we turned to Diversity Outbred (DO) mice; 392 DO mice (156 males, 236 females) were phenotyped using the same reversal learning test utilized previously. Our primary indicator of impulsive responding, a measure that isolates the relative difficulty mice have with reaching performance criteria under reversal conditions, revealed a genome-wide significant QTL on chromosome 7 (max LOD score = 8.73, genome-wide corrected p<0.05). A measure of premature responding akin to that implemented in the 5-choice serial reaction time task yielded a suggestive QTL on chromosome 17 (max LOD score = 9.14, genome-wide corrected <0.1). Candidate genes were prioritized (<i>2900076A07Rik, Wdr73 and Zscan2)</i> based upon expression QTL data we collected in DO and CC mice and analyses using publicly available gene expression and phenotype databases. These findings may advance understanding of the genetics that drive impulsive behavior and enhance risk for substance use disorders.", - "journal_title": "Addiction neuroscience", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/36714272/" - } - ], - "cd3a86a9-5947-4c3a-bf9d-059170f82c5d": [ - { - "pub_id": "36552094", - "title": "Effects of Genetics and Sex on Acute Gene Expression Changes in the Hippocampus Following Neonatal Ethanol Exposure in BXD Recombinant Inbred Mouse Strains.", - "authors": "Jessica A Baker,Jacob T Brettin,Megan K Mulligan,Kristin M Hamre", - "abstract": "Fetal alcohol spectrum disorders (FASD) are prevalent neurodevelopmental disorders. Genetics have been shown to have a role in the severity of alcohol's teratogenic effects on the developing brain. We previously identified recombinant inbred BXD mouse strains that show high (HCD) or low cell death (LCD) in the hippocampus following ethanol exposure. The present study aimed to identify gene networks that influence this susceptibility. On postnatal day 7 (3rd-trimester-equivalent), male and female neonates were treated with ethanol (5.0 g/kg) or saline, and hippocampi were collected 7hrs later. Using the Affymetrix microarray platform, ethanol-induced gene expression changes were identified in all strains with divergent expression sets found between sexes. Genes, such as <i>Bcl2l11</i>, <i>Jun</i>, and <i>Tgfb3</i>, showed significant strain-by-treatment interactions and were involved in many apoptosis pathways. Comparison of HCD versus LCD showed twice as many ethanol-induced genes changes in the HCD. Interestingly, these changes were regulated in the same direction suggesting (1) more perturbed effects in HCD compared to LCD and (2) limited gene expression changes that confer resistance to ethanol-induced cell death in LCD. These results demonstrate that genetic background and sex are important factors that affect differential cell death pathways after alcohol exposure during development that could have long-term consequences.", - "journal_title": "Brain sciences", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/36552094/" - } - ], - "35931156-6164-4500-9972-b6541d6294e5": [ - { - "pub_id": "35289581", - "title": "Alpha- and Beta-thalassemia: Rapid Evidence Review.", - "authors": "Drew C Baird,Stuart H Batten,Steven K Sparks", - "abstract": "Thalassemia is a group of autosomal recessive hemoglobinopathies affecting the production of normal alpha- or beta-globin chains that comprise hemoglobin. Ineffective production of alpha- or beta-globin chains may result in ineffective erythropoiesis, premature red blood cell destruction, and anemia. Chronic, severe anemia in patients with thalassemia may result in bone marrow expansion and extramedullary hematopoiesis. Thalassemia should be suspected in patients with microcytic anemia and normal or elevated ferritin levels. Hemoglobin electrophoresis may reveal common characteristics of different thalassemia subtypes, but genetic testing is required to confirm the diagnosis. Thalassemia is generally asymptomatic in trait and carrier states. Alpha-thalassemia major results in hydrops fetalis and is often fatal at birth. Beta-thalassemia major requires lifelong transfusions starting in early childhood (often before two years of age). Alpha- and beta-thalassemia intermedia have variable presentations based on gene mutation or deletion, with mild forms requiring only monitoring but more severe forms leading to symptomatic anemia and requiring transfusion. Treatment of thalassemia includes transfusions, iron chelation therapy to correct iron overload (from hemolytic anemia, intestinal iron absorption, and repeated transfusions), hydroxyurea, hematopoietic stem cell transplantation, and luspatercept. Thalassemia complications arise from bone marrow expansion, extramedullary hematopoiesis, and iron deposition in peripheral tissues. These complications include morbidities affecting the skeletal system, endocrine organs, heart, and liver. Life expectancy of those with thalassemia has improved dramatically over the past 50 years with increased availability of blood transfusions and iron chelation therapy, and improved iron overload monitoring. Genetic counseling and screening in high-risk populations can assist in reducing the prevalence of thalassemia.", - "journal_title": "American family physician", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/35289581/" - } - ], - "df0d61ac-395a-4a97-97dd-2d9fa16fd7b0": [ - { - "pub_id": "35338705", - "title": "Association of Persistent Rubella Virus With Idiopathic Skin Granulomas in Clinically Immunocompetent Adults.", - "authors": "Karolyn A Wanat,Ludmila Perelygina,Min-Hsin Chen,LiJuan Hao,Emily Abernathy,Nicole R Bender,Bridget E Shields,Barbara D Wilson,David Crosby,John Routes,Sara S Samimi,Paul L Haun,Olayemi Sokumbi,Joseph P Icenogle,Kathleen E Sullivan,Misha Rosenbach,Beth A Drolet", - "abstract": "Vaccine-derived and wild-type rubella virus (RuV) has been identified within granulomas in patients with inborn errors of immunity, but has not been described in granulomas of healthy adults. To determine the association between RuV and atypical granulomatous inflammation in immune-competent adults. This case series, conducted in US academic dermatology clinics from January 2019 to January 2021, investigated the presence of RuV in skin specimens using RuV immunofluorescent staining of paraffin-embedded tissue sections, real-time reverse-transcription polymerase chain reaction, whole-genome sequencing with phylogenetic analyses, and cell culture by the US Centers for Disease Control and Prevention. Rubella immunoglobulin G, immunoglobulin M enzyme-linked immunoassay, and viral neutralization assays were performed for the sera of immunocompetent individuals with treatment refractory cutaneous granulomas and histopathology demonstrating atypical palisaded and necrotizing granulomas. Clinical immune evaluation was performed. Identification, genotyping, and culture of vaccine-derived and wild-type RuV within granulomatous dermatitis of otherwise clinically immune competent adults. Of the 4 total immunocompetent participants, 3 (75%) were women, and the mean (range) age was 61.5 (49.0-73.0) years. The RuV capsid protein was detected by immunohistochemistry in cutaneous granulomas. The presence of RuV RNA was confirmed by real-time reverse-transcription polymerase chain reaction in fresh-frozen skin biopsies and whole-genome sequencing. Phylogenetic analysis of the RuV sequences showed vaccine-derived RuV in 3 cases and wild-type RuV in 1. Live RuV was recovered from the affected skin in 2 participants. Immunology workup results demonstrated no primary immune deficiencies. The case series study results suggest that RuV (vaccine derived and wild type) can persist for years in cutaneous granulomas in clinically immunocompetent adults and is associated with atypical (palisaded and necrotizing type) chronic cutaneous granulomas. These findings represent a potential paradigm shift in the evaluation, workup, and management of atypical granulomatous dermatitis and raises questions regarding the potential transmissibility of persistent live RuV.", - "journal_title": "JAMA dermatology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/35338705/" - } - ], - "99a1393e-3764-4c93-85d5-8d37f31b2b24": [ - { - "pub_id": "36111202", - "title": "Diet X Gene Interactions Control Femoral Bone Adaptation to Low Dietary Calcium.", - "authors": "Krittikan Chanpaisaeng,Perla C Reyes-Fernandez,Brian Dilkes,James C Fleet", - "abstract": "Genetics and dietary calcium (Ca) are each critical regulators of peak bone mass but it is unclear how genetics alters the physiologic response of bone to dietary Ca restriction (RCR). Here, we conducted genetic mapping in C57BL/6J \u00d7 DBA/2J (BXD) recombinant inbred mouse lines to identify environmentally sensitive loci controlling whole-bone mass (bone mineral density [BMD], bone mineral content [BMC]), distal trabecular bone, and cortical bone midshaft of the femur. Mice were fed adequate (basal) or low Ca diets from 4-12\u2009weeks of age. Femurs were then examined by dual-energy X-ray absorptiometry (DXA) and micro-computed tomography (\u03bcCT). Body size-corrected residuals were used for statistical analysis, genetic mapping, and to estimate narrow sense heritability (h<sup>2</sup>). Genetics had a strong impact on femoral traits (eg, bone volume fraction [BV/TV] basal Ca, h<sup>2</sup>\u00a0=\u20090.60) as well as their RCR (eg, BV/TV, h<sup>2</sup>\u00a0=\u20090.32). Quantitative trait locus (QTL) mapping identified up to six loci affecting each bone trait. A subset of loci was detected in both diet groups, providing replication of environmentally robust genetic effects. Several loci control multiple bone phenotypes suggesting the existence of genetic pleiotropy. QTL controlling the bone RCR did not overlap with basal diet QTL, demonstrating genetic independence of those traits. Candidate genes underlying select multi-trait loci were prioritized by protein coding effects or gene expression differences in bone cells. These include candidate alleles in <i>Rictor</i> (chromosome [chr] 15) and <i>Egfl7</i> (chr 2) at loci affecting bone in the basal or low Ca groups and in <i>Msr1</i> (chr 8), <i>Apc</i>, and <i>Camk4</i> (chr 18) at loci affecting RCR. By carefully controlling dietary Ca and measuring traits in age-matched mice we identified novel genetic loci determining bone mass/microarchitecture of the distal femur as well as their physiologic adaptation to inadequate dietary Ca intake. \u00a9 2022 The Authors. <i>JBMR Plus</i> published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.", - "journal_title": "JBMR plus", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/36111202/" - } - ], - "d0deb53b-7286-4fd0-9188-b7b9f366fd76": [ - { - "pub_id": "35456420", - "title": "New Insights on Gene by Environmental Effects of Drugs of Abuse in Animal Models Using GeneNetwork.", - "authors": "Alisha Chunduri,Pamela M Watson,David G Ashbrook", - "abstract": "Gene-by-environment interactions are important for all facets of biology, especially behaviour. Families of isogenic strains of mice, such as the BXD strains, are excellently placed to study these interactions, as the same genome can be tested in multiple environments. BXD strains are recombinant inbred mouse strains derived from crossing two inbred strains-C57BL/6J and DBA/2J mice. Many reproducible genometypes can be leveraged, and old data can be reanalysed with new tools to produce novel insights. We obtained drug and behavioural phenotypes from Philip et al. Genes, Brain and Behaviour 2010, and reanalysed their data with new genotypes from sequencing, as well as new models (Genome-wide Efficient Mixed Model Association (GEMMA) and R/qtl2). We discovered QTLs on chromosomes 3, 5, 9, 11, and 14, not found in the original study. We reduced the candidate genes based on their ability to alter gene expression or protein function. Candidate genes included <i>Slitrk6</i> and <i>Cdk14</i>. <i>Slitrk6</i>, in a Chromosome14 QTL for locomotion, was found to be part of a co-expression network involved in voluntary movement and associated with neuropsychiatric phenotypes. <i>Cdk14</i>, one of only three genes in a Chromosome5 QTL, is associated with handling induced convulsions after ethanol treatment, that is regulated by the anticonvulsant drug valproic acid. By using families of isogenic strains, we can reanalyse data to discover novel candidate genes involved in response to drugs of abuse.", - "journal_title": "Genes", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/35456420/" - } - ], - "419fbc53-0941-4458-97d7-f20a32cf4894": [ - { - "pub_id": "35920089", - "title": "Beta-caryophyllene prevents the defects in trabecular bone caused by Vitamin D deficiency through pathways instated by increased expression of klotho.", - "authors": "Wei Dong,Bradley C Postlethwaite,Patricia A Wheller,David Brand,Yan Jiao,Wei Li,Linda K Myers,Weikuan Gu", - "abstract": "This study investigated the effects of \u03b2-caryophyllene (BCP) on protecting bone from vitamin D deficiency in mice fed on a diet either lacking (D-) or containing (D+) vitamin D. A total of 40 female mice were assigned to four treatment groups (n = 10/group): D+ diet with propylene glycol control, D+ diet with BCP, D-deficient diet with control, and D-deficient diet with BCP. The D+ diet is a commercial basal diet, while the D-deficient diet contains 0.47% calcium, 0.3% phosphorus, and no vitamin D. All the mice were housed in conditions without ultraviolet light. Bone properties were evaluated by X-ray micro-CT. Serum levels of klotho were measured by enzyme-linked immunosorbent assay. Under these conditions, the D-deficient diet enhanced the length of femur and tibia bones (p < 0.050), and increased bone volume (BV; p < 0.010) and trabecular bone volume fraction (BV/TV; p < 0.010) compared to D+ diet. With a diet containing BCP, the mice exhibited higher BV and bone mineral density (BMD; p < 0.050) than control group. The trabecular and cortical bone were also affected by vitamin D and BCP. In addition, inclusion of dietary BCP improved the serum concentrations of klotho (p < 0.050). In mice, klotho regulates the expression level of cannabinoid type 2 receptor (Cnr2) and fibroblast growth factor 23 (Fgf23) through CD300a. In humans, data suggest that klotho is connected to BMD. The expression of klotho is also associated with bone markers. These data indicate that BCP enhances the serum level of klotho, leading to improved bone properties and mineralization in an experimental mouse model.Cite this article: <i>Bone Joint Res</i>\u00a02022;11(8):528-540.", - "journal_title": "Bone & joint research", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/35920089/" - } - ], - "fb63cb0e-844d-4630-9ae8-da798a89ad0e": [ - { - "pub_id": "35285473", - "title": "GeneCup: mining PubMed and GWAS catalog for gene-keyword relationships.", - "authors": "Mustafa H Gunturkun,Efraim Flashner,Tengfei Wang,Megan K Mulligan,Robert W Williams,Pjotr Prins,Hao Chen", - "abstract": "Interpreting and integrating results from omics studies typically requires a comprehensive and time consuming survey of extant literature. GeneCup is a literature mining web service that retrieves sentences containing user-provided gene symbols and keywords from PubMed abstracts. The keywords are organized into an ontology and can be extended to include results from human genome-wide association studies. We provide a drug addiction keyword ontology that contains over 300 keywords as an example. The literature search is conducted by querying the PubMed server using a programming interface, which is followed by retrieving abstracts from a local copy of the PubMed archive. The main results presented to the user are sentences where gene symbol and keywords co-occur. These sentences are presented through an interactive graphical interface or as tables. All results are linked to the original abstract in PubMed. In addition, a convolutional neural network is employed to distinguish sentences describing systemic stress from those describing cellular stress. The automated and comprehensive search strategy provided by GeneCup facilitates the integration of new discoveries from omic studies with existing literature. GeneCup is free and open source software. The source code of GeneCup and the link to a running instance is available at https://github.com/hakangunturkun/GeneCup.", - "journal_title": "G3 (Bethesda, Md.)", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/35285473/" - } - ], - "c802cb60-1a15-4962-8e6d-f06608c00a54": [ - { - "pub_id": "35646540", - "title": "Bile acid coordinates microbiota homeostasis and systemic immunometabolism in cardiometabolic diseases.", - "authors": "Baoyi Guan,Jinlin Tong,Haiping Hao,Zhixu Yang,Keji Chen,Hao Xu,Anlu Wang", - "abstract": "Cardiometabolic disease (CMD), characterized with metabolic disorder triggered cardiovascular events, is a leading cause of death and disability. Metabolic disorders trigger chronic low-grade inflammation, and actually, a new concept of metaflammation has been proposed to define the state of metabolism connected with immunological adaptations. Amongst the continuously increased list of systemic metabolites in regulation of immune system, bile acids (BAs) represent a distinct class of metabolites implicated in the whole process of CMD development because of its multifaceted roles in shaping systemic immunometabolism. BAs can directly modulate the immune system by either boosting or inhibiting inflammatory responses <i>via</i> diverse mechanisms. Moreover, BAs are key determinants in maintaining the dynamic communication between the host and microbiota. Importantly, BAs <i>via</i> targeting Farnesoid X receptor (FXR) and diverse other nuclear receptors play key roles in regulating metabolic homeostasis of lipids, glucose, and amino acids. Moreover, BAs axis <i>per se</i> is susceptible to inflammatory and metabolic intervention, and thereby BAs axis may constitute a reciprocal regulatory loop in metaflammation. We thus propose that BAs axis represents a core coordinator in integrating systemic immunometabolism implicated in the process of CMD. We provide an updated summary and an intensive discussion about how BAs shape both the innate and adaptive immune system, and how BAs axis function as a core coordinator in integrating metabolic disorder to chronic inflammation in conditions of CMD.", - "journal_title": "Acta pharmaceutica Sinica. B", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/35646540/" - } - ], - "9e828c9f-5e04-4df7-b6c3-92825634e603": [ - { - "pub_id": "35663325", - "title": "Microbial Infection and Antibiotic Susceptibility of Diabetic Foot Ulcer in China: Literature Review.", - "authors": "Fang Du,Jing Ma,Hongping Gong,Raju Bista,Panpan Zha,Yan Ren,Yun Gao,Dawei Chen,Xingwu Ran,Chun Wang", - "abstract": "To investigate the microbial spectrum isolated from foot ulcers among diabetic patients in China, which was conducted to help clinicians choose optimal antibiotics empirically. The PubMed, MEDLINE, Web of Science, China Biology Medicine (CBM), China National Knowledge Infrastructure (CNKI), WanFang, and VIP databases were searched for studies published between 2015 to 2019, that report primary data on diabetic foot infection (DFI) and antibiotic susceptibility in China. A total of 63 articles about DFI and antibiotic susceptibility tests among diabetic patients in China were included. There were 11,483 patients with an average age of 60.2 \u00b1 10.1 years and a mean course of 10.6 \u00b1 5.0 years between 2010 and 2019, covering most geographical regions of China. The prevalence of Gram-positive (GP) bacteria (43.4%) was lower than that of Gram-negative (GN) (52.4%). The most prevalent pathogens isolated were Staphylococcus aureus (17.7%), Escherichia coli (10.9%), Pseudomonas aeruginosa (10.5%), Klebsiella pneumoniae (6.2%), Staphylococcus epidermidis (5.3%), Enterococcus faecalis (4.9%), and fungus (3.7%). The prevalence of polymicrobial infection was 22.8%. GP bacteria were sensitive to linezolid, vancomycin, and teicoplanin. More than 50% of GN bacteria were resistant to third-generation cephalosporins, while the resistance rates of piperacillin/tazobactam, amikacin, meropenem, and imipenem were relatively low. Among the 6017 strains of the isolated organisms, 20% had multi-drug resistance (MDR). Staphylococcus aureus (30.4%) was the most predominant MDR bacteria, followed by extended-spectrum \u03b2-lactamase (ESBL) (19.1%). The microbial infection of foot ulcers among diabetic patients in China is diverse. The microbial spectrum is different in different geographic regions and Staphylococcus aureus is the predominant bacteria. Polymicrobial and MDR bacterial infections on the foot ulcers are common. This study could be valuable in guiding the empirical use of antibiotics for diabetic foot infections.", - "journal_title": "Frontiers in endocrinology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/35663325/" - } - ], - "389bdbf3-0224-4edb-a4fb-71a54971ba66": [ - { - "pub_id": "34952508", - "title": "Ginsenoside Rd: A promising natural neuroprotective agent.", - "authors": "Yu-Ying Chen,Qiu-Ping Liu,Pei An,Min Jia,Xin Luan,Jian-Yuan Tang,Hong Zhang", - "abstract": "Neurological diseases seriously affect human health, which are arousing wider attention, and it is a great challenge to discover neuroprotective drugs with minimal side-effects and better efficacies. Natural agents derived from herbs or plants have become unparalleled resources for the discovery of novel drug candidates. Panax ginseng C. A.\u00a0Meyer, a well-known herbal medicine in China, occupies a very important position in traditional Chinese medicines (TCMs) with a long history of clinical application. Ginsenoside Rd is the active compound in P. ginseng known to have broad-spectrum pharmacological effects to reduce neurological damage that can lead to neurological diseases, including Alzheimer's disease, Parkinson's disease, Huntington's disease, depression, cognitive impairment, and cerebral ischemia. To review and discuss the effects and mechanisms of ginsenoside Rd in the treatment of neurological diseases. The related information was compiled by the major scientific databases, such as Chinese National Knowledge Infrastructure (CNKI), Elsevier, ScienceDirect, PubMed, SpringerLink, Web of Science, and GeenMedical. Using 'Ginsenoside Rd', 'Ginsenosides', 'Anti-inflammation', 'Antioxidant', 'Apoptosis' and 'Neuroprotection' as keywords, the correlated literature was extracted and conducted from the databases mentioned above. Through summarizing the existing research progress, we found that the general effects of ginsenoside Rd are anti-inflammatory, antioxidant, anti-apoptosis, inhibition of Ca<sup>2+</sup> influx and protection of mitochondria, and through these pathways, the compound can inhibit excitatory toxicity, regulate nerve growth factor, and promote nerve regeneration. Ginsenoside Rd is a promising natural neuroprotective agent. This review would contribute to the future development of ginsenoside Rd as a novel clinical candidate drug for treating neurological diseases.", - "journal_title": "Phytomedicine : international journal of phytotherapy and phytopharmacology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/34952508/" - } - ], - "b7509816-3c54-4739-a209-2a3a32c3085a": [ - { - "pub_id": "35905178", - "title": "Evidence for a neuromuscular circuit involving hypothalamic interleukin-6 in the control of skeletal muscle metabolism.", - "authors": "Carlos Kiyoshi Katashima,Thayana de Oliveira Micheletti,Renata Rosseto Braga,Rodrigo Stellzer Gaspar,Ludger J E Goeminne,Alexandre Moura-Assis,Barbara Moreira Crisol,Rafael S Br\u00edcola,Vagner Ramon R Silva,Camila de Oliveira Ramos,Alisson L da Rocha,Mariana Rosolen Tavares,Fernando Moreira Simabuco,Valquiria Aparecida Matheus,Lucas Buscaratti,Henrique Marques-Souza,Patricia Pazos,David Gonzalez-Touceda,Sulay Tovar,Mar\u00eda Del Carmen Garc\u00eda,Jose Cesar Rosa Neto,Rui Curi,Sandro Massao Hirabara,Patr\u00edcia Chakur Brum,Patr\u00edcia Oliveira Prada,Leandro P de Moura,Jos\u00e9 Rodrigo Pauli,Adelino S R da Silva,Dennys Esper Cintra,Licio A Velloso,Eduardo Rochete Ropelle", - "abstract": "Hypothalamic interleukin-6 (IL6) exerts a broad metabolic control. Here, we demonstrated that IL6 activates the ERK1/2 pathway in the ventromedial hypothalamus (VMH), stimulating AMPK/ACC signaling and fatty acid oxidation in mouse skeletal muscle. Bioinformatics analysis revealed that the hypothalamic IL6/ERK1/2 axis is closely associated with fatty acid oxidation- and mitochondrial-related genes in the skeletal muscle of isogenic BXD mouse strains and humans. We showed that the hypothalamic IL6/ERK1/2 pathway requires the \u03b12-adrenergic pathway to modify fatty acid skeletal muscle metabolism. To address the physiological relevance of these findings, we demonstrated that this neuromuscular circuit is required to underpin AMPK/ACC signaling activation and fatty acid oxidation after exercise. Last, the selective down-regulation of IL6 receptor in VMH abolished the effects of exercise to sustain AMPK and ACC phosphorylation and fatty acid oxidation in the muscle after exercise. Together, these data demonstrated that the IL6/ERK axis in VMH controls fatty acid metabolism in the skeletal muscle.", - "journal_title": "Science advances", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/35905178/" - } - ], - "0bcdf164-dd98-40cc-84b7-c6b44f82272b": [ - { - "pub_id": "35435317", - "title": "Quantitative proteomics approach reveals novel biomarkers and pathological mechanism of keloid.", - "authors": "Jian Liu,Chunhua Yang,Huayu Zhang,Wei Hu,Jonas Bergquist,Helen Wang,Tingzhi Deng,Xueling Yang,Chao Zhang,Yanping Zhu,Xiaodong Chi,Jia Mi,Yibing Wang", - "abstract": "Keloid is a pathological skin scar formation with complex and unclear molecular pathology mechanism. Novel biomarkers and associated mechanisms are needed to improve current therapies. To identify novel biomarkers and underlying pathological mechanisms of keloids. Six pairs of keloid scar tissues and corresponding normal skin tissues were quantitatively analyzed by a high-resolution label-free mass spectrometry-based proteomics approach. Differential protein expression data was further analyzed by a comprehensive bioinformatics approach to identify novel biomarkers and mechanistic pathways for keloid formation. Candidate biomarkers were validated experimentally. In total, 1359 proteins were identified by proteomic analysis. Of these, 206 proteins exhibited a significant difference in expression between keloid scar and normal skin tissues. RCN3 and CALU were significantly upregulated in keloids. RCN1 and PDGFRL were uniquely expressed in keloids. Pathway analysis suggested that the XBP1-mediated unfolded protein response (UPR) pathway was involved in keloid formation. Moreover, a PDGFRL centric gene coexpression network was constructed to illustrate its function in skin. Our study proposed four novel biomarkers and highlighted the role of XBP1-mediated UPR pathway in the pathology of keloids. It provided novel biological insights that contribute to develop novel therapeutic strategies for keloids.", - "journal_title": "Proteomics. Clinical applications", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/35435317/" - } - ], - "af83c313-40dc-4b13-863a-cd32a018e610": [ - { - "pub_id": "35307206", - "title": "Translational approaches to understanding resilience to Alzheimer's disease.", - "authors": "Sarah M Neuner,Maria Telpoukhovskaia,Vilas Menon,Kristen M S O'Connell,Timothy J Hohman,Catherine C Kaczorowski", - "abstract": "Individuals who maintain cognitive function despite high levels of Alzheimer's disease (AD)-associated pathology are said to be 'resilient' to AD. Identifying mechanisms underlying resilience represents an exciting therapeutic opportunity. Human studies have identified a number of molecular and genetic factors associated with resilience, but the complexity of these cohorts prohibits a complete understanding of which factors are causal or simply correlated with resilience. Genetically and phenotypically diverse mouse models of AD provide new and translationally relevant opportunities to identify and prioritize new resilience mechanisms for further cross-species investigation. This review will discuss insights into resilience gained from both human and animal studies and highlight future approaches that may help translate these insights into therapeutics designed to prevent or delay AD-related dementia.", - "journal_title": "Trends in neurosciences", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/35307206/" - } - ], - "cabbee33-cf97-448d-ae70-23e11db43614": [ - { - "pub_id": "35377872", - "title": "Systems genetics in the rat HXB/BXH family identifies Tti2 as a pleiotropic quantitative trait gene for adult hippocampal neurogenesis and serum glucose.", - "authors": "Anna N Senko,Rupert W Overall,Jan Silhavy,Petr Mlejnek,Hana Mal\u00ednsk\u00e1,Martina H\u00fcttl,Irena Markov\u00e1,Klaus S Fabel,Lu Lu,Ales Stuchlik,Robert W Williams,Michal Pravenec,Gerd Kempermann", - "abstract": "Neurogenesis in the adult hippocampus contributes to learning and memory in the healthy brain but is dysregulated in metabolic and neurodegenerative diseases. The molecular relationships between neural stem cell activity, adult neurogenesis, and global metabolism are largely unknown. Here we applied unbiased systems genetics methods to quantify genetic covariation among adult neurogenesis and metabolic phenotypes in peripheral tissues of a genetically diverse family of rat strains, derived from a cross between the spontaneously hypertensive (SHR/OlaIpcv) strain and Brown Norway (BN-Lx/Cub). The HXB/BXH family is a very well established model to dissect genetic variants that modulate metabolic and cardiovascular diseases and we have accumulated deep phenome and transcriptome data in a FAIR-compliant resource for systematic and integrative analyses. Here we measured rates of precursor cell proliferation, survival of new neurons, and gene expression in the hippocampus of the entire HXB/BXH family, including both parents. These data were combined with published metabolic phenotypes to detect a neurometabolic quantitative trait locus (QTL) for serum glucose and neuronal survival on Chromosome 16: 62.1-66.3 Mb. We subsequently fine-mapped the key phenotype to a locus that includes the Telo2-interacting protein 2 gene (Tti2)-a chaperone that modulates the activity and stability of PIKK kinases. To verify the hypothesis that differences in neurogenesis and glucose levels are caused by a polymorphism in Tti2, we generated a targeted frameshift mutation on the SHR/OlaIpcv background. Heterozygous SHR-Tti2+/- mutants had lower rates of hippocampal neurogenesis and hallmarks of dysglycemia compared to wild-type littermates. Our findings highlight Tti2 as a causal genetic link between glucose metabolism and structural brain plasticity. In humans, more than 800 genomic variants are linked to TTI2 expression, seven of which have associations to protein and blood stem cell factor concentrations, blood pressure and frontotemporal dementia.", - "journal_title": "PLoS genetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/35377872/" - } - ], - "78fa6c3e-5f09-4449-939a-d1d5f4460457": [ - { - "pub_id": "36018159", - "title": "Striatum-specific mechanisms regulate neuronal cell cycle re-entry: the choice between life and death.", - "authors": "Paula Dietrich,Ioannis Dragatsis", - "abstract": "", - "journal_title": "Neural regeneration research", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/36018159/" - } - ], - "b95934dd-cce2-4f9f-b685-0a43abbb4c1b": [ - { - "pub_id": "15177550", - "title": "Genetic regulation of endotoxin-induced airway disease.", - "authors": "Donald N Cook,Shuibang Wang,Yonghong Wang,Gabriel P Howles,Gregory S Whitehead,Katherine G Berman,Tony D Church,Bryan C Frank,Renee M Gaspard,Yan Yu,John Quackenbush,David A Schwartz", - "abstract": "To identify novel genes regulating the biologic response to lipopolysaccharide (LPS), we used a combination of quantitative trait locus (QTL) analysis and microarray-based gene expression studies of C57BL/6J x DBA/2J(BXD) F2 and recombinant inbred (RI) mice. A QTL affecting pulmonary TNF-alpha production was identified on chromosome 2, and a region affecting both polymorphonuclear leukocyte recruitment and TNF-alpha levels was identified on chromosome 11. Microarray analyses of unchallenged and LPS-challenged BXD RI strains identified approximately 500 genes whose expression was significantly changed by inhalation of LPS. Of these genes, 28 reside within the chromosomal regions identified by the QTL analyses, implicating these genes as high priority candidates for functional studies. Additional high priority candidate genes were identified based on their differential expression in mice having high and low responses to LPS. Functional studies of these genes are expected to reveal important molecular mechanisms regulating the magnitude of biologic responses to LPS.", - "journal_title": "Genomics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/15177550/" - } - ], - "0022bfa1-c2e9-41e9-a96a-0e89688bcbe0": [ - { - "pub_id": "16261421", - "title": "A QTL resource and comparison tool for pigs: PigQTLDB.", - "authors": "Zhi-Liang Hu,Svetlana Dracheva,Wonhee Jang,Donna Maglott,John Bastiaansen,Max F Rothschild,James M Reecy", - "abstract": "During the past decade, efforts to map quantitative trait loci (QTL) in pigs have resulted in hundreds of QTL being reported for growth, meat quality, reproduction, disease resistance, and other traits. It is a challenge to locate, interpret, and compare QTL results from different studies. We have developed a pig QTL database (PigQTLdb) that integrates available pig QTL data in the public domain, thus, facilitating the use of this QTL data in future studies. We also developed a pig trait classification system to standardize names of traits and to simplify organization and searching of the trait data. These steps made it possible to compare primary data from diverse sources and methods. We used existing pig map databases and other publicly available data resources (such as PubMed) to avoid redundant developmental work. The PigQTLdb was also designed to include data representing major genes and markers associated with a large effect on economically important traits. To date, over 790 QTL from 73 publications have been curated into the database. Those QTL cover more than 300 different traits. The data have been submitted to the Entrez Gene and the Map Viewer resources at NCBI, where the information about markers was matched to marker records in NCBI's UniSTS database. Having these data in a public resource like NCBI allows regularly updated automatic matching of markers to public sequence data by e-PCR. The submitted data, and the results of these calculations, are retrievable from NCBI via Entrez Gene, Map Viewer, and UniSTS. Efforts were undertaken to improve the integrated functional genomics resources for pigs.", - "journal_title": "Mammalian genome : official journal of the International Mammalian Genome Society", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/16261421/" - } - ], - "7713bd3a-4d0a-41f4-b378-43c271ee35b1": [ - { - "pub_id": "15745951", - "title": "Ethanol-responsive brain region expression networks: implications for behavioral responses to acute ethanol in DBA/2J versus C57BL/6J mice.", - "authors": "Robnet T Kerns,Ajay Ravindranathan,Sajida Hassan,Mary P Cage,Tim York,James M Sikela,Robert W Williams,Michael F Miles", - "abstract": "Activation of the mesolimbic dopamine reward pathway by acute ethanol produces reinforcement and changes in gene expression that appear to be crucial to the molecular basis for adaptive behaviors and addiction. The inbred mouse strains DBA/2J and C57BL/6J exhibit contrasting acute behavioral responses to ethanol. We used oligonucleotide microarrays and bioinformatics methods to characterize patterns of gene expression in three brain regions of the mesolimbic reward pathway of these strains. Expression profiling included examination of both differences in gene expression 4 h after saline injection or acute ethanol (2 g/kg). Using a rigorous stepwise method for microarray analysis, we identified 788 genes differentially expressed in control DBA/2J versus C57BL/6J mice and 307 ethanol-regulated genes in the nucleus accumbens, prefrontal cortex, and ventral tegmental area. There were strikingly divergent patterns of ethanol-responsive gene expression in the two strains. Ethanol-responsive genes also showed clustering at discrete chromosomal regions, suggesting local chromatin effects in regulation. Ethanol-regulated genes were generally related to neuroplasticity, but regulation of discrete functional groups and pathways was brain region specific: glucocorticoid signaling, neurogenesis, and myelination in the prefrontal cortex; neuropeptide signaling and developmental genes, including factor Bdnf, in the nucleus accumbens; and retinoic acid signaling in the ventral tegmental area. Bioinformatics analysis identified several potential candidate genes for quantitative trait loci linked to ethanol behaviors, further supporting a role for expression profiling in identifying genes for complex traits. Brain region-specific changes in signaling and neuronal plasticity may be critical components in development of lasting ethanol behavioral phenotypes such as dependence, sensitization, and craving.", - "journal_title": "The Journal of neuroscience : the official journal of the Society for Neuroscience", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/15745951/" - } - ], - "f8872efb-31cc-4c88-9ad3-277e752588f3": [ - { - "pub_id": "15894267", - "title": "Trp53R172H and KrasG12D cooperate to promote chromosomal instability and widely metastatic pancreatic ductal adenocarcinoma in mice.", - "authors": "Sunil R Hingorani,Lifu Wang,Asha S Multani,Chelsea Combs,Therese B Deramaudt,Ralph H Hruban,Anil K Rustgi,Sandy Chang,David A Tuveson", - "abstract": "To define the genetic requirements for pancreatic ductal adenocarcinoma (PDA), we have targeted concomitant endogenous expression of Trp53(R172H) and Kras(G12D) to the mouse pancreas, revealing the cooperative development of invasive and widely metastatic carcinoma that recapitulates the human disease. The primary carcinomas and metastases demonstrate a high degree of genomic instability manifested by nonreciprocal translocations without obvious telomere erosion-hallmarks of human carcinomas not typically observed in mice. No mutations were discovered in other cardinal tumor suppressor gene pathways, which, together with previous results, suggests that there are distinct genetic pathways to PDA with different biological behaviors. These findings have clear implications for understanding mechanisms of disease pathogenesis, and for the development of detection and targeted treatment strategies.", - "journal_title": "Cancer cell", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/15894267/" - } - ], - "387dcae5-4287-487f-82a5-d4809c7d44cb": [ - { - "pub_id": "16338823", - "title": "Genetic analysis of barrel field size in the first somatosensory area (SI) in inbred and recombinant inbred strains of mice.", - "authors": "Cheng X Li,Xin Wei,Lu Lu,Jeremy L Peirce,Robert W Williams,Robert S Waters", - "abstract": "We measured the combined area of posterior medial barrel subfield (PMBSF) and anterior lateral barrel subfield (ALBSF) areas in four common inbred strains (C3H/HeJ, A /J, C57BL /6J, DBA/2J), B6D2F1, and ten recombinant inbred (RI) strains generated from C57BL/6J and DBA/2J progenitors (BXD) as an initial attempt to examine the genetic influences underlying natural variation in barrel field size in adult mice. These two subfields are associated with the representation of the whisker pad and sinus hairs on the contralateral face. Using cytochrome oxidase labeling to visualize the barrel field, we measured the size of the combined subfields in each mouse strain. We also measured body weight and brain weight in each strain. We report that DBA/2J mice have a larger combined PMBSF/ALBSF area (6.15 +/- 0.10 mm(2), n = 7) than C57BL /6J (5.48 +/- 0.13 mm(2), n = 10), C3H/HeJ (5.37 +/- 0.16 mm(2), n = 10), and A/J mice (5.04 +/- 0.09 mm(2), n = 15), despite the fact that DBA/2J mice have smaller average brain and body sizes. This finding may reflect dissociation between systems that control brain size with those that regulate barrel field area. In addition, BXD strains (average n = 4) and parental strains showed considerable and continuous variation in PMBSF/ALBSF area, suggesting that this trait is polygenic. Furthermore, brain, body, and cortex weights have heritable differences between inbred strains and among BXD strains. PMBSF/ALBSF pattern appears similar among inbred and BXD strains, suggesting that somatosensory patterning reflects a common plan of organization. This data is an important first step in the quantitative genetic analysis of the parcellation of neocortex into diverse cytoarchitectonic zones that vary widely within and between species, and in identifying the genetic factors underlying barrel field size using quantitative trait locus (QTL) analyses.", - "journal_title": "Somatosensory & motor research", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/16338823/" - } - ], - "624ba3ed-0965-4451-a5e1-2150b68ae1b3": [ - { - "pub_id": "16339372", - "title": "Genomics of the future: identification of quantitative trait loci in the mouse.", - "authors": "Lorraine Flaherty,Bruce Herron,Derek Symula", - "abstract": "Positional cloning of quantitative trait loci in rodents is a common approach to identify genes involved in complex phenotypes, including genes important to human disease. However, cloning the causative genes has proved to be more difficult than determining their positions. New tools such as genomic sequence, clone libraries, and new genomic-based methods offer new approaches to identify these genes. Here we review how these new tools and approaches will improve our ability to discover the genes important in complex traits.", - "journal_title": "Genome research", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/16339372/" - } - ], - "58714c13-954b-46b3-bd0e-69ccadd9dc6a": [ - { - "pub_id": "24771276", - "title": "Cohort Profile: Recruitment cohorts in the neuropsychological substudy of the Multicenter AIDS Cohort Study.", - "authors": "James T Becker,Lawrence A Kingsley,Samantha Molsberry,Sandra Reynolds,Aaron Aronow,Andrew J Levine,Eileen Martin,Eric N Miller,Cynthia A Munro,Ann Ragin,Ned Sacktor,Ola A Selnes", - "abstract": "The Multicenter AIDS Cohort Study (MACS) is one of the largest and longest running studies of the natural and treated history of HIV disease. The Neuropsychological (NP) substudy was begun in 1988 following reports of significant adverse neurological consequences of HIV disease, including dementia. The goal was to characterize the neuropsychological deficits among individuals with HIV disease, and track the natural history of the neurological complications over time. There were three distinct MACS recruitment stages that focused on different groups of HIV-infected men, or men at risk for infection. Initially, a subcohort was evaluated semi-annually with NP tests but, beginning in 2005, the entire group of MACS participants have had NP examinations biannually, unless closer follow-up was warranted. The participants complete a battery of NP tests, and are classified as either normal, mildly or severely impaired using the Antinori criteria for HIV-Associated Neurocognitive Disorder (HAND). Additional behavioural data, including mood state and psychoactive substance use, are recorded as part of the main MACS data collection. The MACS public data set (PDS) has been available since 1994 and includes baseline and 6-monthly follow-up data. Beginning in October 1995, the PDS has been released annually with new releases superseding previous versions.", - "journal_title": "International journal of epidemiology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/24771276/" - } - ], - "8ed4ec84-8c84-4b52-bf20-65bcdf9fd64c": [ - { - "pub_id": "16079228", - "title": "A statistical multiprobe model for analyzing cis and trans genes in genetical genomics experiments with short-oligonucleotide arrays.", - "authors": "Rudi Alberts,Peter Terpstra,Leonid V Bystrykh,Gerald de Haan,Ritsert C Jansen", - "abstract": "Short-oligonucleotide arrays typically contain multiple probes per gene. In genetical genomics applications a statistical model for the individual probe signals can help in separating \"true\" differential mRNA expression from \"ghost\" effects caused by polymorphisms, misdesigned probes, and batch effects. It can also help in detecting alternative splicing, start, or termination.", - "journal_title": "Genetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/16079228/" - } - ], - "9e51c1b5-d7d4-4430-ac92-08fa3b2e9f42": [ - { - "pub_id": "16283676", - "title": "Rheumatoid arthritis, a complex multifactorial disease: on the way toward individualized medicine.", - "authors": "Michael O Glocker,Reinhard Guthke,J\u00f6rn Kekow,Hans-J\u00fcrgen Thiesen", - "abstract": "With the availability of the human genome sequence and those of related species like chimpanzee, mouse, and rat, data driven research for tackling the molecular grounds of rheumatoid arthritis (RA), a multifactorial polygenic disease, can be considered a realistic challenge to the scientific community. A comprehensive research strategy is presented enabling the integration of multiple research efforts on studying autoimmunity by so called systems biology approaches. An integrative scientific concept is discussed of how to unravel molecular mechanisms of complex diseases by making use of state-of-the-art methodologies in functional and comparative genomics. A continuous interchange of data-driven and hypothesis-driven research is adjoined to determine the nature of rheumatic diseases with autoimmune background. Instead of studying single genes and proteins, RNA and protein microarray profiles are currently obtained in numerous research projects producing read-outs termed gene signatures rather than DNA and/or protein markers. A comprehensive study of the RNA, protein, and metabolite regimes is undertaken that eventually will lead to a \"holistic\" view of how all respective molecules, pathways and cells themselves interact with each other. Some of the above mentioned research aspects have already been studied by the authors, hopefully leading to new diagnostics and therapeutics in the future.", - "journal_title": "Medicinal research reviews", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/16283676/" - } - ], - "9e199fd8-c191-443a-88a1-eff59fafcaf1": [ - { - "pub_id": "17075077", - "title": "Gene networks involved in drought stress response and tolerance.", - "authors": "Kazuo Shinozaki,Kazuko Yamaguchi-Shinozaki", - "abstract": "Plants respond to survive under water-deficit conditions via a series of physiological, cellular, and molecular processes culminating in stress tolerance. Many drought-inducible genes with various functions have been identified by molecular and genomic analyses in Arabidopsis, rice, and other plants, including a number of transcription factors that regulate stress-inducible gene expression. The products of stress-inducible genes function both in the initial stress response and in establishing plant stress tolerance. In this short review, recent progress resulting from analysis of gene expression during the drought-stress response in plants as well as in elucidating the functions of genes implicated in the stress response and/or stress tolerance are summarized. A description is also provided of how various genes involved in stress tolerance were applied in genetic engineering of dehydration stress tolerance in transgenic Arabidopsis plants.", - "journal_title": "Journal of experimental botany", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/17075077/" - } - ], - "e438b39a-1b0c-4fef-897f-119aa81a494f": [ - { - "pub_id": "17185011", - "title": "Mouse bone marrow and peripheral blood erythroid cell counts are regulated by different autosomal genetic loci.", - "authors": "M Jawad,G Giotopoulos,S Fitch,C Cole,M Plumb,C J Talbot", - "abstract": "Erythropoiesis is under fine control and genetic loci that affect it are likely to be important in a range of conditions. To assess the relative contributions of different genetic loci to parameters of erythropoiesis, we have measured RBC counts in the peripheral circulation and committed erythroid cells (RBC and small normoblasts) in the bone marrow in a cohort of (CBA/H x C57BL/6) F2 mice to map quantitative trait loci (QTL). Candidate genes were assessed using bioinformatics and DNA sequencing. Different autosomal loci affect bone marrow (chromosomes 5, 11 and 19) and peripheral blood (chromosome 4) erythroid cell counts but there may be a common chromosome X locus. Spleen weight QTL were found on chromosomes 3, 15 and 17. Surprisingly, erythropoietin (Epo) is the best candidate quantitative trait gene (QTG) in the chromosome 5 locus that affects bone marrow but not peripheral blood erythroid cell counts. Epo gene expression is known to be genetically regulated in mice, but our data suggest a tissue-specific role for epo in mouse erythropoiesis that is also genetically determined. The identity of the other QTG will be important both to further knowledge of the control of erythropoiesis and as potential modifier genes for haematological disorders.", - "journal_title": "Blood cells, molecules & diseases", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/17185011/" - } - ], - "ce983f99-5b2a-403a-b11a-dc2993a270f0": [ - { - "pub_id": "17722647", - "title": "Concentrative nucleoside transporters (CNTs) in epithelia: from absorption to cell signaling.", - "authors": "M Pastor-Anglada,E Errasti-Murugarren,I Aymerich,F J Casado", - "abstract": "Concentrative and Equilibrative Nucleoside Transporter proteins (CNT and ENT, respectively) are encoded by gene families SLC28 and SLC29. They mediate the uptake of natural nucleosides and a variety of nucleoside-derived drugs, mostly used in anticancer therapy. CNT and ENT proteins are mostly localized in the apical and basolateral sides, respectively, in (re)absorptive epithelia. This anatomic distribution determines nucleoside and nucleoside-derived vectorial flux. CNT expression (particularly CNT2) is associated with differentiation and is also nutritionally regulated in intestinal epithelia, whereas ENT protein amounts (mostly ENT1) are increased when cells are exposed to proliferative stimuli such as EGF, TGF-alpha or wounding. Although all these features suggest a role for NT proteins in nucleoside salvage and (re)absorption, recent data demonstrate that CNT2 might be under purinergic control, in a manner that is dependent on energy metabolism. A physiological link between CNT2 function and intracellular metabolism is also supported by the evidence that extracellular adenosine can activate the AMP-dependent kinase (AMPK), by a mechanism which relies upon adenosine transport and phosphorylation. Thus the complex pattern of NT isoform expression in mammalian cells can fulfill physiological roles other than salvage.", - "journal_title": "Journal of physiology and biochemistry", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/17722647/" - } - ], - "071b4686-f5c4-4759-a038-14d79a45dac7": [ - { - "pub_id": "17436037", - "title": "Mouse Phenotype Database Integration Consortium: integration [corrected] of mouse phenome data resources.", - "authors": " ,John M Hancock,Niels C Adams,Vassilis Aidinis,Andrew Blake,Molly Bogue,Steve D M Brown,Elissa J Chesler,Duncan Davidson,Christopher Duran,Janan T Eppig,Val\u00e9rie Gailus-Durner,Hilary Gates,Georgios V Gkoutos,Simon Greenaway,Martin Hrab\u00e9 de Angelis,George Kollias,Sophie Leblanc,Kirsty Lee,Christoph Lengger,Holger Maier,Ann-Marie Mallon,Hiroshi Masuya,David G Melvin,Werner M\u00fcller,Helen Parkinson,Glenn Proctor,Eli Reuveni,Paul Schofield,Aadya Shukla,Cynthia Smith,Tetsuro Toyoda,Laurent Vasseur,Shigeharu Wakana,Alison Walling,Jacqui White,Joe Wood,Michalis Zouberakis", - "abstract": "Understanding the functions encoded in the mouse genome will be central to an understanding of the genetic basis of human disease. To achieve this it will be essential to be able to characterize the phenotypic consequences of variation and alterations in individual genes. Data on the phenotypes of mouse strains are currently held in a number of different forms (detailed descriptions of mouse lines, first-line phenotyping data on novel mutations, data on the normal features of inbred lines) at many sites worldwide. For the most efficient use of these data sets, we have initiated a process to develop standards for the description of phenotypes (using ontologies) and file formats for the description of phenotyping protocols and phenotype data sets. This process is ongoing and needs to be supported by the wider mouse genetics and phenotyping communities to succeed. We invite interested parties to contact us as we develop this process further.", - "journal_title": "Mammalian genome : official journal of the International Mammalian Genome Society", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/17436037/" - } - ], - "954e43d7-4261-403f-87bc-4c1ce1492cf5": [ - { - "pub_id": "17212828", - "title": "eQTL Viewer: visualizing how sequence variation affects genome-wide transcription.", - "authors": "Wei Zou,David L Aylor,Zhao-Bang Zeng", - "abstract": "Expression Quantitative Trait Locus (eQTL) mapping methods have been used to identify the genetic basis of gene expression variations. To map eQTL, thousands of expression profiles are related with sequence polymorphisms across the genome through their correlated variations. These eQTL distribute in many chromosomal regions, each of which can include many genes. The large number of mapping results produced makes it difficult to consider simultaneously the relationships between multiple genomic regions and multiple expressional profiles. There is a need for informative bioinformatics tools to assist the visualization and interpretation of these mapping results. We have developed a web-based tool, called eQTL Viewer, to visualize the relationships between the expression trait genes and the candidate genes in the eQTL regions using Scalable Vector Graphics. The plot generated by eQTL Viewer has the capacity to display mapping results with high resolutions at a variety of scales, and superimpose biological annotations onto the mapping results dynamically. Our tool provides an efficient and intuitive way for biologists to explore transcriptional regulation patterns, and to generate hypotheses on the genetic basis of transcriptional regulations.", - "journal_title": "BMC bioinformatics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/17212828/" - } - ], - "c09fd192-82f3-4d35-b945-e20dd1a490d2": [ - { - "pub_id": "18560825", - "title": "Combining transcriptional profiling and genetic linkage analysis to uncover gene networks operating in hematopoietic stem cells and their progeny.", - "authors": "Alice Gerrits,Brad Dykstra,Marcel Otten,Leonid Bystrykh,Gerald de Haan", - "abstract": "Stem cells are unique in that they possess both the capacity to self-renew and thereby maintain their original pool as well as the capacity to differentiate into mature cells. In the past number of years, transcriptional profiling of enriched stem cell populations has been extensively performed in an attempt to identify a universal stem cell gene expression signature. While stem-cell-specific transcripts were identified in each case, this approach has thus far been insufficient to identify a universal group of core \"stemness\" genes ultimately responsible for self-renewal and multipotency. Similarly, in the hematopoietic system, comparisons of transcriptional profiles between different hematopoietic cell stages have had limited success in revealing core genes ultimately responsible for the initiation of differentiation and lineage specification. Here, we propose that the combined use of transcriptional profiling and genetic linkage analysis, an approach called \"genetical genomics\", can be a valuable tool to assist in the identification of genes and gene networks that specify \"stemness\" and cell fate decisions. We review past studies of hematopoietic cells that utilized transcriptional profiling and/or genetic linkage analysis, and discuss several potential future applications of genetical genomics.", - "journal_title": "Immunogenetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/18560825/" - } - ], - "46f190d1-f784-45cd-be09-d43a27ec4063": [ - { - "pub_id": "18270580", - "title": "Genome-wide prediction of functional gene-gene interactions inferred from patterns of genetic differentiation in mice and men.", - "authors": "Zolt\u00e1n Bochdanovits,David Sondervan,Sophie Perillous,Toos van Beijsterveldt,Dorret Boomsma,Peter Heutink", - "abstract": "The human genome encodes a limited number of genes yet contributes to individual differences in a vast array of heritable traits. A possible explanation for the capacity our genome to generate this virtually unlimited range of phenotypic variation in complex traits is to assume functional interactions between genes. Therefore we searched two mammalian genomes to identify potential epistatic interactions by looking for co-adapted genes marked by excess two-locus genetic differentiation between populations/lineages using publicly available SNP genotype data. The practical motivation for this effort is to reduce the number of pair-wise tests that need to be performed in genome-wide association studies aimed at detecting GxG interactions, by focusing on pairs predicted to be more likely to jointly affect variation in complex traits. Hence, this approach generates a list of candidate interactions that can be empirically tested. In both the mouse and human data we observed two-locus genetic differentiation in excess of what can be expected from chance alone based on simulations. In an attempt to validate our hypothesis that pairs of genes showing excess genetic divergence represent potential functional interactions, we selected a small set of gene combinations postulated to be interacting based on our analyses and looked for a combined effect of the selected genes on variation in complex traits in both mice and man. In both cases the individual effect of the genes were not significant, instead we observed marginally significant interaction effects. These results show that genome wide searches for gene-gene interactions based on population genetic data are feasible and can generate interesting candidate gene pairs to be further tested for their contribution to phenotypic variation in complex traits.", - "journal_title": "PloS one", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/18270580/" - } - ], - "18047f55-9a4a-4360-afd1-fed7842da1ff": [ - { - "pub_id": "21160056", - "title": "Heart disease and stroke statistics--2011 update: a report from the American Heart Association.", - "authors": "V\u00e9ronique L Roger,Alan S Go,Donald M Lloyd-Jones,Robert J Adams,Jarett D Berry,Todd M Brown,Mercedes R Carnethon,Shifan Dai,Giovanni de Simone,Earl S Ford,Caroline S Fox,Heather J Fullerton,Cathleen Gillespie,Kurt J Greenlund,Susan M Hailpern,John A Heit,P Michael Ho,Virginia J Howard,Brett M Kissela,Steven J Kittner,Daniel T Lackland,Judith H Lichtman,Lynda D Lisabeth,Diane M Makuc,Gregory M Marcus,Ariane Marelli,David B Matchar,Mary M McDermott,James B Meigs,Claudia S Moy,Dariush Mozaffarian,Michael E Mussolino,Graham Nichol,Nina P Paynter,Wayne D Rosamond,Paul D Sorlie,Randall S Stafford,Tanya N Turan,Melanie B Turner,Nathan D Wong,Judith Wylie-Rosett, ", - "abstract": "Each year, the American Heart Association (AHA), in conjunction with the Centers for Disease Control and Prevention, the National Institutes of Health, and other government agencies, brings together the most up-to-date statistics on heart disease, stroke, other vascular diseases, and their risk factors and presents them in its Heart Disease and Stroke Statistical Update. The Statistical Update is a valuable resource for researchers, clinicians, healthcare policy makers, media professionals, the lay public, and many others who seek the best national data available on disease morbidity and mortality and the risks, quality of care, medical procedures and operations, and costs associated with the management of these diseases in a single document. Indeed, since 1999, the Statistical Update has been cited more than 8700 times in the literature (including citations of all annual versions). In 2009 alone, the various Statistical Updates were cited \u22481600 times (data from ISI Web of Science). In recent years, the Statistical Update has undergone some major changes with the addition of new chapters and major updates across multiple areas. For this year\u2019s edition, the Statistics Committee, which produces the document for the AHA, updated all of the current chapters with the most recent nationally representative data and inclusion of relevant articles from the literature over the past year and added a new chapter detailing how family history and genetics play a role in cardiovascular disease (CVD) risk. Also, the 2011 Statistical Update is a major source for monitoring both cardiovascular health and disease in the population, with a focus on progress toward achievement of the AHA\u2019s 2020 Impact Goals. Below are a few highlights from this year\u2019s Update. The 2007 overall death rate from CVD (<i>International Classification of Diseases 10</i>, I00\u2013I99) was 251.2 per 100 000. The rates were 294.0 per 100 000 for white males, 405.9 per 100 000 for black males, 205.7 per 100 000 for white females, and 286.1 per 100 000 for black females. From 1997 to 2007, the death rate from CVD declined 27.8%. Mortality data for 2007 show that CVD (I00\u2013I99; Q20\u2013Q28) accounted for 33.6% (813 804) of all 2 243 712 deaths in 2007, or 1 of every 2.9 deaths in the United States. On the basis of 2007 mortality rate data, more than 2200 Americans die of CVD each day, an average of 1 death every 39 seconds. More than 150 000 Americans killed by CVD (I00\u2013I99) in 2007 were <65 years of age. In 2007, nearly 33% of deaths due to CVD occurred before the age of 75 years, which is well before the average life expectancy of 77.9 years. Coronary heart disease caused \u22481 of every 6 deaths in the United States in 2007. Coronary heart disease mortality in 2007 was 406 351. Each year, an estimated 785 000 Americans will have a new coronary attack, and \u2248470 000 will have a recurrent attack. It is estimated that an additional 195 000 silent first myocardial infarctions occur each year. Approximately every 25 seconds, an American will have a coronary event, and approximately every minute, someone will die of one. Each year, \u2248795 000 people experience a new or recurrent stroke. Approximately 610 000 of these are first attacks, and 185 000 are recurrent attacks. Mortality data from 2007 indicate that stroke accounted for \u22481 of every 18 deaths in the United States. On average, every 40 seconds, someone in the United States has a stroke. From 1997 to 2007, the stroke death rate fell 44.8%, and the actual number of stroke deaths declined 14.7%. In 2007, 1 in 9 death certificates (277 193 deaths) in the United States mentioned heart failure. Data from the National Health and Nutrition Examination Survey (NHANES) 2005\u20132008 indicate that 33.5% of US adults \u226520 years of age have hypertension (Table 7-1). This amounts to an estimated 76 400 000 US adults with hypertension. The prevalence of hypertension is nearly equal between men and women. African American adults have among the highest rates of hypertension in the world, at 44%. Among hypertensive adults, \u224880% are aware of their condition, 71% are using antihypertensive medication, and only 48% of those aware that they have hypertension have their condition controlled. Despite 4 decades of progress, in 2008, among Americans \u226518 years of age, 23.1% of men and 18.3% of women continued to be cigarette smokers. In 2009, 19.5% of students in grades 9 through 12 reported current tobacco use. The percentage of the nonsmoking population with detectable serum cotinine (indicating exposure to secondhand smoke) was 46.4% in 1999 to 2004, with declines occurring, and was highest for those 4 to 11 years of age (60.5%) and those 12 to 19 years of age (55.4%). An estimated 33 600 000 adults \u226520 years of age have total serum cholesterol levels \u2265240 mg/dL, with a prevalence of 15.0% (Table 13-1). In 2008, an estimated 18 300 000 Americans had diagnosed diabetes mellitus, representing 8.0% of the adult population. An additional 7 100 000 had undiagnosed diabetes mellitus, and 36.8% had prediabetes, with abnormal fasting glucose levels. African Americans, Mexican Americans, Hispanic/Latino individuals, and other ethnic minorities bear a strikingly disproportionate burden of diabetes mellitus in the United States (Table 16-1). The estimated prevalence of overweight and obesity in US adults (\u226520 years of age) is 149 300 000, which represents 67.3% of this group in 2008. Fully 33.7% of US adults are obese (body mass index \u226530 kg/m<sup>2</sup>). Men and women of all race/ethnic groups in the population are affected by the epidemic of overweight and obesity (Table 15-1). Among children 2 to 19 years of age, 31.9% are overweight and obese (which represents 23 500 000 children), and 16.3% are obese (12 000 000 children). Mexican American boys and girls and African American girls are disproportionately affected. Over the past 3 decades, the prevalence of obesity in children 6 to 11 years of age has increased from \u22484% to more than 20%. Obesity (body mass index \u226530 kg/m<sup>2</sup>) is associated with marked excess mortality in the US population. Even more notable is the excess morbidity associated with overweight and obesity in terms of risk factor development and incidence of diabetes mellitus, CVD end points (including coronary heart disease, stroke, and heart failure), and numerous other health conditions, including asthma, cancer, degenerative joint disease, and many others. The prevalence of diabetes mellitus is increasing dramatically over time, in parallel with the increases in prevalence of overweight and obesity. On the basis of NHANES 2003\u20132006 data, the age-adjusted prevalence of metabolic syndrome, a cluster of major cardiovascular risk factors related to overweight/obesity and insulin resistance, is 34% (35.1% among men and 32.6% among women). The proportion of youth (\u226418 years of age) who report engaging in no regular physical activity is high, and the proportion increases with age. In 2007, among adolescents in grades 9 through 12, 29.9% of girls and 17.0% of boys reported that they had not engaged in 60 minutes of moderate-to-vigorous physical activity, defined as any activity that increased heart rate or breathing rate, even once in the previous 7 days, despite recommendations that children engage in such activity \u22655 days per week. Thirty-six percent of adults reported engaging in no vigorous activity (activity that causes heavy sweating and a large increase in breathing or heart rate). Data from NHANES indicate that between 1971 and 2004, average total energy consumption among US adults increased by 22% in women (from 1542 to 1886 kcal/d) and by 10% in men (from 2450 to 2693 kcal/d; see Chart 19-1). The increases in calories consumed during this time period are attributable primarily to greater average carbohydrate intake, in particular, of starches, refined grains, and sugars. Other specific changes related to increased caloric intake in the United States include larger portion sizes, greater food quantity and calories per meal, and increased consumption of sugar-sweetened beverages, snacks, commercially prepared (especially fast food) meals, and higher energy-density foods. In light of the current national focus on healthcare utilization, costs, and quality, it is critical to monitor and understand the magnitude of healthcare delivery and costs, as well as the quality of healthcare delivery, related to CVDs. The Update provides these critical data in several sections. Chapter 20 reviews many metrics related to the quality of care delivered to patients with CVDs, as well as healthcare disparities. In particular, quality data are available from the AHA\u2019s \u201cGet With The Guidelines\u201d programs for coronary artery disease and heart failure and the American Stroke Association/ AHA\u2019s \u201cGet With the Guidelines\u201d program for acute stroke. Similar data from the Veterans Healthcare Administration, national Medicare and Medicaid data and National Cardiovascular Data Registry Acute Coronary Treatment and Intervention Outcomes Network - \u201cGet With The Guidelines\u201d Registry data are also reviewed. These data show impressive adherence with guideline recommendations for many, but not all, metrics of quality of care for these hospitalized patients. Data are also reviewed on screening for cardiovascular risk factor levels and control. Chapter 21 provides data on trends and current usage of cardiovascular surgical and invasive procedures. For example, the total number of inpatient cardiovascular operations and procedures increased 27%, from 5 382 000 in 1997 to 6 846 000 in 2007 (National Heart, Lung, and Blood Institute computation based on National Center for Health Statistics annual data). Chapter 22 reviews current estimates of direct and indirect healthcare costs related to CVDs, stroke, and related conditions using Medical Expenditure Panel Survey data. The total direct and indirect cost of CVD and stroke in the United States for 2007 is estimated to be $286 billion. This figure includes health expenditures (direct costs, which include the cost of physicians and other professionals, hospital services, prescribed medications, home health care, and other medical durables) and lost productivity resulting from mortality (indirect costs). By comparison, in 2008, the estimated cost of all cancer and benign neoplasms was $228 billion ($93 billion in direct costs, $19 billion in morbidity indirect costs, and $116 billion in mortality indirect costs). CVD costs more than any other diagnostic group. The AHA, through its Statistics Committee, continuously monitors and evaluates sources of data on heart disease and stroke in the United States to provide the most current data available in the Statistics Update. The 2007 mortality data have been released. More information can be found at the National Center for Health Statistics Web site, http://www.cdc.gov/nchs/data/nvsr/nvsr58/nvsr58_01.pdf. Finally, it must be noted that this annual Statistical Update is the product of an entire year\u2019s worth of effort by dedicated professionals, volunteer physicians and scientists, and outstanding AHA staff members, without whom publication of this valuable resource would be impossible. Their contributions are gratefully acknowledged. V\u00e9ronique L. Roger, MD, MPH, FAHA. Melanie B. Turner, MPH. On behalf of the American Heart Association Heart Disease and Stroke Statistics Writing Group. Note: Population data used in the compilation of NHANES prevalence estimates is for the latest year of the NHANES survey being used. Extrapolations for NHANES prevalence estimates are based on the census resident population for 2008 because this is the most recent year of NHANES data used in the Statistical Update.", - "journal_title": "Circulation", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/21160056/" - } - ], - "8bda5c7d-b579-4d20-afcc-5a157520a7b3": [ - { - "pub_id": "20031544", - "title": "HapMap and mapping genes for cardiovascular disease.", - "authors": "Kiran Musunuru,Sekar Kathiresan", - "abstract": "A key goal of biomedical science is to understand why individuals differ in their susceptibility to disease. Family history is among the established risk factors for most forms of cardiovascular disease, in part because inherited DNA sequence variants play a causal role in disease susceptibility. Consequently, the search for these variants has intensified over the past decade. One class of DNA sequence variants takes the form of single nucleotide changes(single nucleotide polymorphisms, or SNPs), usually with two variants or alleles for each SNP. SNPs are scattered throughout the 23 pairs of chromosomes of the human genome, and roughly 11 million common polymorphisms (ie,those > 1% frequency) are estimated to exist. A combination of SNP alleles along a chromosome is termed a haplotype. The International Haplotype Map Project was designed to create a public genome-wide database of common SNPs and, consequently, enable systematic studies of most common SNPs for their potential role in human disease. We review the following: (1) the concept of linkage disequilibrium orallelic association, (2) the HapMap project, and (3) several examples of the utility of HapMap data in genetic mapping for cardiovascular disease phenotypes.", - "journal_title": "Circulation. Cardiovascular genetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/20031544/" - } - ], - "06637833-6930-48b7-acfb-4a8278085ae1": [ - { - "pub_id": "19737576", - "title": "Genetical toxicogenomics in Drosophila identifies master-modulatory loci that are regulated by developmental exposure to lead.", - "authors": "Douglas M Ruden,Lang Chen,Debra Possidente,Bernard Possidente,Parsa Rasouli,Luan Wang,Xiangyi Lu,Mark D Garfinkel,Helmut V B Hirsch,Grier P Page", - "abstract": "The genetics of gene expression in recombinant inbred lines (RILs) can be mapped as expression quantitative trait loci (eQTLs). So-called \"genetical genomics\" studies have identified locally acting eQTLs (cis-eQTLs) for genes that show differences in steady-state RNA levels. These studies have also identified distantly acting master-modulatory trans-eQTLs that regulate tens or hundreds of transcripts (hotspots or transbands). We expand on these studies by performing genetical genomics experiments in two environments in order to identify trans-eQTL that might be regulated by developmental exposure to the neurotoxin lead. Flies from each of 75 RIL were raised from eggs to adults on either control food (made with 250 microM sodium acetate), or lead-treated food (made with 250 microM lead acetate, PbAc). RNA expression analyses of whole adult male flies (5-10 days old) were performed with Affymetrix DrosII whole genome arrays (18,952 probesets). Among the 1389 genes with cis-eQTL, there were 405 genes unique to control flies and 544 genes unique to lead-treated ones (440 genes had the same cis-eQTLs in both samples). There are 2396 genes with trans-eQTL which mapped to 12 major transbands with greater than 95 genes. Permutation analyses of the strain labels but not the expression data suggests that the total number of eQTL and the number of transbands are more important criteria for validation than the size of the transband. Two transbands, one located on the 2nd chromosome and one on the 3rd chromosome, co-regulate 33 lead-induced genes, many of which are involved in neurodevelopmental processes. For these 33 genes, rather than allelic variation at one locus exerting differential effects in two environments, we found that variation at two different loci are required for optimal effects on lead-induced expression.", - "journal_title": "Neurotoxicology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/19737576/" - } - ], - "ee3d69ed-92bf-4fa2-893b-7cbadc5fb1bc": [ - { - "pub_id": "19361688", - "title": "Chapter 2. Evolution of vertebrate cartilage development.", - "authors": "Guangjun Zhang,B Frank Eames,Martin J Cohn", - "abstract": "Major advances in the molecular genetics, paleobiology, and the evolutionary developmental biology of vertebrate skeletogenesis have improved our understanding of the early evolution and development of the vertebrate skeleton. These studies have involved genetic analysis of model organisms, human genetics, comparative developmental studies of basal vertebrates and nonvertebrate chordates, and both cladistic and histological analyses of fossil vertebrates. Integration of these studies has led to renaissance in the area of skeletal development and evolution. Among the major findings that have emerged is the discovery of an unexpectedly deep origin of the gene network that regulates chondrogenesis. In this chapter, we discuss recent progress in each these areas and identify a number of questions that need to be addressed in order to fill key gaps in our knowledge of early skeletal evolution.", - "journal_title": "Current topics in developmental biology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/19361688/" - } - ], - "4ef6ffae-703d-49c2-bfbb-5c6b39b704e7": [ - { - "pub_id": "19393285", - "title": "Systems genetics analysis of iron regulation in the brain.", - "authors": "Leslie C Jellen,John L Beard,Byron C Jones", - "abstract": "Iron imbalances in the brain, including excess accumulation and deficiency, are associated with neurological disease and dysfunction; yet, their origins are poorly understood. Using systems genetics analysis, we have learned that large individual differences exist in brain iron concentrations, even in the absence of neurological disease. Much of the individual differences can be tied to the genetic makeup of the individual. This genetic-based differential regulation can be modeled in genetic reference populations of rodents. The work in our laboratory centers on iron regulation in the brain and our animal model consists of 25 BXD/Ty recombinant inbred mouse strains. By studying naturally occurring variation in iron phenotypes, such as tissue iron concentration, we can tie that variability to one or more genes by way of quantitative trait loci (QTL) analysis. Moreover, we can conduct genetic correlation analyses between our phenotypes and others previously measured in the BXD/Ty strains. We have observed several suggestive QTL related to ventral midbrain iron content, including one on chromosome 17 that contains btbd9, a gene that in humans has been associated with restless legs syndrome and serum ferritin. We have also observed gene expression correlations with ventral midbrain iron, including btbd9 expression and dopamine receptor expression. In addition, we have observed significant correlations between ventral midbrain iron content and dopamine-related phenotypes. The following is a discussion of iron regulation in the brain and the contributions a systems genetics approach can make toward understanding the genetic underpinnings and relation to neurological disease.", - "journal_title": "Biochimie", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/19393285/" - } - ], - "66fc5ee9-0126-431f-add0-819957499810": [ - { - "pub_id": "20718853", - "title": "Identification of a Chr 11 quantitative trait locus that modulates proliferation in the rostral migratory stream of the adult mouse brain.", - "authors": "Anna Poon,Zhiyou Li,Gregory W Wolfe,Lu Lu,Robert W Williams,Nancy L Hayes,Richard S Nowakowski,Daniel Goldowitz", - "abstract": "Neuron production takes place continuously in the rostral migratory stream (RMS) of the adult mammalian brain. The molecular mechanisms that regulate progenitor cell division and differentiation in the RMS remain largely unknown. Here, we surveyed the mouse genome in an unbiased manner to identify candidate gene loci that regulate proliferation in the adult RMS. We quantified neurogenesis in adult C57BL/6J and A/J mice, and 27 recombinant inbred lines derived from those parental strains. We showed that the A/J RMS had greater numbers of bromodeoxyuridine-labeled cells than that of C57BL/6J mice with similar cell cycle parameters, indicating that the differences in the number of bromodeoxyuridine-positive cells reflected the number of proliferating cells between the strains. AXB and BXA recombinant inbred strains demonstrated even greater variation in the numbers of proliferating cells. Genome-wide mapping of this trait revealed that chromosome 11 harbors a significant quantitative trait locus at 116.75 +/- 0.75 Mb that affects cell proliferation in the adult RMS. The genomic regions that influence RMS proliferation did not overlap with genomic regions regulating proliferation in the adult subgranular zone of the hippocampal dentate gyrus. On the contrary, a different, suggestive locus that modulates cell proliferation in the subgranular zone was mapped to chromosome 3 at 102 +/- 7 Mb. A subset of genes in the chromosome 11 quantitative trait locus region is associated with neurogenesis and cell proliferation. Our findings provide new insights into the genetic control of neural proliferation and an excellent starting point to identify genes critical to this process.", - "journal_title": "The European journal of neuroscience", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/20718853/" - } - ], - "29f5af5f-8dc7-4e53-b0fa-66d37317a3f4": [ - { - "pub_id": "20731870", - "title": "Systems approach to investigating host-pathogen interactions in infections with the biothreat agent Francisella. Constraints-based model of Francisella tularensis.", - "authors": "Anu Raghunathan,Sookil Shin,Simon Daefler", - "abstract": "Francisella tularensis is a prototypic example of a pathogen for which few experimental datasets exist, but for which copious high-throughout data are becoming available because of its re-emerging significance as biothreat agent. The virulence of Francisella tularensis depends on its growth capabilities within a defined environmental niche of the host cell. We reconstructed the metabolism of Francisella as a stoichiometric matrix. This systems biology approach demonstrated that changes in carbohydrate utilization and amino acid metabolism play a pivotal role in growth, acid resistance, and energy homeostasis during infection with Francisella. We also show how varying the expression of certain metabolic genes in different environments efficiently controls the metabolic capacity of F. tularensis. Selective gene-expression analysis showed modulation of sugar catabolism by switching from oxidative metabolism (TCA cycle) in the initial stages of infection to fatty acid oxidation and gluconeogenesis later on. Computational analysis with constraints derived from experimental data revealed a limited set of metabolic genes that are operational during infection. This integrated systems approach provides an important tool to understand the pathogenesis of an ill-characterized biothreat agent and to identify potential novel drug targets when rapid target identification is required should such microbes be intentionally released or become epidemic.", - "journal_title": "BMC systems biology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/20731870/" - } - ], - "3f87a135-cfa0-443c-a6ab-f875eb139bf7": [ - { - "pub_id": "20954177", - "title": "Systems genetics analysis of mouse chondrocyte differentiation.", - "authors": "Jaijam Suwanwela,Charles R Farber,Bau-Lin Haung,Buer Song,Calvin Pan,Karen M Lyons,Aldons J Lusis", - "abstract": "One of the goals of systems genetics is the reconstruction of gene networks that underlie key processes in development and disease. To identify cartilage gene networks that play an important role in bone development, we used a systems genetics approach that integrated microarray gene expression profiles from cartilage and bone phenotypic data from two sets of recombinant inbred strains. Microarray profiles generated from isolated chondrocytes were used to generate weighted gene coexpression networks. This analysis resulted in the identification of subnetworks (modules) of coexpressed genes that then were examined for relationships with bone geometry and density. One module exhibited significant correlation with femur length (r\u2009=\u20090.416), anteroposterior diameter (r\u2009=\u20090.418), mediolateral diameter (r\u2009=\u20090.576), and bone mineral density (r\u2009=\u20090.475). Highly connected genes (n\u2009=\u200928) from this and other modules were tested in vitro using prechondrocyte ATDC5 cells and RNA interference. Five of the 28 genes were found to play a role in chondrocyte differentiation. Two of these, Hspd1 and Cdkn1a, were known previously to function in chondrocyte development, whereas the other three, Bhlhb9, Cugbp1, and Spcs3, are novel genes. Our integrative analysis provided a systems-level view of cartilage development and identified genes that may be involved in bone development.", - "journal_title": "Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/20954177/" - } - ], - "af3ad242-afe4-43f5-9046-98388dd13177": [ - { - "pub_id": "21811473", - "title": "Using animal models to disentangle the role of genetic, epigenetic, and environmental influences on behavioral outcomes associated with maternal anxiety and depression.", - "authors": "Lisa M Tarantino,Patrick F Sullivan,Samantha Meltzer-Brody", - "abstract": "The etiology of complex psychiatric disorders results from both genetics and the environment. No definitive environmental factor has been implicated, but studies suggest that deficits in maternal care and bonding may be an important contributing factor in the development of anxiety and depression. Perinatal mood disorders such as postpartum depression occur in approximately 10% of pregnant women and can result in detriments in infant care and bonding. The consequences of impaired maternal-infant attachment during critical early brain development may lead to adverse effects on socioemotional and neurocognitive development in infants resulting in long-term behavioral and emotional problems, including increased vulnerability for mental illness. The exact mechanisms by which environmental stressors such as poor maternal care increase the risk for psychiatric disorders are not known and studies in humans have proven challenging. Two inbred mouse strains may prove useful for studying the interaction between maternal care and mood disorders. BALB/c (BALB) mice are considered an anxious strain in comparison to C57BL/6 (B6) mice in behavioral models of anxiety. These strain differences are most often attributed to genetics but may also be due to environment and gene by environment interactions. For example, BALB mice are described as poor mothers and B6 mice as good mothers and mothering behavior in rodents has been reported to affect both anxiety and stress behaviors in offspring. Changes in gene methylation patterns in response to maternal care have also been reported, providing evidence for epigenetic mechanisms. Characterization of these two mouse inbred strains over the course of pregnancy and in the postpartum period for behavioral and neuroendocrine changes may provide useful information by which to inform human studies, leading to advances in our understanding of the etiology of anxiety and depression and the role of genetics and the environment.", - "journal_title": "Frontiers in psychiatry", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/21811473/" - } - ], - "ca55dc2b-7dc8-4ac4-8923-1b516eccdfb7": [ - { - "pub_id": "22832735", - "title": "A promoter polymorphism in the Per3 gene is associated with alcohol and stress response.", - "authors": "X Wang,K Mozhui,Z Li,M K Mulligan,J F Ingels,X Zhou,R T Hori,H Chen,M N Cook,R W Williams,L Lu", - "abstract": "The period homolog genes Per1, Per2 and Per3 are important components of the circadian clock system. In addition to their role in maintaining circadian rhythm, these genes have been linked to mood disorders, stress response and vulnerability to addiction and alcoholism. In this study, we combined high-resolution sequence analysis and quantitative trait locus (QTL) mapping of gene expression and behavioral traits to identify Per3 as a compelling candidate for the interaction between circadian rhythm, alcohol and stress response. In the BXD family of mouse strains, sequence variants in Per3 have marked effects on steady-state mRNA and protein levels. As a result, the transcript maps as a cis-acting expression QTL (eQTL). We found that an insertion/deletion (indel) variant in a putative stress response element in the promoter region of Per3 causes local control of transcript abundance. This indel results in differences in protein binding affinities between the two alleles through the Nrf2 transcriptional activator. Variation in Per3 is also associated with downstream differences in the expression of genes involved in circadian rhythm, alcohol, stress response and schizophrenia. We found that the Per3 locus is linked to stress/anxiety traits, and that the basal expression of Per3 is also correlated with several anxiety and addiction-related phenotypes. Treatment with alcohol results in increased expression of Per3 in the hippocampus, and this effect interacts with acute restraint stress. Our data provide strong evidence that variation in the Per3 transcript is causally associated with and also responsive to stress and alcohol.", - "journal_title": "Translational psychiatry", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/22832735/" - } - ], - "eb390ef4-09f1-4760-910b-d99c76732d1d": [ - { - "pub_id": "28617813", - "title": "Identification of Padi2 as a novel angiogenesis-regulating gene by genome association studies in mice.", - "authors": "Mehrdad Khajavi,Yi Zhou,Amy E Birsner,Lauren Bazinet,Amanda Rosa Di Sant,Alex J Schiffer,Michael S Rogers,Subrahmanian Tarakkad Krishnaji,Bella Hu,Vy Nguyen,Leonard Zon,Robert J D'Amato", - "abstract": "Recent findings indicate that growth factor-driven angiogenesis is markedly influenced by genetic variation. This variation in angiogenic responsiveness may alter the susceptibility to a number of angiogenesis-dependent diseases. Here, we utilized the genetic diversity available in common inbred mouse strains to identify the loci and candidate genes responsible for differences in angiogenic response. The corneal micropocket neovascularization assay was performed on 42 different inbred mouse strains using basic fibroblast growth factor (bFGF) pellets. We performed a genome-wide association study utilizing efficient mixed-model association (EMMA) mapping using the induced vessel area from all strains. Our analysis yielded five loci with genome-wide significance on chromosomes 4, 8, 11, 15 and 16. We further refined the mapping on chromosome 4 within a haplotype block containing multiple candidate genes. These genes were evaluated by expression analysis in corneas of various inbred strains and in vitro functional assays in human microvascular endothelial cells (HMVECs). Of these, we found the expression of peptidyl arginine deiminase type II (Padi2), known to be involved in metabolic pathways, to have a strong correlation with a haplotype shared by multiple high angiogenic strains. In addition, inhibition of Padi2 demonstrated a dosage-dependent effect in HMVECs. To investigate its role in vivo, we knocked down Padi2 in transgenic kdrl:zsGreen zebrafish embryos using morpholinos. These embryos had disrupted vessel formation compared to control siblings. The impaired vascular pattern was partially rescued by human PADI2 mRNA, providing evidence for the specificity of the morphant phenotype. Taken together, our study is the first to indicate the potential role of Padi2 as an angiogenesis-regulating gene. The characterization of Padi2 and other genes in associated pathways may provide new understanding of angiogenesis regulation and novel targets for diagnosis and treatment of a wide variety of angiogenesis-dependent diseases.", - "journal_title": "PLoS genetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/28617813/" - } - ], - "f3940d40-0953-4653-8598-270c6ea13936": [ - { - "pub_id": "17143588", - "title": "Databases of free expression.", - "authors": "John R Walker,Tim Wiltshire", - "abstract": "The rapid development of microarray technologies has led to a similar progression in gene expression analysis methods, gene expression applications, and gene expression databases. Public gene expression databases enable any researcher to examine expression of their favorite genes across a wide variety of samples, download sample data for development of new analysis methods, or answer broad questions about gene expression regulation, among other applications. A wide variety of public gene expression databases exist, and they vary in their content, analysis capabilities, and ease of use. This review highlights the current features and describes examples of two broad categories of mammalian microarray databases: tissue gene expression databases and data warehouses.", - "journal_title": "Mammalian genome : official journal of the International Mammalian Genome Society", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/17143588/" - } - ], - "0f478bbe-0ce7-4cc3-82d7-d1be116f7ba7": [ - { - "pub_id": "17131200", - "title": "Genetic and structural analysis of the basolateral amygdala complex in BXD recombinant inbred mice.", - "authors": "Khyobeni Mozhui,Kristin M Hamre,Andrew Holmes,Lu Lu,Robert W Williams", - "abstract": "The amygdala integrates and coordinates emotional and autonomic responses. The genetics that underlie variation in amygdala structure may be coupled to variation in levels of aggression, fear, anxiety, and affiliated behaviors. We systematically quantified the volume and cell populations of the basolateral amygdala complex (BLAc) across 35 BXD recombinant inbred (RI) lines, the parental strains--C57BL/6J (B6) and DBA/2J (D2)--and F1 hybrids (n cases=199, bilateral analysis). Neuron number and volume vary 1.7- to 2-fold among strains (e.g., neuron number ranged from 88,000 to 170,000). Glial and endothelial populations ranged more widely (5- to 8-fold), in part because of higher technical error. A quantitative trait locus (QTL) for the BLAc size is located on chromosome (Chr) 8 near the Large gene. This locus may also influence volume of other regions including hippocampus and cerebellum. Cell populations in the BLAc appear to be modulated more weakly by loci on Chrs 11 and 13. Candidate genes were selected on the basis of correlation with BLAc traits, chromosomal location, single nucleotide polymorphism (SNP) density, and expression patterns in the Allen Brain Atlas. Neurod2, a gene shown to be significant for the formation of the BLAc by knockout studies, is among the candidates genes. Other candidates include Large, and Thra. Responses to drugs of abuse and locomotor activity were the most notable behavioral correlates of the BLAc traits.", - "journal_title": "Behavior genetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/17131200/" - } - ], - "3485665e-4e33-481a-943e-d0fcb7c2f2ac": [ - { - "pub_id": "16730093", - "title": "Mouse genetic models in alcohol research.", - "authors": "Beth Bennett,Chris Downing,Clarissa Parker,Thomas E Johnson", - "abstract": "Animal models offer several advantages for the study of complex human disorders such as alcoholism. No animal model replicates all aspects of alcoholism but different components of the disorder can be investigated using various rodent models. In this article, we review a select subset of the most widely used mouse genetic models in alcohol research. Different genetically defined strains and stocks of mice are useful for genetic, physiologic, behavioral and pharmacological studies of this devastating disorder. In the past decade, numerous genomic regions associated with a tendency for various behavioral components of alcoholism have been identified; recent applications of new methods are shedding light on quantitative trait genes. Many of the underlying genes should be identified in the near future.", - "journal_title": "Trends in genetics : TIG", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/16730093/" - } - ], - "6106ae32-b200-4e5d-8744-3a7c2266b705": [ - { - "pub_id": "16647568", - "title": "Selective expression of cholesterol metabolism genes in normal CD34+CD38- cells with a heterogeneous expression pattern in AML cells.", - "authors": "Susan D P W M Peeters,Dorina M van der Kolk,Gerald de Haan,Leonid Bystrykh,Folkert Kuipers,Elisabeth G E de Vries,Edo Vellenga", - "abstract": "To identify adenosine triphosphate-binding-cassette (ABC) transporters that are selectively expressed in normal and/or leukemic CD34+CD38- stem cells. Microarray experiments on murine stem cells identified 13 ABC transporters with a high expression level. Corresponding human transporters were analyzed in normal CD34+CD38- and CD34+CD38+ bone marrow cells by quantitative reverse transcriptase polymerase chain reaction. Five ABC transporters, including ABCG1, were differentially expressed with a higher expression in CD34+CD38- cells. Besides ABCG1, known to be involved in cholesterol metabolism, expression of another major cholesterol transporter (ABCA1), some cholesterol metabolism genes (3-hydroxy-3-methyl-glutaryl-CoA reductase, low-density lipoprotein receptor), and the transcription factor controlling ABCA1 and ABCG1 expression, liver-X-receptor-alpha (LXR-alpha), were assessed. All these genes were predominantly expressed in the more primitive subpopulation, indicating a high rate of cholesterol metabolism and transport. Conversely in acute myeloid leukemia (AML), a heterogeneous expression pattern was found consisting of a considerably higher expression of particularly LXR-alpha in CD34+ cells and a reverse expression pattern in a subset of AML CD34+CD38+ cells. These data suggest an active cholesterol metabolism and efflux in normal CD34+CD38- cells, although a subgroup of AMLs potentially demonstrate a hyperactive cholesterol metabolism.", - "journal_title": "Experimental hematology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/16647568/" - } - ], - "da46d7f0-5a30-488e-8d8c-a65aa6955c17": [ - { - "pub_id": "17150099", - "title": "Beta2-adrenergic receptor and UCP3 variants modulate the relationship between age and type 2 diabetes mellitus.", - "authors": "Michele Pinelli,Manuela Giacchetti,Fabio Acquaviva,Sergio Cocozza,Giovanna Donnarumma,Emanuela Lapice,Gabriele Riccardi,Geremia Romano,Olga Vaccaro,Antonella Monticelli", - "abstract": "It is widely accepted that Type 2 Diabetes Mellitus (T2DM) and other complex diseases are the product of complex interplay between genetic susceptibility and environmental causes. To cope with such a complexity, all the statistical and conceptual strategies available should be used. The working hypothesis of this study was that two well-known T2DM risk factors could have diverse effect in individuals carrying different genotypes. In particular, our effort was to investigate if a well-defined group of genes, involved in peripheral energy expenditure, could modify the impact of two environmental factors like age and obesity on the risk to develop diabetes. To achieve this aim we exploited a multianalytical approach also using dimensionality reduction strategy and conservative significance correction strategies. We collected clinical data and characterised five genetic variants and 2 environmental factors of 342 ambulatory T2DM patients and 305 unrelated non-diabetic controls. To take in account the role of one of the major co-morbidity conditions we stratified the whole sample according to the presence of obesity, over and above the 30 Kg/m2 BMI threshold. By monofactorial analyses the ADRB2-27 Glu27 homozygotes had a lower frequency of diabetes when compared with Gln27 carriers (Odds Ratio (OR) 0.56, 95% Confidence Interval (CI) 0.36 - 0.91). This difference was even more marked in the obese subsample. Multifactor Dimensionality Reduction method in the non-obese subsample showed an interaction among age, ADRB2-16 and UCP3 polymorphisms. In individuals that were UCP3 T-carriers and ADRB2-16 Arg-carriers the OR increased from 1 in the youngest to 10.84 (95% CI 4.54-25.85) in the oldest. On the contrary, in the ADRB2-16 GlyGly and UCP3 CC double homozygote subjects, the OR for the disease was 1.10 (95% CI 0.53-2.27) in the youngest and 1.61 (95% CI 0.55-4.71) in the oldest. Although our results should be confirmed by further studies, our data suggests that, when properly evaluated, it is possible to identify genetic factors that could influence the effect of common risk factors.", - "journal_title": "BMC medical genetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/17150099/" - } - ], - "fca531d0-d45b-495f-a02c-fbd437617b20": [ - { - "pub_id": "18287701", - "title": "MaizeGDB.", - "authors": "Carolyn J Lawrence", - "abstract": "MaizeGDB is the community database for biological information about the crop plant Zea mays. Genetic, genomic, sequence, gene product, functional characterization, literature reference, and person/organization contact information are among the data types stored at MaizeGDB. At the project's website (http://www.maizegdb.org) are standardized custom interfaces enabling researchers to browse data and to seek out specific information matching explicit search criteria. In addition, pre-compiled reports are made available for particular types of data, and bulletin boards are provided to facilitate communication and coordination among members of the community of maize geneticists.", - "journal_title": "Methods in molecular biology (Clifton, N.J.)", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/18287701/" - } - ], - "d170b70f-5404-4823-b1c1-56679b488cb1": [ - { - "pub_id": "17516061", - "title": "Expression of murine killer immunoglobulin-like receptor KIRL1 on CD1d-independent NK1.1(+) T cells.", - "authors": "Erica B Wilson,Christine A Parachoniak,Carmine Carpenito,Dixie L Mager,Fumio Takei", - "abstract": "Three mouse killer immunoglobulin-like receptors (KIRs), namely, KIR3DL1, KIRL1, and KIRL2, have recently been identified in C56BL/6 (B6) mice. However, only two Kir genes are found in the B6 mouse genome sequence data base. To clarify this discrepancy, we cloned Kir cDNAs from multiple strains of mice. Sequencing of the cDNA clones showed that the Kir3dl1 gene is found in C3H/HeJ and CBA/J but not in B6 mice. Analysis of the single nucleotide polymorphism data base suggested that Kir3dl1 is the C3H/HeJ and CBA/J allele of Kirl1. We generated mAb to the recombinant KIRL1 protein to investigate its expression pattern. The anti-KIRL1 mAb bound to NK1.1(+) T cells but only very weakly or at undetectable levels to other lymphocytes including natural killer (NK) cells and conventional T cells. Among NK1.1(+) T cells, conventional NK T cells stained with CD1d tetramer did not significantly bind anti-KIRL1 mAb, whereas CD1d-tetramer-negative subset was KIRL1-positive. Furthermore, the expression of KIRL1 is readily detected on NK1.1(+) T cells from beta(2)-microglobulin-deficient B6 mice. Thus, KIRL1 is predominantly expressed on CD1d-independent NK1.1(+) T cells.", - "journal_title": "Immunogenetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/17516061/" - } - ], - "5e5149e0-7bb5-4ddb-831d-e963365e8ec5": [ - { - "pub_id": "17262023", - "title": "Latexin is a newly discovered regulator of hematopoietic stem cells.", - "authors": "Gerald de Haan", - "abstract": "", - "journal_title": "Nature genetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/17262023/" - } - ], - "12c7f00e-5c03-4a9f-860d-243514d2a177": [ - { - "pub_id": "17619104", - "title": "Quantitative traits for the tail suspension test: automation, optimization, and BXD RI mapping.", - "authors": "Heena V Lad,Lin Liu,Jos\u00e9 L Pay\u00e1-Cano,Cathy Fernandes,Leonard C Schalkwyk", - "abstract": "Immobility in the tail suspension test (TST) is considered a model of despair in a stressful situation, and acute treatment with antidepressants reduces immobility. Inbred strains of mouse exhibit widely differing baseline levels of immobility in the TST and several quantitative trait loci (QTLs) have been nominated. The labor of manual scoring and various scoring criteria make obtaining robust data and comparisons across different laboratories problematic. Several studies have validated strain gauge and video analysis methods by comparison with manual scoring. We set out to find objective criteria for automated scoring parameters that maximize the biological information obtained, using a video tracking system on tapes of tail suspension tests of 24 lines of the BXD recombinant inbred panel and the progenitor strains C57BL/6J and DBA/2J. The maximum genetic effect size is captured using the highest time resolution and a low mobility threshold. Dissecting the trait further by comparing genetic association of multiple measures reveals good evidence for loci involved in immobility on chromosomes 4 and 15. These are best seen when using a high threshold for immobility, despite the overall better heritability at the lower threshold. A second trial of the test has greater duration of immobility and a completely different genetic profile. Frequency of mobility is also an independent phenotype, with a distal chromosome 1 locus.", - "journal_title": "Mammalian genome : official journal of the International Mammalian Genome Society", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/17619104/" - } - ], - "0265286c-7bac-4ae3-831c-5bf5a4f758c6": [ - { - "pub_id": "25805317", - "title": "Quantitative trait loci mapping of partial resistance to Diamondback moth in cabbage (Brassica oleracea L).", - "authors": "Nirala Ramchiary,Wenxing Pang,Van Dan Nguyen,Xiaonan Li,Su Ryun Choi,Ajay Kumar,Min Kwon,Hye Young Song,Shahnaz Begum,Mechuselie Kehie,Moo-Kyoung Yoon,Jonghyun Na,HyeRan Kim,Yong Pyo Lim", - "abstract": "The resistance to Diamondback moth insect in cabbage is governed by many minor loci in quantitative nature, and at least four genetic loci should be incorporated in marker-assisted breeding program for developing partially resistant DBM cabbage cultivars. The Diamondback moth (DBM), Plutella xylostella (L.), is the most destructive insect infesting cruciferous plants worldwide. Earlier studies have reported that the glossy leaves of cabbage are associated with resistance to this insect. However, until now, genetics of DBM resistance has not been studied in detail, and no QTL/gene mapping for this trait has been reported. In this paper, we report quantitative trait loci (QTL) mapping of DBM-resistant trait using 188 randomly selected segregating F 3 population derived from crossing a partially DBM-resistant glossy leaf cabbage (748) with a susceptible smooth cabbage line (747). Quantitative trait loci mapping using phenotypic data of four consecutive years (2008, 2009, 2010, and 2011) on DBM insect infestation detected a total of eight QTL on five linkage groups suggesting that DBM resistance is a quantitative in nature. Of these QTL, four QTL, i.e., qDbm 1 on LG1, qDbm5 and qDbm6 on LG7, and qDbm8 on LG9, were detected in different tests and years. The QTL, qDbm6 on LG7, was consecutively detected over 3 years. Tightly linked molecular markers have been developed for qDbm8 QTL on LG9 which could be used in marker-assisted breeding program. Our research demonstrated that for desired DBM resistance cultivar breeding, those four genetic loci have to be taken into consideration. Furthermore, the comparative study revealed that DBM resistance QTL is conserved between close relative model plant Arabidopsis thaliana and Brassica oleracea genome.", - "journal_title": "TAG. Theoretical and applied genetics. Theoretische und angewandte Genetik", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/25805317/" - } - ], - "489539fd-f7c5-44eb-bb58-5fc19d50a7cf": [ - { - "pub_id": "26909367", - "title": "Quantitative analysis by next generation sequencing of hematopoietic stem and progenitor cells (LSK) and of splenic B cells transcriptomes from wild-type and Usp3-knockout mice.", - "authors": "Cesare Lancini,Gaetano Gargiulo,Paul C M van den Berk,Elisabetta Citterio", - "abstract": "The data described here provide genome-wide expression profiles of murine primitive hematopoietic stem and progenitor cells (LSK) and of B cell populations, obtained by high throughput sequencing. Cells are derived from wild-type mice and from mice deficient for the ubiquitin-specific protease 3 (USP3; Usp3\u0394/\u0394). Modification of histone proteins by ubiquitin plays a crucial role in the cellular response to DNA damage (DDR) (Jackson and Durocher, 2013) [1]. USP3 is a histone H2A deubiquitinating enzyme (DUB) that regulates ubiquitin-dependent DDR in response to DNA double-strand breaks (Nicassio et al., 2007; Doil et al., 2008) [2], [3]. Deletion of USP3 in mice increases the incidence of spontaneous tumors and affects hematopoiesis [4]. In particular, Usp3-knockout mice show progressive loss of B and T cells and decreased functional potential of hematopoietic stem cells (HSCs) during aging. USP3-deficient cells, including HSCs, display enhanced histone ubiquitination, accumulate spontaneous DNA damage and are hypersensitive to ionizing radiation (Lancini et al., 2014) [4]. To address whether USP3 loss leads to deregulation of specific molecular pathways relevant to HSC homeostasis and/or B cell development, we have employed the RNA-sequencing technology and investigated transcriptional differences between wild-type and Usp3\u0394/\u0394 LSK, na\u00efve B cells or in vitro activated B cells. The data relate to the research article \"Tight regulation of ubiquitin-mediated DNA damage response by USP3 preserves the functional integrity of hematopoietic stem cells\" (Lancini et al., 2014) [4]. The RNA-sequencing and analysis data sets have been deposited in NCBI\u05f3s Gene Expression Omnibus (Edgar et al., 2002) [5] and are accessible through GEO Series accession number GSE58495 (http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE58495). With this article, we present validation of the RNA-seq data set through quantitative real-time PCR and comparative analysis.", - "journal_title": "Data in brief", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/26909367/" - } - ], - "17cc0220-3d8d-4457-9349-93ffe80c47fc": [ - { - "pub_id": "18454193", - "title": "Genome-wide assessments reveal extremely high levels of polymorphism of two active families of mouse endogenous retroviral elements.", - "authors": "Ying Zhang,Irina A Maksakova,Liane Gagnier,Louie N van de Lagemaat,Dixie L Mager", - "abstract": "Endogenous retroviral elements (ERVs) in mice are significant genomic mutagens, causing approximately 10% of all reported spontaneous germ line mutations in laboratory strains. The majority of these mutations are due to insertions of two high copy ERV families, the IAP and ETn/MusD elements. This significant level of ongoing retrotranspositional activity suggests that inbred mice are highly variable in content of these two ERV groups. However, no comprehensive genome-wide studies have been performed to assess their level of polymorphism. Here we compared three test strains, for which sufficient genomic sequence is available, to each other and to the reference C57BL/6J genome and detected very high levels of insertional polymorphism for both ERV families, with an estimated false discovery rate of only 0.4%. Specifically, we found that at least 60% of IAP and 25% of ETn/MusD elements detected in any strain are absent in one or more of the other three strains. The polymorphic nature of a set of 40 ETn/MusD elements found within gene introns was confirmed using genomic PCR on DNA from a panel of mouse strains. For some cases, we detected gene-splicing abnormalities involving the ERV and obtained additional evidence for decreased gene expression in strains carrying the insertion. In total, we identified nearly 700 polymorphic IAP or ETn/MusD ERVs or solitary LTRs that reside in gene introns, providing potential candidates that may contribute to gene expression differences among strains. These extreme levels of polymorphism suggest that ERV insertions play a significant role in genetic drift of mouse lines.", - "journal_title": "PLoS genetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/18454193/" - } - ], - "984b9a87-e487-4861-af85-14b2d4728d7b": [ - { - "pub_id": "18648525", - "title": "NEIBank: genomics and bioinformatics resources for vision research.", - "authors": "Graeme Wistow,Katherine Peterson,James Gao,Patee Buchoff,Cynthia Jaworski,Catherine Bowes-Rickman,Jessica N Ebright,Michael A Hauser,David Hoover", - "abstract": "NEIBank is an integrated resource for genomics and bioinformatics in vision research. It includes expressed sequence tag (EST) data and sequence-verified cDNA clones for multiple eye tissues of several species, web-based access to human eye-specific SAGE data through EyeSAGE, and comprehensive, annotated databases of known human eye disease genes and candidate disease gene loci. All expression- and disease-related data are integrated in EyeBrowse, an eye-centric genome browser. NEIBank provides a comprehensive overview of current knowledge of the transcriptional repertoires of eye tissues and their relation to pathology.", - "journal_title": "Molecular vision", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/18648525/" - } - ], - "c09a3b78-df92-4217-baed-fb3bf10811a0": [ - { - "pub_id": "18301994", - "title": "The Diasporin Pathway: a tumor progression-related transcriptional network that predicts breast cancer survival.", - "authors": "Nigel P S Crawford,Renard C Walker,Luanne Lukes,Jennifer S Officewala,Robert W Williams,Kent W Hunter", - "abstract": "Microarray expression signature analyses have suggested that extracellular matrix (ECM) gene dysregulation is predictive of metastasis in both mouse mammary tumorigenesis and human breast cancer. We have previously demonstrated that such ECM dysregulation is influenced by hereditary germline-encoded variation. To identify novel metastasis efficiency modifiers, we performed expression QTL (eQTL) mapping in recombinant inbred mice by characterizing genetic loci modulating metastasis-predictive ECM gene expression. Three reproducible eQTLs were observed on chromosomes 7, 17 and 18. Candidate genes were identified by correlation analyses and known associations with metastasis. Seven candidates were identified (Ndn, Pi16, Luc7l, Rrp1b, Brd4, Centd3 and Csf1r). Stable transfection of the highly metastatic Mvt-1 mouse mammary tumor cell line with expression vectors encoding each candidate modulated metastasis-predictive ECM gene expression. Implantation of these cells into mice demonstrated that candidate gene ectopic expression impacts tumor progression. Gene expression analyses facilitated the construction of a transcriptional network that we have termed the 'Diasporin Pathway'. This pathway contains the seven candidates, as well as metastasis-predictive ECM genes and metastasis suppressors. Brd4 and Rrp1b appear to form a central node within this network, which likely is a consequence of their physical interaction with the metastasis efficiency modifier Sipa1. Furthermore, we demonstrate that the microarray gene expression signatures induced by activation of ECM eQTL genes in the Mvt-1 cell line can be used to accurately predict survival in a human breast cancer cohort. These data imply that the Diasporin Pathway may be an important nexus in tumor progression in both mice and humans.", - "journal_title": "Clinical & experimental metastasis", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/18301994/" - } - ], - "914bb179-3c2c-4850-b2bd-61422794aaad": [ - { - "pub_id": "19424753", - "title": "Intra- and inter-individual genetic differences in gene expression.", - "authors": "Mark J Cowley,Chris J Cotsapas,Rohan B H Williams,Eva K F Chan,Jeremy N Pulvers,Michael Y Liu,Oscar J Luo,David J Nott,Peter F R Little", - "abstract": "Genetic variation is known to influence the amount of mRNA produced by a gene. Because molecular machines control mRNA levels of multiple genes, we expect genetic variation in components of these machines would influence multiple genes in a similar fashion. We show that this assumption is correct by using correlation of mRNA levels measured from multiple tissues in mouse strain panels to detect shared genetic influences. These correlating groups of genes (CGGs) have collective properties that on average account for 52-79% of the variability of their constituent genes and can contain genes that encode functionally related proteins. We show that the genetic influences are essentially tissue-specific and, consequently, the same genetic variations in one animal may upregulate a CGG in one tissue but downregulate the CGG in a second tissue. We further show similarly paradoxical behaviour of CGGs within the same tissues of different individuals. Thus, this class of genetic variation can result in complex inter- and intraindividual differences. This will create substantial challenges in humans, where multiple tissues are not readily available.", - "journal_title": "Mammalian genome : official journal of the International Mammalian Genome Society", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/19424753/" - } - ], - "e4692dd1-e6c4-4e32-b5ed-6763a24cef56": [ - { - "pub_id": "19723493", - "title": "TGR5-mediated bile acid sensing controls glucose homeostasis.", - "authors": "Charles Thomas,Antimo Gioiello,Lilia Noriega,Axelle Strehle,Julien Oury,Giovanni Rizzo,Antonio Macchiarulo,Hiroyasu Yamamoto,Chikage Mataki,Mark Pruzanski,Roberto Pellicciari,Johan Auwerx,Kristina Schoonjans", - "abstract": "TGR5 is a G protein-coupled receptor expressed in brown adipose tissue and muscle, where its activation by bile acids triggers an increase in energy expenditure and attenuates diet-induced obesity. Using a combination of pharmacological and genetic gain- and loss-of-function studies in vivo, we show here that TGR5 signaling induces intestinal glucagon-like peptide-1 (GLP-1) release, leading to improved liver and pancreatic function and enhanced glucose tolerance in obese mice. In addition, we show that the induction of GLP-1 release in enteroendocrine cells by 6alpha-ethyl-23(S)-methyl-cholic acid (EMCA, INT-777), a specific TGR5 agonist, is linked to an increase of the intracellular ATP/ADP ratio and a subsequent rise in intracellular calcium mobilization. Altogether, these data show that the TGR5 signaling pathway is critical in regulating intestinal GLP-1 secretion in vivo, and suggest that pharmacological targeting of TGR5 may constitute a promising incretin-based strategy for the treatment of diabesity and associated metabolic disorders.", - "journal_title": "Cell metabolism", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/19723493/" - } - ], - "4e1c3260-acfc-4351-be75-af54549d5e5c": [ - { - "pub_id": "20628639", - "title": "Phenotype and genetics of progressive sensorineural hearing loss (Snhl1) in the LXS set of recombinant inbred strains of mice.", - "authors": "Konrad Noben-Trauth,Joseph R Latoche,Harold R Neely,Beth Bennett", - "abstract": "Progressive sensorineural hearing loss is the most common form of acquired hearing impairment in the human population. It is also highly prevalent in inbred strains of mice, providing an experimental avenue to systematically map genetic risk factors and to dissect the molecular pathways that orchestrate hearing in peripheral sensory hair cells. Therefore, we ascertained hearing function in the inbred long sleep (ILS) and inbred short sleep (ISS) strains. Using auditory-evoked brain stem response (ABR) and distortion product otoacoustic emission (DPOAE) measurements, we found that ISS mice developed a high-frequency hearing loss at twelve weeks of age that progressed to lower frequencies by 26 weeks of age in the presence of normal endocochlear potentials and unremarkable inner ear histology. ILS mice exhibited milder hearing loss, showing elevated thresholds and reduced DPOAEs at the higher frequencies by 26 weeks of age. To map the genetic variants that underlie this hearing loss we computed ABR thresholds of 63 recombinant inbred stains derived from the ISS and ILS founder strains. A single locus was linked to markers associated with ISS alleles on chromosome 10 with a highly significant logarithm of odds (LOD) score of 15.8. The 2-LOD confidence interval spans approximately 4 Megabases located at position 54-60 Mb. This locus, termed sensorineural hearing loss 1 (Snhl1), accounts for approximately 82% of the phenotypic variation. In summary, this study identifies a novel hearing loss locus on chromosome 10 and attests to the prevalence and genetic heterogeneity of progressive hearing loss in common mouse strains.", - "journal_title": "PloS one", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/20628639/" - } - ], - "8aa01f11-fef5-4c53-a9af-969881ea1ebd": [ - { - "pub_id": "20516355", - "title": "Teaching bioinformatics and neuroinformatics by using free web-based tools.", - "authors": "William Grisham,Natalie A Schottler,Joanne Valli-Marill,Lisa Beck,Jackson Beatty", - "abstract": "This completely computer-based module's purpose is to introduce students to bioinformatics resources. We present an easy-to-adopt module that weaves together several important bioinformatic tools so students can grasp how these tools are used in answering research questions. Students integrate information gathered from websites dealing with anatomy (Mouse Brain Library), quantitative trait locus analysis (WebQTL from GeneNetwork), bioinformatics and gene expression analyses (University of California, Santa Cruz Genome Browser, National Center for Biotechnology Information's Entrez Gene, and the Allen Brain Atlas), and information resources (PubMed). Instructors can use these various websites in concert to teach genetics from the phenotypic level to the molecular level, aspects of neuroanatomy and histology, statistics, quantitative trait locus analysis, and molecular biology (including in situ hybridization and microarray analysis), and to introduce bioinformatic resources. Students use these resources to discover 1) the region(s) of chromosome(s) influencing the phenotypic trait, 2) a list of candidate genes-narrowed by expression data, 3) the in situ pattern of a given gene in the region of interest, 4) the nucleotide sequence of the candidate gene, and 5) articles describing the gene. Teaching materials such as a detailed student/instructor's manual, PowerPoints, sample exams, and links to free Web resources can be found at http://mdcune.psych.ucla.edu/modules/bioinformatics.", - "journal_title": "CBE life sciences education", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/20516355/" - } - ], - "548164af-e753-4545-8324-3b95e9388ebe": [ - { - "pub_id": "21047393", - "title": "Female-biased expression of long non-coding RNAs in domains that escape X-inactivation in mouse.", - "authors": "Bj\u00f6rn Reinius,Chengxi Shi,Liu Hengshuo,Kuljeet Singh Sandhu,Katarzyna J Radomska,Glenn D Rosen,Lu Lu,Klas Kullander,Robert W Williams,Elena Jazin", - "abstract": "Sexual dimorphism in brain gene expression has been recognized in several animal species. However, the relevant regulatory mechanisms remain poorly understood. To investigate whether sex-biased gene expression in mammalian brain is globally regulated or locally regulated in diverse brain structures, and to study the genomic organisation of brain-expressed sex-biased genes, we performed a large scale gene expression analysis of distinct brain regions in adult male and female mice. This study revealed spatial specificity in sex-biased transcription in the mouse brain, and identified 173 sex-biased genes in the striatum; 19 in the neocortex; 12 in the hippocampus and 31 in the eye. Genes located on sex chromosomes were consistently over-represented in all brain regions. Analysis on a subset of genes with sex-bias in more than one tissue revealed Y-encoded male-biased transcripts and X-encoded female-biased transcripts known to escape X-inactivation. In addition, we identified novel coding and non-coding X-linked genes with female-biased expression in multiple tissues. Interestingly, the chromosomal positions of all of the female-biased non-coding genes are in close proximity to protein-coding genes that escape X-inactivation. This defines X-chromosome domains each of which contains a coding and a non-coding female-biased gene. Lack of repressive chromatin marks in non-coding transcribed loci supports the possibility that they escape X-inactivation. Moreover, RNA-DNA combined FISH experiments confirmed the biallelic expression of one such novel domain. This study demonstrated that the amount of genes with sex-biased expression varies between individual brain regions in mouse. The sex-biased genes identified are localized on many chromosomes. At the same time, sexually dimorphic gene expression that is common to several parts of the brain is mostly restricted to the sex chromosomes. Moreover, the study uncovered multiple female-biased non-coding genes that are non-randomly co-localized on the X-chromosome with protein-coding genes that escape X-inactivation. This raises the possibility that expression of long non-coding RNAs may play a role in modulating gene expression in domains that escape X-inactivation in mouse.", - "journal_title": "BMC genomics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/21047393/" - } - ], - "7af2f25c-82e7-481c-b842-d7f878e9d270": [ - { - "pub_id": "21628518", - "title": "Multigenic control and sex bias in host susceptibility to spore-induced pulmonary anthrax in mice.", - "authors": "Jagjit S Yadav,Suman Pradhan,Renuka Kapoor,Hansraj Bangar,Benjamin B Burzynski,Daniel R Prows,Linda Levin", - "abstract": "Mechanisms underlying susceptibility to anthrax infection are unknown. Using a phylogenetically diverse panel of inbred mice and spores of Bacillus anthracis Ames, we investigated host susceptibility to pulmonary anthrax. Susceptibility profiles for survival time and organ pathogen load differed across strains, indicating distinct genetic controls. Tissue infection kinetics analysis showed greater systemic dissemination in susceptible DBA/2J (D) mice but a higher terminal bacterial load in resistant BALB/cJ (C) mice. Interestingly, the most resistant strains, C and C57BL/6J (B), demonstrated a sex bias for susceptibility. For example, BALB/cJ females had a significantly higher survival time and required 4-fold more spores for 100% mortality compared to BALB/cJ males. To identify genetic regions associated with differential susceptibility, survival time and extent of organ infection were assessed using mice derived from two susceptibility models: (i) BXD advanced recombinant inbred strains and (ii) F2 offspring generated from polar responding C and D strains. Genome-wide analysis of BXD strain survival identified linkage on chromosomes 5, 6, 9, 11, and 14. Quantitative trait locus (QTL) analysis of the C\u00d7DF2 population revealed a significant QTL (designated Rpai1 for resistance to pulmonary anthrax infection, locus 1) for survival time on chromosome 17 and also identified a chromosome 11 locus for lung pathogen burden. The striking difference between genome-wide linkage profiles for these two mouse models of anthrax susceptibility supports our hypothesis that these are multigenic traits. Our data provide the first evidence for a differential sex response to anthrax resistance and further highlight the unlikelihood of a single common genetic contribution for this response across strains.", - "journal_title": "Infection and immunity", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/21628518/" - } - ], - "e74781c8-c332-4888-a2f2-7ff4089f7e8e": [ - { - "pub_id": "21871609", - "title": "Prioritization and association analysis of murine-derived candidate genes in anxiety-spectrum disorders.", - "authors": "John M Hettema,Bradley T Webb,An-Yuan Guo,Zhongming Zhao,Brion S Maher,Xiangning Chen,Seon-Sook An,Cuie Sun,Steven H Aggen,Kenneth S Kendler,Po-Hsiu Kuo,Takeshi Otowa,Jonathan Flint,Edwin J van den Oord", - "abstract": "Anxiety disorders are common psychiatric conditions that are highly comorbid with each other and related phenotypes such as depression, likely due to a shared genetic basis. Fear-related behaviors in mice have long been investigated as potential models of anxiety disorders, making integration of information from both murine and human genetic data a powerful strategy for identifying potential susceptibility genes for these conditions. We combined genome-wide association analysis of fear-related behaviors with strain distribution pattern analysis in heterogeneous stock mice to identify a preliminary list of 52 novel candidate genes. We ranked these according to three complementary sources of prior anxiety-related genetic data: 1) extant linkage and knockout studies in mice, 2) a meta-analysis of human linkage scans, and 3) a preliminary human genome-wide association study. We genotyped tagging single nucleotide polymorphisms covering the nine top-ranked regions in a two-stage association study of 1316 subjects from the Virginia Adult Twin Study of Psychiatric and Substance Use Disorders chosen for high or low genetic loading for anxiety-spectrum phenotypes (anxiety disorders, neuroticism, and major depression). Multiple single nucleotide polymorphisms in the PPARGC1A gene demonstrated association in both stages that survived gene-wise correction for multiple testing. Integration of genetic data across human and murine studies suggests PPARGC1A as a potential susceptibility gene for anxiety-related disorders.", - "journal_title": "Biological psychiatry", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/21871609/" - } - ], - "da60a50d-4145-4393-87e3-63dbf443c76a": [ - { - "pub_id": "16433728", - "title": "Analysis of metallothionein brain gene expression in relation to ethanol preference in mice using cosegregation and gene knockouts.", - "authors": "Kimberly D Loney,Raihan K Uddin,Shiva M Singh", - "abstract": "Metallothioneins (MTs) are ubiquitously expressed intracellular proteins that bind heavy metals and are involved in cytoprotection against several types of stress agents including chemicals, hormones, and oxidants. We have previously reported 1 isoform, MT-II, as a possible candidate gene for ethanol (EtOH) preference (EP) determination in mice. Semiquantitative RT-PCR was used to determine brain mRNA levels of MT-I and MT-III in 4 inbred mouse strains with variable EP. Following this, cosegregation of MT-II brain expression with EP was analyzed in F2 mice from 2 intercrosses (C57BL/6J x BALB/cJ and C57BL/6J x DBA/2J). Studies on MT-I/MT-II knockout (KO) mice were also undertaken to further explore this relationship. Our results suggest that MT-I is responsive to EtOH, with no evidence of basal-level differences between strains. Conversely, MT-III shows no EtOH response, yet indicates a possible strain-specific feature with C57BL/6J having the lowest levels of brain MT-III. Metallothionein-II expression cosegregates with EP in F2 mice from a C57BL/6J (preferring) and DBA/2J (avoiding) intercross. Although F2 mice from a cross with C57BL/6J and BALB/cJ (avoiding) strains follow a similar pattern, the results are not statistically significant. Metallothionein-I/MT-II knockout (MT-KO) mice appear to have smaller litter sizes as well as higher weight compared with controls (129S1/SvImJ) and also show a slight increase in EP. Metallothionein-II remains the primary candidate of the mouse MT gene family for involvement in EP. Its effect on EP appears to be dependent on the genetic background. Such conclusions are based on results from C57BL/6J, BALB/cJ, DBA/2J, and 129 inbred mouse strains. Evidence also points to shared neural pathways involved in weight gain and obesity. The complex interactions between MT-II, EP, and weight gain/obesity remain to be studied.", - "journal_title": "Alcoholism, clinical and experimental research", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/16433728/" - } - ], - "34473d38-3ced-4656-9572-f21169bec735": [ - { - "pub_id": "16888340", - "title": "Design of microarray experiments for genetical genomics studies.", - "authors": "J\u00falio S S Bueno Filho,Steven G Gilmour,Guilherme J M Rosa", - "abstract": "Microarray experiments have been used recently in genetical genomics studies, as an additional tool to understand the genetic mechanisms governing variation in complex traits, such as for estimating heritabilities of mRNA transcript abundances, for mapping expression quantitative trait loci, and for inferring regulatory networks controlling gene expression. Several articles on the design of microarray experiments discuss situations in which treatment effects are assumed fixed and without any structure. In the case of two-color microarray platforms, several authors have studied reference and circular designs. Here, we discuss the optimal design of microarray experiments whose goals refer to specific genetic questions. Some examples are used to illustrate the choice of a design for comparing fixed, structured treatments, such as genotypic groups. Experiments targeting single genes or chromosomic regions (such as with transgene research) or multiple epistatic loci (such as within a selective phenotyping context) are discussed. In addition, microarray experiments in which treatments refer to families or to subjects (within family structures or complex pedigrees) are presented. In these cases treatments are more appropriately considered to be random effects, with specific covariance structures, in which the genetic goals relate to the estimation of genetic variances and the heritability of transcriptional abundances.", - "journal_title": "Genetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/16888340/" - } - ], - "7c7bd405-0749-46dd-b418-ed7289c64cb2": [ - { - "pub_id": "16688532", - "title": "Genetic characterization of a new set of recombinant inbred lines (LGXSM) formed from the inter-cross of SM/J and LG/J inbred mouse strains.", - "authors": "Tomas Hrbek,Reinaldo Alves de Brito,B Wang,L Susan Pletscher,James M Cheverud", - "abstract": "A new set of LGXSM recombinant inbred (RI) strains is presented. The RI strain panel consists of 18 remaining strains of the original 55 founding strains. Strain characterization is based on 506 polymorphic microsatellites and 4,289 single nucleotide polymorphisms (SNPs) distributed across the genome. Average microsatellite inter-marker distance is 4.80+/-4.84 Mb or 2.91+/-3.21 F(2) cM. SNPs are more densely spaced at 0.57+/-1.27 Mb. Ninety-five percent of all microsatellite inter-marker intervals are separated by less than 15.00 Mb or 8.50 F(2) cM, while 95% of the SNPs are less than 0.95 Mb apart. Strains show expected low levels of nonsyntenic association among loci and complete genomic independence. During inbreeding, the RI strains went through strong natural selection on the agouti locus on Chromosome 2, especially when the epistatically interacting tyrosinase locus on Chromosome 7 carried the wild-type allele. The LG/J and SM/J strains differ in a large number of biomedically important traits, and they and their inter-cross progeny have been used in multiple mapping studies. The LGxSM RI strain panel provides a powerful new resource for mapping the genetic bases of complex traits and should prove to be of great biomedical utility in modeling complex human diseases such as obesity and diabetes.", - "journal_title": "Mammalian genome : official journal of the International Mammalian Genome Society", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/16688532/" - } - ], - "9b3b1f72-2b99-45ce-b61b-b861fcf84604": [ - { - "pub_id": "16407118", - "title": "Natural variation and genetic covariance in adult hippocampal neurogenesis.", - "authors": "Gerd Kempermann,Elissa J Chesler,Lu Lu,Robert W Williams,Fred H Gage", - "abstract": "Adult hippocampal neurogenesis is highly variable and heritable among laboratory strains of mice. Adult neurogenesis is also remarkably plastic and can be modulated by environment and activity. Here, we provide a systematic quantitative analysis of adult hippocampal neurogenesis in two large genetic reference panels of recombinant inbred strains (BXD and AXB/BXA, n = 52 strains). We combined data on variation in neurogenesis with a new transcriptome database to extract a set of 190 genes with expression patterns that are also highly variable and that covary with rates of (i) cell proliferation, (ii) cell survival, or the numbers of surviving (iii) new neurons, and (iv) astrocytes. Expression of a subset of these neurogenesis-associated transcripts was controlled in cis across the BXD set. These self-modulating genes are particularly interesting candidates to control neurogenesis. Among these were musashi (Msi1h) and prominin1/CD133 (Prom1), both of which are linked to stem-cell maintenance and division. Twelve neurogenesis-associated transcripts had significant cis-acting quantitative trait loci, and, of these, six had plausible biological association with adult neurogenesis (Prom1, Ssbp2, Kcnq2, Ndufs2, Camk4, and Kcnj9). Only one cis-acting candidate was linked to both neurogenesis and gliogenesis, Rapgef6, a downstream target of ras signaling. The use of genetic reference panels coupled with phenotyping and global transcriptome profiling thus allowed insight into the complexity of the genetic control of adult neurogenesis.", - "journal_title": "Proceedings of the National Academy of Sciences of the United States of America", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/16407118/" - } - ], - "f142a70e-ee38-4f02-9efe-9fb4649ab579": [ - { - "pub_id": "17053075", - "title": "Stability of inbred mouse strain differences in behavior and brain size between laboratories and across decades.", - "authors": "Douglas Wahlsten,Alexander Bachmanov,Deborah A Finn,John C Crabbe", - "abstract": "If we conduct the same experiment in two laboratories or repeat a classical study many years later, will we obtain the same results? Recent research with mice in neural and behavioral genetics yielded different results in different laboratories for certain phenotypes, and these findings suggested to some researchers that behavior may be too unstable for fine-scale genetic analysis. Here we expand the range of data on this question to additional laboratories and phenotypes, and, for the first time in this field, we formally compare recent data with experiments conducted 30-50 years ago. For ethanol preference and locomotor activity, strain differences have been highly stable over a period of 40-50 years, and most strain correlations are in the range of r = 0.85-0.98, as high as or higher than for brain weight. For anxiety-related behavior on the elevated plus maze, on the other hand, strain means often differ dramatically across laboratories or even when the same laboratory is moved to another site within a university. When a wide range of phenotypes is considered, no inbred strain appears to be exceptionally stable or labile across laboratories in any general sense, and there is no tendency to observe higher correlations among studies done more recently. Phenotypic drift over decades for most of the behaviors examined appears to be minimal.", - "journal_title": "Proceedings of the National Academy of Sciences of the United States of America", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/17053075/" - } - ], - "cf380786-3792-4bb4-a7c9-59f59f071952": [ - { - "pub_id": "16503985", - "title": "Genomic regulation of natural variation in cortical and noncortical brain volume.", - "authors": "Jackson Beatty,Rick E Laughlin", - "abstract": "The relative growth of the neocortex parallels the emergence of complex cognitive functions across species. To determine the regions of the mammalian genome responsible for natural variations in cortical volume, we conducted a complex trait analysis using 34 strains of recombinant inbred (Rl) strains of mice (BXD), as well as their two parental strains (C57BL/6J and DBA/2J). We measured both neocortical volume and total brain volume in 155 coronally sectioned mouse brains that were Nissl stained and embedded in celloidin. After correction for shrinkage, the measured cortical and noncortical brain volumes were entered into a multiple regression analysis, which removed the effects of body size and age from the measurements. Marker regression and interval mapping were computed using WebQTL. An ANOVA revealed that more than half of the variance of these regressed phenotypes is genetically determined. We then identified the regions of the genome regulating this heritability. We located genomic regions in which a linkage disequilibrium was present using WebQTL as both a mapping engine and genomic database. For neocortex, we found a genome-wide significant quantitative trait locus (QTL) on chromosome 11 (marker D11Mit19), as well as a suggestive QTL on chromosome 16 (marker D16Mit100). In contrast, for noncortex the effect of chromosome 11 was markedly reduced, and a significant QTL appeared on chromosome 19 (D19Mit22). This classic pattern of double dissociation argues strongly for different genetic factors regulating relative cortical size, as opposed to brain volume more generally. It is likely, however, that the effects of proximal chromosome 11 extend beyond the neocortex strictly defined. An analysis of single nucleotide polymorphisms in these regions indicated that ciliary neurotrophic factor (Cntf) is quite possibly the gene underlying the noncortical QTL. Evidence for a candidate gene modulating neocortical volume was much weaker, but Otx1 deserves further consideration.", - "journal_title": "BMC neuroscience", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/16503985/" - } - ], - "08723f33-aa4f-44ca-8a7c-45469c82284f": [ - { - "pub_id": "17920205", - "title": "Mesencephalic dopamine neuron number and tyrosine hydroxylase content: Genetic control and candidate genes.", - "authors": "C Vadasz,J F Smiley,K Figarsky,M Saito,R Toth,B M Gyetvai,M Oros,K K Kovacs,P Mohan,R Wang", - "abstract": "The mesotelencephalic dopamine system shows substantial genetic variation which fundamentally affects normal and pathological behaviors related to motor function, motivation, and learning. Our earlier radioenzyme assay studies demonstrated significantly higher activity of tyrosine hydroxylase (TH), the first and rate limiting enzyme in the biosynthesis of catecholamine neurotransmitters, in the substantia nigra-ventral tegmental area of BALB/cJ mice in comparison with that of C57BL/6ByJ mice. Here, using quantitative immunoblotting and immunocytochemistry, we tested the hypothesis that mesencephalic TH protein content and number of nigral TH-positive neurons show strain-dependent differences in C57BL/6ByJ and BALB/cJ parallel to those observed in the TH activity studies. Immunoblotting experiments detected significantly higher mesencephalic TH protein content in BALB/cJ in comparison to C57BL/6ByJ (P<0.05). Immunocytochemical studies demonstrated that the number of TH-positive cells in substantia nigra was 31.3% higher in BALB/cJ than that in C57BL/6ByJ (P<0.01), while the average dopamine neuron volume was not significantly different. In a search for candidate genes that modulate TH content and the size of mesencephalic dopamine neuron populations we also studied near-isogenic mouse sublines derived from the C57BL/6ByJ and BALB/cJ progenitor strains. A whole-genome scan with 768 single nucleotide polymorphism markers indicated that two sublines, C4A6/N and C4A6/B, were genetically very similar (98.3%). We found significantly higher mesencephalic TH protein content in C4A6/B in comparison to C4A6/N (P=0.01), and a tendency for higher number of dopamine neurons in the substantia nigra in C4A6/B in comparison to C4A6/N, which, however, did not reach statistical significance. To identify the genetic source of the TH content difference we analyzed the single nucleotide polymorphism (SNP) genotype data of the whole-genome scan, and detected two small differential chromosome segments on chr. 13 and chr. 14. Microarray gene expression studies and bioinformatic analysis of the two differential regions implicated two cis-regulated genes (Spock1 and Cxcl14, chr. 13), and two growth factor genes [bone morphogenetic protein 6 (Bmp6) (chr. 13), and fibroblast growth factor 14 (Fgf14) (chr. 14)]. Taken together, the results suggest that (1) nigral dopamine neuron number and TH protein content may be genetically associated but further studies are needed to establish unequivocally this linkage, and (2) Spock1, Cxcl14, Bmp6, and Fgf14 are novel candidates for modulating the expression and maintenance of TH content in mesencephalic dopamine neurons in vivo.", - "journal_title": "Neuroscience", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/17920205/" - } - ], - "f59ba250-917b-4f86-b840-6384c670488a": [ - { - "pub_id": "17436036", - "title": "The 20th International Mammalian Genome Conference meeting report.", - "authors": "Elizabeth A Hurd,Donna M Martin", - "abstract": "", - "journal_title": "Mammalian genome : official journal of the International Mammalian Genome Society", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/17436036/" - } - ], - "0cffed01-3711-4c7f-94cf-6d32bc41ef66": [ - { - "pub_id": "18762803", - "title": "Correlation analysis between genome-wide expression profiles and cytoarchitectural abnormalities in the prefrontal cortex of psychiatric disorders.", - "authors": "S Kim,M J Webster", - "abstract": "Cytoarchitectural abnormalities have been described in the prefrontal cortex of subjects with schizophrenia, bipolar disorder and depression. However, little is known about the gene expression profiles associated with these abnormalities. Genome-wide expression profiling technology provides an unbiased approach to identifying candidate genes and biological processes that may be associated with complex biological traits such as cytoarchitecture. In this study, we explored expression profiles associated with the abnormalities by using publicly available microarray metadata and cytoarchitectural data from post-mortem samples of the frontal cortex from 54 subjects (schizophrenia, n=14; bipolar disorder, n=13; depression, n=12 and controls n=15). Correlation analysis between genome-wide expression levels and cytoarchitectural traits revealed that 818 genes were significantly correlated with a decrease in the number of perineuronal oligodendrocytes across all subjects. A total of 600 genes were significantly correlated with a decrease in density of calbindin-positive interneurons across all subjects. Multiple biological processes including cellular metabolism, central nervous system development, cell motility and programmed cell death were significantly overrepresented in both correlated gene lists. These findings may provide novel insights into the molecular mechanisms that underlie the cytoarchitectural abnormalities of perineuronal oligodendrocytes and calbindin-containing GABAergic interneurons in the prefrontal cortex of the major psychiatric disorders.", - "journal_title": "Molecular psychiatry", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/18762803/" - } - ], - "da485354-fcdc-49b8-9a41-0f673610156a": [ - { - "pub_id": "19114008", - "title": "WGCNA: an R package for weighted correlation network analysis.", - "authors": "Peter Langfelder,Steve Horvath", - "abstract": "Correlation networks are increasingly being used in bioinformatics applications. For example, weighted gene co-expression network analysis is a systems biology method for describing the correlation patterns among genes across microarray samples. Weighted correlation network analysis (WGCNA) can be used for finding clusters (modules) of highly correlated genes, for summarizing such clusters using the module eigengene or an intramodular hub gene, for relating modules to one another and to external sample traits (using eigengene network methodology), and for calculating module membership measures. Correlation networks facilitate network based gene screening methods that can be used to identify candidate biomarkers or therapeutic targets. These methods have been successfully applied in various biological contexts, e.g. cancer, mouse genetics, yeast genetics, and analysis of brain imaging data. While parts of the correlation network methodology have been described in separate publications, there is a need to provide a user-friendly, comprehensive, and consistent software implementation and an accompanying tutorial. The WGCNA R software package is a comprehensive collection of R functions for performing various aspects of weighted correlation network analysis. The package includes functions for network construction, module detection, gene selection, calculations of topological properties, data simulation, visualization, and interfacing with external software. Along with the R package we also present R software tutorials. While the methods development was motivated by gene expression data, the underlying data mining approach can be applied to a variety of different settings. The WGCNA package provides R functions for weighted correlation network analysis, e.g. co-expression network analysis of gene expression data. The R package along with its source code and additional material are freely available at http://www.genetics.ucla.edu/labs/horvath/CoexpressionNetwork/Rpackages/WGCNA.", - "journal_title": "BMC bioinformatics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/19114008/" - } - ], - "9ea11e01-aa2a-4df8-b356-833fdfcb3d72": [ - { - "pub_id": "18363860", - "title": "Of mice and men, periodic limb movements and iron: how the human genome informs the mouse genome.", - "authors": "L C Jones,C J Earley,R P Allen,B C Jones", - "abstract": "The gene, BTBD9, was recently linked to restless legs syndrome, periodic limb movements and iron status in humans. In a homologous region in mouse, an area containing btbd9 was also identified as being related to iron homeostasis. This finding is important as iron status in brain has been implicated in restless legs syndrome.", - "journal_title": "Genes, brain, and behavior", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/18363860/" - } - ], - "cb27f673-688c-4005-a4ad-214c93868491": [ - { - "pub_id": "18394726", - "title": "The role of 5-HT(1A) receptors in learning and memory.", - "authors": "Sven Ove Ogren,Therese M Eriksson,Elin Elvander-Tottie,Claudio D'Addario,Joanna C Ekstr\u00f6m,Per Svenningsson,Bj\u00f6rn Meister,Jan Kehr,Oliver Stiedl", - "abstract": "The ascending serotonin (5-HT) neurons innervate the cerebral cortex, hippocampus, septum and amygdala, all representing brain regions associated with various domains of cognition. The 5-HT innervation is diffuse and extensively arborized with few synaptic contacts, which indicates that 5-HT can affect a large number of neurons in a paracrine mode. Serotonin signaling is mediated by 14 receptor subtypes with different functional and transductional properties. The 5-HT(1A) subtype is of particular interest, since it is one of the main mediators of the action of 5-HT. Moreover, the 5-HT(1A) receptor regulates the activity of 5-HT neurons via autoreceptors, and it regulates the function of several neurotransmitter systems via postsynaptic receptors (heteroreceptors). This review assesses the pharmacological and genetic evidence that implicates the 5-HT(1A) receptor in learning and memory. The 5-HT(1A) receptors are in the position to influence the activity of glutamatergic, cholinergic and possibly GABAergic neurons in the cerebral cortex, hippocampus and in the septohippocampal projection, thereby affecting declarative and non-declarative memory functions. Moreover, the 5-HT(1A) receptor regulates several transduction mechanisms such as kinases and immediate early genes implicated in memory formation. Based on studies in rodents the stimulation of 5-HT(1A) receptors generally produces learning impairments by interfering with memory-encoding mechanisms. In contrast, antagonists of 5-HT(1A) receptors facilitate certain types of memory by enhancing hippocampal/cortical cholinergic and/or glutamatergic neurotransmission. Some data also support a potential role for the 5-HT(1A) receptor in memory consolidation. Available results also implicate the 5-HT(1A) receptor in the retrieval of aversive or emotional memories, supporting an involvement in reconsolidation. The contribution of 5-HT(1A) receptors in cognitive impairments in various psychiatric disorders is still unclear. However, there is evidence that 5-HT(1A) receptors may play differential roles in normal brain function and in psychopathological states. Taken together, the evidence indicates that the 5-HT(1A) receptor is a target for novel therapeutic advances in several neuropsychiatric disorders characterized by various cognitive deficits.", - "journal_title": "Behavioural brain research", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/18394726/" - } - ], - "d3b364c4-bdd3-4c7c-8b3f-e27bd3460c37": [ - { - "pub_id": "19727342", - "title": "Gene expression in the mouse eye: an online resource for genetics using 103 strains of mice.", - "authors": "Eldon E Geisert,Lu Lu,Natalie E Freeman-Anderson,Justin P Templeton,Mohamed Nassr,Xusheng Wang,Weikuan Gu,Yan Jiao,Robert W Williams", - "abstract": "Individual differences in patterns of gene expression account for much of the diversity of ocular phenotypes and variation in disease risk. We examined the causes of expression differences, and in their linkage to sequence variants, functional differences, and ocular pathophysiology. mRNAs from young adult eyes were hybridized to oligomer microarrays (Affymetrix M430v2). Data were embedded in GeneNetwork with millions of single nucleotide polymorphisms, custom array annotation, and information on complementary cellular, functional, and behavioral traits. The data include male and female samples from 28 common strains, 68 BXD recombinant inbred lines, as well as several mutants and knockouts. We provide a fully integrated resource to map, graph, analyze, and test causes and correlations of differences in gene expression in the eye. Covariance in mRNA expression can be used to infer gene function, extract signatures for different cells or tissues, to define molecular networks, and to map quantitative trait loci that produce expression differences. These data can also be used to connect disease phenotypes with sequence variants. We demonstrate that variation in rhodopsin expression efficiently predicts candidate genes for eight uncloned retinal diseases, including WDR17 for the human RP29 locus. The high level of strain variation in gene expression is a powerful tool that can be used to explore and test molecular networks underlying variation in structure, function, and disease susceptibility. The integration of these data into GeneNetwork provides users with a workbench to test linkages between sequence differences and eye structure and function.", - "journal_title": "Molecular vision", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/19727342/" - } - ], - "d00416be-b990-4901-ad78-578ce7be0197": [ - { - "pub_id": "20228863", - "title": "Herding cats: the sociology of data integration.", - "authors": "Robert W Williams", - "abstract": "", - "journal_title": "Frontiers in neuroscience", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/20228863/" - } - ], - "bb5ed347-0f54-431a-a125-97b9d762b003": [ - { - "pub_id": "23494065", - "title": "Modular Digital Course in Undergraduate Neuroscience Education (MDCUNE): A Website Offering Free Digital Tools for Neuroscience Educators.", - "authors": "William Grisham", - "abstract": "We are providing free digital resources for teaching neuroscience labs at http://mdcune.psych.ucla.edu/. These resources will ultimately include materials for teaching laboratories in electrophysiology of neuronal circuits (SWIMMY), a Neuroinformatics/Bioinformatics module, and two modules for investigating the effects of hormones on early CNS development-one focusing on the development of the song system and one focusing on sex differences in spinal cord motor neurons. All of these modules are inquiry based-students gain from genuine experiences in doing actual studies rather than just simulations. These materials should provide instructors the ability to provide good quality laboratory experiences regardless of resource limitations. Currently, modules on sex differences in the spinal cord and virtual neural circuits (SWIMMY) are available on our website. More will be available in summer 2009 and 2010. SWIMMY was demonstrated at the Faculty for Undergraduate Neuroscience (FUN) Workshop-The Undergraduate Neuroscience Education: Interactions, interdisciplines, and curricular best practices at Macalester College in July 2008.", - "journal_title": "Journal of undergraduate neuroscience education : JUNE : a publication of FUN, Faculty for Undergraduate Neuroscience", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/23494065/" - } - ], - "05fbfd9b-ce25-490e-87d1-1761b33a412d": [ - { - "pub_id": "20939738", - "title": "Sequence variations in mitochondrial ferritin: distribution in healthy controls and different types of patients.", - "authors": "Emanuela Castiglioni,Dario Finazzi,Stefano Goldwurm,Sonia Levi,Gianni Pezzoli,Barbara Garavaglia,Nardo Nardocci,Luca Malcovati,Matteo G Della Porta,Anna Gall\u00ec,Gian Luca Forni,Domenico Girelli,Federica Maccarinelli,Maura Poli,Maurizio Ferrari,Laura Cremonesi,Paolo Arosio", - "abstract": "The storage of iron in the cells is mainly accomplished by cytosolic ferritins. The perturbation of ferritin function may result in accumulation of excess iron in cells and tissues and increased oxidative stress, common features of different genetic and acquired disorders. Mutations in L-ferritin have been associated with neuroferritinopathy, a rare and severe movement disorder with abnormal brain iron storage. Recently, a novel form of ferritin has been discovered, which localizes in the mitochondrial matrix and plays an important role in iron homeostasis in these organelles. The possible association of sequence variations in the mitochondrial ferritin (FtMt) gene with disorders with aberrant iron distribution has not been investigated yet. We set up a denaturing high-performance liquid chromatography (DHPLC)-based screening for FtMt and analyzed the genomic DNA of patients with myelodysplastic syndromes (# 63) or with Parkinson's disease (# 332) and other movement disorders such as pantothenate kinase-associated neurodegeneration (# 7), restless legs syndrome (# 23), and suspected neuroferritinopathy (# 7) and of control subjects (# 342). We detected eight different types of substitution, all at the heterozygous state. Six of them caused amino acid changes, but none of them was predicted to drastically perturb FtMt structure and/or function. The c + 134C > A (P45H) variation, which was the most common (# 28), was less represented in the Parkinson's population, although not significantly (p = 0.07). The analysis suggests that sequence variations in the coding region of FtMt are not involved in the development of myelodysplastic syndromes and Parkinson's disease.", - "journal_title": "Genetic testing and molecular biomarkers", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/20939738/" - } - ], - "a6a275f6-b001-41bc-837e-bcef30359f2f": [ - { - "pub_id": "21081154", - "title": "Importance of genetic background for risk of relapse shown in altered prefrontal cortex gene expression during abstinence following chronic alcohol intoxication.", - "authors": "J G Hashimoto,M R Forquer,M A Tanchuck,D A Finn,K M Wiren", - "abstract": "Alcoholism is a relapsing disorder associated with excessive consumption after periods of abstinence. Neuroadaptations in brain structure, plasticity and gene expression occur with chronic intoxication but are poorly characterized. Here we report identification of pathways altered during abstinence in prefrontal cortex, a brain region associated with cognitive dysfunction and damage in alcoholics. To determine the influence of genetic differences, an animal model was employed with widely divergent responses to alcohol withdrawal, the Withdrawal Seizure-Resistant (WSR) and Withdrawal Seizure-Prone (WSP) lines. Mice were chronically exposed to highly intoxicating concentrations of ethanol and withdrawn, then left abstinent for 21 days. Transcriptional profiling by microarray analyses identified a total of 562 genes as significantly altered during abstinence. Hierarchical cluster analysis revealed that the transcriptional response correlated with genotype/withdrawal phenotype rather than sex. Gene Ontology category overrepresentation analysis identified thyroid hormone metabolism, glutathione metabolism, axon guidance and DNA damage response as targeted classes of genes in low response WSR mice, with acetylation and histone deacetylase complex as highly dimorphic between WSR and WSP mice. Confirmation studies in WSR mice revealed both increased neurotoxicity by histopathologic examination and elevated triidothyronine (T3) levels. Most importantly, relapse drinking was reduced by inhibition of thyroid hormone synthesis in dependent WSR mice compared to controls. These findings provide in vivo physiological and behavioral validation of the pathways identified. Combined, these results indicate a fundamentally distinct neuroadaptive response during abstinence in mice genetically selected for divergent withdrawal severity. Identification of pathways altered in abstinence may aid development of novel therapeutics for targeted treatment of relapse in abstinent alcoholics.", - "journal_title": "Neuroscience", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/21081154/" - } - ], - "3fb5c4ae-2498-4a98-91b2-061950df1f1e": [ - { - "pub_id": "21913117", - "title": "Designing, performing, and interpreting a microarray-based gene expression study.", - "authors": "Giovanni Coppola", - "abstract": "Microarray-based assays have significantly expanded their scope and range of applications over the last 10 years, and--at least for gene expression--can be considered mainstream applications. High-throughput, microarray-based gene expression studies have proven particularly useful in the study of neurodegenerative diseases, for which they have provided key insights in understanding disease pathogenesis, regional and cellular specificity, and identification of therapeutic targets. Even though many experimental steps are currently performed in specialized core facilities, the key steps of a microarray study--experimental design, and data analysis and interpretation--are performed by the primary investigator. Knowledge of the issues related to these key steps is essential to properly perform and interpret a microarray experiment and constitutes the main focus of the present chapter. The basic analytical steps are covered, and annotated R code for the analysis of a published dataset is provided.", - "journal_title": "Methods in molecular biology (Clifton, N.J.)", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/21913117/" - } - ], - "6b827d23-96be-47aa-98f9-2ad72a947e45": [ - { - "pub_id": "21572526", - "title": "Identifying human disease genes through cross-species gene mapping of evolutionary conserved processes.", - "authors": "Martin Poot,Alexandra Badea,Robert W Williams,Martien J Kas", - "abstract": "Understanding complex networks that modulate development in humans is hampered by genetic and phenotypic heterogeneity within and between populations. Here we present a method that exploits natural variation in highly diverse mouse genetic reference panels in which genetic and environmental factors can be tightly controlled. The aim of our study is to test a cross-species genetic mapping strategy, which compares data of gene mapping in human patients with functional data obtained by QTL mapping in recombinant inbred mouse strains in order to prioritize human disease candidate genes. We exploit evolutionary conservation of developmental phenotypes to discover gene variants that influence brain development in humans. We studied corpus callosum volume in a recombinant inbred mouse panel (C57BL/6J\u00d7DBA/2J, BXD strains) using high-field strength MRI technology. We aligned mouse mapping results for this neuro-anatomical phenotype with genetic data from patients with abnormal corpus callosum (ACC) development. From the 61 syndromes which involve an ACC, 51 human candidate genes have been identified. Through interval mapping, we identified a single significant QTL on mouse chromosome 7 for corpus callosum volume with a QTL peak located between 25.5 and 26.7 Mb. Comparing the genes in this mouse QTL region with those associated with human syndromes (involving ACC) and those covered by copy number variations (CNV) yielded a single overlap, namely HNRPU in humans and Hnrpul1 in mice. Further analysis of corpus callosum volume in BXD strains revealed that the corpus callosum was significantly larger in BXD mice with a B genotype at the Hnrpul1 locus than in BXD mice with a D genotype at Hnrpul1 (F\u200a=\u200a22.48, p<9.87*10(-5)). This approach that exploits highly diverse mouse strains provides an efficient and effective translational bridge to study the etiology of human developmental disorders, such as autism and schizophrenia.", - "journal_title": "PloS one", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/21572526/" - } - ], - "e13448fa-4108-4b72-9276-7cd1a6a19c21": [ - { - "pub_id": "22066001", - "title": "Novel candidate genes associated with hippocampal oscillations.", - "authors": "Rick Jansen,Jaap Timmerman,Maarten Loos,Sabine Spijker,Arjen van Ooyen,Arjen B Brussaard,Huibert D Mansvelder, ,August B Smit,Mathisca de Gunst,Klaus Linkenkaer-Hansen", - "abstract": "The hippocampus is critical for a wide range of emotional and cognitive behaviors. Here, we performed the first genome-wide search for genes influencing hippocampal oscillations. We measured local field potentials (LFPs) using 64-channel multi-electrode arrays in acute hippocampal slices of 29 BXD recombinant inbred mouse strains. Spontaneous activity and carbachol-induced fast network oscillations were analyzed with spectral and cross-correlation methods and the resulting traits were used for mapping quantitative trait loci (QTLs), i.e., regions on the genome that may influence hippocampal function. Using genome-wide hippocampal gene expression data, we narrowed the QTLs to eight candidate genes, including Plcb1, a phospholipase that is known to influence hippocampal oscillations. We also identified two genes coding for calcium channels, Cacna1b and Cacna1e, which mediate presynaptic transmitter release and have not been shown to regulate hippocampal network activity previously. Furthermore, we showed that the amplitude of the hippocampal oscillations is genetically correlated with hippocampal volume and several measures of novel environment exploration.", - "journal_title": "PloS one", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/22066001/" - } - ], - "756e6598-0823-4278-a6b5-75920b7cc621": [ - { - "pub_id": "21054686", - "title": "Using the Phenogen website for 'in silico' analysis of morphine-induced analgesia: identifying candidate genes.", - "authors": "Paula L Hoffman,Beth Bennett,Laura M Saba,Sanjiv V Bhave,Phyllis J Carosone-Link,Cheryl K Hornbaker,Katerina J Kechris,Robert W Williams,Boris Tabakoff", - "abstract": "The identification of genes that contribute to polygenic (complex) behavioral phenotypes is a key goal of current genetic research. One approach to this goal is to combine gene expression information with genetic information, i.e. to map chromosomal regions that regulate gene expression levels. This approach has been termed 'genetical genomics', and, when used in conjunction with the identification of genomic regions (QTLs) that regulate the complex physiological trait under investigation, provides a strong basis for candidate gene discovery. In this paper, we describe the implementation of the genetical genomic/phenotypic approach to identify candidate genes for sensitivity to the analgesic effect of morphine in BXD recombinant inbred mice. Our analysis was performed 'in silico', using an online interactive resource called PhenoGen (http://phenogen.ucdenver.edu). We describe in detail the use of this resource, which identified a set of candidate genes, some of whose products regulate the cellular localization and activity of the mu opiate receptor. The results demonstrate how PhenoGen can be used to identify a novel set of genes that can be further investigated for their potential role in pain, morphine analgesia and/or morphine tolerance.", - "journal_title": "Addiction biology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/21054686/" - } - ], - "25481e34-2a45-4448-84f0-32c823cfcd03": [ - { - "pub_id": "29196356", - "title": "The rise of the genome and personalised medicine.", - "authors": "Helen K Brittain,Richard Scott,Ellen Thomas", - "abstract": "Virtually all medical specialties are impacted by genetic disease. Enhanced understanding of the role of genetics in human disease, coupled with rapid advancement in sequencing technology, is transforming the speed of diagnosis for patients and providing increasing opportunities to tailor management. As set out in the <i>Annual report of the Chief Medical Officer 2016: Generation Genome</i><sup>1</sup> and the recent NHS England board paper <i>Creating a genomic medicine service to lay the foundations to deliver personalised interventions and treatments</i>,<sup>2</sup> the increasing 'mainstreaming' of genetic testing into routine practice and plans to embed whole genome sequencing in the NHS mean that the profile and importance of genomics is on the rise for many clinicians. This article provides a brief overview of genomics and its current clinical applications, including its contribution to personalised medicine. Physicians will be signposted to key issues that will allow the successful implementation of genomics for rare disease diagnosis and cancer management.", - "journal_title": "Clinical medicine (London, England)", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/29196356/" - } - ], - "40cb25c4-e046-4275-8ba7-49a9773049f2": [ - { - "pub_id": "16846973", - "title": "Evidence for clustered tumour suppressor gene loci on mouse chromosomes 2 and 4 in radiation-induced acute myeloid leukaemia.", - "authors": "Mays Jawad,Clare Cole,Abigail Zanker,Priscilla Lo,Simon Fitch,Mark Plumb", - "abstract": "To investigate the influence of genetic and epigenetic factors on allelic loss on chromosomes 2 and 4 in mouse radiation-induced acute myeloid leukaemia (r-AML). r-AML that arose in (CBA/HxC57BL/6)F1xCBA/H and F1xC57BL/6 mice were screened for transcription factor PU1 (also known as SPI-1) gene mutations and methylation of the paired box gene 5 (Pax5) gene promoter. We have increased the statistical significance of a genetic linkage analysis of affected F1xCBA/H mice to test for linkage to loci implicated directly or indirectly with r-AML-susceptibility. There was a statistically significant difference ( p < 10-4) in the frequency of PU1 gene mutations in F1xCBA/H and F1xC57BL/6 r-AML, implicating a second linked but genotype-dependent myeloid leukaemia suppressor gene on chromosome 2. A suggestive CBA/H r-AML-resistance locus maps within 10 cM of the minimally deleted region on chromosome 4. The Pax5 gene promoter is subject to ongoing subclonal promoter methylation in the r-AML, evidence that Pax5 gene silencing confers a selective advantage during clonal expansion in vivo. Allelic loss in mouse r-AML and subsequent tumour suppressor gene mutation (PU1) or silencing (Pax5) is strongly influenced by genetic background and/or epigenetic factors, and driven by in vivo clonal selection.", - "journal_title": "International journal of radiation biology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/16846973/" - } - ], - "bc83a282-2722-47b1-8326-7780732b29d2": [ - { - "pub_id": "33557837", - "title": "Cross-talk of four types of RNA modification writers defines tumor microenvironment and pharmacogenomic landscape in colorectal cancer.", - "authors": "Huifang Chen,Jiameng Yao,Rujuan Bao,Yu Dong,Ting Zhang,Yanhua Du,Gaoyang Wang,Duan Ni,Zhenzhen Xun,Xiaoyin Niu,Youqiong Ye,Hua-Bing Li", - "abstract": "The four major RNA\u00a0adenosine modifications, i.e., m<sup>6</sup>A, m<sup>1</sup>A, alternative polyadenylation, and adenosine-to-inosine RNA editing, are mediated mostly by the \"writer\" enzymes and constitute critical mechanisms of epigenetic regulation in immune response and tumorigenesis. However, the cross-talk and potential roles of these \"writers\" in the tumor microenvironment (TME), drug sensitivity, and immunotherapy remain unknown. We systematically characterized mRNA expression and genetic alterations of 26 RNA modification \"writers\" in colorectal cancer (CRC), and evaluated their expression pattern in 1697 CRC samples from 8 datasets. We used an unsupervised clustering method to assign the samples into two patterns of expression of RNA modification \"writers\". Subsequently, we constructed the RNA modification \"writer\" Score (WM_Score) model based on differentially expressed genes (DEGs) responsible for the RNA modification patterns to quantify the RNA modification-related subtypes of individual tumors. Furthermore, we performed association analysis for WM_Score and characteristics of TME, consensus molecular subtypes (CMSs), clinical features, transcriptional and post-transcriptional regulation, drug response, and the efficacy of immunotherapy. We demonstrated that multi-layer alterations of RNA modification \"writer\" are associated with patient survival and TME cell-infiltrating characteristics. We identified two distinct RNA modification patterns, characterized by a high and a low WM_Score. The WM_Score-high group was associated with worse patient overall survival and with the infiltration of inhibitory immune cells, such as M2 macrophages, EMT activation, and metastasis, while the WM_Score-low group was associated with a survival advantage, apoptosis, and cell cycle signaling pathways. WM_Score correlated highly with the regulation of transcription and post-transcriptional events contributing to the development of CRC. \ufeffIn response to anti-cancer drugs, WM_Score highly negatively correlated (drug sensitive) with drugs which targeted oncogenic related pathways, such as MAPK, EGFR, and mTOR signaling pathways, positively correlated (drug resistance) with drugs which targeted in apoptosis and cell cycle. Importantly, the WM_Score was associated with the therapeutic efficacy of PD-L1 blockade, suggesting that the development of potential drugs targeting these \"writers\" to aid the clinical benefits of immunotherapy. Our study is the first to \ufeffprovide a comprehensive analysis of four RNA modifications in CRC. We revealed the potential function of these writers in TME, transcriptional and post-transcriptional events, and identified their therapeutic liability in targeted therapy and immunotherapy. This work highlights the cross-talk and potential clinical utility of RNA modification \"writers\" in cancer therapy.", - "journal_title": "Molecular cancer", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/33557837/" - } - ], - "83dc0ef1-fd5d-4cf1-9311-ebaaa25a5e49": [ - { - "pub_id": "17270037", - "title": "Classification of microarray data using gene networks.", - "authors": "Franck Rapaport,Andrei Zinovyev,Marie Dutreix,Emmanuel Barillot,Jean-Philippe Vert", - "abstract": "Microarrays have become extremely useful for analysing genetic phenomena, but establishing a relation between microarray analysis results (typically a list of genes) and their biological significance is often difficult. Currently, the standard approach is to map a posteriori the results onto gene networks in order to elucidate the functions perturbed at the level of pathways. However, integrating a priori knowledge of the gene networks could help in the statistical analysis of gene expression data and in their biological interpretation. We propose a method to integrate a priori the knowledge of a gene network in the analysis of gene expression data. The approach is based on the spectral decomposition of gene expression profiles with respect to the eigenfunctions of the graph, resulting in an attenuation of the high-frequency components of the expression profiles with respect to the topology of the graph. We show how to derive unsupervised and supervised classification algorithms of expression profiles, resulting in classifiers with biological relevance. We illustrate the method with the analysis of a set of expression profiles from irradiated and non-irradiated yeast strains. Including a priori knowledge of a gene network for the analysis of gene expression data leads to good classification performance and improved interpretability of the results.", - "journal_title": "BMC bioinformatics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/17270037/" - } - ], - "b3c2189b-270c-4b4a-9d40-cdc0dceebd9e": [ - { - "pub_id": "18199428", - "title": "Genetic regulation of hypothalamic cocaine and amphetamine-regulated transcript (CART) in BxD inbred mice.", - "authors": "Ericka M Boone,Brian W Hawks,Wei Li,Steven J Garlow", - "abstract": "Cocaine and Amphetamine-Regulated Transcript (CART) peptides are implicated in a wide range of behaviors including in the reinforcing properties of psychostimulants, feeding and energy balance and stress and anxiety responses. We conducted a complex trait analysis to examine natural variation in the regulation of CART transcript abundance (CARTta) in the hypothalamus. CART transcript abundance was measured in total hypothalamic RNA from 26 BxD recombinant inbred (RI) mouse strains and in the C57BL/6 (B6) and DBA/2J (D2) progenitor strains. The strain distribution pattern for CARTta was continuous across the RI panel, which is consistent with this being a quantitative trait. Marker regression and interval mapping revealed significant quantitative trait loci (QTL) on mouse chromosome 4 (around 58.2 cM) and chromosome 11 (between 20-36 cM) that influence CARTta and account for 31% of the between strain variance in this phenotype. There are numerous candidate genes and QTL in these chromosomal regions that may indicate shared genetic regulation between CART expression and other neurobiological processes referable to known actions of this neuropeptide.", - "journal_title": "Brain research", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/18199428/" - } - ], - "9d099959-b0d0-45b1-b2f7-0e30ad63d48e": [ - { - "pub_id": "17598886", - "title": "Morphine effects on striatal transcriptome in mice.", - "authors": "Michal Korostynski,Marcin Piechota,Dorota Kaminska,Wojciech Solecki,Ryszard Przewlocki", - "abstract": "Chronic opiate use produces molecular and cellular adaptations in the nervous system that lead to tolerance, physical dependence, and addiction. Genome-wide comparison of morphine-induced changes in brain transcription of mouse strains with different opioid-related phenotypes provides an opportunity to discover the relationship between gene expression and behavioral response to the drug. Here, we analyzed the effects of single and repeated morphine administrations in selected inbred mouse strains (129P3/J, DBA/2J, C57BL/6J, and SWR/J). Using microarray-based gene expression profiling in striatum, we found 618 (false discovery rate < 1%) morphine-responsive transcripts. Through ontologic classification, we linked particular sets of genes to biologic functions, including metabolism, transmission of nerve impulse, and cell-cell signaling. We identified numerous novel morphine-regulated genes (for instance, Olig2 and Camk1g), and a number of transcripts with strain-specific changes in expression (for instance, Hspa1a and Fzd2). Moreover, transcriptional activation of a pattern of co-expressed genes (for instance, Tsc22d3 and Nfkbia) was identified as being mediated via the glucocorticoid receptor (GR). Further studies revealed that blockade of the GR altered morphine-induced locomotor activity and development of physical dependence. Our results indicate that there are differences between strains in the magnitude of transcriptional response to acute morphine treatment and in the degree of tolerance in gene expression observed after chronic morphine treatment. Using whole-genome transcriptional analysis of morphine effects in the striatum, we were able to reveal multiple physiological factors that may influence opioid-related phenotypes and to relate particular gene networks to this complex trait. The results also suggest the possible involvement of GR-regulated genes in mediating behavioral response to morphine.", - "journal_title": "Genome biology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/17598886/" - } - ], - "81bb21fb-1ccf-4fa1-9a60-c3b12cb99634": [ - { - "pub_id": "34986597", - "title": "HMDB 5.0: the Human Metabolome Database for 2022.", - "authors": "David S Wishart,AnChi Guo,Eponine Oler,Fei Wang,Afia Anjum,Harrison Peters,Raynard Dizon,Zinat Sayeeda,Siyang Tian,Brian L Lee,Mark Berjanskii,Robert Mah,Mai Yamamoto,Juan Jovel,Claudia Torres-Calzada,Mickel Hiebert-Giesbrecht,Vicki W Lui,Dorna Varshavi,Dorsa Varshavi,Dana Allen,David Arndt,Nitya Khetarpal,Aadhavya Sivakumaran,Karxena Harford,Selena Sanford,Kristen Yee,Xuan Cao,Zachary Budinski,Jaanus Liigand,Lun Zhang,Jiamin Zheng,Rupasri Mandal,Naama Karu,Maija Dambrova,Helgi B Schi\u00f6th,Russell Greiner,Vasuk Gautam", - "abstract": "The Human Metabolome Database or HMDB (https://hmdb.ca) has been providing comprehensive reference information about human metabolites and their associated biological, physiological and chemical properties since 2007. Over the past 15 years, the HMDB has grown and evolved significantly to meet the needs of the metabolomics community and respond to continuing changes in internet and computing technology. This year's update, HMDB 5.0, brings a number of important improvements and upgrades to the database. These should make the HMDB more useful and more appealing to a larger cross-section of users. In particular, these improvements include: (i) a significant increase in the number of metabolite entries (from 114 100 to 217 920 compounds); (ii) enhancements to the quality and depth of metabolite descriptions; (iii) the addition of new structure, spectral and pathway visualization tools; (iv) the inclusion of many new and much more accurately predicted spectral data sets, including predicted NMR spectra, more accurately predicted MS spectra, predicted retention indices and predicted collision cross section data and (v) enhancements to the HMDB's search functions to facilitate better compound identification. Many other minor improvements and updates to the content, the interface, and general performance of the HMDB website have also been made. Overall, we believe these upgrades and updates should greatly enhance the HMDB's ease of use and its potential applications not only in human metabolomics but also in exposomics, lipidomics, nutritional science, biochemistry and clinical chemistry.", - "journal_title": "Nucleic acids research", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/34986597/" - } - ], - "0de2ad4a-b7e3-484e-8778-5ea47e42a4e4": [ - { - "pub_id": "18379576", - "title": "A genome-wide panel of congenic mice reveals widespread epistasis of behavior quantitative trait loci.", - "authors": "G D Gale,R D Yazdi,A H Khan,A J Lusis,R C Davis,D J Smith", - "abstract": "Understanding the genetics of behavioral variation remains a fascinating but difficult problem with considerable theoretical and practical implications. We used the genome-tagged mice (GTM) and an extensive test battery of well-validated behavioral assays to scan the genome for behavioral quantitative trait loci (QTLs). The GTM are a panel of 'speed congenic' mice consisting of over 60 strains spanning the entire autosomal genome. Each strain harbors a small (approximately 23 cM) DBA/2J donor segment on a uniform C57BL/6J background. The panel allows for mapping to regions as small as 5 cM and provides a powerful new tool for increasing mapping power and replicability in the analysis of QTLs. A total of 97 loci were mapped for a variety of complex behavioral traits including hyperactivity, anxiety, prepulse inhibition, avoidance and conditional fear. A larger number of loci were recovered than generally attained from standard mapping crosses. In addition, a surprisingly high proportion of loci, 63%, showed phenotypes unlike either of the parental strains. These data suggest that epistasis decreases sensitivity of locus detection in traditional crosses and demonstrate the utility of the GTM for mapping complex behavioral traits with high sensitivity and precision.", - "journal_title": "Molecular psychiatry", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/18379576/" - } - ], - "d0edfb1d-cab7-4f2c-8640-ccc1e484df3c": [ - { - "pub_id": "19079254", - "title": "Cost-effective strategies for completing the interactome.", - "authors": "Ariel S Schwartz,Jingkai Yu,Kyle R Gardenour,Russell L Finley,Trey Ideker", - "abstract": "Comprehensive protein-interaction mapping projects are underway for many model species and humans. A key step in these projects is estimating the time, cost and personnel required for obtaining an accurate and complete map. Here we modeled the cost of interaction-map completion for various experimental designs. We showed that current efforts may require up to 20 independent tests covering each protein pair to approach completion. We explored designs for reducing this cost substantially, including prioritization of protein pairs, probability thresholding and interaction prediction. The best experimental designs lowered cost by fourfold overall and >100-fold in early stages of mapping. We demonstrate the best strategy in an ongoing project in Drosophila melanogaster, in which we mapped 450 high-confidence interactions using 47 microtiter plates, versus thousands of plates expected using current designs. This study provides a framework for assessing the feasibility of interaction mapping projects and for future efforts to increase their efficiency.", - "journal_title": "Nature methods", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/19079254/" - } - ], - "069247f3-7209-4dbb-85e3-e9f11e273812": [ - { - "pub_id": "18179704", - "title": "Genetic analysis of posterior medial barrel subfield (PMBSF) size in somatosensory cortex (SI) in recombinant inbred strains of mice.", - "authors": "Taha A Jan,Lu Lu,Cheng-Xiang Li,Robert W Williams,Robert S Waters", - "abstract": "Quantitative trait locus (QTL) mapping is an important tool for identifying potential candidate genes linked to complex traits. QTL mapping has been used to identify genes associated with cytoarchitecture, cell number, brain size, and brain volume. Previously, QTL mapping was utilized to examine variation of barrel field size in the somatosensory cortex in a limited number of recombinant inbred (RI) strains of mice. In order to further elucidate the underlying natural variation in mouse primary somatosensory cortex, we measured the size of the posterior medial barrel subfield (PMBSF), associated with the representation of the large mystacial vibrissae, in an expanded sample set that included 42 BXD RI strains, two parental strains (C57BL/6J and DBA/2J), and one F1 strain (B6D2F1). Cytochrome oxidase labeling was used to visualize barrels within the PMBSF. We observed a 33% difference between the largest and smallest BXD RI strains with continuous variation in-between. Using QTL linkage analysis from WebQTL, we generated linkage maps of raw total PMBSF and brain weight adjusted total PMBSF areas. After removing the effects of brain weight, we detected a suggestive QTL (likelihood ratio statistic [LRS]: 14.20) on the proximal arm of chromosome 4. Candidate genes under the suggestive QTL peak for PMBSF area were selected based on the number of single nucleotide polymorphisms (SNPs) present and the biological relevance of each gene. Among the candidate genes are Car8 and Rab2. More importantly, mRNA expression profiles obtained using GeneNetwork indicated a strong correlation between total PMBSF area and two genes (Adcy1 and Gap43) known to be important in mouse cortex development. GAP43 has been shown to be critical during neurodevelopment of the somatosensory cortex, while knockout Adcy1 mice have disrupted barrel field patterns. We detected a novel suggestive QTL on chromosome 4 that is linked to PMBSF size. The present study is an important step towards identifying genes underlying the size and possible development of cortical structures.", - "journal_title": "BMC neuroscience", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/18179704/" - } - ], - "dd878d66-c3af-4e2f-a6f8-9de6edc3dc60": [ - { - "pub_id": "18721260", - "title": "High-resolution genetic mapping of mammalian motor activity levels in mice.", - "authors": "M J H Kas,J G de Mooij-van Malsen,M de Krom,K L I van Gassen,H A van Lith,B Olivier,H Oppelaar,J Hendriks,M de Wit,M J A Groot Koerkamp,F C P Holstege,B A van Oost,P N E de Graan", - "abstract": "The generation of motor activity levels is under tight neural control to execute essential behaviors, such as movement toward food or for social interaction. To identify novel neurobiological mechanisms underlying motor activity levels, we studied a panel of chromosome substitution (CS) strains derived from mice with high (C57BL/6J strain) or low motor activity levels (A/J strain) using automated home cage behavioral registration. In this study, we genetically mapped the expression of baseline motor activity levels (horizontal distance moved) to mouse chromosome 1. Further genetic mapping of this trait revealed an 8.3-Mb quantitative trait locus (QTL) interval. This locus is distinct from the QTL interval for open-field anxiety-related motor behavior on this chromosome. By data mining, an existing phenotypic and genotypic data set of 2445 genetically heterogeneous mice (http://gscan.well.ox.ac.uk/), we confirmed linkage to the peak marker at 79 970 253 bp and refined the QTL to a 312-kb interval containing a single gene (A830043J08Rik). Sequence analysis showed a nucleotide deletion in the 3' untranslated region of the Riken gene. Genome-wide microarray gene expression profiling in brains of discordant F(2) individuals from CS strain 1 showed a significant upregulation of Epha4 in low-active F(2) individuals. Inclusion of a genetic marker for Epha4 confirmed that this gene is located outside of the QTL interval. Both Epha4 and A830043J08Rik are expressed in brain motor circuits, and similar to Epha4 mutants, we found linkage between reduced motor neurons number and A/J chromosome 1. Our findings provide a novel QTL and a potential downstream target underlying motor circuitry development and the expression of physical activity levels.", - "journal_title": "Genes, brain, and behavior", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/18721260/" - } - ], - "b7f1f9b3-0ee0-40d8-ad3c-74b0b189d312": [ - { - "pub_id": "18439298", - "title": "Overexpression of Scg5 increases enzymatic activity of PCSK2 and is inversely correlated with body weight in congenic mice.", - "authors": "Charles R Farber,James Chitwood,Sang-Nam Lee,Ricardo A Verdugo,Alma Islas-Trejo,Gonzalo Rincon,Iris Lindberg,Juan F Medrano", - "abstract": "The identification of novel genes is critical to understanding the molecular basis of body weight. Towards this goal, we have identified secretogranin V (Scg5; also referred to as Sgne1), as a candidate gene for growth traits. Through a combination of DNA microarray analysis and quantitative PCR we identified a strong expression quantitative trait locus (eQTL) regulating Scg5 expression in two mouse chromosome 2 congenic strains and three additional F2 intercrosses. More importantly, the eQTL was coincident with a body weight QTL in congenic mice and Scg5 expression was negatively correlated with body weight in two of the F2 intercrosses. Analysis of haplotype blocks and genomic sequencing of Scg5 in high (C3H/HeJ, DBA/2J, BALB/cByJ, CAST/EiJ) and low (C57BL/6J) expressing strains revealed mutations unique to C57BL/6J and possibly responsible for the difference in mRNA abundance. To evaluate the functional consequence of Scg5 overexpression we measured the pituitary levels of 7B2 protein and PCSK2 activity and found both to be increased. In spite of this increase, the level of pituitary alpha-MSH, a PCSK2 processing product, was unaltered. Together, these data support a role for Scg5 in the modulation of body weight.", - "journal_title": "BMC genetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/18439298/" - } - ], - "beb7a242-21fe-4a66-8b44-7f228c0d3640": [ - { - "pub_id": "19017390", - "title": "Towards systems genetic analyses in barley: Integration of phenotypic, expression and genotype data into GeneNetwork.", - "authors": "Arnis Druka,Ilze Druka,Arthur G Centeno,Hongqiang Li,Zhaohui Sun,William T B Thomas,Nicola Bonar,Brian J Steffenson,Steven E Ullrich,Andris Kleinhofs,Roger P Wise,Timothy J Close,Elena Potokina,Zewei Luo,Carola Wagner,G\u00fcnther F Schweizer,David F Marshall,Michael J Kearsey,Robert W Williams,Robbie Waugh", - "abstract": "A typical genetical genomics experiment results in four separate data sets; genotype, gene expression, higher-order phenotypic data and metadata that describe the protocols, processing and the array platform. Used in concert, these data sets provide the opportunity to perform genetic analysis at a systems level. Their predictive power is largely determined by the gene expression dataset where tens of millions of data points can be generated using currently available mRNA profiling technologies. Such large, multidimensional data sets often have value beyond that extracted during their initial analysis and interpretation, particularly if conducted on widely distributed reference genetic materials. Besides quality and scale, access to the data is of primary importance as accessibility potentially allows the extraction of considerable added value from the same primary dataset by the wider research community. Although the number of genetical genomics experiments in different plant species is rapidly increasing, none to date has been presented in a form that allows quick and efficient on-line testing for possible associations between genes, loci and traits of interest by an entire research community. Using a reference population of 150 recombinant doubled haploid barley lines we generated novel phenotypic, mRNA abundance and SNP-based genotyping data sets, added them to a considerable volume of legacy trait data and entered them into the GeneNetwork http://www.genenetwork.org. GeneNetwork is a unified on-line analytical environment that enables the user to test genetic hypotheses about how component traits, such as mRNA abundance, may interact to condition more complex biological phenotypes (higher-order traits). Here we describe these barley data sets and demonstrate some of the functionalities GeneNetwork provides as an easily accessible and integrated analytical environment for exploring them. By integrating barley genotypic, phenotypic and mRNA abundance data sets directly within GeneNetwork's analytical environment we provide simple web access to the data for the research community. In this environment, a combination of correlation analysis and linkage mapping provides the potential to identify and substantiate gene targets for saturation mapping and positional cloning. By integrating datasets from an unsequenced crop plant (barley) in a database that has been designed for an animal model species (mouse) with a well established genome sequence, we prove the importance of the concept and practice of modular development and interoperability of software engineering for biological data sets.", - "journal_title": "BMC genetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/19017390/" - } - ], - "8488ee18-ce6d-4a00-a97f-f4d2ec5d5175": [ - { - "pub_id": "18367649", - "title": "Modulation of voluntary ethanol consumption by beta-arrestin 2.", - "authors": "K Bj\u00f6rk,R Rimondini,A C Hansson,A Terasmaa,P Hyyti\u00e4,M Heilig,W H Sommer", - "abstract": "Beta-arrestin 2 is a multifunctional key component of the G protein-coupled receptor complex and is involved in mu-opiate and dopamine D2 receptor signaling, both of which are thought to mediate the rewarding effects of ethanol consumption. We identified elevated expression of the beta-arrestin 2 gene (Arrb2) in the striatum and the hippocampus of ethanol-preferring AA rats compared to their nonpreferring counterpart ANA line. Differential mRNA expression was accompanied by different levels of Arrb2 protein. The elevated expression was associated with a 7-marker haplotype in complete linkage disequilibrium, which segregated fully between the lines, and was unique to the preferring line. Furthermore, a single, distinct, and highly significant quantitative trait locus for Arrb2 expression in hippocampus and striatum was identified at the locus of this gene, providing evidence that genetic variation may affect a cis-regulatory mechanism for expression and regional control of Arrb2. These findings were functionally validated using mice lacking Arrb2, which displayed both reduced voluntary ethanol consumption and ethanol-induced psychomotor stimulation. Our results demonstrate that beta-arrestin 2 modulates acute responses to ethanol and is an important mediator of ethanol reward.", - "journal_title": "FASEB journal : official publication of the Federation of American Societies for Experimental Biology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/18367649/" - } - ], - "78b2381f-e66f-49a8-9dcb-8202b5fbe625": [ - { - "pub_id": "19295534", - "title": "Genes and addictions.", - "authors": "L Bevilacqua,D Goldman", - "abstract": "", - "journal_title": "Clinical pharmacology and therapeutics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/19295534/" - } - ], - "550c099f-88d0-483f-865a-01ef7362e2be": [ - { - "pub_id": "19958391", - "title": "High-throughput behavioral phenotyping in the expanded panel of BXD recombinant inbred strains.", - "authors": "V M Philip,S Duvvuru,B Gomero,T A Ansah,C D Blaha,M N Cook,K M Hamre,W R Lariviere,D B Matthews,G Mittleman,D Goldowitz,E J Chesler", - "abstract": "Genetic reference populations, particularly the BXD recombinant inbred (BXD RI) strains derived from C57BL/6J and DBA/2J mice, are a valuable resource for the discovery of the bio-molecular substrates and genetic drivers responsible for trait variation and covariation. This approach can be profitably applied in the analysis of susceptibility and mechanisms of drug and alcohol use disorders for which many predisposing behaviors may predict the occurrence and manifestation of increased preference for these substances. Many of these traits are modeled by common mouse behavioral assays, facilitating the detection of patterns and sources of genetic coregulation of predisposing phenotypes and substance consumption. Members of the Tennessee Mouse Genome Consortium (TMGC) have obtained phenotype data from over 250 measures related to multiple behavioral assays across several batteries: response to, and withdrawal from cocaine, 3,4-methylenedioxymethamphetamine; \"ecstasy\" (MDMA), morphine and alcohol; novelty seeking; behavioral despair and related neurological phenomena; pain sensitivity; stress sensitivity; anxiety; hyperactivity and sleep/wake cycles. All traits have been measured in both sexes in approximately 70 strains of the recently expanded panel of BXD RI strains. Sex differences and heritability estimates were obtained for each trait, and a comparison of early (N = 32) and recent (N = 37) BXD RI lines was performed. Primary data are publicly available for heritability, sex difference and genetic analyses using the MouseTrack database, and are also available in GeneNetwork.org for quantitative trait locus (QTL) detection and genetic analysis of gene expression. Together with the results of related studies, these data form a public resource for integrative systems genetic analysis of neurobehavioral traits.", - "journal_title": "Genes, brain, and behavior", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/19958391/" - } - ], - "793e0349-bbb7-4edb-bc2d-778ac5e3ba49": [ - { - "pub_id": "20808911", - "title": "A transposon in Comt generates mRNA variants and causes widespread expression and behavioral differences among mice.", - "authors": "Zhengsheng Li,Megan K Mulligan,Xusheng Wang,Michael F Miles,Lu Lu,Robert W Williams", - "abstract": "Catechol-O-methyltransferase (COMT) is a key enzyme responsible for the degradation of dopamine and norepinephrine. COMT activity influences cognitive and emotional states in humans and aggression and drug responses in mice. This study identifies the key sequence variant that leads to differences in Comt mRNA and protein levels among mice, and that modulates synaptic function and pharmacological and behavioral traits. We examined Comt expression in multiple tissues in over 100 diverse strains and several genetic crosses. Differences in expression map back to Comt and are generated by a 230 nt insertion of a B2 short interspersed element (B2 SINE) in the proximal 3' UTR of Comt in C57BL/6J. This transposon introduces a premature polyadenylation signal and creates a short 3' UTR isoform. The B2 SINE is shared by a subset of strains, including C57BL/6J, A/J, BALB/cByJ, and AKR/J, but is absent in others, including DBA/2J, FVB/NJ, SJL/J, and wild subspecies. The short isoform is associated with increased protein expression in prefrontal cortex and hippocampus relative to the longer ancestral isoform. The Comt variant causes downstream differences in the expression of genes involved in synaptic function, and also modulates phenotypes such as dopamine D1 and D2 receptor binding and pharmacological responses to haloperidol. We have precisely defined the B2 SINE as the source of variation in Comt and demonstrated that a transposon in a 3' UTR can alter mRNA isoform use and modulate behavior. The recent fixation of the variant in a subset of strains may have contributed to the rapid divergence of inbred strains.", - "journal_title": "PloS one", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/20808911/" - } - ], - "e7bc9d83-6c3b-405c-a552-29874b927860": [ - { - "pub_id": "20801210", - "title": "Genome-wide analysis of hepatic gene silencing in mammalian cell hybrids.", - "authors": "Gary A Bulla,Quang Luong,Sushma Shrestha,Sarah Reeb,Sharon Hickman", - "abstract": "Silencing of tissue-specific gene expression in mammalian somatic cell hybrids is a well-documented epigenetic phenomenon which is both profound (involving a large number of genes) and enigmatic. Our aim was to utilize whole-genome microarray analyses to determine the true extent of gene silencing on a genomic level. By comparing gene expression profiles of hepatoma\u00d7fibroblast cell hybrids with those of parental cells, we have identified over 300 liver-enriched genes that are repressed at least 5-fold in the cell hybrids, the majority of which are repressed at least 10-fold. Also, we identify nearly 200 fibroblast-enriched genes that are repressed at least 5-fold. Silenced hepatic genes include several that encode transcription factors and proteins involved in signal transduction pathways. These data suggest that extensive reprogramming occurs in cell hybrids, leading to a nearly global (although not complete) loss of tissue-specific gene expression.", - "journal_title": "Genomics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/20801210/" - } - ], - "79cc9995-ef16-4555-acef-6e0f28a2b5e8": [ - { - "pub_id": "20184719", - "title": "Systems genetics analyses predict a transcription role for P2P-R: molecular confirmation that P2P-R is a transcriptional co-repressor.", - "authors": "Philippos Peidis,Thomas Giannakouros,Matthew E Burow,Robert W Williams,Robert E Scott", - "abstract": "The 250 kDa P2P-R protein (also known as PACT and Rbbp6) was cloned over a decade ago and was found to bind both the p53 and Rb1 tumor suppressor proteins. In addition, P2P-R has been associated with multiple biological functions, such as mitosis, mRNA processing, translation and ubiquitination. In the current studies, the online GeneNetwork system was employed to further probe P2P-R biological functions. Molecular studies were then performed to confirm the GeneNetwork evaluations. GeneNetwork and associated gene ontology links were used to investigate the coexpression of P2P-R with distinct functional sets of genes in an adipocyte genetic reference panel of HXB/BXH recombinant strains of rats and an eye genetic reference panel of BXD recombinant inbred strains of mice. The results establish that biological networks of 75 and 135 transcription-associated gene products that include P2P-R are co-expressed in a genetically-defined manner in rat adipocytes and in the mouse eye, respectively. Of this large set of transcription-associated genes, >10% are associated with hormone-mediated transcription. Since it has been previously reported that P2P-R can bind the SRC-1 transcription co-regulatory factor (steroid receptor co-activator 1, [Ncoa1]), the possible effects of P2P-R on estrogen-induced transcription were evaluated. Estrogen-induced transcription was repressed 50-70% by the transient transfection of P2P-R plasmid constructs into four different cell types. In addition, knockdown of P2P-R expression using an antisense oligonucleotide increased estrogen-mediated transcription. Co-immunoprecipitation assays confirmed that P2P-R interacts with SRC-1 and also demonstrated that P2P-R interacts with estrogen receptor alpha. The findings presented in this study provide strong support for the value of systems genetics, especially GeneNetwork, in discovering new functions of genes that can be confirmed by molecular analysis. More specifically, these data provide evidence that the expression of P2P-R co-varies in a genetically-defined manner with large transcription networks and that P2P-R can function as a co-repressor of estrogen-dependent transcription.", - "journal_title": "BMC systems biology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/20184719/" - } - ], - "c22b0145-99a3-458b-a977-d1e926985ab7": [ - { - "pub_id": "21799923", - "title": "An evolutionary conserved role for anaplastic lymphoma kinase in behavioral responses to ethanol.", - "authors": "Amy W Lasek,Jana Lim,Christopher L Kliethermes,Karen H Berger,Geoff Joslyn,Gerry Brush,Liquan Xue,Margaret Robertson,Monica S Moore,Karen Vranizan,Stephan W Morris,Marc A Schuckit,Raymond L White,Ulrike Heberlein", - "abstract": "Anaplastic lymphoma kinase (Alk) is a gene expressed in the nervous system that encodes a receptor tyrosine kinase commonly known for its oncogenic function in various human cancers. We have determined that Alk is associated with altered behavioral responses to ethanol in the fruit fly Drosophila melanogaster, in mice, and in humans. Mutant flies containing transposon insertions in dAlk demonstrate increased resistance to the sedating effect of ethanol. Database analyses revealed that Alk expression levels in the brains of recombinant inbred mice are negatively correlated with ethanol-induced ataxia and ethanol consumption. We therefore tested Alk gene knockout mice and found that they sedate longer in response to high doses of ethanol and consume more ethanol than wild-type mice. Finally, sequencing of human ALK led to the discovery of four polymorphisms associated with a low level of response to ethanol, an intermediate phenotype that is predictive of future alcohol use disorders (AUDs). These results suggest that Alk plays an evolutionary conserved role in ethanol-related behaviors. Moreover, ALK may be a novel candidate gene conferring risk for AUDs as well as a potential target for pharmacological intervention.", - "journal_title": "PloS one", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/21799923/" - } - ], - "18da99ad-f985-4aba-831e-35de60e36949": [ - { - "pub_id": "21494628", - "title": "Genetic analysis of the neurosteroid deoxycorticosterone and its relation to alcohol phenotypes: identification of QTLs and downstream gene regulation.", - "authors": "Patrizia Porcu,Todd K O'Buckley,Soomin C Song,Jo Lynne Harenza,Lu Lu,Xusheng Wang,Robert W Williams,Michael F Miles,A Leslie Morrow", - "abstract": "Deoxycorticosterone (DOC) is an endogenous neurosteroid found in brain and serum, precursor of the GABAergic neuroactive steroid (3\u03b1,5\u03b1)-3,21-dihydroxypregnan-20-one (tetrahydrodeoxycorticosterone, THDOC) and the glucocorticoid corticosterone. These steroids are elevated following stress or ethanol administration, contribute to ethanol sensitivity, and their elevation is blunted in ethanol dependence. To systematically define the genetic basis, regulation, and behavioral significance of DOC levels in plasma and cerebral cortex we examined such levels across 47 young adult males from C57BL/6J (B6)\u00d7DBA/2J (D2) (BXD) mouse strains for quantitative trait loci (QTL) and bioinformatics analyses of behavior and gene regulation. Mice were injected with saline or 0.075 mg/kg dexamethasone sodium salt at 8:00 am and were sacrificed 6 hours later. DOC levels were measured by radioimmunoassay. Basal cerebral cortical DOC levels ranged between 1.4 and 12.2 ng/g (8.7-fold variation, p<0.0001) with a heritability of \u223c0.37. Basal plasma DOC levels ranged between 2.8 and 12.1 ng/ml (4.3-fold variation, p<0.0001) with heritability of \u223c0.32. QTLs for basal DOC levels were identified on chromosomes 4 (cerebral cortex) and 14 (plasma). Dexamethasone-induced changes in DOC levels showed a 4.4-fold variation in cerebral cortex and a 4.1-fold variation in plasma, but no QTLs were identified. DOC levels across BXD strains were further shown to be co-regulated with networks of genes linked to neuronal, immune, and endocrine function. DOC levels and its responses to dexamethasone were associated with several behavioral measures of ethanol sensitivity previously determined across the BXD strains by multiple laboratories. Both basal and dexamethasone-suppressed DOC levels are positively correlated with ethanol sensitivity suggesting that the neurosteroid DOC may be a putative biomarker of alcohol phenotypes. DOC levels were also strongly correlated with networks of genes associated with neuronal function, innate immune pathways, and steroid metabolism, likely linked to behavioral phenotypes.", - "journal_title": "PloS one", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/21494628/" - } - ], - "2223858e-6e3b-4257-9f6d-2c267b2397d9": [ - { - "pub_id": "28834773", - "title": "Genome-wide DNA methylation variation in maternal and cord blood of gestational diabetes population.", - "authors": "Jessica Kang,Chien-Nan Lee,Hung-Yuan Li,Kai-Han Hsu,Shin-Yu Lin", - "abstract": "Gestational diabetes mellitus (GDM) has always been a concerning issue for pregnant women. In recent studies, GDM was found to be related to epigenetic modifications, which would alter gene expressions, thus affecting the patients' and their offspring's health, leading to a higher probability of developing metabolic syndromes and diabetes later in life. In this study, we collected both maternal and cord blood samples from 16 pregnant women and their newborns, including eight exposed to GDM. GDM was diagnosed via a 75g oral glucose tolerance test (OGTT) at 24-28weeks of pregnancy. DNA methylation was measured at 841,573 CpG sites via the Infinium HumanMethylationEPIC BeadChip. An Ingenuity Pathway Analysis was conducted afterwards to identify genes and pathways epigenetically affected by GDM. We identified the top 200 loci and their corresponding genes in the maternal blood group (n=151) and cord blood group (n=167), both of which were methylated differently in the GDM and unexposed group. Metabolic disease-related pathways and molecules, such as interleukin-6 and interleukin-10 were identified in both groups. These results suggested that GDM has epigenetic effects on both mother and their offspring, which might result in future metabolic syndromes or diabetes. The high-throughput platform enabled us to analyze methylation sites throughout the genome and identify the most promising genes and pathways associated with GDM.", - "journal_title": "Diabetes research and clinical practice", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/28834773/" - } - ], - "6e7686d2-6d27-465b-97c2-df53f9e62d84": [ - { - "pub_id": "16237383", - "title": "Association between the casein kinase 1 epsilon gene region and subjective response to D-amphetamine.", - "authors": "Jeremy Veenstra-VanderWeele,Asfia Qaadir,Abraham A Palmer,Edwin H Cook,Harriet de Wit", - "abstract": "Animal models suggest that the casein kinase 1 epsilon gene (Csnk1e) contributes to variability in stimulant response. Csnk1e is a key component in the Darpp-32 (Dopamine-And-cAMP-Regulated-Phosphoprotein-32 kDa) second messenger pathway and has been implicated in previous pharmacological and pharmacogenetic studies in mice. Mice bred for methamphetamine sensitivity showed linkage to the region of chromosome 15 that contains Csnk1e and also showed a 10-fold increase in expression of Csnk1e. We used a double-blind, crossover design in healthy human volunteers to test association between polymorphisms in the CSNK1E region and subjective response to placebo, 10, or 20 mg of oral D-amphetamine. Repeated-measures ANOVA was used to analyze interactions between genotype and drug response. The primary outcome measure, subjects' ratings of whether they felt a drug effect (Drug Effects Questionnaire (DEQ)), revealed a significant effect (p=0.010) at one single-nucleotide polymorphism (rs135745). Subjects with more copies of the rs135745 C allele were more sensitive to the low dose of D-amphetamine (p=0.001), which corresponded to a leftward shift in the dose-response curve. These findings demonstrate the successful translation of pharmacogenetic results from mice to humans.", - "journal_title": "Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/16237383/" - } - ], - "89fdce49-cd76-446e-bc47-9484071f9d3e": [ - { - "pub_id": "16783631", - "title": "Expression genetics and the phenotype revolution.", - "authors": "Robert W Williams", - "abstract": "Genetic analysis of variation demands large numbers of individuals and even larger numbers of genotypes. The identification of alleles associated with Mendelian disorders has involved sample sizes of a thousand or more. Pervasive and common diseases that afflict human populations--cancer, heart disease, diabetes, neurodegeneration, addiction--are all polygenic and are even more demanding of large numbers. DeCode Genetics (http://www.decode.com) has harnessed the human resources of Iceland to unravel genetic and molecular causes of complex disease. The UK BioBank project (http://www.ukbiobank.ac.uk/) will incorporate 500,000 adult volunteers. The murine Collaborative Cross is the experimental equivalent of these human populations and will consist of a panel of approximately 1000 recombinant strains, expandable by intercrossing to much larger numbers of isogenic but heterozygous F(1)s. Massive projects of these types require efficient technologies. We have made enormous progress on the genotyping front, and it is now important to focus energy on devising ultrahigh-throughput methods to phenotype. Molecular phenotyping of the transcriptome has matured, and it is now possible to acquire hundreds of thousands of mRNA phenotypes at a cost matching those of SNPs. Proteomic and cell-based assays are also maturing rapidly. The acquisition of a personal genome along with a personal molecular phenome will provide an effective foundation for personalized medicine. Rodent models will be essential to test our ability to predict susceptibility and disease outcome using SNP data, molecular phenomes, and environmental exposures. These models will also be essential to test new treatments in a robust systems context that accounts for genetic variation.", - "journal_title": "Mammalian genome : official journal of the International Mammalian Genome Society", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/16783631/" - } - ], - "0cff6ce0-2ccd-4ad0-b6fc-952c9157087a": [ - { - "pub_id": "17107940", - "title": "Systems biology of circadian rhythms: an outlook.", - "authors": "Luciano De Haro,Satchidananda Panda", - "abstract": "The circadian system in higher organisms temporally orchestrates rhythmic changes in a vast number of genes and gene products in different organs. Complex interactions between these components, both within and among cells, ultimately lead to rhythmic behavior and physiology. Identifying the plethora of circadian targets and mapping their interactions with one another is therefore essential to comprehend the molecular mechanisms of circadian regulation. The emergence of new technology for unbiased identification of biomolecules and for mapping interactions at the genome-wide scale is offering powerful tools to decipher the regulatory networks underpinning circadian rhythms. In this review, the authors discuss the potential application of these genome-wide approaches in the study of circadian rhythms.", - "journal_title": "Journal of biological rhythms", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/17107940/" - } - ], - "c4097a2e-d5c7-4a9b-8b0a-51b868be7f24": [ - { - "pub_id": "17426116", - "title": "Collateral density, remodeling, and VEGF-A expression differ widely between mouse strains.", - "authors": "Dan Chalothorn,Jason A Clayton,Hua Zhang,Daniel Pomp,James E Faber", - "abstract": "Substantial variability exists in collateral density and ischemia-induced collateral growth among species. To begin to probe the underlying mechanisms, which are unknown, we characterized two mouse strains with marked differences in both parameters. Immediately after femoral artery ligation, collateral and foot perfusion were lower in BALB/c than C57BL/6 (P < 0.05 here and below), suggesting fewer pre-existing collaterals. This was confirmed with angiography and immunohistochemistry (approximately 35% fewer collaterals in the BALB/c's thigh). Recovery of hindlimb perfusion was attenuated in BALB/c, in association with 54% less collateral remodeling, reduced angiogenesis, greater ischemia, and more impaired hindlimb use. Densities of CD45+ and CD4+ leukocytes around collaterals increased similarly, but TNF-alpha expression was 50% lower in BALB/c, which may contribute to reduced collateral remodeling. In normal tissues, compared with C57BL/6, BALB/c exhibit an altered arterial branching pattern and, like skeletal muscle above, have 30% fewer collaterals in intestine and, remarkably, almost none in pial circulation, resulting in greatly impaired perfusion after cerebral artery occlusion. Ischemic induction of VEGF-A was attenuated in BALB/c. Analysis of a C57BL/6 x BALB/c recombinant inbred strain dataset identified a quantitative trait locus for VEGF-A mRNA abundance at or near the Vegfa locus that associates with lower expression in BALB/c. This suggests a cis-acting polymorphism in the Vegfa gene in BALB/c could contribute to reduced VEGF-A expression and, in turn, the above deficiencies in this strain. These findings suggest these strains offer a model to investigate genetic determinants of collateral formation and growth in ischemia.", - "journal_title": "Physiological genomics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/17426116/" - } - ], - "bbd1d762-faab-409d-9243-bc94023e16c0": [ - { - "pub_id": "17542012", - "title": "Genome-level analysis of genetic regulation of liver gene expression networks.", - "authors": "Daniel Gatti,Akira Maki,Elissa J Chesler,Roumyana Kirova,Oksana Kosyk,Lu Lu,Kenneth F Manly,Robert W Williams,Andy Perkins,Michael A Langston,David W Threadgill,Ivan Rusyn", - "abstract": "The liver is the primary site for the metabolism of nutrients, drugs, and chemical agents. Although metabolic pathways are complex and tightly regulated, genetic variation among individuals, reflected in variations in gene expression levels, introduces complexity into research on liver disease. This study dissected genetic networks that control liver gene expression through the combination of large-scale quantitative mRNA expression analysis with genetic mapping in a reference population of BXD recombinant inbred mouse strains for which extensive single-nucleotide polymorphism, haplotype, and phenotypic data are publicly available. We profiled gene expression in livers of naive mice of both sexes from C57BL/6J, DBA/2J, B6D2F1, and 37 BXD strains using Agilent oligonucleotide microarrays. These data were used to map quantitative trait loci (QTLs) responsible for variations in the expression of about 19,000 transcripts. We identified polymorphic local and distant QTLs, including several loci that control the expression of large numbers of genes in liver, by comparing the physical transcript position with the location of the controlling QTL. The data are available through a public web-based resource (www.genenetwork.org) that allows custom data mining, identification of coregulated transcripts and correlated phenotypes, cross-tissue, and cross-species comparisons, as well as testing of a broad array of hypotheses.", - "journal_title": "Hepatology (Baltimore, Md.)", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/17542012/" - } - ], - "6f7ca779-0421-49eb-bef8-73eb0d513c60": [ - { - "pub_id": "17216419", - "title": "Nf1 expression is dependent on strain background: implications for tumor suppressor haploinsufficiency studies.", - "authors": "Jessica J Hawes,Robert G Tuskan,Karlyne M Reilly", - "abstract": "Neurofibromatosis type 1 (NF1) is the most common cancer predisposition syndrome affecting the nervous system, with elevated risk for both astrocytoma and peripheral nerve sheath tumors. NF1 is caused by a germline mutation in the NF1 gene, with tumors showing loss of the wild type copy of NF1. In addition, NF1 heterozygosity in surrounding stroma is important for tumor formation, suggesting an additional role of haploinsufficiency for NF1. Studies in mouse models and NF1 families have implicated modifier genes unlinked to NF1 in the severity of the disease and in susceptibility to astrocytoma and peripheral nerve sheath tumors. To determine if differences in Nf1 expression may contribute to the strain-specific effects on tumor predisposition, we examined the levels of Nf1 gene expression in mouse strains with differences in tumor susceptibility using quantitative polymerase chain reaction. The data presented in this paper demonstrate that strain background has as much effect on Nf1 expression levels as mutation of one Nf1 allele, indicating that studies of haploinsufficiency must be carefully interpreted with respect to strain background. Because expression levels do not correlate entirely with the susceptibility or resistance to tumors observed in the strain, these data suggest that either variation in Nf1 levels is not responsible for the differences in astrocytoma and peripheral nerve sheath tumor susceptibility in Nf1-/+;Trp53-/+cis mice, or that certain mouse strains have evolved compensatory mechanisms for differences in Nf1 expression.", - "journal_title": "Neurogenetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/17216419/" - } - ], - "fef6662c-0378-4827-a142-f2898f8785ed": [ - { - "pub_id": "17625601", - "title": "The genetic basis of variation in susceptibility to infection with Histoplasma capsulatum in the mouse.", - "authors": "J A Mayfield,J Rine", - "abstract": "The pathogenic fungus Histoplasma capsulatum causes disease ranging from mild to fatal in healthy and immunocompromised humans. Infection rates reach 80% in endemic areas, including the Midwestern United States. We used inbred mice to identify a 300-fold difference in fungal burden. A/J mice showed lower fungal burden and morbidity than C57BL/6J mice, a reversal of the trend observed for many bacterial pathogens. We mapped the differences in fungal burden to discrete locations on chromosomes 1, 6, 15 and 17 with high significance. Substitution of a single resistant chromosome 17 onto the susceptible background was sufficient to lower fungal burden. These loci will allow dissection of the fungal-specific immune program.", - "journal_title": "Genes and immunity", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/17625601/" - } - ], - "2a7da18e-3756-45c5-b18c-a2231685fefd": [ - { - "pub_id": "18972748", - "title": "Gene-environment interaction and the metabolic syndrome.", - "authors": "Kristi B Adamo,Fr\u00e9d\u00e9rique Tesson", - "abstract": "The metabolic syndrome, which has been shown to affect as many as 20% of the general adult US population, is generally described as a cluster of cardiovascular risks factors, most notably obesity, type 2 diabetes or resistance to insulin-stimulated glucose uptake (insulin resistance), dyslipidaemia and hypertension. All these risk factors are under both genetic and environmental control; they are considered individually as complex genetic diseases. Prior to pharmacological interventions for hypertension, diabetes and dyslipidaemia, lifestyle changes, in particular weight loss (or weight maintenance) and physical activity, were prioritized and constituted an effective first-line intervention strategy. Here we want to focus on three clinical components of the metabolic syndrome and the environmental factors that are considered to be the most significant targets for primary interventions: type 2 diabetes and exercise, obesity and diet, and hypertension and salt. Our experimental approach is to go from candidate gene strategy to genome-wide association. The identification of the genetic component of these risk factors is a major challenge, and it is hoped that this would help unravel mechanistic pathways that can ultimately serve as new targets for therapeutic intervention.", - "journal_title": "Novartis Foundation symposium", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/18972748/" - } - ], - "edbc01cb-82e1-4ee4-9e0a-124c15b0e0d8": [ - { - "pub_id": "18541997", - "title": "Insight into the genetics of hypertension, a core component of the metabolic syndrome.", - "authors": "Michal Pravenec,Enrico Petretto", - "abstract": "To provide insight into genetics of essential hypertension, including discussion of methods used both in human and animal experimental studies and interpretation of results. On the basis of recent progress in sequencing of human genome, detection of millions of single nucleotide polymorphism markers, determination of the extend of linkage disequilibrium (haplotypes), efficient genotyping technology, collection of DNA from thousands of rigorously phenotyped patients and controls and designing sound statistical methods, genome-wide associations studies were widely applied to analyses of common diseases including essential hypertension for the first time in 2007. Concurrently, new experimental approaches combined gene expression profiling with linkage and correlation analyses to identify quantitative trait loci underlying complex traits at the molecular level. These new approaches yielded new exciting results but also posed questions regarding data analyses, interpretation and clinical significance.", - "journal_title": "Current opinion in clinical nutrition and metabolic care", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/18541997/" - } - ], - "e074ba47-cd7a-4bb2-8bcb-9a15da69cc2d": [ - { - "pub_id": "18565787", - "title": "Discovery and verification of functional single nucleotide polymorphisms in regulatory genomic regions: current and developing technologies.", - "authors": "Brian N Chorley,Xuting Wang,Michelle R Campbell,Gary S Pittman,Maher A Noureddine,Douglas A Bell", - "abstract": "The most common form of genetic variation, single nucleotide polymorphisms or SNPs, can affect the way an individual responds to the environment and modify disease risk. Although most of the millions of SNPs have little or no effect on gene regulation and protein activity, there are many circumstances where base changes can have deleterious effects. Non-synonymous SNPs that result in amino acid changes in proteins have been studied because of their obvious impact on protein activity. It is well known that SNPs within regulatory regions of the genome can result in disregulation of gene transcription. However, the impact of SNPs located in putative regulatory regions, or rSNPs, is harder to predict for two primary reasons. First, the mechanistic roles of non-coding genomic sequence remain poorly defined. Second, experimental validation of the functional consequences of rSNPs is often slow and laborious. In this review, we summarize traditional and novel methodologies for candidate rSNPs selection, in particular in silico techniques that aid in candidate rSNP selection. Additionally we will discuss molecular biological techniques that assess the impact of rSNPs on binding of regulatory machinery, as well as functional consequences on transcription. Standard techniques such as EMSA and luciferase reporter constructs are still widely used to assess effects of rSNPs on binding and gene transcription; however, these protocols are often bottlenecks in the discovery process. Therefore, we highlight novel and developing high-throughput protocols that promise to aid in shortening the process of rSNP validation. Given the large amount of genomic information generated from a multitude of re-sequencing and genome-wide SNP array efforts, future focus should be to develop validation techniques that will allow greater understanding of the impact these polymorphisms have on human health and disease.", - "journal_title": "Mutation research", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/18565787/" - } - ], - "0b0e5343-4604-43ff-bc26-c87516dda690": [ - { - "pub_id": "19010566", - "title": "Unraveling the molecular mechanisms of alcohol dependence.", - "authors": "Gursharan Kalsi,Carol A Prescott,Kenneth S Kendler,Brien P Riley", - "abstract": "Alcohol dependence (AD) is a common, chronic, relapsing disorder. Compelling epidemiological evidence indicates that >50% of the risk for becoming alcoholic stems from genetic susceptibility and genetic studies have identified several risk genes. Alcohol intake alters gene expression patterns, thereby producing long-lasting cellular and molecular adaptations that might explain the development and maintenance of AD. The heterogeneous nature of AD indicates a complex etiology involving mechanisms related to motivational behavior, reward and learning, adaptations in signaling pathways owing to interactions between alcohol and target molecules, and chromatin remodeling. Emerging methodologies present opportunities to determine how alcohol might disrupt the synergistic actions of molecular systems and to assess gene-environment interactions for elucidating the behavioral and physiological dysfunctions underlying AD.", - "journal_title": "Trends in genetics : TIG", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/19010566/" - } - ], - "5e3ad5bb-135a-4980-b605-208101c3b315": [ - { - "pub_id": "21330339", - "title": "Updating and validating the Charlson comorbidity index and score for risk adjustment in hospital discharge abstracts using data from 6 countries.", - "authors": "Hude Quan,Bing Li,Chantal M Couris,Kiyohide Fushimi,Patrick Graham,Phil Hider,Jean-Marie Januel,Vijaya Sundararajan", - "abstract": "With advances in the effectiveness of treatment and disease management, the contribution of chronic comorbid diseases (comorbidities) found within the Charlson comorbidity index to mortality is likely to have changed since development of the index in 1984. The authors reevaluated the Charlson index and reassigned weights to each condition by identifying and following patients to observe mortality within 1 year after hospital discharge. They applied the updated index and weights to hospital discharge data from 6 countries and tested for their ability to predict in-hospital mortality. Compared with the original Charlson weights, weights generated from the Calgary, Alberta, Canada, data (2004) were 0 for 5 comorbidities, decreased for 3 comorbidities, increased for 4 comorbidities, and did not change for 5 comorbidities. The C statistics for discriminating in-hospital mortality between the new score generated from the 12 comorbidities and the Charlson score were 0.825 (new) and 0.808 (old), respectively, in Australian data (2008), 0.828 and 0.825 in Canadian data (2008), 0.878 and 0.882 in French data (2004), 0.727 and 0.723 in Japanese data (2008), 0.831 and 0.836 in New Zealand data (2008), and 0.869 and 0.876 in Swiss data (2008). The updated index of 12 comorbidities showed good-to-excellent discrimination in predicting in-hospital mortality in data from 6 countries and may be more appropriate for use with more recent administrative data.", - "journal_title": "American journal of epidemiology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/21330339/" - } - ], - "eef5a903-68f2-45d5-9a27-73e5b32aa644": [ - { - "pub_id": "19829370", - "title": "Neuroscience in the era of functional genomics and systems biology.", - "authors": "Daniel H Geschwind,Genevieve Konopka", - "abstract": "Advances in genetics and genomics have fuelled a revolution in discovery-based, or hypothesis-generating, research that provides a powerful complement to the more directly hypothesis-driven molecular, cellular and systems neuroscience. Genetic and functional genomic studies have already yielded important insights into neuronal diversity and function, as well as disease. One of the most exciting and challenging frontiers in neuroscience involves harnessing the power of large-scale genetic, genomic and phenotypic data sets, and the development of tools for data integration and mining. Methods for network analysis and systems biology offer the promise of integrating these multiple levels of data, connecting molecular pathways to nervous system function.", - "journal_title": "Nature", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/19829370/" - } - ], - "e2eaa1f2-1a1c-42b7-ab7f-e69a0394f748": [ - { - "pub_id": "20452416", - "title": "Genetic dissection of dietary restriction in mice supports the metabolic efficiency model of life extension.", - "authors": "Brad A Rikke,Chen-Yu Liao,Matthew B McQueen,James F Nelson,Thomas E Johnson", - "abstract": "Dietary restriction (DR) has been used for decades to retard aging in rodents, but its mechanism of action remains an enigma. A principal roadblock has been that DR affects many different processes, making it difficult to distinguish cause and effect. To address this problem, we applied a quantitative genetics approach utilizing the ILSXISS series of mouse recombinant inbred strains. Across 42 strains, mean female lifespan ranged from 380 to 1070days on DR (fed 60% of ad libitum [AL]) and from 490 to 1020days on an AL diet. Longevity under DR and AL is under genetic control, showing 34% and 36% heritability, respectively. There was no correlation between lifespans on DR and AL; thus different genes modulate longevity under the two regimens. DR lifespans are significantly correlated with female fertility after return to an AL diet after various periods of DR (R=0.44, P=0.006). We assessed fuel efficiency (FE, ability to maintain growth and body weight independent of absolute food intake) using a multivariate approach and found it to be correlated with longevity and female fertility, suggesting possible causality. We found several quantitative trait loci responsible for these traits, mapping to chromosomes 7, 9, and 15. We present a metabolic model in which the anti-aging effects of DR are consistent with the ability to efficiently utilize dietary resources.", - "journal_title": "Experimental gerontology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/20452416/" - } - ], - "56d79cf3-50fc-4803-9c5c-6e5a8a04879b": [ - { - "pub_id": "21176225", - "title": "MBAT: a scalable informatics system for unifying digital atlasing workflows.", - "authors": "Daren Lee,Seth Ruffins,Queenie Ng,Nikhil Sane,Steve Anderson,Arthur Toga", - "abstract": "Digital atlases provide a common semantic and spatial coordinate system that can be leveraged to compare, contrast, and correlate data from disparate sources. As the quality and amount of biological data continues to advance and grow, searching, referencing, and comparing this data with a researcher's own data is essential. However, the integration process is cumbersome and time-consuming due to misaligned data, implicitly defined associations, and incompatible data sources. This work addressing these challenges by providing a unified and adaptable environment to accelerate the workflow to gather, align, and analyze the data. The MouseBIRN Atlasing Toolkit (MBAT) project was developed as a cross-platform, free open-source application that unifies and accelerates the digital atlas workflow. A tiered, plug-in architecture was designed for the neuroinformatics and genomics goals of the project to provide a modular and extensible design. MBAT provides the ability to use a single query to search and retrieve data from multiple data sources, align image data using the user's preferred registration method, composite data from multiple sources in a common space, and link relevant informatics information to the current view of the data or atlas. The workspaces leverage tool plug-ins to extend and allow future extensions of the basic workspace functionality. A wide variety of tool plug-ins were developed that integrate pre-existing as well as newly created technology into each workspace. Novel atlasing features were also developed, such as supporting multiple label sets, dynamic selection and grouping of labels, and synchronized, context-driven display of ontological data. MBAT empowers researchers to discover correlations among disparate data by providing a unified environment for bringing together distributed reference resources, a user's image data, and biological atlases into the same spatial or semantic context. Through its extensible tiered plug-in architecture, MBAT allows researchers to customize all platform components to quickly achieve personalized workflows.", - "journal_title": "BMC bioinformatics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/21176225/" - } - ], - "de0aeb5f-dc8f-4629-b683-8c8ad3a42122": [ - { - "pub_id": "20811929", - "title": "Systems genetics, bioinformatics and eQTL mapping.", - "authors": "Hong Li,Hongwen Deng", - "abstract": "Jansen and Nap (Trends Genet 17(7):388-391, 2001) and Jansen (Nat Rev Genet 4:145-151, 2003) first proposed the concept of genetical genomics, or genome-wide genetic analysis of gene expression data, which is also called transcriptome mapping. In this approach, microarrays are used for measuring gene expression levels across genetic mapping populations. These gene expression patterns have been used for genome-wide association analysis, an analysis referred to as expression QTL (eQTL) mapping. Recent progress in genomics and experimental biology has brought exponential growth of the biological information available for computational analysis in public genomics databases. Bioinformatics is essential to genome-wide analysis of gene expression data and used as an effective tool for eQTL mapping. The use of Plabsoft database, EcoTILLING, GNARE and FastMap allowed for dramatic reduction of time in genome analysis. Some web-based tools (e.g., Lirnet, eQTL Viewer) provide efficient and intuitive ways for biologists to explore transcriptional regulation patterns, and to generate hypotheses on the genetic basis of transcriptional regulations. Expression quantitative trait loci (eQTL) mapping concerns finding genomic variation to elucidate variation of expression traits. This problem poses significant challenges due to high dimensionality of both the gene expression and the genomic marker data. The core challenges in understanding and explaining eQTL associations are the fine mapping and the lack of mechanistic explanation. But with the development of genetical genomics and computer technology, many new approaches for eQTL mapping will emerge. The statistical methods used for the analysis of expression QTL will become mature in the future.", - "journal_title": "Genetica", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/20811929/" - } - ], - "ed5a72d3-dc17-4812-a188-01574dbe6aa6": [ - { - "pub_id": "21839162", - "title": "Annotating individual human genomes.", - "authors": "Ali Torkamani,Ashley A Scott-Van Zeeland,Eric J Topol,Nicholas J Schork", - "abstract": "Advances in DNA sequencing technologies have made it possible to rapidly, accurately and affordably sequence entire individual human genomes. As impressive as this ability seems, however, it will not likely amount to much if one cannot extract meaningful information from individual sequence data. Annotating variations within individual genomes and providing information about their biological or phenotypic impact will thus be crucially important in moving individual sequencing projects forward, especially in the context of the clinical use of sequence information. In this paper we consider the various ways in which one might annotate individual sequence variations and point out limitations in the available methods for doing so. It is arguable that, in the foreseeable future, DNA sequencing of individual genomes will become routine for clinical, research, forensic, and personal purposes. We therefore also consider directions and areas for further research in annotating genomic variants.", - "journal_title": "Genomics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/21839162/" - } - ], - "26c6a28f-79d5-4f49-b0f4-df47acf79a8d": [ - { - "pub_id": "21392734", - "title": "Genetic dissection of behavioral flexibility: reversal learning in mice.", - "authors": "Rick E Laughlin,Tara L Grant,Robert W Williams,J David Jentsch", - "abstract": "Behavioral inflexibility is a feature of schizophrenia, attention-deficit/hyperactivity disorder, and behavior addictions that likely results from heritable deficits in the inhibitory control over behavior. Here, we investigate the genetic basis of individual differences in flexibility, measured using an operant reversal learning task. We quantified discrimination acquisition and subsequent reversal learning in a cohort of 51 BXD strains of mice (2-5 mice/strain, n = 176) for which we have matched data on sequence, gene expression in key central nervous system regions, and neuroreceptor levels. Strain variation in trials to criterion on acquisition and reversal was high, with moderate heritability (\u223c.3). Acquisition and reversal learning phenotypes did not covary at the strain level, suggesting that these traits are effectively under independent genetic control. Reversal performance did covary with dopamine D2 receptor levels in the ventral midbrain, consistent with a similar observed relationship between impulsivity and D2 receptors in humans. Reversal, but not acquisition, is linked to a locus on mouse chromosome 10 with a peak likelihood ratio statistic at 86.2 megabase (p < .05 genome-wide). Variance in messenger RNA levels of select transcripts expressed in neocortex, hippocampus, and striatum correlated with the reversal learning phenotype, including Syn3, Nt5dc3, and Hcfc2. This work demonstrates the clear trait independence between, and genetic control of, discrimination acquisition and reversal and illustrates how globally coherent data sets for a single panel of highly related strains can be interrogated and integrated to uncover genetic sources and molecular and neuropharmacological candidates of complex behavioral traits relevant to human psychopathology.", - "journal_title": "Biological psychiatry", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/21392734/" - } - ], - "a4e2c0f5-be37-46de-87ad-83d7070aec69": [ - { - "pub_id": "21371552", - "title": "Genetic-based, differential susceptibility to paraquat neurotoxicity in mice.", - "authors": "Lina Yin,Lu Lu,Kavita Prasad,Eric K Richfield,Erica L Unger,Jialin Xu,Byron C Jones", - "abstract": "Paraquat (PQ) is an herbicide used extensively in agriculture. This agent is also suspected to be a risk factor for Parkinson's disease (PD) by harming nigro-striatal dopamine neurons. There is likely, genetic-based, individual variability in susceptibility to PQ neurotoxicity related PD. In this study, we measured the delivery of PQ to the brain after three weekly injections of PQ at 5 mg kg(-1), PQ-related neural toxicity after three weekly injections of PQ at 1 mg kg(-1)or 5 mg kg(-1), PQ-related iron accumulation and PQ-related gene expression in midbrain of DBA/2J (D2) and C57BL/6J (B6) inbred mouse strains after a single injection of PQ at 15 mg kg(-1) and 10 mg kg(-1), respectively. Results showed that compared to controls, PQ-treated B6 mice lost greater numbers of dopaminergic neurons in the substantia nigra pars compacta than D2 mice; however, distribution of PQ to the midbrain was equal between the strains. PQ also significantly increased iron concentration in the midbrain of B6 but not D2 mice. Microarray analysis of the ventral midbrain showed greater PQ-induced changes in gene expression in B6 compared to D2 mice. This is the first study to report genetically-based differences in susceptibility to PQ neurotoxicity and to understanding individual differences in vulnerability to PQ neurotoxicity and its relation to PD in humans.", - "journal_title": "Neurotoxicology and teratology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/21371552/" - } - ], - "8df298ea-4052-4a4a-bcd3-2e36818844f4": [ - { - "pub_id": "16616787", - "title": "Attentional performance of C57BL/6 and DBA/2 mice in the 5-choice serial reaction time task.", - "authors": "S Patel,I P Stolerman,P Asherson,F Sluyter", - "abstract": "C57BL/6 and DBA/2 were compared in the 5-choice serial reaction time task for differences in performance related to attention and impulsivity. The goal was to examine behavioural processes in mice that may relate to ADHD in humans. Groups of male mice were trained to nose-poke in response to a stimulus light presented randomly in one of five holes; correct responses were reinforced with food. During training the stimulus duration (SD) was reduced progressively from 60 to 0.5s. The C57BL/6 and DBA/2 mice did not differ during early stages of training when attentional demands were low (SD of 60, 10 or 5s). As task demands increased, strain differences emerged; C57BL/6 mice were more accurate than DBA/2 mice with stimuli of 2, 1 and 0.5s. DBA/2 mice also made more anticipatory (impulsive) responses during inter-trial intervals than C57BL/6 mice at SD of 5, 2, 1 and 0.5s. The ability to carry out the task was present in both strains of mice but they differed significantly in the levels of performance that were achieved. It is argued that the differences in accuracy and anticipatory responding were closely related and that the primary difference between the strains may be in impulsivity.", - "journal_title": "Behavioural brain research", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/16616787/" - } - ], - "d9e0fe62-0bba-4c9f-a608-dca70a2454d4": [ - { - "pub_id": "16465594", - "title": "Expression profiling identifies novel candidate genes for ethanol sensitivity QTLs.", - "authors": "Erik J MacLaren,Beth Bennett,Thomas E Johnson,James M Sikela", - "abstract": "The Inbred Long Sleep (ILS) and Inbred Short Sleep (ISS) mouse strains have a 16-fold difference in duration of loss of the righting response (LORR) following administration of a sedative dose of ethanol. Four quantitative trait loci (QTLs) have been mapped in these strains for this trait. Underlying each of these QTLs must be one or more genetic differences (polymorphisms in either gene coding or regulatory regions) influencing ethanol sensitivity. Because prior studies have tended to focus on differences in coding regions, genome-wide expression profiling in cerebellum was used here to identify candidate genes for regulatory region differences in these two strains. Fifteen differentially expressed genes were found that map to the QTL regions and polymorphisms were identified in the promoter regions of four of these genes by direct sequencing of ILS and ISS genomic DNA. Polymorphisms in the promoters of three of these genes, Slc22a4, Rassf2, and Tax1bp3, disrupt putative transcription factor binding sites. Slc22a4 and another candidate, Xrcc5, have human orthologs that map to genomic regions associated with human ethanol sensitivity in genetic linkage studies. These genes represent novel candidates for the LORR phenotype and provide new targets for future studies into the neuronal processes underlying ethanol sensitivity.", - "journal_title": "Mammalian genome : official journal of the International Mammalian Genome Society", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/16465594/" - } - ], - "810a8c3f-5ec5-4ce8-9ad1-149ce98a573d": [ - { - "pub_id": "16978410", - "title": "Geometric morphometrics defines shape differences in the cortical area map of C57BL/6J and DBA/2J inbred mice.", - "authors": "David C Airey,Fangbai Wu,Monica Guan,Christine E Collins", - "abstract": "We previously described planar areal differences in adult mouse visual, somatosensory, and neocortex that collectively discriminated C57BL/6J and DBA/2J inbred strain identity. Here we use a novel application of established methods of two-dimensional geometric morphometrics to examine shape differences in the cortical area maps of these inbred strains. We used Procrustes superimposition to align a reliable set of landmarks in the plane of the cortical sheet from tangential sections stained for the cytochrome oxidase enzyme. Procrustes superimposition translates landmark configurations to a common origin, scales them to a common size, and rotates them to minimize an estimate of error. Remaining variation represents shape differences. We compared the variation in shape between C57BL/6J and DBA/2J relative to that within each strain using a permutation test of Goodall's F statistic. Significant differences in shape in the posterior medial barrel subfield (PMBSF), as well as differences in shape across primary sensory areas, characterize the cortical area maps of these common inbred, isogenic strains. C57BL/6J and DBA/2J have markedly different cortical area maps, in both size and shape. These differences suggest polymorphism in genetic factors underlying cortical specification, even between common isogenic strains. Comparing cortical phenotypes between normally varying inbred mice or between genetically modified mice can identify genetic contributions to cortical specification. Geometric morphometric analysis of shape represents an additional quantitative tool for the study of cortical development, regardless of whether it is studied from phenotype to gene or gene to phenotype.", - "journal_title": "BMC neuroscience", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/16978410/" - } - ], - "c4000f65-4126-4cf5-b789-e23227f2e7d1": [ - { - "pub_id": "17936574", - "title": "Glutamate receptor metabotropic 7 is cis-regulated in the mouse brain and modulates alcohol drinking.", - "authors": "Csaba Vadasz,Mariko Saito,Beatrix M Gyetvai,Melinda Oros,Istvan Szakall,Krisztina M Kovacs,Vidudala V T S Prasad,Reka Toth", - "abstract": "Alcoholism is a heritable disease that afflicts about 8% of the adult population. Its development and symptoms, such as craving, loss of control, physical dependence, and tolerance, have been linked to changes in mesolimbic, mesocortical neurotransmitter systems utilizing biogenic amines, GABA, and glutamate. Identification of genes predisposing to alcoholism, or to alcohol-related behaviors in animal models, has been elusive because of variable interactions of multiple genes with relatively small individual effect size and sensitivity of the predisposing genotype to lifestyle and environmental factors. Here, using near-isogenic advanced animal models with reduced genetic background interactions, we integrate gene mapping and gene mRNA expression data in segregating and congenic mice and identify glutamate receptor metabotropic 7 (Grm7) as a cis-regulated gene for alcohol consumption. Traditionally, the mesoaccumbal dopamine reward hypothesis of addiction and the role of the ionotropic glutamate receptors have been emphasized. Our results lend support to an emerging direction of research on the role of metabotropic glutamate receptors in alcoholism and drug addiction. These data suggest for the first time that Grm7 is a risk factor for alcohol drinking and a new target in addiction therapy.", - "journal_title": "Genomics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/17936574/" - } - ], - "cb217bfd-395f-4a10-9465-a960585c46fe": [ - { - "pub_id": "17688316", - "title": "Prediction of transcription factor binding sites using genetical genomics methods.", - "authors": "Peter von Rohr,Markus T Friberg,Haja N Kadarmideen", - "abstract": "In this paper, we wanted to test whether it is possible to use genetical genomics information such as expression quantitative trait loci (eQTL) mapping results as input to a transcription factor binding site (TFBS) prediction algorithm. Furthermore, this new approach was compared to the more traditional cluster based TFBS prediction. The results of eQTL mapping are used as input to one of the top ranking TFBS prediction algorithms. Genes with observed expression profiles showing the same eQTL region are collected into eQTL groups. The promoter sequences of all the genes within the same eQTL group are used as input in the transcription factor binding site search. This approach is tested with a real data set of a recombinant inbred line population of Arabidopsis thaliana. The predicted motifs are compared to results obtained from the conventional approach of first clustering the gene expression values and then using the promoter sequences of the genes within the same cluster as input for the transcription factor binding site prediction. Our eQTL based approach produced different motifs compared to the cluster based method. Furthermore the score of the eQTL based motifs was higher than the score of the cluster based motifs. In a comparison to already predicted motifs from the AtcisDB database, the eQTL based and the cluster based method produced about the same number of hits with binding sites from AtcisDB. In conclusion, the results of this study clearly demonstrate the usefulness of eQTL to predict transcription factor binding sites.", - "journal_title": "Journal of bioinformatics and computational biology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/17688316/" - } - ], - "acfbb3e9-6eeb-4541-bd1f-9f460de09958": [ - { - "pub_id": "18369453", - "title": "Genetic networks of liver metabolism revealed by integration of metabolic and transcriptional profiling.", - "authors": "Christine T Ferrara,Ping Wang,Elias Chaibub Neto,Robert D Stevens,James R Bain,Brett R Wenner,Olga R Ilkayeva,Mark P Keller,Daniel A Blasiole,Christina Kendziorski,Brian S Yandell,Christopher B Newgard,Alan D Attie", - "abstract": "Although numerous quantitative trait loci (QTL) influencing disease-related phenotypes have been detected through gene mapping and positional cloning, identification of the individual gene(s) and molecular pathways leading to those phenotypes is often elusive. One way to improve understanding of genetic architecture is to classify phenotypes in greater depth by including transcriptional and metabolic profiling. In the current study, we have generated and analyzed mRNA expression and metabolic profiles in liver samples obtained in an F2 intercross between the diabetes-resistant C57BL/6 leptin(ob/ob) and the diabetes-susceptible BTBR leptin(ob/ob) mouse strains. This cross, which segregates for genotype and physiological traits, was previously used to identify several diabetes-related QTL. Our current investigation includes microarray analysis of over 40,000 probe sets, plus quantitative mass spectrometry-based measurements of sixty-seven intermediary metabolites in three different classes (amino acids, organic acids, and acyl-carnitines). We show that liver metabolites map to distinct genetic regions, thereby indicating that tissue metabolites are heritable. We also demonstrate that genomic analysis can be integrated with liver mRNA expression and metabolite profiling data to construct causal networks for control of specific metabolic processes in liver. As a proof of principle of the practical significance of this integrative approach, we illustrate the construction of a specific causal network that links gene expression and metabolic changes in the context of glutamate metabolism, and demonstrate its validity by showing that genes in the network respond to changes in glutamine and glutamate availability. Thus, the methods described here have the potential to reveal regulatory networks that contribute to chronic, complex, and highly prevalent diseases and conditions such as obesity and diabetes.", - "journal_title": "PLoS genetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/18369453/" - } - ], - "8f8e3312-9697-44c3-9286-70fa9d381c9a": [ - { - "pub_id": "18397884", - "title": "Regulation of TIP60 by ATF2 modulates ATM activation.", - "authors": "Anindita Bhoumik,Netai Singha,Matthew J O'Connell,Ze'ev A Ronai", - "abstract": "TIP60 (HTATIP) is a histone acetyltransferase (HAT) whose function is critical in regulating ataxia-telangiectasia mutated (ATM) activation, gene expression, and chromatin acetylation in DNA repair. Here we show that under non-stressed conditions, activating transcription factor-2 (ATF2) in cooperation with Cul3 ubiquitin ligase promotes degradation of TIP60, thereby attenuating its HAT activity. Inhibiting either ATF2 or Cul3 expression by small interfering RNA stabilizes the TIP60 protein. ATF2 association with TIP60 on chromatin is decreased following exposure to ionizing radiation (IR), resulting in enhanced TIP60 stability and activity. We also identified a panel of melanoma and prostate cancer cell lines whose ATF2 expression is inversely correlated with TIP60 levels and ATM activation after IR. Inhibition of ATF2 expression in these lines restored TIP60 protein levels and both basal and IR-induced levels of ATM activity. Our study provides novel insight into regulation of ATM activation by ATF2-dependent control of TIP60 stability and activity.", - "journal_title": "The Journal of biological chemistry", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/18397884/" - } - ], - "1b31c086-dbd1-4b0d-8b51-c33b074b8e9d": [ - { - "pub_id": "18817551", - "title": "Using gene expression databases for classical trait QTL candidate gene discovery in the BXD recombinant inbred genetic reference population: mouse forebrain weight.", - "authors": "Lu Lu,Lai Wei,Jeremy L Peirce,Xusheng Wang,Jianhua Zhou,Ramin Homayouni,Robert W Williams,David C Airey", - "abstract": "Successful strategies for QTL gene identification benefit from combined experimental and bioinformatic approaches. Unique design aspects of the BXD recombinant inbred line mapping panel allow use of archived gene microarray expression data to filter likely from unlikely candidates. This prompted us to propose a simple five-filter protocol for candidate nomination. To filter more likely from less likely candidates, we required candidate genes near to the QTL to have mRNA abundance that correlated with the phenotype among the BXD lines as well as differed between the parental lines C57BL/6J and DBA/2J. We also required verification of mRNA abundance by an independent method, and finally we required either differences in protein levels or confirmed DNA sequence differences. QTL mapping of mouse forebrain weight in 34 BXD RI lines found significant association on chromosomes 1 and 11, with each C57BL/6J allele increasing weight by more than half a standard deviation. The intersection of gene lists that were within +/- 10 Mb of the strongest associated location, that had forebrain mRNA abundance correlated with forebrain weight among the BXD, and that had forebrain mRNA abundance differing between C57BL/6J and DBA/2J, produced two candidates, Tnni1 (troponin 1) and Asb3 (ankyrin repeat and SOCS box-containing protein 3). Quantitative RT-PCR confirmed the direction of an increased expression in C57BL/6J genotype over the DBA/2J genotype for both genes, a difference that translated to a 2-fold difference in Asb3 protein. Although Tnni1 protein differences could not be confirmed, a 273 bp indel polymorphism was discovered 1 Kb upstream of the transcription start site. Delivery of well supported candidate genes following a single quantitative trait locus mapping experiment is difficult. However, by combining available gene expression data with QTL mapping, we illustrated a five-filter protocol that nominated Asb3 and Tnni1 as candidates affecting increased mouse forebrain weight. We recommend our approach when (1) investigators are working with phenotypic differences between C57BL/6J and DBA/2J, and (2) gene expression data are available on http://www.genenetwork.org that relate to the phenotype of interest. Under these circumstances, measurement of the phenotype in the BXD lines will likely also deliver excellent candidate genes.", - "journal_title": "BMC genomics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/18817551/" - } - ], - "b69858f3-885e-4f80-9e59-7c713c18aa10": [ - { - "pub_id": "19266052", - "title": "A common and unstable copy number variant is associated with differences in Glo1 expression and anxiety-like behavior.", - "authors": "Richard Williams,Jackie E Lim,Bettina Harr,Claudia Wing,Ryan Walters,Margaret G Distler,Meike Teschke,Chunlei Wu,Tim Wiltshire,Andrew I Su,Greta Sokoloff,Lisa M Tarantino,Justin O Borevitz,Abraham A Palmer", - "abstract": "Glyoxalase 1 (Glo1) has been implicated in anxiety-like behavior in mice and in multiple psychiatric diseases in humans. We used mouse Affymetrix exon arrays to detect copy number variants (CNV) among inbred mouse strains and thereby identified a approximately 475 kb tandem duplication on chromosome 17 that includes Glo1 (30,174,390-30,651,226 Mb; mouse genome build 36). We developed a PCR-based strategy and used it to detect this duplication in 23 of 71 inbred strains tested, and in various outbred and wild-caught mice. Presence of the duplication is associated with a cis-acting expression QTL for Glo1 (LOD>30) in BXD recombinant inbred strains. However, evidence for an eQTL for Glo1 was not obtained when we analyzed single SNPs or 3-SNP haplotypes in a panel of 27 inbred strains. We conclude that association analysis in the inbred strain panel failed to detect an eQTL because the duplication was present on multiple highly divergent haplotypes. Furthermore, we suggest that non-allelic homologous recombination has led to multiple reversions to the non-duplicated state among inbred strains. We show associations between multiple duplication-containing haplotypes, Glo1 expression and anxiety-like behavior in both inbred strain panels and outbred CD-1 mice. Our findings provide a molecular basis for differential expression of Glo1 and further implicate Glo1 in anxiety-like behavior. More broadly, these results identify problems with commonly employed tests for association in inbred strains when CNVs are present. Finally, these data provide an example of biologically significant phenotypic variability in model organisms that can be attributed to CNVs.", - "journal_title": "PloS one", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/19266052/" - } - ], - "9ac0b7e7-6294-4cfb-97e3-e5a4546af324": [ - { - "pub_id": "19671078", - "title": "Genetic architecture for hole-board behaviors across substantial time intervals in young, middle-aged and old mice.", - "authors": "J E Foreman,A Lionikas,D H Lang,J P Gyekis,M Krishnan,N A Sharkey,G S Gerhard,M D Grant,G P Vogler,H A Mack,J T Stout,J W Griffith,J M Lakoski,S M Hofer,G E McClearn,D J Vandenbergh,D A Blizard", - "abstract": "A quantitative trait locus (QTL) analysis of behaviors across the life span was conducted in F(2) mice from a C57BL/6J x DBA/2J cross and 22 BXD recombinant inbred (RI) strains. Mice of three age groups were tested in a hole-board apparatus for 3 min on three occasions approximately 1 month apart (average age at test 150, 450 and 750 days, approximately 400 mice per group, divided equally by sex). Quantitative trait loci with small effect size were found on 11 chromosomes for hole-board activity (Hbact) and hole-board rearing (Hbrear). Analysis of 22 RI strains tested at 150 and 450 days of age found only suggestive linkage, with four QTL for Hbact overlapping with those from the F(2) analysis. There was a significant phenotypic correlation between Hbact and Hbrear (approximately 0.55-0.69) and substantial commonality among QTL for the two behaviors. QTL analyses of head-pokes (HP) and fecal boli (FB) only identified QTL at the suggestive level of significance. Age accounted for approximately 15% of the phenotypic variance (sex approximately 3%), and there were genotype by age interactions at approximately 25% of the Hbact and Hbrear QTL. Quantitative trait loci for Hbrear were relatively stable across the three measurement occasions (those for Hbact somewhat less so), although mean levels of each index declined markedly comparing the first to subsequent trials. Considered as a whole, the polygenic system influencing exploratory behaviors accounts for approximately the same amount of phenotypic variance as age (within the range studied), is stable across substantial periods of time, and acts, for the most part, independently of age and sex.", - "journal_title": "Genes, brain, and behavior", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/19671078/" - } - ], - "febf219d-fe24-4612-9731-63b1b1631a0c": [ - { - "pub_id": "19706712", - "title": "Host genetic variation affects resistance to infection with a highly pathogenic H5N1 influenza A virus in mice.", - "authors": "Adrianus C M Boon,Jennifer deBeauchamp,Anna Hollmann,Jennifer Luke,Malak Kotb,Sarah Rowe,David Finkelstein,Geoffrey Neale,Lu Lu,Robert W Williams,Richard J Webby", - "abstract": "Despite the prevalence of H5N1 influenza viruses in global avian populations, comparatively few cases have been diagnosed in humans. Although viral factors almost certainly play a role in limiting human infection and disease, host genetics most likely contribute substantially. To model host factors in the context of influenza virus infection, we determined the lethal dose of a highly pathogenic H5N1 virus (A/Hong Kong/213/03) in C57BL/6J and DBA/2J mice and identified genetic elements associated with survival after infection. The lethal dose in these hosts varied by 4 logs and was associated with differences in replication kinetics and increased production of proinflammatory cytokines CCL2 and tumor necrosis factor alpha in susceptible DBA/2J mice. Gene mapping with recombinant inbred BXD strains revealed five loci or Qivr (quantitative trait loci for influenza virus resistance) located on chromosomes 2, 7, 11, 15, and 17 associated with resistance to H5N1 virus. In conjunction with gene expression profiling, we identified a number of candidate susceptibility genes. One of the validated genes, the hemolytic complement gene, affected virus titer 7 days after infection. We conclude that H5N1 influenza virus-induced pathology is affected by a complex and multigenic host component.", - "journal_title": "Journal of virology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/19706712/" - } - ], - "f7eb4341-2ac1-46c2-aa53-f10df79fbaa8": [ - { - "pub_id": "19702091", - "title": "[Transition of studying on Shen deficiency syndrome and aging from holistic concept to systematic biologic viewpoint].", - "authors": "Zi-Yin Shen,Jian-Hua Huang,Wei Lin", - "abstract": "Holistic concept is a characteristic contribution of Chinese medicine to medical science. Based on holistic concept, we investigated the correlation of Shenyang deficiency syndrome with the hypothalamus-pituitary-target gland axis; and revealed by gene chip technique the molecular network regulatory rule of intervention with Chinese drugs on hypothalamus-pituitary-adrenal-thymus axis in aged rats as a model for Shen deficiency syndrome; also the two major gene regulation pathways, namely, the neuro-endocrine-immune pathway and the neuro-endocrine-bone metabolic pathway, in hypothalamus, pituitary, adrenal, lymphocytes, kidney, liver, bone of aged rats, so as to advance the holistic research on Chinese medicine syndromes. Recently, based on the dynamic, intervention and multi-layer integration requirement of systematic biology, the common rule of aging was found at three different levels, the whole genomic transcription level, the metabolic level and the single ageing signaling pathway level. Meanwhile, it was demonstrated that the temporal and spatial association of genes will be weakened gradually along with aging. And Epimedium Flavonoids (EF), an extracts from Epimedium have been proved to be capable of effectively reversing both of these systemic changes. Thus, the transition of study from holistic concept to systematic biologic viewpoint could surely promote the progression of Chinese medicine to modern life science.", - "journal_title": "Zhongguo Zhong xi yi jie he za zhi Zhongguo Zhongxiyi jiehe zazhi = Chinese journal of integrated traditional and Western medicine", - "languages": [ - "chi" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/19702091/" - } - ], - "b73879de-43a6-48b0-ad69-98afadbfb997": [ - { - "pub_id": "20392957", - "title": "Strain differences in stress responsivity are associated with divergent amygdala gene expression and glutamate-mediated neuronal excitability.", - "authors": "Khyobeni Mozhui,Rose-Marie Karlsson,Thomas L Kash,Jessica Ihne,Maxine Norcross,Sachin Patel,Mollee R Farrell,Elizabeth E Hill,Carolyn Graybeal,Kathryn P Martin,Marguerite Camp,Paul J Fitzgerald,Daniel C Ciobanu,Rolf Sprengel,Masayoshi Mishina,Cara L Wellman,Danny G Winder,Robert W Williams,Andrew Holmes", - "abstract": "Stress is a major risk factor for numerous neuropsychiatric diseases. However, susceptibility to stress and the qualitative nature of stress effects on behavior differ markedly among individuals. This is partly because of the moderating influence of genetic factors. Inbred mouse strains provide a relatively stable and restricted range of genetic and environmental variability that is valuable for disentangling gene-stress interactions. Here, we screened a panel of inbred strains for anxiety- and depression-related phenotypes at baseline (trait) and after exposure to repeated restraint. Two strains, DBA/2J and C57BL/6J, differed in trait and restraint-induced anxiety-related behavior (dark/light exploration, elevated plus maze). Gene expression analysis of amygdala, medial prefrontal cortex, and hippocampus revealed divergent expression in DBA/2J and C57BL/6J both at baseline and after repeated restraint. Restraint produced strain-dependent expression alterations in various genes including glutamate receptors (e.g., Grin1, Grik1). To elucidate neuronal correlates of these strain differences, we performed ex vivo analysis of glutamate excitatory neurotransmission in amygdala principal neurons. Repeated restraint augmented amygdala excitatory postsynaptic signaling and altered metaplasticity (temporal summation of NMDA receptor currents) in DBA/2J but not C57BL/6J. Furthermore, we found that the C57BL/6J-like changes in anxiety-related behavior after restraint were absent in null mutants lacking the modulatory NMDA receptor subunit Grin2a, but not the AMPA receptor subunit Gria1. Grin2a null mutants exhibited significant ( approximately 30%) loss of dendritic spines on amygdala principal neurons under nonrestraint conditions. Collectively, our data support a model in which genetic variation in glutamatergic neuroplasticity in corticolimbic circuitry underlies phenotypic variation in responsivity to stress.", - "journal_title": "The Journal of neuroscience : the official journal of the Society for Neuroscience", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/20392957/" - } - ], - "eb9f360b-8084-4749-a2e7-e9ae0f18bd08": [ - { - "pub_id": "20387131", - "title": "The NIF DISCO Framework: facilitating automated integration of neuroscience content on the web.", - "authors": "Luis Marenco,Rixin Wang,Gordon M Shepherd,Perry L Miller", - "abstract": "This paper describes the capabilities of DISCO, an extensible approach that supports integrative Web-based information dissemination. DISCO is a component of the Neuroscience Information Framework (NIF), an NIH Neuroscience Blueprint initiative that facilitates integrated access to diverse neuroscience resources via the Internet. DISCO facilitates the automated maintenance of several distinct capabilities using a collection of files 1) that are maintained locally by the developers of participating neuroscience resources and 2) that are \"harvested\" on a regular basis by a central DISCO server. This approach allows central NIF capabilities to be updated as each resource's content changes over time. DISCO currently supports the following capabilities: 1) resource descriptions, 2) \"LinkOut\" to a resource's data items from NCBI Entrez resources such as PubMed, 3) Web-based interoperation with a resource, 4) sharing a resource's lexicon and ontology, 5) sharing a resource's database schema, and 6) participation by the resource in neuroscience-related RSS news dissemination. The developers of a resource are free to choose which DISCO capabilities their resource will participate in. Although DISCO is used by NIF to facilitate neuroscience data integration, its capabilities have general applicability to other areas of research.", - "journal_title": "Neuroinformatics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/20387131/" - } - ], - "a31cb6a7-34c4-45d4-9b4b-819122346ede": [ - { - "pub_id": "21836635", - "title": "CREB and ChREBP oppositely regulate SIRT1 expression in response to energy availability.", - "authors": "Lilia G Noriega,J\u00e9r\u00f4me N Feige,Carles Canto,Hiroyasu Yamamoto,Jiujiu Yu,Mark A Herman,Chikage Mataki,Barbara B Kahn,Johan Auwerx", - "abstract": "The nicotinamide adenine dinucleotide (NAD(+))-dependent deacetylase SIRT1 is a major metabolic regulator activated by energy stresses such as fasting or calorie restriction. SIRT1 activation during fasting not only relies on the increase in the NAD(+)/NADH ratio caused by energy deprivation but also involves an upregulation of SIRT1 mRNA and protein levels in various metabolic tissues. We demonstrate that SIRT1 expression is controlled systemically by the activation of the cyclic AMP response-element-binding protein upon low nutrient availability. Conversely, in the absence of energetic stress, the carbohydrate response-element-binding protein represses the expression of SIRT1. Altogether, these results demonstrate that SIRT1 expression is tightly controlled at the transcriptional level by nutrient availability and further underscore that SIRT1 is a crucial metabolic checkpoint connecting the energetic status with transcriptional programmes.", - "journal_title": "EMBO reports", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/21836635/" - } - ], - "c359caaa-2db5-474b-8c55-00a55522cb43": [ - { - "pub_id": "21576457", - "title": "Genetic modulation of horizontal cell number in the mouse retina.", - "authors": "Irene E Whitney,Mary A Raven,Daniel C Ciobanu,Ross A Poch\u00e9,Qian Ding,Yasser Elshatory,Lin Gan,Robert W Williams,Benjamin E Reese", - "abstract": "Neuronal populations display conspicuous variability in their size among individuals, but the genetic sources of this variation are largely undefined. We demonstrate a large and highly heritable variation in neuron number within the mouse retina, affecting a critical population of interneurons, the horizontal cells. Variation in the size of this population maps to the distal end of chromosome (Chr) 13, a region homologous to human Chr 5q11.1-11.2. This region contains two genes known to modulate retinal cell number. Using conditional knock-out mice, we demonstrate that one of these genes, the LIM homeodomain gene Islet-1 (Isl1), plays a role in regulating horizontal cell number. Genetic differences in Isl1 expression are high during the period of horizontal cell production, and cis-regulation of Isl1 expression within the retina is demonstrated directly. We identify a single nucleotide polymorphism in the 5' UTR of Isl1 that creates an E-box sequence as a candidate causal variant contributing to this variation in horizontal cell number.", - "journal_title": "Proceedings of the National Academy of Sciences of the United States of America", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/21576457/" - } - ], - "27e062d0-d5ed-4ee9-8783-f22882284865": [ - { - "pub_id": "22098762", - "title": "Independent genetic loci for sensorimotor gating and attentional performance in BXD recombinant inbred strains.", - "authors": "M Loos,J Staal,T Pattij, ,A B Smit,S Spijker", - "abstract": "A startle reflex in response to an intense acoustic stimulus is inhibited when a barely detectable pulse precedes the startle stimulus by 30-500 ms. It has been theorized that this phenomenon, named prepulse inhibition (PPI) of a startle response, is an automatic early-stage gating process contributing to the ability to focus attention. Deficits in PPI may therefore contribute to deficits in attentional processing. Both deficits are observed in schizophrenia spectrum disorders. Here, we investigated whether there is overlap in genetic control of PPI and attentional processing phenotypes in the panel of BXD recombinant inbred strains of mice. Using an individually titrated prepulse intensity to handle differences in perceived prepulse intensities among strains, we identified a significant quantitative trait locus (QTL) for PPI at the mid-distal end of chromosome 17. A measure of attentional processing in the five-choice serial reaction time task, response variability, mapped to a different locus on proximal-mid chromosome 16. In addition, the estimated genetic and environmental correlations between PPI and several attentional phenotypes were low and not significant. Taken together, the observation of separate genetic loci for PPI and attention and the absence of genetic and environmental correlations indicate that differences in sensorimotor gating do not contribute to differences in attentional performance. Therefore, it is worth pursuing the causative genes residing in both attention and PPI QTL, as these may contribute to separate molecular pathways implicated in neuropsychiatric diseases, such as schizophrenia.", - "journal_title": "Genes, brain, and behavior", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/22098762/" - } - ], - "a45d0b06-9da2-4864-8548-37867c322dca": [ - { - "pub_id": "21374699", - "title": "Peripheral reduction of \u03b2-amyloid is sufficient to reduce brain \u03b2-amyloid: implications for Alzheimer's disease.", - "authors": "J Gregor Sutcliffe,Peter B Hedlund,Elizabeth A Thomas,Floyd E Bloom,Brian S Hilbush", - "abstract": "Three loci that modify \u03b2-amyloid (A\u03b2) accumulation and deposition in the brains of a mouse model of Alzheimer's disease have been previously described. One encompasses the Psen2 gene encoding presenilin 2, a component of the \u03b3-secretase activity responsible for generating A\u03b2 by proteolysis. We show that the activity of mouse Psen2, as measured by levels of mRNA accumulation, unexpectedly is heritable in the liver but not the brain, suggesting liver as the origin of brain A\u03b2 deposits. Administration of STI571, a cancer therapeutic that does not cross the blood-brain barrier, reduced accumulation of A\u03b2 in both the blood and the brain, confirming brain A\u03b2's peripheral origin and suggesting that STI571 and related compounds might have therapeutic/prophylactic value in human Alzheimer's disease. The genes Cib1 and Zfhx1b reside within the other modifier loci and also exhibit heritable expression in the liver, suggesting that they too contribute to A\u03b2 accumulation.", - "journal_title": "Journal of neuroscience research", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/21374699/" - } - ], - "0358c20a-0b2f-42cc-81b1-10b61377695e": [ - { - "pub_id": "27476875", - "title": "A genome-wide association study of heat stress-associated SNPs in catfish.", - "authors": "Y Jin,T Zhou,X Geng,S Liu,A Chen,J Yao,C Jiang,S Tan,B Su,Z Liu", - "abstract": "Heat tolerance is a complex and economically important trait for catfish genetic breeding programs. With global climate change, it is becoming an increasingly important trait. To better understand the molecular basis of heat stress, a genome-wide association study (GWAS) was carried out using the 250\u00a0K catfish SNP array with interspecific backcross progenies, which derived from crossing female channel catfish with male F1 hybrid catfish (female channel catfish\u00a0\u00d7\u00a0male blue catfish). Three significant associated SNPs were detected by performing an EMMAX approach for GWAS. The SNP located on linkage group 14 explained 12.1% of phenotypical variation. The other two SNPs, located on linkage group 16, explained 11.3 and 11.5% of phenotypical variation respectively. A total of 14 genes with heat stress related functions were detected within the significant associated regions. Among them, five genes-TRAF2, FBXW5, ANAPC2, UBR1 and KLHL29- have known functions in the protein degradation process through the ubiquitination pathway. Other genes related to heat stress include genes involved in protein biosynthesis (PRPF4 and SYNCRIP), protein folding (DNAJC25), molecule and iron transport (SLC25A46 and CLIC5), cytoskeletal reorganization (COL12A1) and energy metabolism (COX7A2, PLCB1 and PLCB4) processes. The results provide fundamental information about genes and pathways that is useful for further investigation into the molecular mechanisms of heat stress. The associated SNPs could be promising candidates for selecting heat-tolerant catfish lines after validating their effects on larger and various catfish populations.", - "journal_title": "Animal genetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/27476875/" - } - ], - "f2027d4b-0be7-4b5b-98e1-c7bb91997948": [ - { - "pub_id": "16854212", - "title": "Extracting gene networks for low-dose radiation using graph theoretical algorithms.", - "authors": "Brynn H Voy,Jon A Scharff,Andy D Perkins,Arnold M Saxton,Bhavesh Borate,Elissa J Chesler,Lisa K Branstetter,Michael A Langston", - "abstract": "Genes with common functions often exhibit correlated expression levels, which can be used to identify sets of interacting genes from microarray data. Microarrays typically measure expression across genomic space, creating a massive matrix of co-expression that must be mined to extract only the most relevant gene interactions. We describe a graph theoretical approach to extracting co-expressed sets of genes, based on the computation of cliques. Unlike the results of traditional clustering algorithms, cliques are not disjoint and allow genes to be assigned to multiple sets of interacting partners, consistent with biological reality. A graph is created by thresholding the correlation matrix to include only the correlations most likely to signify functional relationships. Cliques computed from the graph correspond to sets of genes for which significant edges are present between all members of the set, representing potential members of common or interacting pathways. Clique membership can be used to infer function about poorly annotated genes, based on the known functions of better-annotated genes with which they share clique membership (i.e., \"guilt-by-association\"). We illustrate our method by applying it to microarray data collected from the spleens of mice exposed to low-dose ionizing radiation. Differential analysis is used to identify sets of genes whose interactions are impacted by radiation exposure. The correlation graph is also queried independently of clique to extract edges that are impacted by radiation. We present several examples of multiple gene interactions that are altered by radiation exposure and thus represent potential molecular pathways that mediate the radiation response.", - "journal_title": "PLoS computational biology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/16854212/" - } - ], - "e112d62d-d8d7-4560-ae8e-caa4e66c3401": [ - { - "pub_id": "16721604", - "title": "ITGB3 shows genetic and expression interaction with SLC6A4.", - "authors": "Lauren A Weiss,Carole Ober,Edwin H Cook", - "abstract": "Autism affects more males than females and is associated with disturbances of the serotonin system. The integrin beta3 (ITGB3) and serotonin transporter (SLC6A4) genes were both recently identified as male quantitative trait loci (QTLs) for serotonin levels and alleles of each have been associated with autism. Here, we use publicly available genomic resources to determine whether regulation of expression level could be the mechanism behind association between serotonin level and noncoding variation in ITGB3. We also examine whether ITGB3 might interact with SLC6A4 to contribute to autism susceptibility. Using murine and human expression data, we observe that ITGB3 and SLC6A4 expression levels are correlated (0.38<r<0.78). Moreover, genetic variation in ITGB3 is associated with expression of both ITGB3 (P=0.012) and SLC6A4 (P=0.008) in unrelated CEPH individuals. We also show preliminary evidence that genotypes at the ITGB3 and SLC6A4 loci may interact to affect autism susceptibility (P=0.033).", - "journal_title": "Human genetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/16721604/" - } - ], - "c319cee1-8224-46ea-a27e-26a231f9d443": [ - { - "pub_id": "17132818", - "title": "Population and systems genetics analyses of cortisol in pigs divergently selected for stress.", - "authors": "Haja N Kadarmideen,Luc L G Janss", - "abstract": "This study presents a systems genetic analysis on the physiology of cortisol in mice and pigs with an aim to show the potential of a comprehensive computational approach to quickly identify candidate genes and avoid a costly whole-genome quantitative trait locus (QTL) mapping. Population genetics analyses were performed on measurements of cortisol from a pig selection experiment. Expression QTL were mapped and gene networks were built using gene expressions for Crhr1 (corticotrophin-releasing hormone receptor) gene and single nucleotide polymorphisms from public mouse data. Results from mouse data were used to infer potential candidate regulatory genes involved in pig cortisol regulation, using a comparative or translational systems genetics approach. The pig data used were from a 10-yr divergent genetic selection experiment, providing data on 417 individuals. Population genetics analysis showed that cortisol is highly genetically determined with heritabilities of 0.40-0.70. Furthermore, a major gene with an additive effect of 86 ng/ml is segregating. Genetical-genomics investigations revealed two trans-acting eQTL for Crhr1 gene expression on chromosomes 2 and 13. Candidate gene search under trans-eQTL peaks yielded 63 genes for Crhr1 expression phenotypes. Functional links for Crhr1 genes with other genes/proteins in the gene network using mouse data were shown for the first 10 statistically significant genes involved. Results show translational or comparative systems genetics approaches reduce costs and time in large-scale genetics and \"-omics\" investigations. This is the first study to report a strong genetic basis for cortisol physiology using a systems approach.", - "journal_title": "Physiological genomics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/17132818/" - } - ], - "45d48c10-def5-4b02-bc91-0bc6983ce75d": [ - { - "pub_id": "18974798", - "title": "A formal ontology of subcellular neuroanatomy.", - "authors": "Stephen D Larson,Lisa L Fong,Amarnath Gupta,Christopher Condit,William J Bug,Maryann E Martone", - "abstract": "The complexity of the nervous system requires high-resolution microscopy to resolve the detailed 3D structure of nerve cells and supracellular domains. The analysis of such imaging data to extract cellular surfaces and cell components often requires the combination of expert human knowledge with carefully engineered software tools. In an effort to make better tools to assist humans in this endeavor, create a more accessible and permanent record of their data, and to aid the process of constructing complex and detailed computational models, we have created a core of formalized knowledge about the structure of the nervous system and have integrated that core into several software applications. In this paper, we describe the structure and content of a formal ontology whose scope is the subcellular anatomy of the nervous system (SAO), covering nerve cells, their parts, and interactions between these parts. Many applications of this ontology to image annotation, content-based retrieval of structural data, and integration of shared data across scales and researchers are also described.", - "journal_title": "Frontiers in neuroinformatics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/18974798/" - } - ], - "026429a1-4a80-470a-88e9-985aa037605e": [ - { - "pub_id": "17299415", - "title": "How to infer gene networks from expression profiles.", - "authors": "Mukesh Bansal,Vincenzo Belcastro,Alberto Ambesi-Impiombato,Diego di Bernardo", - "abstract": "Inferring, or 'reverse-engineering', gene networks can be defined as the process of identifying gene interactions from experimental data through computational analysis. Gene expression data from microarrays are typically used for this purpose. Here we compared different reverse-engineering algorithms for which ready-to-use software was available and that had been tested on experimental data sets. We show that reverse-engineering algorithms are indeed able to correctly infer regulatory interactions among genes, at least when one performs perturbation experiments complying with the algorithm requirements. These algorithms are superior to classic clustering algorithms for the purpose of finding regulatory interactions among genes, and, although further improvements are needed, have reached a discreet performance for being practically useful.", - "journal_title": "Molecular systems biology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/17299415/" - } - ], - "4d7252b9-48d1-45f2-b891-c87a2a945c5b": [ - { - "pub_id": "17641048", - "title": "The p47 GTPases Iigp2 and Irgb10 regulate innate immunity and inflammation to murine Chlamydia psittaci infection.", - "authors": "Isao Miyairi,Venkat R R Arva Tatireddigari,Olaimatu S Mahdi,Lorne A Rose,Robert J Belland,Lu Lu,Robert W Williams,Gerald I Byrne", - "abstract": "C57BL/6J mice were 10(5)-fold more resistant to Chlamydia psittaci infection than DBA/2J mice by LD(100) determinations. Linkage analysis using BXD recombinant inbred strains revealed a single effector locus at a 1.5-Mbp region on chromosome 11 encoding a cluster of three p47 GTPases (Irgb10, Igtp, and Iigp2). Western blots of infected tissue showed that Irgb10 was elevated in resistant mice and one of the two possible Iigp2 protein isoforms was preferentially expressed in susceptible mice. The BXD39 strain, susceptible at Irgb10 and resistant at Iigp2, had an intermediate phenotype implicating the nonredundant role of these p47 GTPases. C57BL/6J and DBA/2J exhibited a difference in IFN-gamma-dependent chlamydial control, which was reversible by Iigp2 small interfering RNA knockdown. Microarrays of infected peritoneal lavage revealed >10-fold up-regulation of neutrophil-recruiting chemokines in susceptible mice and >100-fold increase in macrophage differentiation genes in resistant mice, indicating that the susceptibility pattern involves the stimulation of different inflammatory cell-recruiting pathways. Massive neutrophil recruitment was seen in susceptible mice by histology and flow cytometry, and neutrophil chemokine receptor (CXCR2) knockout mice on a susceptible background survived a lethal challenge, confirming that neutrophil recruitment was required for susceptibility. Congenic Igtp knockout mice also susceptible at Irgb10 and Iigp2 on a resistant background recruited neutrophils and succumbed to infection. We conclude that Irgb10 and Iigp2 act together to confer differential susceptibility against murine chlamydial infection. Data indicate that these p47 GTPases have cell-autonomous effects that result in vastly different inflammatory stimulations, leading to either recovery or death.", - "journal_title": "Journal of immunology (Baltimore, Md. : 1950)", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/17641048/" - } - ], - "890e3fd6-1482-43e9-891d-8598ae90baaa": [ - { - "pub_id": "18397380", - "title": "Alcohol trait and transcriptional genomic analysis of C57BL/6 substrains.", - "authors": "M K Mulligan,I Ponomarev,S L Boehm,J A Owen,P S Levin,A E Berman,Y A Blednov,J C Crabbe,R W Williams,M F Miles,S E Bergeson", - "abstract": "C57BL/6 inbred mice have been widely used as research models; however, widespread demand has led to the creation of several B6 substrains with markedly different phenotypes. In this study, we report that two substrains of C57BL/6 mice, C57BL/6J (B6J) and C57BL/6NCrl (B6C), separated over 50 years ago at two different breeding facilities differ significantly in alcohol consumption and alcohol preference. The genomes of these two substrains are estimated to differ by only 1-2% of all gene loci, providing a unique opportunity to extract particular expression signatures between these substrains that are associated with quantifiable behavioral differences. Expression profiling of the cortex and striatum, hippocampus, cerebellum and the ventral brain region from alcohol-na\u00efve B6C and B6J mice showed intervals on three chromosomes that are enriched in clusters of coregulated transcripts significantly divergent between the substrains. Additional analysis identified two genomic regions containing putative copy number differences between the substrains. One such region on chromosome 14 contained an estimated 3n copy number in the B6J genome compared with B6C. Within this interval, a gene of unknown function, D14Ertd449e, was found to be both associated with alcohol preference and vary in copy number across several inbred strain lineages. H2afz, Psen1, Wdfy1 and Clu were also identified as candidate genes that may be involved in influencing alcohol consumption.", - "journal_title": "Genes, brain, and behavior", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/18397380/" - } - ], - "660eeb26-fd19-4360-992f-13c499a17467": [ - { - "pub_id": "18599919", - "title": "Dynamic visualization of coexpression in systems genetics data.", - "authors": "Joshua New,Wesley Kendall,Jian Huang,Elissa Chesler", - "abstract": "Biologists hope to address grand scientific challenges by exploring the abundance of data made available through modern microarray technology and other high-throughput techniques. The impact of this data, however, is limited unless researchers can effectively assimilate such complex information and integrate it into their daily research; interactive visualization tools are called for to support the effort. Specifically, typical studies of gene co-expression require novel visualization tools that enable the dynamic formulation and fine-tuning of hypotheses to aid the process of evaluating sensitivity of key parameters. These tools should allow biologists to develop an intuitive understanding of the structure of biological networks and discover genes residing in critical positions in networks and pathways. By using a graph as a universal representation of correlation in gene expression, our system employs several techniques that when used in an integrated manner provide innovative analytical capabilities. Our tool for interacting with gene co-expression data integrates techniques such as: graph layout, qualitative subgraph extraction through a novel 2D user interface, quantitative subgraph extraction using graph-theoretic algorithms or by compound queries, dynamic level-of-detail abstraction, and template-based fuzzy classification. We demonstrate our system using a real-world workflow from a large-scale, systems genetics study of mammalian gene co-expression.", - "journal_title": "IEEE transactions on visualization and computer graphics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/18599919/" - } - ], - "e6029f9d-936f-411e-b55f-828a638e68d6": [ - { - "pub_id": "18189309", - "title": "Genetic analysis reveals polygenic influences on iron, copper, and zinc in mouse hippocampus with neurobiological implications.", - "authors": "Leslie C Jones,John L Beard,Byron C Jones", - "abstract": "Fe, Cu, and Zn are of widespread neurobiological importance, but must be regulated closely as too much or too little of these metals can have adverse effects on brain function. Recent evidence from nutritional models notes that the hippocampus is particularly vulnerable to Fe and Zn deficiencies. We recently performed a quantitative trait loci (QTL) analysis as a preliminary step in identifying genes that contribute to natural variation in hippocampal Fe, Cu, and Zn content. We used ICP-MS to measure the concentrations of these metals in 120-day-old mice from 30 strains of the BXD/TY panel. The BXD/Ty recombinant inbred strain panel is well-suited for complex trait analysis, as all strains are genotyped with a dense marker set and have been phenotyped extensively for neurobehavioral traits and hippocampal gene expression. We observed a wide-range of hippocampal Fe, Cu, and Zn concentrations across the BXD strains. These concentrations were related to systemic Fe status, but not to Fe, Cu, and Zn elsewhere in the brain. The three metals also showed strong covariance, suggestive of overlap in their regulatory pathways. We identified two QTL, on chromosomes 14 and 9, most strongly associated with Cu but also suggestively associated with Fe (chr. 14) and Zn (chr. 9). We also performed genetic correlational analyses with existing data on these strains and revealed associations with cognitive, anxiety-related, and alcohol-related phenotypes. Covariance of these metals with gene expression is also discussed. This work shows that hippocampal Fe, Cu, and Zn are under polygenic influence and that trace metal regulation is associated with hippocampus-related behaviors. Future work will elucidate the genes underlying the two QTL identified, to aid in identifying homologous genetic variants in human populations, which may underlie altered trace metal homeostasis and related neurological disease.", - "journal_title": "Hippocampus", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/18189309/" - } - ], - "bec58804-181a-4683-8e51-0ec6d381da69": [ - { - "pub_id": "23584877", - "title": "Integrative genetic analysis of alcohol dependence using the GeneNetwork Web resources.", - "authors": "Robert W Williams,Lu Lu", - "abstract": "Not long ago, the idea that alcoholism had a genetic basis-even in part-was highly controversial (Goodwin 1971, 1975). Over the past 35 years, however, the contribution of genetic factors has become conventional wisdom. This change to a large extent results from compelling experimental studies utilizing inbred and recombinant inbred (RI) strains of rats and mice (e.g., Crabbe et al. 1983; Crabbe 1983; McClearn 1972). Over the last decade, the focus of genetic research in the alcohol field has shifted away from epidemiological and statistical estimates of alcoholism heritability to molecular studies of single gene variants that have explanatory, predictive, and even therapeutic utility. Large-scale genetic studies such as the Collaborative Study on the Genetics of Alcoholism (COGA) have highlighted variations (i.e., polymorphisms) in numerous genes that are related to alcohol use, abuse, and risk of dependence (for a review, see Edenberg and Foroud 2006). And the list of candidate genes keeps growing. However, just compiling lists of such genes is not satisfying. What is needed is an in-depth understanding of how DNA variants cause differences in alcohol dependence, especially in the context of a myriad of environmental contributing factors, such as diet, stressors, and previous drinking history. This article summarizes some of the challenges associated with generating this understanding and presents a Web-based resource that may aid researchers in better understanding the mechanisms through which alcohol acts on the body and how different genes influence this process.", - "journal_title": "Alcohol research & health : the journal of the National Institute on Alcohol Abuse and Alcoholism", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/23584877/" - } - ], - "c43b0bae-6942-4b17-a598-1f92eec59251": [ - { - "pub_id": "22142176", - "title": "Deletion of alpha-synuclein decreases impulsivity in mice.", - "authors": "Y Pe\u00f1a-Oliver,V L Buchman,J W Dalley,T W Robbins,G Schumann,T L Ripley,S L King,D N Stephens", - "abstract": "The presynaptic protein alpha-synuclein, associated with Parkinson's Disease (PD), plays a role in dopaminergic neurotransmission and is implicated in impulse control disorders (ICDs) such as drug addiction. In this study we investigated a potential causal relationship between alpha-synuclein and impulsivity, by evaluating differences in motor impulsivity in the 5-choice serial reaction time task (5-CSRTT) in strains of mice that differ in the expression of the alpha-synuclein gene. C57BL/6JOlaHsd mice differ from their C57BL/6J ancestors in possessing a chromosomal deletion resulting in the loss of two genes, snca, encoding alpha-synuclein, and mmrn1, encoding multimerin-1. C57BL/6J mice displayed higher impulsivity (more premature responding) than C57BL/6JOlaHsd mice when the pre-stimulus waiting interval was increased in the 5-CSRTT. In order to ensure that the reduced impulsivity was indeed related to snca, and not adjacent gene deletion, wild type (WT) and mice with targeted deletion of alpha-synuclein (KO) were tested in the 5-CSRTT. Similarly, WT mice were more impulsive than mice with targeted deletion of alpha-synuclein. Interrogation of our ongoing analysis of impulsivity in BXD recombinant inbred mouse lines revealed an association of impulsive responding with levels of alpha-synuclein expression in hippocampus. Expression of beta- and gamma-synuclein, members of the synuclein family that may substitute for alpha-synuclein following its deletion, revealed no differential compensations among the mouse strains. These findings suggest that alpha-synuclein may contribute to impulsivity and potentially, to ICDs which arise in some PD patients treated with dopaminergic medication.", - "journal_title": "Genes, brain, and behavior", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/22142176/" - } - ], - "638b3811-7054-4788-a42d-2ccc7bfce1c7": [ - { - "pub_id": "20214801", - "title": "XGAP: a uniform and extensible data model and software platform for genotype and phenotype experiments.", - "authors": "Morris A Swertz,K Joeri van der Velde,Bruno M Tesson,Richard A Scheltema,Danny Arends,Gonzalo Vera,Rudi Alberts,Martijn Dijkstra,Paul Schofield,Klaus Schughart,John M Hancock,Damian Smedley,Katy Wolstencroft,Carole Goble,Engbert O de Brock,Andrew R Jones,Helen E Parkinson, , ,Ritsert C Jansen", - "abstract": "We present an extensible software model for the genotype and phenotype community, XGAP. Readers can download a standard XGAP (http://www.xgap.org) or auto-generate a custom version using MOLGENIS with programming interfaces to R-software and web-services or user interfaces for biologists. XGAP has simple load formats for any type of genotype, epigenotype, transcript, protein, metabolite or other phenotype data. Current functionality includes tools ranging from eQTL analysis in mouse to genome-wide association studies in humans.", - "journal_title": "Genome biology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/20214801/" - } - ], - "621d8b0a-821b-45f8-ae91-aba0cdcdda10": [ - { - "pub_id": "34803653", - "title": "Academic Publication of Neurodegenerative Diseases From a Bibliographic Perspective: A Comparative Scientometric Analysis.", - "authors": "Zhenxin Liao,Wei Wei,Mengling Yang,Xuyuan Kuang,Jian Shi", - "abstract": "<b>Background:</b> For measuring the impact in clinical and scientific research, the citation count of the articles is used in the bibliometric analysis, although there is no comprehensive summary of neurodegenerative disease research. This study intends to provide the neuroscientists and investigators with a practical reference guide to appraise the most important and influential articles written on this subject through a macroscopic view of the research activities on neurodegenerative diseases. <b>Materials and Methods:</b> The Clarivate Analytics Web of Science was searched in July 2020. To ensure the breadth of the search scope, the search terms were confirmed as \"multiple sclerosis\" (MS) or \"amyotrophic lateral sclerosis\" (ALS) or \"Parkinson's\" or \"Alzheimer's\" or \"Huntington's\" or \"neurodegenerative.\" After excluding completely unrelated articles, the top-cited articles were collected and evaluated from special characteristics. The data analysis was performed using SPSS 18.0. The articles were characterized by citation number, publication year, topic, study type, authorship, journal, country, and institute of responding author and foundation. <b>Results:</b> The query identified 593,050 articles. A total of 45% of the top-cited articles were published during 2000-2009, followed by 30 articles from 1990-1999. Diagnosis and pathology were the main research categories (<i>n</i> = 62). Alzheimer's disease (AD) was the main study topic (<i>n</i> = 43). Meanwhile, the United States confirmed the tremendous impact on the field of neurodegenerative diseases. Notably, 69 of 100 articles were studied in the United States, and the National Institutes of Health sponsored 49 articles. There were only 22 articles that can be divided by evidence level. No article was categorized as level 1 evidence. In the journal list with multiple articles, seven of 15 were general journals. The 58 authors, who contributed to more than one article, have been identified by VOSviewer, and the clusters of authors reveal the evolution of research focus in neurodegenerative diseases. <b>Conclusions:</b> This study analyzed the bibliometric characteristics and connections of 100 top-cited articles in the field of neurodegenerative diseases in the Web of Science. Their main outcomes were as follows: First, the pathology and diagnostic researches took a major role in top-cited articles while the therapy articles are relatively less. Second, the United States confirmed the tremendous impact on the field of neurodegenerative diseases. Third, researchers also submitted their researches to general journals, not just focused on specialty journals.", - "journal_title": "Frontiers in aging neuroscience", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/34803653/" - } - ], - "85ee9743-b34d-4d49-9017-d7d2e5d4b996": [ - { - "pub_id": "19303049", - "title": "Detection and interpretation of expression quantitative trait loci (eQTL).", - "authors": "Jacob J Michaelson,Salvatore Loguercio,Andreas Beyer", - "abstract": "Analysis of expression quantitative trait loci (eQTL) provides a means for detecting transcriptional regulatory relationships at a genome-wide scale. Here we explain the eQTL analysis pipeline, we introduce publicly available tools for the statistical analysis, and we discuss issues that might complicate the eQTL mapping process. The detection and interpretation of eQTL requires careful consideration of a range of potentially confounding effects. Particularly population substructure and batch effects may lead to the detection of many false-positive eQTL if not accounted for. Traditionally, most eQTL mapping methods only check for the correlation of single loci with gene expression. In order to detect (epistatic) interactions between distant genetic loci one has to take into account several loci simultaneously. Here, we present the Random Forest regression method as a way of accounting for interacting loci. Next, we introduce analysis methods aiding the biological interpretation of detected eQTL. For example, the notion of local (cis) and distant (trans) eQTL has been very useful for interpreting the causes and implications of eQTL in many studies. In addition, Bayesian networks have been used extensively to infer causal relationships among eQTL and between eQTL and other genetic associations (e.g. disease associated loci). Also, the integration of eQTL with complementary information such as physical protein interaction data may significantly improve statistical power and provide insight into possible molecular mechanisms linking the regulator to its target gene. The eQTL approach is potentially very powerful for the analysis of regulatory pathways affecting disease susceptibility and other relevant traits. However, careful analysis is required to unleash its full potential.", - "journal_title": "Methods (San Diego, Calif.)", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/19303049/" - } - ], - "667f6bd2-ad5e-485a-a0e0-c065d6fea3e0": [ - { - "pub_id": "20148776", - "title": "Human and laboratory rodent low response to alcohol: is better consilience possible?", - "authors": "John C Crabbe,Richard L Bell,Cindy L Ehlers", - "abstract": "If people are brought into the laboratory and given alcohol, there are pronounced differences among individuals in many responses to the drug. Some participants in alcohol challenge protocols show a cluster of 'low level of responses to alcohol' determined by observing post-drinking-related changes in subjective, motor and physiological effects at a given dose level. Those individuals characterized as having low level of response (LR) to alcohol have been shown to be at increased risk for a lifetime diagnosis of alcohol dependence (AD), and this relationship between low LR and AD appears to be in part genetic. LR to alcohol is an area where achieving greater consilience between the human and the rodent phenotypes would seem to be highly likely. However, despite extensive data from both human and rodent studies, few attempts have been made to evaluate the human and animal data systematically in order to understand which aspects of LR appear to be most directly comparable across species and thus the most promising for further study. We review four general aspects of LR that could be compared between humans and laboratory animals: (1) behavioral measures of subjective intoxication; (2) body sway; (3) endocrine responses; and (4) stimulant, autonomic and electrophysiological responses. None of these aspects of LR provide completely face-valid direct comparisons across species. Nevertheless, one of the most replicated findings in humans is the low subjective response, but, as it may reflect either aversively valenced and/or positively valenced responses to alcohol as usually assessed, it is unclear which rodent responses are analogous. Stimulated heart rate appears to be consistent in animal and human studies, although at-risk subjects appear to be more rather than less sensitive to alcohol using this measure. The hormone and electrophysiological data offer strong possibilities of understanding the neurobiological mechanisms, but the rodent data in particular are rather sparse and unsystematic. Therefore, we suggest that more effort is still needed to collect data using refined measures designed to be more directly comparable in humans and animals. Additionally, the genetically mediated mechanisms underlying this endophenotype need to be characterized further across species.", - "journal_title": "Addiction biology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/20148776/" - } - ], - "d45fac79-891e-4890-b8d8-4e1a60edcd2f": [ - { - "pub_id": "21732193", - "title": "Genetic analysis of iron-deficiency effects on the mouse spleen.", - "authors": "Jennifer N Gibson,Leslie C Jellen,Erica L Unger,Grant Morahan,Munish Mehta,Christopher J Earley,Richard P Allen,Lu Lu,Byron C Jones", - "abstract": "Iron homeostasis is crucial to many biological functions in nearly all organisms, with roles ranging from oxygen transport to immune function. Disruption of iron homeostasis may result in iron overload or iron deficiency. Iron deficiency may have severe consequences, including anemia or changes in immune or neurotransmitter systems. Here we report on the variability of phenotypic iron tissue loss and splenomegaly and the associated quantitative trait loci (QTLs), polymorphic areas in the mouse genome that may contain one or more genes that play a role in spleen iron concentration or spleen weight under each dietary treatment. Mice from 26 BXD/Ty recombinant inbred strains, including the parent C57BL/6 and DBA/2 strains, were randomly assigned to adequate iron or iron-deficient diets at weaning. After 120 days, splenomegaly was measured by spleen weight, and spleen iron was assessed using a modified spectrophotometry technique. QTL analyses and gene expression comparisons were then conducted using the WebQTL GeneNetwork. We observed wide, genetic-based variability in splenomegaly and spleen iron loss in BXD/Ty recombinant inbred strains fed an iron-deficient diet. Moreover, we identified several suggestive QTLs. Matching our QTLs with gene expression data from the spleen revealed candidate genes. Our work shows that individual differences in splenomegaly response to iron deficiency are influenced at least partly by genetic constitution. We propose mechanistic hypotheses by which splenomegaly may result from iron deficiency.", - "journal_title": "Mammalian genome : official journal of the International Mammalian Genome Society", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/21732193/" - } - ], - "99857e5b-0e73-4928-9ab2-eccadb50c2fd": [ - { - "pub_id": "19798565", - "title": "Hybrid mice as genetic models of high alcohol consumption.", - "authors": "Y A Blednov,A R Ozburn,D Walker,S Ahmed,J K Belknap,R A Harris", - "abstract": "We showed that F1 hybrid genotypes may provide a broader variety of ethanol drinking phenotypes than the inbred progenitor strains used to create the hybrids (Blednov et al. in Alcohol Clin Exp Res 29:1949-1958, 2005). To extend this work, we characterized alcohol consumption as well as intake of other tastants (saccharin, quinine and sodium chloride) in five inbred strains of mice (FVB, SJL, B6, BUB, NZB) and in their reciprocal F1 hybrids with B6 (FVBxB6; B6xFVB; NZBxB6; B6xNZB; BUBxB6; B6xBUB; SJLxB6; B6xSJL). We also compared ethanol intake in these mice for several concentrations before and after two periods of abstinence. F1 hybrid mice derived from the crosses of B6 and FVB and also B6 and SJL drank higher levels of ethanol than their progenitor strains, demonstrating overdominance for two-bottle choice drinking test. The B6 and NZB hybrid showed additivity in two-bottle choice drinking, whereas the hybrid of B6 and BUB demonstrated full or complete dominance. Genealogical origin, as well as non-alcohol taste preferences (sodium chloride), predicted ethanol consumption. Mice derived from the crosses of B6 and FVB showed high sustained alcohol preference and the B6 and NZB hybrids showed reduced alcohol preference after periods of abstinence. These new genetic models offer some advantages over inbred strains because they provide high, sustained, alcohol intake, and should allow mapping of loci important for the genetic architecture of these traits.", - "journal_title": "Behavior genetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/19798565/" - } - ], - "59829328-fc8d-4007-8109-6d114368e6fc": [ - { - "pub_id": "20813242", - "title": "Genetic variation and brain gene expression in rodent models of alcoholism implications for medication development.", - "authors": "Karl Bj\u00f6rk,Anita C Hansson,Wolfgang H Sommer", - "abstract": "Much research on experimental animals that is aimed to decipher genetic factors involved in alcoholism has been devoted to either models of innate alcohol-related phenotypes or responses after acute alcohol challenge. Such focus has, however, limitations when it comes to the pathogenetic mechanism underlying alcohol addiction, because the progression into the disorder takes years and genetic as well as environmental factors may exert different influences along this trajectory. Animal models of the neuroadaptations involved in the development of dependence exist, but have been difficult to implement for genetic and genomics analysis. Consequently, currently available data have been difficult to reconcile with the human condition and could be misleading in predicting targets for medication development. This review will illustrate strengths and pitfalls of genomic approaches in rodent models of alcoholism and emphasize the need for convergent lines of evidence to improve the predictive value of such studies. Examples of a convergent research approach include validation studies for Agt, Arrb2, Crhr1, Grin3a, and Npy.", - "journal_title": "International review of neurobiology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/20813242/" - } - ], - "0fafb156-8996-4942-8c90-a60dcf0dd8c9": [ - { - "pub_id": "19349225", - "title": "Genetic dissection of the mouse brain using high-field magnetic resonance microscopy.", - "authors": "A Badea,G A Johnson,R W Williams", - "abstract": "Magnetic resonance (MR) imaging has demonstrated that variation in brain structure is associated with differences in behavior and disease state. However, it has rarely been practical to prospectively test causal models that link anatomical and functional differences in humans. In the present study we have combined classical mouse genetics with high-field MR to systematically explore and test such structure-functional relations across multiple brain regions. We segmented 33 regions in two parental strains-C57BL/6J (B) and DBA/2J (D)-and in nine BXD recombinant inbred strains. All strains have been studied extensively for more than 20 years using a battery of genetic, functional, anatomical, and behavioral assays. We compared levels of variation within and between strains and sexes, by region, and by system. Average within-strain variation had a coefficient of variation (CV) of 1.6% for the whole brain; while the CV ranged from 2.3 to 3.6% for olfactory bulbs, cortex and cerebellum, and up to approximately 18% for septum and laterodorsal thalamic nucleus. Variation among strain averages ranged from 6.7% for cerebellum, 7.6% for whole brain, 9.0% for cortex, up to approximately 26% for the ventricles, laterodorsal thalamic nucleus, and the interpeduncular nucleus. Heritabilities averaged 0.60+/-0.18. Sex differences were not significant with the possible (and unexpected) exception of the pons ( approximately 20% larger in males). A correlation matrix of regional volumes revealed high correlations among functionally related parts of the CNS (e.g., components of the limbic system), and several high correlations between regions that are not anatomically connected, but that may nonetheless be functionally or genetically coupled.", - "journal_title": "NeuroImage", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/19349225/" - } - ], - "aef0c2a6-b419-431d-973c-2fd8c8995357": [ - { - "pub_id": "26140590", - "title": "The Convergence of Systems and Reductionist Approaches in Complex Trait Analysis.", - "authors": "Evan G Williams,Johan Auwerx", - "abstract": "Research into the genetic and environmental factors behind complex trait variation has traditionally been segregated into distinct scientific camps. The reductionist approach aims to decrypt phenotypic variability bit by bit, founded on the underlying hypothesis that genome-to-phenome relations are largely constructed from the additive effects of their molecular players. In contrast, the systems approach aims to examine large-scale interactions of many components simultaneously, on the premise that interactions in gene networks can be both linear and non-linear. Both approaches are complementary, and they are becoming increasingly intertwined due to developments in gene editing tools, omics technologies, and population resources. Together, these strategies are beginning to drive the next era in complex trait research, paving the way to improve agriculture and toward more personalized medicine.", - "journal_title": "Cell", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/26140590/" - } - ], - "6cf55c68-43c4-4c0c-a10c-e1c8b80d478a": [ - { - "pub_id": "20055895", - "title": "A catalogue of reporting guidelines for health research.", - "authors": "I Simera,D Moher,J Hoey,K F Schulz,D G Altman", - "abstract": "Growing evidence demonstrates widespread deficiencies in the reporting of health research studies. The EQUATOR Network is an international initiative that aims to enhance the reliability and value of the published health research literature. EQUATOR provides resources, education and training to facilitate good research reporting and assists in the development, dissemination and implementation of robust reporting guidelines. This paper presents a collection of tools and guidelines available on the EQUATOR website (http://www.equator-network.org) that have been developed to increase the accuracy and transparency of health research reporting.", - "journal_title": "European journal of clinical investigation", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/20055895/" - } - ], - "9b830769-1d42-4dce-b529-4e07902c0743": [ - { - "pub_id": "20393561", - "title": "Dissection of genetically complex traits with extremely large pools of yeast segregants.", - "authors": "Ian M Ehrenreich,Noorossadat Torabi,Yue Jia,Jonathan Kent,Stephen Martis,Joshua A Shapiro,David Gresham,Amy A Caudy,Leonid Kruglyak", - "abstract": "Most heritable traits, including many human diseases, are caused by multiple loci. Studies in both humans and model organisms, such as yeast, have failed to detect a large fraction of the loci that underlie such complex traits. A lack of statistical power to identify multiple loci with small effects is undoubtedly one of the primary reasons for this problem. We have developed a method in yeast that allows the use of much larger sample sizes than previously possible and hence permits the detection of multiple loci with small effects. The method involves generating very large numbers of progeny from a cross between two Saccharomyces cerevisiae strains and then phenotyping and genotyping pools of these offspring. We applied the method to 17 chemical resistance traits and mitochondrial function, and identified loci for each of these phenotypes. We show that the level of genetic complexity underlying these quantitative traits is highly variable, with some traits influenced by one major locus and others by at least 20 loci. Our results provide an empirical demonstration of the genetic complexity of a number of traits and show that it is possible to identify many of the underlying factors using straightforward techniques. Our method should have broad applications in yeast and can be extended to other organisms.", - "journal_title": "Nature", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/20393561/" - } - ], - "47c12133-5a30-45b9-bcb8-b96f00737f31": [ - { - "pub_id": "17634591", - "title": "Quantitative trait locus (QTL) mapping in aging systems.", - "authors": "Hui-Chen Hsu,Lu Lu,Nengjun Yi,Gary Van Zant,Robert W Williams,John D Mountz", - "abstract": "Understanding the genetic basis of the effects of aging on the decline in the immune response is an enormous undertaking. The most prominent age-related change in the immune system is thymic involution. This chapter will focus on the use of C57BL/6 J X DBA/2 J (BXD) recombinant inbred (RI) strains of mice to map genetic loci associated with age-related thymic involution in mice. Strategies to improve the power and precision in which complex traits such as the age-related decline in the immune response have been applied to the large set of BXD RI strains to detect quantitative trait loci (QTLs) that underlie thymic involution. More importantly, approaches have been developed to enable higher resolution mapping of these QTLs and, in some cases, may be adequate to carry out direct identification of candidate genes. It is likely that, given the complexity of the immune system development, the number of cells involved in an immune response, and especially the changes in the immune system with aging, multiple genetic loci and genes will contribute to the age-related changes in the immune response. This chapter outlines ongoing and general quantitative genetic linkage strategies that can be used for mapping and identification of the quantitative trait loci that may have a significant impact on age-related alteration of the immune system.", - "journal_title": "Methods in molecular biology (Clifton, N.J.)", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/17634591/" - } - ], - "e8b25f12-846b-4504-978c-8f27ebb889c9": [ - { - "pub_id": "18229682", - "title": "SGDI: system for genomic data integration.", - "authors": "V J Carey,J Gentry,R Sarkar,D Gentleman,S Ramaswamy", - "abstract": "This paper describes a framework for collecting, annotating, and archiving high-throughput assays from multiple experiments conducted on one or more series of samples. Specific applications include support for large-scale surveys of related transcriptional profiling studies, for investigations of the genetics of gene expression and for joint analysis of copy number variation and mRNA abundance. Our approach consists of data capture and modeling processes rooted in R/Bioconductor, sample annotation and sequence constituent ontology management based in R, secure data archiving in PostgreSQL, and browser-based workspace creation and management rooted in Zope. This effort has generated a completely transparent, extensible, and customizable interface to large archives of high-throughput assays. Sources and prototype interfaces are accessible at www.sgdi.org/software.", - "journal_title": "Pacific Symposium on Biocomputing. Pacific Symposium on Biocomputing", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/18229682/" - } - ], - "d333b766-b7e4-4ab5-96a8-50a8a1d805f1": [ - { - "pub_id": "20336428", - "title": "The genetics of pain and analgesia in laboratory animals.", - "authors": "William R Lariviere,Jeffrey S Mogil", - "abstract": "Pain and analgesia traits are heritable in humans and in mice. To better understand the mechanisms of heritability, animal models that provide greater control than is possible in humans over genotype, previous history, environment, and stimulus parameters are available. This chapter will highlight several common methods to study the genetic mechanisms of heritable sensitivity to pain and pain-related traits in rodents. Methods to demonstrate and estimate the heritability of a trait are discussed, as are genetic correlation analysis and linkage mapping. Practical concerns are highlighted throughout this chapter. Due to limitations on the use of humans for similarly powered experiments, these and other animal models remain an essential component in the study of heritable mechanisms of pain and analgesia.", - "journal_title": "Methods in molecular biology (Clifton, N.J.)", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/20336428/" - } - ], - "92adc5ce-c0ec-4ae9-a671-8aa99942215e": [ - { - "pub_id": "16462896", - "title": "Integrative strategies to identify candidate genes in rodent models of human alcoholism.", - "authors": "Julie A Treadwell", - "abstract": "The search for genes underlying alcohol-related behaviours in rodent models of human alcoholism has been ongoing for many years with only limited success. Recently, new strategies that integrate several of the traditional approaches have provided new insights into the molecular mechanisms underlying ethanol's actions in the brain. We have used alcohol-preferring C57BL/6J (B6) and alcohol-avoiding DBA/2J (D2) genetic strains of mice in an integrative strategy combining high-throughput gene expression screening, genetic segregation analysis, and mapping to previously published quantitative trait loci to uncover candidate genes for the ethanol-preference phenotype. In our study, 2 genes, retinaldehyde binding protein 1 (Rlbp1) and syntaxin 12 (Stx12), were found to be strong candidates for ethanol preference. Such experimental approaches have the power and the potential to greatly speed up the laborious process of identifying candidate genes for the animal models of human alcoholism.", - "journal_title": "Genome", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/16462896/" - } - ], - "dc920d9b-f538-460f-9ad8-7c82ea162567": [ - { - "pub_id": "20955750", - "title": "Cross-species behavioural genetics: A starting point for unravelling the neurobiology of human psychiatric disorders.", - "authors": "Annetrude J G de Mooij-van Malsen,Christiaan H Vinkers,Danielle P Peterse,Berend Olivier,Martien J H Kas", - "abstract": "Identifying the genetic and neurobiological mechanisms underlying certain behavioural traits is an important strategy to understand the aetiology of various psychiatric disorders and to find potential new treatment possibilities. It has proven a great challenge to develop paradigms that allow translational research for behavioural phenotypes that are relevant for disorders across the psychiatric spectrum. Recently, there has been increasing attention for studies that implement rodent behavioural paradigms in the home cage to assess the association between genetic backgrounds and behavioural traits. The application of interspecies genetics to unravel these traits has revealed novel insights in the genetic mechanisms that are encoding phenotypes relevant to biological processes underlying psychiatric disorders. By means of two examples, namely the stress-induced hyperthermia paradigm and the home cage environment, this review aims to show that by using individual genetic variations with phenotypes obtained from mice and across categories of neuropsychiatric disorders, novel insights in the neurobiological trajectory of psychiatric disorders can be obtained.", - "journal_title": "Progress in neuro-psychopharmacology & biological psychiatry", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/20955750/" - } - ], - "f7a4ae8c-250f-45b5-94cb-15512485b726": [ - { - "pub_id": "19386926", - "title": "Identification of candidate genes and gene networks specifically associated with analgesic tolerance to morphine.", - "authors": "Jenica D Tapocik,Noah Letwin,Cheryl L Mayo,Bryan Frank,Troung Luu,Ovokeraye Achinike,Carrie House,Russell Williams,Greg I Elmer,Norman H Lee", - "abstract": "Chronic morphine administration may alter the expression of hundreds to thousands of genes. However, only a subset of these genes is likely involved in analgesic tolerance. In this report, we used a behavior genetics strategy to identify candidate genes specifically linked to the development of morphine tolerance. Two inbred genotypes [C57BL/6J (B6), DBA2/J (D2)] and two reciprocal congenic genotypes (B6D2, D2B6) with the proximal region of chromosome 10 (Chr10) introgressed into opposing backgrounds served as the behavior genetic filter. Tolerance after therapeutically relevant doses of morphine developed most rapidly in the B6 followed by the B6D2 genotype and did not develop in the D2 mice and only slightly in the D2B6 animals indicating a strong influence of the proximal region of Chr10 in the development of tolerance. Gene expression profiling and pattern matching identified 64, 53, 86, and 123 predisposition genes and 81, 96, 106, and 82 tolerance genes in the periaqueductal gray (PAG), prefrontal cortex, temporal lobe, and ventral striatum, respectively. A potential gene network was identified in the PAG in which 19 of the 34 genes were strongly associated with tolerance. Eleven of the network genes were found to reside in quantitative trait loci previously associated with morphine-related behaviors, whereas seven were predictive of tolerance (morphine-naive condition). Overall, the genes modified by chronic morphine administration show a strong presence in canonical pathways representative of neuroadaptation. A potentially significant role for the micro-RNA and epigenetic mechanisms in response to chronic administration of pharmacologically relevant doses of morphine was highlighted by candidate genes Dicer and H19.", - "journal_title": "The Journal of neuroscience : the official journal of the Society for Neuroscience", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/19386926/" - } - ], - "a660c093-3ccd-4e57-8734-d25518d7c63a": [ - { - "pub_id": "16643512", - "title": "Defining the dopamine transporter proteome by convergent biochemical and in silico analyses.", - "authors": "R Maiya,I Ponomarev,K D Linse,R A Harris,R D Mayfield", - "abstract": "Monoamine transporters play a key role in neuronal signaling by mediating reuptake of neurotransmitters from the synapse. The function of the dopamine transporter (DAT), an important member of this family of transporters, is regulated by multiple signaling mechanisms, which result in altered cell surface trafficking of DAT. Protein-protein interactions are likely critical for this mode of transporter regulation. In this study, we identified proteins associated with DAT by immunoprecipitation (IP) followed by mass spectrometry. We identified 20 proteins with diverse cellular functions that can be classified as trafficking proteins, cytoskeletal proteins, ion channels and extracellular matrix-associated proteins. DAT was found to associate with the voltage-gated potassium channel Kv2.1 and synapsin Ib, a protein involved in regulating neurotransmitter release. An in silico analysis provided evidence for common transcriptional regulation of the DAT proteome genes. In summary, this study identified a network of proteins that are primary candidates for functional regulation of the DAT, an important player in mechanisms of mental disorders and drug addiction.", - "journal_title": "Genes, brain, and behavior", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/16643512/" - } - ], - "cd11423a-8554-45f6-86c4-0fffd38cc09d": [ - { - "pub_id": "20651944", - "title": "Identifying Genomic Regulators of Set-Wise Co-Expression.", - "authors": "Jung Hoon Woo,Tian Zheng,Ju Han Kim", - "abstract": "The genetical genomics approach has been used to study the genetic basis of variation in gene expression, where putative transcriptional regulators of genes are identified via genetic quantitative trait mapping. The genetic regulators identified through such efforts can partially account for an individual gene's natural variation. However, genes in a molecular pathway often exhibit coordinated activities, the patterns and levels of which are also regulated. In an effort to understand these complicated mechanisms, we propose a method that searches for the genomic regulators of set-wise co-expression of related genes, based on current genetical genomics data. Using this method, we studied genomic regulators of 233 biological pathways for a BXD RI data set. For 15 pathways, we obtained significant regulatory loci after controlling for the false discovery rate. The results presented in this paper constitute important evidence of the heritability of mRNA co-expression between individuals. We have shown that, by defining new phenotypes using existing genetical genomics data, evidence on regulation of co-expression can be derived.", - "journal_title": "Proceedings. IEEE International Symposium on Bioinformatics and Bioengineering", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/20651944/" - } - ], - "7c763113-f03d-4afd-a1aa-7008cfad975e": [ - { - "pub_id": "16783637", - "title": "From genetical genomics to systems genetics: potential applications in quantitative genomics and animal breeding.", - "authors": "Haja N Kadarmideen,Peter von Rohr,Luc L G Janss", - "abstract": "This article reviews methods of integration of transcriptomics (and equally proteomics and metabolomics), genetics, and genomics in the form of systems genetics into existing genome analyses and their potential use in animal breeding and quantitative genomic modeling of complex traits. Genetical genomics or the expression quantitative trait loci (eQTL) mapping method and key findings in this research are reviewed. Various procedures and potential uses of eQTL mapping, global linkage clustering, and systems genetics are illustrated using actual analysis on recombinant inbred lines of mice with data on gene expression (for diabetes- and obesity-related genes), pathway, and single nucleotide polymorphism (SNP) linkage maps. Experimental and bioinformatics difficulties and possible solutions are discussed. The main uses of this systems genetics approach in quantitative genomics were shown to be in refinement of the identified QTL, candidate gene and SNP discovery, understanding gene-environment and gene-gene interactions, detection of candidate regulator genes/eQTL, discriminating multiple QTL/eQTL, and detection of pleiotropic QTL/eQTL, in addition to its use in reconstructing regulatory networks. The potential uses in animal breeding are direct selection on heritable gene expression measures, termed \"expression assisted selection,\" and genetical genomic selection of both QTL and eQTL based on breeding values of the respective genes, termed \"expression-assisted evaluation.\"", - "journal_title": "Mammalian genome : official journal of the International Mammalian Genome Society", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/16783637/" - } - ], - "a9f319e8-f1a4-471e-b2d8-36fe965ba725": [ - { - "pub_id": "16293602", - "title": "The Polycomb group gene Ezh2 prevents hematopoietic stem cell exhaustion.", - "authors": "Leonie M Kamminga,Leonid V Bystrykh,Aletta de Boer,Sita Houwer,Jos\u00e9 Douma,Ellen Weersing,Bert Dontje,Gerald de Haan", - "abstract": "The molecular mechanism responsible for a decline of stem cell functioning after replicative stress remains unknown. We used mouse embryonic fibroblasts (MEFs) and hematopoietic stem cells (HSCs) to identify genes involved in the process of cellular aging. In proliferating and senescent MEFs one of the most differentially expressed transcripts was Enhancer of zeste homolog 2 (Ezh2), a Polycomb group protein (PcG) involved in histone methylation and deacetylation. Retroviral overexpression of Ezh2 in MEFs resulted in bypassing of the senescence program. More importantly, whereas normal HSCs were rapidly exhausted after serial transplantations, overexpression of Ezh2 completely conserved long-term repopulating potential. Animals that were reconstituted with 3 times serially transplanted control bone marrow cells all died due to hematopoietic failure. In contrast, similarly transplanted Ezh2-overexpressing stem cells restored stem cell quality to normal levels. In a \"genetic genomics\" screen, we identified novel putative Ezh2 target or partner stem cell genes that are associated with chromatin modification. Our data suggest that stabilization of the chromatin structure preserves HSC potential after replicative stress.", - "journal_title": "Blood", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/16293602/" - } - ], - "4ecc93d3-af5b-4646-b40d-b557377af0b1": [ - { - "pub_id": "18700840", - "title": "Genetic control of experience-dependent plasticity in the visual cortex.", - "authors": "J A Heimel,J M Hermans,J-P Sommeijer, ,C N Levelt", - "abstract": "Depriving one eye of visual experience during a sensitive period of development results in a shift in ocular dominance (OD) in the primary visual cortex (V1). To assess the heritability of this form of cortical plasticity and identify the responsible gene loci, we studied the influence of monocular deprivation on OD in a large number of recombinant inbred mouse strains derived from mixed C57BL/6J and DBA/2J backgrounds (BXD). The strength of imaged intrinsic signal responses in V1 to visual stimuli was strongly heritable as were various elements of OD plasticity. This has important implications for the use of mice of mixed genetic backgrounds for studying OD plasticity. C57BL/6J showed the most significant shift in OD, while some BXD strains did not show any shift at all. Interestingly, the increase in undeprived ipsilateral eye responses was not correlated to the decrease in deprived contralateral eye responses, suggesting that the size of these components of OD plasticity are not genetically controlled by only a single mechanism. We identified a quantitative trait locus regulating the change in response to the deprived eye. The locus encompasses 13 genes, two of which--Stch and Nrip1--contain missense polymorphisms. The expression levels of Stch and to a lesser extent Nrip1 in whole brain correlate with the trait identifying them as novel candidate plasticity genes.", - "journal_title": "Genes, brain, and behavior", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/18700840/" - } - ], - "78fd5c90-6189-498c-b22d-bc2a958af438": [ - { - "pub_id": "19763934", - "title": "eQTL analysis in mice and rats.", - "authors": "Bruno M Tesson,Ritsert C Jansen", - "abstract": "Since the introduction of genetical genomics in 2001, many studies have been published on various organisms, including mouse and rat. Genetical genomics makes use of the latest microarray profiling technologies and combines vast amounts of genotype and gene expression information, a strategy that has proven very successful in inbred line crosses. The data are analyzed using standard tools for linkage analysis to map the genetic determinants of gene expression variation. Typically, studies have singled out hundreds of genomic loci regulating the expression of nearby and distant genes (called local and distant expression quantitative trait loci, respectively; eQTLs). In this chapter, we provide a step-by-step guide to performing genome-wide linkage analysis in an eQTL mapping experiment by using the R statistical software framework.", - "journal_title": "Methods in molecular biology (Clifton, N.J.)", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/19763934/" - } - ], - "f0bf9619-6bb9-41c7-9d2b-51d9b650d5b2": [ - { - "pub_id": "19609828", - "title": "Replication and narrowing of gene expression quantitative trait loci using inbred mice.", - "authors": "Daniel M Gatti,Alison H Harrill,Fred A Wright,David W Threadgill,Ivan Rusyn", - "abstract": "Gene expression quantitative trait locus (eQTL) mapping has become a powerful tool in systems biology. While many authors have made important discoveries using this approach, one persistent challenge in eQTL studies is the selection of loci and genes that should receive further biological investigation. In this study we compared eQTL generated from gene expression profiling in the livers of two panels of mouse strains: 41 BXD recombinant inbred and 36 Mouse Diversity Panel (MDP) strains. Cis-eQTL, loci in which the transcript and its maximum QTL are colocated, have been shown to be more reproducible than trans-eQTL, which are not colocated with the transcript. We observed that between 9.9 and 12.1% of cis-eQTL and between 2.0 and 12.6% of trans-eQTL replicated between the two panels depending on the degree of statistical stringency. Notably, a significant eQTL hotspot on distal chromosome 12 observed in the BXD panel was reproduced in the MDP. Furthermore, the shorter linkage disequilibrium in the MDP strains allowed us to considerably narrow the locus and limit the number of candidate genes to a cluster of Serpin genes, which code for extracellular proteases. We conclude that this strategy has some utility in increasing confidence and resolution in eQTL mapping studies; however, due to the high false-positive rate in the MDP, eQTL mapping in inbred strains is best carried out in combination with an eQTL linkage study.", - "journal_title": "Mammalian genome : official journal of the International Mammalian Genome Society", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/19609828/" - } - ], - "1fb6e4db-79c1-49c9-a358-3414f6a674da": [ - { - "pub_id": "19191878", - "title": "Genetic modulation of striatal volume by loci on Chrs 6 and 17 in BXD recombinant inbred mice.", - "authors": "G D Rosen,C J Pung,C B Owens,J Caplow,H Kim,K Mozhui,L Lu,R W Williams", - "abstract": "Natural variation in the absolute and relative size of different parts of the human brain is substantial, with a range that often exceeds a factor of 2. Much of this variation is generated by the cumulative effects of sets of unknown gene variants that modulate the proliferation, growth and death of neurons and glial cells. Discovering and testing the functions of these genes should contribute significantly to our understanding of differences in brain development, behavior and disease susceptibility. We have exploited a large population of genetically well-characterized strains of mice (BXD recombinant inbred strains) to map gene variants that influence the volume of the dorsal striatum (caudate-putamen without nucleus accumbens). We used unbiased methods to estimate volumes bilaterally in a sex-balanced sample taken from the Mouse Brain Library (www.mbl.org). We generated a matched microarray data set to efficiently evaluate candidate genes (www.genenetwork.org). As in humans, volume of the striatum is highly heritable, with greater than twofold differences among strains. We mapped a locus that modulates striatal volume on chromosome (Chr) 6 at 88 +/- 5 Mb. We also uncovered an epistatic interaction between loci on Chr 6 and Chr 17 that modulates striatal volume. Using bioinformatic tools and the corresponding expression database, we have identified positional candidates in these quantitative trait locus intervals.", - "journal_title": "Genes, brain, and behavior", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/19191878/" - } - ], - "ce9c656d-58a8-44ea-b4a4-36206f1177cf": [ - { - "pub_id": "18059552", - "title": "Analysis of behavior using genetical genomics in mice as a model: from alcohol preferences to gene expression differences.", - "authors": "Shiva M Singh,Julie Treadwell,Morgan L Kleiber,Michelle Harrison,Raihan K Uddin", - "abstract": "Most familial behavioral phenotypes result from the complex interaction of multiple genes. Studies of such phenotypes involving human subjects are often inconclusive owing to complexity of causation and experimental limitations. Studies of animal models argue for the use of established genetic strains as a powerful tool for genetic dissection of behavioral disorders and have led to the identification of rare genes and genetic mechanisms implicated in such phenotypes. We have used microarrays to study global gene expression in adult brains of four genetic strains of mice (C57BL/6J, DBA/2J, A/J, and BALB/c). Our results demonstrate that different strains show expression differences for a number of genes in the brain, and that closely related strains have similar patterns of gene expression as compared with distantly related strains. In addition, among the 24 000 genes and ESTs on the microarray, 77 showed at least a 1.5-fold increase in the brains of C57BL/6J mice as compared with those of DBA/2J mice. These genes fall into such functional categories as gene regulation, metabolism, cell signaling, neurotransmitter transport, and DNA/RNA binding. The importance of these findings as a novel genetic resource and their use and application in the genetic analysis of complex behavioral phenotypes, susceptibilities, and responses to drugs and chemicals are discussed.", - "journal_title": "Genome", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/18059552/" - } - ], - "8cb01ffe-ccb5-46cc-be9f-cbc85d3a470b": [ - { - "pub_id": "17676974", - "title": "Aging hematopoietic stem cells decline in function and exhibit epigenetic dysregulation.", - "authors": "Stuart M Chambers,Chad A Shaw,Catherine Gatza,C Joseph Fisk,Lawrence A Donehower,Margaret A Goodell", - "abstract": "Age-related defects in stem cells can limit proper tissue maintenance and hence contribute to a shortened lifespan. Using highly purified hematopoietic stem cells from mice aged 2 to 21 mo, we demonstrate a deficit in function yet an increase in stem cell number with advancing age. Expression analysis of more than 14,000 genes identified 1,500 that were age-induced and 1,600 that were age-repressed. Genes associated with the stress response, inflammation, and protein aggregation dominated the up-regulated expression profile, while the down-regulated profile was marked by genes involved in the preservation of genomic integrity and chromatin remodeling. Many chromosomal regions showed coordinate loss of transcriptional regulation; an overall increase in transcriptional activity with age and inappropriate expression of genes normally regulated by epigenetic mechanisms was also observed. Hematopoietic stem cells from early-aging mice expressing a mutant p53 allele reveal that aging of stem cells can be uncoupled from aging at an organismal level. These studies show that hematopoietic stem cells are not protected from aging. Instead, loss of epigenetic regulation at the chromatin level may drive both functional attenuation of cells, as well as other manifestations of aging, including the increased propensity for neoplastic transformation.", - "journal_title": "PLoS biology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/17676974/" - } - ], - "e17b5b05-4676-4b3d-a625-74d453c342bd": [ - { - "pub_id": "17158111", - "title": "Marker-assisted selection to improve drought adaptation in maize: the backcross approach, perspectives, limitations, and alternatives.", - "authors": "Jean-Marcel Ribaut,Michel Ragot", - "abstract": "A number of different marker-assisted selection (MAS) approaches do exist for the improvement of polygenic traits. Results of a marker-assisted backcross (MABC) selection experiment aimed at improving grain yield under drought conditions in tropical maize are presented and compared with alternative MAS strategies. The introgression of favourable alleles at five target regions involved in the expression of yield components and flowering traits increased grain yield and reduced the asynchrony between male and female flowering under water-limited conditions. Eighty-five per cent of the recurrent parent's genotype at non-target loci was recovered in only four generations of MABC by screening large segregating populations (2200 individuals) for three of the four generations. Selected MABC-derived BC(2)F(3) families were crossed with two testers and evaluated under different water regimes. Mean grain yield of MABC-derived hybrids was consistently higher than that of control hybrids (crosses from the recurrent parent to the same two testers as the MABC-derived families) under severe water stress conditions. Under those conditions, the best five MABC-derived hybrids yielded, on average, at least 50% more than control hybrids. Under mild water stress, defined as resulting in <50% yield reduction, no difference was observed between MABC-derived hybrids and the control plants, thus confirming that the genetic regulation for drought tolerance is dependent on stress intensity. MABC conversions involving several target regions are likely to result in partial rather than complete line conversion. Simulations were conducted to assess the utility of such partial conversions, i.e. containing favourable donor alleles at non-target regions, for subsequent phenotypic selection. The results clearly showed that selecting several genotypes (10-20) at each MABC cycle was most efficient. In the light of these results, alternative approaches to MABC are discussed, including recurrent selection, illustrated by an example of improving the adaptation of maize to low temperatures. Given the current approaches for MAS and the choices of marker technologies available now and potential for future developments, the use of MAS techniques in further improving grain yield under abiotic stresses in maize appears very promising.", - "journal_title": "Journal of experimental botany", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/17158111/" - } - ], - "4b92915e-2b8c-4d82-a8a3-5beefb7b6335": [ - { - "pub_id": "25837970", - "title": "Prediction of Juvenile-Onset Myopia.", - "authors": "Karla Zadnik,Loraine T Sinnott,Susan A Cotter,Lisa A Jones-Jordan,Robert N Kleinstein,Ruth E Manny,J Daniel Twelker,Donald O Mutti, ", - "abstract": "Myopia (nearsightedness) has its onset in childhood and affects about one-third of adults in the United States. Along with its high prevalence, myopia is expensive to correct and is associated with ocular diseases that include glaucoma and retinal detachment. To determine the best set of predictors for myopia onset in school-aged children. The Collaborative Longitudinal Evaluation of Ethnicity and Refractive Error (CLEERE) Study was an observational cohort study of ocular development and myopia onset conducted at 5 clinical sites from September 1, 1989, through May 22, 2010. Data were collected from 4512 ethnically diverse, nonmyopic school-aged children from grades 1 through 8 (baseline grades 1 through 6) (ages 6 through 13 years [baseline, 6 through 11 years]). We evaluated 13 candidate risk factors for their ability to predict the onset of myopia. Myopia onset was defined as -0.75 diopters or more of myopia in each principal meridian in the right eye as measured by cycloplegic autorefraction at any visit after baseline until grade 8 (age 13 years). We evaluated risk factors using odds ratios from discrete time survival analysis, the area under the curve, and cross validation. A total of 414 children became myopic from grades 2 through 8 (ages 7 through 13 years). Of the 13 factors evaluated, 10 were associated with the risk for myopia onset (P\u2009<\u2009.05). Of these 10 factors, 8 retained their association in multivariate models: spherical equivalent refractive error at baseline, parental myopia, axial length, corneal power, crystalline lens power, ratio of accommodative convergence to accommodation (AC/A ratio), horizontal/vertical astigmatism magnitude, and visual activity. A less hyperopic/more myopic baseline refractive error was consistently associated with risk of myopia onset in multivariate models (odds ratios from 0.02 to 0.13, P\u2009<\u2009.001), while near work, time outdoors, and having myopic parents were not. Spherical equivalent refractive error was the single best predictive factor that performed as well as all 8 factors together, with an area under the curve (C statistic) ranging from 0.87 to 0.93 (95% CI, 0.79-0.99). Future myopia can be predicted in a nonmyopic child using a simple, single measure of refractive error. Future trials for prevention of myopia should target the child with low hyperopia as the child at risk.", - "journal_title": "JAMA ophthalmology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/25837970/" - } - ], - "425aaeb9-f6db-42e8-8613-3878131421f6": [ - { - "pub_id": "17911164", - "title": "Insights from spatially mapped gene expression in the mouse brain.", - "authors": "Susan M Sunkin,John G Hohmann", - "abstract": "The growing number of publicly available databases of murine gene expression arising from genomic-scale transcriptome/proteome profiling projects allows open access to information about genes potentially involved in diseases and disorders of the brain. The use of various methodologies by myriad projects provides complementary types of information, ranging from easily quantifiable microarray data for gross brain regions, to transcript tag analysis and proteomic characterization. One mode of gene expression analysis that has recently been widely adopted is the utilization of colorimetric in situ hybridization. This approach is adaptable for high throughput production, and provides a reproducible, scaleable platform for large datasets. The Allen Brain Atlas in particular has utilized this technology to produce a genomic-scale anatomical digital atlas of gene expression in the adult male mouse brain. The availability of global datasets with cellular level spatial resolution, which can be easily parsed due to accessible informatics-derived image analysis tools, can provide both high level and detailed insights into gene regulation. This article reviews various gene expression profiling projects in the mouse brain, how these data sets are increasingly used to complement other studies and applications of these datasets to further understanding of neurological disease.", - "journal_title": "Human molecular genetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/17911164/" - } - ], - "4e9e4661-4312-47d1-ad0e-eb40ac674012": [ - { - "pub_id": "15714040", - "title": "Alcohol effects on central nervous system gene expression in genetic animal models.", - "authors": "William J McBride,Robnet T Kerns,Zachary A Rodd,Wendy N Strother,Howard J Edenberg,Joel G Hashimoto,Kristine M Wiren,Michael F Miles", - "abstract": "This article summarizes the proceedings of a symposium presented at the 2004 annual meeting of the Research Society on Alcoholism in Vancouver, British Columbia, Canada. The organizers and chairs were William J. McBride and Michael F. Miles. The presentations were (1) Molecular Triangulation on Gene Expression Patterns in Behavioral Responses to Acute Ethanol, by Robnet T. Kerns; (2) Gene Expression in Limbic Regions After Ethanol Self-Infusion Into the Posterior Ventral Tegmental Area, by Zachary A. Rodd; (3) Microarray Analysis of CNS Limbic Regions of Inbred Alcohol-Preferring and -Nonpreferring rats and Effects of Alcohol Drinking, by Wendy N. Strother and Howard J. Edenberg; and (4) Microarray Analysis of Mouse Lines Selected for Chronic Ethanol Withdrawal Severity: The Convergence of Basal, Ethanol Regulated, and Proximity to Ethanol Quantitative Trait Loci to Identify Candidate Genes, by Joel G. Hashimoto and Kristine M. Wiren.", - "journal_title": "Alcoholism, clinical and experimental research", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/15714040/" - } - ], - "98e1aa99-f179-455d-9d0b-ab63d2bf19e6": [ - { - "pub_id": "22052878", - "title": "Cardiac physiologic and genetic predictors of hyperoxia-induced acute lung injury in mice.", - "authors": "Reuben Howden,Hye-Youn Cho,Laura Miller-DeGraff,Christopher Walker,James A Clark,Page H Myers,D Clay Rouse,Steven R Kleeberger", - "abstract": "Exposure of mice to hyperoxia produces pulmonary toxicity similar to acute lung injury/acute respiratory distress syndrome, but little is known about the interactions within the cardiopulmonary system. This study was designed to characterize the cardiopulmonary response to hyperoxia, and to identify candidate susceptibility genes in mice. Electrocardiogram and ventilatory data were recorded continuously from 4 inbred and 29 recombinant inbred strains during 96 hours of hyperoxia (100% oxygen). Genome-wide linkage analysis was performed in 27 recombinant inbred strains against response time indices (TIs) calculated from each cardiac phenotype. Reductions in minute ventilation, heart rate (HR), low-frequency (LF) HR variability (HRV), high-frequency HRV, and total power HRV were found in all mice during hyperoxia exposure, but the lag time before these changes began was strain dependent. Significant (chromosome 9) or suggestive (chromosomes 3 and 5) quantitative trait loci were identified for the HRTI and LFTI. Functional polymorphisms in several candidate susceptibility genes were identified within the quantitative trait loci and were associated with hyperoxia susceptibility. This is the first study to report highly significant interstrain variation in hyperoxia-induced changes in minute ventilation, HR, and HRV, and to identify polymorphisms in candidate susceptibility genes that associate with cardiac responses. Results indicate that changes in HR and LF HRV could be important predictors of subsequent adverse outcome during hyperoxia exposure, specifically the pathogenesis of acute lung injury. Understanding the genetic mechanisms of these responses may have significant diagnostic clinical value.", - "journal_title": "American journal of respiratory cell and molecular biology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/22052878/" - } - ], - "3278febd-171a-485d-bd6e-0cbb523d73ec": [ - { - "pub_id": "20849587", - "title": "Data-driven assessment of eQTL mapping methods.", - "authors": "Jacob J Michaelson,Rudi Alberts,Klaus Schughart,Andreas Beyer", - "abstract": "The analysis of expression quantitative trait loci (eQTL) is a potentially powerful way to detect transcriptional regulatory relationships at the genomic scale. However, eQTL data sets often go underexploited because legacy QTL methods are used to map the relationship between the expression trait and genotype. Often these methods are inappropriate for complex traits such as gene expression, particularly in the case of epistasis. Here we compare legacy QTL mapping methods with several modern multi-locus methods and evaluate their ability to produce eQTL that agree with independent external data in a systematic way. We found that the modern multi-locus methods (Random Forests, sparse partial least squares, lasso, and elastic net) clearly outperformed the legacy QTL methods (Haley-Knott regression and composite interval mapping) in terms of biological relevance of the mapped eQTL. In particular, we found that our new approach, based on Random Forests, showed superior performance among the multi-locus methods. Benchmarks based on the recapitulation of experimental findings provide valuable insight when selecting the appropriate eQTL mapping method. Our battery of tests suggests that Random Forests map eQTL that are more likely to be validated by independent data, when compared to competing multi-locus and legacy eQTL mapping methods.", - "journal_title": "BMC genomics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/20849587/" - } - ], - "34424b41-1c8b-4c76-8d37-883ab85a2758": [ - { - "pub_id": "18542913", - "title": "Exploiting regulatory variation to identify genes underlying quantitative resistance to the wheat stem rust pathogen Puccinia graminis f. sp. tritici in barley.", - "authors": "Arnis Druka,Elena Potokina,Zewei Luo,Nicola Bonar,Ilze Druka,Ling Zhang,David F Marshall,Brian J Steffenson,Timothy J Close,Roger P Wise,Andris Kleinhofs,Robert W Williams,Michael J Kearsey,Robbie Waugh", - "abstract": "We previously mapped mRNA transcript abundance traits (expression-QTL or eQTL) using the Barley1 Affymetrix array and 'whole plant' tissue from 139 progeny of the Steptoe x Morex (St/Mx) reference barley mapping population. Of the 22,840 probesets (genes) on the array, 15,987 reported transcript abundance signals that were suitable for eQTL analysis, and this revealed a genome-wide distribution of 23,738 significant eQTLs. Here we have explored the potential of using these mRNA abundance eQTL traits as surrogates for the identification of candidate genes underlying the interaction between barley and the wheat stem rust fungus Puccinia graminis f. sp. tritici. We re-analysed quantitative 'resistance phenotype' data collected on this population in 1990/1991 and identified six loci associated with barley's reaction to stem rust. One of these coincided with the major stem rust resistance locus Rpg1, that we had previously positionally cloned using this population. Correlation analysis between phenotype values for rust infection and mRNA abundance values reported by the 22,840 GeneChip probe sets placed Rpg1, which is on the Barley1 GeneChip, in the top five candidate genes for the major QTL on chromosome 7H corresponding to the location of Rpg1. A second co-located with the rpg4/Rpg5 stem rust resistance locus that has been mapped in a different population and the remaining four were novel. Correlation analyses identified candidate genes for the rpg4/Rpg5 locus on chromosome 5H. By combining our data with additional published mRNA profiling data sets, we identify a putative sensory transduction histidine kinase as a strong candidate for a novel resistance locus on chromosome 2H and compile candidate gene lists for the other three loci.", - "journal_title": "TAG. Theoretical and applied genetics. Theoretische und angewandte Genetik", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/18542913/" - } - ], - "f93a3518-76b8-4ef8-b3dd-d2131829ac97": [ - { - "pub_id": "16803863", - "title": "Confirmation and fine mapping of ethanol sensitivity quantitative trait loci, and candidate gene testing in the LXS recombinant inbred mice.", - "authors": "Beth Bennett,Phyllis Carosone-Link,Nancy R Zahniser,Thomas E Johnson", - "abstract": "In previous studies, we have mapped quantitative trait loci (QTLs) for hypnotic sensitivity to ethanol using a small recombinant inbred (RI) panel and a large F(2) backcross. Alcohol sensitivity is a major predictor of long-term risk for alcoholism. We remapped hypnotic sensitivity using a new set of 75 RI strains, the LXS, derived from Inbred Long Sleep and Inbred Short Sleep strains. We expected to improve mapping resolution in the QTL regions and to identify novel QTLs for loss of the righting reflex due to ethanol. We used three common mapping algorithms (R/qtl, QTL Cartographer, and WebQTL) to map QTLs in the LXS, and we compared the results. Most mapping studies use only a single algorithm, an approach that may result in failure to identify minor QTLs. We confirmed most of our previously reported QTLs, although one major QTL from earlier work (Lore2) failed to replicate, possibly because it represented multiple linked genes separated by recombination in the RI strains. We also report narrowed confidence intervals, based on mapping with a new genetic resource of more than 4000 polymorphic single-nucleotide polymorphism markers. These narrowed confidence intervals will facilitate candidate gene identification and assessment of overlap with human regions specifying risk for alcoholism. Finally, we present an approach for using these RI strains to assess evidence for candidate genes in the narrowed intervals, and we apply this method to a strong candidate, the serotonin transporter.", - "journal_title": "The Journal of pharmacology and experimental therapeutics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/16803863/" - } - ], - "a440a3fa-74e7-4fd8-8a7f-d0391300d6ed": [ - { - "pub_id": "19339679", - "title": "Experimental evolution with Drosophila.", - "authors": "Molly K Burke,Michael R Rose", - "abstract": "Experimental evolution is a powerful approach that can be used for the study of adaptation. Evolutionary biologists often use Drosophila as a model organism in experiments that test theories about the evolution of traits related to fitness. Such evolution experiments can take three forms: direct selection for a trait of interest; surveys of traits of interest in populations selected for other traits; and reverse selection. We review some of the Drosophila experiments that have provided insight into both the evolution of particular physiological traits and the correlations between physiological and life history traits, focusing on stress resistance. The most common artifacts that can obscure the results from evolution experiments are discussed. We also include a treatment of genomic technologies that are now available for the Drosophila model. The primary goal of this review is to introduce the kind of experimental evolution strategies and technologies that evolutionary physiologists might use in the future.", - "journal_title": "American journal of physiology. Regulatory, integrative and comparative physiology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/19339679/" - } - ], - "9981a933-8fdf-4107-a6fd-3f9ef71f5d08": [ - { - "pub_id": "19733230", - "title": "Ontological Discovery Environment: a system for integrating gene-phenotype associations.", - "authors": "Erich J Baker,Jeremy J Jay,Vivek M Philip,Yun Zhang,Zuopan Li,Roumyana Kirova,Michael A Langston,Elissa J Chesler", - "abstract": "The wealth of genomic technologies has enabled biologists to rapidly ascribe phenotypic characters to biological substrates. Central to effective biological investigation is the operational definition of the process under investigation. We propose an elucidation of categories of biological characters, including disease relevant traits, based on natural endogenous processes and experimentally observed biological networks, pathways and systems rather than on externally manifested constructs and current semantics such as disease names and processes. The Ontological Discovery Environment (ODE) is an Internet accessible resource for the storage, sharing, retrieval and analysis of phenotype-centered genomic data sets across species and experimental model systems. Any type of data set representing gene-phenotype relationships, such quantitative trait loci (QTL) positional candidates, literature reviews, microarray experiments, ontological or even meta-data, may serve as inputs. To demonstrate a use case leveraging the homology capabilities of ODE and its ability to synthesize diverse data sets, we conducted an analysis of genomic studies related to alcoholism. The core of ODE's gene set similarity, distance and hierarchical analysis is the creation of a bipartite network of gene-phenotype relations, a unique discrete graph approach to analysis that enables set-set matching of non-referential data. Gene sets are annotated with several levels of metadata, including community ontologies, while gene set translations compare models across species. Computationally derived gene sets are integrated into hierarchical trees based on gene-derived phenotype interdependencies. Automated set identifications are augmented by statistical tools which enable users to interpret the confidence of modeled results. This approach allows data integration and hypothesis discovery across multiple experimental contexts, regardless of the face similarity and semantic annotation of the experimental systems or species domain.", - "journal_title": "Genomics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/19733230/" - } - ], - "3e0963bf-5926-4986-a4c2-a6a4afd8e3ea": [ - { - "pub_id": "16910173", - "title": "Quantitative genetic analysis of brain copper and zinc in BXD recombinant inbred mice.", - "authors": "Leslie C Jones,Kristin A McCarthy,John L Beard,Carl L Keen,Byron C Jones", - "abstract": "Copper and zinc are trace nutrients essential for normal brain function, yet an excess of these elements can be toxic. It is important therefore that these metals be closely regulated. We recently conducted a quantitative trait loci (QTL) analysis to identify chromosomal regions in the mouse containing possible regulatory genes. The animals came from 15 strains of the BXD/Ty recombinant inbred (RI) strain panel and the brain regions analyzed were frontal cortex, caudate-putamen, nucleus accumbens and ventral midbrain. Several QTL were identified for copper and/or zinc, most notably on chromosomes 1, 8, 16 and 17. Genetic correlational analysis also revealed associations between these metals and dopamine, cocaine responses, saccharine preference, immune response and seizure susceptibility. Notably, the QTL on chromosome 17 is also associated with seizure susceptibility and contains the histocompatibility H2 complex. This work shows that regulation of zinc and copper is under polygenic influence and is intimately related to CNS function. Future work will reveal genes underlying the QTL and how they interact with other genes and the environment. More importantly, revelation of the genetic underpinnings of copper and zinc brain homeostasis will aid our understanding of neurological diseases that are related to copper and zinc imbalance.", - "journal_title": "Nutritional neuroscience", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/16910173/" - } - ], - "c01dd79e-7dbb-40e1-b493-08f8e4fe05fc": [ - { - "pub_id": "17175815", - "title": "From gene to behavior and back again: new perspectives on GABAA receptor subunit selectivity of alcohol actions.", - "authors": "Stephen L Boehm,Igor Ponomarev,Yuri A Blednov,R Adron Harris", - "abstract": "gamma-Aminobutyric acid A (GABA(A)) receptors are believed to mediate a number of alcohol's behavioral actions. Because the subunit composition of GABA(A) receptors determines receptor pharmacology, behavioral sensitivity to alcohol (ethanol) may depend on which subunits are present (or absent). A number of knockout and/or transgenic mouse models have been developed (alpha1, alpha2, alpha5, alpha6, beta2, beta3, gamma2S, gamma2L, delta) and tested for behavioral sensitivity to ethanol. Here we review the current GABA(A) receptor subunit knockout and transgenic literature for ethanol sensitivity, and integrate these results into those obtained using quantitative trait loci (QTL) analysis and gene expression assays. Converging evidence from these three approaches support the notion that different behavioral actions of ethanol are mediated by specific subunits, and suggest that new drugs that target specific GABA(A subunits may selectively alter some behavioral actions of ethanol without altering others. Current data sets provide stronge)st evidence for a role of alpha1 subunits in ethanol-induced loss of righting reflex and alpha5 subunits in ethanol-stimulated locomotion. Nevertheless, three-way validation is hampered by the incomplete behavioral characterization of many of the mutant mice, and additional subunits are likely to be linked to alcohol actions as behavioral testing progresses.", - "journal_title": "Advances in pharmacology (San Diego, Calif.)", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/17175815/" - } - ], - "e81206a2-0f93-4d28-a319-c17c3a9860ff": [ - { - "pub_id": "21796100", - "title": "The neuropeptide galanin and variants in the GalR1 gene are associated with nicotine dependence.", - "authors": "Kia J Jackson,Xiangning Chen,Michael F Miles,JoLynne Harenza,M Imad Damaj", - "abstract": "The neuropeptide galanin and its receptors are expressed in brain regions implicated in drug dependence. Indeed, several lines of evidence support a role for galanin in modulating the effects of drugs of abuse, including morphine, cocaine, amphetamine, and alcohol. Despite these findings, the role of galanin and its receptors in the effects of nicotine is largely underexplored. Here, using mouse models of nicotine reward and withdrawal, we show that there is a significant correlation between mecamylamine-precipitated nicotine withdrawal somatic signs and basal galanin or galanin receptor 1 (GALR1) expression in mesolimbocortical dopamine regions across the BXD battery of recombinant inbred mouse lines. The non-peptide galanin receptor agonist, galnon, also blocks nicotine rewarding effects and reverses mecamylamine-precipitated nicotine withdrawal signs in ICR mice. Additionally, we conducted a meta-analysis using smoking information from six European-American and African-American data sets. In support of our animal data, results from the association study show that variants in the GALR1 gene are associated with a protective effect in nicotine dependence (ND). Taken together, our data suggest that galanin has a protective role against progression to ND, and these effects may be mediated through GALR1.", - "journal_title": "Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/21796100/" - } - ], - "908b6626-4948-40c7-8255-f0f49855c100": [ - { - "pub_id": "21347846", - "title": "The genetic basis of adrenal gland weight and structure in BXD recombinant inbred mice.", - "authors": "Domenico L Di Curzio,Daniel Goldowitz", - "abstract": "Adrenal gland function is mediated through secreted hormones, which play a vital role in the autonomic and hypothalamic-pituitary-adrenal (HPA)-axis-mediated stress response. The genetic underpinnings of the stress response can be approached using a quantitative trait locus (QTL) analysis. This method has been used to investigate genomic regions associated with variation in complex phenotypes, but it has not been used to explore the structure of the adrenal. We used QTL analyses to identify candidate genes underlying adrenal weight and adrenal cortical zone and medulla widths. We used 64 BXD recombinant inbred (RI) strains of mice (n = 528) and 2 parental strains (C57BL/6J and DBA/2J; n = 20) to measure adrenal weights and adrenal zone widths. For adrenal weight, we found significant QTLs on chromosome 3 for females (Fawq1) and Chr 4 for males (Mawq1) and suggestive QTLs on Chrs 1, 3, 10, and 14 for females and Chrs 2, 4, 10, 17, and X for males. We identified a significant QTL on Chr 10 (Mawdq1) and a suggestive QTL on Chr 13 for male adrenal total width. For male adrenal medulla width, we found a significant QTL on Chr 5 (Mmwdq1) and a suggestive QTL on Chr 1. We also identified significant QTLs on Chrs 10 (Mxwdq1) and 14 (Mxwdq2) for male X-zone width. There are 113 genes that mapped within the significant QTL intervals, and we identified 4 candidate genes associated with adrenal structure and/or function. In summary, this study is an important first step for detecting genetic factors influencing the structure of the adrenal component of the HPA axis using QTL analyses, which may relate to adrenal function and provide further insights into elucidating genes critical for stress-related phenotypes.", - "journal_title": "Mammalian genome : official journal of the International Mammalian Genome Society", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/21347846/" - } - ], - "3c1ac812-43c0-4e7e-bd71-7ba3a3a0f28b": [ - { - "pub_id": "18363857", - "title": "Genetic dissection of quantitative trait locus for ethanol sensitivity in long- and short-sleep mice.", - "authors": "B Bennett,P Carosone-Link,M Beeson,L Gordon,N Phares-Zook,T E Johnson", - "abstract": "Interval-specific congenic strains (ISCS) allow fine mapping of a quantitative trait locus (QTL), narrowing its confidence interval by an order of magnitude or more. In earlier work, we mapped four QTL specifying differential ethanol sensitivity, assessed by loss of righting reflex because of ethanol (LORE), in the inbred long-sleep (ILS) and inbred short-sleep (ISS) strains, accounting for approximately 50% of the genetic variance for this trait. Subsequently, we generated reciprocal congenic strains in which each full QTL interval from ILS was bred onto the ISS background and vice versa. An earlier paper reported construction and results of the ISCS on the ISS background; here, we describe this process and report results on the ILS background. We developed multiple ISCS for each Lore QTL in which the QTL interval was broken into a number of smaller intervals. For each of the four QTL regions (chromosomes 1, 2, 11 and 15), we were successful in reducing the intervals significantly. Multiple, positive strains were overlapped to generate a single, reduced interval. Subsequently, this reduced region was overlaid on previous reductions from the ISS background congenics, resulting in substantial reductions in all QTL regions by approximately 75% from the initial mapping study. Genes with sequence or expression polymorphisms in the reduced intervals are potential candidates; evidence for these is presented. Genetic background effects can be important in detection of single QTL; combining this information with the generation of congenics on both backgrounds, as described here, is a powerful approach for fine mapping QTL.", - "journal_title": "Genes, brain, and behavior", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/18363857/" - } - ], - "07c2b888-b1b9-4f13-87c5-f33cb3c0e681": [ - { - "pub_id": "21878392", - "title": "Strain differences in seizure-induced cell death following pilocarpine-induced status epilepticus.", - "authors": "P Elyse Schauwecker", - "abstract": "Mouse strains differ from one another in their susceptibility to seizure-induced excitotoxic cell death. Previously, we have demonstrated that mature inbred strains of mice show remarkable genetic differences in susceptibility to the neuropathological consequences of seizures in the kainate model of status epilepticus. At present, while the cellular mechanisms underlying strain-dependent differences in susceptibility remain unclear, some of this variation is assumed to have a genetic basis. However, it remains unclear whether strain differences in susceptibility to seizure-induced cell death observed following kainate administration are observed following systemic administration of other chemoconvulsants. In rodents, the cholinomimetic convulsant pilocarpine is widely used to induce status epilepticus (SE), followed by hippocampal damage and spontaneous recurrent seizures, resembling temporal lobe epilepsy. This model has initially been described in rats, but is increasingly used in mice. We characterized neuronal pathologies after pilocarpine-induced status epilepticus (SE) in eight inbred strains of mice focusing on the hippocampus. A ramping-up dose protocol for pilocarpine was used and behavior was monitored for 4-5 h. While we did not observe any significant differences in seizure latency or duration to pilocarpine among the inbred strains, we did observe a significant difference in susceptibility to the neuropathological consequences of pilocarpine-induced SE. Of the eight genetically diverse mouse strains screened for pilocarpine-induced status, BALB/cJ and BALB/cByJ were the only two strains that were resistant to the neuropathological consequences of seizure-induced cell death. Additional studies of these murine strains may be useful for investigating genetic influences on pilocarpine-induced status epilepticus.", - "journal_title": "Neurobiology of disease", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/21878392/" - } - ], - "5f9977a0-90a1-4d17-a2ff-847ab1b33160": [ - { - "pub_id": "16618939", - "title": "Toward understanding the genetics of alcohol drinking through transcriptome meta-analysis.", - "authors": "Megan K Mulligan,Igor Ponomarev,Robert J Hitzemann,John K Belknap,Boris Tabakoff,R Adron Harris,John C Crabbe,Yuri A Blednov,Nicholas J Grahame,Tamara J Phillips,Deborah A Finn,Paula L Hoffman,Vishwanath R Iyer,George F Koob,Susan E Bergeson", - "abstract": "Much evidence from studies in humans and animals supports the hypothesis that alcohol addiction is a complex disease with both hereditary and environmental influences. Molecular determinants of excessive alcohol consumption are difficult to study in humans. However, several rodent models show a high or low degree of alcohol preference, which provides a unique opportunity to approach the molecular complexities underlying the genetic predisposition to drink alcohol. Microarray analyses of brain gene expression in three selected lines, and six isogenic strains of mice known to differ markedly in voluntary alcohol consumption provided >4.5 million data points for a meta-analysis. A total of 107 arrays were obtained and arranged into six experimental data sets, allowing the identification of 3,800 unique genes significantly and consistently changed between all models of high or low amounts of alcohol consumption. Several functional groups, including mitogen-activated protein kinase signaling and transcription regulation pathways, were found to be significantly overrepresented and may play an important role in establishing a high level of voluntary alcohol drinking in these mouse models. Data from the general meta-analysis was further filtered by a congenic strain microarray set, from which cis-regulated candidate genes for an alcohol preference quantitative trait locus on chromosome 9 were identified: Arhgef12, Carm1, Cryab, Cox5a, Dlat, Fxyd6, Limd1, Nicn1, Nmnat3, Pknox2, Rbp1, Sc5d, Scn4b, Tcf12, Vps11, and Zfp291 and four ESTs. The present study demonstrates the use of (i) a microarray meta-analysis to analyze a behavioral phenotype (in this case, alcohol preference) and (ii) a congenic strain for identification of cis regulation.", - "journal_title": "Proceedings of the National Academy of Sciences of the United States of America", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/16618939/" - } - ], - "d4cda573-c50b-47d3-8e37-c4d3cff0c503": [ - { - "pub_id": "19632178", - "title": "CD47 is upregulated on circulating hematopoietic stem cells and leukemia cells to avoid phagocytosis.", - "authors": "Siddhartha Jaiswal,Catriona H M Jamieson,Wendy W Pang,Christopher Y Park,Mark P Chao,Ravindra Majeti,David Traver,Nico van Rooijen,Irving L Weissman", - "abstract": "Macrophages clear pathogens and damaged or aged cells from the blood stream via phagocytosis. Cell-surface CD47 interacts with its receptor on macrophages, SIRPalpha, to inhibit phagocytosis of normal, healthy cells. We find that mobilizing cytokines and inflammatory stimuli cause CD47 to be transiently upregulated on mouse hematopoietic stem cells (HSCs) and progenitors just prior to and during their migratory phase, and that the level of CD47 on these cells determines the probability that they are engulfed in vivo. CD47 is also constitutively upregulated on mouse and human myeloid leukemias, and overexpression of CD47 on a myeloid leukemia line increases its pathogenicity by allowing it to evade phagocytosis. We conclude that CD47 upregulation is an important mechanism that provides protection to normal HSCs during inflammation-mediated mobilization, and that leukemic progenitors co-opt this ability in order to evade macrophage killing.", - "journal_title": "Cell", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/19632178/" - } - ], - "ed140f66-fbad-4fd7-8ae3-4d9cac4f63ac": [ - { - "pub_id": "20205870", - "title": "Towards the integration of mouse databases - definition and implementation of solutions to two use-cases in mouse functional genomics.", - "authors": "Michael Gruenberger,Rudi Alberts,Damian Smedley,Morris Swertz,Paul Schofield, ,Klaus Schughart", - "abstract": "The integration of information present in many disparate biological databases represents a major challenge in biomedical research. To define the problems and needs, and to explore strategies for database integration in mouse functional genomics, we consulted the biologist user community and implemented solutions to two user-defined use-cases. We organised workshops, meetings and used a questionnaire to identify the needs of biologist database users in mouse functional genomics. As a result, two use-cases were developed that can be used to drive future designs or extensions of mouse databases. Here, we present the use-cases and describe some initial computational solutions for them. The application for the gene-centric use-case, \"MUSIG-Gen\" starts from a list of gene names and collects a wide range of data types from several distributed databases in a \"shopping cart\"-like manner. The iterative user-driven approach is a response to strongly articulated requests from users, especially those without computational biology backgrounds. The application for the phenotype-centric use-case, \"MUSIG-Phen\", is based on a similar concept and starting from phenotype descriptions retrieves information for associated genes. The use-cases created, and their prototype software implementations should help to better define biologists' needs for database integration and may serve as a starting point for future bioinformatics solutions aimed at end-user biologists.", - "journal_title": "BMC research notes", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/20205870/" - } - ], - "0b7aefc6-ec2a-419f-b6e9-343c327a6ac9": [ - { - "pub_id": "17142838", - "title": "A new module for on-line manipulation and display of molecular information in the brain architecture management system.", - "authors": "Mihail Bota,Larry W Swanson", - "abstract": "A new \"Molecules\" module of the Brain Architecture Management System (BAMS; http://brancusi.usc.edu/bkms) is described. With this module, BAMS becomes the first online knowledge management system to handle central nervous system (CNS) region and celltype chemoarchitectonic data in the context of axonal connections between regions and cell types, in multiple species. The \"Molecules\" module implements a general knowledge representation schema for data and metadata collated from published and unpublished material, and allows insertion of complex reports about the presence of molecules collated from the literature. For different CNS neural regions and cell types, the module's database structure includes representation of molecule expression revealed by various techniques including in situ hybridization and immunohistochemistry, molecule coexpression and time-dependent level changes, and physiological state of subjects. The metadata representation allows online comparison and evaluation of inserted experiments, and \"Molecules\"structure allows rapid development of data transfer protocols enabling neuroinformatics visualization tools to display gene expression patterns residing in BAMS, in terms of levels of expressed molecules and in situ hybridization data. The module's web interface allows users to construct lists of CNS regions containing a molecule (depending on physiological state), retrieve further details about inserted records, compare time-dependent data within and across experiments, reconstruct gene expression patterns, and construct complex reports from individual experiments.", - "journal_title": "Neuroinformatics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/17142838/" - } - ], - "ad7aa535-9bf7-421d-896f-5304841c6380": [ - { - "pub_id": "19834560", - "title": "Expression quantitative trait loci are highly sensitive to cellular differentiation state.", - "authors": "Alice Gerrits,Yang Li,Bruno M Tesson,Leonid V Bystrykh,Ellen Weersing,Albertina Ausema,Bert Dontje,Xusheng Wang,Rainer Breitling,Ritsert C Jansen,Gerald de Haan", - "abstract": "Genetical genomics is a strategy for mapping gene expression variation to expression quantitative trait loci (eQTLs). We performed a genetical genomics experiment in four functionally distinct but developmentally closely related hematopoietic cell populations isolated from the BXD panel of recombinant inbred mouse strains. This analysis allowed us to analyze eQTL robustness/sensitivity across different cellular differentiation states. Although we identified a large number (365) of \"static\" eQTLs that were consistently active in all four cell types, we found a much larger number (1,283) of \"dynamic\" eQTLs showing cell-type-dependence. Of these, 140, 45, 531, and 295 were preferentially active in stem, progenitor, erythroid, and myeloid cells, respectively. A detailed investigation of those dynamic eQTLs showed that in many cases the eQTL specificity was associated with expression changes in the target gene. We found no evidence for target genes that were regulated by distinct eQTLs in different cell types, suggesting that large-scale changes within functional regulatory networks are uncommon. Our results demonstrate that heritable differences in gene expression are highly sensitive to the developmental stage of the cell population under study. Therefore, future genetical genomics studies should aim at studying multiple well-defined and highly purified cell types in order to construct as comprehensive a picture of the changing functional regulatory relationships as possible.", - "journal_title": "PLoS genetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/19834560/" - } - ], - "d7e9efe9-041a-46e3-8fe1-d4b84943fc82": [ - { - "pub_id": "16723524", - "title": "Transcriptional signatures of cellular plasticity in mice lacking the alpha1 subunit of GABAA receptors.", - "authors": "Igor Ponomarev,Rajani Maiya,Mark T Harnett,Gwen L Schafer,Andrey E Ryabinin,Yuri A Blednov,Hitoshi Morikawa,Stephen L Boehm,Gregg E Homanics,Ari E Berman,Kerrie H Lodowski,Susan E Bergeson,R Adron Harris", - "abstract": "GABAA receptors mediate the majority of inhibitory neurotransmission in the CNS. Genetic deletion of the alpha1 subunit of GABAA receptors results in a loss of alpha1-mediated fast inhibitory currents and a marked reduction in density of GABAA receptors. A grossly normal phenotype of alpha1-deficient mice suggests the presence of neuronal adaptation to these drastic changes at the GABA synapse. We used cDNA microarrays to identify transcriptional fingerprints of cellular plasticity in response to altered GABAergic inhibition in the cerebral cortex and cerebellum of alpha1 mutants. In silico analysis of 982 mutation-regulated transcripts highlighted genes and functional groups involved in regulation of neuronal excitability and synaptic transmission, suggesting an adaptive response of the brain to an altered inhibitory tone. Public gene expression databases permitted identification of subsets of transcripts enriched in excitatory and inhibitory neurons as well as some glial cells, providing evidence for cellular plasticity in individual cell types. Additional analysis linked some transcriptional changes to cellular phenotypes observed in the knock-out mice and suggested several genes, such as the early growth response 1 (Egr1), small GTP binding protein Rac1 (Rac1), neurogranin (Nrgn), sodium channel beta4 subunit (Scn4b), and potassium voltage-gated Kv4.2 channel (Kcnd2) as cell type-specific markers of neuronal plasticity. Furthermore, transcriptional activation of genes enriched in Bergman glia suggests an active role of these astrocytes in synaptic plasticity. Overall, our results suggest that the loss of alpha1-mediated fast inhibition produces diverse transcriptional responses that act to regulate neuronal excitability of individual neurons and stabilize neuronal networks, which may account for the lack of severe abnormalities in alpha1 null mutants.", - "journal_title": "The Journal of neuroscience : the official journal of the Society for Neuroscience", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/16723524/" - } - ], - "299c7b2f-4a13-4891-a62b-36d429e960cb": [ - { - "pub_id": "19636343", - "title": "Systems genetics analysis of cancer susceptibility: from mouse models to humans.", - "authors": "David Quigley,Allan Balmain", - "abstract": "Genetic studies of cancer susceptibility have shown that most heritable risk cannot be explained by the main effects of common alleles. This may be due to unknown gene-gene or gene-environment interactions and the complex roles of many genes at different stages of cancer. Studies using mouse models of cancer suggest that methods that integrate genetic analysis and genomic networks with knowledge of cancer biology can help to extend our understanding of heritable cancer susceptibility.", - "journal_title": "Nature reviews. Genetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/19636343/" - } - ], - "19fe5592-288f-4af9-8300-5148b25dc063": [ - { - "pub_id": "18923511", - "title": "The molecular neurobiology of depression.", - "authors": "Vaishnav Krishnan,Eric J Nestler", - "abstract": "Unravelling the pathophysiology of depression is a unique challenge. Not only are depressive syndromes heterogeneous and their aetiologies diverse, but symptoms such as guilt and suicidality are impossible to reproduce in animal models. Nevertheless, other symptoms have been accurately modelled, and these, together with clinical data, are providing insight into the neurobiology of depression. Recent studies combining behavioural, molecular and electrophysiological techniques reveal that certain aspects of depression result from maladaptive stress-induced neuroplastic changes in specific neural circuits. They also show that understanding the mechanisms of resilience to stress offers a crucial new dimension for the development of fundamentally novel antidepressant treatments.", - "journal_title": "Nature", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/18923511/" - } - ], - "f95847dd-c216-4b47-9bb1-88b88221435a": [ - { - "pub_id": "17703239", - "title": "Integrating physical and genetic maps: from genomes to interaction networks.", - "authors": "Andreas Beyer,Sourav Bandyopadhyay,Trey Ideker", - "abstract": "Physical and genetic mapping data have become as important to network biology as they once were to the Human Genome Project. Integrating physical and genetic networks currently faces several challenges: increasing the coverage of each type of network; establishing methods to assemble individual interaction measurements into contiguous pathway models; and annotating these pathways with detailed functional information. A particular challenge involves reconciling the wide variety of interaction types that are currently available. For this purpose, recent studies have sought to classify genetic and physical interactions along several complementary dimensions, such as ordered versus unordered, alleviating versus aggravating, and first versus second degree.", - "journal_title": "Nature reviews. Genetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/17703239/" - } - ], - "027566e2-bdf0-438b-8104-8eb2b0b83730": [ - { - "pub_id": "17175052", - "title": "Meta-analysis for microarray studies of the genetics of complex traits.", - "authors": "Michael F Miles,Robert W Williams", - "abstract": "In comparison to other complex disease traits, alcoholism and alcohol abuse are influenced by the combined effects of many genes that alter susceptibility, phenotypic expression and associated morbidity, respectively. Many genetic studies, in both animal models and humans, have identified genetic intervals containing genes that influence alcoholism or behavioral responses to ethanol. Concurrently, a growing number of microarray studies have identified gene expression differences related to ethanol drinking or other ethanol behaviors. However, concerns about the statistical power of these experiments, combined with the complexity of the underlying phenotypes, have greatly hampered the identification of candidate genes underlying ethanol behaviors. Meta-analysis approaches using recent compilations of large datasets of microarray, behavioral and genetic data promise improved statistical power for detecting the genes or gene networks affecting ethanol behaviors and other complex traits.", - "journal_title": "Trends in biotechnology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/17175052/" - } - ], - "b3fed034-39e7-4cf7-9b10-54e24c5d08bf": [ - { - "pub_id": "17406662", - "title": "Quantitative trait loci linked to thalamus and cortex gray matter volumes in BXD recombinant inbred mice.", - "authors": "H Dong,M V Martin,J Colvin,Z Ali,L Wang,L Lu,R W Williams,G D Rosen,J G Csernansky,J M Cheverud", - "abstract": "To investigate whether there are separate or shared genetic influences on the development of the thalamus and cerebral cortex, we identified quantitative trait loci (QTLs) for relevant structural volumes in BXD recombinant inbred (RI) strains of mice. In 34 BXD RI strains and two parental strains (C57BL/6J and DBA/2J), we measured the volumes of the entire thalamus and cortex gray matter using point counting and Cavalieri's rule. Heritability was calculated using analysis of variance (ANOVA), and QTL analysis was carried out using WebQTL (http://www.genenetwork.org). The heritability of thalamus volume was 36%, and three suggestive QTLs for thalamus volume were identified on chromosomes 10, 11 and 16. The heritability of cortical gray matter was 43%, and four suggestive QTLs for cortex gray matter volume were identified on chromosomes 2, 8, 16 and 19. The genetic correlation between thalamus and cortex gray matter volumes was 0.64. Also, a single QTL on chromosome 16 (D16Mit100) was identified for thalamus volume, cortex gray matter volume and Morris water maze search-time preference (r=0.71). These results suggest that there are separate and shared genetic influences on the development of the thalamus and cerebral cortex.", - "journal_title": "Heredity", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/17406662/" - } - ], - "8ec43c84-e565-4b47-a07a-0ddd99da6728": [ - { - "pub_id": "19920989", - "title": "Comparing quantitative trait Loci and gene expression data.", - "authors": "Bing Han,Naomi S Altman,Jessica A Mong,Laura Cousino Klein,Donald W Pfaff,David J Vandenbergh", - "abstract": "We develop methods to compare the positions of quantitative trait loci (QTL) with a set of genes selected by other methods, such as microarray experiments, from a sequenced genome. We apply our methods to QTL for addictive behavior in mouse, and a set of genes upregulated in a region of the brain associated with addictive behavior, the nucleus accumbens (NA). The association between the QTL and NA genes is not significantly stronger than expected by chance. However, chromosomes 2 and 16 do show strong associations suggesting that genes on these chromosomes might be associated with addictive behavior. The statistical methodology developed for this study can be applied to similar studies to assess the mutual information in microarray and QTL analyses.", - "journal_title": "Advances in bioinformatics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/19920989/" - } - ], - "d8079209-0478-417b-ab45-d0e1e4f4dd7b": [ - { - "pub_id": "21283795", - "title": "Dissecting genetic networks underlying complex phenotypes: the theoretical framework.", - "authors": "Fan Zhang,Hu-Qu Zhai,Andrew H Paterson,Jian-Long Xu,Yong-Ming Gao,Tian-Qing Zheng,Rong-Ling Wu,Bin-Ying Fu,Jauhar Ali,Zhi-Kang Li", - "abstract": "Great progress has been made in genetic dissection of quantitative trait variation during the past two decades, but many studies still reveal only a small fraction of quantitative trait loci (QTLs), and epistasis remains elusive. We integrate contemporary knowledge of signal transduction pathways with principles of quantitative and population genetics to characterize genetic networks underlying complex traits, using a model founded upon one-way functional dependency of downstream genes on upstream regulators (the principle of hierarchy) and mutual functional dependency among related genes (functional genetic units, FGU). Both simulated and real data suggest that complementary epistasis contributes greatly to quantitative trait variation, and obscures the phenotypic effects of many 'downstream' loci in pathways. The mathematical relationships between the main effects and epistatic effects of genes acting at different levels of signaling pathways were established using the quantitative and population genetic parameters. Both loss of function and \"co-adapted\" gene complexes formed by multiple alleles with differentiated functions (effects) are predicted to be frequent types of allelic diversity at loci that contribute to the genetic variation of complex traits in populations. Downstream FGUs appear to be more vulnerable to loss of function than their upstream regulators, but this vulnerability is apparently compensated by different FGUs of similar functions. Other predictions from the model may account for puzzling results regarding responses to selection, genotype by environment interaction, and the genetic basis of heterosis.", - "journal_title": "PloS one", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/21283795/" - } - ], - "07d409f4-91f9-4701-bb39-1421845a6321": [ - { - "pub_id": "25326635", - "title": "Molecular findings among patients referred for clinical whole-exome sequencing.", - "authors": "Yaping Yang,Donna M Muzny,Fan Xia,Zhiyv Niu,Richard Person,Yan Ding,Patricia Ward,Alicia Braxton,Min Wang,Christian Buhay,Narayanan Veeraraghavan,Alicia Hawes,Theodore Chiang,Magalie Leduc,Joke Beuten,Jing Zhang,Weimin He,Jennifer Scull,Alecia Willis,Megan Landsverk,William J Craigen,Mir Reza Bekheirnia,Asbjorg Stray-Pedersen,Pengfei Liu,Shu Wen,Wendy Alcaraz,Hong Cui,Magdalena Walkiewicz,Jeffrey Reid,Matthew Bainbridge,Ankita Patel,Eric Boerwinkle,Arthur L Beaudet,James R Lupski,Sharon E Plon,Richard A Gibbs,Christine M Eng", - "abstract": "Clinical whole-exome sequencing is increasingly used for diagnostic evaluation of patients with suspected genetic disorders. To perform clinical whole-exome sequencing and report (1) the rate of molecular diagnosis among phenotypic groups, (2) the spectrum of genetic alterations contributing to disease, and (3) the prevalence of medically actionable incidental findings such as FBN1 mutations causing Marfan syndrome. Observational study of 2000 consecutive patients with clinical whole-exome sequencing analyzed between June 2012 and August 2014. Whole-exome sequencing tests were performed at a clinical genetics laboratory in the United States. Results were reported by clinical molecular geneticists certified by the American Board of Medical Genetics and Genomics. Tests were ordered by the patient's physician. The patients were primarily pediatric (1756 [88%]; mean age, 6 years; 888 females [44%], 1101 males [55%], and 11 fetuses [1% gender unknown]), demonstrating diverse clinical manifestations most often including nervous system dysfunction such as developmental delay. Whole-exome sequencing diagnosis rate overall and by phenotypic category, mode of inheritance, spectrum of genetic events, and reporting of incidental findings. A molecular diagnosis was reported for 504 patients (25.2%) with 58% of the diagnostic mutations not previously reported. Molecular diagnosis rates for each phenotypic category were 143/526 (27.2%; 95% CI, 23.5%-31.2%) for the neurological group, 282/1147 (24.6%; 95% CI, 22.1%-27.2%) for the neurological plus other organ systems group, 30/83 (36.1%; 95% CI, 26.1%-47.5%) for the specific neurological group, and 49/244 (20.1%; 95% CI, 15.6%-25.8%) for the nonneurological group. The Mendelian disease patterns of the 527 molecular diagnoses included 280 (53.1%) autosomal dominant, 181 (34.3%) autosomal recessive (including 5 with uniparental disomy), 65 (12.3%) X-linked, and 1 (0.2%) mitochondrial. Of 504 patients with a molecular diagnosis, 23 (4.6%) had blended phenotypes resulting from 2 single gene defects. About 30% of the positive cases harbored mutations in disease genes reported since 2011. There were 95 medically actionable incidental findings in genes unrelated to the phenotype but with immediate implications for management in 92 patients (4.6%), including 59 patients (3%) with mutations in genes recommended for reporting by the American College of Medical Genetics and Genomics. Whole-exome sequencing provided a potential molecular diagnosis for 25% of a large cohort of patients referred for evaluation of suspected genetic conditions, including detection of rare genetic events and new mutations contributing to disease. The yield of whole-exome sequencing may offer advantages over traditional molecular diagnostic approaches in certain patients.", - "journal_title": "JAMA", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/25326635/" - } - ], - "47a15e69-dc83-452e-95d8-c605e61f43c0": [ - { - "pub_id": "18368372", - "title": "An informatics approach to systems neurogenetics.", - "authors": "Glenn D Rosen,Elissa J Chesler,Kenneth F Manly,Robert W Williams", - "abstract": "We outline the theory behind complex trait analysis and systems genetics and describe web-accessible resources including GeneNetwork (GN) that can be used for rapid exploratory analysis and hypothesis testing. GN, in particular, is a tightly integrated suite of bioinformatics tools and data sets, which supports the investigation of complex networks of gene variants, molecules, and cellular processes that modulate complex traits, including behavior and disease susceptibility. Using various statistical tools, users are able to analyze gene expression in various brain regions and tissues, map loci that modulate these traits, and explore genetic covariance among traits. Taken together, these tools enable the user to begin to assess complex interactions of gene networks, and facilitate analysis of traits using a systems approach.", - "journal_title": "Methods in molecular biology (Clifton, N.J.)", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/18368372/" - } - ], - "d72cbfae-eed0-4c41-ae93-bb77a6e17e9b": [ - { - "pub_id": "16874319", - "title": "Normalization procedures and detection of linkage signal in genetical-genomics experiments.", - "authors": "Rohan B H Williams,Chris J Cotsapas,Mark J Cowley,Eva Chan,David J Nott,Peter F R Little", - "abstract": "", - "journal_title": "Nature genetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/16874319/" - } - ], - "b4713290-fd5b-4330-a8b1-7a341a9dc118": [ - { - "pub_id": "22347157", - "title": "Candidate genes in ocular dominance plasticity.", - "authors": "M Liset Rietman,J-P Sommeijer, ,Christiaan N Levelt,J Alexander Heimel", - "abstract": "Many studies have been devoted to the identification of genes involved in experience-dependent plasticity in the visual cortex. To discover new candidate genes, we have reexamined data from one such study on ocular dominance (OD) plasticity in recombinant inbred BXD mouse strains. We have correlated the level of plasticity with the gene expression data in the neocortex that have become available for these same strains. We propose that genes with a high correlation are likely to play a role in OD plasticity. We have tested this hypothesis for genes whose inactivation is known to affect OD plasticity. The expression levels of these genes indeed correlated with OD plasticity if their levels showed strong differences between the BXD strains. To narrow down our candidate list of correlated genes, we have selected only those genes that were previously found to be regulated by visual experience and associated with pathways implicated in OD plasticity. This resulted in a list of 32 candidate genes. The list contained unproven, but not unexpected candidates such as the genes for IGF-1, NCAM1, NOGO-A, the gamma2 subunit of the GABA(A) receptor, acetylcholine esterase, and the catalytic subunit of cAMP-dependent protein kinase A. This demonstrates the viability of our approach. More interestingly, the following novel candidate genes were identified: Akap7, Akt1, Camk2d, Cckbr, Cd44, Crim1, Ctdsp2, Dnajc5, Gnai1, Itpka, Mapk8, Nbea, Nfatc3, Nlk, Npy5r, Phf21a, Phip, Ppm1l, Ppp1r1b, Rbbp4, Slc1a3, Slit2, Socs2, Spock3, St8sia1, Zfp207. Whether all these novel candidates indeed function in OD plasticity remains to be established, but possible roles of some of them are discussed in the article.", - "journal_title": "Frontiers in neuroscience", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/22347157/" - } - ], - "44cd18d6-8e57-4c16-aefa-3d5167e4619c": [ - { - "pub_id": "21152031", - "title": "Evidence for varied aetiologies regulating the transmission of prion disease: implications for understanding the heritable basis of prion incubation times.", - "authors": "Conrad O Iyegbe,Oduola O Abiola,Chris Towlson,John F Powell,Steven A Whatley", - "abstract": "Transmissible Spongiform Encephalopathies (TSEs) are a group of progressive fatal neurodegenerative disorders, triggered by abnormal folding of the endogenous prion protein molecule. The encoding gene is a major biological factor influencing the length of the asymptomatic period after infection. It remains unclear the extent to which the variation between quantitative trait loci (QTLs) reported in mouse models is due to methodological differences between approaches or genuine differences between traits. With this in mind, our approach to identifying genetic factors has sought to extend the linkage mapping approach traditionally applied, to a series of additional traits, while minimising methodological variability between them. Our approach allows estimations of heritability to be derived, as well as predictions to be made about possible existence of genetic overlap between the various traits. Our data indicate a surprising degree of heritability (up to 60%). Correlations between traits are also identified. A series of QTLs on chromosomes 1, 2, 3, 4, 6, 11 and 18 accompany our heritability estimates. However, only a locus on chromosome 11 has a general effect across all 4 models explored. We have achieved some success in detecting novel and pre-existing QTLs associated with incubation time. However, aside from the general effects described, the model-specific nature of the broader host genetic architecture has also been brought into clearer focus. This suggests that genetic overlap can only partially account for the general heritability of incubation time when factors, such as the nature of the TSE agent and the route of administration are considered. This point is highly relevant to vCJD (a potential threat to public health) where the route of primary importance is oral, while the QTLs being sought derive exclusively from studies of the ic route. Our results highlight the limitations of a single-model approach to QTL-mapping of TSEs.", - "journal_title": "PloS one", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/21152031/" - } - ], - "9507b9ec-449e-4a79-8f04-f70d85273b74": [ - { - "pub_id": "16891421", - "title": "Convergent evidence that oligodendrocyte lineage transcription factor 2 (OLIG2) and interacting genes influence susceptibility to schizophrenia.", - "authors": "Lyudmila Georgieva,Valentina Moskvina,Tim Peirce,Nadine Norton,Nicholas J Bray,Lesley Jones,Peter Holmans,Stuart Macgregor,Stanley Zammit,Jennifer Wilkinson,Hywel Williams,Ivan Nikolov,Nigel Williams,Dobril Ivanov,Kenneth L Davis,Vahram Haroutunian,Joseph D Buxbaum,Nick Craddock,George Kirov,Michael J Owen,Michael C O'Donovan", - "abstract": "Abnormal oligodendrocyte function has been postulated as a primary etiological event in schizophrenia. Oligodendrocyte lineage transcription factor 2 (OLIG2) encodes a transcription factor central to oligodendrocyte development. Analysis of OLIG2 in a case-control sample (n = approximately 1,400) in the U.K. revealed several SNPs to be associated with schizophrenia (minimum P = 0.0001, gene-wide P = 0.0009). To obtain independent support for this association, we sought evidence for genetic interaction between OLIG2 and three genes of relevance to oligodendrocyte function for which we have reported evidence for association with schizophrenia: CNP, NRG1, and ERBB4. We found interaction effects on disease risk between OLIG2 and CNP (minimum P = 0.0001, corrected P = 0.008) for interaction with ERBB4 (minimum P = 0.002, corrected P = 0.04) but no evidence for interaction with NRG1. To investigate the biological plausibility of the interactions, we sought correlations between the expression of the genes. The results were similar to those of the genetic interaction analysis. OLIG2 expression significantly correlated in cerebral cortex with CNP (P < 10(-7)) and ERBB4 (P = 0.002, corrected P = 0.038) but not NRG1. In mouse striatum, Olig2 and Cnp expression also was correlated, and linkage analysis for trans-effects on gene expression suggests that each locus regulates the other's expression. Our data provide strong convergent evidence that variation in OLIG2 confers susceptibility to schizophrenia alone and as part of a network of genes implicated in oligodendrocyte function.", - "journal_title": "Proceedings of the National Academy of Sciences of the United States of America", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/16891421/" - } - ], - "f2ee9988-3894-48ca-98b7-ad71a95e7552": [ - { - "pub_id": "18362899", - "title": "Genetic factors influencing alcohol dependence.", - "authors": "R D Mayfield,R A Harris,M A Schuckit", - "abstract": "Plentiful data from both animal and human studies support the importance of genetic influences in substance abuse and dependence (Bierut et al., 1998; Tsuang et al., 1998; Kendler et al., 2003). This review summarizes the evidence supporting such genetic influences, places them into perspective regarding animal and human studies, discusses the importance of both genes and environment, and highlights some specific genes of interest regarding the vulnerabilities for problems associated with alcohol use disorders. A long history of repetitive heavy use of alcohol exists across generations as well as the high prevalence of alcohol-related problems in Western societies. Moreover, the information offered here addresses the importance of more general issues regarding genetics and gene expression related to alcohol abuse and dependence.", - "journal_title": "British journal of pharmacology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/18362899/" - } - ], - "0eeb744b-585c-449e-918e-ebaf167715e6": [ - { - "pub_id": "21960957", - "title": "Adult Hippocampal Neurogenesis and Plasticity in the Infrapyramidal Bundle of the Mossy Fiber Projection: II. Genetic Covariation and Identification of Nos1 as Linking Candidate Gene.", - "authors": "Julia Krebs,Benedikt R\u00f6mer,Rupert W Overall,Klaus Fabel,Harish Babu,Moritz D Brandt,Robert W Williams,Sebastian Jessberger,Gerd Kempermann", - "abstract": "The hippocampus of adult rodents harbors two systems exhibiting structural plasticity beyond the level of synapses and dendrites. First, the persistent generation of granule cells (adult neurogenesis); second, dynamic changes in the mossy fibers (MF), in particular in the infrapyramidal mossy fiber (IMF) tract. Because MFs are the axons of granule cells, the question arises whether these two types of plasticity are linked. In the first part of this study (R\u00f6mer et al., 2011) we have asked how both traits are regulated in relation to each other. In the present part, we asked whether, besides activity-dependent co-regulation, there would also be signs of genetic co-regulation and co-variance. For this purpose we used the BXD panel of recombinant inbred strains of mice, a unique genetic reference population that allows genetic association studies. In 31 BXD strains we did not find correlations between the traits describing the volume of the MF subfields and measures of adult neurogenesis. When we carried out quantitative trait locus mapping for these traits, we found that the map for IMF volume showed little overlap with the maps for the other parts of the projection or for adult neurogenesis, suggesting that to a large degree the IMF is regulated independently. The highest overlapping peak in the genome-wide association maps for IMF volume and the number of new neurons was on distal chromosome 5 (118.3-199.2\u2009Mb) with an LRS score of 5.5 for IMF and 6.0 for new neurons. Within this interval we identified Nos1 (neuronal nitric oxide synthase) as a cis-acting (i.e., presumably autoregulatory) candidate gene. The expression of Nos1 is has been previously linked with both IMF and adult neurogenesis, supporting our findings. Despite explaining on its own very little of the variance in the highly multigenic traits studied, our results suggest Nos1 may play a part in the complex genetic control of adult neurogenesis and IMF morphology.", - "journal_title": "Frontiers in neuroscience", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/21960957/" - } - ], - "06852861-fe65-403c-b8ce-b655c67da477": [ - { - "pub_id": "19662162", - "title": "Identification of the UBP1 locus as a critical blood pressure determinant using a combination of mouse and human genetics.", - "authors": "Hana Koutnikova,Markku Laakso,Lu Lu,Roy Combe,Jussi Paananen,Teemu Kuulasmaa,Johanna Kuusisto,Hans-Ulrich H\u00e4ring,Torben Hansen,Oluf Pedersen,Ulf Smith,Markolf Hanefeld,Robert W Williams,Johan Auwerx", - "abstract": "Hypertension is a major health problem of largely unknown genetic origins. To identify new genes responsible for hypertension, genetic analysis of recombinant inbred strains of mice followed by human association studies might prove powerful and was exploited in our current study. Using a set of 27 recombinant BXD strains of mice we identified a quantitative trait locus (QTL) for blood pressure (BP) on distal chromosome 9. The association analysis of markers encompassing the syntenic region on human chromosome 3 gave in an additive genetic model the strongest association for rs17030583 C/T and rs2291897 G/A, located within the UBP1 locus, with systolic and diastolic BP (rs17030583: 1.3+/-0.4 mmHg p<0.001, 0.8+/-0.3 mmHg p = 0.006, respectively and rs2291897: 1.5+/-0.4 mmHg p<0.001, 0.8+/-0.3 mmHg p = 0.003, respectively) in three separate studies. Our study, which underscores the marked complementarities of mouse and human genetic approaches, identifies the UBP1 locus as a critical blood pressure determinant. UBP1 plays a role in cholesterol and steroid metabolism via the transcriptional activation of CYP11A, the rate-limiting enzyme in pregnenolone and aldosterone biosynthesis. We suggest that UBP1 and its functional partners are components of a network controlling blood pressure.", - "journal_title": "PLoS genetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/19662162/" - } - ], - "ba63ee7a-e039-4751-93c5-45271e412717": [ - { - "pub_id": "27933543", - "title": "Integrative Analysis of Genetic, Genomic, and Phenotypic Data for Ethanol Behaviors: A Network-Based Pipeline for Identifying Mechanisms and Potential Drug Targets.", - "authors": "James W Bogenpohl,Kristin M Mignogna,Maren L Smith,Michael F Miles", - "abstract": "Complex behavioral traits, such as alcohol abuse, are caused by an interplay of genetic and environmental factors, producing deleterious functional adaptations in the central nervous system. The long-term behavioral consequences of such changes are of substantial cost to both the individual and society. Substantial progress has been made in the last two decades in understanding elements of brain mechanisms underlying responses to ethanol in animal models and risk factors for alcohol use disorder (AUD) in humans. However, treatments for AUD remain largely ineffective and few medications for this disease state have been licensed. Genome-wide genetic polymorphism analysis (GWAS) in humans, behavioral genetic studies in animal models and brain gene expression studies produced by microarrays or RNA-seq have the potential to produce nonbiased and novel insight into the underlying neurobiology of AUD. However, the complexity of such information, both statistical and informational, has slowed progress toward identifying new targets for intervention in AUD. This chapter describes one approach for integrating behavioral, genetic, and genomic information across animal model and human studies. The goal of this approach is to identify networks of genes functioning in the brain that are most relevant to the underlying mechanisms of a complex disease such as AUD. We illustrate an example of how genomic studies in animal models can be used to produce robust gene networks that have functional implications, and to integrate such animal model genomic data with human genetic studies such as GWAS for AUD. We describe several useful analysis tools for such studies: ComBAT, WGCNA, and EW_dmGWAS. The end result of this analysis is a ranking of gene networks and identification of their cognate hub genes, which might provide eventual targets for future therapeutic development. Furthermore, this combined approach may also improve our understanding of basic mechanisms underlying gene x environmental interactions affecting brain functioning in health and disease.", - "journal_title": "Methods in molecular biology (Clifton, N.J.)", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/27933543/" - } - ], - "024c0e0e-26ea-45ae-a9e5-3718ade3eca1": [ - { - "pub_id": "23791960", - "title": "Rats are the smart choice: Rationale for a renewed focus on rats in behavioral genetics.", - "authors": "Clarissa C Parker,Hao Chen,Shelly B Flagel,Aron M Geurts,Jerry B Richards,Terry E Robinson,Leah C Solberg Woods,Abraham A Palmer", - "abstract": "Due in part to their rich behavioral repertoire rats have been widely used in behavioral studies of drug abuse-related traits for decades. However, the mouse became the model of choice for researchers exploring the genetic underpinnings of addiction after the first mouse study was published demonstrating the capability of engineering the mouse genome through embryonic stem cell technology. The sequencing of the mouse genome and more recent re-sequencing of numerous inbred mouse strains have further cemented the status of mice as the premier mammalian organism for genetic studies. As a result, many of the behavioral paradigms initially developed and optimized for rats have been adapted to mice. However, numerous complex and interesting drug abuse-related behaviors that can be studied in rats are very difficult or impossible to adapt for use in mice, impeding the genetic dissection of those traits. Now, technological advances have removed many of the historical limitations of genetic studies in rats. For instance, the rat genome has been sequenced and many inbred rat strains are now being re-sequenced and outbred rat stocks are being used to fine-map QTLs. In addition, it is now possible to create \"knockout\" rats using zinc finger nucleases (ZFN), transcription activator-like effector nucleases (TALENs) and related techniques. Thus, rats can now be used to perform quantitative genetic studies of sophisticated behaviors that have been difficult or impossible to study in mice. This article is part of a Special Issue entitled 'NIDA 40th Anniversary Issue'.", - "journal_title": "Neuropharmacology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/23791960/" - } - ], - "5677f7ee-d9b9-443f-b350-488e1b077007": [ - { - "pub_id": "23062308", - "title": "Age-related changes of gene expression in the neocortex: preliminary data on RNA-Seq of the transcriptome in three functionally distinct cortical areas.", - "authors": "Oksana Yu Naumova,Dean Palejev,Natalia V Vlasova,Maria Lee,Sergei Yu Rychkov,Olga N Babich,Flora M Vaccarino,Elena L Grigorenko", - "abstract": "The study of gene expression (i.e., the study of the transcriptome) in different cells and tissues allows us to understand the molecular mechanisms of their differentiation, development and functioning. In this article, we describe some studies of gene-expression profiling for the purposes of understanding developmental (age-related) changes in the brain using different technologies (e.g., DNA-Microarray) and the new and increasingly popular RNA-Seq. We focus on advancements in studies of gene expression in the human brain, which have provided data on the structure and age-related variability of the transcriptome in the brain. We present data on RNA-Seq of the transcriptome in three distinct areas of the neocortex from different ages: mature and elderly individuals. We report that most age-related transcriptional changes affect cellular signaling systems, and, as a result, the transmission of nerve impulses. In general, the results demonstrate the high potential of RNA-Seq for the study of distinctive features of gene expression among cortical areas and the changes in expression through normal and atypical development of the central nervous system.", - "journal_title": "Development and psychopathology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/23062308/" - } - ], - "90ff8fd2-d24f-4df6-9ac8-75e38151740b": [ - { - "pub_id": "22160604", - "title": "Naturally occurring genetic variability in expression of Gsta4 is associated with differential survival of axotomized rat motoneurons.", - "authors": "Mikael Str\u00f6m,Faiez Al Nimer,Rickard Lindblom,Jens Randel Nyengaard,Fredrik Piehl", - "abstract": "A large number of molecular pathways have been implicated in the degeneration of axotomized motoneurons. We previously have demonstrated substantial differences in the survival rate of axotomized motoneurons across different rat strains. Identification of genetic differences underlying such naturally occurring strain differences is a powerful approach, also known as forward genetics, to gain knowledge of mechanisms relevant for complex diseases, like injury-induced neurodegeneration. Overlapping congenic rat strains were used to fine map a gene region on rat chromosome eight previously shown to regulate motoneuron survival after ventral root avulsion. The smallest genetic fragment, R5, contains 35 genes and displays a highly significant regulatory effect on motoneuron survival. Furthermore, expression profiling in a F2(DAxPVG) intercross demonstrates one single cis-regulated gene within the R5 fragment; Gsta4, encoding glutathione S-transferase alpha-4. Confirmation with real-time PCR shows higher Gsta4 expression in PVG compared with DA both in na\u00efve animals and at several time points after injury. Immunolabeling with a custom made rat Gsta4 antibody demonstrates a neuronal staining pattern, with a strong cytoplasmic labeling of motoneurons. These results demonstrate and map naturally occurring genetic differences in the expression of Gsta4 is associated both with a highly significant increase in the survival of axotomized motoneurons and with a trans-regulation of several molecular pathways involved in neurodegenerative processes. This adds to a large body of evidence implicating lipid peroxidation as an important pathway for neurodegeneration.", - "journal_title": "Neuromolecular medicine", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/22160604/" - } - ], - "89ebb63a-7ed1-46f1-8fd1-075d1f0cf04b": [ - { - "pub_id": "36193764", - "title": "Biomineralized Two-Enzyme Nanoparticles Regulate Tumor Glycometabolism Inducing Tumor Cell Pyroptosis and Robust Antitumor Immunotherapy.", - "authors": "Sijia Zhang,Ying Zhang,Yuanji Feng,Jiayan Wu,Yingying Hu,Lin Lin,Caina Xu,Jie Chen,Zhaohui Tang,Huayu Tian,Xuesi Chen", - "abstract": "Currently, immune checkpoint therapy combined with chemotherapy and radiotherapy is a useful strategy for improving immunotherapy's therapeutic efficacy. However, chemotherapy and radiotherapy cause serious side effects, so finding safe and effective methods to combine with immunotherapy is critical. In this work,\u00a0regulating tumor glycometabolism is found to induce tumor cell pyroptosis and regulate the degree of expression of programmed death-ligand 1 (PD-L1). Therefore, how to treat tumors by regulating tumor glycometabolism in combination with anti-PD-L1 therapy is investigated here. First, the biomineralization-like method is used to construct nanoparticles with two-enzymatic activity by hybridizing nanozymes and glucose oxidase (GOx). It has the ability to self-amplify regulation of the glycometabolism of tumor cells. It can also induce tumor cell pyroptosis and increase the expression of PD-L1 in tumor cells. To treat tumors, nanoparticles are further combined with anti-PD-L1, which substantially inhibits tumor development and significantly increases \u00a0the survival time of mice. Combination therapy also has a significant immunological memory effect, successfully preventing tumor recurrence and metastasis. This is thought to be the first study that combines tumor glycometabolism with immunocheckpoint blocking in cancer therapy. This innovative, safe, low-toxic, and highly effective anti-tumor strategy can have good prospects in clinical applications.", - "journal_title": "Advanced materials (Deerfield Beach, Fla.)", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/36193764/" - } - ], - "7a451204-390c-4ff2-8a1d-b4de62b73503": [ - { - "pub_id": "22932714", - "title": "Trevo versus Merci retrievers for thrombectomy revascularisation of large vessel occlusions in acute ischaemic stroke (TREVO 2): a randomised trial.", - "authors": "Raul G Nogueira,Helmi L Lutsep,Rishi Gupta,Tudor G Jovin,Gregory W Albers,Gary A Walker,David S Liebeskind,Wade S Smith, ", - "abstract": "Present mechanical devices are unable to achieve recanalisation in up to 20-40% of large vessel occlusion strokes. We compared efficacy and safety of the Trevo Retriever, a new stent-like device, with its US Food and Drug Administration-cleared predecessor, the Merci Retriever. In this open-label randomised controlled trial, we recruited patients at 26 sites in the USA and one in Spain. We included adults aged 18-85 years with angiographically confirmed large vessel occlusion strokes and US National Institutes of Health Stroke Scale (NIHSS) scores of 8-29 within 8 h of symptom onset. We randomly assigned patients (1:1) with sequentially numbered sealed envelopes to thrombectomy with Trevo or Merci devices. Randomisation was stratified by age (\u226468 years vs 69-85 years) and NIHSS scores (\u226418 vs 19-29) with alternating blocks of various sizes. The primary efficacy endpoint, assessed by an unmasked core laboratory, was thrombolysis in cerebral infarction (TICI) scores of 2 or greater reperfusion with the assigned device alone. The primary safety endpoint was a composite of procedure-related adverse events. Analyses were done by intention to treat. This study is registered with ClinicalTrials.gov, number NCT01270867. Between Feb 3, 2011, and Dec 1, 2011, we randomly assigned 88 patients to the Trevo Retriever group and 90 patients to Merci Retriever group. 76 (86%) patients in the Trevo group and 54 (60%) in the Merci group met the primary endpoint after the assigned device was used (odds ratio 4\u00b722, 95% CI 1\u00b792-9\u00b769; p(superiority)<0\u00b70001). Incidence of the primary safety endpoint did not differ between groups (13 [15%] patients in the Trevo group vs 21 [23%] in the Merci group; p=0\u00b71826). Patients who have had large vessel occlusion strokes but are ineligible for (or refractory to) intravenous tissue plasminogen activator should be treated with the Trevo Retriever in preference to the Merci Retriever. Stryker Neurovascular.", - "journal_title": "Lancet (London, England)", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/22932714/" - } - ], - "c3034036-4dab-4ac7-8857-56e6f1ca0837": [ - { - "pub_id": "24703509", - "title": "Neuregulin-3 in the mouse medial prefrontal cortex regulates impulsive action.", - "authors": "Maarten Loos,Thomas Mueller,Yvonne Gouwenberg,Ruud Wijnands,Rolinka J van der Loo, ,Carmen Birchmeier,August B Smit,Sabine Spijker", - "abstract": "A deficit in impulse control is a prominent, heritable symptom in several psychiatric disorders, such as addiction, attention-deficit/hyperactivity disorder, and schizophrenia. Here, we aimed to identify genes regulating impulsivity, specifically of impulsive action, in mice. Using the widely used 5-choice serial reaction time task, we measured impulsive action in 1) a panel of 41 BXD recombinant inbred strains of mice (n = 13.7 \u00b1 .8 per strain; n = 654 total) to detect underlying genetic loci; 2) congenic mice (n = 23) to replicate the identified locus; 3) mice overexpressing the Nrg3 candidate gene in the medial prefrontal cortex (n = 21); and 4) a Nrg3 loss-of-function mutant (n = 59) to functionally implicate the Nrg3 candidate gene in impulsivity. Genetic mapping of impulsive action in the BXD panel identified a locus on chromosome 14 (34.5-41.4 Mb), syntenic with the human 10q22-q23 schizophrenia-susceptibility locus. Congenic mice carrying the impulsivity locus (Impu1) confirmed its influence on impulsive action. Increased impulsivity was associated with increased Nrg3 gene expression in the medial prefrontal cortex (mPFC). Viral overexpression of Nrg3 in the mPFC increased impulsivity, whereas a constitutive Nrg3 loss-of-function mutation decreased it. The causal relation between Nrg3 expression in the mPFC and level of impulsive action shown here provides a mechanism by which polymorphism in NRG3 in humans contributes to a specific cognitive deficit seen in several psychiatric diseases, such as addiction, attention-deficit/hyperactivity disorder, and schizophrenia.", - "journal_title": "Biological psychiatry", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/24703509/" - } - ], - "481b8001-d5cb-477e-8d9c-33d08d5084b2": [ - { - "pub_id": "25561905", - "title": "Impulsivity and comorbid traits: a multi-step approach for finding putative responsible microRNAs in the amygdala.", - "authors": "Andrzej Z Pietrzykowski,Sabine Spijker", - "abstract": "Malfunction of synaptic plasticity in different brain regions, including the amygdala plays a role in impulse control deficits that are characteristics of several psychiatric disorders, such as ADHD, schizophrenia, depression and addiction. Previously, we discovered a locus for impulsivity (Impu1) containing the neuregulin 3 (Nrg3) gene, of which the level of expression determines levels of inhibitory control. MicroRNAs (miRNAs) are potent regulators of gene expression, and have recently emerged as important factors contributing to the development of psychiatric disorders. However, their role in impulsivity, as well as control of Nrg3 expression or malfunction of the amygdala, is not well established. Here, we used the GeneNetwork database of BXD mice to search for correlated traits with impulsivity using an overrepresentation analysis to filter for biologically meaningful traits. We determined that inhibitory control was significantly correlated with expression of miR-190b, -28a, -340, -219a, and -491 in the amygdala, and that the overrepresented correlated traits showed a specific pattern of coregulation with these miRNAs. A bioinformatics analysis identified that miR-190b, by targeting an Nrg3-related network, could affect synaptic plasticity in the amygdala, targeting bot impulsive and compulsive traits. Moreover, miR-28a, -340, -219a, and possibly -491 could act on synaptic function by determining the balance between neuronal outgrowth and differentiation. We propose that these miRNAs are attractive candidates of regulation of amygdala synaptic plasticity, possibly during development but also in maintaining the impulsive phenotype. These results can help us to better understand mechanisms of synaptic dysregulation in psychiatric disorders.", - "journal_title": "Frontiers in neuroscience", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/25561905/" - } - ], - "7c604451-0939-4030-b6dd-fa7dcc656d03": [ - { - "pub_id": "22321699", - "title": "A novel significance score for gene selection and ranking.", - "authors": "Yufei Xiao,Tzu-Hung Hsiao,Uthra Suresh,Hung-I Harry Chen,Xiaowu Wu,Steven E Wolf,Yidong Chen", - "abstract": "When identifying differentially expressed (DE) genes from high-throughput gene expression measurements, we would like to take both statistical significance (such as P-value) and biological relevance (such as fold change) into consideration. In gene set enrichment analysis (GSEA), a score that can combine fold change and P-value together is needed for better gene ranking. We defined a gene significance score \u03c0-value by combining expression fold change and statistical significance (P-value), and explored its statistical properties. When compared to various existing methods, \u03c0-value based approach is more robust in selecting DE genes, with the largest area under curve in its receiver operating characteristic curve. We applied \u03c0-value to GSEA and found it comparable to P-value and t-statistic based methods, with added protection against false discovery in certain situations. Finally, in a gene functional study of breast cancer profiles, we showed that using \u03c0-value helps elucidating otherwise overlooked important biological functions. http://gccri.uthscsa.edu/Pi_Value_Supplementary.asp xy@ieee.org, cheny8@uthscsa.edu Supplementary data are available at Bioinformatics online.", - "journal_title": "Bioinformatics (Oxford, England)", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/22321699/" - } - ], - "b7ef2e02-5be5-4a76-b8d9-3f305e2982a3": [ - { - "pub_id": "23195119", - "title": "Biological databases for behavioral neurobiology.", - "authors": "Erich J Baker", - "abstract": "Databases are, at their core, abstractions of data and their intentionally derived relationships. They serve as a central organizing metaphor and repository, supporting or augmenting nearly all bioinformatics. Behavioral domains provide a unique stage for contemporary databases, as research in this area spans diverse data types, locations, and data relationships. This chapter provides foundational information on the diversity and prevalence of databases, how data structures support the various needs of behavioral neuroscience analysis and interpretation. The focus is on the classes of databases, data curation, and advanced applications in bioinformatics using examples largely drawn from research efforts in behavioral neuroscience.", - "journal_title": "International review of neurobiology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/23195119/" - } - ], - "3d7595c8-8632-40bc-8794-89746944cc6e": [ - { - "pub_id": "26063738", - "title": "Sequence determinants of improved CRISPR sgRNA design.", - "authors": "Han Xu,Tengfei Xiao,Chen-Hao Chen,Wei Li,Clifford A Meyer,Qiu Wu,Di Wu,Le Cong,Feng Zhang,Jun S Liu,Myles Brown,X Shirley Liu", - "abstract": "The CRISPR/Cas9 system has revolutionized mammalian somatic cell genetics. Genome-wide functional screens using CRISPR/Cas9-mediated knockout or dCas9 fusion-mediated inhibition/activation (CRISPRi/a) are powerful techniques for discovering phenotype-associated gene function. We systematically assessed the DNA sequence features that contribute to single guide RNA (sgRNA) efficiency in CRISPR-based screens. Leveraging the information from multiple designs, we derived a new sequence model for predicting sgRNA efficiency in CRISPR/Cas9 knockout experiments. Our model confirmed known features and suggested new features including a preference for cytosine at the cleavage site. The model was experimentally validated for sgRNA-mediated mutation rate and protein knockout efficiency. Tested on independent data sets, the model achieved significant results in both positive and negative selection conditions and outperformed existing models. We also found that the sequence preference for CRISPRi/a is substantially different from that for CRISPR/Cas9 knockout and propose a new model for predicting sgRNA efficiency in CRISPRi/a experiments. These results facilitate the genome-wide design of improved sgRNA for both knockout and CRISPRi/a studies.", - "journal_title": "Genome research", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/26063738/" - } - ], - "2c774a55-3077-4ad9-90c9-7c59bfae54dc": [ - { - "pub_id": "27224245", - "title": "Von Willebrand Factor Gene Variants Associate with Herpes simplex Encephalitis.", - "authors": "Nada Abdelmagid,Biborka Bereczky-Veress,Santosh Atanur,Alena Musilov\u00e1,V\u00e1clav Z\u00eddek,Laura Saba,Andreas Warnecke,Mohsen Khademi,Marie Studahl,Elisabeth Aurelius,Anders Hjalmarsson,Ana Garcia-Diaz,C\u00e9cile V Denis,Tomas Bergstr\u00f6m,Birgit Sk\u00f6ldenberg,Ingrid Kockum,Timothy Aitman,Norbert H\u00fcbner,Tomas Olsson,Michal Pravenec,Margarita Diez", - "abstract": "Herpes simplex encephalitis (HSE) is a rare complication of Herpes simplex virus type-1 infection. It results in severe parenchymal damage in the brain. Although viral latency in neurons is very common in the population, it remains unclear why certain individuals develop HSE. Here we explore potential host genetic variants predisposing to HSE. In order to investigate this we used a rat HSE model comparing the HSE susceptible SHR (Spontaneously Hypertensive Rats) with the asymptomatic infection of BN (Brown Norway). Notably, both strains have HSV-1 spread to the CNS at four days after infection. A genome wide linkage analysis of 29 infected HXB/BXH RILs (recombinant inbred lines-generated from the prior two strains), displayed variable susceptibility to HSE enabling the definition of a significant QTL (quantitative trait locus) named Hse6 towards the end of chromosome 4 (160.89-174Mb) containing the Vwf (von Willebrand factor) gene. This was the only gene in the QTL with both cis-regulation in the brain and included several non-synonymous SNPs (single nucleotide polymorphism). Intriguingly, in human chromosome 12 several SNPs within the intronic region between exon 43 and 44 of the VWF gene were associated with human HSE pathogenesis. In particular, rs917859 is nominally associated with an odds ratio of 1.5 (95% CI 1.11-2.02; p-value = 0.008) after genotyping in 115 HSE cases and 428 controls. Although there are possibly several genetic and environmental factors involved in development of HSE, our study identifies variants of the VWF gene as candidates for susceptibility in experimental and human HSE.", - "journal_title": "PloS one", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/27224245/" - } - ], - "2715e261-b26c-46d6-918f-c6aa47688f0c": [ - { - "pub_id": "24332121", - "title": "Clinical trial design for the development of new therapies for nonmuscle-invasive bladder cancer: report of a Food and Drug Administration and American Urological Association public workshop.", - "authors": "Jonathan P Jarow,Seth P Lerner,Paul G Kluetz,Ke Liu,Rajeshwari Sridhara,Dean Bajorin,Sam Chang,Colin P N Dinney,Susan Groshen,Ronald A Morton,Michael O'Donnell,Diane Zipursky Quale,Mark Schoenberg,John Seigne,Bhadrasain Vikram", - "abstract": "To summarize the discussion at a public workshop, cosponsored by the U.S. Food and Drug Administration (FDA) and the American Urological Association, reviewing potential trial designs for the development of new therapies for non-muscle-invasive bladder cancer (NMIBC). There have been only 3 drug approvals for NMIBC in the last 30 years, and product development for this disease has been stymied by difficulties in trial design and patient accrual. A workshop evaluating potential trial design for the development of therapies for NMIBC was held in San Diego, CA, in May 2013. Invited experts representing all stakeholders, including urology, medical oncology, radiation oncology, industry, and patient advocates, discussed development of products for all risk strata of NMIBC. The panel responded to specific questions from the FDA, discussing eligibility criteria, efficacy endpoints, and trial design for patients with a mix of high-grade papillary disease and carcinoma in situ, Bacillus Calmette-Guerin (BCG)-refractory disease, and intermediate-risk disease. Panel members also addressed the magnitude of response that would be clinically meaningful for various disease strata and trial design options for perioperative intravesical chemotherapy instillation at the time of resection of bladder tumors. Expert commentary provided by panel members will inform a planned FDA guidance on pathways for drug and biologic development for NMIBC and will be discussed at meetings of the FDA's Oncologic Drugs Advisory Committee. FDA intends to develop a set of principles that can be used to promote the development of new products for this disease.", - "journal_title": "Urology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/24332121/" - } - ], - "35e79c80-e59e-47ba-8f34-9c82e03a5a33": [ - { - "pub_id": "27733864", - "title": "Genetic Networks in Mouse Retinal Ganglion Cells.", - "authors": "Felix L Struebing,Richard K Lee,Robert W Williams,Eldon E Geisert", - "abstract": "Retinal ganglion cells (RGCs) are the output neuron of the eye, transmitting visual information from the retina through the optic nerve to the brain. The importance of RGCs for vision is demonstrated in blinding diseases where RGCs are lost, such as in glaucoma or after optic nerve injury. In the present study, we hypothesize that normal RGC function is transcriptionally regulated. To test our hypothesis, we examine large retinal expression microarray datasets from recombinant inbred mouse strains in GeneNetwork and define transcriptional networks of RGCs and their subtypes. Two major and functionally distinct transcriptional networks centering around <i>Thy1</i> and <i>Tubb3</i> (Class III beta-tubulin) were identified. Each network is independently regulated and modulated by unique genomic loci. Meta-analysis of publically available data confirms that RGC subtypes are differentially susceptible to death, with alpha-RGCs and intrinsically photosensitive RGCs (ipRGCs) being less sensitive to cell death than other RGC subtypes in a mouse model of glaucoma.", - "journal_title": "Frontiers in genetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/27733864/" - } - ], - "cadf5405-2d07-4972-8b0f-0f97e00188a8": [ - { - "pub_id": "24405699", - "title": "Quantitative trait loci mapping and gene network analysis implicate protocadherin-15 as a determinant of brain serotonin transporter expression.", - "authors": "R Ye,A M D Carneiro,Q Han,D Airey,E Sanders-Bush,B Zhang,L Lu,R Williams,R D Blakely", - "abstract": "Presynaptic serotonin (5-hydroxytryptamine, 5-HT) transporters (SERT) regulate 5-HT signaling via antidepressant-sensitive clearance of released neurotransmitter. Polymorphisms in the human SERT gene (SLC6A4) have been linked to risk for multiple neuropsychiatric disorders, including depression, obsessive-compulsive disorder and autism. Using BXD recombinant inbred mice, a genetic reference population that can support the discovery of novel determinants of complex traits, merging collective trait assessments with bioinformatics approaches, we examine phenotypic and molecular networks associated with SERT gene and protein expression. Correlational analyses revealed a network of genes that significantly associated with SERT mRNA levels. We quantified SERT protein expression levels and identified region- and gender-specific quantitative trait loci (QTLs), one of which associated with male midbrain SERT protein expression, centered on the protocadherin-15 gene (Pcdh15), overlapped with a QTL for midbrain 5-HT levels. Pcdh15 was also the only QTL-associated gene whose midbrain mRNA expression significantly associated with both SERT protein and 5-HT traits, suggesting an unrecognized role of the cell adhesion protein in the development or function of 5-HT neurons. To test this hypothesis, we assessed SERT protein and 5-HT traits in the Pcdh15 functional null line (Pcdh15(av-) (3J) ), studies that revealed a strong, negative influence of Pcdh15 on these phenotypes. Together, our findings illustrate the power of multidimensional profiling of recombinant inbred lines in the analysis of molecular networks that support synaptic signaling, and that, as in the case of Pcdh15, can reveal novel relationships that may underlie risk for mental illness.", - "journal_title": "Genes, brain, and behavior", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/24405699/" - } - ], - "0b070626-11b0-4be4-bc50-126c1d31a10b": [ - { - "pub_id": "23207275", - "title": "Development of a murine model for aerosolized ebolavirus infection using a panel of recombinant inbred mice.", - "authors": "Elizabeth E Zumbrun,Nourtan F Abdeltawab,Holly A Bloomfield,Taylor B Chance,Donald K Nichols,Paige E Harrison,Malak Kotb,Aysegul Nalca", - "abstract": "Countering aerosolized filovirus infection is a major priority of biodefense research. Aerosol models of filovirus infection have been developed in knock-out mice, guinea pigs and non-human primates; however, filovirus infection of immunocompetent mice by the aerosol route has not been reported. A murine model of aerosolized filovirus infection in mice should be useful for screening vaccine candidates and therapies. In this study, various strains of wild-type and immunocompromised mice were exposed to aerosolized wild-type (WT) or mouse-adapted (MA) Ebola virus (EBOV). Upon exposure to aerosolized WT-EBOV, BALB/c, C57BL/6 (B6), and DBA/2 (D2) mice were unaffected, but 100% of severe combined immunodeficiency (SCID) and 90% of signal transducers and activators of transcription (Stat1) knock-out (KO) mice became moribund between 7-9 days post-exposure (dpe). Exposure to MA-EBOV caused 15% body weight loss in BALB/c, but all mice recovered. In contrast, 10-30% lethality was observed in B6 and D2 mice exposed to aerosolized MA-EBOV, and 100% of SCID, Stat1KO, interferon (IFN)-\u03b3 KO and Perforin KO mice became moribund between 7-14 dpe. In order to identify wild-type, inbred, mouse strains in which exposure to aerosolized MA-EBOV is uniformly lethal, 60 BXD (C57BL/6 crossed with DBA2) recombinant inbred (RI) and advanced RI (ARI) mouse strains were exposed to aerosolized MA-EBOV, and monitored for disease severity. A complete spectrum of disease severity was observed. All BXD strains lost weight but many recovered. However, infection was uniformly lethal within 7 to 12 days post-exposure in five BXD strains. Aerosol exposure of these five BXD strains to 10-fold less MA-EBOV resulted in lethality ranging from 0% in two strains to 90-100% lethality in two strains. Analysis of post-mortem tissue from BXD strains that became moribund and were euthanized at the lower dose of MA-EBOV, showed liver damage in all mice as well as lung lesions in two of the three strains. The two BXD strains that exhibited 90-100% mortality, even at a low dose of airborne MA-EBOV will be useful mouse models for testing vaccines and therapies. Additionally, since disease susceptibility is affected by complex genetic traits, a systems genetics approach was used to identify preliminary gene loci modulating disease severity among the panel BXD strains. Preliminary quantitative trait loci (QTLs) were identified that are likely to harbor genes involved in modulating differential susceptibility to Ebola infection.", - "journal_title": "Viruses", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/23207275/" - } - ], - "b5c36c1e-458e-4009-818e-9c0c2ee23e45": [ - { - "pub_id": "22457016", - "title": "Systems genetic analysis of the effects of iron deficiency in mouse brain.", - "authors": "Leslie C Jellen,Erica L Unger,Lu Lu,Robert W Williams,Sarah Rousseau,Xusheng Wang,Christopher J Earley,Richard P Allen,Michael F Miles,Byron C Jones", - "abstract": "Iron regulation in the brain is both necessary and highly complex. Too little or too much iron can compromise neurological function, yet we still do not know all of the regulatory processes. In our research, we seek to identify genes and gene networks underlying individual differences in brain iron regulation. To this end, we fed mice from 20+ inbred strains a diet low in iron from weaning to 4 months of age. At sacrifice, we measured iron content in the ventral midbrain (VMB). The VMB contains the substantia nigra, a region particularly vulnerable to iron imbalance. The results showed high, inter-strain variability in dietary iron reduction, from almost no loss to more than 40 % vs. control. When we performed quantitative trait loci (QTL) analysis, we observed a significant area on chromosome 2. Within this QTL, we selected glial high-affinity glutamate transporter 1 (Glt1) as the leading candidate. Expression of this gene is both correlated with VMB iron and is also cis-modulated by local sequence variants that segregate in the BXD family. VMB expression differences of Glt1 in six strains covary with differential susceptibility to VMB iron loss.", - "journal_title": "Neurogenetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/22457016/" - } - ], - "9b2a48a0-f85e-4104-944f-0c47a3b03a9b": [ - { - "pub_id": "21535883", - "title": "Genome-wide analysis of the mouse lung transcriptome reveals novel molecular gene interaction networks and cell-specific expression signatures.", - "authors": "Rudi Alberts,Lu Lu,Robert W Williams,Klaus Schughart", - "abstract": "The lung is critical in surveillance and initial defense against pathogens. In humans, as in mice, individual genetic differences strongly modulate pulmonary responses to infectious agents, severity of lung disease, and potential allergic reactions. In a first step towards understanding genetic predisposition and pulmonary molecular networks that underlie individual differences in disease vulnerability, we performed a global analysis of normative lung gene expression levels in inbred mouse strains and a large family of BXD strains that are widely used for systems genetics. Our goal is to provide a key community resource on the genetics of the normative lung transcriptome that can serve as a foundation for experimental analysis and allow predicting genetic predisposition and response to pathogens, allergens, and xenobiotics. Steady-state polyA+ mRNA levels were assayed across a diverse and fully genotyped panel of 57 isogenic strains using the Affymetrix M430 2.0 array. Correlations of expression levels between genes were determined. Global expression QTL (eQTL) analysis and network covariance analysis was performed using tools and resources in GeneNetwork http://www.genenetwork.org. Expression values were highly variable across strains and in many cases exhibited a high heritability factor. Several genes which showed a restricted expression to lung tissue were identified. Using correlations between gene expression values across all strains, we defined and extended memberships of several important molecular networks in the lung. Furthermore, we were able to extract signatures of immune cell subpopulations and characterize co-variation and shared genetic modulation. Known QTL regions for respiratory infection susceptibility were investigated and several cis-eQTL genes were identified. Numerous cis- and trans-regulated transcripts and chromosomal intervals with strong regulatory activity were mapped. The Cyp1a1 P450 transcript had a strong trans-acting eQTL (LOD 11.8) on Chr 12 at 36 \u00b1 1 Mb. This interval contains the transcription factor Ahr that has a critical mis-sense allele in the DBA/2J haplotype and evidently modulates transcriptional activation by AhR. Large-scale gene expression analyses in genetic reference populations revealed lung-specific and immune-cell gene expression profiles and suggested specific gene regulatory interactions.", - "journal_title": "Respiratory research", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/21535883/" - } - ], - "688ecd25-fdc4-424f-97b0-fe074647a8a5": [ - { - "pub_id": "22142972", - "title": "The age of the \"ome\": genome, transcriptome and proteome data set collection and analysis.", - "authors": "Amanda J Myers", - "abstract": "The current state of human genetic studies is both a marvel and a morass. A marvel in that with the completion of the human genome sequence, projects that used to take years now take months or weeks; however, this creates a wealth of data concomitant to a black hole of meaning. In terms of the well used analogy: the human genome sequence is a library in an ancient language with no Rosetta stone. Researchers have readily exploited the human genome map and thousands of candidate gene studies for a multitude of diseases have been performed. However, many of those studies have found that the variants associated with disease risk are not obvious coding changes. The question now becomes: what do these associations mean? One approach to the downstream mapping of associations is to use additional information to map which variant might truly be causative of risk and what that risk variant is doing. This review will summarize the current state of both data set collection and analysis for the understanding of DNA variants and their downstream effects on transcripts and proteins. This article is part of a Special Issue entitled 'Transcriptome'.", - "journal_title": "Brain research bulletin", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/22142972/" - } - ], - "8725811e-e1aa-4aaf-98ed-f6b4a295e1fe": [ - { - "pub_id": "22988948", - "title": "Genetic linkages for thyroxine released in response to thyrotropin stimulation in three sets of recombinant inbred mice provide evidence for shared and novel genes controlling thyroid function.", - "authors": "Sepehr Hamidi,Holly A Aliesky,Robert W Williams,Basil Rapoport,Sandra M McLachlan", - "abstract": "Graves' hyperthyroidism is induced by immunizing mice with adenovirus expressing the human thyrotropin (TSH)-receptor. Using families of recombinant-inbred mice, we previously discovered that genetic susceptibility to induced thyroid-stimulating antibodies and hyperthyroidism are linked to loci on different chromosomes, indicating a fundamental genetic difference in thyroid sensitivity to ligand stimulation. An approach to assess thyroid sensitivity involves challenging genetically diverse lines of mice with TSH and measuring the genotype/strain-specific increase in serum thyroxine (T4). We investigated genetic susceptibility and genetic control of T4 stimulation by 10 mU bovine TSH in female mice of the CXB, BXH, and AXB/BXA strain families, all previously studied for induced Graves' hyperthyroidism. Before TSH injection, T4 levels must be suppressed by inhibiting endogenous TSH secretion. Three daily intraperitoneal L-triiodothyronine injections efficiently suppressed serum T4 in females of 50 of 51 recombinant inbred strains. T4 stimulation by TSH was more strongly linked in CXB and BXH sets, derived from parental strains with divergent T4 stimulation, than in AXB/BXA strains generated from parents with similar TSH-induced responses. Genetic loci linked to the acute TSH-induced T4 response (hours) were not the same as those linked to induced hyperthyroidism (which develops over months). Genetic susceptibility for thyroid sensitivity to TSH stimulation was distinct for three families of inbred mouse lines. These observations parallel the human situation with multiple genetic loci contributing to the same trait and different loci associated with the same trait in different ethnic groups. Of the genetic loci highlighted in mice, three overlap with, or are located up or downstream, of human TSH-controlling genes. Other studies show that human disease genes can be identified through cross-species gene mapping of evolutionary conserved processes. Consequently, our findings suggest that novel thyroid function genes may yet be revealed in humans.", - "journal_title": "Thyroid : official journal of the American Thyroid Association", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/22988948/" - } - ], - "1fc0816f-fdc6-4c24-8585-b03ca5e003b6": [ - { - "pub_id": "26126603", - "title": "Identification of quantitative trait loci influencing inflammation-mediated alveolar bone loss: insights into polygenic inheritance of host-biofilm disequilibria in periodontitis.", - "authors": "C Sima,Q Cheng,J Rautava,C Levesque,P Sherman,M Glogauer", - "abstract": "The relative contribution of genetic and environmental factors to the onset and progression of periodontitis is inconclusive. Despite the high prevalence, phenotypic heterogeneity and significant local and systemic implications of this disease, early detection and individualized therapy are problematic. Using a murine model of periodontitis in a panel of 17 recombinant inbred mice, the current study addressed the heritability of, and oral dysbiosis associated with, inflammation-mediated alveolar bone loss (iABL), the hallmark of periodontitis. Quantitative trait locus (QTL) genomics and quantitative PCR for over 99% of known murine oral microbiota were used. It was found that iABL is a polygenic trait with 32.7% heritability. One suggestive QTL, nicknamed inflammation-mediated alveolar bone loss locus (iABLL), was identified on chromosome 2. Eleven genes involved in innate immune responses and bone metabolism, particularly related to macrophage and osteoblast function, namely Etl4, Pdss1, Cobll1, 9330158F14Rik, Xirp2, Stk39, Mettl5, Metapl1, Itga6, Pdk1 and Sp3, were found in the iABLL using cis expression QTL and nonsynonymous single nucleotide polymorphism analyses. Specific oral microbiome shifts in saliva and tongue mucosa are associated with disease in this model. Our results indicate that complex host-biofilm interactions generate pathogenic states that extend beyond subgingival biofilms and periodontal tissues. Although no temporal relationship between the onset of iABL and microbiome changes were established, our findings suggest that host factors may be responsible for pathogenic shifts in subgingival biofilms when persistent and undisturbed.", - "journal_title": "Journal of periodontal research", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/26126603/" - } - ], - "78acf3c9-239e-45b4-951d-a08b92663ea8": [ - { - "pub_id": "23665904", - "title": "Genome-wide gene expression profiles in antioxidant pathways and their potential sex differences and connections to vitamin C in mice.", - "authors": "Yan Jiao,Hong Chen,Jian Yan,Lishi Wang,Yue Huang,Xiaoyun Liu,Robert W Williams,Lu Lu,Yongjun Wang,Weikuan Gu", - "abstract": "Vitamin C (VC) is well known as an antioxidant in humans, primates and guinea pigs. Studies have suggested gender differences in VC requirements in humans, and gender differences in oxidant injury vulnerability in early life may represent a biological mechanism contributing to gender disparity in later life. Using spontaneous bone fracture (sfx) mice, which lack the gene for L-Gulonolactone oxidase (Gulo), we studied the potential sex difference in expression profiles of oxidative genes at the whole-genome level. Then, we analyzed data of gene expressions in a mouse population of recombinant inbred (RI) strains originally derived by crossing C57BL/6J (B6) and DBA/2J (D2) mice. Our data indicated that there were sex differences in the regulation of pre- and pro-oxidative genes in sfx mice. The associations of expression levels among Gulo, its partner genes and oxidative genes in the BXD (B6 \u00d7 D2) RI strains showed a sex difference. Transcriptome mapping suggests that Gulo was regulated differently between female and male mice in BXD RI strains. Our study indicates the importance of investigating sex differences in Gulo and its oxidative function by using available mouse models.", - "journal_title": "International journal of molecular sciences", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/23665904/" - } - ], - "095349ec-5f83-42e4-a4a1-dcae2c7d464e": [ - { - "pub_id": "22413943", - "title": "Quantitative trait locus mapping for ethanol teratogenesis in BXD recombinant inbred mice.", - "authors": "Chris Downing,Christina Balderrama-Durbin,Alexi Kimball,Jami Biers,Hali Wright,David Gilliam,Thomas E Johnson", - "abstract": "Individual differences in susceptibility to the detrimental effects of prenatal ethanol (EtOH) exposure have been demonstrated. Many factors, including genetics, play a role in susceptibility and resistance. We have previously shown that C57BL/6J (B6) mice display a number of morphological malformations following an acute dose of EtOH in utero, while DBA/2J (D2) mice are relatively resistant. Here, we present the results of quantitative trait locus (QTL) mapping for EtOH teratogenesis in recombinant inbred strains derived from a cross between B6 and D2 (BXD RIs). Pregnant dams were intubated with either maltose-dextrin or 5.8 g/kg EtOH on day 9 of gestation (GD9). On GD 18, dams were sacrificed and fetuses and placentae were removed. Placentae and fetuses were weighed; fetuses were sexed and examined for gross morphological malformations. Fetuses were then either placed in Bouin's fixative for subsequent soft-tissue analyses or eviscerated and placed in EtOH for subsequent skeletal examinations. QTL mapping for maternal weight gain (MWG), prenatal mortality, fetal weight (FW) at c-section, placental weight (PW), and several morphological malformations was performed using WebQTL. Heritability for our traits ranged from 0.06 for PW to 0.39 for MWG. We found suggestive QTLs mediating all phenotypes and significant QTLs for FW and digit and rib malformations. While most QTL regions are large, several intriguing candidate genes emerged based on polymorphisms between B6 and D2 and gene function. In this first mapping study for EtOH teratogenesis, several QTLs were identified. Future studies will further characterize these regions. Identification of genes and epigenetic modifications mediating susceptibility to the teratogenic effects of alcohol in mice will provide targets to examine in human populations.", - "journal_title": "Alcoholism, clinical and experimental research", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/22413943/" - } - ], - "e2d9190f-cf34-4cfe-b4ee-bd5e0b748cc0": [ - { - "pub_id": "23409935", - "title": "Glyoxalase 1 and its substrate methylglyoxal are novel regulators of seizure susceptibility.", - "authors": "Margaret G Distler,Naomi Gorfinkle,Ligia A Papale,Gerald E Wuenschell,John Termini,Andrew Escayg,Melodie R Winawer,Abraham A Palmer", - "abstract": "Epilepsy is a complex disease characterized by a predisposition toward seizures. There are numerous barriers to the successful treatment of epilepsy. For instance, current antiepileptic drugs have adverse side effects and variable efficacies. Furthermore, the pathophysiologic basis of epilepsy remains largely elusive. Therefore, investigating novel genes and biologic processes underlying epilepsy may provide valuable insight and enable the development of new therapeutic agents. We previously identified methylglyoxal (MG) as an endogenous \u03b3-aminobutyric acid (GABAA ) receptor agonist. Here, we investigated the role of MG and its catabolic enzyme, glyoxalase 1 (GLO1), in seizures. We pretreated mice with MG before seizure induction with picrotoxin or pilocarpine and then assessed seizures behaviorally or by electroencephalography (EEG). We then investigated the role of GLO1 in seizures by treating mice with a pharmacologic inhibitor of GLO1 before seizure induction with pilocarpine and measured subsequent seizure phenotypes. Next, we explored the genetic relationship between Glo1 expression and seizures. We analyzed seizure phenotypes among C57BL/6J \u00d7 DBA/2J (BXD) recombinant inbred (RI) mice with differential Glo1 expression. Lastly, we investigated a causal role for Glo1 in seizures by administering pilocarpine to transgenic (Tg) mice that overexpress Glo1. Pretreatment with MG attenuated pharmacologically-induced seizures at both the behavioral and EEG levels. GLO1 inhibition, which increases MG concentration in vivo, also attenuated seizures. Among BXD RI mice, high Glo1 expression was correlated with increased seizure susceptibility. Tg mice overexpressing Glo1 displayed reduced MG concentration in the brain and increased seizure severity. These data identify MG as an endogenous regulator of seizures. Similarly, inhibition of GLO1 attenuates seizures, suggesting that this may be a novel therapeutic approach for epilepsy. Furthermore, this system may represent an endogenous negative feedback loop whereby high metabolic activity increases inhibitory tone via local accumulation of MG. Finally, Glo1 may contribute to the genetic architecture of epilepsy, as Glo1 expression regulates both MG concentration and seizure severity.", - "journal_title": "Epilepsia", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/23409935/" - } - ], - "cb30afe8-6efe-474b-b6b3-f73a9f5d33ee": [ - { - "pub_id": "21829384", - "title": "Quantitative and qualitative stem rust resistance factors in barley are associated with transcriptional suppression of defense regulons.", - "authors": "Matthew J Moscou,Nick Lauter,Brian Steffenson,Roger P Wise", - "abstract": "Stem rust (Puccinia graminis f. sp. tritici; Pgt) is a devastating fungal disease of wheat and barley. Pgt race TTKSK (isolate Ug99) is a serious threat to these Triticeae grain crops because resistance is rare. In barley, the complex Rpg-TTKSK locus on chromosome 5H is presently the only known source of qualitative resistance to this aggressive Pgt race. Segregation for resistance observed on seedlings of the Q21861 \u00d7 SM89010 (QSM) doubled-haploid (DH) population was found to be predominantly qualitative, with little of the remaining variance explained by loci other than Rpg-TTKSK. In contrast, analysis of adult QSM DH plants infected by field inoculum of Pgt race TTKSK in Njoro, Kenya, revealed several additional quantitative trait loci that contribute to resistance. To molecularly characterize these loci, Barley1 GeneChips were used to measure the expression of 22,792 genes in the QSM population after inoculation with Pgt race TTKSK or mock-inoculation. Comparison of expression Quantitative Trait Loci (eQTL) between treatments revealed an inoculation-dependent expression polymorphism implicating Actin depolymerizing factor3 (within the Rpg-TTKSK locus) as a candidate susceptibility gene. In parallel, we identified a chromosome 2H trans-eQTL hotspot that co-segregates with an enhancer of Rpg-TTKSK-mediated, adult plant resistance discovered through the Njoro field trials. Our genome-wide eQTL studies demonstrate that transcript accumulation of 25% of barley genes is altered following challenge by Pgt race TTKSK, but that few of these genes are regulated by the qualitative Rpg-TTKSK on chromosome 5H. It is instead the chromosome 2H trans-eQTL hotspot that orchestrates the largest inoculation-specific responses, where enhanced resistance is associated with transcriptional suppression of hundreds of genes scattered throughout the genome. Hence, the present study associates the early suppression of genes expressed in this host-pathogen interaction with enhancement of R-gene mediated resistance.", - "journal_title": "PLoS genetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/21829384/" - } - ], - "c3265667-d400-44d8-b8c6-2b74be34dbe1": [ - { - "pub_id": "22239914", - "title": "Chloride intracellular channels modulate acute ethanol behaviors in Drosophila, Caenorhabditis elegans and mice.", - "authors": "P Bhandari,J S Hill,S P Farris,B Costin,I Martin,C-L Chan,J T Alaimo,J C Bettinger,A G Davies,M F Miles,M Grotewiel", - "abstract": "Identifying genes that influence behavioral responses to alcohol is critical for understanding the molecular basis of alcoholism and ultimately developing therapeutic interventions for the disease. Using an integrated approach that combined the power of the Drosophila, Caenorhabditis elegans and mouse model systems with bioinformatics analyses, we established a novel, conserved role for chloride intracellular channels (CLICs) in alcohol-related behavior. CLIC proteins might have several biochemical functions including intracellular chloride channel activity, modulation of transforming growth factor (TGF)-\u03b2 signaling, and regulation of ryanodine receptors and A-kinase anchoring proteins. We initially identified vertebrate Clic4 as a candidate ethanol-responsive gene via bioinformatic analysis of data from published microarray studies of mouse and human ethanol-related genes. We confirmed that Clic4 expression was increased by ethanol treatment in mouse prefrontal cortex and also uncovered a correlation between basal expression of Clic4 in prefrontal cortex and the locomotor activating and sedating properties of ethanol across the BXD mouse genetic reference panel. Furthermore, we found that disruption of the sole Clic Drosophila orthologue significantly blunted sensitivity to alcohol in flies, that mutations in two C. elegans Clic orthologues, exc-4 and exl-1, altered behavioral responses to acute ethanol in worms and that viral-mediated overexpression of Clic4 in mouse brain decreased the sedating properties of ethanol. Together, our studies demonstrate key roles for Clic genes in behavioral responses to acute alcohol in Drosophila, C. elegans and mice.", - "journal_title": "Genes, brain, and behavior", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/22239914/" - } - ], - "d2f9c5cf-835c-450a-bb42-a2454a99e058": [ - { - "pub_id": "22810696", - "title": "Comprehensive molecular characterization of human colon and rectal cancer.", - "authors": " ", - "abstract": "To characterize somatic alterations in colorectal carcinoma, we conducted a genome-scale analysis of 276 samples, analysing exome sequence, DNA copy number, promoter methylation and messenger RNA and microRNA expression. A subset of these samples (97) underwent low-depth-of-coverage whole-genome sequencing. In total, 16% of colorectal carcinomas were found to be hypermutated: three-quarters of these had the expected high microsatellite instability, usually with hypermethylation and MLH1 silencing, and one-quarter had somatic mismatch-repair gene and polymerase \u03b5 (POLE) mutations. Excluding the hypermutated cancers, colon and rectum cancers were found to have considerably similar patterns of genomic alteration. Twenty-four genes were significantly mutated, and in addition to the expected APC, TP53, SMAD4, PIK3CA and KRAS mutations, we found frequent mutations in ARID1A, SOX9 and FAM123B. Recurrent copy-number alterations include potentially drug-targetable amplifications of ERBB2 and newly discovered amplification of IGF2. Recurrent chromosomal translocations include the fusion of NAV2 and WNT pathway member TCF7L1. Integrative analyses suggest new markers for aggressive colorectal carcinoma and an important role for MYC-directed transcriptional activation and repression.", - "journal_title": "Nature", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/22810696/" - } - ], - "c04e1cdc-f962-4b37-a0e0-fa6021ec1f7a": [ - { - "pub_id": "24102824", - "title": "Evaluation of heritable determinants of blood and brain serotonin homeostasis using recombinant inbred mice.", - "authors": "R Ye,A M D Carneiro,D Airey,E Sanders-Bush,R W Williams,L Lu,J Wang,B Zhang,R D Blakely", - "abstract": "The biogenic amine serotonin (5-HT, 5-hydroxytryptamine) exerts powerful, modulatory control over multiple physiological functions in the brain and periphery, ranging from mood and appetite to vasoconstriction and gastrointestinal motility. In order to gain insight into shared and distinct molecular and phenotypic networks linked to variations in 5-HT homeostasis, we capitalized on the stable genetic variation present in recombinant inbred mouse strains. This family of strains, all derived from crosses between C57BL/6J and DBA/2J (BXD) parents, represents a unique, community resource with approximately 40\u2009years of assembled phenotype data that can be exploited to explore and test causal relationships in silico. We determined levels of 5-HT and 5-hydroxyindoleacetic acid from whole blood, midbrain and thalamus/hypothalamus (diencephalon) of 38 BXD lines and both sexes. All 5-HT measures proved highly heritable in each region, although both gender and region significantly impacted between-strain correlations. Our studies identified both expected and novel biochemical, anatomical and behavioral phenotypes linked to 5-HT traits, as well as distinct quantitative trait loci. Analyses of these loci nominate a group of genes likely to contribute to gender- and region-specific capacities for 5-HT signaling. Analysis of midbrain mRNA variations across strains revealed overlapping gene expression networks linked to 5-HT synthesis and metabolism. Altogether, our studies provide a rich profile of genomic, molecular and phenotypic networks that can be queried for novel relationships contributing risk for disorders linked to perturbed 5-HT signaling.", - "journal_title": "Genes, brain, and behavior", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/24102824/" - } - ], - "d9476207-1f53-4b08-b261-5c52ad191e08": [ - { - "pub_id": "25691144", - "title": "Differential regional and cellular distribution of TFF3 peptide in the human brain.", - "authors": "Hans-Gert Bernstein,Henrik Dobrowolny,Kurt Tr\u00fcbner,Johann Steiner,Bernhard Bogerts,Werner Hoffmann", - "abstract": "TFF3 is a member of the trefoil factor family (TFF) predominantly secreted by mucous epithelia. Minute amounts are also expressed in the immune system and the brain. In the latter, particularly the hypothalamo-pituitary axis has been investigated in detail in the past. Functionally, cerebral TFF3 has been reported to be involved in several processes such as fear, depression, learning and object recognition, and opiate addiction. Furthermore, TFF3 has been linked with neurodegenerative and neuropsychiatric disorders (e.g., Alzheimer's disease, schizophrenia, and alcoholism). Here, using immunohistochemistry, a systematic survey of the TFF3 localization in the adult human brain is presented focusing on extrahypothalamic brain areas. In addition, the distribution of TFF3 in the developing human brain is described. Taken together, neurons were identified as the predominant cell type to express TFF3, but to different extent; TFF3 was particularly enriched in various midbrain and brain stem nuclei. Besides, TFF3 immunostaining staining was observed in oligodendroglia and the choroid plexus epithelium. The wide cerebral distribution should help to explain its multiple effects in the CNS.", - "journal_title": "Amino acids", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/25691144/" - } - ], - "002bbd9a-f6f8-454b-9c3e-c63e2229ec24": [ - { - "pub_id": "25513972", - "title": "TRPC3 channels critically regulate hippocampal excitability and contextual fear memory.", - "authors": "Sarah M Neuner,Lynda A Wilmott,Kevin A Hope,Brian Hoffmann,Jayhong A Chong,Joel Abramowitz,Lutz Birnbaumer,Kristen M O'Connell,Andrew K Tryba,Andrew S Greene,C Savio Chan,Catherine C Kaczorowski", - "abstract": "Memory formation requires de novo protein synthesis, and memory disorders may result from misregulated synthesis of critical proteins that remain largely unidentified. Plasma membrane ion channels and receptors are likely candidates given their role in regulating neuron excitability, a candidate memory mechanism. Here we conduct targeted molecular monitoring and quantitation of hippocampal plasma membrane proteins from mice with intact or impaired contextual fear memory to identify putative candidates. Here we report contextual fear memory deficits correspond to increased Trpc3 gene and protein expression, and demonstrate TRPC3 regulates hippocampal neuron excitability associated with memory function. These data provide a mechanistic explanation for enhanced contextual fear memory reported herein following knockdown of TRPC3 in hippocampus. Collectively, TRPC3 modulates memory and may be a feasible target to enhance memory and treat memory disorders.", - "journal_title": "Behavioural brain research", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/25513972/" - } - ], - "d1c44568-c447-404f-939d-4e7a4d11ffde": [ - { - "pub_id": "23503680", - "title": "Deciphering molecular circuits from genetic variation underlying transcriptional responsiveness to stimuli.", - "authors": "Irit Gat-Viks,Nicolas Chevrier,Roni Wilentzik,Thomas Eisenhaure,Raktima Raychowdhury,Yael Steuerman,Alex K Shalek,Nir Hacohen,Ido Amit,Aviv Regev", - "abstract": "Individual genetic variation affects gene responsiveness to stimuli, often by influencing complex molecular circuits. Here we combine genomic and intermediate-scale transcriptional profiling with computational methods to identify variants that affect the responsiveness of genes to stimuli (responsiveness quantitative trait loci or reQTLs) and to position these variants in molecular circuit diagrams. We apply this approach to study variation in transcriptional responsiveness to pathogen components in dendritic cells from recombinant inbred mouse strains. We identify reQTLs that correlate with particular stimuli and position them in known pathways. For example, in response to a virus-like stimulus, a trans-acting variant responds as an activator of the antiviral response; using RNA interference, we identify Rgs16 as the likely causal gene. Our approach charts an experimental and analytic path to decipher the mechanisms underlying genetic variation in circuits that control responses to stimuli.", - "journal_title": "Nature biotechnology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/23503680/" - } - ], - "9588738f-b0d2-4b37-9554-f0699a66c4fb": [ - { - "pub_id": "21655357", - "title": "Genetic networks in the mouse retina: growth associated protein 43 and phosphatase tensin homolog network.", - "authors": "Natalie E Freeman,Justin P Templeton,William E Orr,Lu Lu,Robert W Williams,Eldon E Geisert", - "abstract": "The present study examines the structure and covariance of endogenous variation in gene expression across the recently expanded family of C57BL/6J (B) X DBA/2J (D) Recombinant Inbred (BXD RI) strains of mice. This work is accompanied by a highly interactive database that can be used to generate and test specific hypotheses. For example, we define the genetic network regulating growth associated protein 43 (Gap43) and phosphatase tensin homolog (Pten). The Hamilton Eye Institute (HEI) Retina Database within GeneNetwork features the data analysis of 346 Illumina Sentrix BeadChip Arrays (mouse whole genome-6 version 2). Eighty strains of mice are presented, including 75 BXD RI strains, the parental strains (C57BL/6J and DBA/2J), the reciprocal crosses, and the BALB/cByJ mice. Independent biologic samples for at least two animals from each gender were obtained with a narrow age range (48 to 118 days). Total RNA was prepared followed by the production of biotinylated cRNAs, which were pipetted into the Mouse WG-6V2 arrays. The data was globally normalized with rank invariant and stabilization (2z+8). The HEI Retina Database is located on the GeneNetwork website. The database was used to extract unique transcriptome signatures for specific cell types in the retina (retinal pigment epithelial, amacrine, and retinal ganglion cells). Two genes associated with axonal outgrowth (Gap43 and Pten) were used to display the power of this new retina database. Bioinformatic tools located within GeneNetwork in conjunction with the HEI Retina Database were used to identify the unique signature Quantitative Trait Loci (QTLs) for Gap43 and Pten on chromosomes 1, 2, 12, 15, 16, and 19. Gap43 and Pten possess networks that are similar to ganglion cell networks that may be associated with axonal growth in the mouse retina. This network involves high correlations of transcription factors (SRY sex determining region Y-box 2 [Sox2], paired box gene 6 [Pax6], and neurogenic differentiation 1 [Neurod1]), and genes involved in DNA binding (proliferating cell nuclear antigen [Pcna] and zinc finger, BED-type containing 4 [Zbed4]), as well as an inhibitor of DNA binding (inhibitor of DNA binding 2, dominant negative helix-loop-helix protein [Id2]). Furthermore, we identified the potential upstream modifiers on chromosome 2 (teashirt zinc finger homeobox 2 [Tshz2], RNA export 1 homolog [Rae1] and basic helix-loop-helix domain contatining, class B4 [Bhlhb4]) on chromosome 15 (RAB, member of RAS oncogene family-like 2a [Rabl2a], phosphomannomutase 1 [Pmm1], copine VIII [Cpne8], and fibulin 1 [Fbln1]). The endogenous variation in mRNA levels among BXD RI strains can be used to explore and test expression networks underlying variation in retina structure, function, and disease susceptibility. The Gap43 and Pten network highlights the covariance of gene expression and forms a molecular network associated with axonal outgrowth in the adult retina.", - "journal_title": "Molecular vision", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/21655357/" - } - ], - "ae0831bd-6862-4a26-9288-e1c1bf1d2cc9": [ - { - "pub_id": "27829151", - "title": "A Genetic Screen Identifies Hypothalamic Fgf15 as a Regulator of Glucagon Secretion.", - "authors": "Alexandre Picard,Josselin Soyer,Xavier Berney,David Tarussio,Simon Quenneville,Maxime Jan,Eric Grouzmann,Fr\u00e9d\u00e9ric Burdet,Mark Ibberson,Bernard Thorens", - "abstract": "The counterregulatory response to hypoglycemia, which restores normal blood glucose levels to ensure sufficient provision of glucose to the brain, is critical for survival. To discover underlying brain regulatory systems, we performed a genetic screen in recombinant inbred mice for quantitative trait loci (QTL) controlling glucagon secretion in response to neuroglucopenia. We identified a QTL on the distal part of chromosome 7 and combined this genetic information with transcriptomic analysis of hypothalami. This revealed Fgf15 as the strongest candidate to control the glucagon response. Fgf15 was expressed by neurons of the dorsomedial hypothalamus and the perifornical area. Intracerebroventricular injection of FGF19, the human ortholog of Fgf15, reduced activation by neuroglucopenia of dorsal vagal complex neurons, of the parasympathetic nerve, and lowered glucagon secretion. In contrast, silencing Fgf15 in the dorsomedial hypothalamus increased neuroglucopenia-induced glucagon secretion. These data identify hypothalamic Fgf15 as a regulator of glucagon secretion.", - "journal_title": "Cell reports", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/27829151/" - } - ], - "6f36586c-f060-4dec-ae9b-e30a25e1decd": [ - { - "pub_id": "28298516", - "title": "Precision Medicine in Breast Cancer.", - "authors": "Teresa G Odle", - "abstract": "Breast cancer care has improved markedly in recent decades, but new advancements in diagnosis and treatment depend on translating genomics and precision medicine into clinical care. This article discusses the basics of genomics, breast cancer biomarkers and subtypes, and the effects of genomic advancements on future breast cancer diagnosis, treatment, and survival. The article also presents challenges related to introducing precision medicine into cancer care and the role of imaging in breast cancer diagnosis and treatment in precision medicine.", - "journal_title": "Radiologic technology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/28298516/" - } - ], - "d4e871aa-bab3-4954-b109-3b521644a8d0": [ - { - "pub_id": "22419334", - "title": "Mirror therapy for improving motor function after stroke.", - "authors": "Holm Thieme,Jan Mehrholz,Marcus Pohl,Johann Behrens,Christian Dohle", - "abstract": "Mirror therapy is used to improve motor function after stroke. During mirror therapy, a mirror is placed in the patient's midsagittal plane, thus reflecting movements of the non-paretic side as if it were the affected side. To summarise the effectiveness of mirror therapy for improving motor function, activities of daily living, pain and visuospatial neglect in patients after stroke. We searched the Cochrane Stroke Group's Trials Register (June 2011), the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2011, Issue 2), MEDLINE (1950 to June 2011), EMBASE (1980 to June 2011), CINAHL (1982 to June 2011), AMED (1985 to June 2011), PsycINFO (1806 to June 2011) and PEDro (June 2011). We also handsearched relevant conference proceedings, trials and research registers, checked reference lists and contacted trialists, researchers and experts in our field of study. We included randomised controlled trials (RCTs) and randomised cross-over trials comparing mirror therapy with any control intervention for patients after stroke. Two review authors independently selected trials based on the inclusion criteria, documented the methodological quality of studies and extracted data. We analysed the results as standardised mean differences (SMDs) for continuous variables. We included 14 studies with a total of 567 participants that compared mirror therapy with other interventions. When compared with all other interventions, mirror therapy may have a significant effect on motor function (post-intervention data: SMD 0.61; 95% confidence interval (CI) 0.22 to 1.0; P = 0.002; change scores: SMD 1.04; 95% CI 0.57 to 1.51; P < 0.0001). However, effects on motor function are influenced by the type of control intervention. Additionally, mirror therapy may improve activities of daily living (SMD 0.33; 95% CI 0.05 to 0.60; P = 0.02). We found a significant positive effect on pain (SMD -1.10; 95% CI -2.10 to -0.09; P = 0.03) which is influenced by patient population. We found limited evidence for improving visuospatial neglect (SMD 1.22; 95% CI 0.24 to 2.19; P = 0.01). The effects on motor function were stable at follow-up assessment after six months. The results indicate evidence for the effectiveness of mirror therapy for improving upper extremity motor function, activities of daily living and pain, at least as an adjunct to normal rehabilitation for patients after stroke. Limitations are due to small sample sizes of most included studies, control interventions that are not used routinely in stroke rehabilitation and some methodological limitations of the studies.", - "journal_title": "The Cochrane database of systematic reviews", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/22419334/" - } - ], - "81e5290c-cf59-4c1c-888c-53e3299b5759": [ - { - "pub_id": "27798178", - "title": "Differential Expression of Munc13-2 Produces Unique Synaptic Phenotypes in the Basolateral Amygdala of C57BL/6J and DBA/2J Mice.", - "authors": "Dominic A Gioia,Nancy J Alexander,Brian A McCool", - "abstract": "C57BL/6J (B6) and DBA/2J (D2) mice are well known to differentially express a number of behavioral phenotypes, including anxiety-like behavior, fear conditioning, and drug self-administration. However, the cellular mechanisms contributing to these differences remain unclear. Given the basolateral amygdala (BLA) contributes to these behaviors, we characterized strain-dependent differences in presynaptic and postsynaptic function in BLA neurons by integrating electrophysiological, biochemical, and genetic approaches to identify specific molecular mechanisms. We found that D2 glutamatergic synapses expressed enhanced release probability and lower sensitivity to both the inhibitory effects of low extracellular calcium and facilitation by phorbol esters. Furthermore, repetitive stimulation of BLA afferents at low (2 Hz) or high (40 Hz) frequencies revealed that B6 terminals, relative to D2 terminals, were more sensitive to synaptic fatigue principally because of reduced vesicle recycling rates. Additionally, B6 synapses exhibited more robust augmentation of spontaneous release after repetitive stimulation relative to the D2 strain. In silico analysis of the inheritance of synaptic physiology from an array of BXD recombinant inbred strains (Jansen et al., 2011) identified a segment on chromosome 4 containing the gene encoding Munc13-2, which has calcium-/phorbol ester-binding domains and controls presynaptic function. We subsequently found that B6 mice express substantially higher levels of Munc13-2 compared with the D2 strain whereas expression of several release-related proteins, including Munc13-1, was equivalent. We then knocked down the expression of Munc13-2 in B6 mice using a short hairpin RNA and found this recapitulated the presynaptic phenotype of D2 BLA synapses. DBA/2J and C57BL/6J mice have been used to understand the genetic mechanisms controlling behaviors related to a number of psychiatric illnesses. However, the fundamental neurobiological mechanisms producing these behavioral characteristics remain unresolved. Here we identify a critical family of presynaptic proteins differentially expressed by these strains that control strain-dependent synaptic physiology. This family of proteins regulates excitation/secretion coupling, vesicle recycling, and short-term plasticity throughout the CNS. Thus, differential inheritance of proteins like Munc13-2 has broad implications for genetic control over a wide variety of pathological behaviors. Importantly, these proteins also contain a large number of modulatory sites, making them attractive potential targets for the development of novel neuropharmaceutical treatments.", - "journal_title": "The Journal of neuroscience : the official journal of the Society for Neuroscience", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/27798178/" - } - ], - "a9308129-c197-4737-bc2b-9046e3fb94d6": [ - { - "pub_id": "25662840", - "title": "KCNN Genes that Encode Small-Conductance Ca2+-Activated K+ Channels Influence Alcohol and Drug Addiction.", - "authors": "Audrey E Padula,William C Griffin,Marcelo F Lopez,Sudarat Nimitvilai,Reginald Cannady,Natalie S McGuier,Elissa J Chesler,Michael F Miles,Robert W Williams,Patrick K Randall,John J Woodward,Howard C Becker,Patrick J Mulholland", - "abstract": "Small-conductance Ca(2+)-activated K(+) (KCa2) channels control neuronal excitability and synaptic plasticity, and have been implicated in substance abuse. However, it is unknown if genes that encode KCa2 channels (KCNN1-3) influence alcohol and drug addiction. In the present study, an integrative functional genomics approach shows that genetic datasets for alcohol, nicotine, and illicit drugs contain the family of KCNN genes. Alcohol preference and dependence QTLs contain KCNN2 and KCNN3, and Kcnn3 transcript levels in the nucleus accumbens (NAc) of genetically diverse BXD strains of mice predicted voluntary alcohol consumption. Transcript levels of Kcnn3 in the NAc negatively correlated with alcohol intake levels in BXD strains, and alcohol dependence enhanced the strength of this association. Microinjections of the KCa2 channel inhibitor apamin into the NAc increased alcohol intake in control C57BL/6J mice, while spontaneous seizures developed in alcohol-dependent mice following apamin injection. Consistent with this finding, alcohol dependence enhanced the intrinsic excitability of medium spiny neurons in the NAc core and reduced the function and protein expression of KCa2 channels in the NAc. Altogether, these data implicate the family of KCNN genes in alcohol, nicotine, and drug addiction, and identify KCNN3 as a mediator of voluntary and excessive alcohol consumption. KCa2.3 channels represent a promising novel target in the pharmacogenetic treatment of alcohol and drug addiction.", - "journal_title": "Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/25662840/" - } - ], - "5fc36313-6f0c-4bbe-8fb0-3977fdcbd829": [ - { - "pub_id": "22354577", - "title": "Advances in biotechnology and linking outputs to variation in complex traits: Plant and Animal Genome meeting January 2012.", - "authors": "R Appels,R Barrero,M Bellgard", - "abstract": "The Plant and Animal Genome (PAG, held annually) meeting in January 2012 provided insights into the advances in plant, animal, and microbe genome studies particularly as they impact on our understanding of complex biological systems. The diverse areas of biology covered included the advances in technologies, variation in complex traits, genome change in evolution, and targeting phenotypic changes, across the broad spectrum of life forms. This overview aims to summarize the major advances in research areas presented in the plenary lectures and does not attempt to summarize the diverse research activities covered throughout the PAG in workshops, posters, presentations, and displays by suppliers of cutting-edge technologies.", - "journal_title": "Functional & integrative genomics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/22354577/" - } - ], - "081924f4-cdcc-4fce-9223-744c6ecffe4e": [ - { - "pub_id": "25104319", - "title": "Scoring the collective effects of SNPs: association of minor alleles with complex traits in model organisms.", - "authors": "DeJian Yuan,ZuoBin Zhu,XiaoHua Tan,Jie Liang,Chen Zeng,JieGen Zhang,Jun Chen,Long Ma,Ayca Dogan,Gudrun Brockmann,Oliver Goldmann,Eva Medina,Amanda D Rice,Richard W Moyer,Xian Man,Ke Yi,YanKe Li,Qing Lu,YiMin Huang,Shi Huang", - "abstract": "It has long been assumed that most parts of a genome and most genetic variations or SNPs are non-functional with regard to reproductive fitness. However, the collective effects of SNPs have yet to be examined by experimental science. We here developed a novel approach to examine the relationship between traits and the total amount of SNPs in panels of genetic reference populations. We identified the minor alleles (MAs) in each panel and the MA content (MAC) that each inbred strain carried for a set of SNPs with genotypes determined in these panels. MAC was nearly linearly linked to quantitative variations in numerous traits in model organisms, including life span, tumor susceptibility, learning and memory, sensitivity to alcohol and anti-psychotic drugs, and two correlated traits poor reproductive fitness and strong immunity. These results suggest that the collective effects of SNPs are functional and do affect reproductive fitness.", - "journal_title": "Science China. Life sciences", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/25104319/" - } - ], - "581f83bc-3521-4cb3-ad3c-d905a90ecc29": [ - { - "pub_id": "23517691", - "title": "Community-associated MRSA: what makes them special?", - "authors": "Michael Otto", - "abstract": "While infections with methicillin-resistant Staphylococcus aureus (MRSA) were traditionally restricted to the hospital setting, novel MRSA strains emerged over the last two decades that have the capacity to infect otherwise healthy people outside of the hospital setting. These community-associated (CA-)MRSA strains combine methicillin resistance with enhanced virulence and fitness. Interestingly, CA-MRSA strains emerged globally and from different backgrounds, indicating that the \"trade-off\" between maintaining sufficient levels of methicillin resistance and obtaining enhanced virulence at a low fitness cost was achieved on several occasions in convergent evolution. However, frequently this process comprised similar changes. First and foremost, all CA-MRSA strains typically carry a novel type of methicillin resistance locus that appears to cause less of a fitness burden. Additionally, acquisition of specific toxin genes, most notably that encoding Panton-Valentine leukocidin (PVL), and adaptation of gene expression of genome-encoded toxins, such as alpha-toxin and phenol-soluble modulins (PSMs), further contributed to the evolution of CA-MRSA. Finally, the exceptional epidemiological success of the USA300 CA-MRSA clone in particular may have been due to yet another gene acquisition, namely that of the speG gene, which is located on the arginine catabolic mobile element (ACME) and involved in detoxifying harmful host-derived polyamines.", - "journal_title": "International journal of medical microbiology : IJMM", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/23517691/" - } - ], - "a77f7391-6c27-4861-a0ac-72f0f2cdeb31": [ - { - "pub_id": "26786964", - "title": "Impact of genetic variation on synaptic protein levels in genetically diverse mice.", - "authors": "Maarten Loos,Ka Wan Li,Roel van der Schors,Yvonne Gouwenberg,Rolinka van der Loo,Robert W Williams,August B Smit,Sabine Spijker", - "abstract": "The relative abundance of synaptic proteins shapes protein complex formation and is essential for synapse function and behavioral fitness. Here, we have used a panel of highly diverse inbred strains of mice-NOD/LtJ, A/J, 129S1/SvImJ, FVB/NJ, C57BL/6J, WSB/EiJ, PWK/PhJ, and CAST/EiJ-to quantify the effects of genetic variation on the synaptic proteome between strains. Using iTRAQ-based quantitative proteome analyses, we detected significant differences in \u223c20% of 400 core synaptic proteins. Surprisingly, the differentially abundant proteins showed a modest range of variation across strains, averaging about 1.3-fold. Analysis of protein abundance covariation across the eight strains identified known protein-protein relations (proteins of Arp2/3 complex), as well as novel relations (e.g. Dlg family, Fscn1). Moreover, covariation of synaptic proteins was substantially tighter (\u223cfourfold more dense than chance level) than corresponding networks of synaptic transcripts (\u223ctwofold more dense than chance). The tight stoichiometry and coherent synaptic protein covariation networks suggest more intense evolutionary selection at this level of molecular organization. In conclusion, genetic diversity in the mouse genome differentially affects the transcriptome and proteome, and only partially penetrates the synaptic proteome. Protein abundance correlation analyses in genetically divergent strains can complement protein-protein interaction network analyses, to provide insight into protein interactomes.", - "journal_title": "Proteomics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/26786964/" - } - ], - "91ceb0b1-5cb3-4c36-a3cd-d613e044962e": [ - { - "pub_id": "27276234", - "title": "Intensive Blood-Pressure Lowering in Patients with Acute Cerebral Hemorrhage.", - "authors": "Adnan I Qureshi,Yuko Y Palesch,William G Barsan,Daniel F Hanley,Chung Y Hsu,Renee L Martin,Claudia S Moy,Robert Silbergleit,Thorsten Steiner,Jose I Suarez,Kazunori Toyoda,Yongjun Wang,Haruko Yamamoto,Byung-Woo Yoon, ", - "abstract": "Limited data are available to guide the choice of a target for the systolic blood-pressure level when treating acute hypertensive response in patients with intracerebral hemorrhage. We randomly assigned eligible participants with intracerebral hemorrhage (volume, <60 cm(3)) and a Glasgow Coma Scale (GCS) score of 5 or more (on a scale from 3 to 15, with lower scores indicating worse condition) to a systolic blood-pressure target of 110 to 139 mm Hg (intensive treatment) or a target of 140 to 179 mm Hg (standard treatment) in order to test the superiority of intensive reduction of systolic blood pressure to standard reduction; intravenous nicardipine to lower blood pressure was administered within 4.5 hours after symptom onset. The primary outcome was death or disability (modified Rankin scale score of 4 to 6, on a scale ranging from 0 [no symptoms] to 6 [death]) at 3 months after randomization, as ascertained by an investigator who was unaware of the treatment assignments. Among 1000 participants with a mean (\u00b1SD) systolic blood pressure of 200.6\u00b127.0 mm Hg at baseline, 500 were assigned to intensive treatment and 500 to standard treatment. The mean age of the patients was 61.9 years, and 56.2% were Asian. Enrollment was stopped because of futility after a prespecified interim analysis. The primary outcome of death or disability was observed in 38.7% of the participants (186 of 481) in the intensive-treatment group and in 37.7% (181 of 480) in the standard-treatment group (relative risk, 1.04; 95% confidence interval, 0.85 to 1.27; analysis was adjusted for age, initial GCS score, and presence or absence of intraventricular hemorrhage). Serious adverse events occurring within 72 hours after randomization that were considered by the site investigator to be related to treatment were reported in 1.6% of the patients in the intensive-treatment group and in 1.2% of those in the standard-treatment group. The rate of renal adverse events within 7 days after randomization was significantly higher in the intensive-treatment group than in the standard-treatment group (9.0% vs. 4.0%, P=0.002). The treatment of participants with intracerebral hemorrhage to achieve a target systolic blood pressure of 110 to 139 mm Hg did not result in a lower rate of death or disability than standard reduction to a target of 140 to 179 mm Hg. (Funded by the National Institute of Neurological Disorders and Stroke and the National Cerebral and Cardiovascular Center; ATACH-2 ClinicalTrials.gov number, NCT01176565 .).", - "journal_title": "The New England journal of medicine", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/27276234/" - } - ], - "8d7f6840-3de0-4e1f-952b-65443f15c58f": [ - { - "pub_id": "26660115", - "title": "Dynamic Behavior of the RNA Polymerase II and the Ubiquitin Proteasome System During the Neuronal DNA Damage Response to Ionizing Radiation.", - "authors": "I\u00f1igo Casafont,Ana Palanca,Vanesa Lafarga,Jorge Mata-Garrido,Maria T Berciano,Miguel Lafarga", - "abstract": "Neurons are highly vulnerable to genotoxic agents. To restore genome integrity upon DNA lesions, neurons trigger a DNA damage response (DDR) that requires chromatin modifications and transcriptional silencing at DNA damage sites. To study the reorganization of the active RNA polymerase II (Pol II), which transcribes all mRNA-encoding genes, and the participation of the ubiquitin-proteasome system (UPS) in the neuronal DDR, we have used rat sensory ganglion neurons exposed to X-rays (4\u00a0Gy) ionizing radiation (IR). In control neurons, Pol II appears concentrated in numerous chromatin microfoci identified as transcription factories by the incorporation of 5'-fluorouridine into nascent RNA. Upon IR treatment, numerous IR-induced foci (IRIF), which were immunoreactive for \u03b3H2AX and 53BP1, were observed as early as 30\u00a0min post-IR; their number progressively reduced at 3\u00a0h, 1\u00a0day, and 3\u00a0days post-IR. The formation of IRIF was associated with a decrease in Pol II levels by both immunofluorescence and Western blotting. Treatment with the proteasome inhibitor bortezomib strongly increased Pol II levels in both control and irradiated neurons, suggesting that proteasome plays a proteolytic role by clearing stalled Pol II complexes at DNA damage sites, as a prelude to DNA repair. Neuronal IRIF recruited ubiquitylated proteins, including ubiquitylated histone H2A (Ub-H2A), and the catalytic proteasome 20S. Ub-H2A has been associated with transcriptional silencing at DNA damage sites. On the other hand, the participation of UPS in neuronal DDR may be essential for the ubiquitylation of Pol II and other proteasome substrates of the DNA repair machinery and their subsequent proteasome-mediated degradation.", - "journal_title": "Molecular neurobiology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/26660115/" - } - ], - "4d7120a6-a298-4d48-aa38-ee3474f7408f": [ - { - "pub_id": "26701914", - "title": "Genetic variation in offspring indirectly influences the quality of maternal behaviour in mice.", - "authors": "David George Ashbrook,Beatrice Gini,Reinmar Hager", - "abstract": "Conflict over parental investment between parent and offspring is predicted to lead to selection on genes expressed in offspring for traits influencing maternal investment, and on parentally expressed genes affecting offspring behaviour. However, the specific genetic variants that indirectly modify maternal or offspring behaviour remain largely unknown. Using a cross-fostered population of mice, we map maternal behaviour in genetically uniform mothers as a function of genetic variation in offspring and identify loci on offspring chromosomes 5 and 7 that modify maternal behaviour. Conversely, we found that genetic variation among mothers influences offspring development, independent of offspring genotype. Offspring solicitation and maternal behaviour show signs of coadaptation as they are negatively correlated between mothers and their biological offspring, which may be linked to costs of increased solicitation on growth found in our study. Overall, our results show levels of parental provisioning and offspring solicitation are unique to specific genotypes.", - "journal_title": "eLife", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/26701914/" - } - ], - "adc6d8db-4f67-4130-b5a2-3cc421d2af45": [ - { - "pub_id": "26980469", - "title": "QTL Mapping of Endocochlear Potential Differences between C57BL/6J and BALB/cJ mice.", - "authors": "Kevin K Ohlemiller,Anna L Kiener,Patricia M Gagnon", - "abstract": "We reported earlier that the endocochlear potential (EP) differs between C57BL/6J (B6) and BALB/cJ (BALB) mice, being lower in BALBs by about 10\u00a0mV (Ohlemiller et al. Hear Res 220: 10-26, 2006). This difference corresponds to strain differences with respect to the density of marginal cells in cochlear stria vascularis. After about 1\u00a0year of age, BALB mice also tend toward EP reduction that correlates with further marginal cell loss. We therefore suggested that early sub-clinical features of the BALB stria vascularis may predispose these mice to a condition modeling Schuknecht's strial presbycusis. We further reported (Ohlemiller et al. J Assoc Res Otolaryngol 12: 45-58, 2011) that the acute effects of a 2-h 110 dB SPL noise exposure differ between B6 and BALB mice, such that the EP remains unchanged in B6 mice, but is reduced by 40-50\u00a0mV in BALBs. In about 25\u00a0% of BALBs, the EP does not completely recover, so that permanent EP reduction may contribute to noise-induced permanent threshold shifts in BALBs. To identify genes and alleles that may promote natural EP variation as well as noise-related EP reduction in BALB mice, we have mapped related quantitative trait loci (QTLs) using 12 recombinant inbred (RI) strains formed from B6 and BALB (CxB1-CxB12). EP and strial marginal cell density were measured in B6 mice, BALB mice, their F1 hybrids, and RI mice without noise exposure, and 1-3 h after broadband noise (4-45 kHz, 110 dB SPL, 2 h). For unexposed mice, the strain distribution patterns for EP and marginal cell density were used to generate preliminary QTL maps for both EP and marginal cell density. Six QTL regions were at least statistically suggestive, including a significant QTL for marginal cell density on chromosome 12 that overlapped a weak QTL for EP variation. This region, termed Maced (Marginal cell density QTL) supports the notion of marginal cell density as a genetically influenced contributor to natural EP variation. Candidate genes for Maced notably include Foxg1, Foxa1, Akap6, Nkx2-1, and Pax9. Noise exposure produced significant EP reductions in two RI strains as well as significant EP increases in two RI strains. QTL mapping of the EP in noise-exposed RI mice yielded four suggestive regions. Two of these overlapped with QTL regions we previously identified for noise-related EP reduction in CBA/J mice (Ohlemiller et al. Hear Res 260: 47-53, 2010) on chromosomes 5 and 18 (Nirep). The present map may narrow the Nirep interval to a ~10-Mb region of proximal Chr. 18 that includes Zeb1, Arhgap12, Mpp7, and Gjd4. This study marks the first exploration of natural gene variants that modulate the EP. Their orthologs may underlie some human hearing loss that originates in the lateral wall.", - "journal_title": "Journal of the Association for Research in Otolaryngology : JARO", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/26980469/" - } - ], - "58739762-ae96-4638-973e-4e6b45d36cae": [ - { - "pub_id": "26079812", - "title": "Variable impact of chronic stress on spatial learning and memory in BXD mice.", - "authors": "Chloe J A Shea,Kimberly A K Carhuatanta,Jessica Wagner,Naomi Bechmann,Raquel Moore,James P Herman,Ryan Jankord", - "abstract": "The effects of chronic stress on learning are highly variable across individuals. This variability stems from gene-environment interactions. However, the mechanisms by which stress affects genetic predictors of learning are unclear. Thus, we aim to determine whether the genetic pathways that predict spatial memory performance are altered by previous exposure to chronic stress. Sixty-two BXD recombinant inbred strains of mice, as well as parent strains C57BL/6J and DBA/2J, were randomly assigned as behavioral control or to a chronic variable stress paradigm and then underwent behavioral testing to assess spatial memory and learning performance using the Morris water maze. Quantitative trait loci (QTL) mapping was completed for average escape latency times for both control and stress animals. Loci on chromosomes 5 and 10 were found in both control and stress environmental populations; eight additional loci were found to be unique to either the control or stress environment. In sum, results indicate that certain genetic loci predict spatial memory performance regardless of prior stress exposure, while exposure to stress also reveals unique genetic predictors of training during the memory task. Thus, we find that genetic predictors contributing to spatial learning and memory are susceptible to the presence of chronic stress.", - "journal_title": "Physiology & behavior", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/26079812/" - } - ], - "68ee5f38-46a1-4343-8af9-7746d89e8451": [ - { - "pub_id": "28270566", - "title": "Orbitofrontal Neuroadaptations and Cross-Species Synaptic Biomarkers in Heavy-Drinking Macaques.", - "authors": "Sudarat Nimitvilai,Joachim D Uys,John J Woodward,Patrick K Randall,Lauren E Ball,Robert W Williams,Byron C Jones,Lu Lu,Kathleen A Grant,Patrick J Mulholland", - "abstract": "Cognitive impairments, uncontrolled drinking, and neuropathological cortical changes characterize alcohol use disorder. Dysfunction of the orbitofrontal cortex (OFC), a critical cortical subregion that controls learning, decision-making, and prediction of reward outcomes, contributes to executive cognitive function deficits in alcoholic individuals. Electrophysiological and quantitative synaptomics techniques were used to test the hypothesis that heavy drinking produces neuroadaptations in the macaque OFC. Integrative bioinformatics and reverse genetic approaches were used to identify and validate synaptic proteins with novel links to heavy drinking in BXD mice. In drinking monkeys, evoked firing of OFC pyramidal neurons was reduced, whereas the amplitude and frequency of postsynaptic currents were enhanced compared with controls. Bath application of alcohol reduced evoked firing in neurons from control monkeys, but not drinking monkeys. Profiling of the OFC synaptome identified alcohol-sensitive proteins that control glutamate release (e.g., SV2A, synaptogyrin-1) and postsynaptic signaling (e.g., GluA1, PRRT2) with no changes in synaptic GABAergic proteins. Western blot analysis confirmed the increase in GluA1 expression in drinking monkeys. An exploratory analysis of the OFC synaptome found cross-species genetic links to alcohol intake in discrete proteins (e.g., C2CD2L, DIRAS2) that discriminated between low- and heavy-drinking monkeys. Validation studies revealed that BXD mouse strains with the <i>D</i> allele at the <i>C2cd2l</i> interval drank less alcohol than <i>B</i> allele strains. Thus, by profiling of the OFC synaptome, we identified changes in proteins controlling glutamate release and postsynaptic signaling and discovered several proteins related to heavy drinking that have potential as novel targets for treating alcohol use disorder.<b>SIGNIFICANCE STATEMENT</b> Clinical research identified cognitive deficits in alcoholic individuals as a risk factor for relapse, and alcoholic individuals display deficits on cognitive tasks that are dependent upon the orbitofrontal cortex (OFC). To identify neurobiological mechanisms that underpin OFC dysfunction, this study used electrophysiology and integrative synaptomics in a translational nonhuman primate model of heavy alcohol consumption. We found adaptations in synaptic proteins that control glutamatergic signaling in chronically drinking monkeys. Our functional genomic exploratory analyses identified proteins with genetic links to alcohol and cocaine intake across mice, monkeys, and humans. Future work is necessary to determine whether targeting these novel targets reduces excessive and harmful levels of alcohol drinking.", - "journal_title": "The Journal of neuroscience : the official journal of the Society for Neuroscience", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/28270566/" - } - ], - "a6601776-d40f-4537-b0df-2bb48303c869": [ - { - "pub_id": "23758785", - "title": "ATR-FTIR spectroscopy reveals genomic loci regulating the tissue response in high fat diet fed BXD recombinant inbred mouse strains.", - "authors": "Ayca Dogan,Peter Lasch,Christina Neuschl,Marion K Millrose,Rudi Alberts,Klaus Schughart,Dieter Naumann,Gudrun A Brockmann", - "abstract": "Obesity-associated organ-specific pathological states can be ensued from the dysregulation of the functions of the adipose tissues, liver and muscle. However, the influence of genetic differences underlying gross-compositional differences in these tissues is largely unknown. In the present study, the analytical method of ATR-FTIR spectroscopy has been combined with a genetic approach to identify genetic differences responsible for phenotypic alterations in adipose, liver and muscle tissues. Mice from 29 BXD recombinant inbred mouse strains were put on high fat diet and gross-compositional changes in adipose, liver and muscle tissues were measured by ATR-FTIR spectroscopy. The analysis of genotype-phenotype correlations revealed significant quantitative trait loci (QTL) on chromosome 12 for the content of fat and collagen, collagen integrity, and the lipid to protein ratio in adipose tissue and on chromosome 17 for lipid to protein ratio in liver. Using gene expression and sequence information, we suggest Rsad2 (viperin) and Colec11 (collectin-11) on chromosome 12 as potential quantitative trait candidate genes. Rsad2 may act as a modulator of lipid droplet contents and lipid biosynthesis; Colec11 might play a role in apoptopic cell clearance and maintenance of adipose tissue. An increased level of Rsad2 transcripts in adipose tissue of DBA/2J compared to C57BL/6J mice suggests a cis-acting genetic variant leading to differential gene activation. The results demonstrate that the analytical method of ATR-FTIR spectroscopy effectively contributed to decompose the macromolecular composition of tissues that accumulate fat and to link this information with genetic determinants. The candidate genes in the QTL regions may contribute to obesity-related diseases in humans, in particular if the results can be verified in a bigger BXD cohort.", - "journal_title": "BMC genomics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/23758785/" - } - ], - "0bdb51db-25a9-48f5-95c5-8e0e9bd2c3b6": [ - { - "pub_id": "22593731", - "title": "Sex-specific modulation of gene expression networks in murine hypothalamus.", - "authors": "Khyobeni Mozhui,Lu Lu,William E Armstrong,Robert W Williams", - "abstract": "The hypothalamus contains nuclei and cell populations that are critical in reproduction and that differ significantly between the sexes in structure and function. To examine the molecular and genetic basis for these differences, we quantified gene expression in the hypothalamus of 39 pairs of adult male and female mice belonging to the BXD strains. This experimental design enabled us to define hypothalamic gene coexpression networks and provided robust estimates of absolute expression differences. As expected, sex has the strongest effect on the expression of genes on the X and Y chromosomes (e.g., Uty, Xist, Kdm6a). Transcripts associated with the endocrine system and neuropeptide signaling also differ significantly. Sex-differentiated transcripts often have well delimited expression within specific hypothalamic nuclei that have roles in reproduction. For instance, the estrogen receptor (Esr1) and neurokinin B (Tac2) genes have intense expression in the medial preoptic and arcuate nuclei and comparatively high expression in females. Despite the strong effect of sex on single transcripts, the global pattern of covariance among transcripts is well preserved, and consequently, males and females have well matched coexpression modules. However, there are sex-specific hub genes in functionally equivalent modules. For example, only in males is the Y-linked gene, Uty, a highly connected transcript in a network that regulates chromatin modification and gene transcription. In females, the X chromosome paralog, Kdm6a, takes the place of Uty in the same network. We also find significant effect of sex on genetic regulation and the same network in males and females can be associated with markedly different regulatory loci. With the exception of a few sex-specific modules, our analysis reveals a system in which sets of functionally related transcripts are organized into stable sex-independent networks that are controlled at a higher level by sex-specific modulators.", - "journal_title": "Frontiers in neuroscience", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/22593731/" - } - ], - "505c3e21-2afe-482e-9983-9b0131f154ce": [ - { - "pub_id": "22723961", - "title": "Murine gut microbiota is defined by host genetics and modulates variation of metabolic traits.", - "authors": "Autumn M McKnite,Maria Elisa Perez-Munoz,Lu Lu,Evan G Williams,Simon Brewer,P\u00e9n\u00e9lope A Andreux,John W M Bastiaansen,Xusheng Wang,Stephen D Kachman,Johan Auwerx,Robert W Williams,Andrew K Benson,Daniel A Peterson,Daniel C Ciobanu", - "abstract": "The gastrointestinal tract harbors a complex and diverse microbiota that has an important role in host metabolism. Microbial diversity is influenced by a combination of environmental and host genetic factors and is associated with several polygenic diseases. In this study we combined next-generation sequencing, genetic mapping, and a set of physiological traits of the BXD mouse population to explore genetic factors that explain differences in gut microbiota and its impact on metabolic traits. Molecular profiling of the gut microbiota revealed important quantitative differences in microbial composition among BXD strains. These differences in gut microbial composition are influenced by host-genetics, which is complex and involves many loci. Linkage analysis defined Quantitative Trait Loci (QTLs) restricted to a particular taxon, branch or that influenced the variation of taxa across phyla. Gene expression within the gastrointestinal tract and sequence analysis of the parental genomes in the QTL regions uncovered candidate genes with potential to alter gut immunological profiles and impact the balance between gut microbial communities. A QTL region on Chr 4 that overlaps several interferon genes modulates the population of Bacteroides, and potentially Bacteroidetes and Firmicutes-the predominant BXD gut phyla. Irak4, a signaling molecule in the Toll-like receptor pathways is a candidate for the QTL on Chr15 that modulates Rikenellaceae, whereas Tgfb3, a cytokine modulating the barrier function of the intestine and tolerance to commensal bacteria, overlaps a QTL on Chr 12 that influence Prevotellaceae. Relationships between gut microflora, morphological and metabolic traits were uncovered, some potentially a result of common genetic sources of variation.", - "journal_title": "PloS one", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/22723961/" - } - ], - "93dc581e-5e45-48b4-b82f-35e32d7bd58e": [ - { - "pub_id": "33197607", - "title": "The genomic landscape of pediatric acute lymphoblastic leukemia and precision medicine opportunities.", - "authors": "Thai Hoa Tran,Stephen P Hunger", - "abstract": "Acute lymphoblastic leukemia (ALL) is the most common childhood cancer and constitutes approximately 25 % of cancer diagnoses among children under the age of 15 (Howlader et al., 2013) [1]. Overall, about half of ALL cases occur in children and adolescents and it is the most common acute leukemia until the early 20s, after which acute myeloid leukemia predominates. ALL is the most successful treatment paradigm in pediatric cancer medicine as illustrated by the significant survival rate improvement from \u223c10 % in the 1960s to >90 % today (Hunger et al., 2015) [2]. This remarkable success stems from the progressive improvement in the efficacy of risk-adapted multiagent chemotherapy regimens with effective central nervous system (CNS) prophylaxis via well-designed randomized clinical trials conducted by international collaborative consortia, enhanced supportive care measures to decrease treatment-related mortality, in-depth understanding of the genetic basis of ALL, and refinement in treatment response assessment through serial minimal residual disease (MRD) monitoring (Pui et al., 2015) [3]. These advances collectively contribute to a decline in mortality rate of 23.5% for children diagnosed with ALL in the US from 2000 to 2010 (Smith et al., 2014) [4]. Nevertheless, outcomes of older adolescents and young adults with ALL still lag behind those of their younger counterparts despite pediatric-inspired chemotherapy regimens (Stock et al., 2019) [5], relapsed/refractory childhood ALL is associated with poor outcomes (Rheingold et al., 2019) [6], and ALL still represents the leading causes of cancer-related deaths (Smith et al., 2010) [7]. The last two decades have witnessed important genomic discoveries in ALL, enabled by advances in next-generation sequencing (NGS) technologies to characterize the landscape of germline and somatic alterations in ALL, some of which have important diagnostic, prognostic and therapeutic implications. Comprehensive genomic analysis of large cohorts of children and adults with ALL has revised the taxonomy of ALL in the molecular era by identifying novel clonal, subtype-defined chromosomal alterations associated with distinct gene expression signatures, thus reducing the proportion of patients previously labelled as \"Others\" from 25 % to approximately 5 % (Mullighan et al., 2019) [8]. Insights into the genomics of ALL further provide compelling biologic rationale to expand the scope of precision medicine therapies for childhood ALL. Herein, we summarize a decade of genomic discoveries to highlight three different facets of precision medicine in pediatric ALL: 1) inherited predispositions of ALL; 2) relevant molecularly targeted therapies in genomically-defined ALL subtypes; and 3) treatment response monitoring via pharmacogenomics and novel MRD biomarkers.", - "journal_title": "Seminars in cancer biology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/33197607/" - } - ], - "9f834d4a-1e18-4c3d-a28e-2a1237d590d3": [ - { - "pub_id": "21195549", - "title": "Genomic loci and candidate genes underlying inflammatory nociception.", - "authors": "Harsha K Nair,Heather Hain,Raymond M Quock,Vivek M Philip,Elissa J Chesler,John K Belknap,William R Lariviere", - "abstract": "Heritable genetic factors contribute significantly to inflammatory nociception. To determine candidate genes underlying inflammatory nociception, the current study used a mouse model of abdominal inflammatory pain. BXD recombinant inbred (RI) mouse strains were administered the intraperitoneal acetic acid test, and genome-wide quantitative trait locus (QTL) mapping was performed on the mean number of abdominal contraction and extension movements in 3 distinct groups of BXD RI mouse strains in 2 separate experiments. Combined mapping results detected 2 QTLs on chromosomes (Chr) 3 and 10 across experiments and groups of mice; an additional sex-specific QTL was detected on Chr 16. The results replicate previous findings of a significant QTL, Nociq2, on distal Chr 10 for formalin-induced inflammatory nociception and will aid in identification of the underlying candidate genes. Comparisons of sensitivity to intraperitoneal acetic acid in BXD RI mouse strains with microarray mRNA transcript expression profiles in specific brain areas detected covarying expression of candidate genes that are also found in the detected QTL confidence intervals. The results indicate that common and distinct genetic mechanisms underlie heritable sensitivity to diverse inflammatory insults, and provide a discrete set of high-priority candidate genes to investigate further in rodents and human association studies. Novel genomic regions linked to inflammatory nociception were detected, a previously reported locus was confirmed, and high-priority candidate genes for inflammatory nociception and pain were identified.", - "journal_title": "Pain", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/21195549/" - } - ], - "43407486-b9c2-487b-b19c-b605c4d201c6": [ - { - "pub_id": "27933521", - "title": "GeneNetwork: A Toolbox for Systems Genetics.", - "authors": "Megan K Mulligan,Khyobeni Mozhui,Pjotr Prins,Robert W Williams", - "abstract": "The goal of systems genetics is to understand the impact of genetic variation across all levels of biological organization, from mRNAs, proteins, and metabolites, to higher-order physiological and behavioral traits. This approach requires the accumulation and integration of many types of data, and also requires the use of many types of statistical tools to extract relevant patterns of covariation and causal relations as a function of genetics, environment, stage, and treatment. In this protocol we explain how to use the GeneNetwork web service, a powerful and free online resource for systems genetics. We provide workflows and methods to navigate massive multiscalar data sets and we explain how to use an extensive systems genetics toolkit for analysis and synthesis. Finally, we provide two detailed case studies that take advantage of human and mouse cohorts to evaluate linkage between gene variants, addiction, and aging.", - "journal_title": "Methods in molecular biology (Clifton, N.J.)", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/27933521/" - } - ], - "ba7e3b08-be65-474d-9c8a-d132b8168722": [ - { - "pub_id": "27460150", - "title": "Systems genetics identifies Hp1bp3 as a novel modulator of cognitive aging.", - "authors": "Sarah M Neuner,Benjamin P Garfinkel,Lynda A Wilmott,Bogna M Ignatowska-Jankowska,Ami Citri,Joseph Orly,Lu Lu,Rupert W Overall,Megan K Mulligan,Gerd Kempermann,Robert W Williams,Kristen M S O'Connell,Catherine C Kaczorowski", - "abstract": "An individual's genetic makeup plays an important role in determining susceptibility to cognitive aging. Identifying the specific genes that contribute to cognitive aging may aid in early diagnosis of at-risk patients, as well as identify novel therapeutics targets to treat or prevent development of symptoms. Challenges to identifying these specific genes in human studies include complex genetics, difficulty in controlling environmental factors, and limited access to human brain tissue. Here, we identify Hp1bp3 as a novel modulator of cognitive aging using a genetically diverse population of mice and confirm that HP1BP3 protein levels are significantly reduced in the hippocampi of cognitively impaired elderly humans relative to cognitively intact controls. Deletion of functional Hp1bp3 in mice recapitulates memory deficits characteristic of aged impaired mice and humans, further supporting the idea that Hp1bp3 and associated molecular networks are modulators of cognitive aging. Overall, our results suggest Hp1bp3 may serve as a potential target against cognitive aging and demonstrate the utility of genetically diverse animal models for the study of complex human disease.", - "journal_title": "Neurobiology of aging", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/27460150/" - } - ], - "d40f3764-9b8c-4f20-9200-a5d14cb0cf02": [ - { - "pub_id": "22438999", - "title": "Host genetics and Chlamydia disease: prediction and validation of disease severity mechanisms.", - "authors": "Isao Miyairi,Jesse Ziebarth,Jonathan D Laxton,Xiaofei Wang,Nico van Rooijen,Robert W Williams,Lu Lu,Gerald I Byrne,Yan Cui", - "abstract": "Genetic mapping studies may provide association between sequence variants and disease susceptibility that can, with further experimental and computational analysis, lead to discovery of causal mechanisms and effective intervention. We have previously demonstrated that polymorphisms in immunity-related GTPases (IRG) confer a significant difference in susceptibility to Chlamydia psittaci infection in BXD recombinant mice. Here we combine genetic mapping and network modeling to identify causal pathways underlying this association. We infected a large panel of BXD strains with C. psittaci and assessed host genotype, IRG protein polymorphisms, pathogen load, expression of 32 cytokines, inflammatory cell populations, and weight change. Proinflammatory cytokines correlated with each other and were controlled by a novel genetic locus on chromosome 1, but did not affect disease status, as quantified by weight change 6 days after infection In contrast, weight change correlated strongly with levels of inflammatory cell populations and pathogen load that were controlled by an IRG encoding genetic locus (Ctrq3) on chromosome 11. These data provided content to generate a predictive model of infection using a Bayesian framework incorporating genotypes, immune system parameters, and weight change as a measure of disease severity. Two predictions derived from the model were tested and confirmed in a second round of experiments. First, strains with the susceptible IRG haplotype lost weight as a function of pathogen load whereas strains with the resistant haplotype were almost completely unaffected over a very wide range of pathogen load. Second, we predicted that macrophage activation by Ctrq3 would be central in conferring pathogen tolerance. We demonstrated that macrophage depletion in strains with the resistant haplotype led to neutrophil influx and greater weight loss despite a lower pathogen burden. Our results show that genetic mapping and network modeling can be combined to identify causal pathways underlying chlamydial disease susceptibility.", - "journal_title": "PloS one", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/22438999/" - } - ], - "e56c9675-5d7a-4845-adfc-42a6c4fbc806": [ - { - "pub_id": "21920449", - "title": "Host genetic background and the innate inflammatory response of lung to influenza virus.", - "authors": "Rita A Trammell,Teresa A Liberati,Linda A Toth", - "abstract": "Many studies of influenza severity have focused on viral properties that confer virulence, whereas the contributory role of the host genetic background on infection severity remains largely unexplored. In this study, we measure the impact of inoculation with influenza virus in four strains of inbred mice - BALB/cByJ, C57BL/6J, A/J, and DBA/2J. To evaluate the extent to which responses are inherent to lung per se, as opposed to effects of the systemic response to lung infection, we also measured cytokines and chemokines in lung slices exposed to the virus in vitro. Finally, we evaluate the in vivo responses of recombinant inbred (RI) and select consomic strains of mice to search for genomic loci that contribute to phenotypic variance in response to influenza infection. We found marked variation among mouse strains after challenge with virus strain A/HKX31(H3N2), consistent with previous reports using more virulent strains. Furthermore, response patterns differ after in vivo versus in vitro exposure of lung to virus, supporting a predominant role of the systemic host inflammatory response in generating the strain differences. These results add to the body of information pointing to host genotype as a crucial factor in mediating the severity of influenza infections.", - "journal_title": "Microbes and infection", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/21920449/" - } - ], - "99bb4b2a-6c1d-46d4-8165-2201bc1f0299": [ - { - "pub_id": "27294413", - "title": "Human genome meeting 2016 : Houston, TX, USA. 28 February - 2 March 2016.", - "authors": "A. K. Srivastava,Y. Wang,R. Huang,C. Skinner,T. Thompson,L. Pollard,T. Wood,F. Luo,R. Stevenson,R. Polimanti,J. Gelernter,X. Lin,I. Y. Lim,Y. Wu,A. L. Teh,L. Chen,I. M. Aris,S. E. Soh,M. T. Tint,J. L. MacIsaac,F. Yap,K. Kwek,S. M. Saw,M. S. Kobor,M. J. Meaney,K. M. Godfrey,Y. S. Chong,J. D. Holbrook,Y. S. Lee,P. D. Gluckman,N. Karnani, ,A. Kapoor,D. Lee,A. Chakravarti,C. Maercker,F. Graf,M. Boutros,G. Stamoulis,F. Santoni,P. Makrythanasis,A. Letourneau,M. Guipponi,N. Panousis,M. Garieri,P. Ribaux,E. Falconnet,C. Borel,S. E. Antonarakis,S. Kumar,J. Curran,J. Blangero,S. Chatterjee,A. Kapoor,J. Akiyama,D. Auer,C. Berrios,L. Pennacchio,A. Chakravarti,T. R. Donti,G. Cappuccio,M. Miller,P. Atwal,A. Kennedy,A. Cardon,C. Bacino,L. Emrick,J. Hertecant,F. Baumer,B. Porter,M. Bainbridge,P. Bonnen,B. Graham,R. Sutton,Q. Sun,S. Elsea,Z. Hu,P. Wang,Y. Zhu,J. Zhao,M. Xiong,David A. Bennett,A. Hidalgo-Miranda,S. Romero-Cordoba,S. Rodriguez-Cuevas,R. Rebollar-Vega,E. Tagliabue,M. Iorio,E. D\u2019Ippolito,S. Baroni,B. Kaczkowski,Y. Tanaka,H. Kawaji,A. Sandelin,R. Andersson,M. Itoh,T. Lassmann, ,Y. Hayashizaki,P. Carninci,A. R. R. Forrest,C. A. Semple,E. A. Rosenthal,B. Shirts,L. Amendola,C. Gallego,M. Horike-Pyne,A. Burt,P. Robertson,P. Beyers,C. Nefcy,D. Veenstra,F. Hisama,R. Bennett,M. Dorschner,D. Nickerson,J. Smith,K. Patterson,D. Crosslin,R. Nassir,N. Zubair,T. Harrison,U. Peters,G. Jarvik, ,F. Menghi,K. Inaki,X. Woo,P. Kumar,K. Grzeda,A. Malhotra,H. Kim,D. Ucar,P. Shreckengast,K. Karuturi,J. Keck,J. Chuang,E. T. Liu,B. Ji,A. Tyler,G. Ananda,G. Carter,H. Nikbakht,M. Montagne,M. Zeinieh,A. Harutyunyan,M. Mcconechy,N. Jabado,P. Lavigne,J. Majewski,J. B. Goldstein,M. Overman,G. Varadhachary,R. Shroff,R. Wolff,M. Javle,A. Futreal,D. Fogelman,L. Bravo,W. Fajardo,H. Gomez,C. Castaneda,C. Rolfo,J. A. Pinto,K. C. Akdemir,L. Chin,A. Futreal, ,S. Patterson,C. Statz,S. Mockus,S. N. Nikolaev,X. I. Bonilla,L. Parmentier,B. King,F. Bezrukov,G. Kaya,V. Zoete,V. Seplyarskiy,H. Sharpe,T. McKee,A. Letourneau,P. Ribaux,K. Popadin,N. Basset-Seguin,R. Ben Chaabene,F. Santoni,M. Andrianova,M. Guipponi,M. Garieri,C. Verdan,K. Grosdemange,O. Sumara,M. Eilers,I. Aifantis,O. Michielin,F. de Sauvage,S. Antonarakis,S. Likhitrattanapisal,S. Lincoln,A. Kurian,A. Desmond,S. Yang,Y. Kobayashi,J. Ford,L. Ellisen,T. L. Peters,K. R. Alvarez,E. F. Hollingsworth,D. H. Lopez-Terrada,A. Hastie,Z. Dzakula,A. W. Pang,E. T. Lam,T. Anantharaman,M. Saghbini,H. Cao, ,C. Gonzaga-Jauregui,L. Ma,A. King,E. Berman Rosenzweig,U. Krishnan,J. G. Reid,J. D. Overton,F. Dewey,W. K. Chung,K. Small,A. DeLuca,F. Cremers,R. A. Lewis,V. Puech,B. Bakall,R. Silva-Garcia,K. Rohrschneider,M. Leys,F. S. Shaya,E. Stone,N. L. Sobreira,F. Schiettecatte,H. Ling,E. Pugh,D. Witmer,K. Hetrick,P. Zhang,K. Doheny,D. Valle,A. Hamosh,S. N. Jhangiani,Z. Coban Akdemir,M. N. Bainbridge,W. Charng,W. Wiszniewski,T. Gambin,E. Karaca,Y. Bayram,M. K. Eldomery,J. Posey,H. Doddapaneni,J. Hu,V. R. Sutton,D. M. Muzny,E. A. Boerwinkle,D. Valle,J. R. Lupski,R. A. Gibbs,S. Shekar,W. Salerno,A. English,A. Mangubat,J. Bruestle,A. Thorogood,B. M. Knoppers, ,H. Takahashi,K. R. Nitta,A. Kozhuharova,A. M. Suzuki,H. Sharma,D. Cotella,C. Santoro,S. Zucchelli,S. Gustincich,P. Carninci,J. J. Mulvihill,G. Baynam,W. Gahl,S. C. Groft,K. Kosaki,P. Lasko,B. Melegh,D. Taruscio,R. Ghosh,S. Plon,S. Scherer,X. Qin,R. Sanghvi,K. Walker,T. Chiang,D. Muzny,L. Wang,J. Black,E. Boerwinkle,R. Weinshilboum,R. Gibbs,T. Karpinets,T. Calderone,K. Wani,X. Yu,C. Creasy,C. Haymaker,M. Forget,V. Nanda,J. Roszik,J. Wargo,L. Haydu,X. Song,A. Lazar,J. Gershenwald,M. Davies,C. Bernatchez,J. Zhang,A. Futreal,S. Woodman,E. J. Chesler,T. Reynolds,J. A. Bubier,C. Phillips,M. A. Langston,E. J. Baker,M. Xiong,L. Ma,N. Lin,C. Amos,N. Lin,P. Wang,Y. Zhu,J. Zhao,V. Calhoun,M. Xiong,O. Dobretsberger,M. Egger,F. Leimgruber,S. Sadedin,A. Oshlack, ,V. A. A. Antonio,N. Ono, ,Z. Ahmed,M. Bolisetty,S. Zeeshan,E. Anguiano,D. Ucar,A. Sarkar,M. R. Nandineni,C. Zeng,J. Shao,H. Cao,A. Hastie,A. W. Pang,E. T. Lam,T. Liang,K. Pham,M. Saghbini,Z. Dzakula,Y. Chee-Wei,L. Dongsheng,W. Lai-Ping,D. Lian,R. O. Twee Hee,Y. Yunus,F. Aghakhanian,S. S. Mokhtar,C. V. Lok-Yung,J. Bhak,M. Phipps,X. Shuhua,T. Yik-Ying,V. Kumar,H. Boon-Peng,I. Campbell,M. -A. Young,P. James, ,M. Rain,G. Mohammad,R. Kukreti,Q. Pasha,A. R. Akilzhanova,C. Guelly,Z. Abilova,S. Rakhimova,A. Akhmetova,U. Kairov,S. Trajanoski,Z. Zhumadilov,M. Bekbossynova,C. Schumacher,S. Sandhu,T. Harkins,V. Makarov,H. Doddapaneni,R. Glenn,Z. Momin,B. Dilrukshi,H. Chao,Q. Meng,B. Gudenkauf,R. Kshitij,J. Jayaseelan,C. Nessner,S. Lee,K. Blankenberg,L. Lewis,J. Hu,Y. Han,H. Dinh,S. Jireh,K. Walker,E. Boerwinkle,D. Muzny,R. Gibbs,J. Hu,K. Walker,C. Buhay,X. Liu,Q. Wang,R. Sanghvi,H. Doddapaneni,Y. Ding,N. Veeraraghavan,Y. Yang,E. Boerwinkle,A. L. Beaudet,C. M. Eng,D. M. Muzny,R. A. Gibbs,K. C. C. Worley,Y. Liu,D. S. T. Hughes,S. C. Murali,R. A. Harris,A. C. English,X. Qin,O. A. Hampton,P. Larsen,C. Beck,Y. Han,M. Wang,H. Doddapaneni,C. L. Kovar,W. J. Salerno,A. Yoder,S. Richards,J. Rogers,J. R. Lupski,D. M. Muzny,R. A. Gibbs,Q. Meng,M. Bainbridge,M. Wang,H. Doddapaneni,Y. Han,D. Muzny,R. Gibbs,R. A. Harris,M. Raveenedran,C. Xue,M. Dahdouli,L. Cox,G. Fan,B. Ferguson,J. Hovarth,Z. Johnson,S. Kanthaswamy,M. Kubisch,M. Platt,D. Smith,E. Vallender,R. Wiseman,X. Liu,J. Below,D. Muzny,R. Gibbs,F. Yu,J. Rogers,J. Lin,Y. Zhang,Z. Ouyang,A. Moore,Z. Wang,J. Hofmann,M. Purdue,R. Stolzenberg-Solomon,S. Weinstein,D. Albanes,C. S. Liu,W. L. Cheng,T. T. Lin,Q. Lan,N. Rothman,S. Berndt,E. S. Chen,H. Bahrami,A. Khoshzaban,S. Heidari Keshal,H. Bahrami,A. Khoshzaban,S. Heidari Keshal,K. K. R. Alharbi,M. Zhalbinova,A. Akilzhanova,S. Rakhimova,M. Bekbosynova,S. Myrzakhmetova,M. Matar,N. Mili,R. Molinari,Y. Ma,S. Guerrier,N. Elhawary,M. Tayeb,N. Bogari,N. Qotb,S. A. McClymont,P. W. Hook,L. A. Goff,A. McCallion,Y. Kong,J. R. Charette,W. L. Hicks,J. K. Naggert,L. Zhao,P. M. Nishina,B. M. Edrees,M. Athar,F. A. Al-Allaf,M. M. Taher,W. Khan,A. Bouazzaoui,N. A. Harbi,R. Safar,H. Al-Edressi,A. Anazi,N. Altayeb,M. A. Ahmed,K. Alansary,Z. Abduljaleel,A. Kratz,P. Beguin,S. Poulain,M. Kaneko,C. Takahiko,A. Matsunaga,S. Kato,A. M. Suzuki,N. Bertin,T. Lassmann,R. Vigot,P. Carninci,C. Plessy,T. Launey,D. Graur,D. Lee,A. Kapoor,A. Chakravarti,J. Friis-Nielsen,J. M. Izarzugaza,S. Brunak,A. Chakraborty,J. Basak,A. Mukhopadhyay,B. S. Soibam,D. Das,N. Biswas,S. Das,S. Sarkar,A. Maitra,C. Panda,P. Majumder,H. Morsy,A. Gaballah,M. Samir,M. Shamseya,H. Mahrous,A. Ghazal,W. Arafat,M. Hashish,J. J. Gruber,N. Jaeger,M. Snyder,K. Patel,S. Bowman,T. Davis,D. Kraushaar,A. Emerman,S. Russello,N. Henig,C. Hendrickson,K. Zhang,M. Rodriguez-Dorantes,C. D. Cruz-Hernandez,C. D. P. Garcia-Tobilla,S. Solorzano-Rosales,N. J\u00e4ger,J. Chen,R. Haile,M. Hitchins,J. D. Brooks,M. Snyder,S. Jim\u00e9nez-Morales,M. Ram\u00edrez,J. Nu\u00f1ez,V. Bekker,Y. Leal,E. Jim\u00e9nez,A. Medina,A. Hidalgo,J. Mej\u00eda,V. Halytskiy,J. Naggert,G. B. Collin,K. DeMauro,R. Hanusek,P. M. Nishina,K. Belhassa,K. Belhassan,L. Bouguenouch,I. Samri,H. Sayel,FZ. moufid,I. El Bouchikhi,S. Trhanint,H. Hamdaoui,I. Elotmani,I. Khtiri,O. Kettani,L. Quibibo,M. Ahagoud,M. Abbassi,K. Ouldim,A. V. Marusin,A. N. Kornetov,M. Swarovskaya,K. Vagaiceva,V. Stepanov,E. M. Cutiongco De La Paz,R. Sy,J. Nevado,P. Reganit,L. Santos,J. D. Magno,F. E. Punzalan,D. Ona,E. Llanes,R. L. Santos-Cortes,R. Tiongco,J. Aherrera,L. Abrahan,P. Pagauitan-Alan, ,K. H. Morelli,J. S. Domire,N. Pyne,S. Harper,R. Burgess,M. Zhalbinova,A. Akilzhanova,S. Rakhimova,M. Bekbosynova,S. Myrzakhmetova,M. A. Gari,A. Dallol,H. Alsehli,A. Gari,M. Gari,A. Abuzenadah,M. Thomas,M. Sukhai,S. Garg,M. Misyura,T. Zhang,A. Schuh,T. Stockley,S. Kamel-Reid,S. Sherry,C. Xiao,D. Slotta,K. Rodarmer,M. Feolo,M. Kimelman,G. Godynskiy,C. O\u2019Sullivan,E. Yaschenko,C. Xiao,E. Yaschenko,S. Sherry,C. Rangel-Escare\u00f1o,H. Rueda-Zarate,I. A. Tayubi,R. Mohammed, ,I. Ahmed,T. Ahmed,S. Seth,S. Amin,X. Song,X. Mao,H. Sun,R. G. Verhaak,A. Futreal,J. Zhang,S. J. Whiite,T. Chiang,A. English,J. Farek,Z. Kahn,W. Salerno,N. Veeraraghavan,E. Boerwinkle,R. Gibbs,T. Kasukawa,M. Lizio,J. Harshbarger,S. Hisashi,J. Severin,A. Imad,S. Sahin,T. C. Freeman,K. Baillie,A. Sandelin,P. Carninci,A. R. R. Forrest,H. Kawaji, ,W. Salerno,A. English,S. N. Shekar,A. Mangubat,J. Bruestle,E. Boerwinkle,R. A. Gibbs,A. H. Salem,M. Ali,A. Ibrahim,M. Ibrahim,H. A. Barrera,L. Garza,J. A. Torres,V. Barajas,A. Ulloa-Aguirre,D. Kershenobich,Shahroj Mortaji,Pedro Guizar,Eliezer Loera,Karen Moreno,Adriana De Le\u00f3n,Daniela Monsiv\u00e1is,Jackeline G\u00f3mez,Raquel Cardiel,J. C. Fernandez-Lopez,V. Bonifaz-Pe\u00f1a,C. Rangel-Escare\u00f1o,A. Hidalgo-Miranda,A. V. Contreras,L. Polfus, ,X. Wang,V. Philip,G. Carter,A. A. Abuzenadah,M. Gari,R. Turki,A. Dallol,A. Uyar,A. Kaygun,S. Zaman,E. Marquez,J. George,D. Ucar,C. L. Hendrickson,A. Emerman,D. Kraushaar,S. Bowman,N. Henig,T. Davis,S. Russello,K. Patel,D. B. Starr,M. Baird,B. Kirkpatrick,K. Sheets,R. Nitsche,L. Prieto-Lafuente,M. Landrum,J. Lee,W. Rubinstein,D. Maglott,P. K. R. Thavanati,A. Escoto de Dios,R. E. Navarro Hernandez,M. E. Aguilar Aldrate,M. R. Ruiz Mejia,K. R. R. Kanala,Z. Abduljaleel,W. Khan,F. A. Al-Allaf,M. Athar,M. M. Taher,N. Shahzad,A. Bouazzaoui,E. Huber,A. Dan,F. A. Al-Allaf,W. Herr,G. Sprotte,J. K\u00f6stler,A. Hiergeist,A. Gessner,R. Andreesen,E. Holler,F. Al-Allaf,A. Alashwal,Z. Abduljaleel,M. Taher,A. Bouazzaoui,H. Abalkhail,A. Al-Allaf,R. Bamardadh,M. Athar,O. Filiptsova,M. Kobets,Y. Kobets,I. Burlaka,I. Timoshyna,O. Filiptsova,M. N. Kobets,Y. Kobets,I. Burlaka,I. Timoshyna,O. Filiptsova,M. N. Kobets,Y. Kobets,I. Burlaka,I. Timoshyna,F. A. Al-allaf,M. T. Mohiuddin,A. Zainularifeen,A. Mohammed,H. Abalkhail,T. Owaidah,A. Bouazzaoui", - "abstract": "O1 The metabolomics approach to autism: identification of biomarkers for early detection of autism spectrum disorder A. K. Srivastava, Y. Wang, R. Huang, C. Skinner, T. Thompson, L. Pollard, T. Wood, F. Luo, R. Stevenson O2 Phenome-wide association study for smoking- and drinking-associated genes in 26,394 American women with African, Asian, European, and Hispanic descents R. Polimanti, J. Gelernter O3 Effects of prenatal environment, genotype and DNA methylation on birth weight and subsequent postnatal outcomes: findings from GUSTO, an Asian birth cohort X. Lin, I. Y. Lim, Y. Wu, A. L. Teh, L. Chen, I. M. Aris, S. E. Soh, M. T. Tint, J. L. MacIsaac, F. Yap, K. Kwek, S. M. Saw, M. S. Kobor, M. J. Meaney, K. M. Godfrey, Y. S. Chong, J. D. Holbrook, Y. S. Lee, P. D. Gluckman, N. Karnani, GUSTO study group O4 High-throughput identification of specific qt interval modulating enhancers at the SCN5A locus A. Kapoor, D. Lee, A. Chakravarti O5 Identification of extracellular matrix components inducing cancer cell migration in the supernatant of cultivated mesenchymal stem cells C. Maercker, F. Graf, M. Boutros O6 Single cell allele specific expression (ASE) IN T21 and common trisomies: a novel approach to understand DOWN syndrome and other aneuploidies G. Stamoulis, F. Santoni, P. Makrythanasis, A. Letourneau, M. Guipponi, N. Panousis, M. Garieri, P. Ribaux, E. Falconnet, C. Borel, S. E. Antonarakis O7 Role of microRNA in LCL to IPSC reprogramming S. Kumar, J. Curran, J. Blangero O8 Multiple enhancer variants disrupt gene regulatory network in Hirschsprung disease S. Chatterjee, A. Kapoor, J. Akiyama, D. Auer, C. Berrios, L. Pennacchio, A. Chakravarti O9 Metabolomic profiling for the diagnosis of neurometabolic disorders T. R. Donti, G. Cappuccio, M. Miller, P. Atwal, A. Kennedy, A. Cardon, C. Bacino, L. Emrick, J. Hertecant, F. Baumer, B. Porter, M. Bainbridge, P. Bonnen, B. Graham, R. Sutton, Q. Sun, S. Elsea O10 A novel causal methylation network approach to Alzheimer\u2019s disease Z. Hu, P. Wang, Y. Zhu, J. Zhao, M. Xiong, David A Bennett O11 A microRNA signature identifies subtypes of triple-negative breast cancer and reveals MIR-342-3P as regulator of a lactate metabolic pathway A. Hidalgo-Miranda, S. Romero-Cordoba, S. Rodriguez-Cuevas, R. Rebollar-Vega, E. Tagliabue, M. Iorio, E. D\u2019Ippolito, S. Baroni O12 Transcriptome analysis identifies genes, enhancer RNAs and repetitive elements that are recurrently deregulated across multiple cancer types B. Kaczkowski, Y. Tanaka, H. Kawaji, A. Sandelin, R. Andersson, M. Itoh, T. Lassmann, the FANTOM5 consortium, Y. Hayashizaki, P. Carninci, A. R. R. Forrest O13 Elevated mutation and widespread loss of constraint at regulatory and architectural binding sites across 11 tumour types C. A. Semple O14 Exome sequencing provides evidence of pathogenicity for genes implicated in colorectal cancer E. A. Rosenthal, B. Shirts, L. Amendola, C. Gallego, M. Horike-Pyne, A. Burt, P. Robertson, P. Beyers, C. Nefcy, D. Veenstra, F. Hisama, R. Bennett, M. Dorschner, D. Nickerson, J. Smith, K. Patterson, D. Crosslin, R. Nassir, N. Zubair, T. Harrison, U. Peters, G. Jarvik, NHLBI GO Exome Sequencing Project O15 The tandem duplicator phenotype as a distinct genomic configuration in cancer F. Menghi, K. Inaki, X. Woo, P. Kumar, K. Grzeda, A. Malhotra, H. Kim, D. Ucar, P. Shreckengast, K. Karuturi, J. Keck, J. Chuang, E. T. Liu O16 Modeling genetic interactions associated with molecular subtypes of breast cancer B. Ji, A. Tyler, G. Ananda, G. Carter O17 Recurrent somatic mutation in the MYC associated factor X in brain tumors H. Nikbakht, M. Montagne, M. Zeinieh, A. Harutyunyan, M. Mcconechy, N. Jabado, P. Lavigne, J. Majewski O18 Predictive biomarkers to metastatic pancreatic cancer treatment J. B. Goldstein, M. Overman, G. Varadhachary, R. Shroff, R. Wolff, M. Javle, A. Futreal, D. Fogelman O19 DDIT4 gene expression as a prognostic marker in several malignant tumors L. Bravo, W. Fajardo, H. Gomez, C. Castaneda, C. Rolfo, J. A. Pinto O20 Spatial organization of the genome and genomic alterations in human cancers K. C. Akdemir, L. Chin, A. Futreal, ICGC PCAWG Structural Alterations Group O21 Landscape of targeted therapies in solid tumors S. Patterson, C. Statz, S. Mockus O22 Genomic analysis reveals novel drivers and progression pathways in skin basal cell carcinoma S. N. Nikolaev, X. I. Bonilla, L. Parmentier, B. King, F. Bezrukov, G. Kaya, V. Zoete, V. Seplyarskiy, H. Sharpe, T. McKee, A. Letourneau, P. Ribaux, K. Popadin, N. Basset-Seguin, R. Ben Chaabene, F. Santoni, M. Andrianova, M. Guipponi, M. Garieri, C. Verdan, K. Grosdemange, O. Sumara, M. Eilers, I. Aifantis, O. Michielin, F. de Sauvage, S. Antonarakis O23 Identification of differential biomarkers of hepatocellular carcinoma and cholangiocarcinoma via transcriptome microarray meta-analysis S. Likhitrattanapisal O24 Clinical validity and actionability of multigene tests for hereditary cancers in a large multi-center study S. Lincoln, A. Kurian, A. Desmond, S. Yang, Y. Kobayashi, J. Ford, L. Ellisen O25 Correlation with tumor ploidy status is essential for correct determination of genome-wide copy number changes by SNP array T. L. Peters, K. R. Alvarez, E. F. Hollingsworth, D. H. Lopez-Terrada O26 Nanochannel based next-generation mapping for interrogation of clinically relevant structural variation A. Hastie, Z. Dzakula, A. W. Pang, E. T. Lam, T. Anantharaman, M. Saghbini, H. Cao, BioNano Genomics O27 Mutation spectrum in a pulmonary arterial hypertension (PAH) cohort and identification of associated truncating mutations in TBX4 C. Gonzaga-Jauregui, L. Ma, A. King, E. Berman Rosenzweig, U. Krishnan, J. G. Reid, J. D. Overton, F. Dewey, W. K. Chung O28 NORTH CAROLINA macular dystrophy (MCDR1): mutations found affecting PRDM13 K. Small, A. DeLuca, F. Cremers, R. A. Lewis, V. Puech, B. Bakall, R. Silva-Garcia, K. Rohrschneider, M. Leys, F. S. Shaya, E. Stone O29 PhenoDB and genematcher, solving unsolved whole exome sequencing data N. L. Sobreira, F. Schiettecatte, H. Ling, E. Pugh, D. Witmer, K. Hetrick, P. Zhang, K. Doheny, D. Valle, A. Hamosh O30 Baylor-Johns Hopkins Center for Mendelian genomics: a four year review S. N. Jhangiani, Z. Coban Akdemir, M. N. Bainbridge, W. Charng, W. Wiszniewski, T. Gambin, E. Karaca, Y. Bayram, M. K. Eldomery, J. Posey, H. Doddapaneni, J. Hu, V. R. Sutton, D. M. Muzny, E. A. Boerwinkle, D. Valle, J. R. Lupski, R. A. Gibbs O31 Using read overlap assembly to accurately identify structural genetic differences in an ashkenazi jewish trio S. Shekar, W. Salerno, A. English, A. Mangubat, J. Bruestle O32 Legal interoperability: a sine qua non for international data sharing A. Thorogood, B. M. Knoppers, Global Alliance for Genomics and Health - Regulatory and Ethics Working Group O33 High throughput screening platform of competent sineups: that can enhance translation activities of therapeutic target H. Takahashi, K. R. Nitta, A. Kozhuharova, A. M. Suzuki, H. Sharma, D. Cotella, C. Santoro, S. Zucchelli, S. Gustincich, P. Carninci O34 The undiagnosed diseases network international (UDNI): clinical and laboratory research to meet patient needs J. J. Mulvihill, G. Baynam, W. Gahl, S. C. Groft, K. Kosaki, P. Lasko, B. Melegh, D. Taruscio O36 Performance of computational algorithms in pathogenicity predictions for activating variants in oncogenes versus loss of function mutations in tumor suppressor genes R. Ghosh, S. Plon O37 Identification and electronic health record incorporation of clinically actionable pharmacogenomic variants using prospective targeted sequencing S. Scherer, X. Qin, R. Sanghvi, K. Walker, T. Chiang, D. Muzny, L. Wang, J. Black, E. Boerwinkle, R. Weinshilboum, R. Gibbs O38 Melanoma reprogramming state correlates with response to CTLA-4 blockade in metastatic melanoma T. Karpinets, T. Calderone, K. Wani, X. Yu, C. Creasy, C. Haymaker, M. Forget, V. Nanda, J. Roszik, J. Wargo, L. Haydu, X. Song, A. Lazar, J. Gershenwald, M. Davies, C. Bernatchez, J. Zhang, A. Futreal, S. Woodman O39 Data-driven refinement of complex disease classification from integration of heterogeneous functional genomics data in GeneWeaver E. J. Chesler, T. Reynolds, J. A. Bubier, C. Phillips, M. A. Langston, E. J. Baker O40 A general statistic framework for genome-based disease risk prediction M. Xiong, L. Ma, N. Lin, C. Amos O41 Integrative large-scale causal network analysis of imaging and genomic data and its application in schizophrenia studies N. Lin, P. Wang, Y. Zhu, J. Zhao, V. Calhoun, M. Xiong O42 Big data and NGS data analysis: the cloud to the rescue O. Dobretsberger, M. Egger, F. Leimgruber O43 Cpipe: a convergent clinical exome pipeline specialised for targeted sequencing S. Sadedin, A. Oshlack, Melbourne Genomics Health Alliance O44 A Bayesian classification of biomedical images using feature extraction from deep neural networks implemented on lung cancer data V. A. A. Antonio, N. Ono, Clark Kendrick C. Go O45 MAV-SEQ: an interactive platform for the Management, Analysis, and Visualization of sequence data Z. Ahmed, M. Bolisetty, S. Zeeshan, E. Anguiano, D. Ucar O47 Allele specific enhancer in EPAS1 intronic regions may contribute to high altitude adaptation of Tibetans C. Zeng, J. Shao O48 Nanochannel based next-generation mapping for structural variation detection and comparison in trios and populations H. Cao, A. Hastie, A. W. Pang, E. T. Lam, T. Liang, K. Pham, M. Saghbini, Z. Dzakula O49 Archaic introgression in indigenous populations of Malaysia revealed by whole genome sequencing Y. Chee-Wei, L. Dongsheng, W. Lai-Ping, D. Lian, R. O. Twee Hee, Y. Yunus, F. Aghakhanian, S. S. Mokhtar, C. V. Lok-Yung, J. Bhak, M. Phipps, X. Shuhua, T. Yik-Ying, V. Kumar, H. Boon-Peng O50 Breast and ovarian cancer prevention: is it time for population-based mutation screening of high risk genes? I. Campbell, M.-A. Young, P. James, Lifepool O53 Comprehensive coverage from low DNA input using novel NGS library preparation methods for WGS and WGBS C. Schumacher, S. Sandhu, T. Harkins, V. Makarov O54 Methods for large scale construction of robust PCR-free libraries for sequencing on Illumina HiSeqX platform H. DoddapaneniR. Glenn, Z. Momin, B. Dilrukshi, H. Chao, Q. Meng, B. Gudenkauf, R. Kshitij, J. Jayaseelan, C. Nessner, S. Lee, K. Blankenberg, L. Lewis, J. Hu, Y. Han, H. Dinh, S. Jireh, K. Walker, E. Boerwinkle, D. Muzny, R. Gibbs O55 Rapid capture methods for clinical sequencing J. Hu, K. Walker, C. Buhay, X. Liu, Q. Wang, R. Sanghvi, H. Doddapaneni, Y. Ding, N. Veeraraghavan, Y. Yang, E. Boerwinkle, A. L. Beaudet, C. M. Eng, D. M. Muzny, R. A. Gibbs O56 A diploid personal human genome model for better genomes from diverse sequence data K. C. C. Worley, Y. Liu, D. S. T. Hughes, S. C. Murali, R. A. Harris, A. C. English, X. Qin, O. A. Hampton, P. Larsen, C. Beck, Y. Han, M. Wang, H. Doddapaneni, C. L. Kovar, W. J. Salerno, A. Yoder, S. Richards, J. Rogers, J. R. Lupski, D. M. Muzny, R. A. Gibbs O57 Development of PacBio long range capture for detection of pathogenic structural variants Q. Meng, M. Bainbridge, M. Wang, H. Doddapaneni, Y. Han, D. Muzny, R. Gibbs O58 Rhesus macaques exhibit more non-synonymous variation but greater impact of purifying selection than humans R. A. Harris, M. Raveenedran, C. Xue, M. Dahdouli, L. Cox, G. Fan, B. Ferguson, J. Hovarth, Z. Johnson, S. Kanthaswamy, M. Kubisch, M. Platt, D. Smith, E. Vallender, R. Wiseman, X. Liu, J. Below, D. Muzny, R. Gibbs, F. Yu, J. Rogers O59 Assessing RNA structure disruption induced by single-nucleotide variation J. Lin, Y. Zhang, Z. Ouyang P1 A meta-analysis of genome-wide association studies of mitochondrial dna copy number A. Moore, Z. Wang, J. Hofmann, M. Purdue, R. Stolzenberg-Solomon, S. Weinstein, D. Albanes, C.-S. Liu, W.-L. Cheng, T.-T. Lin, Q. Lan, N. Rothman, S. Berndt P2 Missense polymorphic genetic combinations underlying down syndrome susceptibility E. S. Chen P4 The evaluation of alteration of ELAM-1 expression in the endometriosis patients H. Bahrami, A. Khoshzaban, S. Heidari Keshal P5 Obesity and the incidence of apolipoprotein E polymorphisms in an assorted population from Saudi Arabia population K. K. R. Alharbi P6 Genome-associated personalized antithrombotical therapy for patients with high risk of thrombosis and bleeding M. Zhalbinova, A. Akilzhanova, S. Rakhimova, M. Bekbosynova, S. Myrzakhmetova P7 Frequency of Xmn1 polymorphism among sickle cell carrier cases in UAE population M. Matar P8 Differentiating inflammatory bowel diseases by using genomic data: dimension of the problem and network organization N. Mili, R. Molinari, Y. Ma, S. Guerrier P9 Vulnerability of genetic variants to the risk of autism among Saudi children N. Elhawary, M. Tayeb, N. Bogari, N. Qotb P10 Chromatin profiles from ex vivo purified dopaminergic neurons establish a promising model to support studies of neurological function and dysfunction S. A. McClymont, P. W. Hook, L. A. Goff, A. McCallion P11 Utilization of a sensitized chemical mutagenesis screen to identify genetic modifiers of retinal dysplasia in homozygous Nr2e3<sup>rd7</sup> mice Y. Kong, J. R. Charette, W. L. Hicks, J. K. Naggert, L. Zhao, P. M. Nishina P12 Ion torrent next generation sequencing of recessive polycystic kidney disease in Saudi patients B. M. Edrees, M. Athar, F. A. Al-Allaf, M. M. Taher, W. Khan, A. Bouazzaoui, N. A. Harbi, R. Safar, H. Al-Edressi, A. Anazi, N. Altayeb, M. A. Ahmed, K. Alansary, Z. Abduljaleel P13 Digital expression profiling of Purkinje neurons and dendrites in different subcellular compartments A. Kratz, P. Beguin, S. Poulain, M. Kaneko, C. Takahiko, A. Matsunaga, S. Kato, A. M. Suzuki, N. Bertin, T. Lassmann, R. Vigot, P. Carninci, C. Plessy, T. Launey P14 The evolution of imperfection and imperfection of evolution: the functional and functionless fractions of the human genome D. Graur P16 Species-independent identification of known and novel recurrent genomic entities in multiple cancer patients J. Friis-Nielsen, J. M. Izarzugaza, S. Brunak P18 Discovery of active gene modules which are densely conserved across multiple cancer types reveal their prognostic power and mutually exclusive mutation patterns B. S. Soibam P19 Whole exome sequencing of dysplastic leukoplakia tissue indicates sequential accumulation of somatic mutations from oral precancer to cancer D. Das, N. Biswas, S. Das, S. Sarkar, A. Maitra, C. Panda, P. Majumder P21 Epigenetic mechanisms of carcinogensis by hereditary breast cancer genes J. J. Gruber, N. Jaeger, M. Snyder P22 RNA direct: a novel RNA enrichment strategy applied to transcripts associated with solid tumors K. Patel, S. Bowman, T. Davis, D. Kraushaar, A. Emerman, S. Russello, N. Henig, C. Hendrickson P23 RNA sequencing identifies gene mutations for neuroblastoma K. Zhang P24 Participation of SFRP1 in the modulation of TMPRSS2-ERG fusion gene in prostate cancer cell lines M. Rodriguez-Dorantes, C. D. Cruz-Hernandez, C. D. P. Garcia-Tobilla, S. Solorzano-Rosales P25 Targeted Methylation Sequencing of Prostate Cancer N. J\u00e4ger, J. Chen, R. Haile, M. Hitchins, J. D. Brooks, M. Snyder P26 Mutant TPMT alleles in children with acute lymphoblastic leukemia from M\u00e9xico City and Yucat\u00e1n, Mexico S. Jim\u00e9nez-Morales, M. Ram\u00edrez, J. Nu\u00f1ez, V. Bekker, Y. Leal, E. Jim\u00e9nez, A. Medina, A. Hidalgo, J. Mej\u00eda P28 Genetic modifiers of Alstr\u00f6m syndrome J. Naggert, G. B. Collin, K. DeMauro, R. Hanusek, P. M. Nishina P31 Association of genomic variants with the occurrence of angiotensin-converting-enzyme inhibitor (ACEI)-induced coughing among Filipinos E. M. Cutiongco De La Paz, R. Sy, J. Nevado, P. Reganit, L. Santos, J. D. Magno, F. E. Punzalan , D. Ona , E. Llanes, R. L. Santos-Cortes , R. Tiongco, J. Aherrera, L. Abrahan, P. Pagauitan-Alan; Philippine Cardiogenomics Study Group P32 The use of \u201chumanized\u201d mouse models to validate disease association of a de novo GARS variant and to test a novel gene therapy strategy for Charcot-Marie-Tooth disease type 2D K. H. Morelli, J. S. Domire, N. Pyne, S. Harper, R. Burgess P34 Molecular regulation of chondrogenic human induced pluripotent stem cells M. A. Gari, A. Dallol, H. Alsehli, A. Gari, M. Gari, A. Abuzenadah P35 Molecular profiling of hematologic malignancies: implementation of a variant assessment algorithm for next generation sequencing data analysis and clinical reporting M. Thomas, M. Sukhai, S. Garg, M. Misyura, T. Zhang, A. Schuh, T. Stockley, S. Kamel-Reid P36 Accessing genomic evidence for clinical variants at NCBI S. Sherry, C. Xiao, D. Slotta, K. Rodarmer, M. Feolo, M. Kimelman, G. Godynskiy, C. O\u2019Sullivan, E. Yaschenko P37 NGS-SWIFT: a cloud-based variant analysis framework using control-accessed sequencing data from DBGAP/SRA C. Xiao, E. Yaschenko, S. Sherry P38 Computational assessment of drug induced hepatotoxicity through gene expression profiling C. Rangel-Escare\u00f1o, H. Rueda-Zarate P40 Flowr: robust and efficient pipelines using a simple language-agnostic approach;ultraseq; fast modular pipeline for somatic variation calling using flowr S. Seth, S. Amin, X. Song, X. Mao, H. Sun, R. G. Verhaak, A. Futreal, J. Zhang P41 Applying \u201cBig data\u201d technologies to the rapid analysis of heterogenous large cohort data S. J. Whiite, T. Chiang, A. English, J. Farek, Z. Kahn, W. Salerno, N. Veeraraghavan, E. Boerwinkle, R. Gibbs P42 FANTOM5 web resource for the large-scale genome-wide transcription start site activity profiles of wide-range of mammalian cells T. Kasukawa, M. Lizio, J. Harshbarger, S. Hisashi, J. Severin, A. Imad, S. Sahin, T. C. Freeman, K. Baillie, A. Sandelin, P. Carninci, A. R. R. Forrest, H. Kawaji, The FANTOM Consortium P43 Rapid and scalable typing of structural variants for disease cohorts W. Salerno, A. English, S. N. Shekar, A. Mangubat, J. Bruestle, E. Boerwinkle, R. A. Gibbs P44 Polymorphism of glutathione S-transferases and sulphotransferases genes in an Arab population A. H. Salem, M. Ali, A. Ibrahim, M. Ibrahim P46 Genetic divergence of CYP3A5*3 pharmacogenomic marker for native and admixed Mexican populations J. C. Fernandez-Lopez, V. Bonifaz-Pe\u00f1a, C. Rangel-Escare\u00f1o, A. Hidalgo-Miranda, A. V. Contreras P47 Whole exome sequence meta-analysis of 13 white blood cell, red blood cell, and platelet traits L. Polfus, CHARGE and NHLBI Exome Sequence Project Working Groups P48 Association of adipoq gene with type 2 diabetes and related phenotypes in african american men and women: The jackson heart study S. Davis, R. Xu, S. Gebeab, P Riestra, A Gaye, R. Khan, J. Wilson, A. Bidulescu P49 Common variants in casr gene are associated with serum calcium levels in koreans S. H. Jung, N. Vinayagamoorthy, S. H. Yim, Y. J. Chung P50 Inference of multiple-wave population admixture by modeling decay of linkage disequilibrium with multiple exponential functions Y. Zhou, S. Xu P51 A Bayesian framework for generalized linear mixed models in genome-wide association studies X. Wang, V. Philip, G. Carter P52 Targeted sequencing approach for the identification of the genetic causes of hereditary hearing impairment A. A. Abuzenadah, M. Gari, R. Turki, A. Dallol P53 Identification of enhancer sequences by ATAC-seq open chromatin profiling A. Uyar, A. Kaygun, S. Zaman, E. Marquez, J. George, D. Ucar P54 Direct enrichment for the rapid preparation of targeted NGS libraries C. L. Hendrickson, A. Emerman, D. Kraushaar, S. Bowman, N. Henig, T. Davis, S. Russello, K. Patel P56 Performance of the Agilent D5000 and High Sensitivity D5000 ScreenTape assays for the Agilent 4200 Tapestation System R. Nitsche, L. Prieto-Lafuente P57 ClinVar: a multi-source archive for variant interpretation M. Landrum, J. Lee, W. Rubinstein, D. Maglott P59 Association of functional variants and protein physical interactions of human MUTY homolog linked with familial adenomatous polyposis and colorectal cancer syndrome Z. Abduljaleel, W. Khan, F. A. Al-Allaf, M. Athar , M. M. Taher, N. Shahzad P60 Modification of the microbiom constitution in the gut using chicken IgY antibodies resulted in a reduction of acute graft-versus-host disease after experimental bone marrow transplantation A. Bouazzaoui, E. Huber, A. Dan, F. A. Al-Allaf, W. Herr, G. Sprotte, J. K\u00f6stler, A. Hiergeist, A. Gessner, R. Andreesen, E. Holler P61 Compound heterozygous mutation in the <i>LDLR</i> gene in Saudi patients suffering severe hypercholesterolemia F. Al-Allaf, A. Alashwal, Z. Abduljaleel, M. Taher, A. Bouazzaoui, H. Abalkhail, A. Al-Allaf, R. Bamardadh, M. Athar", - "journal_title": "Human genomics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/27294413/" - } - ], - "1d3f76c8-87f6-402c-a488-4f6266bb7c9c": [ - { - "pub_id": "23238466", - "title": "Effects of morphine on immediate-early gene expression in the striatum of C57BL/6J and DBA/2J mice.", - "authors": "Barbara Zi\u00f3\u0142kowska,Micha\u0142 Korosty\u0144ski,Marcin Piechota,Jakub Kubik,Ryszard Przew\u0142ocki", - "abstract": "Immediate early gene (IEG) induction elicited by drugs of abuse may contribute to development of plastic changes in the brain responsible for drug-induced behavioral changes leading to addiction. The aim of the present study was to characterize the changes in IEG expression in the striatum and nucleus accumbens produced by an acute or chronic administration of morphine. In order to search for a possible relationship between morphine-induced IEG expression and behavior, the experiment was performed on two inbred strains of mice, C57BL/6J and DBA/2J, which differ markedly in their sensitivity to the rewarding and locomotor stimulatory actions of opiates. Gene expression was assessed using RT-PCR and DNA microarrays. The experiments demonstrated a prolonged or a delayed up-regulation of 14 IEG in the striatum at 4 h after morphine administration. Among them, a cluster of 8 genes, including 6 inducible transcription factors (c-fos, fra-2, junB, zif268 (egr1), egr2, NGFI-B) and 2 effector IEG (arc and mkp1) seemed to be regulated in concert in response to morphine. This group of genes was induced to a greater degree after chronic than acute morphine administration selectively in C57BL/6J mice and the difference bore apparently no relationship to opiate-produced locomotor activation. The strain-selective regulation was also demonstrated for cyclin L2 and tPA after an acute morphine injection. Our data indicate that morphine up-regulates many IEG in the mouse striatum at a strikingly delayed time-point and that these changes are genotype-dependent. They also suggest inter-strain differences in the development of striatal neuroadaptations to chronic morphine treatment.", - "journal_title": "Pharmacological reports : PR", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/23238466/" - } - ], - "4c9c2f49-ce64-4d69-9f9f-d5bb2b985112": [ - { - "pub_id": "22989164", - "title": "A novel QTL underlying early-onset, low-frequency hearing loss in BXD recombinant inbred strains.", - "authors": "A P Nagtegaal,S Spijker,T T H Crins, ,J G G Borst", - "abstract": "The DBA/2J inbred strain of mice has been used extensively in hearing research as it suffers from early-onset, progressive hearing loss. Initially, it mostly affects high frequencies, but already at 2-3\u2009months hearing loss becomes broad. In search for hearing loss genes other than Cadherin 23 (otocadherin) and fascin-2, which make a large contribution to the high-frequency deficits, we used a large set of the genetic reference population of BXD recombinant inbred strains. For frequencies 4, 8, 16 and 32 kHz, auditory brainstem response hearing thresholds were longitudinally determined from 2-3 up to 12\u2009weeks of age. Apart from a significant, broad quantitative trait locus (QTL) for high-frequency hearing loss on chromosome 11 containing the fascin-2 gene, we found a novel, small QTL for low-frequency hearing loss on chromosome 18, from hereon called ahl9. Real-time quantitative polymerase chain reaction of organs of Corti, isolated from a subset of strains, showed that a limited number of genes at the QTL were expressed in the organ of Corti. Of those genes, several showed significant expression differences based on the parental line contributing to the allele. Our results may aid in the future identification of genes involved in low-frequency, early-onset hearing loss.", - "journal_title": "Genes, brain, and behavior", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/22989164/" - } - ], - "64310cb2-e665-4a34-815d-633dc2be5f16": [ - { - "pub_id": "24779608", - "title": "Pharmacogenetic analysis of captopril effects on blood pressure: possible role of the Ednrb (endothelin receptor type B) candidate gene.", - "authors": "J Zicha,Z Dobe\u0161ov\u00e1,V Z\u00eddek,J Silhav\u00fd,M Sim\u00e1kov\u00e1,P Mlejnek,I Van\u011b\u010dkov\u00e1,J Kune\u0161,M Pravenec", - "abstract": "The objective of the current study was to search for genetic determinants associated with antihypertensive effects of angiotensin-converting enzyme (ACE) inhibitor captopril. Linkage and correlation analyses of captopril-induced effects on blood pressure (BP) with renal transcriptome were performed in the BXH/HXB recombinant inbred (RI) strains derived from spontaneously hypertensive rat (SHR) and Brown Norway (BN-Lx) progenitors. Variability of blood pressure lowering effects of captopril among RI strains was continuous suggesting a polygenic mode of inheritance. Linkage analysis of captopril-induced BP effects revealed a significant quantitative trait locus (QTL) on chromosome 15. This QTL colocalized with cis regulated expression QTL (eQTL) for the Ednrb (endothelin receptor type B) gene in the kidney (SHR allele was associated with increased renal expression) and renal expression of Ednrb correlated with captopril-induced BP effects. These results suggest that blood pressure lowering effects of ACE inhibitor captopril may be modulated by the variants at the Ednrb locus.", - "journal_title": "Physiological research", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/24779608/" - } - ], - "b7727a79-9619-4876-a65c-e0ec743306c3": [ - { - "pub_id": "26754954", - "title": "Meta-analysis of genome-wide association studies of anxiety disorders.", - "authors": "T Otowa,K Hek,M Lee,E M Byrne,S S Mirza,M G Nivard,T Bigdeli,S H Aggen,D Adkins,A Wolen,A Fanous,M C Keller,E Castelao,Z Kutalik,S Van der Auwera,G Homuth,M Nauck,A Teumer,Y Milaneschi,J-J Hottenga,N Direk,A Hofman,A Uitterlinden,C L Mulder,A K Henders,S E Medland,S Gordon,A C Heath,P A F Madden,M L Pergadia,P J van der Most,I M Nolte,F V A van Oort,C A Hartman,A J Oldehinkel,M Preisig,H J Grabe,C M Middeldorp,B W J H Penninx,D Boomsma,N G Martin,G Montgomery,B S Maher,E J van den Oord,N R Wray,H Tiemeier,J M Hettema", - "abstract": "Anxiety disorders (ADs), namely generalized AD, panic disorder and phobias, are common, etiologically complex conditions with a partially genetic basis. Despite differing on diagnostic definitions based on clinical presentation, ADs likely represent various expressions of an underlying common diathesis of abnormal regulation of basic threat-response systems. We conducted genome-wide association analyses in nine samples of European ancestry from seven large, independent studies. To identify genetic variants contributing to genetic susceptibility shared across interview-generated DSM-based ADs, we applied two phenotypic approaches: (1) comparisons between categorical AD cases and supernormal controls, and (2) quantitative phenotypic factor scores (FS) derived from a multivariate analysis combining information across the clinical phenotypes. We used logistic and linear regression, respectively, to analyze the association between these phenotypes and genome-wide single nucleotide polymorphisms. Meta-analysis for each phenotype combined results across the nine samples for over 18\u2009000 unrelated individuals. Each meta-analysis identified a different genome-wide significant region, with the following markers showing the strongest association: for case-control contrasts, rs1709393 located in an uncharacterized non-coding RNA locus on chromosomal band 3q12.3 (P=1.65 \u00d7 10(-8)); for FS, rs1067327 within CAMKMT encoding the calmodulin-lysine N-methyltransferase on chromosomal band 2p21 (P=2.86 \u00d7 10(-9)). Independent replication and further exploration of these findings are needed to more fully understand the role of these variants in risk and expression of ADs.", - "journal_title": "Molecular psychiatry", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/26754954/" - } - ], - "0dd5f2bc-ac6b-4728-b42e-557b276702d6": [ - { - "pub_id": "27092175", - "title": "Mouse and Human Genetic Analyses Associate Kalirin with Ventral Striatal Activation during Impulsivity and with Alcohol Misuse.", - "authors": "Yolanda Pe\u00f1a-Oliver,Fabiana M Carvalho,Sandra Sanchez-Roige,Erin B Quinlan,Tianye Jia,Tom Walker-Tilley,Stuart L Rulten,Frances M G Pearl,Tobias Banaschewski,Gareth J Barker,Arun L W Bokde,Christian B\u00fcchel,Patricia J Conrod,Herta Flor,J\u00fcrgen Gallinat,Hugh Garavan,Andreas Heinz,Penny Gowland,Marie-Laure Paillere Martinot,Tom\u00e1\u0161 Paus,Marcella Rietschel,Trevor W Robbins,Michael N Smolka,Gunter Schumann,David N Stephens, ", - "abstract": "Impulsivity is associated with a spectrum of psychiatric disorders including drug addiction. To investigate genetic associations with impulsivity and initiation of drug taking, we took a two-step approach. First, we identified genes whose expression level in prefrontal cortex, striatum and accumbens were associated with impulsive behavior in the 5-choice serial reaction time task across 10 BXD recombinant inbred (BXD RI) mouse strains and their progenitor C57BL/6J and DBA2/J strains. Behavioral data were correlated with regional gene expression using GeneNetwork (www.genenetwork.org), to identify 44 genes whose probability of association with impulsivity exceeded a false discovery rate of < 0.05. We then interrogated the IMAGEN database of 1423 adolescents for potential associations of SNPs in human homologs of those genes identified in the mouse study, with brain activation during impulsive performance in the Monetary Incentive Delay task, and with novelty seeking scores from the Temperament and Character Inventory, as well as alcohol experience. There was a significant overall association between the human homologs of impulsivity-related genes and percentage of premature responses in the MID task and with fMRI BOLD-response in ventral striatum (VS) during reward anticipation. In contrast, no significant association was found between the polygenic scores and anterior cingulate cortex activation. Univariate association analyses revealed that the G allele (major) of the intronic SNP rs6438839 in the KALRN gene was significantly associated with increased VS activation. Additionally, the A-allele (minor) of KALRN intronic SNP rs4634050, belonging to the same haplotype block, was associated with increased frequency of binge drinking.", - "journal_title": "Frontiers in genetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/27092175/" - } - ], - "41b8faf1-ee34-458b-8c99-48688b2dbcc9": [ - { - "pub_id": "23433184", - "title": "Transcriptome analysis of Inbred Long Sleep and Inbred Short Sleep mice.", - "authors": "T M Darlington,M A Ehringer,C Larson,T L Phang,R A Radcliffe", - "abstract": "Many studies have utilized the Inbred Long Sleep and Inbred Short Sleep mouse strains to model the genetic influence on initial sensitivity to ethanol. The mechanisms underlying this divergent phenotype are still not completely understood. In this study, we attempt to identify genes that are differentially expressed between these two strains and to identify baseline networks of co-expressed genes, which may provide insight regarding their phenotypic differences. We examined the whole brain and striatal transcriptomes of both strains, using next generation RNA sequencing techniques. Many genes were differentially expressed between strains, including several in chromosomal regions previously shown to influence initial sensitivity to ethanol. These results are in concordance with a similar sample of striatal transcriptomes measured using microarrays. In addition to the higher dynamic range, RNA-Seq is not hindered by high background noise or polymorphisms in probesets as with microarray technology, and we are able to analyze exome sequence of abundant genes. Furthermore, utilizing Weighted Gene Co-expression Network Analysis, we identified several modules of co-expressed genes corresponding to strain differences. Several candidate genes were identified, including protein phosphatase 1 regulatory unit 1b (Ppp1r1b), prodynorphin (Pdyn), proenkephalin (Penk), ras association (RalGDS/AF-6) domain family member 2 (Rassf2), myosin 1d (Myo1d) and transthyretin (Ttr). In addition, we propose a role for potassium channel activity as well as map kinase signaling in the observed phenotypic differences between the two strains.", - "journal_title": "Genes, brain, and behavior", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/23433184/" - } - ], - "f21523aa-0c42-49c3-b2c1-4b6732c5c57f": [ - { - "pub_id": "24515897", - "title": "Genetics of low spinal muscular atrophy carrier frequency in sub-Saharan Africa.", - "authors": "Modibo Sangar\u00e9,Brant Hendrickson,Hammadoun Ali Sango,Kelian Chen,Jonathan Nofziger,Abdelbasset Amara,Amalia Dutra,Alice B Schindler,Aldiouma Guindo,Mahamadou Traor\u00e9,George Harmison,Evgenia Pak,Fatoumata N'Go Yaro,Katherine Bricceno,Christopher Grunseich,Guibin Chen,Manfred Boehm,Kristen Zukosky,Nouhoum Bocoum,Katherine G Meilleur,Fatoumata Daou,Koumba Bagayogo,Yaya Ibrahim Coulibaly,Mahamadou Diakit\u00e9,Michael P Fay,Hee-Suk Lee,Ali Saad,Moez Gribaa,Andrew B Singleton,Youssoufa Maiga,Sungyoung Auh,Guida Landour\u00e9,Rick M Fairhurst,Barrington G Burnett,Thomas Scholl,Kenneth H Fischbeck", - "abstract": "Spinal muscular atrophy (SMA) is one of the most common severe hereditary diseases of infancy and early childhood in North America, Europe, and Asia. SMA is usually caused by deletions of the survival motor neuron 1 (SMN1) gene. A closely related gene, SMN2, modifies the disease severity. SMA carriers have only 1 copy of SMN1 and are relatively common (1 in 30-50) in populations of European and Asian descent. SMN copy numbers and SMA carrier frequencies have not been reliably estimated in Malians and other sub-Saharan Africans. We used a quantitative polymerase chain reaction assay to determine SMN1 and SMN2 copy numbers in 628 Malians, 120 Nigerians, and 120 Kenyans. We also explored possible mechanisms for SMN1 and SMN2 copy number differences in Malians, and investigated their effects on SMN mRNA and protein levels. The SMA carrier frequency in Malians is 1 in 209, lower than in Eurasians. Malians and other sub-Saharan Africans are more likely to have \u22653 copies of SMN1 than Eurasians, and more likely to lack SMN2 than Europeans. There was no evidence of gene conversion, gene locus duplication, or natural selection from malaria resistance to account for the higher SMN1 copy numbers in Malians. High SMN1 copy numbers were not associated with increased SMN mRNA or protein levels in human cell lines. SMA carrier frequencies are much lower in sub-Saharan Africans than in Eurasians. This finding is important to consider in SMA genetic counseling in individuals with black African ancestry.", - "journal_title": "Annals of neurology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/24515897/" - } - ], - "e70f7c61-1734-4048-8a79-382e9b381686": [ - { - "pub_id": "23582180", - "title": "Genetic modulation of the iris transillumination defect: a systems genetics analysis using the expanded family of BXD glaucoma strains.", - "authors": "Shankar Swaminathan,Hong Lu,Robert W Williams,Lu Lu,Monica M Jablonski", - "abstract": "We investigated the contributions of Tyrp1 and Gpnmb to the iris transillumination defect (TID) in five age cohorts of BXD mice. Using systems genetics, we also evaluated the role of other known pigmentation genes (PGs). Mapping studies indicate that Tyrp1 contributes to the phenotype at all ages, yet the TID maps to Gpnmb only in the oldest cohort. Composite interval mapping reveals secondary loci viz. Oca2, Myo5a, Prkcz, and Zbtb20 that modulate the phenotype in the age groups up to 10-13\u00a0months. The contributions of Tyrp1 and Gpnmb were highly significant in all age cohorts. Moreover, in young mice, all six gene candidates had substantial interactions in our model. Our model accounted for 71-88% of the explained variance of the TID phenotype across the age bins. These results demonstrate that along with Tyrp1 and Gpnmb, Oca2, Myo5a, Prkcz, and Zbtb20 modulate the TID in an age-dependent manner.", - "journal_title": "Pigment cell & melanoma research", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/23582180/" - } - ], - "dc88f26d-1c44-486a-b61f-edcb10a42be8": [ - { - "pub_id": "25258021", - "title": "Inhibition of monoacylglycerol lipase reduces nicotine withdrawal.", - "authors": "P P Muldoon,J Chen,J L Harenza,R A Abdullah,L J Sim-Selley,B F Cravatt,M F Miles,X Chen,A H Lichtman,M I Damaj", - "abstract": "Abrupt discontinuation of nicotine, the main psychoactive component in tobacco, induces a withdrawal syndrome in nicotine-dependent animals, consisting of somatic and affective signs, avoidance of which contributes to drug maintenance. While blockade of fatty acid amide hydrolase, the primary catabolic enzyme of the endocannabinoid arachidonoylethanolamine (anandamide), exacerbates withdrawal responses in nicotine-dependent mice, the role of monoacylglycerol lipase (MAGL), the main hydrolytic enzyme of a second endocannabinoid 2-arachidonylglycerol (2-AG), in nicotine withdrawal remains unexplored. To evaluate the role of MAGL enzyme inhibition in nicotine withdrawal, we initially performed a genetic correlation approach using the BXD recombinant inbred mouse panel. We then assessed nicotine withdrawal intensity in the mouse after treatment with the selective MAGL inhibitor, JZL184, and after genetic deletion of the enzyme. Lastly, we assessed the association between genotypes and smoking withdrawal phenotypes in two human data sets. BXD mice displayed significant positive correlations between basal MAGL mRNA expression and nicotine withdrawal responses, consistent with the idea that increased 2-AG brain levels may attenuate withdrawal responses. Strikingly, the MAGL inhibitor, JZL184, dose-dependently reduced somatic and aversive withdrawal signs, which was blocked by rimonabant, indicating a CB1 receptor-dependent mechanism. MAGL-knockout mice also showed attenuated nicotine withdrawal. Lastly, genetic analyses in humans revealed associations of the MAGL gene with smoking withdrawal in humans. Overall, our findings suggest that MAGL inhibition maybe a promising target for treatment of nicotine dependence.", - "journal_title": "British journal of pharmacology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/25258021/" - } - ], - "a3541fba-f802-4e93-8274-1c2c8f58fb13": [ - { - "pub_id": "27286934", - "title": "Common genes regulate food and ethanol intake in Drosophila.", - "authors": "Morgan L Sekhon,Omoteniola Lamina,Kerry E Hogan,Christopher L Kliethermes", - "abstract": "The abuse liability of alcohol (ethanol) is believed to result in part from its actions on neurobiological substrates that underlie the motivation toward food and other natural reinforcers, and a growing body of evidence indicates that these substrates are broadly conserved among animal phyla. Understanding the extent to which the substrates regulating ethanol and food intake overlap is an important step toward developing therapeutics that selectively reduce ethanol intake. In the current experiments, we measured food and ethanol intake in Recombinant Inbred (RI) lines of Drosophila melanogaster using several assays, and then calculated genetic correlations to estimate the degree to which common genes might underlie behavior in these assays. We found that food intake and ethanol intake as measured in the capillary assay are genetically correlated traits in D.\u00a0melanogaster, as well as in a panel of 11 Drosophila species that we tested subsequently. RI line differences in food intake in a dyed food assay were genetically unrelated to ethanol intake in the capillary assay or to ethanol preference measured using an olfactory trap apparatus. Using publicly available gene expression data, we found that expression profiles across the RI lines of a number of genes (including the D2-like dopamine receptor, DOPA decarboxylase, and fruitless) correlated with the RI line differences in food and ethanol intake we measured, while the expression profiles of other genes, including NPF, and the NPF and 5-HT2 receptors, correlated only with ethanol intake or preference. Our results suggest that food and ethanol intake are regulated by some common genes in Drosophila, but that other genes regulate ethanol intake independently of food intake. These results have implications toward the development of therapeutics that preferentially reduce ethanol intake.", - "journal_title": "Alcohol (Fayetteville, N.Y.)", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/27286934/" - } - ], - "64472bd6-af60-47c9-bfa4-3d6ea2b6cf8c": [ - { - "pub_id": "26730594", - "title": "Time-Course Analysis of Brain Regional Expression Network Responses to Chronic Intermittent Ethanol and Withdrawal: Implications for Mechanisms Underlying Excessive Ethanol Consumption.", - "authors": "Maren L Smith,Marcelo F Lopez,Kellie J Archer,Aaron R Wolen,Howard C Becker,Michael F Miles", - "abstract": "Long lasting abusive consumption, dependence, and withdrawal are characteristic features of alcohol use disorders (AUD). Mechanistically, persistent changes in gene expression are hypothesized to contribute to brain adaptations leading to ethanol toxicity and AUD. We employed repeated chronic intermittent ethanol (CIE) exposure by vapor chamber as a mouse model to simulate the cycles of ethanol exposure and withdrawal commonly seen with AUD. This model has been shown to induce progressive ethanol consumption in rodents. Brain CIE-responsive expression networks were identified by microarray analysis across five regions of the mesolimbic dopamine system and extended amygdala with tissue harvested from 0-hours to 7-days following CIE. Weighted Gene Correlated Network Analysis (WGCNA) was used to identify gene networks over-represented for CIE-induced temporal expression changes across brain regions. Differential gene expression analysis showed that long-lasting gene regulation occurred 7-days after the final cycle of ethanol exposure only in prefrontal cortex (PFC) and hippocampus. Across all brain regions, however, ethanol-responsive expression changes occurred mainly within the first 8-hours after removal from ethanol. Bioinformatics analysis showed that neuroinflammatory responses were seen across multiple brain regions at early time-points, whereas co-expression modules related to neuroplasticity, chromatin remodeling, and neurodevelopment were seen at later time-points and in specific brain regions (PFC or HPC). In PFC a module containing Bdnf was identified as highly CIE responsive in a biphasic manner, with peak changes at 0 hours and 5 days following CIE, suggesting a possible role in mechanisms underlying long-term molecular and behavioral response to CIE. Bioinformatics analysis of this network and several other modules identified Let-7 family microRNAs as potential regulators of gene expression changes induced by CIE. Our results suggest a complex temporal and regional pattern of widespread gene network responses involving neuroinflammatory and neuroplasticity related genes as contributing to physiological and behavioral responses to chronic ethanol.", - "journal_title": "PloS one", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/26730594/" - } - ], - "3df1bffa-3d23-4b6b-9d59-6ef8b0001f48": [ - { - "pub_id": "22304583", - "title": "Computational tools for discovery and interpretation of expression quantitative trait loci.", - "authors": "Fred A Wright,Andrey A Shabalin,Ivan Rusyn", - "abstract": "Expression quantitative trait locus (eQTL) analysis is rapidly moving from a cutting-edge concept in genomics to a mature area of investigation, with important connections to genome-wide association studies for human disease, pharmacogenomics and toxicogenomics. Despite the importance of the topic, many investigators must develop their own code or use tools not specifically suited for eQTL analysis. Convenient computational tools are becoming available, but they are not widely publicized, and investigators who are interested in discovery or eQTL, or in using them to interpret genome-wide association study results may have difficulty navigating the available resources. The purpose of this review is to help investigators find appropriate programs for eQTL analysis and interpretation.", - "journal_title": "Pharmacogenomics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/22304583/" - } - ], - "d543e168-744d-44f5-82cc-c3c1a60ee5a7": [ - { - "pub_id": "25808367", - "title": "Cell cycle gene expression networks discovered using systems biology: Significance in carcinogenesis.", - "authors": "Robert E Scott,Prachi N Ghule,Janet L Stein,Gary S Stein", - "abstract": "The early stages of carcinogenesis are linked to defects in the cell cycle. A series of cell cycle checkpoints are involved in this process. The G1/S checkpoint that serves to integrate the control of cell proliferation and differentiation is linked to carcinogenesis and the mitotic spindle checkpoint is associated with the development of chromosomal instability. This paper presents the outcome of systems biology studies designed to evaluate if networks of covariate cell cycle gene transcripts exist in proliferative mammalian tissues including mice, rats, and humans. The GeneNetwork website that contains numerous gene expression datasets from different species, sexes, and tissues represents the foundational resource for these studies (www.genenetwork.org). In addition, WebGestalt, a gene ontology tool, facilitated the identification of expression networks of genes that co-vary with key cell cycle targets, especially Cdc20 and Plk1 (www.bioinfo.vanderbilt.edu/webgestalt). Cell cycle expression networks of such covariate mRNAs exist in multiple proliferative tissues including liver, lung, pituitary, adipose, and lymphoid tissues among others but not in brain or retina that have low proliferative potential. Sixty-three covariate cell cycle gene transcripts (mRNAs) compose the average cell cycle network with P\u2009=\u2009e(-13) to e(-36) . Cell cycle expression networks show species, sex and tissue variability, and they are enriched in mRNA transcripts associated with mitosis, many of which are associated with chromosomal instability.", - "journal_title": "Journal of cellular physiology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/25808367/" - } - ], - "421e1acd-7273-4c4a-b280-b0e5a132cbab": [ - { - "pub_id": "22952935", - "title": "Systems genetics of the lateral septal nucleus in mouse: heritability, genetic control, and covariation with behavioral and morphological traits.", - "authors": "Alexander Talishinsky,Glenn D Rosen", - "abstract": "The lateral septum has strong efferent projections to hypothalamic and midbrain regions, and has been associated with modulation of social behavior, anxiety, fear conditioning, memory-related behaviors, and the mesolimbic reward pathways. Understanding natural variation of lateral septal anatomy and function, as well as its genetic modulation, may provide important insights into individual differences in these evolutionarily important functions. Here we address these issues by using efficient and unbiased stereological probes to estimate the volume of the lateral septum in the BXD line of recombinant inbred mice. Lateral septum volume is a highly variable trait, with a 2.5-fold difference among animals. We find that this trait covaries with a number of behavioral and physiological phenotypes, many of which have already been associated with behaviors modulated by the lateral septum, such as spatial learning, anxiety, and reward-seeking. Heritability of lateral septal volume is moderate (h(2) = 0.52), and much of the heritable variation is caused by a locus on the distal portion of chromosome (Chr) 1. Composite interval analysis identified a secondary interval on Chr 2 that works additively with the Chr 1 locus to increase lateral septum volume. Using bioinformatic resources, we identified plausible candidate genes in both intervals that may influence the volume of this key nucleus, as well as associated behaviors.", - "journal_title": "PloS one", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/22952935/" - } - ], - "d8d2d389-b374-41d1-9eb6-557c6c392b66": [ - { - "pub_id": "25942439", - "title": "Quantitative Trait Loci and Candidate Genes for Neutrophil Recruitment in Sterile Inflammation Mapped in AXB-BXA Recombinant Inbred Mice.", - "authors": "Quyen Cheng,Ze'ev Seltzer,Corneliu Sima,Flavia S Lakschevitz,Michael Glogauer", - "abstract": "Neutrophil recruitment (NR) to sites of sterile inflammation plays a key role in tissue damage and healing potential of lesions characteristic to non-infectious inflammatory diseases. Previous studies suggested significant genetic control of neutrophil survival, function, and migration in inflammatory responses to endogenous and exogenous stimuli. We have mapped the murine genome for quantitative trait loci (QTLs) harbouring genetic determinants that regulate NR in SI using a murine model of chemically-induced peritonitis. NR was quantified in 16 AXB-BXA recombinant inbred strains and their progenitors, A/J (A) and C57BL/6J (B). A continuous distribution of NR was found among the strains, with parent B showing higher NR and parent A showing lower NR (3.0-fold difference, p=0.05). Within the progeny strains, a 5.5-fold difference in NR was observed between the lowest, BXA1, and the highest responders AXB19 (p<0.001). This data was analyzed using GeneNetwork, which linked NR to one significant QTL on chromosome 12 (Peritoneal Neutrophil Recruitment 1, PNR1) and two suggestive QTLs (PNR2, PNR3) on chromosomes 12 and 16 respectively. Sixty-four candidate genes within PNR1 were cross-referenced with currently published data, mRNA expression from two NR microarrays, and single nucleotide polymorphism analysis. The present study brings new light into the genetics of NR in response to cell injury and highlights potential candidate genes Hif1\u03b1, Fntb, and Prkch and their products for further studies on neutrophil infiltration and inflammation resolution in sterile inflammation.", - "journal_title": "PloS one", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/25942439/" - } - ], - "638b711b-cdd9-4c0b-9884-0e450fa6ed31": [ - { - "pub_id": "22183389", - "title": "Networks modulating the retinal response to injury: insights from microarrays, expression genetics, and bioinformatics.", - "authors": "F\u00e9lix R V\u00e1zquez-Chona,Eldon E Geisert", - "abstract": "", - "journal_title": "Advances in experimental medicine and biology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/22183389/" - } - ], - "268c735a-5e56-4b7b-90c3-e5925917d9b7": [ - { - "pub_id": "24651695", - "title": "A forward phenotypically driven unbiased genetic analysis of host genes that moderate herpes simplex virus virulence and stromal keratitis in mice.", - "authors": "Richard L Thompson,Robert W Williams,Malak Kotb,Nancy M Sawtell", - "abstract": "Both viral and host genetics affect the outcome of herpes simplex virus type 1 (HSV-1) infection in humans and experimental models. Little is known about specific host gene variants and molecular networks that influence herpetic disease progression, severity, and episodic reactivation. To identify such host gene variants we have initiated a forward genetic analysis using the expanded family of BXD strains, all derived from crosses between C57BL/6J and DBA/2J strains of mice. One parent is highly resistant and one highly susceptible to HSV-1. Both strains have also been fully sequenced, greatly facilitating the search for genetic modifiers that contribute to differences in HSV-1 infection. We monitored diverse disease phenotypes following infection with HSV-1 strain 17syn+ including percent mortality (herpes simplex encephalitis, HSE), body weight loss, severity of herpetic stromal keratitis (HSK), spleen weight, serum neutralizing antibody titers, and viral titers in tear films in BXD strains. A significant quantitative trait locus (QTL) on chromosome (Chr) 16 was found to associate with both percent mortality and HSK severity. Importantly, this QTL maps close to a human QTL and the gene proposed to be associated with the frequency of recurrent herpetic labialis (cold sores). This suggests that a single host locus may influence these seemingly diverse HSV-1 pathogenic phenotypes by as yet unknown mechanisms. Additional suggestive QTLs for percent mortality were identified--one on Chr X that is epistatically associated with that on Chr 16. As would be anticipated the Chr 16 QTL also modulated weight loss, reaching significance in females. A second significant QTL for maximum weight loss in male and female mice was mapped to Chr 12. To our knowledge this is the first report of a host genetic locus that modulates the severity of both herpetic disease in the nervous system and herpetic stromal keratitis.", - "journal_title": "PloS one", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/24651695/" - } - ], - "bd93e797-5d14-4c84-ba92-e9988d46f1f4": [ - { - "pub_id": "29184056", - "title": "Functional mapping and annotation of genetic associations with FUMA.", - "authors": "Kyoko Watanabe,Erdogan Taskesen,Arjen van Bochoven,Danielle Posthuma", - "abstract": "A main challenge in genome-wide association studies (GWAS) is to pinpoint possible causal variants. Results from GWAS typically do not directly translate into causal variants because the majority of hits are in non-coding or intergenic regions, and the presence of linkage disequilibrium leads to effects being statistically spread out across multiple variants. Post-GWAS annotation facilitates the selection of most likely causal variant(s). Multiple resources are available for post-GWAS annotation, yet these can be time consuming and do not provide integrated visual aids for data interpretation. We, therefore, develop FUMA: an integrative web-based platform using information from multiple biological resources to facilitate functional annotation of GWAS results, gene prioritization and interactive visualization. FUMA accommodates positional, expression quantitative trait loci (eQTL) and chromatin interaction mappings, and provides gene-based, pathway and tissue enrichment results. FUMA results directly aid in generating hypotheses that are testable in functional experiments aimed at proving causal relations.", - "journal_title": "Nature communications", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/29184056/" - } - ], - "606ddac6-6250-4510-8896-f89dc9077edb": [ - { - "pub_id": "28181539", - "title": "Dissecting the brown adipogenic regulatory network using integrative genomics.", - "authors": "Rachana N Pradhan,Johannes J Bues,Vincent Gardeux,Petra C Schwalie,Daniel Alpern,Wanze Chen,Julie Russeil,Sunil K Raghav,Bart Deplancke", - "abstract": "Brown adipocytes regulate energy expenditure via mitochondrial uncoupling, which makes them attractive therapeutic targets to tackle obesity. However, the regulatory mechanisms underlying brown adipogenesis are still poorly understood. To address this, we profiled the transcriptome and chromatin state during mouse brown fat cell differentiation, revealing extensive gene expression changes and chromatin remodeling, especially during the first day post-differentiation. To identify putatively causal regulators, we performed transcription factor binding site overrepresentation analyses in active chromatin regions and prioritized factors based on their expression correlation with the bona-fide brown adipogenic marker Ucp1 across multiple mouse and human datasets. Using loss-of-function assays, we evaluated both the phenotypic effect as well as the transcriptomic impact of several putative regulators on the differentiation process, uncovering ZFP467, HOXA4 and Nuclear Factor I A (NFIA) as novel transcriptional regulators. Of these, NFIA emerged as the regulator yielding the strongest molecular and cellular phenotypes. To examine its regulatory function, we profiled the genomic localization of NFIA, identifying it as a key early regulator of terminal brown fat cell differentiation.", - "journal_title": "Scientific reports", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/28181539/" - } - ], - "6ed23619-350d-48e3-9e5f-ce831889b448": [ - { - "pub_id": "23060902", - "title": "Recombinant inbred systems can advance research in behavioral ecology.", - "authors": "Beatrice Gini,Reinmar Hager", - "abstract": "Recombinant inbred (RI) systems such as the BXD mouse family represent a population with defined genetic architecture and variation that approximates those of natural populations. With the development of novel RI lines and sophisticated methods that conjointly analyze phenotype, gene sequence, and expression data, RI systems such as BXD are a timely and powerful tool to advance the field of behavioral ecology. The latter traditionally focused on functional questions such as the adaptive value of behavior but largely ignored underlying genetics and mechanisms. In this perspective, we argue that using RI systems to address questions in behavioral ecology and evolutionary biology has great potential to advance research in these fields. We outline key questions and how they can be tackled using RI systems and BXD in particular. The unique opportunity to analyze genetic and phenotypic data from studies conducted in different laboratories and at different times is a key benefit of RI systems and may lead the way to a better understanding of how adaptive phenotypes arise from genetic and environmental factors.", - "journal_title": "Frontiers in genetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/23060902/" - } - ], - "5e29f3d3-3602-4315-9390-5b218122e523": [ - { - "pub_id": "27884493", - "title": "Initial genetic dissection of serum neuroactive steroids following chronic intermittent ethanol across BXD mouse strains.", - "authors": "Patrizia Porcu,Todd K O'Buckley,Marcelo F Lopez,Howard C Becker,Michael F Miles,Robert W Williams,A Leslie Morrow", - "abstract": "Neuroactive steroids modulate alcohol's impact on brain function and behavior. Ethanol exposure alters neuroactive steroid levels in rats, humans, and some mouse strains. We conducted an exploratory analysis of the neuroactive steroids (3\u03b1,5\u03b1)-3-hydroxypregnan-20-one (3\u03b1,5\u03b1-THP), (3\u03b1,5\u03b1)-3,21-dihydroxypregnan-20-one (3\u03b1,5\u03b1-THDOC), and pregnenolone across 126-158 individuals and 19 fully inbred strains belonging to the BXD family, which were subjected to air exposure, or chronic intermittent ethanol (CIE) exposure. Neuroactive steroids were measured by gas chromatography-mass spectrometry in serum following five cycles of CIE or air exposure (CTL). Pregnenolone levels in CTLs range from 272 to 578\u00a0pg/mL (strain variation of 2.1 fold with p\u00a0=\u00a00.049 for strain main effect), with heritability of 0.20\u00a0\u00b1\u00a00.006 (SEM), whereas in CIE cases values range from 304 to 919\u00a0pg/mL (3.0-fold variation, p\u00a0=\u00a00.007), with heritability of 0.23\u00a0\u00b1\u00a00.005. 3\u03b1,5\u03b1-THP levels in CTLs range from 375 to 1055\u00a0pg/mL (2.8-fold variation, p\u00a0=\u00a00.0007), with heritability of 0.28\u00a0\u00b1\u00a00.01; in CIE cases they range from 460 to 1022\u00a0pg/mL (2.2-fold variation, p\u00a0=\u00a00.004), with heritability of 0.23\u00a0\u00b1\u00a00.005. 3\u03b1,5\u03b1-THDOC levels in CTLs range from 94 to 448\u00a0pg/mL (4.8-fold variation, p\u00a0=\u00a00.002), with heritability of 0.30\u00a0\u00b1\u00a00.01, whereas levels in CIE cases do not differ significantly. However, global averages across all BXD strains do not differ between CTL and CIE for any of the steroids. 3\u03b1,5\u03b1-THDOC levels were lower in females than males in both groups (CTL\u00a0-53%, CIE\u00a0-55%, p\u00a0<\u00a00.001). Suggestive quantitative trait loci are identified for pregnenolone and 3\u03b1,5\u03b1-THP levels. Genetic variation in 3\u03b1,5\u03b1-THP was not correlated with two-bottle choice ethanol consumption in CTL or CIE-exposed animals. However, individual variation in 3\u03b1,5\u03b1-THP correlated negatively with ethanol consumption in both groups. Moreover, strain variation in neuroactive steroid levels correlated with numerous behavioral phenotypes of anxiety sensitivity accessed in GeneNetwork, consistent with evidence that neuroactive steroids modulate anxiety-like behavior.", - "journal_title": "Alcohol (Fayetteville, N.Y.)", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/27884493/" - } - ], - "14a9de52-cff1-4397-bb2c-8c2e34bb05bf": [ - { - "pub_id": "21765459", - "title": "The future of model organisms in human disease research.", - "authors": "Timothy J Aitman,Charles Boone,Gary A Churchill,Michael O Hengartner,Trudy F C Mackay,Derek L Stemple", - "abstract": "Model organisms have played a huge part in the history of studies of human genetic disease, both in identifying disease genes and characterizing their normal and abnormal functions. But is the importance of model organisms diminishing? The direct discovery of disease genes and variants in humans has been revolutionized, first by genome-wide association studies and now by whole-genome sequencing. Not only is it now much easier to directly identify potential disease genes in humans, but the genetic architecture that is being revealed in many cases is hard to replicate in model organisms. Furthermore, disease modelling can be done with increasing effectiveness using human cells. Where does this leave non-human models of disease?", - "journal_title": "Nature reviews. Genetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/21765459/" - } - ], - "40ebee6a-ba5a-4f21-86d1-78d421288687": [ - { - "pub_id": "34475573", - "title": "Large-scale cis- and trans-eQTL analyses identify thousands of genetic loci and polygenic scores that regulate blood gene expression.", - "authors": "Urmo V\u00f5sa,Annique Claringbould,Harm-Jan Westra,Marc Jan Bonder,Patrick Deelen,Biao Zeng,Holger Kirsten,Ashis Saha,Roman Kreuzhuber,Seyhan Yazar,Harm Brugge,Roy Oelen,Dylan H de Vries,Monique G P van der Wijst,Silva Kasela,Natalia Pervjakova,Isabel Alves,Marie-Julie Fav\u00e9,Mawuss\u00e9 Agbessi,Mark W Christiansen,Rick Jansen,Ilkka Sepp\u00e4l\u00e4,Lin Tong,Alexander Teumer,Katharina Schramm,Gibran Hemani,Joost Verlouw,Hanieh Yaghootkar,Reyhan S\u00f6nmez Flitman,Andrew Brown,Viktorija Kukushkina,Anette Kalnapenkis,Sina R\u00fceger,Eleonora Porcu,Jaanika Kronberg,Johannes Kettunen,Bernett Lee,Futao Zhang,Ting Qi,Jose Alquicira Hernandez,Wibowo Arindrarto,Frank Beutner, , ,Julia Dmitrieva,Mahmoud Elansary,Benjamin P Fairfax,Michel Georges,Bastiaan T Heijmans,Alex W Hewitt,Mika K\u00e4h\u00f6nen,Yungil Kim,Julian C Knight,Peter Kovacs,Knut Krohn,Shuang Li,Markus Loeffler,Urko M Marigorta,Hailang Mei,Yukihide Momozawa,Martina M\u00fcller-Nurasyid,Matthias Nauck,Michel G Nivard,Brenda W J H Penninx,Jonathan K Pritchard,Olli T Raitakari,Olaf Rotzschke,Eline P Slagboom,Coen D A Stehouwer,Michael Stumvoll,Patrick Sullivan,Peter A C 't Hoen,Joachim Thiery,Anke T\u00f6njes,Jenny van Dongen,Maarten van Iterson,Jan H Veldink,Uwe V\u00f6lker,Robert Warmerdam,Cisca Wijmenga,Morris Swertz,Anand Andiappan,Grant W Montgomery,Samuli Ripatti,Markus Perola,Zoltan Kutalik,Emmanouil Dermitzakis,Sven Bergmann,Timothy Frayling,Joyce van Meurs,Holger Prokisch,Habibul Ahsan,Brandon L Pierce,Terho Lehtim\u00e4ki,Dorret I Boomsma,Bruce M Psaty,Sina A Gharib,Philip Awadalla,Lili Milani,Willem H Ouwehand,Kate Downes,Oliver Stegle,Alexis Battle,Peter M Visscher,Jian Yang,Markus Scholz,Joseph Powell,Greg Gibson,T\u00f5nu Esko,Lude Franke", - "abstract": "Trait-associated genetic variants affect complex phenotypes primarily via regulatory mechanisms on the transcriptome. To investigate the genetics of gene expression, we performed cis- and trans-expression quantitative trait locus (eQTL) analyses using blood-derived expression from 31,684 individuals through the eQTLGen Consortium. We detected cis-eQTL for 88% of genes, and these were replicable in numerous tissues. Distal trans-eQTL (detected for 37% of 10,317 trait-associated variants tested) showed lower replication rates, partially due to low replication power and confounding by cell type composition. However, replication analyses in single-cell RNA-seq data prioritized intracellular trans-eQTL. Trans-eQTL exerted their effects via several mechanisms, primarily through regulation by transcription factors. Expression of 13% of the genes correlated with polygenic scores for 1,263 phenotypes, pinpointing potential drivers for those traits. In summary, this work represents a large eQTL resource, and its results serve as a starting point for in-depth interpretation of complex phenotypes.", - "journal_title": "Nature genetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/34475573/" - } - ], - "e1d38edf-d807-49f6-b81f-da1d086c3136": [ - { - "pub_id": "24733291", - "title": "R PheWAS: data analysis and plotting tools for phenome-wide association studies in the R environment.", - "authors": "Robert J Carroll,Lisa Bastarache,Joshua C Denny", - "abstract": "Phenome-wide association studies (PheWAS) have been used to replicate known genetic associations and discover new phenotype associations for genetic variants. This PheWAS implementation allows users to translate ICD-9 codes to PheWAS case and control groups, perform analyses using these and/or other phenotypes with covariate adjustments and plot the results. We demonstrate the methods by replicating a PheWAS on rs3135388 (near HLA-DRB, associated with multiple sclerosis) and performing a novel PheWAS using an individual's maximum white blood cell count (WBC) as a continuous measure. Our results for rs3135388 replicate known associations with more significant results than the original study on the same dataset. Our PheWAS of WBC found expected results, including associations with infections, myeloproliferative diseases and associated conditions, such as anemia. These results demonstrate the performance of the improved classification scheme and the flexibility of PheWAS encapsulated in this package. This R package is freely available under the Gnu Public License (GPL-3) from http://phewascatalog.org. It is implemented in native R and is platform independent.", - "journal_title": "Bioinformatics (Oxford, England)", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/24733291/" - } - ], - "a516e1d9-bd3d-4d53-aa55-9ec98c38b8ab": [ - { - "pub_id": "25057212", - "title": "Sox2 regulates cholinergic amacrine cell positioning and dendritic stratification in the retina.", - "authors": "Irene E Whitney,Patrick W Keeley,Ace J St John,Amanda G Kautzman,Jeremy N Kay,Benjamin E Reese", - "abstract": "The retina contains two populations of cholinergic amacrine cells, one positioned in the ganglion cell layer (GCL) and the other in the inner nuclear layer (INL), that together comprise \u223c1/2 of a percent of all retinal neurons. The present study examined the genetic control of cholinergic amacrine cell number and distribution between these two layers. The total number of cholinergic amacrine cells was quantified in the C57BL/6J and A/J inbred mouse strains, and in 25 recombinant inbred strains derived from them, and variations in their number and ratio (GCL/INL) across these strains were mapped to genomic loci. The total cholinergic amacrine cell number was found to vary across the strains, from 27,000 to 40,000 cells, despite little variation within individual strains. The number of cells was always lower within the GCL relative to the INL, and the sizes of the two populations were strongly correlated, yet there was variation in their ratio between the strains. Approximately 1/3 of that variation in cell ratio was mapped to a locus on chromosome 3, where Sex determining region Y box 2 (Sox2) was identified as a candidate gene due to the presence of a 6-nucleotide insertion in the protein-coding sequence in C57BL/6J and because of robust and selective expression in cholinergic amacrine cells. Conditionally deleting Sox2 from the population of nascent cholinergic amacrine cells perturbed the normal ratio of cells situated in the GCL versus the INL and induced a bistratifying morphology, with dendrites distributed to both ON and OFF strata within the inner plexiform layer.", - "journal_title": "The Journal of neuroscience : the official journal of the Society for Neuroscience", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/25057212/" - } - ], - "f880f290-4cc7-43f8-a7e6-788b072efd83": [ - { - "pub_id": "29100054", - "title": "Systems Phytohormone Responses to Mitochondrial Proteotoxic Stress.", - "authors": "Xu Wang,Johan Auwerx", - "abstract": "Mitochondrial function is controlled by two separate genomes. This feature makes mitochondria prone to proteotoxic stress when a stoichiometric imbalance occurs in the protein complexes that perform oxidative phosphorylation, which consist of both nuclear- and mitochondrial-encoded proteins. Such a proteotoxic stress is known to induce the mitochondrial unfolded protein response (UPR<sup>mt</sup>) in animals. It is unknown whether UPR<sup>mt</sup> occurs in plants. Here, we induced a mitonuclear protein imbalance in Arabidopsis through chemical or genetic interference. Mitochondrial proteotoxic stress activated a plant-specific UPR<sup>mt</sup> and impaired plant growth and development. The plant UPR<sup>mt</sup> pathway is triggered by a transient oxidative burst, activating MAPK and hormonal (involving ethylene and auxin) signaling, which are all geared to repair proteostasis. This also establishes phytohormones as bona fide plant mitokines. Our data ascertain that mitochondrial protein quality control pathways, such as the UPR<sup>mt</sup>, are conserved in plants and that hormone signaling is an essential mediator that regulates mitochondrial proteostasis.", - "journal_title": "Molecular cell", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/29100054/" - } - ], - "6dbbf0bc-eea3-4930-be75-925410bc34ea": [ - { - "pub_id": "24338665", - "title": "Genetic dissection of sleep homeostasis.", - "authors": "G\u00e9raldine M Mang,Paul Franken", - "abstract": "Sleep is a complex behavior both in its manifestation and regulation, that is common to almost all animal species studied thus far. Sleep is not a unitary behavior and has many different aspects, each of which is tightly regulated and influenced by both genetic and environmental factors. Despite its essential role for performance, health, and well-being, genetic mechanisms underlying this complex behavior remain poorly understood. One important aspect of sleep concerns its homeostatic regulation, which ensures that levels of sleep need are kept within a range still allowing optimal functioning during wakefulness. Uncovering the genetic pathways underlying the homeostatic aspect of sleep is of particular importance because it could lead to insights concerning sleep's still elusive function and is therefore a main focus of current sleep research. In this chapter, we first give a definition of sleep homeostasis and describe the molecular genetics techniques that are used to examine it. We then provide a conceptual discussion on the problem of assessing a sleep homeostatic phenotype in various animal models. We finally highlight some of the studies with a focus on clock genes and adenosine signaling molecules.", - "journal_title": "Current topics in behavioral neurosciences", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/24338665/" - } - ], - "23f1c487-4011-4149-9e86-ce8f77c3687e": [ - { - "pub_id": "27182044", - "title": "MPTP neurotoxicity is highly concordant between the sexes among BXD recombinant inbred mouse strains.", - "authors": "Gelareh Alam,Diane B Miller,James P O'Callaghan,Lu Lu,Robert W Williams,Byron C Jones", - "abstract": "Continuing our previous work in which we showed wide-ranging strain differences in MPTP neurotoxicity in male mice among ten BXD recombinant inbred strains, we replicated our work in females from nine of the same strains. Mice received a single s.c. injection of 12.5mg/kg MPTP or saline. Forty-eight hours later the striatum was dissected for neurochemical analysis. Striatal dopamine (DA) and its metabolites, DOPAC and HVA, striatal serotonin (5-HT) and its metabolite, 5-HIAA, were analyzed using HPLC. Tyrosine hydroxylase (TH) and glial fibrillary acidic protein (GFAP), an astrocytic protein that increases during the astroglial response to neural injury, were measured using ELISA. There were wide genetic variations in the DA, DOPAC, HVA, TH and GFAP responses to MPTP. We also performed principal component analysis (PCA) on the difference values, saline minus MPTP, for DA, DOPAC, HVA and TH and mapped the dominant principal component to a suggestive QTL on chromosome 1 at the same location that we observed previously for males. Moreover, there were significant correlations between the sexes for the effect of MPTP on DA, HVA, and TH. Our findings suggest that the systems genetic approach as utilized here can help researchers understand the role of sex in individual differences. The same approach can pave the way to understand and pinpoint the genetic bases for individual differences in pathology attributable to toxicants. Such systems genetics approach has broad implications for elucidating gene-environment contributions to neurodegenerative diseases.", - "journal_title": "Neurotoxicology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/27182044/" - } - ], - "2c086fa1-4fcd-4cbb-aec5-d42e352d567b": [ - { - "pub_id": "26822446", - "title": "Epigenetic Patterns Modulate the Connection Between Developmental Dynamics of Parenting and Offspring Psychosocial Adjustment.", - "authors": "Oksana Yu Naumova,Sascha Hein,Matthew Suderman,Baptiste Barbot,Maria Lee,Adam Raefski,Pavel V Dobrynin,Pamela J Brown,Moshe Szyf,Suniya S Luthar,Elena L Grigorenko", - "abstract": "This study attempted to establish and quantify the connections between parenting, offspring psychosocial adjustment, and the epigenome. The participants, 35 African American young adults (19 females and 16 males; age = 17-29.5 years), represented a subsample of a 3-wave longitudinal 15-year study on the developmental trajectories of low-income urban mother-offspring dyads. Mothers were assessed on their perceptions of maternal stress at each wave. Offspring were assessed on their perceptions of maternal parenting at each wave and on their adaptive and maladaptive behavior at the last wave. Genome-wide DNA methylation in peripheral T lymphocytes at the third wave was assayed using Methyl Binding Domain(MBD) sequencing. Statistically significant associations were identified between the change in offspring's perception of parenting from middle childhood to adulthood and the DNA methylation in offspring's adult genomes. Specifically, the slope of perceived parental rejection across the 3 time points was related to an increase in methylation, or a potential downregulation, of 565 genes thought to be involved in the control of a broad spectrum of biological functions generally related to cellular signaling. A subset of these epigenetic marks, clustered in 23 genes, some of which participate in the development and functioning of the CNS, were in turn associated with psychosocial adjustment as captured by interpersonal relationships and emotional self-evaluation. This appears to be one of the first investigations of the modulating role of the methylome in associations between developmental dynamics of parenting throughout the formative years of child and adolescent development and psychosocial adjustment in adulthood.", - "journal_title": "Child development", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/26822446/" - } - ], - "70179190-ca31-4859-a181-34641564de59": [ - { - "pub_id": "25862617", - "title": "Genome-wide search followed by replication reveals genetic interaction of CD80 and ALOX5AP associated with systemic lupus erythematosus in Asian populations.", - "authors": "Yan Zhang,Jing Yang,Jing Zhang,Liangdan Sun,Nattiya Hirankarn,Hai-Feng Pan,Chak Sing Lau,Tak Mao Chan,Tsz Leung Lee,Alexander Moon Ho Leung,Chi Chiu Mok,Lu Zhang,Yongfei Wang,Jiangshan Jane Shen,Sik Nin Wong,Ka Wing Lee,Marco Hok Kung Ho,Pamela Pui Wah Lee,Brian Hon-Yin Chung,Chun Yin Chong,Raymond Woon Sing Wong,Mo Yin Mok,Wilfred Hing Sang Wong,Kwok Lung Tong,Niko Kei Chiu Tse,Xiang-Pei Li,Yingyos Avihingsanon,Pornpimol Rianthavorn,Thavatchai Deekajorndej,Kanya Suphapeetiporn,Vorasuk Shotelersuk,Shirley King Yee Ying,Samuel Ka Shun Fung,Wai Ming Lai,Chun-Ming Wong,Irene Oi Lin Ng,Maria-Merce Garcia-Barcelo,Stacey S Cherny,Yong Cui,Pak Chung Sham,Sen Yang,Dong-Qing Ye,Xue-Jun Zhang,Yu Lung Lau,Wanling Yang", - "abstract": "Genetic interaction has been considered as a hallmark of the genetic architecture of systemic lupus erythematosus (SLE). Based on two independent genome-wide association studies (GWAS) on Chinese populations, we performed a genome-wide search for genetic interactions contributing to SLE susceptibility. The study involved a total of 1\u2005659 cases and 3\u2005398 controls in the discovery stage and 2\u2005612 cases and 3\u2005441 controls in three cohorts for replication. Logistic regression and multifactor dimensionality reduction were used to search for genetic interaction. Interaction of CD80 (rs2222631) and ALOX5AP (rs12876893) was found to be significantly associated with SLE (OR_int=1.16, P_int_all=7.7E-04 at false discovery rate<0.05). Single nuclear polymorphism rs2222631 was found associated with SLE with genome-wide significance (P_all=4.5E-08, OR=0.86) and is independent of rs6804441 in CD80, whose association was reported previously. Significant correlation was observed between expression of these two genes in healthy controls and SLE cases, together with differential expression of these genes between cases and controls, observed from individuals from the Hong Kong cohort. Genetic interactions between BLK (rs13277113) and DDX6 (rs4639966), and between TNFSF4 (rs844648) and PXK (rs6445975) were also observed in both GWAS data sets. Our study represents the first genome-wide evaluation of epistasis interactions on SLE and the findings suggest interactions and independent variants may help partially explain missing heritability for complex diseases.", - "journal_title": "Annals of the rheumatic diseases", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/25862617/" - } - ], - "3f15bf2e-985a-44fa-808c-b4432930a820": [ - { - "pub_id": "24388149", - "title": "SIRT1 and other sirtuins in metabolism.", - "authors": "Hung-Chun Chang,Leonard Guarente", - "abstract": "Sirtuins such as SIRT1 are conserved protein NAD(+)-dependent deacylases and thus their function is intrinsically linked to cellular metabolism. Over the past two decades, accumulating evidence has indicated that sirtuins are not only important energy status sensors but also protect cells against metabolic stresses. Sirtuins regulate the aging process and are themselves regulated by diet and environmental stress. The versatile functions of sirtuins including, more specifically, SIRT1 are supported by their diverse cellular location allowing cells to sense changes in energy levels in the nucleus, cytoplasm, and mitochondrion. SIRT1 plays a critical role in metabolic health by deacetylating many target proteins in numerous tissues, including liver, muscle, adipose tissue, heart, and endothelium. This sirtuin also exerts important systemic effects via the hypothalamus. This review will cover these topics and suggest that strategies to maintain sirtuin activity may be on the horizon to forestall diseases of aging.", - "journal_title": "Trends in endocrinology and metabolism: TEM", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/24388149/" - } - ], - "88bf3e0f-3251-4f63-99d3-32944b522a16": [ - { - "pub_id": "25705179", - "title": "Screening and personalizing nootropic drugs and cognitive modulator regimens in silico.", - "authors": "Leslie C Jellen,Alexander Aliper,Anton Buzdin,Alex Zhavoronkov", - "abstract": "The go-to cognitive enhancers of today are those that are widely available rather than optimal for the user, including drugs typically prescribed for treatment of ADHD (e.g., methylphenidate) and sleep disturbances such as narcolepsy (modafinil). While highly effective in their intended therapeutic role, performance gains in healthy populations are modest at best and profoundly inconsistent across subgroups and individuals. We propose a method for in silico screening of possible novel cognitive enhancers followed by high-throughput in vivo and in vitro validation. The proposed method uses gene expression data to evaluate the the collection of activated or suppressed signaling pathways in tissues or neurons of the cognitively enhanced brain. An algorithm maps expression data onto signaling pathways and quantifies their individual activation strength. The collective pathways and their activation form what we term the signaling pathway cloud, a biological fingerprint of cognitive enhancement (or any other condition of interest). Drugs can then be screened and ranked based on their ability to minimize, mimic, or exaggerate pathway activation or suppression within that cloud. Using this approach, one may predict the efficacy of many drugs that may enhance various aspects of cognition before costly preclinical studies and clinical trials are undertaken.", - "journal_title": "Frontiers in systems neuroscience", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/25705179/" - } - ], - "6d850ba3-9219-4250-b17f-7cf4867ca354": [ - { - "pub_id": "22461179", - "title": "Systems genetic analysis of multivariate response to iron deficiency in mice.", - "authors": "Lina Yin,Erica L Unger,Leslie C Jellen,Christopher J Earley,Richard P Allen,Ann Tomaszewicz,James C Fleet,Byron C Jones", - "abstract": "The aim of this study was to identify genes that influence iron regulation under varying dietary iron availability. Male and female mice from 20+ BXD recombinant inbred strains were fed iron-poor or iron-adequate diets from weaning until 4 mo of age. At death, the spleen, liver, and blood were harvested for the measurement of hemoglobin, hematocrit, total iron binding capacity, transferrin saturation, and liver, spleen and plasma iron concentration. For each measure and diet, we found large, strain-related variability. A principal-components analysis (PCA) was performed on the strain means for the seven parameters under each dietary condition for each sex, followed by quantitative trait loci (QTL) analysis on the factors. Compared with the iron-adequate diet, iron deficiency altered the factor structure of the principal components. QTL analysis, combined with PosMed (a candidate gene searching system) published gene expression data and literature citations, identified seven candidate genes, Ptprd, Mdm1, Picalm, lip1, Tcerg1, Skp2, and Frzb based on PCA factor, diet, and sex. Expression of each of these is cis-regulated, significantly correlated with the corresponding PCA factor, and previously reported to regulate iron, directly or indirectly. We propose that polymorphisms in multiple genes underlie individual differences in iron regulation, especially in response to dietary iron challenge. This research shows that iron management is a highly complex trait, influenced by multiple genes. Systems genetics analysis of iron homeostasis holds promise for developing new methods for prevention and treatment of iron deficiency anemia and related diseases.", - "journal_title": "American journal of physiology. Regulatory, integrative and comparative physiology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/22461179/" - } - ], - "fc80e801-d9d7-4193-bbb8-6620883a85c4": [ - { - "pub_id": "27577878", - "title": "Primary immunodeficiency diseases: Genomic approaches delineate heterogeneous Mendelian disorders.", - "authors": "Asbj\u00f8rg Stray-Pedersen,Hanne S\u00f8rmo Sorte,Pubudu Samarakoon,Tomasz Gambin,Ivan K Chinn,Zeynep H Coban Akdemir,Hans Christian Erichsen,Lisa R Forbes,Shen Gu,Bo Yuan,Shalini N Jhangiani,Donna M Muzny,Olaug Kristin R\u00f8dningen,Ying Sheng,Sarah K Nicholas,Lenora M Noroski,Filiz O Seeborg,Carla M Davis,Debra L Canter,Emily M Mace,Timothy J Vece,Carl E Allen,Harshal A Abhyankar,Philip M Boone,Christine R Beck,Wojciech Wiszniewski,B\u00f8rre Fevang,P\u00e5l Aukrust,Geir E Tj\u00f8nnfjord,Tobias Gedde-Dahl,Henrik Hjorth-Hansen,Ingunn Dybedal,Ingvild Nord\u00f8y,Silje F J\u00f8rgensen,Tore G Abrahamsen,Torstein \u00d8verland,Anne Grete Bechensteen,Vegard Skogen,Liv T N Osnes,Mari Ann Kulseth,Trine E Prescott,Cecilie F Rustad,Ketil R Heimdal,John W Belmont,Nicholas L Rider,Javier Chinen,Tram N Cao,Eric A Smith,Maria Soledad Caldirola,Liliana Bezrodnik,Saul Oswaldo Lugo Reyes,Francisco J Espinosa Rosales,Nina Denisse Guerrero-Cursaru,Luis Alberto Pedroza,Cecilia M Poli,Jose L Franco,Claudia M Trujillo Vargas,Juan Carlos Aldave Becerra,Nicola Wright,Thomas B Issekutz,Andrew C Issekutz,Jordan Abbott,Jason W Caldwell,Diana K Bayer,Alice Y Chan,Alessandro Aiuti,Caterina Cancrini,Eva Holmberg,Christina West,Magnus Burstedt,Ender Karaca,G\u00f6zde Yesil,Hasibe Artac,Yavuz Bayram,Mehmed Musa Atik,Mohammad K Eldomery,Mohammad S Ehlayel,Stephen Jolles,Berit Flat\u00f8,Alison A Bertuch,I Celine Hanson,Victor W Zhang,Lee-Jun Wong,Jianhong Hu,Magdalena Walkiewicz,Yaping Yang,Christine M Eng,Eric Boerwinkle,Richard A Gibbs,William T Shearer,Robert Lyle,Jordan S Orange,James R Lupski", - "abstract": "Primary immunodeficiency diseases (PIDDs) are clinically and genetically heterogeneous disorders thus far associated with mutations in more than 300 genes. The clinical phenotypes derived from distinct genotypes can overlap. Genetic etiology can be a prognostic indicator of disease severity and can influence treatment decisions. We sought to investigate the ability of whole-exome screening methods to detect disease-causing variants in patients with PIDDs. Patients with PIDDs from 278 families from 22 countries were investigated by using whole-exome sequencing. Computational copy number variant (CNV) prediction pipelines and an exome-tiling chromosomal microarray were also applied to identify intragenic CNVs. Analytic approaches initially focused on 475 known or candidate PIDD genes but were nonexclusive and further tailored based on clinical data, family history, and immunophenotyping. A likely molecular diagnosis was achieved in 110 (40%) unrelated probands. Clinical diagnosis was revised in about half (60/110) and management was directly altered in nearly a quarter (26/110) of families based on molecular findings. Twelve PIDD-causing CNVs were detected, including 7 smaller than 30\u00a0Kb that would not have been detected with conventional diagnostic CNV arrays. This high-throughput genomic approach enabled detection of disease-related variants in unexpected genes; permitted detection of low-grade constitutional, somatic, and revertant mosaicism; and provided evidence of a mutational burden in mixed PIDD immunophenotypes.", - "journal_title": "The Journal of allergy and clinical immunology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/27577878/" - } - ], - "1219788a-2944-4948-a06a-f8e0297e3c3b": [ - { - "pub_id": "24586654", - "title": "Systems genetics of liver fibrosis: identification of fibrogenic and expression quantitative trait loci in the BXD murine reference population.", - "authors": "Rabea A Hall,Roman Liebe,Katrin Hochrath,Andrey Kazakov,Rudi Alberts,Ulrich Laufs,Michael B\u00f6hm,Hans-Peter Fischer,Robert W Williams,Klaus Schughart,Susanne N Weber,Frank Lammert", - "abstract": "The progression of liver fibrosis in response to chronic injury varies considerably among individual patients. The underlying genetics is highly complex due to large numbers of potential genes, environmental factors and cell types involved. Here, we provide the first toxicogenomic analysis of liver fibrosis induced by carbon tetrachloride in the murine 'genetic reference panel' of recombinant inbred BXD lines. Our aim was to define the core of risk genes and gene interaction networks that control fibrosis progression. Liver fibrosis phenotypes and gene expression profiles were determined in 35 BXD lines. Quantitative trait locus (QTL) analysis identified seven genomic loci influencing fibrosis phenotypes (pQTLs) with genome-wide significance on chromosomes 4, 5, 7, 12, and 17. Stepwise refinement was based on expression QTL mapping with stringent selection criteria, reducing the number of 1,351 candidate genes located in the pQTLs to a final list of 11 cis-regulated genes. Our findings demonstrate that the BXD reference population represents a powerful experimental resource for shortlisting the genes within a regulatory network that determine the liver's vulnerability to chronic injury.", - "journal_title": "PloS one", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/24586654/" - } - ], - "45ccb967-3a5e-4274-9009-e4fda677bba0": [ - { - "pub_id": "23943854", - "title": "Systems genetics of hepatocellular damage in vivo and in vitro: identification of a critical network on chromosome 11 in mouse.", - "authors": "Roman Liebe,Rabea A Hall,Robert W Williams,Steven Dooley,Frank Lammert", - "abstract": "Quantitative trait locus (QTL) mapping is a powerful method to find modifier loci that influence disease risk and progression without prior knowledge of underlying genetic mechanisms. The aim of this study is to identify gene loci that contribute to individual differences in liver fibrosis following chronic liver damage. For this purpose, we carried out a mapping study across a panel of 21 BXD recombinant inbred strains using primary hepatocytes challenged with transforming growth factor (TGF)-\u03b2 for 48 h. We identified a 6 Mb interval on chromosome 11 that is a major modifier of TGF-\u03b2-induced hepatocyte injury. Corresponding in vivo genetic analysis of fibrosis after chronic hepatotoxic injury by carbon tetrachloride (CCl4 ip for 6 wk) highlighted the same locus. Expression QTL (eQTL) analysis in liver tissues in the BXD family identified six polymorphisms in this region that are associated with strong cis eQTLs and that correlate well with gene expression in liver after both 6 wk CCl4 treatment and acute ethanol damage of the liver. Within this interval we rank two genes containing coding sequence variants as strong candidates that may modulate the severity of liver fibrosis: 1) the extracellular proteinase inhibitor gene Expi (also known as Wdnm1 or Wfdc18) and 2) musashi RNA-binding protein 2 (Msi2). The powerful combination of experimental, genetics, and bioinformatics methods, as well as combined in vitro and in vivo approaches can be used to define QTLs, genes, and even candidate sequence variants linked to hepatotoxicity and fibrosis.", - "journal_title": "Physiological genomics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/23943854/" - } - ], - "28f42f39-c6a4-440b-b43a-017f622db6da": [ - { - "pub_id": "24338393", - "title": "Critical evaluation of transcription factor Atf2 as a candidate modulator of alcohol preference in mouse and human populations.", - "authors": "L S Wang,Y Jiao,Y Huang,X Y Liu,G Gibson,B Bennett,K M Hamre,D W Li,H Y Zhao,J Gelernter,H R Kranzler,L A Farrer,L Lu,Y J Wang,W K Gu", - "abstract": "In prior work, congenic strains carrying the DBA/2Igb (D2) region of chromosome 2 (Chr2) for alcohol preference were bred onto a C57BL/6Ibg (B6) background and as predicted were found to reduce voluntary consumption. Subsequently, interval-specific congenic recombinant strains (ISCRS) were generated and also tested. These ISCRS strains reduced the quantitative trait loci (QTL) interval to a comparatively small 3.4 Mb region. Here, we have exploited an integrative approach using both murine and human populations to critically evaluate candidate genes within this region. First, we used bioinformatics tools to search for genes relevant to alcohol preference within the QTL region. Second, we searched for single nucleotide polymorphisms (SNPs) within exons of every gene in this region. Third, we conducted follow-up microarray analyses to identify differentially expressed genes between the B6 and ISCRS strains in mice from each group. Fourth, we analyzed correlations between the expression level of candidate genes and phenotypes of alcohol preference in a large family of BXD recombinant inbred strains derived from B6 and D2. Finally, we evaluated SNP segregation in both BXD mouse strains and in humans who were heavy alcohol drinkers or non-drinkers. Among several potential candidate genes in this region, we identified activating transcription factor 2 (Atf2) as the most plausible gene that would influence alcohol preference. However, the candidacy of Atf2 was only weakly supported when we used a genetic network approach and by focused reanalysis of genome-wide association study data from European-American and African-American populations. Thus, we cannot conclude that Atf2 plays a role in the regulation of the QTL of mouse Chr2.", - "journal_title": "Genetics and molecular research : GMR", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/24338393/" - } - ], - "1e363501-86fc-451e-88df-9a76dfecaedf": [ - { - "pub_id": "22737048", - "title": "Therapeutic siRNA: principles, challenges, and strategies.", - "authors": "Kseniya Gavrilov,W Mark Saltzman", - "abstract": "RNA interference (RNAi) is a remarkable endogenous regulatory pathway that can bring about sequence-specific gene silencing. If harnessed effectively, RNAi could result in a potent targeted therapeutic modality with applications ranging from viral diseases to cancer. The major barrier to realizing the full medicinal potential of RNAi is the difficulty of delivering effector molecules, such as small interfering RNAs (siRNAs), in vivo. An effective delivery strategy for siRNAs must address limitations that include poor stability and non-targeted biodistribution, while protecting against the stimulation of an undesirable innate immune response. The design of such a system requires rigorous understanding of all mechanisms involved. This article reviews the mechanistic principles of RNA interference, its potential, the greatest challenges for use in biomedical applications, and some of the work that has been done toward engineering delivery systems that overcome some of the hurdles facing siRNA-based therapeutics.", - "journal_title": "The Yale journal of biology and medicine", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/22737048/" - } - ], - "e8191a94-dd17-4c40-8afd-c9b7fb7266c9": [ - { - "pub_id": "22942082", - "title": "Genomic dissection and prioritizing of candidate genes of QTL for regulating spontaneous arthritis on chromosome 1 in mice deficient for interleukin-1 receptor antagonist.", - "authors": "Yanhong Cao,Jifei Zhang,Yan Jiao,Jian Yan,Feng Jiao,Xiaoyun Liu,Robert W Williams,Karen A Hasty,John M Stuart,Weikuan Gu", - "abstract": "Rheumatoid arthritis is a heterogeneous disease with clinical and biological polymorphisms. IL-1RN is a protein that binds to interleukin-1 (IL-1) receptors and inhibits the binding of IL-1-alpha and IL-1-beta. IL-1RN levels are elevated in the blood of patients with a variety of infectious, immune, and traumatic conditions. Balb/c mice deficient in IL-1ra (mouse gene of IL-1RN) develop spontaneous autoimmune arthritis while DBA/1 mice deficient in IL-1ra do not. Previously, we identified a major QTL that regulates the susceptibility to arthritis in Balb/c mice with IL-1ra deficiency. In this study, we found that the QTL may contain two peaks that are regulated by two sets of candidate genes. By haplotype analysis, the total genomic regions of candidate genes were reduced from about 19 Mbp to approximately 9 Mbp. The total number of candidate genes was reduced from 208 to 21.", - "journal_title": "Journal of genetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/22942082/" - } - ], - "98dfe1c7-3be6-427d-bf8f-749460667d4c": [ - { - "pub_id": "25414627", - "title": "Neuroinformatic analyses of common and distinct genetic components associated with major neuropsychiatric disorders.", - "authors": "Amit Lotan,Michaela Fenckova,Janita Bralten,Aet Alttoa,Luanna Dixson,Robert W Williams,Monique van der Voet", - "abstract": "Major neuropsychiatric disorders are highly heritable, with mounting evidence suggesting that these disorders share overlapping sets of molecular and cellular underpinnings. In the current article we systematically test the degree of genetic commonality across six major neuropsychiatric disorders-attention deficit hyperactivity disorder (ADHD), anxiety disorders (Anx), autistic spectrum disorders (ASD), bipolar disorder (BD), major depressive disorder (MDD), and schizophrenia (SCZ). We curated a well-vetted list of genes based on large-scale human genetic studies based on the NHGRI catalog of published genome-wide association studies (GWAS). A total of 180 genes were accepted into the analysis on the basis of low but liberal GWAS p-values (<10(-5)). 22% of genes overlapped two or more disorders. The most widely shared subset of genes-common to five of six disorders-included ANK3, AS3MT, CACNA1C, CACNB2, CNNM2, CSMD1, DPCR1, ITIH3, NT5C2, PPP1R11, SYNE1, TCF4, TENM4, TRIM26, and ZNRD1. Using a suite of neuroinformatic resources, we showed that many of the shared genes are implicated in the postsynaptic density (PSD), expressed in immune tissues and co-expressed in developing human brain. Using a translational cross-species approach, we detected two distinct genetic components that were both shared by each of the six disorders; the 1st component is involved in CNS development, neural projections and synaptic transmission, while the 2nd is implicated in various cytoplasmic organelles and cellular processes. Combined, these genetic components account for 20-30% of the genetic load. The remaining risk is conferred by distinct, disorder-specific variants. Our systematic comparative analysis of shared and unique genetic factors highlights key gene sets and molecular processes that may ultimately translate into improved diagnosis and treatment of these debilitating disorders.", - "journal_title": "Frontiers in neuroscience", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/25414627/" - } - ], - "0760894c-d8de-4b3b-93fc-db0bb6d6ef8c": [ - { - "pub_id": "25255223", - "title": "An evolutionarily conserved role for the aryl hydrocarbon receptor in the regulation of movement.", - "authors": "Evan G Williams,Laurent Mouchiroud,Michael Frochaux,Ashutosh Pandey,P\u00e9n\u00e9lope A Andreux,Bart Deplancke,Johan Auwerx", - "abstract": "The BXD genetic reference population is a recombinant inbred panel descended from crosses between the C57BL/6 (B6) and DBA/2 (D2) strains of mice, which segregate for about 5 million sequence variants. Recently, some of these variants have been established with effects on general metabolic phenotypes such as glucose response and bone strength. Here we phenotype 43 BXD strains and observe they have large variation (-5-fold) in their spontaneous activity during waking hours. QTL analyses indicate that -40% of this variance is attributable to a narrow locus containing the aryl hydrocarbon receptor (Ahr), a basic helix-loop-helix transcription factor with well-established roles in development and xenobiotic metabolism. Strains with the D2 allele of Ahr have reduced gene expression compared to those with the B6 allele, and have significantly higher spontaneous activity. This effect was also observed in B6 mice with a congenic D2 Ahr interval, and in B6 mice with a humanized AHR allele which, like the D2 allele, is expressed much less and has less enzymatic activity than the B6 allele. Ahr is highly conserved in invertebrates, and strikingly inhibition of its orthologs in D. melanogaster and C. elegans (spineless and ahr-1) leads to marked increases in basal activity. In mammals, Ahr has numerous ligands, but most are either non-selective (e.g. resveratrol) or highly toxic (e.g., 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)). Thus, we chose to examine a major environmental influence--long term feeding with high fat diet (HFD)--to see if the effects of Ahr are dependent on major metabolic differences. Interestingly, while HFD robustly halved movement across all strains, the QTL position and effects of Ahr remained unchanged, indicating that the effects are independent. The highly consistent effects of Ahr on movement indicate that changes in its constitutive activity have a role on spontaneous movement and may influence human behavior.", - "journal_title": "PLoS genetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/25255223/" - } - ], - "2278b390-3cf6-4082-a956-7b06b6cc1286": [ - { - "pub_id": "25590037", - "title": "Identification of Srp9 as a febrile seizure susceptibility gene.", - "authors": "Ellen V S Hessel,Marina de Wit,Inge G Wolterink-Donselaar,Henk Karst,Esther de Graaff,Hein A van Lith,Ewart de Bruijn,Sophietje de Sonnaville,Nienke E Verbeek,Dick Lindhout,Carolien G F de Kovel,Bobby P C Koeleman,Marjan van Kempen,Eva Brilstra,Edwin Cuppen,Maarten Loos,Sabine S Spijker,Anne A Kan,Susanne E Baars,Peter C van Rijen,Peter H Gosselaar,Marian J A Groot Koerkamp,Frank C P Holstege,Cornelia van Duijn,Jeanette Vergeer,Henriette A Moll,Erik Taub\u00f8ll,Kjell Heuser,Geert M J Ramakers,R Jeroen Pasterkamp,Onno van Nieuwenhuizen,Casper C Hoogenraad,Martien J H Kas,Pierre N E de Graan", - "abstract": "Febrile seizures (FS) are the most common seizure type in young children. Complex FS are a risk factor for mesial temporal lobe epilepsy (mTLE). To identify new FS susceptibility genes we used a forward genetic strategy in mice and subsequently analyzed candidate genes in humans. We mapped a quantitative trait locus (QTL1) for hyperthermia-induced FS on mouse chromosome 1, containing the signal recognition particle 9 (Srp9) gene. Effects of differential Srp9 expression were assessed in vivo and in vitro. Hippocampal SRP9 expression and genetic association were analyzed in FS and mTLE patients. Srp9 was differentially expressed between parental strains C57BL/6J and A/J. Chromosome substitution strain 1 (CSS1) mice exhibited lower FS susceptibility and Srp9 expression than C57BL/6J mice. In vivo knockdown of brain Srp9 reduced FS susceptibility. Mice with reduced Srp9 expression and FS susceptibility, exhibited reduced hippocampal AMPA and NMDA currents. Downregulation of neuronal Srp9 reduced surface expression of AMPA receptor subunit GluA1. mTLE patients with antecedent FS had higher SRP9 expression than patients without. SRP9 promoter SNP rs12403575(G/A) was genetically associated with FS and mTLE. Our findings identify SRP9 as a novel FS susceptibility gene and indicate that SRP9 conveys its effects through endoplasmic reticulum (ER)-dependent synthesis and trafficking of membrane proteins, such as glutamate receptors. Discovery of this new FS gene and mechanism may provide new leads for early diagnosis and treatment of children with complex FS at risk for mTLE.", - "journal_title": "Annals of clinical and translational neurology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/25590037/" - } - ], - "4de669b7-da76-42ef-a88a-afebf1e86734": [ - { - "pub_id": "22422471", - "title": "Accelerating discovery for complex neurological and behavioral disorders through systems genetics and integrative genomics in the laboratory mouse.", - "authors": "Jason A Bubier,Elissa J Chesler", - "abstract": "Recent advances in systems genetics and integrative functional genomics have greatly improved the study of complex neurological and behavioral traits. The methods developed for the integrated characterization of new, high-resolution mouse genetic reference populations and systems genetics enable behavioral geneticists an unprecedented opportunity to address questions of the molecular basis of neurological and psychiatric disorders and their comorbidities. Integrative genomics augment these strategies by enabling rapid informatics-assisted candidate gene prioritization, cross-species translation, and mechanistic comparison across related disorders from a wealth of existing data in mouse and other model organisms. Ultimately, through these complementary approaches, finding the mechanisms and sources of genetic variation underlying complex neurobehavioral disease related traits is becoming tractable. Furthermore, these methods enable categorization of neurobehavioral disorders through their underlying biological basis. Together, these model organism-based approaches can lead to a refinement of diagnostic categories and targeted treatment of neurological and psychiatric disease.", - "journal_title": "Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/22422471/" - } - ], - "6ee86c77-b359-45f1-bd54-b1cd9b260ae6": [ - { - "pub_id": "23698443", - "title": "Mitonuclear protein imbalance as a conserved longevity mechanism.", - "authors": "Riekelt H Houtkooper,Laurent Mouchiroud,Dongryeol Ryu,Norman Moullan,Elena Katsyuba,Graham Knott,Robert W Williams,Johan Auwerx", - "abstract": "Longevity is regulated by a network of closely linked metabolic systems. We used a combination of mouse population genetics and RNA interference in Caenorhabditis elegans to identify mitochondrial ribosomal protein S5 (Mrps5) and other mitochondrial ribosomal proteins as metabolic and longevity regulators. MRP knockdown triggers mitonuclear protein imbalance, reducing mitochondrial respiration and activating the mitochondrial unfolded protein response. Specific antibiotics targeting mitochondrial translation and ethidium bromide (which impairs mitochondrial DNA transcription) pharmacologically mimic mrp knockdown and extend worm lifespan by inducing mitonuclear protein imbalance, a stoichiometric imbalance between nuclear and mitochondrially encoded proteins. This mechanism was also conserved in mammalian cells. In addition, resveratrol and rapamycin, longevity compounds acting on different molecular targets, similarly induced mitonuclear protein imbalance, the mitochondrial unfolded protein response and lifespan extension in C. elegans. Collectively these data demonstrate that MRPs represent an evolutionarily conserved protein family that ties the mitochondrial ribosome and mitonuclear protein imbalance to the mitochondrial unfolded protein response, an overarching longevity pathway across many species.", - "journal_title": "Nature", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/23698443/" - } - ], - "8604652e-2477-4552-8f43-f5f19e421df2": [ - { - "pub_id": "26151842", - "title": "Differences between Mice and Humans in Regulation and the Molecular Network of Collagen, Type III, Alpha-1 at the Gene Expression Level: Obstacles that Translational Research Must Overcome.", - "authors": "Lishi Wang,Hongchao Liu,Yan Jiao,Erjian Wang,Stephen H Clark,Arnold E Postlethwaite,Weikuan Gu,Hong Chen", - "abstract": "Collagen, type III, alpha-1 (COL3A1) is essential for normal collagen I fibrillogenesis in many organs. There are differences in phenotypes of mutations in the COL3A1 gene in humans and mutations in mice. In order to investigate whether the regulation and gene network of COL3A1 is the same in healthy populations of mice and humans, we compared the quantitative trait loci (QTL) that regulate the expression level of COL3A1 and the gene network of COL3A1 pathways between humans and mice using whole genome expression profiles. Our results showed that, for the regulation of expression of Col3a1 in mice, an eQTL on chromosome (Chr) 12 regulates the expression of Col3a1. However, expression of genes in the syntenic region on human Chr 7 has no association with the expression level of COL3A1. For the gene network comparison, we identified 44 top genes whose expression levels are strongly associated with that of Col3a1 in mice. We next identified 41 genes strongly associated with the expression level of COL3A1 in humans. There are a few but significant differences in the COL3A1 gene network between humans and mice. Several genes showed opposite association with expression of COL3A1. These genes are known to play important roles in development and function of the extracellular matrix of the lung. Difference in the molecular pathway of key genes in the COL3A1 gene network in humans and mice suggest caution should be used in extrapolating results from models of human lung diseases in mice to clinical lung diseases in humans. These differences may influence the efficacy of drugs in humans whose development employed mouse models.", - "journal_title": "International journal of molecular sciences", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/26151842/" - } - ], - "8aadf051-0956-4a48-aefe-9bcd458afdbb": [ - { - "pub_id": "22434064", - "title": "Overexpression of insulin like growth factor binding protein 5 reduces liver fibrosis in chronic cholangiopathy.", - "authors": "Aleksandar Sokolovi\u0107,Paula S Montenegro-Miranda,Dirk Rudi de Waart,Radha M N Cappai,Suzanne Duijst,Milka Sokolovi\u0107,Piter J Bosma", - "abstract": "The ATP-binding cassette, sub-family B member 4 knock-out mouse (Abcb4(-/-)) is a relevant model for chronic cholangiopathy in man. Due to the lack of this P-glycoprotein in the canalicular membrane of hepatocytes, the secretion of phospholipids into bile is absent, resulting in increased bile toxicity. Expression of insulin like growth factor binding protein 5 (Igfbp5) increases in time in the livers of these mice. It is unclear whether this induction is a consequence of or plays a role in the progression of liver pathology. The aim of this study was therefore to investigate the effect of IGFBP5 induction on the progression of liver fibrosis caused by chronic cholangiopathy. IGFBP5 and, as a control, green fluorescent protein were overexpressed in the hepatocytes of Abcb4(-/-) mice, using an adeno-associated viral vector (AAV). Progression of liver fibrosis was studied 3, 6, and 12 weeks after vector injection by analyzing serum parameters, collagen deposition, expression of pro-fibrotic genes, inflammation and oxidative stress. A single administration of the AAV vectors provided prolonged expression of IGFBP5 and GFP in the livers of Abcb4(-/-) mice. Compared to GFP control, fractional liver weight, extracellular matrix deposition and amount of activated hepatic stellate cells significantly decreased in IGFBP5 overexpressing mice even 12 weeks after treatment. This effect was not due to a change in bile composition, but driven by reduced inflammation, oxidative stress, and proliferation. Overexpression of IGFBP5 seems to have a protective effect on liver pathology in this model for chronic cholangiopathy.", - "journal_title": "Biochimica et biophysica acta", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/22434064/" - } - ], - "bb955075-4d64-49b8-97f1-e3d69ee90b45": [ - { - "pub_id": "24927528", - "title": "Pituitary tumor-transforming gene 1 regulates the patterning of retinal mosaics.", - "authors": "Patrick W Keeley,Cuiqi Zhou,Lu Lu,Robert W Williams,Shlomo Melmed,Benjamin E Reese", - "abstract": "Neurons are commonly organized as regular arrays within a structure, and their patterning is achieved by minimizing the proximity between like-type cells, but molecular mechanisms regulating this process have, until recently, been unexplored. We performed a forward genetic screen using recombinant inbred (RI) strains derived from two parental A/J and C57BL/6J mouse strains to identify genomic loci controlling spacing of cholinergic amacrine cells, which is a subclass of retinal interneuron. We found conspicuous variation in mosaic regularity across these strains and mapped a sizeable proportion of that variation to a locus on chromosome 11 that was subsequently validated with a chromosome substitution strain. Using a bioinformatics approach to narrow the list of potential candidate genes, we identified pituitary tumor-transforming gene 1 (Pttg1) as the most promising. Expression of Pttg1 was significantly different between the two parental strains and correlated with mosaic regularity across the RI strains. We identified a seven-nucleotide deletion in the Pttg1 promoter in the C57BL/6J mouse strain and confirmed a direct role for this motif in modulating Pttg1 expression. Analysis of Pttg1 KO mice revealed a reduction in the mosaic regularity of cholinergic amacrine cells, as well as horizontal cells, but not in two other retinal cell types. Together, these results implicate Pttg1 in the regulation of homotypic spacing between specific types of retinal neurons. The genetic variant identified creates a binding motif for the transcriptional activator protein 1 complex, which may be instrumental in driving differential expression of downstream processes that participate in neuronal spacing.", - "journal_title": "Proceedings of the National Academy of Sciences of the United States of America", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/24927528/" - } - ], - "2e0bbb7b-45cd-4208-b2f0-e229df86d8ff": [ - { - "pub_id": "22511924", - "title": "Genetic dissection of acute ethanol responsive gene networks in prefrontal cortex: functional and mechanistic implications.", - "authors": "Aaron R Wolen,Charles A Phillips,Michael A Langston,Alex H Putman,Paul J Vorster,Nathan A Bruce,Timothy P York,Robert W Williams,Michael F Miles", - "abstract": "Individual differences in initial sensitivity to ethanol are strongly related to the heritable risk of alcoholism in humans. To elucidate key molecular networks that modulate ethanol sensitivity we performed the first systems genetics analysis of ethanol-responsive gene expression in brain regions of the mesocorticolimbic reward circuit (prefrontal cortex, nucleus accumbens, and ventral midbrain) across a highly diverse family of 27 isogenic mouse strains (BXD panel) before and after treatment with ethanol. Acute ethanol altered the expression of ~2,750 genes in one or more regions and 400 transcripts were jointly modulated in all three. Ethanol-responsive gene networks were extracted with a powerful graph theoretical method that efficiently summarized ethanol's effects. These networks correlated with acute behavioral responses to ethanol and other drugs of abuse. As predicted, networks were heavily populated by genes controlling synaptic transmission and neuroplasticity. Several of the most densely interconnected network hubs, including Kcnma1 and Gsk3\u03b2, are known to influence behavioral or physiological responses to ethanol, validating our overall approach. Other major hub genes like Grm3, Pten and Nrg3 represent novel targets of ethanol effects. Networks were under strong genetic control by variants that we mapped to a small number of chromosomal loci. Using a novel combination of genetic, bioinformatic and network-based approaches, we identified high priority cis-regulatory candidate genes, including Scn1b, Gria1, Sncb and Nell2. The ethanol-responsive gene networks identified here represent a previously uncharacterized intermediate phenotype between DNA variation and ethanol sensitivity in mice. Networks involved in synaptic transmission were strongly regulated by ethanol and could contribute to behavioral plasticity seen with chronic ethanol. Our novel finding that hub genes and a small number of loci exert major influence over the ethanol response of gene networks could have important implications for future studies regarding the mechanisms and treatment of alcohol use disorders.", - "journal_title": "PloS one", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/22511924/" - } - ], - "ec378fcc-c1a6-46c9-9119-f26d9814e209": [ - { - "pub_id": "36258033", - "title": "Global epidemiology of alcohol-associated cirrhosis and HCC: trends, projections and risk factors.", - "authors": "Daniel Q Huang,Philippe Mathurin,Helena Cortez-Pinto,Rohit Loomba", - "abstract": "Heavy alcohol consumption is a major cause of morbidity and mortality. Globally, alcohol per-capita consumption rose from 5.5\u2009litres in 2005 to 6.4\u2009litres in 2016 and is projected to increase further to 7.6\u2009litres in 2030. In 2019, an estimated 25% of global cirrhosis deaths were associated with alcohol. The global estimated age-standardized death rate (ASDR) of alcohol-associated cirrhosis was 4.5 per 100,000 population, with the highest and lowest ASDR in Africa and the Western Pacific, respectively. The annual incidence of hepatocellular carcinoma (HCC) among patients with alcohol-associated cirrhosis ranged from 0.9% to 5.6%. Alcohol was associated with approximately one-fifth of global HCC-related deaths in 2019. Between 2012 and 2017, the global estimated ASDR for alcohol-associated cirrhosis declined, but the ASDR for alcohol-associated liver cancer increased. Measures are required to curb heavy alcohol consumption to reduce the burden of alcohol-associated cirrhosis and HCC. Degree of alcohol intake, sex, older age, obesity, type 2 diabetes mellitus, gut microbial dysbiosis and genetic variants are key factors in the development of alcohol-associated cirrhosis and HCC. In this Review, we discuss the global epidemiology, projections and risk factors for alcohol-associated cirrhosis and HCC.", - "journal_title": "Nature reviews. Gastroenterology & hepatology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/36258033/" - } - ], - "b19b8482-6999-4274-b194-8a53ce5cb1e5": [ - { - "pub_id": "22359631", - "title": "Treatment- and population-dependent activity patterns of behavioral and expression QTLs.", - "authors": "Jesse D Ziebarth,Melloni N Cook,Xusheng Wang,Robert W Williams,Lu Lu,Yan Cui", - "abstract": "Genetic control of gene expression and higher-order phenotypes is almost invariably dependent on environment and experimental conditions. We use two families of recombinant inbred strains of mice (LXS and BXD) to study treatment- and genotype-dependent control of hippocampal gene expression and behavioral phenotypes. We analyzed responses to all combinations of two experimental perturbations, ethanol and restraint stress, in both families, allowing for comparisons across 8 combinations of treatment and population. We introduce the concept of QTL activity patterns to characterize how associations between genomic loci and traits vary across treatments. We identified several significant behavioral QTLs and many expression QTLs (eQTLs). The behavioral QTLs are highly dependent on treatment and population. We classified eQTLs into three groups: cis-eQTLs (expression variation that maps to within 5 Mb of the cognate gene), syntenic trans-eQTLs (the gene and the QTL are on the same chromosome but not within 5 Mb), and non-syntenic trans-eQTLs (the gene and the QTL are on different chromosomes). We found that most non-syntenic trans-eQTLs were treatment-specific whereas both classes of syntenic eQTLs were more conserved across treatments. We also found there was a correlation between regions along the genome enriched for eQTLs and SNPs that were conserved across the LXS and BXD families. Genes with eQTLs that co-localized with the behavioral QTLs and displayed similar QTL activity patterns were identified as potential candidate genes associated with the phenotypes, yielding identification of novel genes as well as genes that have been previously associated with responses to ethanol.", - "journal_title": "PloS one", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/22359631/" - } - ], - "5f10ca6d-3a51-4401-a808-9a90b432ca16": [ - { - "pub_id": "23223171", - "title": "Measuring behavior of animal models: faults and remedies.", - "authors": "Ehud Fonio,Ilan Golani,Yoav Benjamini", - "abstract": "Widely used behavioral assays need re-evaluation and validation against their intended use. We focus here on measures of chronic anxiety in mouse models and posit that widely used assays such as the open-field test are performed at the wrong time, for inadequate durations and using inappropriate mouse strains. We propose that behavioral assays be screened for usefulness on the basis of their replicability across laboratories.", - "journal_title": "Nature methods", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/23223171/" - } - ], - "28defd12-1ab9-4579-8f30-9f049b6bc3a0": [ - { - "pub_id": "26190982", - "title": "A cross-species genetic analysis identifies candidate genes for mouse anxiety and human bipolar disorder.", - "authors": "David G Ashbrook,Robert W Williams,Lu Lu,Reinmar Hager", - "abstract": "Bipolar disorder (BD) is a significant neuropsychiatric disorder with a lifetime prevalence of ~1%. To identify genetic variants underlying BD genome-wide association studies (GWAS) have been carried out. While many variants of small effect associated with BD have been identified few have yet been confirmed, partly because of the low power of GWAS due to multiple comparisons being made. Complementary mapping studies using murine models have identified genetic variants for behavioral traits linked to BD, often with high power, but these identified regions often contain too many genes for clear identification of candidate genes. In the current study we have aligned human BD GWAS results and mouse linkage studies to help define and evaluate candidate genes linked to BD, seeking to use the power of the mouse mapping with the precision of GWAS. We use quantitative trait mapping for open field test and elevated zero maze data in the largest mammalian model system, the BXD recombinant inbred mouse population, to identify genomic regions associated with these BD-like phenotypes. We then investigate these regions in whole genome data from the Psychiatric Genomics Consortium's bipolar disorder GWAS to identify candidate genes associated with BD. Finally we establish the biological relevance and pathways of these genes in a comprehensive systems genetics analysis. We identify four genes associated with both mouse anxiety and human BD. While TNR is a novel candidate for BD, we can confirm previously suggested associations with CMYA5, MCTP1, and RXRG. A cross-species, systems genetics analysis shows that MCTP1, RXRG, and TNR coexpress with genes linked to psychiatric disorders and identify the striatum as a potential site of action. CMYA5, MCTP1, RXRG, and TNR are associated with mouse anxiety and human BD. We hypothesize that MCTP1, RXRG, and TNR influence intercellular signaling in the striatum.", - "journal_title": "Frontiers in behavioral neuroscience", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/26190982/" - } - ], - "5ff7155e-a6c9-45c4-8e0f-e551dd3ec602": [ - { - "pub_id": "24289814", - "title": "Genetic variation within the Chrna7 gene modulates nicotine reward-like phenotypes in mice.", - "authors": "J L Harenza,P P Muldoon,M De Biasi,M I Damaj,M F Miles", - "abstract": "Mortality from tobacco smoking remains the leading cause of preventable death in the world, yet current cessation therapies are only modestly successful, suggesting new molecular targets are needed. Genetic analysis of gene expression and behavior identified Chrna7 as potentially modulating nicotine place conditioning in the BXD panel of inbred mice. We used gene targeting and pharmacological tools to confirm the role of Chrna7 in nicotine conditioned place preference (CPP). To identify molecular events downstream of Chrna7 that may modulate nicotine preference, we performed microarray analysis of \u03b17 knock-out (KO) and wild-type (WT) nucleus accumbens (NAc) tissue, followed by confirmation with quantitative polymerase chain reaction (PCR) and immunoblotting. In the BXD panel, we found a putative cis expression quantitative trait loci (eQTL) for Chrna7 in NAc that correlated inversely to nicotine CPP. We observed that gain-of-function \u03b17 mice did not display nicotine preference at any dose tested, whereas conversely, \u03b17 KO mice demonstrated nicotine place preference at a dose below that routinely required to produce preference. In B6 mice, the \u03b17 nicotinic acetylcholine receptor (nAChR)-selective agonist, PHA-543613, dose-dependently blocked nicotine CPP, which was restored using the \u03b17 nAChR-selective antagonist, methyllycaconitine citrate (MLA). Our genomic studies implicated a messenger RNA (mRNA) co-expression network regulated by Chrna7 in NAc. Mice lacking Chrna7 demonstrate increased insulin signaling in the NAc, which may modulate nicotine place preference. Our studies provide novel targets for future work on development of more effective therapeutic approaches to counteract the rewarding properties of nicotine for smoking cessation.", - "journal_title": "Genes, brain, and behavior", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/24289814/" - } - ], - "8f6e8785-25fe-44f6-89e6-7972b19a9608": [ - { - "pub_id": "25423485", - "title": "Cerebellar oxidative DNA damage and altered DNA methylation in the BTBR T+tf/J mouse model of autism and similarities with human post mortem cerebellum.", - "authors": "Svitlana Shpyleva,Samuil Ivanovsky,Aline de Conti,Stepan Melnyk,Volodymyr Tryndyak,Frederick A Beland,S Jill James,Igor P Pogribny", - "abstract": "The molecular pathogenesis of autism is complex and involves numerous genomic, epigenomic, proteomic, metabolic, and physiological alterations. Elucidating and understanding the molecular processes underlying the pathogenesis of autism is critical for effective clinical management and prevention of this disorder. The goal of this study is to investigate key molecular alterations postulated to play a role in autism and their role in the pathophysiology of autism. In this study we demonstrate that DNA isolated from the cerebellum of BTBR T+tf/J mice, a relevant mouse model of autism, and from human post-mortem cerebellum of individuals with autism, are both characterized by an increased levels of 8-oxo-7-hydrodeoxyguanosine (8-oxodG), 5-methylcytosine (5mC), and 5-hydroxymethylcytosine (5hmC). The increase in 8-oxodG and 5mC content was associated with a markedly reduced expression of the 8-oxoguanine DNA-glycosylase 1 (Ogg1) and increased expression of de novo DNA methyltransferases 3a and 3b (Dnmt3a and Dnmt3b). Interestingly, a rise in the level of 5hmC occurred without changes in the expression of ten-eleven translocation expression 1 (Tet1) and Tet2 genes, but significantly correlated with the presence of 8-oxodG in DNA. This finding and similar elevation in 8-oxodG in cerebellum of individuals with autism and in the BTBR T+tf/J mouse model warrant future large-scale studies to specifically address the role of OGG1 alterations in pathogenesis of autism.", - "journal_title": "PloS one", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/25423485/" - } - ], - "138d4420-0dba-4bed-bf49-d91ad75f1e23": [ - { - "pub_id": "25644094", - "title": "Gene network of a phosphoglycerate mutase in muscle wasting in mice.", - "authors": "Lishi Wang,Yan Jiao,Shuqiu Sun,Harry W Jarrett,Dianjun Sun,Weikuan Gu", - "abstract": "We previously identified the insertion of an intracisternal A-particle retrotransposons (IAPs) sequence in a gene, 9630033F20Rik, that contains domains involved in glycolysis from a mouse model called lethal wasting (lew). However, because both IAP insertion and the muation of vesicle-associated membrane protein 1 (VAMP1) were discovered from lew, the impact of the IAP insertion and Vamp1 on the lew mouse phenotype needs further investigation. In this study, the effect of the 9630033F20Rik and Vamp1 on glycolysis and muscle-wasting genes in heart, muscle, and brain tissues was further investigated using data of gene expression profiles in these tissues. Our data indicated that the expression levels of 9630033F20Rik and Vamp1 are not associated with each other. While 9630033F20Rik affects the expression of several key genes in pathways of glycolysis and muscle wasting, Vamp1 affects a different set of genes, with fewer numbers. In situ hybridization indicated that the expression of 9630033F20Rik is different in musculoskeletal tissues between the muscle-wasting mouse model and the wild-type model. Our data indicated that 9630033F20Rik may play an important role in muscle wasting and that it has a distinguished characterization of gene network. Our data also suggest that both 9630033F20Rik and Vamp1 play functional roles in muscle development and lead to the muscle-wasting phenotype when they are mutated.", - "journal_title": "Cell biology international", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/25644094/" - } - ], - "cf1f67cf-e0f9-4de9-82d4-100f910d0763": [ - { - "pub_id": "29193773", - "title": "Post-genomic behavioral genetics: From revolution to routine.", - "authors": "D G Ashbrook,M K Mulligan,R W Williams", - "abstract": "What was once expensive and revolutionary-full-genome sequence-is now affordable and routine. Costs will continue to drop, opening up new frontiers in behavioral genetics. This shift in costs from the genome to the phenome is most notable in large clinical studies of behavior and associated diseases in cohorts that exceed hundreds of thousands of subjects. Examples include the Women's Health Initiative (www.whi.org), the Million Veterans Program (www. va.gov/MVP), the 100\u2009000 Genomes Project (genomicsengland.co.uk) and commercial efforts such as those by deCode (www.decode.com) and 23andme (www.23andme.com). The same transition is happening in experimental neuro- and behavioral genetics, and sample sizes of many hundreds of cases are becoming routine (www.genenetwork.org, www.mousephenotyping.org). There are two major consequences of this new affordability of massive omics datasets: (1) it is now far more practical to explore genetic modulation of behavioral differences and the key role of gene-by-environment interactions. Researchers are already doing the hard part-the quantitative analysis of behavior. Adding the omics component can provide powerful links to molecules, cells, circuits and even better treatment. (2) There is an acute need to highlight and train behavioral scientists in how best to exploit new omics approaches. This review addresses this second issue and highlights several new trends and opportunities that will be of interest to experts in animal and human behaviors.", - "journal_title": "Genes, brain, and behavior", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/29193773/" - } - ], - "3e95286d-e2f7-44e9-9178-9c5f44d65abb": [ - { - "pub_id": "26092689", - "title": "A QTL on Chr 5 modifies hearing loss associated with the fascin-2 variant of DBA/2J mice.", - "authors": "Kenneth R Johnson,Chantal M Longo-Guess,Leona H Gagnon", - "abstract": "Inbred mouse strains serve as important models for human presbycusis or age-related hearing loss. We previously mapped a locus (ahl8) contributing to the progressive hearing loss of DBA/2J (D2) mice and later showed that a missense variant of the Fscn2 gene, unique to the D2 inbred strain, was responsible for the ahl8 effect. Although ahl8 can explain much of the hearing loss difference between C57BL/6J (B6) and D2 strain mice, other loci also contribute. Here, we present results of our linkage analyses to map quantitative trait loci (QTLs) that modify the severity of hearing loss associated with the D2 strain Fscn2 (ahl8) allele. We searched for modifier loci by analyzing 31 BXD recombinant inbred (RI) lines fixed for the predisposing D2-derived Fscn2 (ahl8/ahl8) genotype and found a statistically significant linkage association of threshold means with a QTL on Chr 5, which we designated M5ahl8. The highest association (LOD 4.6) was with markers at the 84-90\u00a0Mb position of Chr 5, which could explain about 46\u00a0% of the among-RI strain variation in auditory brainstem response (ABR) threshold means. The semidominant nature of the modifying effect of M5ahl8 on the Fscn2 (ahl8/ahl8) phenotype was demonstrated by analysis of a backcross involving D2 and B6.D2-Chr11D/LusJ strain mice. The Chr 5 map position of M5ahl8 and the D2 origin of its susceptibility allele correspond to Tmc1m4, a previously reported QTL that modifies outer hair cell degeneration in Tmc1 (Bth) mutant mice, suggesting that M5ahl8 and Tmc1m4 may represent the same gene affecting maintenance of stereocilia structure and function during aging.", - "journal_title": "Mammalian genome : official journal of the International Mammalian Genome Society", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/26092689/" - } - ], - "ae202e58-4233-4abe-9231-c17f802e8d61": [ - { - "pub_id": "26510153", - "title": "Transcriptional and Linkage Analyses Identify Loci that Mediate the Differential Macrophage Response to Inflammatory Stimuli and Infection.", - "authors": "Musa A Hassan,Kirk D Jensen,Vincent Butty,Kenneth Hu,Erwan Boedec,Pjotr Prins,Jeroen P J Saeij", - "abstract": "Macrophages display flexible activation states that range between pro-inflammatory (classical activation) and anti-inflammatory (alternative activation). These macrophage polarization states contribute to a variety of organismal phenotypes such as tissue remodeling and susceptibility to infectious and inflammatory diseases. Several macrophage- or immune-related genes have been shown to modulate infectious and inflammatory disease pathogenesis. However, the potential role that differences in macrophage activation phenotypes play in modulating differences in susceptibility to infectious and inflammatory disease is just emerging. We integrated transcriptional profiling and linkage analyses to determine the genetic basis for the differential murine macrophage response to inflammatory stimuli and to infection with the obligate intracellular parasite Toxoplasma gondii. We show that specific transcriptional programs, defined by distinct genomic loci, modulate macrophage activation phenotypes. In addition, we show that the difference between AJ and C57BL/6J macrophages in controlling Toxoplasma growth after stimulation with interferon gamma and tumor necrosis factor alpha mapped to chromosome 3, proximal to the Guanylate binding protein (Gbp) locus that is known to modulate the murine macrophage response to Toxoplasma. Using an shRNA-knockdown strategy, we show that the transcript levels of an RNA helicase, Ddx1, regulates strain differences in the amount of nitric oxide produced by macrophage after stimulation with interferon gamma and tumor necrosis factor. Our results provide a template for discovering candidate genes that modulate macrophage-mediated complex traits.", - "journal_title": "PLoS genetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/26510153/" - } - ], - "86b86235-b7a8-4dfc-be13-d119dc31b377": [ - { - "pub_id": "30420800", - "title": "Born to Cry: A Genetic Dissection of Infant Vocalization.", - "authors": "David George Ashbrook,Snigdha Roy,Brittany G Clifford,Tobias Riede,Maria Luisa Scattoni,Detlef H Heck,Lu Lu,Robert W Williams", - "abstract": "Infant vocalizations are one of the most fundamental and innate forms of behavior throughout avian and mammalian orders. They have a critical role in motivating parental care and contribute significantly to fitness and reproductive success. Dysregulation of these vocalizations has been reported to predict risk of central nervous system pathologies such as hypoxia, meningitis, or autism spectrum disorder. Here, we have used the expanded BXD family of mice, and a diallel cross between DBA/2J and C57BL/6J parental strains, to begin the process of genetically dissecting the numerous facets of infant vocalizations. We calculate heritability, estimate the role of parent-of-origin effects, and identify novel quantitative trait loci (QTLs) that control ultrasonic vocalizations (USVs) on postnatal days 7, 8, and 9; a stage that closely matches human infants at birth. Heritability estimates for the number and frequency of calls are low, suggesting that these traits are under high selective pressure. In contrast, duration and amplitude of calls have higher heritabilities, indicating lower selection, or their importance for kin recognition. We find suggestive evidence that amplitude of infant calls is dependent on the maternal genotype, independent of shared genetic variants. Finally, we identify two loci on Chrs 2 and 14 influencing call frequency, and a third locus on Chr 8 influencing the amplitude of vocalizations. All three loci contain strong candidate genes that merit further analysis. Understanding the genetic control of infant vocalizations is not just important for understanding the evolution of parent-offspring interactions, but also in understanding the earliest innate behaviors, the development of parent-offspring relations, and the early identification of behavioral abnormalities.", - "journal_title": "Frontiers in behavioral neuroscience", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/30420800/" - } - ], - "4a8b34bf-b6c6-4f71-b6f6-b6538001efdb": [ - { - "pub_id": "22506031", - "title": "Complex control of GABA(A) receptor subunit mRNA expression: variation, covariation, and genetic regulation.", - "authors": "Megan K Mulligan,Xusheng Wang,Adrienne L Adler,Khyobeni Mozhui,Lu Lu,Robert W Williams", - "abstract": "GABA type-A receptors are essential for fast inhibitory neurotransmission and are critical in brain function. Surprisingly, expression of receptor subunits is highly variable among individuals, but the cause and impact of this fluctuation remains unknown. We have studied sources of variation for all 19 receptor subunits using massive expression data sets collected across multiple brain regions and platforms in mice and humans. Expression of Gabra1, Gabra2, Gabrb2, Gabrb3, and Gabrg2 is highly variable and heritable among the large cohort of BXD strains derived from crosses of fully sequenced parents--C57BL/6J and DBA/2J. Genetic control of these subunits is complex and highly dependent on tissue and mRNA region. Remarkably, this high variation is generally not linked to phenotypic differences. The single exception is Gabrb3, a locus that is linked to anxiety. We identified upstream genetic loci that influence subunit expression, including three unlinked regions of chromosome 5 that modulate the expression of nine subunits in hippocampus, and that are also associated with multiple phenotypes. Candidate genes within these loci include, Naaa, Nos1, and Zkscan1. We confirmed a high level of coexpression for subunits comprising the major channel--Gabra1, Gabrb2, and Gabrg2--and identified conserved members of this expression network in mice and humans. Gucy1a3, Gucy1b3, and Lis1 are novel and conserved associates of multiple subunits that are involved in inhibitory signaling. Finally, proximal and distal regions of the 3' UTRs of single subunits have remarkably independent expression patterns in both species. However, corresponding regions of different subunits often show congruent genetic control and coexpression (proximal-to-proximal or distal-to-distal), even in the absence of sequence homology. Our findings identify novel sources of variation that modulate subunit expression and highlight the extraordinary capacity of biological networks to buffer 4-100 fold differences in mRNA levels.", - "journal_title": "PloS one", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/22506031/" - } - ], - "0a259da5-fb6d-4fe6-a06d-6e2e9e174184": [ - { - "pub_id": "25963977", - "title": "Genomic regulation of senescence and innate immunity signaling in the retinal pigment epithelium.", - "authors": "Edward Chaum,Christina S Winborn,Sujoy Bhattacharya", - "abstract": "The tumor suppressor p53 is a major regulator of genes important for cell cycle arrest, senescence, apoptosis, and innate immunity, and has recently been implicated in retinal aging. In this study we sought to identify the genetic networks that regulate p53 function in the retina using quantitative trait locus (QTL) analysis. First we examined age-associated changes in the activation and expression levels of p53; known p53 target proteins and markers of innate immune system activation in primary retinal pigment epithelial (RPE) cells that were harvested from young and aged human donors. We observed increased expression of p53, activated caspase-1, CDKN1A, CDKN2A (p16INK4a), TLR4, and IFN\u03b1 in aged primary RPE cell lines. We used the Hamilton Eye Institute (HEI) retinal dataset ( www.genenetwork.org ) to identify genomic loci that modulate expression of genes in the p53 pathway in recombinant inbred BXD mouse strains using a QTL systems biology-based approach. We identified a significant trans-QTL on chromosome 1 (region 172-177 Mb) that regulates the expression of Cdkn1a. Many of the genes in this QTL locus are involved in innate immune responses, including Fc receptors, interferon-inducible family genes, and formin 2. Importantly, we found an age-related increase in FCGR3A and FMN2 and a decrease in IFI16 levels in RPE cultures. There is a complex multigenic innate immunity locus that controls expression of genes in the p53 pathway in the RPE, which may play an important role in modulating age-related changes in the retina.", - "journal_title": "Mammalian genome : official journal of the International Mammalian Genome Society", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/25963977/" - } - ], - "aff0a2a1-516d-4d97-a3a2-350d02652e9e": [ - { - "pub_id": "28292619", - "title": "Obesity and female infertility: potential mediators of obesity's impact.", - "authors": "Darcy E Broughton,Kelle H Moley", - "abstract": "The worldwide upward trend in obesity has been dramatic, now affecting more than 20% of American women of reproductive age. Obesity is associated with many adverse maternal and fetal effects prenatally, but it also exerts a negative influence on female fertility. Obese women are more likely to have ovulatory dysfunction due to dysregulation of the hypothalamic-pituitary-ovarian axis. Women with polycystic ovarian syndrome who are also obese demonstrate a more severe metabolic and reproductive phenotype. Obese women have reduced fecundity even when eumenorrheic and demonstrate poorer outcomes with the use of in\u00a0vitro fertilization. Obesity appears to affect the oocyte and the preimplantation embryo, with disrupted meiotic spindle formation and mitochondrial dynamics. Excess free fatty acids may have a toxic effect in reproductive tissues, leading to cellular damage and a chronic low-grade inflammatory state. Altered levels of adipokines, such as leptin, in the obese state can affect steroidogenesis and directly affect the developing embryo. The endometrium is also susceptible, with evidence of impaired stromal decidualization in obese women. This may explain subfecundity due to impaired receptivity, and may lead to placental abnormalities as manifested by higher rates of miscarriage, stillbirth, and preeclampsia\u00a0in the obese population. Many interventions have been explored to mitigate the effect of obesity on infertility, including weight loss, physical activity, dietary factors, and bariatric surgery. These data are largely mixed, with few high quality studies to guide us. As we improve our understanding of the pathophysiology of obesity in human reproduction we hope to identify novel treatment strategies.", - "journal_title": "Fertility and sterility", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/28292619/" - } - ], - "e7030862-fb3c-48cc-bbd1-e30ac5ed5864": [ - { - "pub_id": "25871848", - "title": "Constraint and divergence of global gene expression in the mammalian embryo.", - "authors": "Noah Spies,Cheryl L Smith,Jesse M Rodriguez,Julie C Baker,Serafim Batzoglou,Arend Sidow", - "abstract": "The effects of genetic variation on gene regulation in the developing mammalian embryo remain largely unexplored. To globally quantify these effects, we crossed two divergent mouse strains and asked how genotype of the mother or of the embryo drives gene expression phenotype genomewide. Embryonic expression of 331 genes depends on the genotype of the mother. Embryonic genotype controls allele-specific expression of 1594 genes and a highly overlapping set of cis-expression quantitative trait loci (eQTL). A marked paucity of trans-eQTL suggests that the widespread expression differences do not propagate through the embryonic gene regulatory network. The cis-eQTL genes exhibit lower-than-average evolutionary conservation and are depleted for developmental regulators, consistent with purifying selection acting on expression phenotype of pattern formation genes. The widespread effect of maternal and embryonic genotype in conjunction with the purifying selection we uncovered suggests that embryogenesis is an important and understudied reservoir of phenotypic variation.", - "journal_title": "eLife", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/25871848/" - } - ], - "7fc7babc-51be-4358-bae4-ca1058c36da7": [ - { - "pub_id": "26862054", - "title": "Netter: re-ranking gene network inference predictions using structural network properties.", - "authors": "Joeri Ruyssinck,Piet Demeester,Tom Dhaene,Yvan Saeys", - "abstract": "Many algorithms have been developed to infer the topology of gene regulatory networks from gene expression data. These methods typically produce a ranking of links between genes with associated confidence scores, after which a certain threshold is chosen to produce the inferred topology. However, the structural properties of the predicted network do not resemble those typical for a gene regulatory network, as most algorithms only take into account connections found in the data and do not include known graph properties in their inference process. This lowers the prediction accuracy of these methods, limiting their usability in practice. We propose a post-processing algorithm which is applicable to any confidence ranking of regulatory interactions obtained from a network inference method which can use, inter alia, graphlets and several graph-invariant properties to re-rank the links into a more accurate prediction. To demonstrate the potential of our approach, we re-rank predictions of six different state-of-the-art algorithms using three simple network properties as optimization criteria and show that Netter can improve the predictions made on both artificially generated data as well as the DREAM4 and DREAM5 benchmarks. Additionally, the DREAM5 E.coli. community prediction inferred from real expression data is further improved. Furthermore, Netter compares favorably to other post-processing algorithms and is not restricted to correlation-like predictions. Lastly, we demonstrate that the performance increase is robust for a wide range of parameter settings. Netter is available at http://bioinformatics.intec.ugent.be. Network inference from high-throughput data is a long-standing challenge. In this work, we present Netter, which can further refine network predictions based on a set of user-defined graph properties. Netter is a flexible system which can be applied in unison with any method producing a ranking from omics data. It can be tailored to specific prior knowledge by expert users but can also be applied in general uses cases. Concluding, we believe that Netter is an interesting second step in the network inference process to further increase the quality of prediction.", - "journal_title": "BMC bioinformatics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/26862054/" - } - ], - "30f22ded-c402-47b8-a92b-85b27ef45bb8": [ - { - "pub_id": "23754949", - "title": "Impact of natural genetic variation on gene expression dynamics.", - "authors": "Marit Ackermann,Weronika Sikora-Wohlfeld,Andreas Beyer", - "abstract": "DNA sequence variation causes changes in gene expression, which in turn has profound effects on cellular states. These variations affect tissue development and may ultimately lead to pathological phenotypes. A genetic locus containing a sequence variation that affects gene expression is called an \"expression quantitative trait locus\" (eQTL). Whereas the impact of cellular context on expression levels in general is well established, a lot less is known about the cell-state specificity of eQTL. Previous studies differed with respect to how \"dynamic eQTL\" were defined. Here, we propose a unified framework distinguishing static, conditional and dynamic eQTL and suggest strategies for mapping these eQTL classes. Further, we introduce a new approach to simultaneously infer eQTL from different cell types. By using murine mRNA expression data from four stages of hematopoiesis and 14 related cellular traits, we demonstrate that static, conditional and dynamic eQTL, although derived from the same expression data, represent functionally distinct types of eQTL. While static eQTL affect generic cellular processes, non-static eQTL are more often involved in hematopoiesis and immune response. Our analysis revealed substantial effects of individual genetic variation on cell type-specific expression regulation. Among a total number of 3,941 eQTL we detected 2,729 static eQTL, 1,187 eQTL were conditionally active in one or several cell types, and 70 eQTL affected expression changes during cell type transitions. We also found evidence for feedback control mechanisms reverting the effect of an eQTL specifically in certain cell types. Loci correlated with hematological traits were enriched for conditional eQTL, thus, demonstrating the importance of conditional eQTL for understanding molecular mechanisms underlying physiological trait variation. The classification proposed here has the potential to streamline and unify future analysis of conditional and dynamic eQTL as well as many other kinds of QTL data.", - "journal_title": "PLoS genetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/23754949/" - } - ], - "adfe9118-5dff-452a-9922-d782957267ea": [ - { - "pub_id": "27894806", - "title": "Genetic divergence in the transcriptional engram of chronic alcohol abuse: A laser-capture RNA-seq study of the mouse mesocorticolimbic system.", - "authors": "Megan K Mulligan,Khyobeni Mozhui,Ashutosh K Pandey,Maren L Smith,Suzhen Gong,Jesse Ingels,Michael F Miles,Marcelo F Lopez,Lu Lu,Robert W Williams", - "abstract": "Genetic factors that influence the transition from initial drinking to dependence remain enigmatic. Recent studies have leveraged chronic intermittent ethanol (CIE) paradigms to measure changes in brain gene expression in a single strain at 0, 8, 72\u00a0h, and even 7 days following CIE. We extend these findings using LCM RNA-seq to profile expression in 11 brain regions in two inbred strains - C57BL/6J (B6) and DBA/2J (D2) - 72\u00a0h following multiple cycles of ethanol self-administration and CIE. Linear models identified differential expression based on treatment, region, strain, or interactions with treatment. Nearly 40% of genes showed a robust effect (FDR\u00a0<\u00a00.01) of region, and hippocampus CA1, cortex, bed nucleus stria terminalis, and nucleus accumbens core had the highest number of differentially expressed genes after treatment. Another 8% of differentially expressed genes demonstrated a robust effect of strain. As expected, based on similar studies in B6, treatment had a much smaller impact on expression; only 72 genes (p\u00a0<\u00a00.01) are modulated by treatment (independent of region or strain). Strikingly, many more genes (415) show a strain-specific and largely opposite response to treatment and are enriched in processes related to RNA metabolism, transcription factor activity, and mitochondrial function. Over 3 times as many changes in gene expression were detected in D2 compared to B6, and weighted gene co-expression network analysis (WGCNA) module comparison identified more modules enriched for treatment effects in D2. Substantial strain differences exist in the temporal pattern of transcriptional neuroadaptation to CIE, and these may drive individual differences in risk of addiction following excessive alcohol consumption.", - "journal_title": "Alcohol (Fayetteville, N.Y.)", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/27894806/" - } - ], - "8c75f4ad-9116-4126-9729-5062aa6bc036": [ - { - "pub_id": "26581503", - "title": "Systems genetics of intravenous cocaine self-administration in the BXD recombinant inbred mouse panel.", - "authors": "Price E Dickson,Mellessa M Miller,Michele A Calton,Jason A Bubier,Melloni N Cook,Daniel Goldowitz,Elissa J Chesler,Guy Mittleman", - "abstract": "Cocaine addiction is a major public health problem with a substantial genetic basis for which the biological mechanisms remain largely unknown. Systems genetics is a powerful method for discovering novel mechanisms underlying complex traits, and intravenous drug self-administration (IVSA) is the gold standard for assessing volitional drug use in preclinical studies. We have integrated these approaches to identify novel genes and networks underlying cocaine use in mice. Mice from 39 BXD strains acquired cocaine IVSA (0.56\u00a0mg/kg/infusion). Mice from 29 BXD strains completed a full dose-response curve (0.032-1.8\u00a0mg/kg/infusion). We identified independent genetic correlations between cocaine IVSA and measures of environmental exploration and cocaine sensitization. We identified genome-wide significant quantitative trait loci (QTL) on chromosomes 7 and 11 associated with shifts in the dose-response curve and on chromosome 16 associated with sessions to acquire cocaine IVSA. Using publicly available gene expression data from the nucleus accumbens, midbrain, and prefrontal cortex of drug-na\u00efve mice, we identified Aplp1 and Cyfip2 as positional candidates underlying the behavioral QTL on chromosomes 7 and 11, respectively. A genome-wide significant trans-eQTL linking Fam53b (a GWAS candidate for human cocaine dependence) on chromosome 7 to the cocaine IVSA behavioral QTL on chromosome 11 was identified in the midbrain; Fam53b and Cyfip2 were co-expressed genome-wide significantly in the midbrain. This finding indicates that cocaine IVSA studies using mice can identify genes involved in human cocaine use. These data provide novel candidate genes underlying cocaine IVSA in mice and suggest mechanisms driving human cocaine use.", - "journal_title": "Psychopharmacology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/26581503/" - } - ], - "13036fc5-c31c-4d21-a5f0-5ddfe11663d2": [ - { - "pub_id": "28757171", - "title": "Genetic determinants of cholangiopathies: Molecular and systems genetics.", - "authors": "Matthias C Reichert,Rabea A Hall,Marcin Krawczyk,Frank Lammert", - "abstract": "Familial cholangiopathies are rare but potentially severe diseases. Their spectrum ranges from fairly benign conditions as, for example, benign recurrent intrahepatic cholestasis to low-phospholipid associated cholelithiasis and progressive familial intrahepatic cholestasis (PFIC). Many cholangiopathies such as primary biliary cholangitis (PBC) or primary sclerosing cholangitis (PSC) affect first the bile ducts (\"ascending pathophysiology\") but others, such as PFIC, start upstream in hepatocytes and cause progressive damage \"descending\" down the biliary tree and leading to end-stage liver disease. In recent years our understanding of cholestatic diseases has improved, since we have been able to pinpoint numerous disease-causing mutations that cause familial cholangiopathies. Accordingly, six PFIC subtypes (PFIC type 1-6) have now been defined. Given the availability of genotyping resources, these findings can be introduced in the diagnostic work-up of patients with peculiar cholestasis. In addition, functional studies have defined the pathophysiological consequences of some of the detected variants. Furthermore, ABCB4 variants do not only cause PFIC type 3 but confer an increased risk for chronic liver disease in general. In the near future these findings will serve to develop new therapeutic strategies for patients with liver diseases. Here we present the latest data on the genetic background of familial cholangiopathies and discuss their application in clinical practice for the differential diagnosis of cholestasis of unknown aetiology. As look in the future we present \"system genetics\" as a novel experimental tool for the study of cholangiopathies and disease-modifying genes. This article is part of a Special Issue entitled: Cholangiocytes in Health and Disease edited by Jesus Banales, Marco Marzioni, Nicholas LaRusso and Peter Jansen.", - "journal_title": "Biochimica et biophysica acta. Molecular basis of disease", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/28757171/" - } - ], - "919b4136-a032-4f86-83ee-959609c1fb73": [ - { - "pub_id": "24821406", - "title": "A candidate syntenic genetic locus is associated with voluntary exercise levels in mice and humans.", - "authors": "E Kostrzewa,M K Brandys,H A van Lith,M J H Kas", - "abstract": "Individual levels of physical activity, and especially of voluntary physical exercise, highly contribute to the susceptibility for developing metabolic, cardiovascular diseases, and potentially to psychiatric disorders. Here, we applied a cross-species approach to explore a candidate genetic region for voluntary exercise levels. First, a panel of mouse chromosome substitution strains was used to map a genomic region on mouse chromosome 2 that contributes to voluntary wheel running levels - a behavioral readout considered a model of voluntary exercise in humans. Subsequently, we tested the syntenic region (HSA20: 51,212,545-55,212,986) in a human sample (Saint Thomas Twin Register; n=3038) and found a significant association between voluntary exercise levels (categorized into excessive and non-excessive exercise) and an intergenic SNP rs459465 (adjusted P-value of 0.001). Taking under consideration the methodological challenges embedded in this translational approach in the research of complex phenotypes, we wanted to further test the validity of this finding. Therefore, we repeated the analysis in an independent human population (ALSPAC data set; n=2557). We found a significant association of excessive exercise with two SNPs in the same genomic region (rs6022999, adjusted P-value of P=0.011 and rs6092090, adjusted P-value of 0.012). We explored the locus for possible candidate genes by means of literature search and bioinformatics analysis of gene function and of trans-regulatory elements. We propose three potential human candidate genes for voluntary physical exercise levels (MC3R, CYP24A1, and GRM8). To conclude, the identified genetic variance in the human locus 20q13.2 may affect voluntary exercise levels.", - "journal_title": "Behavioural brain research", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/24821406/" - } - ], - "23d6aba8-ca17-4606-9504-789b071c4923": [ - { - "pub_id": "29691636", - "title": "Genome-wide association for testis weight in the diversity outbred mouse population.", - "authors": "Joshua T Yuan,Daniel M Gatti,Vivek M Philip,Steven Kasparek,Andrew M Kreuzman,Benjamin Mansky,Kayvon Sharif,Dominik Taterra,Walter M Taylor,Mary Thomas,Jeremy O Ward,Andrew Holmes,Elissa J Chesler,Clarissa C Parker", - "abstract": "Testis weight is a genetically mediated trait associated with reproductive efficiency across numerous species. We sought to evaluate the genetically diverse, highly recombinant Diversity Outbred (DO) mouse population as a tool to identify and map quantitative trait loci (QTLs) associated with testis weight. Testis weights were recorded for 502 male DO mice and the mice were genotyped on the GIGAMuga array at ~\u2009143,000 SNPs. We performed a genome-wide association analysis and identified one significant and two suggestive QTLs associated with testis weight. Using bioinformatic approaches, we developed a list of candidate genes and identified those with known roles in testicular size and development. Candidates of particular interest include the RNA demethylase gene Alkbh5, the cyclin-dependent kinase inhibitor gene Cdkn2c, the dynein axonemal heavy chain gene Dnah11, the phospholipase D gene Pld6, the trans-acting transcription factor gene Sp4, and the spermatogenesis-associated gene Spata6, each of which has a human ortholog. Our results demonstrate the utility of DO mice in high-resolution genetic mapping of complex traits, enabling us to identify developmentally important genes in adult mice. Understanding how genetic variation in these genes influence testis weight could aid in the understanding of mechanisms of mammalian reproductive function.", - "journal_title": "Mammalian genome : official journal of the International Mammalian Genome Society", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/29691636/" - } - ], - "2a92d7b5-946c-4a22-a4b9-26e950b0f757": [ - { - "pub_id": "26449520", - "title": "Systems genetic analysis of hippocampal neuroanatomy and spatial learning in mice.", - "authors": "A Delprato,B Bonheur,M-P Alg\u00e9o,P Rosay,L Lu,R W Williams,W E Crusio", - "abstract": "Variation in hippocampal neuroanatomy correlates well with spatial learning ability in mice. Here, we have studied both hippocampal neuroanatomy and behavior in 53 isogenic BXD recombinant strains derived from C57BL/6J and DBA/2J parents. A combination of experimental, neuroinformatic and systems genetics methods was used to test the genetic bases of variation and covariation among traits. Data were collected on seven hippocampal subregions in CA3 and CA4 after testing spatial memory in an eight-arm radial maze task. Quantitative trait loci were identified for hippocampal structure, including the areas of the intra- and infrapyramidal mossy fibers (IIPMFs), stratum radiatum and stratum pyramidale, and for a spatial learning parameter, error rate. We identified multiple loci and gene variants linked to either structural differences or behavior. Gpc4 and Tenm2 are strong candidate genes that may modulate IIPMF areas. Analysis of gene expression networks and trait correlations highlight several processes influencing morphometrical variation and spatial learning.", - "journal_title": "Genes, brain, and behavior", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/26449520/" - } - ], - "c450262d-8736-4582-ac34-1c8b375b0140": [ - { - "pub_id": "22675444", - "title": "Genetic control of a central pattern generator: rhythmic oromotor movement in mice is controlled by a major locus near Atp1a2.", - "authors": "John D Boughter,Megan K Mulligan,Steven J St John,Kenichi Tokita,Lu Lu,Detlef H Heck,Robert W Williams", - "abstract": "Fluid licking in mice is a rhythmic behavior that is controlled by a central pattern generator (CPG) located in a complex of brainstem nuclei. C57BL/6J (B6) and DBA/2J (D2) strains differ significantly in water-restricted licking, with a highly heritable difference in rates (h(2)\u22650.62) and a corresponding 20% difference in interlick interval (mean \u00b1 SEM\u200a=\u200a116.3\u00b11 vs 95.4\u00b11.1 ms). We systematically quantified motor output in these strains, their F(1) hybrids, and a set of 64 BXD progeny strains. The mean primary interlick interval (MPI) varied continuously among progeny strains. We detected a significant quantitative trait locus (QTL) for a CPG controlling lick rate on Chr 1 (Lick1), and a suggestive locus on Chr 10 (Lick10). Linkage was verified by testing of B6.D2-1D congenic stock in which a segment of Chr 1 of the D2 strain was introgressed onto the B6 parent. The Lick1 interval on distal Chr 1 contains several strong candidate genes. One of these is a sodium/potassium pump subunit (Atp1a2) with widespread expression in astrocytes, as well as in a restricted population of neurons. Both this subunit and the entire Na(+)/K(+)-ATPase molecule have been implicated in rhythmogenesis for respiration and locomotion. Sequence variants in or near Apt1a2 strongly modulate expression of the cognate mRNA in multiple brain regions. This gene region has recently been sequenced exhaustively and we have cataloged over 300 non-coding and synonymous mutations segregating among BXD strains, one or more of which is likely to contribute to differences in central pattern generator tempo.", - "journal_title": "PloS one", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/22675444/" - } - ], - "09c07844-b8d8-46a9-842e-eb9c16f2ab25": [ - { - "pub_id": "28847732", - "title": "Variable cardiac \u03b1-actin (Actc1) expression in early adult skeletal muscle correlates with promoter methylation.", - "authors": "Jordan K Boutilier,Rhonda L Taylor,Ramesh Ram,Elyshia McNamara,Quang Nguyen,Hayley Goull\u00e9e,David Chandler,Munish Mehta,Lois Balmer,Nigel G Laing,Grant Morahan,Kristen J Nowak", - "abstract": "Different genes encode the \u03b1-actin isoforms that are predominantly expressed in heart and skeletal muscle. Mutations in the skeletal muscle \u03b1-actin gene (ACTA1) cause muscle diseases that are mostly lethal in the early postnatal period. We previously demonstrated that the disease phenotype of ACTA1 mouse models could be rescued by transgenic over-expression of cardiac \u03b1-actin (ACTC1). ACTC1 is the predominant striated \u03b1-actin isoform in the heart but is also expressed in developing skeletal muscle. To develop a translatable therapy, we investigated the genetic regulation of Actc1 expression. Using strains from The Collaborative Cross (CC) genetic resource, we found that Actc1 varies in expression by up to 24-fold in skeletal muscle. We defined significant expression quantitative trait loci (eQTL) associated with early adult Actc1 expression in soleus and heart. eQTL in both heart and soleus mapped to the Actc1 locus and replicate an eQTL mapped for Actc1 in BXD heart and quadriceps. We built on this previous work by analysing genes within the eQTL peak regions to prioritise likely candidates for modifying Actc1 expression. Additionally we interrogated the CC founder haplotype contributions to enable prioritisation of genetic variants for functional analyses. Methylation around the Actc1 transcriptional start site in early adult skeletal muscle negatively correlated with Actc1 expression in a strain-dependent manner, while other marks of regulatory potential (histone modification and chromatin accessibility) were unaltered. This study provides novel insights into the complex genetic regulation of Actc1 expression in early adult skeletal muscles.", - "journal_title": "Biochimica et biophysica acta. Gene regulatory mechanisms", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/28847732/" - } - ], - "1752ff08-bac2-4d6b-b86d-bcfc69e932c4": [ - { - "pub_id": "24836470", - "title": "Analysis of somatic hypermutations in the IgM switch region in human B cells.", - "authors": "Katsuyuki Horiuchi,Kohsuke Imai,Kanako Mitsui-Sekinaka,Tzu-Wen Yeh,Hans D Ochs,Anne Durandy,Shigeaki Nonoyama", - "abstract": "The molecular mechanism of class-switch recombination (CSR) in human subjects has not been fully elucidated. The CSR-induced mutations occurring in the switch region of the IgM gene (Smu-SHMs) in in vitro CSR-activated and in vivo switched B cells have been analyzed in mice but not in human subjects. We sought to better characterize the molecular mechanism of CSR in human subjects. Smu-SHMs were analyzed in vitro and in vivo by using healthy control subjects and patients with molecularly defined CSR defects. We found that Smu-SHMs can be induced in vitro by means of CSR activation in human subjects. We also found large amounts of Smu-SHMs in in vivo class-switched memory B cells, smaller (although significant) amounts in unswitched memory B cells, and very low amounts in naive B cells. In class-switched memory B cells a high frequency of Smu-SHMs was found throughout the Smu. In unswitched memory B cells, the Smu-SHM frequency was significantly decreased in the 5' part of the Smu. The difference between switched and unswitched B cells suggests that the extension of somatic hypermutation (SHM) to the 5' upstream region of the Smu might be associated with the effective induction of CSR. The analysis of the pattern of mutations within and outside the WRCY/RGYW (W, A/T; R, A/G; and Y, C/T) motifs, as well as the Smu-SHMs, in CD27(+) B cells from CD40 ligand (CD40L)-, activation-induced cytidine deaminase (AID)-, and uracil-DNA glycosylase (UNG)-deficient patients revealed the dependence of Smu-SHM on CD40L, AID, UNG, and the mismatch repair system in human subjects. CD40L-, AID-, UNG-, and mismatch repair system-dependent Smu-SHMs and extension to the 5' region of Smu are necessary to accomplish effective CSR in human subjects.", - "journal_title": "The Journal of allergy and clinical immunology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/24836470/" - } - ], - "130b4836-2fb1-432f-be62-c9d29dbd3b72": [ - { - "pub_id": "27933535", - "title": "Systems Genetics Analysis to Identify the Genetic Modulation of a Glaucoma-Associated Gene.", - "authors": "Sumana R Chintalapudi,Monica M Jablonski", - "abstract": "Loss of retinal ganglion cells (RGCs) is one of the hallmarks of retinal neurodegenerative diseases, glaucoma being one of the most common. Recently, \u03b3-synuclein (SNCG) was shown to be highly expressed in the somas and axons of RGCs. In various mouse models of glaucoma, downregulation of Sncg gene expression correlates with RGC loss. To investigate the regulation of Sncg in RGCs, we used a systems genetics approach to identify a gene that modulates the expression of Sncg, followed by confirmatory studies in both healthy and diseased retinas. We found that chromosome 1 harbors an eQTL that modulates the expression of Sncg in the mouse retina and identified Pfdn2 as the candidate upstream modulator of Sncg expression. Downregulation of Pfdn2 in enriched RGCs causes a concomitant reduction in Sncg. In this chapter, we describe our strategy and methods for identifying and confirming a genetic modulation of a glaucoma-associated gene. A similar method can be applied to other genes expressed in other tissues.", - "journal_title": "Methods in molecular biology (Clifton, N.J.)", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/27933535/" - } - ], - "aab09eb6-a95e-4258-b35f-b9fec7b0de5c": [ - { - "pub_id": "27881077", - "title": "Sex difference in EGFR pathways in mouse kidney-potential impact on the immune system.", - "authors": "Fengxia Liu,Yan Jiao,Yun Jiao,Franklin Garcia-Godoy,Weikuan Gu,Qingyi Liu", - "abstract": "Epidermal growth factor receptor (Egfr) has been the target of several drugs for cancers. The potential gender differences in genes in the Egfr axis have been suggested in humans and in animal models. Female and male mice from the same recombinant inbred (RI) strain have the same genomic components except the sex difference. A population of different RI mouse strains allows to conduct precise analysis of molecular pathways and regulation of Egfr between female and male mice. The whole genome expression profiles of 70 genetically diverse RI strains of mice were used to compare three major molecular aspects of Egfr gene: the relative expression levels, gene network and expression quantitative trait loci (eQTL) that regulate the expression of Egfr between female and male mice. Our data showed that there is a significant sex difference in the expression levels in kidney. A considerable number of genes in the gene network of Egfr are sex differentially expressed. The expression levels of Egfr in mice are statistical significant different between C57BL/6\u00a0J (B6) and DBA/2\u00a0J (D2) genotypes in male while no difference in female mice. The eQTLs that regulate the expression levels of Egfr between female and male mice are also different. Furthermore, the differential expression levels of Egfr showed significantly different correlations with two known biological traits between male and female mice. Overall there is a substantial sex difference in the Egfr pathways in mice. These data may have significant impact on drug target design, development, formulation, and dosage determinant for women and men in clinical trials.", - "journal_title": "BMC genetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/27881077/" - } - ], - "16276556-20fb-41de-8a48-16eeba247ea7": [ - { - "pub_id": "23011133", - "title": "Genetic architecture supports mosaic brain evolution and independent brain-body size regulation.", - "authors": "Reinmar Hager,Lu Lu,Glenn D Rosen,Robert W Williams", - "abstract": "The mammalian brain consists of distinct parts that fulfil different functions. Finlay and Darlington have argued that evolution of the mammalian brain is constrained by developmental programs, suggesting that different brain parts are not free to respond individually to selection and evolve independent of other parts or overall brain size. However, comparisons among mammals with matched brain weights often reveal greater differences in brain part size, arguing against strong developmental constraints. Here we test these hypotheses using a quantitative genetic approach involving over 10,000 mice. We identify independent loci for size variation in seven key parts of the brain, and observe that brain parts show low or no phenotypic correlation, as is predicted by a mosaic scenario. We also demonstrate that variation in brain size is independently regulated from body size. The allometric relations seen at higher phylogenetic levels are thus unlikely to be the product of strong developmental constraints.", - "journal_title": "Nature communications", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/23011133/" - } - ], - "43d5140a-ad39-438e-8ba6-76dd3c7c42bc": [ - { - "pub_id": "25995165", - "title": "A Chromosome 13 locus is associated with male-specific mortality in mice.", - "authors": "Joseph P Gyekis,Dean H Lang,David J Vandenbergh,Glenn S Gerhard,James W Griffith,Jeffery W Dodds,Zakaria K Shihabi,Mera K Tilley,David A Blizard", - "abstract": "Mortality is a highly complex trait influenced by a wide array of genetic factors. We examined a population of 1200 mice that were F2 generation offspring of a 4-way reciprocal cross between C57BL6/J and DBA2/J strains. Animals were sacrificed at age 200, 500, or 800\u00a0days and genotyped at 96 markers. The 800\u00a0days old cohort, which were the survivors of a much larger breeding group, were examined for enriched frequency of alleles that benefit survival and depletion of alleles that reduce survival. Loci on Chr 13 in males and on Chr X in females were significantly distorted from Mendelian expectations, even after conservative correction for multiple testing. DBA2/J alleles between 35 and 80\u00a0Mb on Chr 13 were underrepresented in the age 800 male animals. D2 genotypes in this region were also associated with premature death during behavioral testing. Furthermore, confirmatory analysis showed BXD recombinant inbred strains carrying the D2 alleles in this region had shorter median survival. Exploration of available pathology data indicated that a syndrome involving dental malocclusions, pancreatic islet hypertrophy, and kidney lipidosis may have mediated the effects of DBA alleles on mortality specifically in male mice. The heterozygote advantage locus on the X Chr was not found to be associated with any pathology. These results suggest a novel locus influencing survival in the B6/D2 genetic background, perhaps via a metabolic disorder that emerges by 200\u00a0days of age in male animals.", - "journal_title": "Aging clinical and experimental research", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/25995165/" - } - ], - "5ef1d2e1-67d2-4d12-b171-d2b1bb21887f": [ - { - "pub_id": "24416236", - "title": "Trps1 differentially modulates the bone mineral density between male and female mice and its polymorphism associates with BMD differently between women and men.", - "authors": "Lishi Wang,Wenli Lu,Lei Zhang,Yue Huang,Rachel Scheib,Xiaoyun Liu,Linda Myers,Lu Lu,Charles R Farber,Gaifen Liu,Cong-Yi Wang,Hongwen Deng,Robert W Williams,Yongjun Wang,Weikuan Gu,Yan Jiao", - "abstract": "The objective of our study was to identify genetic factors that regulate bone mineral density (BMD) in mice using well defined recombinant inbred strains. For this purpose we chose the BXD recombinant inbred (RI) strains derived from progeny of the C57BL/6J (B6) and DBA/2J (D2) progenitor strains. We sampled both male and female mice (\u223c4 each) of 46 strains at 3 months-of-age, measured their BMD, and conducted QTL mapping. The data were analyzed to identify candidates genes contained within the most significant quantitative trait locus (QTL). Evaluation of candidate genes included functional assessment, single nucleotide polymorphism (SNP) genotyping and direct sequencing. We established that there was a QTL for BMD in males on chromosome 15 that has the impact larger than QTLs on all other chromosomes. The QTL on chromosome 15 was narrowed to a genomic region between 38 Mbp and 52 Mbp. By examining transcripts within this region, we found an important candidate gene: trichorhinophalangeal syndrome, type I (Trps1). SNP analysis identified a nonsynonymous SNP (rs32398060) in Trps1 that co-segregated with bone mineral density. Analysis of association between this SNP within TRPS1 and BMD in a human population confirmed its significance.", - "journal_title": "PloS one", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/24416236/" - } - ], - "10402a43-f390-4b98-856e-da51d30e0f6b": [ - { - "pub_id": "27933542", - "title": "Complex Genetics of Behavior: BXDs in the Automated Home-Cage.", - "authors": "Maarten Loos,Matthijs Verhage,Sabine Spijker,August B Smit", - "abstract": "This chapter describes a use case for the genetic dissection and automated analysis of complex behavioral traits using the genetically diverse panel of BXD mouse recombinant inbred strains. Strains of the BXD resource differ widely in terms of gene and protein expression in the brain, as well as in their behavioral repertoire. A large mouse resource opens the possibility for gene finding studies underlying distinct behavioral phenotypes, however, such a resource poses a challenge in behavioral phenotyping. To address the specifics of large-scale screening we describe how to investigate: (1) how to assess mouse behavior systematically in addressing a large genetic cohort, (2) how to dissect automation-derived longitudinal mouse behavior into quantitative parameters, and (3) how to map these quantitative traits to the genome, deriving loci underlying aspects of behavior.", - "journal_title": "Methods in molecular biology (Clifton, N.J.)", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/27933542/" - } - ], - "c8021173-fee9-4029-aa3c-223a99c25d4a": [ - { - "pub_id": "26780340", - "title": "A novel heat shock protein alpha 8 (Hspa8) molecular network mediating responses to stress- and ethanol-related behaviors.", - "authors": "Kyle R Urquhart,Yinghong Zhao,Jessica A Baker,Ye Lu,Lei Yan,Melloni N Cook,Byron C Jones,Kristin M Hamre,Lu Lu", - "abstract": "Genetic differences mediate individual differences in susceptibility and responses to stress and ethanol, although, the specific molecular pathways that control these responses are not fully understood. Heat shock protein alpha 8 (Hspa8) is a molecular chaperone and member of the heat shock protein family that plays an integral role in the stress response and that has been implicated as an ethanol-responsive gene. Therefore, we assessed its role in mediating responses to stress and ethanol across varying genetic backgrounds. The hippocampus is an important mediator of these responses, and thus, was examined in the BXD family of mice in this study. We conducted bioinformatic analyses to dissect genetic factors modulating Hspa8 expression, identify downstream targets of Hspa8, and examined its role. Hspa8 is trans-regulated by a gene or genes on chromosome 14 and is part of a molecular network that regulates stress- and ethanol-related behaviors. To determine additional components of this network, we identified direct or indirect targets of Hspa8 and show that these genes, as predicted, participate in processes such as protein folding and organic substance metabolic processes. Two phenotypes that map to the Hspa8 locus are anxiety-related and numerous other anxiety- and/or ethanol-related behaviors significantly correlate with Hspa8 expression. To more directly assay this relationship, we examined differences in gene expression following exposure to stress or alcohol and showed treatment-related differential expression of Hspa8 and a subset of the members of its network. Our findings suggest that Hspa8 plays a vital role in genetic differences in responses to stress and ethanol and their interactions.", - "journal_title": "Neurogenetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/26780340/" - } - ], - "7ac007e5-35bf-4894-9856-67d182b0a32a": [ - { - "pub_id": "26134616", - "title": "Predominant contribution of cis-regulatory divergence in the evolution of mouse alternative splicing.", - "authors": "Qingsong Gao,Wei Sun,Marlies Ballegeer,Claude Libert,Wei Chen", - "abstract": "Divergence of alternative splicing represents one of the major driving forces to shape phenotypic diversity during evolution. However, the extent to which these divergences could be explained by the evolving cis-regulatory versus trans-acting factors remains unresolved. To globally investigate the relative contributions of the two factors for the first time in mammals, we measured splicing difference between C57BL/6J and SPRET/EiJ mouse strains and allele-specific splicing pattern in their F1 hybrid. Out of 11,818 alternative splicing events expressed in the cultured fibroblast cells, we identified 796 with significant difference between the parental strains. After integrating allele-specific data from F1 hybrid, we demonstrated that these events could be predominately attributed to cis-regulatory variants, including those residing at and beyond canonical splicing sites. Contrary to previous observations in Drosophila, such predominant contribution was consistently observed across different types of alternative splicing. Further analysis of liver tissues from the same mouse strains and reanalysis of published datasets on other strains showed similar trends, implying in general the predominant contribution of cis-regulatory changes in the evolution of mouse alternative splicing.", - "journal_title": "Molecular systems biology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/26134616/" - } - ], - "d3cb3e50-af73-4320-a6c3-09400e99663e": [ - { - "pub_id": "25032693", - "title": "Limitation of number of strains and persistence of false positive loci in QTL mapping using recombinant inbred strains.", - "authors": "Lishi Wang,Yan Jiao,Yanhong Cao,Gaifen Liu,Yongjun Wang,Weikuan Gu", - "abstract": "While the identification of causal genes of quantitative trait loci (QTL) remains a difficult problem in the post-genome era, the number of QTL continues to accumulate, mainly identified using the recombinant inbred (RI) strains. Over the last decade, hundreds of publications have reported nearly a thousand QTL identified from RI strains. We hypothesized that the inaccuracy of most of these QTL makes it difficult to identify causal genes. Using data from RI strains derived from C57BL/6J (B6) X DBA/2J (D2), we tested the possibility of detection of reliable QTL with different numbers of strains in the same trait in five different traits. Our results indicated that studies using RI strains of less than 30 in general have a higher probability of failing to detect reliable QTL. Errors in many studies could include false positive loci, switches between QTL with small and major effects, and missing the real major loci. The similar data was obtained from a RI strain population derived from a different pair of parents and a RI strain population of rat. Thus, thousands of reported QTL from studies of RI strains may need to be double-checked for accuracy before proceeding to causal gene identification.", - "journal_title": "PloS one", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/25032693/" - } - ], - "7b278ba7-05ad-474a-992d-2493f7712927": [ - { - "pub_id": "25133246", - "title": "Genome wide analysis of sex difference in gene expression profiles of bone formations using sfx mice and BXD RI strains.", - "authors": "Yue Huang,Xiaodong Zhu,Lishi Wang,Xiaoyun Liu,Lu Lu,Weikuan Gu,Yan Jiao", - "abstract": "The objective of this study is to identify sex differentially expressed genes in bone using a mouse model of spontaneous fracture, sfx, which lacks the gene for L-gulonolactone oxidase (Gulo), a key enzyme in the ascorbic acid (AA) synthesis pathway. We first identified the genes that are differentially expressed in the femur between female and male in sfx mice. We then analyzed the potential gene network among those differentially expressed genes with whole genome expression profiles generated using spleens of female and male mice of a total of 67 BXD (C57BL/6J X DBA/2J) recombinant inbred (RI) and other strains. Our result indicated that there was a sex difference in the whole genome profiles in sfx mice as measured by the proportion of up- and downregulated genes. Several genes in the pathway of bone development are differentially expressed between the male and female of sfx mice. Comparison of gene network of up- and downregulated bone relevant genes also suggests a sex difference.", - "journal_title": "TheScientificWorldJournal", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/25133246/" - } - ], - "88f53bb9-0e45-412e-832e-3b11a8221657": [ - { - "pub_id": "23002780", - "title": "Effects of glaucoma on Chrna6 expression in the retina.", - "authors": "Gustavo C Munguba,Eldon E Geisert,Robert W Williams,Mary L Tapia,Daisy K Lam,Sanjoy K Bhattacharya,Richard K Lee", - "abstract": "Recent advances in technology now provide tools capable of tracking genome-wide expression changes occurring in progressive pathological processes. The present experiments were carried out to determine if acetylcholine receptor \u03b1 6 subunit (Chrna6) is a reliable retinal ganglion cell (RGC) marker in adult mouse eyes and if Chrna6 expression can be used to track progressive loss of RGCs, such as is observed in the DBA/2J glaucoma model. Data sets derived from the BXD strains were used to extract gene expression signatures for RGCs. Pooled retinas from DBA/2J or C57BL/6J cases at 1-3 months, 12 months, and 16-17 months were prepared for gene-array and RT-PCR analysis. Globes were fixed in paraformaldehyde and sectioned for immunofluorescence with antibodies against Chrna6. Chrna6 has a cellular expression signature for RGCs with high correlation to Thy1 (r = 0.65), a recognized RGC marker. Immunofluorescence experiments confirm that in the young and adult mouse retina, Chrna6 is preferentially expressed by RGCs. We further show that C3H/HeJ retinas, which lack photoreceptors, also express Chrna6 in the RGC layer. Gene expression array analyses, confirmed by RT-PCR, show progressive loss of Chrna6 expression in retinas of the DBA/2J glaucomatous mouse retinas. Quantitative trait locus analysis provides support for Chrna6 as a RGC marker. Chrna6 expression decreases with death of RGCs in glaucomatous DBA/2J mice and after optic nerve crush injury, further supporting Chrna6 as a reliable RGC marker. High expression of RGC Chrna6 in the absence of photoreceptors is suggestive that Chrna6 expression by RGCs is independent of photoreceptor-derived stimuli.", - "journal_title": "Current eye research", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/23002780/" - } - ], - "5bd8262b-b2cd-4098-a494-ede168941a9a": [ - { - "pub_id": "29269609", - "title": "Identification of quantitative trait loci associated with the susceptibility of mouse spermatozoa to cryopreservation.", - "authors": "Jinsha Liu,Keiji Mochida,Ayumi Hasegawa,Kimiko Inoue,Atsuo Ogura", - "abstract": "Although it is known that the susceptibility of mouse spermatozoa to freezing-thawing varies greatly with genetic background, the underlying mechanisms remain to be elucidated. In this study, to map genetic regions responsible for the susceptibility of spermatozoa to freezing-thawing, we performed in vitro fertilization using spermatozoa from recombinant inbred mice derived from the C57BL/6J and DBA/2J strains, whose spermatozoa showed distinct fertilization abilities after freezing. Genome-wide interval mapping identified two suggestive quantitative trait loci (QTL) associated with fertilization on chromosomes 1 and 11. The strongest QTL on chromosome 11 included 70 genes at 59.237260-61.324742 Mb and another QTL on chromosome 1 included 43 genes at 153.969506-158.217850 Mb. These regions included at least 15 genes involved with testicular expression and possibly with capacitation or sperm motility. Specifically, the Abl2 gene on chromosome 1, which may affect subcellular actin distribution, had polymorphisms between C57BL/6J and DBA/2J that caused at least three amino acid substitutions. A correlation analysis using recombinant inbred strains revealed that the fertilization rate was strongly correlated with the capacitation rate of frozen-thawed spermatozoa after preincubation. This result is consistent with the fact that C57BL/6J frozen-thawed spermatozoa recover their fertilization capacity following treatment with methyl-\u03b2-cyclodextrin to enhance sperm capacitation. Thus, our data provide important clues to the molecular mechanisms underlying cryodamage to mouse spermatozoa.", - "journal_title": "The Journal of reproduction and development", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/29269609/" - } - ], - "08a01aae-9754-4eb1-a385-9fa446460c59": [ - { - "pub_id": "24628794", - "title": "Sex-dependent genetic effects on immune responses to a parasitic nematode.", - "authors": "Kelly S Hayes,Reinmar Hager,Richard K Grencis", - "abstract": "Many disease aetiologies have sex specific effects, which have important implications for disease management. It is now becoming increasingly evident that such effects are the result of the differential expression of autosomal genes rather than sex-specific genes. Such sex-specific variation in the response to Trichuris muris, a murine parasitic nematode infection and model for the human parasitic nematode T. trichiura, has been well documented, however, the underlying genetic causes of these differences have been largely neglected. We used the BXD mouse set of recombinant inbred strains to identify sex-specific loci that contribute to immune phenotypes in T. muris infection. Response phenotypes to T. muris infection were found to be highly variable between different lines of BXD mice. A significant QTL on chromosome 5 (TM5) associated with IFN-\u03b3 production was found in male mice but not in female mice. This QTL was in the same location as a suggestive QTL for TNF-\u03b1 and IL-6 production in male mice suggesting a common control of these pro-inflammatory cytokines. A second QTL was identified on chromosome 4 (TM4) affecting worm burden in both male and female cohorts. We have identified several genes as potential candidates for modifying responses to T. muris infection. We have used the largest mammalian genetic model system, the BXD mouse population, to identify candidate genes with sex-specific effects in immune responses to T. muris infection. Some of these genes may be differentially expressed in male and female mice leading to the difference in immune response between the sexes reported in previous studies. Our study further highlights the importance of considering sex as an important factor in investigations of immune response at the genome-wide level, in particular the bias that can be introduced when generalizing results obtained from only one sex or a mixed sex population. Rather, analyses of interaction effects between sex and genotype should be part of future studies.", - "journal_title": "BMC genomics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/24628794/" - } - ], - "00df208f-bec0-4f4c-b941-76a92d1c5b6c": [ - { - "pub_id": "24397210", - "title": "Expression of alcoholism-relevant genes in the liver are differently correlated to different parts of the brain.", - "authors": "Lishi Wang,Yue Huang,Yan Jiao,Hong Chen,Yanhong Cao,Beth Bennett,Yongjun Wang,Weikuan Gu", - "abstract": "The purpose of this study is to investigate whether expression profiles of alcoholism-relevant genes in different parts of the brain are correlated differently with those in the liver. Four experiments were conducted. First, we used gene expression profiles from five parts of the brain (striatum, prefrontal cortex, nucleus accumbens, hippocampus, and cerebellum) and from liver in a population of recombinant inbred mouse strains to examine the expression association of 10 alcoholism-relevant genes. Second, we conducted the same association analysis between brain structures and the lung. Third, using five randomly selected, nonalcoholism-relevant genes, we conducted the association analysis between brain and liver. Finally, we compared the expression of 10 alcoholism-relevant genes in hippocampus and cerebellum between an alcohol preference strain and a wild-type control. We observed a difference in correlation patterns in expression levels of 10 alcoholism-relevant genes between different parts of the brain with those of liver. We then examined the association of gene expression between alcohol dehydrogenases (Adh1, Adh2, Adh5, and Adh7) and different parts of the brain. The results were similar to those of the 10 genes. Then, we found that the association of those genes between brain structures and lung was different from that of liver. Next, we found that the association patterns of five alcoholism-nonrelevant genes were different from those of 10 alcoholism-relevant genes. Finally, we found that the expression level of 10 alcohol-relevant genes is influenced more in hippocampus than in cerebellum in the alcohol preference strain. Our results show that the expression of alcoholism-relevant genes in liver is differently associated with the expression of genes in different parts of the brain. Because different structural changes in different parts of the brain in alcoholism have been reported, it is important to investigate whether those structural differences in the brains of those with alcoholism are due to the difference in the associations of gene expression between genes in liver and in different parts of the brain.", - "journal_title": "Gene expression", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/24397210/" - } - ], - "dee36885-b2f4-4311-b70a-17e228034820": [ - { - "pub_id": "26310165", - "title": "What Animal Models Can Tell Us About Glaucoma.", - "authors": "Felix L Struebing,Eldon E Geisert", - "abstract": "Well defined animal models facilitate the study of ocular diseases. Each model brings a unique perspective to the understanding of the disease process, and in some cases, the models are critical to the development of therapeutic approaches for treatments. This is especially the case for glaucoma. Glaucoma is a family of diseases that can be caused by very different biological processes. The one thing in common is the end result, the loss of retinal ganglion cells and blindness. In this review, we will attempt to relate the findings from a number of animal models to specific types of glaucoma, emphasizing the contributions that each of the models makes to our overall understanding of the complex collection of diseases we call glaucoma.", - "journal_title": "Progress in molecular biology and translational science", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/26310165/" - } - ], - "a1ddc50c-de3e-4938-8956-0b1eab6086b0": [ - { - "pub_id": "25109285", - "title": "Sirt1 induction confers resistance to etoposide-induced genotoxic apoptosis in thyroid cancers.", - "authors": "Ki Hwan Kweon,Cho Rok Lee,Soo Jung Jung,Eun Jeong Ban,Sang-Wook Kang,Jong Ju Jeong,Kee-Hyun Nam,Young Suk Jo,Jandee Lee,Woong Youn Chung", - "abstract": "Despite the favorable therapeutic outcomes reported in differentiated thyroid cancer (DTC), a significant proportion of DTC patients present with refractory behavior to conventional therapy. The sirtuin (Sirt) family has recently been implicated in the maintenance of cellular homeostasis under genotoxic stress. Here, we investigated the induction of Sirt1 expression by etoposide-induced genotoxic stress to gain insights into thyroid carcinogenesis and identify novel therapeutic targets. Immunohistochemical staining analyses of Sirt1 and Sirt3 were performed using human thyroid cancer tissues and matched normal tissues, and bioinformatic analyses were done using public repositories, including the Human Protein Atlas, BioGPS, NCBI Gene Expression Omnibus (GEO) profiles, and GeneNetwork. TPC1, FTC133 and FRO cells were used for molecular biological experiments including apoptosis assays, MTT, immunofluorescence staining and qRT-PCR assays. The IHC data and public repositories data consistently showed variable Sirt1 and Sirt3 expression patterns in normal thyroid follicular cells and papillary thyroid cancer cells. The induction of Sirt1 and Sirt3 was cell type-specific and the expression levels of these genes correlated with apoptotic cell death and cell viability after etoposide-induced genotoxic stress. Sirt1\u2011Foxp3 signaling-mediated regulation of Bax and p21 mRNA expression was a signature molecular event in TPC1 cells, which showed remarkable resistance to etoposide-induced genotoxic stress. The induction of Sirt1 and Sirt3 may be a determinant of thyroid cancer cell survival under genotoxic stress conditions. Further examination of the Sirt1-Foxp3 signal may improve our understanding of thyroid carcinogenesis and help identify new druggable targets.", - "journal_title": "International journal of oncology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/25109285/" - } - ], - "1161637c-7c9e-494a-b063-7f82280a78c7": [ - { - "pub_id": "22781695", - "title": "Oncolytic virotherapy.", - "authors": "Stephen J Russell,Kah-Whye Peng,John C Bell", - "abstract": "Oncolytic virotherapy is an emerging treatment modality that uses replication-competent viruses to destroy cancers. Recent advances include preclinical proof of feasibility for a single-shot virotherapy cure, identification of drugs that accelerate intratumoral virus propagation, strategies to maximize the immunotherapeutic action of oncolytic viruses and clinical confirmation of a critical viremic threshold for vascular delivery and intratumoral virus replication. The primary clinical milestone has been completion of accrual in a phase 3 trial of intratumoral herpes simplex virus therapy using talimogene laherparepvec for metastatic melanoma. Key challenges for the field are to select 'winners' from a burgeoning number of oncolytic platforms and engineered derivatives, to transiently suppress but then unleash the power of the immune system to maximize both virus spread and anticancer immunity, to develop more meaningful preclinical virotherapy models and to manufacture viruses with orders-of-magnitude higher yields than is currently possible.", - "journal_title": "Nature biotechnology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/22781695/" - } - ], - "1024c1ee-1f36-4f06-9ae1-cd231b51d602": [ - { - "pub_id": "26502875", - "title": "Complement receptor 2 is up regulated in the spinal cord following nerve root injury and modulates the spinal cord response.", - "authors": "Rickard P F Lindblom,Alexander Berg,Mikael Str\u00f6m,Shahin Aeinehband,Cecilia A Dominguez,Faiez Al Nimer,Nada Abdelmagid,Matthias Heinig,Johan Zelano,Karin Harnesk,Norbert H\u00fcbner,Bo Nilsson,Kristina Nilsson Ekdahl,Margarita Diez,Staffan Cullheim,Fredrik Piehl", - "abstract": "Activation of the complement system has been implicated in both acute and chronic states of neurodegeneration. However, a detailed understanding of this complex network of interacting components is still lacking. Large-scale global expression profiling in a rat F2(DAxPVG) intercross identified a strong cis-regulatory influence on the local expression of complement receptor 2 (Cr2) in the spinal cord after ventral root avulsion (VRA). Expression of Cr2 in the spinal cord was studied in a separate cohort of DA and PVG rats at different time-points after VRA, and also following sciatic nerve transection (SNT) in the same strains. Consequently, Cr2 (-/-) mice and Wt controls were used to further explore the role of Cr2 in the spinal cord following SNT. The in vivo experiments were complemented by astrocyte and microglia cell cultures. Expression of Cr2 in na\u00efve spinal cord was low but strongly up regulated at 5-7 days after both VRA and SNT. Levels of Cr2 expression, as well as astrocyte activation, was higher in PVG rats than DA rats following both VRA and SNT. Subsequent in vitro studies proposed astrocytes as the main source of Cr2 expression. A functional role for Cr2 is suggested by the finding that transgenic mice lacking Cr2 displayed increased loss of synaptic nerve terminals following nerve injury. We also detected increased levels of soluble CR2 (sCR2) in the cerebrospinal fluid of rats following VRA. These results demonstrate that local expression of Cr2 in the central nervous system is part of the axotomy reaction and is suggested to modulate subsequent complement mediated effects.", - "journal_title": "Journal of neuroinflammation", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/26502875/" - } - ], - "c0d0b807-c671-4495-b874-8c315611b833": [ - { - "pub_id": "25374516", - "title": "Unique genetic loci identified for emotional behavior in control and chronic stress conditions.", - "authors": "Kimberly A K Carhuatanta,Chloe J A Shea,James P Herman,Ryan Jankord", - "abstract": "An individual's genetic background affects their emotional behavior and response to stress. Although studies have been conducted to identify genetic predictors for emotional behavior or stress response, it remains unknown how prior stress history alters the interaction between an individual's genome and their emotional behavior. Therefore, the purpose of this study is to identify chromosomal regions that affect emotional behavior and are sensitive to stress exposure. We utilized the BXD behavioral genetics mouse model to identify chromosomal regions that predict fear learning and emotional behavior following exposure to a control or chronic stress environment. 62 BXD recombinant inbred strains and C57BL/6 and DBA/2 parental strains underwent behavioral testing including a classical fear conditioning paradigm and the elevated plus maze. Distinct quantitative trait loci (QTLs) were identified for emotional learning, anxiety and locomotion in control and chronic stress populations. Candidate genes, including those with already known functions in learning and stress were found to reside within the identified QTLs. Our data suggest that chronic stress history reveals novel genetic predictors of emotional behavior.", - "journal_title": "Frontiers in behavioral neuroscience", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/25374516/" - } - ], - "654458c3-6932-45c2-829d-389617a9f519": [ - { - "pub_id": "25262641", - "title": "Genetic regulatory network analysis reveals that low density lipoprotein receptor-related protein 11 is involved in stress responses in mice.", - "authors": "Jian Xu,Rixin Cai,Lu Lu,Chengwei Duan,Xuelei Tao,Dongjian Chen,Yonghua Liu,Xiaodong Wang,Maohong Cao,Ying Chen", - "abstract": "To study whether Lrp11 is involved in stress response and find its expression regulatory network, the model of stress has been built using C57BL/6J (B6) and DBA/2 (D2) mice. Western blotting, qPCR and immunohistochemistry were used to investigate the expression variation of Lrp11 in amygdala tissue after exposure to stress. We found the quantity of Lrp11 was more obvious in stress models than that in normal mice (P<0.05) which suggests Lrp11 might participate in the process of stress response. The expression of Lrp11 is controlled by a cis-acting quantitative trait locus (cis-eQTL). We identified four genes that are regulated by Lrp11 and the expression of 66 genes highly correlated with Lrp11, seven of which have previously been implicated in stress pathways. To evaluate the relationship between Lrp11 and its downstream genes or network members, we transfected HEK 293T cells and SH-SY5Y cells with Lrp11 siRNA leading to down-regulation of Lrp11mRNA and were able to confirm a significant influence of Lrp11 depletion on the expression of Xpnpep1, Maneal, Pgap1 and Uprt. These validated downstream targets and members of Lrp11 gene network provide new insight into the biological role of Lrp11 and may be an important risk factor in the development of stress.", - "journal_title": "Psychiatry research", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/25262641/" - } - ], - "3f41ee30-86e5-437b-b7b2-4f4c5b9c1041": [ - { - "pub_id": "27148351", - "title": "POEM: Identifying Joint Additive Effects on Regulatory Circuits.", - "authors": "Maya Botzman,Aharon Nachshon,Avital Brodt,Irit Gat-Viks", - "abstract": "Expression Quantitative Trait Locus (eQTL) mapping tackles the problem of identifying variation in DNA sequence that have an effect on the transcriptional regulatory network. Major computational efforts are aimed at characterizing the joint effects of several eQTLs acting in concert to govern the expression of the same genes. Yet, progress toward a comprehensive prediction of such joint effects is limited. For example, existing eQTL methods commonly discover interacting loci affecting the expression levels of a module of co-regulated genes. Such \"modularization\" approaches, however, are focused on epistatic relations and thus have limited utility for the case of additive (non-epistatic) effects. Here we present POEM (Pairwise effect On Expression Modules), a methodology for identifying pairwise eQTL effects on gene modules. POEM is specifically designed to achieve high performance in the case of additive joint effects. We applied POEM to transcription profiles measured in bone marrow-derived dendritic cells across a population of genotyped mice. Our study reveals widespread additive, trans-acting pairwise effects on gene modules, characterizes their organizational principles, and highlights high-order interconnections between modules within the immune signaling network. These analyses elucidate the central role of additive pairwise effect in regulatory circuits, and provide computational tools for future investigations into the interplay between eQTLs. The software described in this article is available at csgi.tau.ac.il/POEM/.", - "journal_title": "Frontiers in genetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/27148351/" - } - ], - "8039b6dc-c179-43e9-a6ae-08b39d7840e3": [ - { - "pub_id": "25781485", - "title": "Linking traits based on their shared molecular mechanisms.", - "authors": "Yael Oren,Aharon Nachshon,Amit Frishberg,Roni Wilentzik,Irit Gat-Viks", - "abstract": "There is growing recognition that co-morbidity and co-occurrence of disease traits are often determined by shared genetic and molecular mechanisms. In most cases, however, the specific mechanisms that lead to such trait-trait relationships are yet unknown. Here we present an analysis of a broad spectrum of behavioral and physiological traits together with gene-expression measurements across genetically diverse mouse strains. We develop an unbiased methodology that constructs potentially overlapping groups of traits and resolves their underlying combination of genetic loci and molecular mechanisms. For example, our method predicts that genetic variation in the Klf7 gene may influence gene transcripts in bone marrow-derived myeloid cells, which in turn affect 17 behavioral traits following morphine injection; this predicted effect of Klf7 is consistent with an in vitro perturbation of Klf7 in bone marrow cells. Our analysis demonstrates the utility of studying hidden causative mechanisms that lead to relationships between complex traits.", - "journal_title": "eLife", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/25781485/" - } - ], - "14796b9d-f931-4ca5-9acc-0a5c9121d21d": [ - { - "pub_id": "25991709", - "title": "Identification of candidate genes that underlie the QTL on chromosome 1 that mediates genetic differences in stress-ethanol interactions.", - "authors": "Melloni N Cook,Jessica A Baker,Scott A Heldt,Robert W Williams,Kristin M Hamre,Lu Lu", - "abstract": "Alcoholism, stress, and anxiety are strongly interacting heritable, polygenetic traits. In a previous study, we identified a quantitative trait locus (QTL) on murine chromosome (Chr) 1 between 23.0 and 31.5 Mb that modulates genetic differences in the effects of ethanol on anxiety-related phenotypes. The goal of the present study was to extend the analysis of this locus with a focus on identifying candidate genes using newly available data and tools. Anxiety-like behavior was evaluated with an elevated zero maze following saline or ethanol injections (1.8 g/kg) in C57BL/6J, DBA2J, and 72 BXD strains. We detected significant effects of strain and treatment and their interaction on anxiety-related behaviors, although surprisingly, sex was not a significant factor. The Chr1 QTL is specific to the ethanol-treated cohort. Candidate genes in this locus were evaluated using now standard bioinformatic criteria. Collagen 19a1 (Col19a1) and family sequence 135a (Fam135a) met most criteria but have lower expression levels and lacked biological verification and, therefore, were considered less likely candidates. In contrast, two other genes, the prenylated protein tyrosine phosphate family member Ptp4a1 (protein tyrosine phosphate 4a1) and the zinc finger protein Phf3 (plant homeoDomain finger protein 3) met each of our bioinformatic criteria and are thus strong candidates. These findings are also of translational relevance because both Ptp4a1 and Phf3 have been nominated as candidates genes for alcohol dependence in a human genome-wide association study. Our findings support the hypothesis that variants in one or both of these genes modulate heritable differences in the effects of ethanol on anxiety-related behaviors.", - "journal_title": "Physiological genomics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/25991709/" - } - ], - "1f1c086b-a965-4f42-80db-95e678171b87": [ - { - "pub_id": "23656637", - "title": "Genetic variability in the rat Aplec C-type lectin gene cluster regulates lymphocyte trafficking and motor neuron survival after traumatic nerve root injury.", - "authors": "Rickard P F Lindblom,Shahin Aeinehband,Roham Parsa,Mikael Str\u00f6m,Faiez Al Nimer,Xing-Mei Zhang,Cecilia A Dominguez,Sevasti Flytzani,Margarita Diez,Fredrik Piehl", - "abstract": "C-type lectin (CLEC) receptors are important for initiating and shaping immune responses; however, their role in inflammatory reactions in the central nervous system after traumatic injuries is not known. The antigen-presenting lectin-like receptor gene complex (Aplec) contains a few CLEC genes, which differ genetically among inbred rat strains. It was originally thought to be a region that regulates susceptibility to autoimmune arthritis, autoimmune neuroinflammation and infection. The inbred rat strains DA and PVG differ substantially in degree of spinal cord motor neuron death following ventral root avulsion (VRA), which is a reproducible model of localized nerve root injury. A large F2 (DAxPVG) intercross was bred and genotyped after which global expressional profiling was performed on spinal cords from F2 rats subjected to VRA. A congenic strain, Aplec, created by transferring a small PVG segment containing only seven genes, all C-type lectins, ontoDA background, was used for further experiments together with the parental strains. Global expressional profiling of F2 (DAxPVG) spinal cords after VRA and genome-wide eQTL mapping identified a strong cis-regulated difference in the expression of Clec4a3 (Dcir3), a C-type lectin gene that is a part of the Aplec cluster. Second, we demonstrate significantly improved motor neuron survival and also increased T-cell infiltration into the spinal cord of congenic rats carrying Aplec from PVG on DA background compared to the parental DA strain. In vitro studies demonstrate that the Aplec genes are expressed on microglia and upregulated upon inflammatory stimuli. However, there were no differences in expression of general microglial activation markers between Aplec and parental DA rats, suggesting that the Aplec genes are involved in the signaling events rather than the primary activation of microglia occurring upon nerve root injury. In summary, we demonstrate that a genetic variation in Aplec occurring among inbred strains regulates both survival of axotomized motor neurons and the degree of lymphocyte infiltration. These results demonstrate a hitherto unknown role for CLECs for intercellular communication that occurs after damage to the nervous system, which is relevant for neuronal survival.", - "journal_title": "Journal of neuroinflammation", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/23656637/" - } - ], - "454c6361-2274-4d5e-93b5-c0391499a682": [ - { - "pub_id": "27556512", - "title": "Coupling of LETM1 up-regulation with oxidative phosphorylation and platelet-derived growth factor receptor signaling via YAP1 transactivation.", - "authors": "Jandee Lee,Woo Kyung Lee,Mi-Youn Seol,Seul Gi Lee,Daham Kim,Hyunji Kim,Jongsun Park,Sang Geun Jung,Woong Youn Chung,Eun Jig Lee,Young Suk Jo", - "abstract": "Persistent cellular proliferation and metabolic reprogramming are essential processes in carcinogenesis. Here, we performed Gene Set Enrichment Analysis (GSEA) and found that that LETM1, a mitochondrial calcium transporter, is associated with cellular growth signals such as platelet-derived growth factor (PDGF) receptor signaling and insulin signaling pathways. These results were then verified by qRT-PCR and immnunoblotting. Mechanistically, up-regulation of LETM1 induced YAP1 nuclear accumulation, increasing the expression of PDGFB, PDGFRB and THBS4. Consistent with this, LETM1 silencing caused loss of YAP1 nuclear signal, decreasing the expression of PDGFB, PDGFRB and THBS4. Immunohistochemical staining consistently indicated a positive association between LETM1 up-regulation, YAP1 nuclear localization and high PDGFB expression. In clinical data analysis, LETM1 up-regulation in thyroid cancer was found to be related to aggressive tumor features such as lymphovascular invasion (LVI, P < 0.001) and lymph node metastasis (LNM, P = 0.011). Multivariate analysis demonstrated that LETM1 up-regulation increases the risk of LVI and LNM (OR = 3.455, 95% CI = 1.537-7.766 and OR = 3.043, 95% CI = 1.282-7.225, respectively). Collectively, these data suggest that up-regulation of LETM1 induces sustained activation of proliferative signaling pathways, such as PDGF signal pathway by AKT induced YAP1 transactivation, resulting in aggressive thyroid cancer phenotypes.", - "journal_title": "Oncotarget", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/27556512/" - } - ], - "4edce587-031c-439a-903f-253cf62bd9f3": [ - { - "pub_id": "23221088", - "title": "A fast ranking algorithm for predicting gene functions in biomolecular networks.", - "authors": "Matteo Re,Marco Mesiti,Giorgio Valentini", - "abstract": "Ranking genes in functional networks according to a specific biological function is a challenging task raising relevant performance and computational complexity problems. To cope with both these problems we developed a transductive gene ranking method based on kernelized score functions able to fully exploit the topology and the graph structure of biomolecular networks and to capture significant functional relationships between genes. We run the method on a network constructed by integrating multiple biomolecular data sources in the yeast model organism, achieving significantly better results than the compared state-of-the-art network-based algorithms for gene function prediction, and with relevant savings in computational time. The proposed approach is general and fast enough to be in perspective applied to other relevant node ranking problems in large and complex biological networks.", - "journal_title": "IEEE/ACM transactions on computational biology and bioinformatics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/23221088/" - } - ], - "5405cdac-fb5d-4e14-9bb9-83bdbf8df8c9": [ - { - "pub_id": "25505662", - "title": "Convergent functional genomics in addiction research - a translational approach to study candidate genes and gene networks.", - "authors": "Rainer Spanagel", - "abstract": "Convergent functional genomics (CFG) is a translational methodology that integrates in a Bayesian fashion multiple lines of evidence from studies in human and animal models to get a better understanding of the genetics of a disease or pathological behavior. Here the integration of data sets that derive from forward genetics in animals and genetic association studies including genome wide association studies (GWAS) in humans is described for addictive behavior. The aim of forward genetics in animals and association studies in humans is to identify mutations (e.g. SNPs) that produce a certain phenotype; i.e. \"from phenotype to genotype\". Most powerful in terms of forward genetics is combined quantitative trait loci (QTL) analysis and gene expression profiling in recombinant inbreed rodent lines or genetically selected animals for a specific phenotype, e.g. high vs. low drug consumption. By Bayesian scoring genomic information from forward genetics in animals is then combined with human GWAS data on a similar addiction-relevant phenotype. This integrative approach generates a robust candidate gene list that has to be functionally validated by means of reverse genetics in animals; i.e. \"from genotype to phenotype\". It is proposed that studying addiction relevant phenotypes and endophenotypes by this CFG approach will allow a better determination of the genetics of addictive behavior.", - "journal_title": "In silico pharmacology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/25505662/" - } - ], - "2b2d5893-7362-4881-a53a-55c2b01c0a26": [ - { - "pub_id": "26875678", - "title": "Unravelling the human genome-phenome relationship using phenome-wide association studies.", - "authors": "William S Bush,Matthew T Oetjens,Dana C Crawford", - "abstract": "Advances in genotyping technology have, over the past decade, enabled the focused search for common genetic variation associated with human diseases and traits. With the recently increased availability of detailed phenotypic data from electronic health records and epidemiological studies, the impact of one or more genetic variants on the phenome is starting to be characterized both in clinical and population-based settings using phenome-wide association studies (PheWAS). These studies reveal a number of challenges that will need to be overcome to unlock the full potential of PheWAS for the characterization of the complex human genome-phenome relationship.", - "journal_title": "Nature reviews. Genetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/26875678/" - } - ], - "667ac3eb-7d19-4359-98b7-e76871637910": [ - { - "pub_id": "25076964", - "title": "Molecular pathways underpinning ethanol-induced neurodegeneration.", - "authors": "Dan Goldowitz,Alexandre A Lussier,Julia K Boyle,Kaelan Wong,Scott L Lattimer,Candis Dubose,Lu Lu,Michael S Kobor,Kristin M Hamre", - "abstract": "While genetics impacts the type and severity of damage following developmental ethanol exposure, little is currently known about the molecular pathways that mediate these effects. Traditionally, research in this area has used a candidate gene approach and evaluated effects on a gene-by-gene basis. Recent studies, however, have begun to use unbiased approaches and genetic reference populations to evaluate the roles of genotype and epigenetic modifications in phenotypic changes following developmental ethanol exposure, similar to studies that evaluated numerous alcohol-related phenotypes in adults. Here, we present work assessing the role of genetics and chromatin-based alterations in mediating ethanol-induced apoptosis in the developing nervous system. Utilizing the expanded family of BXD recombinant inbred mice, animals were exposed to ethanol at postnatal day 7 via subcutaneous injection (5.0 g/kg in 2 doses). Tissue was collected 7 h after the initial ethanol treatment and analyzed by activated caspase-3 immunostaining to visualize dying cells in the cerebral cortex and hippocampus. In parallel, the levels of two histone modifications relevant to apoptosis, \u03b3H2AX and H3K14 acetylation, were examined in the cerebral cortex using protein blot analysis. Activated caspase-3 staining identified marked differences in cell death across brain regions between different mouse strains. Genetic analysis of ethanol susceptibility in the hippocampus led to the identification of a quantitative trait locus on chromosome 12, which mediates, at least in part, strain-specific differential vulnerability to ethanol-induced apoptosis. Furthermore, analysis of chromatin modifications in the cerebral cortex revealed a global increase in \u03b3H2AX levels following ethanol exposure, but did not show any change in H3K14 acetylation levels. Together, these findings provide new insights into the molecular mechanisms and genetic contributions underlying ethanol-induced neurodegeneration.", - "journal_title": "Frontiers in genetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/25076964/" - } - ], - "2a03c53c-2bf7-4086-9b2d-b0fdba2d3cf6": [ - { - "pub_id": "30564271", - "title": "Ethanol's Effect on <i>Coq7</i> Expression in the Hippocampus of Mice.", - "authors": "Diana Zhou,Yinghong Zhao,Michael Hook,Wenyuan Zhao,Athena Starlard-Davenport,Melloni N Cook,Byron C Jones,Kristin M Hamre,Lu Lu", - "abstract": "Coenzyme Q (CoQ) is a well-studied molecule, present in every cell membrane in the body, best known for its roles as a mitochondrial electron transporter and a potent membrane anti-oxidant. Much of the previous work was done <i>in vitro</i> in yeast and more recent work has suggested that CoQ may have additional roles prompting calls for a re-assessment of its role using <i>in vivo</i> systems in mammals. Here we investigated the putative role of Coenzyme Q in ethanol-induced effects <i>in vivo</i> using BXD RI mice. We examined hippocampal expression of <i>Coq7</i> in saline controls and after an acute ethanol treatment, noting enriched biologic processes and pathways following ethanol administration. We also identified 45 ethanol-related phenotypes that were significantly correlated with <i>Coq7</i> expression, including six phenotypes related to conditioned taste aversion and ethanol preference. This analysis highlights the need for further investigation of <i>Coq7</i> and related genes <i>in vivo</i> as well as previously unrecognized roles that it may play in the hippocampus.", - "journal_title": "Frontiers in genetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/30564271/" - } - ], - "9e26e81b-f443-4ac2-b5d2-6b19d05a968c": [ - { - "pub_id": "27314978", - "title": "The pathophysiology of post-stroke aphasia: A network approach.", - "authors": "Alexander Thiel,Anna Zumbansen", - "abstract": "Post-stroke aphasia syndromes as a clinical entity arise from the disruption of brain networks specialized in language production and comprehension due to permanent focal ischemia. This approach to post-stroke aphasia is based on two pathophysiological concepts: 1) Understanding language processing in terms of distributed networks rather than language centers and 2) understanding the molecular pathophysiology of ischemic brain injury as a dynamic process beyond the direct destruction of network centers and their connections. While considerable progress has been made in the past 10 years to develop such models on a systems as well as a molecular level, the influence of these approaches on understanding and treating clinical aphasia syndromes has been limited. In this article, we review current pathophysiological concepts of ischemic brain injury, their relationship to altered information processing in language networks after ischemic stroke and how these mechanisms may be influenced therapeutically to improve treatment of post-stroke aphasia. Understanding the pathophysiological mechanism of post-stroke aphasia on a neurophysiological systems level as well as on the molecular level becomes more and more important for aphasia treatment, as the field moves from standardized therapies towards more targeted individualized treatment strategies comprising behavioural therapies as well as non-invasive brain stimulation (NIBS).", - "journal_title": "Restorative neurology and neuroscience", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/27314978/" - } - ], - "57a57f72-7f93-46db-9388-72e4181666b4": [ - { - "pub_id": "28954905", - "title": "Offspring genes indirectly influence sibling and maternal behavioural strategies over resource share.", - "authors": "David G Ashbrook,Naorin Sharmin,Reinmar Hager", - "abstract": "Family members show behavioural strategies predicted to maximize individual fitness. These behaviours depend directly on genes expressed in focal individuals but also indirectly on genes expressed in other family members. However, how sibling and parental behavioural strategies are modified by genes expressed in family members, and to what degree, remains unclear. To answer this question, we have used a split litter design in an experimental population of genetically variable mouse families, and identified loci that indirectly affected sibling and maternal behaviour simultaneously. These loci map to genomic regions that also show a direct effect on offspring behaviour. Directly and indirectly affected traits were significantly correlated at the phenotypic level, illustrating how indirect effects are caused. Genetic variants in offspring that influence solicitation also impacted their siblings' and maternal behaviour. However, in contrast to predictions from sibling competition, unrelated litter mates benefited from increased solicitation. Overall, such indirect genetic effects explained a large proportion of variation seen in behaviours, with candidate genes involved in metabolism to neuronal development. These results reveal that we need to view behavioural strategies as the result of conjoint selection on genetic variation in all interacting family members.", - "journal_title": "Proceedings. Biological sciences", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/28954905/" - } - ], - "beb4fcfb-a920-470f-9c72-0e189e6b3fb0": [ - { - "pub_id": "23641250", - "title": "Prospects for advancing defense to cereal rusts through genetical genomics.", - "authors": "Elsa Ballini,Nick Lauter,Roger Wise", - "abstract": "Rusts are one of the most severe threats to cereal crops because new pathogen races emerge regularly, resulting in infestations that lead to large yield losses. In 1999, a new race of stem rust, Puccinia graminis f. sp. tritici (Pgt TTKSK or Ug99), was discovered in Uganda. Most of the wheat and barley cultivars grown currently worldwide are susceptible to this new race. Pgt TTKSK has already spread northward into Iran and will likely spread eastward throughout the Indian subcontinent in the near future. This scenario is not unique to stem rust; new races of leaf rust (Puccinia triticina) and stripe rust (Puccinia striiformis) have also emerged recently. One strategy for countering the persistent adaptability of these pathogens is to stack complete- and partial-resistance genes, which requires significant breeding efforts in order to reduce deleterious effects of linkage drag. These varied resistance combinations are typically more difficult for the pathogen to defeat, since they would be predicted to apply lower selection pressure. Genetical genomics or expression Quantitative Trait Locus (eQTL) analysis enables the identification of regulatory loci that control the expression of many to hundreds of genes. Integrated deployment of these technologies coupled with efficient phenotyping offers significant potential to elucidate the regulatory nodes in genetic networks that orchestrate host defense responses. The focus of this review will be to present advances in genetical genomic experimental designs and analysis, particularly as they apply to the prospects for discovering partial disease resistance alleles in cereals.", - "journal_title": "Frontiers in plant science", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/23641250/" - } - ], - "b1625eb7-f7be-4161-9a11-49aa39876337": [ - { - "pub_id": "26667416", - "title": "Genetic Variation in Renal Expression of Folate Receptor 1 (Folr1) Gene Predisposes Spontaneously Hypertensive Rats to Metabolic Syndrome.", - "authors": "Michal Pravenec,Viktor Ko\u017eich,Jakub Krijt,Jitka Sokolov\u00e1,V\u00e1clav Z\u00eddek,Vladim\u00edr Landa,Petr Mlejnek,Jan \u0160ilhav\u00fd,Miroslava \u0160im\u00e1kov\u00e1,Vojt\u011bch \u0160kop,Jaroslava Trnovsk\u00e1,Ludmila Kazdov\u00e1,Takashi Kajiya,Jiaming Wang,Theodore W Kurtz", - "abstract": "Metabolism of homocysteine and other sulfur amino acids is closely associated with metabolism of folates. In this study, we analyzed the possible role of folates and sulfur amino acids in the development of features of the metabolic syndrome in the BXH/HXB recombinant inbred strains derived from the spontaneously hypertensive rat (SHR) and Brown Norway progenitors. We mapped a quantitative trait locus for cysteine concentrations to a region of chromosome 1 that contains a cis-acting expression quantitative trait locus regulating mRNA levels of folate receptor 1 (Folr1) in the kidney. Sequence analysis revealed a deletion variant in the Folr1 promoter region of the SHR. Transfection studies demonstrated that the SHR-promoter region of Folr1 is less effective in driving luciferase reporter gene expression than the Brown Norway promoter region of Folr1. Results in the SHR.BN-chr.1 congenic strain confirmed that the SHR variant in Folr1 cosegregates with markedly reduced renal expression of Folr1 and renal folate reabsorption, decreased serum levels of folate, increased serum levels of cysteine and homocysteine, increased adiposity, ectopic fat accumulation in liver and muscle, reduced muscle insulin sensitivity, and increased blood pressure. Transgenic rescue experiments performed by expressing a Folr1 transgene in the SHR ameliorated most of the metabolic disturbances. These findings are consistent with the hypothesis that inherited variation in the expression of Folr1 in the kidney influences the development of the metabolic syndrome and constitutes a previously unrecognized genetic mechanism that may contribute to increased risk for diabetes mellitus and cardiovascular disease.", - "journal_title": "Hypertension (Dallas, Tex. : 1979)", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/26667416/" - } - ], - "0a3b2a6a-c894-4bd7-9c46-339a4fbf1f16": [ - { - "pub_id": "22998986", - "title": "Toxidromes.", - "authors": "Christopher P Holstege,Heather A Borek", - "abstract": "The critical care physician is often called to care for poisoned patients. This article reviews the general approach to the poisoned patient, specifically focusing on the utility of the toxidrome. A toxidrome is a constellation of findings, either from the physical examination or from ancillary testing, which may result from any poison. There are numerous toxidromes defined in the medical literature. This article focuses on the more common toxidromes described in clinical toxicology. Although these toxidromes can aid the clinician in narrowing the differential diagnosis, care must be exercised to realize the exceptions and limitations associated with each.", - "journal_title": "Critical care clinics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/22998986/" - } - ], - "51efbb16-ba2b-43c2-8652-f84e91601cd5": [ - { - "pub_id": "28376796", - "title": "AHCODA-DB: a data repository with web-based mining tools for the analysis of automated high-content mouse phenomics data.", - "authors": "Bastijn Koopmans,August B Smit,Matthijs Verhage,Maarten Loos", - "abstract": "Systematic, standardized and in-depth phenotyping and data analyses of rodent behaviour empowers gene-function studies, drug testing and therapy design. However, no data repositories are currently available for standardized quality control, data analysis and mining at the resolution of individual mice. Here, we present AHCODA-DB, a public data repository with standardized quality control and exclusion criteria aimed to enhance robustness of data, enabled with web-based mining tools for the analysis of individually and group-wise collected mouse phenotypic data. AHCODA-DB allows monitoring in vivo effects of compounds collected from conventional behavioural tests and from automated home-cage experiments assessing spontaneous behaviour, anxiety and cognition without human interference. AHCODA-DB includes such data from mutant mice (transgenics, knock-out, knock-in), (recombinant) inbred strains, and compound effects in wildtype mice and disease models. AHCODA-DB provides real time statistical analyses with single mouse resolution and versatile suite of data presentation tools. On March 9th, 2017 AHCODA-DB contained 650\u00a0k data points on 2419 parameters from 1563 mice. AHCODA-DB provides users with tools to systematically explore mouse behavioural data, both with positive and negative outcome, published and unpublished, across time and experiments with single mouse resolution. The standardized (automated) experimental settings and the large current dataset (1563 mice) in AHCODA-DB provide a unique framework for the interpretation of behavioural data and drug effects. The use of common ontologies allows data export to other databases such as the Mouse Phenome Database. Unbiased presentation of positive and negative data obtained under the highly standardized screening conditions increase cost efficiency of publicly funded mouse screening projects and help to reach consensus conclusions on drug responses and mouse behavioural phenotypes. The website is publicly accessible through https://public.sylics.com and can be viewed in every recent version of all commonly used browsers.", - "journal_title": "BMC bioinformatics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/28376796/" - } - ], - "8a35f162-6a46-4c52-870a-931c8d6a123f": [ - { - "pub_id": "25854887", - "title": "The interface between genetics and psychology: lessons from developmental dyslexia.", - "authors": "D V M Bishop", - "abstract": "Developmental dyslexia runs in families, and twin studies have confirmed that there is a substantial genetic contribution to poor reading. The way in which discoveries in molecular genetics are reported can be misleading, encouraging us to think that there are specific genes that might be used to screen for disorder. However, dyslexia is not a classic Mendelian disorder that is caused by a mutation in a single gene. Rather, like many other common disorders, it appears to involve combined effects of many genes and environmental factors, each of which has a small influence, possibly supplemented by rare variants that have larger effects but apply to only a minority of cases. Furthermore, to see clearer relationships between genotype and phenotype, we may need to move beyond the clinical category of dyslexia to look at underlying cognitive deficits that may be implicated in other neurodevelopmental disorders.", - "journal_title": "Proceedings. Biological sciences", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/25854887/" - } - ], - "6cbdc6cc-ae54-41c7-ba18-8f7308d53a07": [ - { - "pub_id": "23847651", - "title": "Expression, covariation, and genetic regulation of miRNA Biogenesis genes in brain supports their role in addiction, psychiatric disorders, and disease.", - "authors": "Megan K Mulligan,Candice Dubose,Junming Yue,Michael F Miles,Lu Lu,Kristin M Hamre", - "abstract": "The role of miRNA and miRNA biogenesis genes in the adult brain is just beginning to be explored. In this study we have performed a comprehensive analysis of the expression, genetic regulation, and co-expression of major components of the miRNA biogenesis pathway using human and mouse data sets and resources available on the GeneNetwork web site (genenetwork.org). We found a wide range of variation in expression in both species for key components of the pathway-Drosha, Pasha, and Dicer. Across species, tissues, and expression platforms all three genes are generally well-correlated. No single genetic locus exerts a strong and consistent influence on the expression of these key genes across murine brain regions. However, in mouse striatum, many members of the miRNA pathway are correlated-including Dicer, Drosha, Pasha, Ars2 (Srrt), Eif2c1 (Ago1), Eif2c2 (Ago2), Zcchc11, and Snip1. The expression of these genes may be partly influenced by a locus on Chromosome 9 (105.67-106.32 Mb). We explored ~1500 brain phenotypes available for the C57BL/6J \u00d7 DBA/2J (BXD) genetic mouse population in order to identify miRNA biogenesis genes correlated with traits related to addiction and psychiatric disorders. We found a significant association between expression of Dicer and Drosha in several brain regions and the response to many drugs of abuse, including ethanol, cocaine, and methamphetamine. Expression of Dicer, Drosha, and Pasha in most of the brain regions explored is strongly correlated with the expression of key members of the dopamine system. Drosha, Pasha, and Dicer expression is also correlated with the expression of behavioral traits measuring depression and sensorimotor gating, impulsivity, and anxiety, respectively. Our study provides a global survey of the expression and regulation of key miRNA biogenesis genes in brain and provides preliminary support for the involvement of these genes and their product miRNAs in addiction and psychiatric disease processes.", - "journal_title": "Frontiers in genetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/23847651/" - } - ], - "f4e26cf0-d214-41bf-b392-9c63a903b0b8": [ - { - "pub_id": "23134046", - "title": "Identifying gene networks underlying the neurobiology of ethanol and alcoholism.", - "authors": "Aaron R Wolen,Michael F Miles", - "abstract": "For complex disorders such as alcoholism, identifying the genes linked to these diseases and their specific roles is difficult. Traditional genetic approaches, such as genetic association studies (including genome-wide association studies) and analyses of quantitative trait loci (QTLs) in both humans and laboratory animals already have helped identify some candidate genes. However, because of technical obstacles, such as the small impact of any individual gene, these approaches only have limited effectiveness in identifying specific genes that contribute to complex diseases. The emerging field of systems biology, which allows for analyses of entire gene networks, may help researchers better elucidate the genetic basis of alcoholism, both in humans and in animal models. Such networks can be identified using approaches such as high-throughput molecular profiling (e.g., through microarray-based gene expression analyses) or strategies referred to as genetical genomics, such as the mapping of expression QTLs (eQTLs). Characterization of gene networks can shed light on the biological pathways underlying complex traits and provide the functional context for identifying those genes that contribute to disease development.", - "journal_title": "Alcohol research : current reviews", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/23134046/" - } - ], - "7ff645bd-dde4-4eac-a0a0-1c3469142fc2": [ - { - "pub_id": "27432260", - "title": "Differential potassium channel gene regulation in BXD mice reveals novel targets for pharmacogenetic therapies to reduce heavy alcohol drinking.", - "authors": "Jennifer A Rinker,Diana B Fulmer,Heather Trantham-Davidson,Maren L Smith,Robert W Williams,Marcelo F Lopez,Patrick K Randall,L Judson Chandler,Michael F Miles,Howard C Becker,Patrick J Mulholland", - "abstract": "Alcohol (ethanol) dependence is a chronic relapsing brain disorder partially influenced by genetics and characterized by an inability to regulate harmful levels of drinking. Emerging evidence has linked genes that encode K<sub>V</sub>7, K<sub>IR</sub>, and K<sub>Ca</sub>2 K<sup>+</sup> channels with variation in alcohol-related behaviors in rodents and humans. This led us to experimentally test relations between K<sup>+</sup> channel genes and escalation of drinking in a chronic-intermittent ethanol (CIE) exposure model of dependence in BXD recombinant inbred strains of mice. Transcript levels for K<sup>+</sup> channel genes in the prefrontal cortex (PFC) and nucleus accumbens (NAc) covary with voluntary ethanol drinking in a non-dependent cohort. Transcripts that encode K<sub>V</sub>7 channels covary negatively with drinking in non-dependent BXD strains. Using a pharmacological approach to validate the genetic findings, C57BL/6J mice were allowed intermittent access to ethanol to establish baseline consumption before they were treated with retigabine, an FDA-approved K<sub>V</sub>7 channel positive modulator. Systemic administration significantly reduced drinking, and consistent with previous evidence, retigabine was more effective at reducing voluntary consumption in high-drinking than low-drinking subjects. We evaluated the specific K<sup>+</sup> channel genes that were most sensitive to CIE exposure and identified a gene subset in the NAc and PFC that were dysregulated in the alcohol-dependent BXD cohort. CIE-induced modulation of nine genes in the NAc and six genes in the PFC covaried well with the changes in drinking induced by ethanol dependence. Here we identified novel candidate genes in the NAc and PFC that are regulated by ethanol dependence and correlate with voluntary drinking in non-dependent and dependent BXD mice. The findings that Kcnq expression correlates with drinking and that retigabine reduces consumption suggest that K<sub>V</sub>7 channels could be pharmacogenetic targets to treat individuals with alcohol addiction.", - "journal_title": "Alcohol (Fayetteville, N.Y.)", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/27432260/" - } - ], - "33814fad-d831-46f5-b41f-ff31626a82ca": [ - { - "pub_id": "25181545", - "title": "The pore-domain of TRPA1 mediates the inhibitory effect of the antagonist 6-methyl-5-(2-(trifluoromethyl)phenyl)-1H-indazole.", - "authors": "Hans Moldenhauer,Ramon Latorre,J\u00f6rg Grandl", - "abstract": "The transient receptor potential ion channel TRPA1 confers the ability to detect tissue damaging chemicals to sensory neurons and as a result mediates chemical nociception in vivo. Mouse TRPA1 is activated by electrophilic compounds such as mustard-oil and several physical stimuli such as cold temperature. Due to its sensory function inhibition of TRPA1 activity might provide an effective treatment against chronic and inflammatory pain. Therefore, TRPA1 has become a target for the development of analgesic drugs. 6-Methyl-5-(2-(trifluoromethyl)phenyl)-1H-indazole (Compound 31) has been identified by a chemical screen and lead optimization as an inhibitor of chemical activation of TRPA1. However, the structures or domains of TRPA1 that mediate the inhibitory effect of Compound 31 are unknown. Here, we screened 12,000 random mutant clones of mouse TRPA1 for their sensitivity to mustard-oil and the ability of Compound 31 to inhibit chemical activation by mustard-oil. In addition, we separately screened this mutant library while stimulating it with cold temperatures. We found that the single-point mutation I624N in the N-terminus of TRPA1 specifically affects the sensitivity to mustard-oil, but not to cold temperatures. This is evidence that sensitivity of TRPA1 to chemicals and cold temperatures is conveyed by separable mechanisms. We also identified five mutations located within the pore domain that cause loss of inhibition by Compound 31. This result demonstrates that the pore-domain is a regulator of chemical activation and suggests that Compound 31 might be acting directly on the pore-domain.", - "journal_title": "PloS one", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/25181545/" - } - ], - "5e2ae646-2c4a-499c-a22a-6cb88c6fa49c": [ - { - "pub_id": "23978599", - "title": "A crystallin gene network in the mouse retina.", - "authors": "Justin P Templeton,XiangDi Wang,Natalie E Freeman,Zhiwei Ma,Anna Lu,Fielding Hejtmancik,Eldon E Geisert", - "abstract": "The present study was designed to examine the regulation of crystallin genes and protein in the mouse retina using the BXD recombinant inbred (RI) strains. Illumina Sentrix BeadChip Arrays (MouseWG-6v2) were used to analyze mRNA levels in 75 BXD RI strains along with the parental strains (C57Bl/6J and DBA/2J), and the reciprocal crosses in the Hamilton Eye Institute (HEI) Retina Dataset (www.genenetwork.org). Protein levels were investigated using immunoblots to quantify levels of proteins and indirect immunohistochemistry to define the distribution of protein. Algorithms in the Genomatix program were used to identify transcription factor binding sites common to the regulatory sequences in the 5' regions of co-regulated set of crystallin and other genes as compared to a set of control genes. As subset of genes, including many encoding lens crystallins is part of a tightly co-regulated network that is active in the retina. Expression of this crystallin network appears to be binary in nature, being expressed either at relatively low levels or being highly upregulated. Relative to a control set of genes, the 5' regulatory sequences of the crystallin network genes show an increased frequency of a set of common transcription factor-binding sites, the most common being those of the Maf family. Chromatin immunoprecipitation of human lens epithelial cells (HLEC) and rat retinal ganglion cells (RGC) confirmed the functionality of these sites, showing that MafA binds the predicted sites of CRYGA and CRYGD in HLE and CRYAB, CRYGA, CRYBA1, and CRYBB3 in RGC cells. In the retina there is a highly correlated group of genes containing many members of the \u03b1- \u03b2- and \u03b3-crystallin families. These genes can be dramatically upregulated in the retina. One transcription factor that appears to be involved in this coordinated expression is the MAF family transcription of factors associated with both lens and extralenticular expression of crystallin genes.", - "journal_title": "Experimental eye research", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/23978599/" - } - ], - "72540038-5deb-4d24-b932-f094615d9d60": [ - { - "pub_id": "26506367", - "title": "The Mental Health Outcomes of Drought: A Systematic Review and Causal Process Diagram.", - "authors": "Holly Vins,Jesse Bell,Shubhayu Saha,Jeremy J Hess", - "abstract": "Little is understood about the long term, indirect health consequences of drought (a period of abnormally dry weather). In particular, the implications of drought for mental health via pathways such as loss of livelihood, diminished social support, and rupture of place bonds have not been extensively studied, leaving a knowledge gap for practitioners and researchers alike. A systematic review of literature was performed to examine the mental health effects of drought. The systematic review results were synthesized to create a causal process diagram that illustrates the pathways linking drought effects to mental health outcomes. Eighty-two articles using a variety of methods in different contexts were gathered from the systematic review. The pathways in the causal process diagram with greatest support in the literature are those focusing on the economic and migratory effects of drought. The diagram highlights the complexity of the relationships between drought and mental health, including the multiple ways that factors can interact and lead to various outcomes. The systematic review and resulting causal process diagram can be used in both practice and theory, including prevention planning, public health programming, vulnerability and risk assessment, and research question guidance. The use of a causal process diagram provides a much needed avenue for integrating the findings of diverse research to further the understanding of the mental health implications of drought.", - "journal_title": "International journal of environmental research and public health", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/26506367/" - } - ], - "d09e59f1-14d1-4391-8419-90c6d6bc2fde": [ - { - "pub_id": "29046401", - "title": "Reconstructing the Molecular Function of Genetic Variation in Regulatory Networks.", - "authors": "Roni Wilentzik,Chun Jimmie Ye,Irit Gat-Viks", - "abstract": "Over the past decade, genetic studies have recognized hundreds of polymorphic DNA loci called response QTLs (reQTLs) as potential contributors to interindividual variation in transcriptional responses to stimulations. Such reQTLs commonly affect the transduction of signals along the regulatory network that controls gene transcription. Identifying the pathways through which reQTLs perturb the underlying network has been a major challenge. Here, we present GEVIN (\"Genome-wide Embedding of Variation In Networks\"), a methodology that simultaneously identifies a reQTL and the particular pathway in which the reQTL affects downstream signal transduction along the network. Using synthetic data, we show that this algorithm outperforms existing pathway identification and reQTL identification methods. We applied GEVIN to the analysis of murine and human dendritic cells in response to pathogenic components. These analyses revealed significant reQTLs together with their perturbed Toll-like receptor signaling pathways. GEVIN thus offers a powerful framework that renders a comprehensive picture of disease-related DNA loci and their molecular functions within regulatory networks.", - "journal_title": "Genetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/29046401/" - } - ], - "083e1297-ba25-498f-b9e0-77089e04b049": [ - { - "pub_id": "25418976", - "title": "A novel genetic locus linked to pro-inflammatory cytokines after virulent H5N1 virus infection in mice.", - "authors": "Adrianus C M Boon,Robert W Williams,David S Sinasac,Richard J Webby", - "abstract": "Genetic variation in the human population is a key determinant of influenza disease severity. A single nucleotide polymorphism in the antiviral gene IFITM3 was linked to outcomes during the 2009 H1N1 pandemic. To identify variant host genes associated with increased virus replication and severe disease, we performed a quantitative trait locus analysis on pro-inflammatory cytokine production 48 hours after intranasal infection with highly pathogenic H5N1 influenza virus. Pro-inflammatory cytokines CCL2, TNF\u03b1 and IFN-\u03b1, were measured by ELISA in lung homogenates of DBA/2J (D2), C57BL/6J (B6) and 44 different BXD recombinant inbred mouse strains. Virus titer was also assessed in a subset of these animals. CCL2 (8-fold), TNF\u03b1 (24-fold) and IFN-\u03b1 (8-fold) concentrations varied significantly among the different BXD RI strains. Importantly, cytokine concentration correlated very well (r =0.86-0.96, P <0.0001) with virus titer suggesting that early cytokine production is due to increased virus infection and replication. Linkage analysis of cytokine concentration revealed a significant locus on chromosome 6 associated with differences in TNF\u03b1, IFN-\u03b1 and CCL2 cytokine concentration (LRS =26). This locus accounted for nearly 20% of the observed phenotypic variation in the BXD population studied. Sequence and RNA expression analysis identified several candidate host genes containing missense mutations or deletions; Samd9l, Ica1, and Slc25a13. To study the role of Slc25a13, we obtained Slc25a13 knockout line, but upon challenge with H5N1 influenza virus observed no effect on CCL2 production, or morbidity and mortality. A novel genetic locus on chromosome 6 modulates early pro-inflammatory cytokine production and virus replication after highly pathogenic influenza virus infection. Candidate genes, Samd9l and Ica1, may be important for the control of influenza virus infection and pathogenesis.", - "journal_title": "BMC genomics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/25418976/" - } - ], - "65d16255-3edd-46fb-a100-2ab8ba6abcdd": [ - { - "pub_id": "27663419", - "title": "Inhibiting poly ADP-ribosylation increases fatty acid oxidation and protects against fatty liver disease.", - "authors": "Karim Gariani,Dongryeol Ryu,Keir J Menzies,Hyon-Seung Yi,Sokrates Stein,Hongbo Zhang,Alessia Perino,Vera Lemos,Elena Katsyuba,Pooja Jha,Sandrine Vijgen,Laura Rubbia-Brandt,Yong Kyung Kim,Jung Tae Kim,Koon Soon Kim,Minho Shong,Kristina Schoonjans,Johan Auwerx", - "abstract": "To date, no pharmacological therapy has been approved for non-alcoholic fatty liver disease (NAFLD). The aim of the present study was to evaluate the therapeutic potential of poly ADP-ribose polymerase (PARP) inhibitors in mouse models of NAFLD. As poly ADP-ribosylation (PARylation) of proteins by PARPs consumes nicotinamide adenine dinucleotide (NAD<sup>+</sup>), we hypothesized that overactivation of PARPs drives NAD<sup>+</sup> depletion in NAFLD. Therefore, we assessed the effectiveness of PARP inhibition to replenish NAD<sup>+</sup> and activate NAD<sup>+</sup>-dependent sirtuins, hence improving hepatic fatty acid oxidation. To do this, we examined the preventive and therapeutic benefits of the PARP inhibitor (PARPi), olaparib, in different models of NAFLD. The induction of NAFLD in C57BL/6J mice using a high-fat high-sucrose (HFHS)-diet increased PARylation of proteins by PARPs. As such, increased PARylation was associated with reduced NAD<sup>+</sup> levels and mitochondrial function and content, which was concurrent with elevated hepatic lipid content. HFHS diet supplemented with PARPi reversed NAFLD through repletion of NAD<sup>+</sup>, increasing mitochondrial biogenesis and \u03b2-oxidation in liver. Furthermore, PARPi reduced reactive oxygen species, endoplasmic reticulum stress and fibrosis. The benefits of PARPi treatment were confirmed in mice fed with a methionine- and choline-deficient diet and in mice with lipopolysaccharide-induced hepatitis; PARP activation was attenuated and the development of hepatic injury was delayed in both models. Using Sirt1<sup>hep-/-</sup> mice, the beneficial effects of a PARPi-supplemented HFHS diet were found to be Sirt1-dependent. Our study provides a novel and practical pharmacological approach for treating NAFLD, fueling optimism for potential clinical studies. Non-alcoholic fatty liver disease (NAFLD) is now considered to be the most common liver disease in the Western world and has no approved pharmacological therapy. PARP inhibitors given as a treatment in two different mouse models of NAFLD confer a protection against its development. PARP inhibitors may therefore represent a novel and practical pharmacological approach for treating NAFLD.", - "journal_title": "Journal of hepatology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/27663419/" - } - ], - "8b73f48b-0ecf-4d0a-93bc-b028b2725b89": [ - { - "pub_id": "25681686", - "title": "PTPN21 exerts pro-neuronal survival and neuritic elongation via ErbB4/NRG3 signaling.", - "authors": "Janice Hiu-Chor Plani-Lam,Tai-Cheong Chow,Kam-Leung Siu,Wing Hin Chau,Ming-Him James Ng,Suying Bao,Cheung Toa Ng,Pak Sham,Daisy Kwok-Yan Shum,Evan Ingley,Dong-Yan Jin,You-Qiang Song", - "abstract": "Although expression quantitative trait locus, eQTL, serves as an explicit indicator of gene-gene associations, challenges remain to disentangle the mechanisms by which genetic variations alter gene expression. Here we combined eQTL and molecular analyses to identify an association between two seemingly non-associated genes in brain expression data from BXD inbred mice, namely Ptpn21 and Nrg3. Using biotinylated receptor tracking and immunoprecipitation analyses, we determined that PTPN21 de-phosphorylates the upstream receptor tyrosine kinase ErbB4 leading to the up-regulation of its downstream signaling. Conversely, kinase-dead ErbB4 (K751R) or phosphatase-dead PTPN21 (C1108S) mutants impede PTPN21-dependent signaling. Furthermore, PTPN21 also induced Elk-1 activation in embryonic cortical neurons and a novel Elk-1 binding motif was identified in a region located 1919bp upstream of the NRG3 initiation codon. This enables PTPN21 to promote NRG3 expression through Elk-1, which provides a biochemical mechanism for the PTPN21-NRG3 association identified by eQTL. Biologically, PTPN21 positively influences cortical neuronal survival and, similar to Elk-1, it also enhances neuritic length. Our combined approaches show for the first time, a link between NRG3 and PTPN21 within a signaling cascade. This may explain why these two seemingly unrelated genes have previously been identified as risk genes for schizophrenia.", - "journal_title": "The international journal of biochemistry & cell biology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/25681686/" - } - ], - "5774f996-3411-4ae4-993e-8d54ade94dbf": [ - { - "pub_id": "26802973", - "title": "Genetic expression analysis of E2F-associated phosphoprotein in stress responses in the mouse.", - "authors": "Chengwei Duan,Ying Chen,Aiguo Shen,Jian Xu,Yinghong Zhao,Rixin Cai,Yonghua Liu,Li Zhou,Yan Lei,Kristin Hamre,Lu Lu", - "abstract": "Dysfunction of the monoaminergic system is critical in stress and anxiety disorders, but the role of each family member in the development of stress-related psychopathologies is not sufficiently understood. Eapp has been reported to be a transcriptional repressor of monoamine oxidase B (Maob) and down-regulates Maob via the Maob core promoter. In the present study, we more specifically examine the role of Eapp in stress responses by testing the hypothesis that Eapp may be involved in the occurrence and development of stress responses. Western blotting, qPCR and immunohistochemistry were used to investigate the expression variation of Eapp in hypothalamus tissue after exposure to stress. The expression of Eapp is controlled by a cis-acting quantitative trait locus (cis-eQTL). Two genes Sphk2 and Nosip, had trans-eQTLs that mapped to the location of Eapp and altered expression of these two genes was shown following siRNA knockdown of Eapp. Additionally, Mmp9, Npy, Npy5r and Maob were shown to have different expression levels in the Eapp knock-down experiments. Our data provide strong evidence that the cis-modulated gene, Eapp, is associated with stress responses, and that validated downstream targets and members of Eapp gene network may also be involved in the development of stress.", - "journal_title": "Gene", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/26802973/" - } - ], - "f92e167e-0375-45b7-9d91-f8a4d0e1fbba": [ - { - "pub_id": "25565948", - "title": "Transcript co-variance with Nestin in two mouse genetic reference populations identifies Lef1 as a novel candidate regulator of neural precursor cell proliferation in the adult hippocampus.", - "authors": "David G Ashbrook,Anna Delprato,Claudia Grellmann,Marieke Klein,Richard Wetzel,Rupert W Overall,Alexandra Badea", - "abstract": "Adult neurogenesis, the lifelong production of new neurons in the adult brain, is under complex genetic control but many of the genes involved remain to be identified. In this study, we have integrated publicly available gene expression data from the BXD and CXB recombinant inbred mouse lines to discover genes co-expressed in the adult hippocampus with Nestin, a common marker of the neural precursor cell population. In addition, we incorporated spatial expression information to restrict candidates to genes with high differential gene expression in the hippocampal dentate gyrus. Incorporating data from curated protein-protein interaction databases revealed interactions between our candidate genes and those already known to be involved in adult neurogenesis. Enrichment analysis suggested a link to the Wnt/\u03b2-catenin pathway, known to be involved in adult neurogenesis. In particular, our candidates were enriched in targets of Lef1, a modulator of the Wnt pathway. In conclusion, our combination of bioinformatics approaches identified six novel candidate genes involved in adult neurogenesis; Amer3, Eya3, Mtdh, Nr4a3, Polr2a, and Tbkbp1. Further, we propose a role for Lef1 transcriptional control in the regulation of adult hippocampal precursor cell proliferation.", - "journal_title": "Frontiers in neuroscience", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/25565948/" - } - ], - "0477b96a-60c8-4ed3-860b-d4cc34370872": [ - { - "pub_id": "22792880", - "title": "The social life of neurons: synaptic communication deficits as a common denominator of autism, schizophrenia, and other cognitive disorders.", - "authors": "Detlef H Heck,Lu Lu", - "abstract": "", - "journal_title": "Biological psychiatry", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/22792880/" - } - ], - "57943aca-38a5-4030-bf34-c760f0e7f775": [ - { - "pub_id": "24954025", - "title": "Independent genomic control of neuronal number across retinal cell types.", - "authors": "Patrick W Keeley,Irene E Whitney,Nils R Madsen,Ace J St John,Sarra Borhanian,Stephanie A Leong,Robert W Williams,Benjamin E Reese", - "abstract": "The sizes of different neuronal populations within the CNS are precisely controlled, but whether neuronal number is coordinated between cell types is unknown. We examined the covariance structure of 12 different retinal cell types across 30 genetically distinct lines of mice, finding minimal covariation when comparing synaptically connected or developmentally related cell types. Variation mapped to one or more genomic loci for each cell type, but rarely were these shared, indicating minimal genetic coregulation of final number. Multiple genes, therefore, participate in the specification of the size of every population of retinal neuron, yet genetic variants work largely independent of one another during development to modulate those numbers, yielding substantial variability in the convergence ratios between pre- and postsynaptic populations. Density-dependent cellular interactions in the outer plexiform layer overcome this variability to ensure the formation of neuronal circuits that maintain constant retinal coverage and complete afferent sampling.", - "journal_title": "Developmental cell", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/24954025/" - } - ], - "1577c7cc-1c4a-45a8-8770-6638a924e6da": [ - { - "pub_id": "23437185", - "title": "Elevated expression of H19 and Igf2 in the female mouse eye.", - "authors": "Bj\u00f6rn Reinius,Chandrasekhar Kanduri", - "abstract": "The catalogue of genes expressed at different levels in the two sexes is growing, and the mechanisms underlying sex differences in regulation of the mammalian transcriptomes are being explored. Here we report that the expression of the imprinted non-protein-coding maternally expressed gene H19 was female-biased specifically in the female mouse eye (1.9-fold, p = 3.0E-6) while not being sex-biased in other somatic tissues. The female-to-male expression fold-change of H19 fell in the range expected from an effect of biallelic versus monoallelic expression. Recently, the possibility of sex-specific parent-of-origin allelic expression has been debated. This led us to hypothesize that H19 might express biallelically in the female mouse eye, thus escape its silencing imprint on the paternal allele specifically in this tissue. We therefore performed a sex-specific imprinting assay of H19 in female and male eye derived from a cross between Mus musculus and Mus spretus. However, this analysis demonstrated that H19 was exclusively expressed from the maternal gene copy, disproving the escape hypothesis. Instead, this supports that the female-biased expression of H19 is the result of upregulation of the single maternal. Furthermore, if H19 would have been expressed from both gene copies in the female eye, an associated downregulation of Insulin-like growth factor 2 (Igf2) was expected, since H19 and Igf2 compete for a common enhancer element located in the H19/Igf2 imprinted domain. On the contrary we found that also Igf2 was significantly upregulated in its expression in the female eye (1.2-fold, p = 6.1E-3), in further agreement with the conclusion that H19 is monoallelically elevated in females. The female-biased expression of H19 and Igf2 specifically in the eye may contribute to our understanding of sex differences in normal as well as abnormal eye physiology and processes.", - "journal_title": "PloS one", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/23437185/" - } - ], - "f135bf11-96d4-4c0d-b058-7b97b3dbb388": [ - { - "pub_id": "27503415", - "title": "Quantitative trait gene Slit2 positively regulates murine hematopoietic stem cell numbers.", - "authors": "Amanda Waterstrat,Kyle Rector,Hartmut Geiger,Ying Liang", - "abstract": "Hematopoietic stem cells (HSC) demonstrate natural variation in number and function. The genetic factors responsible for the variations (or quantitative traits) are largely unknown. We previously identified a gene whose differential expression underlies the natural variation of HSC numbers in C57BL/6 (B6) and DBA/2 (D2) mice. We now report the finding of another gene, Slit2, on chromosome 5 that also accounts for variation in HSC number. In reciprocal chromosome 5 congenic mice, introgressed D2 alleles increased HSC numbers, whereas B6 alleles had the opposite effect. Using gene array and quantitative polymerase chain reaction, we identified Slit2 as a quantitative trait gene whose expression was positively correlated with the number of HSCs. Ectopic expression of Slit2 not only increased the number of the long-term colony forming HSCs, but also enhanced their repopulation capacity upon transplantation. Therefore, Slit2 is a novel quantitative trait gene and a positive regulator of the number and function of murine HSCs. This finding suggests that Slit2 may be a potential therapeutic target for the effective in vitro and in vivo expansion of HSCs without compromising normal hematopoiesis.", - "journal_title": "Scientific reports", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/27503415/" - } - ], - "58479ce8-1153-46ae-b83a-606b446d55e2": [ - { - "pub_id": "26829228", - "title": "The Genetic Architecture of Murine Glutathione Transferases.", - "authors": "Lu Lu,Ashutosh K Pandey,M Trevor Houseal,Megan K Mulligan", - "abstract": "Glutathione S-transferase (GST) genes play a protective role against oxidative stress and may influence disease risk and drug pharmacokinetics. In this study, massive multiscalar trait profiling across a large population of mice derived from a cross between C57BL/6J (B6) and DBA2/J (D2)--the BXD family--was combined with linkage and bioinformatic analyses to characterize mechanisms controlling GST expression and to identify downstream consequences of this variation. Similar to humans, mice show a wide range in expression of GST family members. Variation in the expression of Gsta4, Gstt2, Gstz1, Gsto1, and Mgst3 is modulated by local expression QTLs (eQTLs) in several tissues. Higher expression of Gsto1 in brain and liver of BXD strains is strongly associated (P < 0.01) with inheritance of the B6 parental allele whereas higher expression of Gsta4 and Mgst3 in brain and liver, and Gstt2 and Gstz1 in brain is strongly associated with inheritance of the D2 parental allele. Allele-specific assays confirmed that expression of Gsto1, Gsta4, and Mgst3 are modulated by sequence variants within or near each gene locus. We exploited this endogenous variation to identify coexpression networks and downstream targets in mouse and human. Through a combined systems genetics approach, we provide new insight into the biological role of naturally occurring variants in GST genes.", - "journal_title": "PloS one", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/26829228/" - } - ], - "778e63d4-18ec-4c0d-a221-bddffd5335f6": [ - { - "pub_id": "28135824", - "title": "Primer in Genetics and Genomics, Article 2-Advancing Nursing Research With Genomic Approaches.", - "authors": "Hyunhwa Lee,Jessica Gill,Taura Barr,Sijung Yun,Hyungsuk Kim", - "abstract": "Nurses investigate reasons for variable patient symptoms and responses to treatments to inform how best to improve outcomes. Genomics has the potential to guide nursing research exploring contributions to individual variability. This article is meant to serve as an introduction to the novel methods available through genomics for addressing this critical issue and includes a review of methodological considerations for selected genomic approaches. This review presents essential concepts in genetics and genomics that will allow readers to identify upcoming trends in genomics nursing research and improve research practice. It introduces general principles of genomic research and provides an overview of the research process. It also highlights selected nursing studies that serve as clinical examples of the use of genomic technologies. Finally, the authors provide suggestions about how to apply genomic technology in nursing research along with directions for future research. Using genomic approaches in nursing research can advance the understanding of the complex pathophysiology of disease susceptibility and different patient responses to interventions. Nurses should be incorporating genomics into education, clinical practice, and research as the influence of genomics in health-care research and practice continues to grow. Nurses are also well placed to translate genomic discoveries into improved methods for patient assessment and intervention.", - "journal_title": "Biological research for nursing", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/28135824/" - } - ], - "3ce6e8a4-aaf9-40c5-9a0d-d2f4e41427bb": [ - { - "pub_id": "32605855", - "title": "Reply.", - "authors": "Valentin Navel,Fr\u00e9d\u00e9ric Chiambaretta,Fr\u00e9d\u00e9ric Dutheil", - "abstract": "", - "journal_title": "The Journal of allergy and clinical immunology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/32605855/" - } - ], - "219dcc39-dac7-45a5-bc1d-c08a842e8c41": [ - { - "pub_id": "35388180", - "title": "Corticolimbic DCC gene co-expression networks as predictors of impulsivity in children.", - "authors": "Jose M Restrepo-Lozano,Irina Pokhvisneva,Zihan Wang,Sachin Patel,Michael J Meaney,Patricia P Silveira,Cecilia Flores", - "abstract": "Inhibitory control deficits are prevalent in multiple neuropsychiatric conditions. The communication- as well as the connectivity- between corticolimbic regions of the brain are fundamental for eliciting inhibitory control behaviors, but early markers of vulnerability to this behavioral trait are yet to be discovered. The gradual maturation of the prefrontal cortex (PFC), in particular of the mesocortical dopamine innervation, mirrors the protracted development of inhibitory control; both are present early in life, but reach full maturation by early adulthood. Evidence suggests the involvement of the Netrin-1/DCC signaling pathway and its associated gene networks in corticolimbic development. Here we investigated whether an expression-based polygenic score (ePRS) based on corticolimbic-specific DCC gene co-expression networks associates with impulsivity-related phenotypes in community samples of children. We found that lower ePRS scores associate with higher measurements of impulsive choice in 6-year-old children tested in the Information Sampling Task and with\u00a0impulsive action in 6- and 10-year-old children tested in the Stop Signal Task. We also found the ePRS to be a better overall predictor of impulsivity when compared to a conventional PRS score comparable in size to the ePRS (4515 SNPs in our discovery cohort) and\u00a0derived from the latest GWAS for ADHD. We propose that the corticolimbic DCC-ePRS can serve as a novel type of marker for impulsivity-related phenotypes in children. By adopting a systems biology approach based on gene co-expression networks and genotype-gene expression (rather than genotype-disease) associations, these results further validate our methodology to construct polygenic scores linked to the overall biological function of tissue-specific gene networks.", - "journal_title": "Molecular psychiatry", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/35388180/" - } - ], - "64886b4e-8599-4f61-84e6-9add7663a1b3": [ - { - "pub_id": "30962542", - "title": "Highly efficient expression of circular RNA aptamers in cells using autocatalytic transcripts.", - "authors": "Jacob L Litke,Samie R Jaffrey", - "abstract": "RNA aptamers and RNA aptamer-based devices can be genetically encoded and expressed in cells to probe and manipulate cellular function. However, their usefulness in the mammalian cell is limited by low expression and rapid degradation. Here we describe the Tornado (Twister-optimized RNA for durable overexpression) expression system for achieving rapid RNA circularization, resulting in RNA aptamers with high stability and expression levels. Tornado-expressed transcripts contain an RNA of interest flanked by Twister ribozymes. The ribozymes rapidly undergo autocatalytic cleavage, leaving termini that are ligated by the ubiquitous endogenous RNA ligase RtcB. Using this approach, protein-binding aptamers that otherwise have minimal effects in cells become potent inhibitors of cellular signaling. Additionally, an RNA-based fluorescent metabolite biosensor for S-adenosyl methionine (SAM) that is expressed at low levels when expressed as a linear RNA achieves levels sufficient for detection of intracellular SAM dynamics when expressed as a circular RNA. The Tornado expression system thus markedly enhances the utility of RNA-based approaches in the mammalian cell.", - "journal_title": "Nature biotechnology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/30962542/" - } - ], - "823584b3-e9c5-469e-a1dc-ce7f617bd2fa": [ - { - "pub_id": "32615731", - "title": "Serotonin Regulates De Novo Lipogenesis in Adipose Tissues through Serotonin Receptor 2A.", - "authors": "Ko Eun Shong,Chang-Myung Oh,Jun Namkung,Sangkyu Park,Hail Kim", - "abstract": "Obesity is defined as excessive fat mass and is a major cause of many chronic diseases such as diabetes, cardiovascular disease, and cancer. Increasing energy expenditure and regulating adipose tissue metabolism are important targets for the treatment of obesity. Serotonin (5-hydroxytryptophan [5-HT]) is a monoamine metabolite of the essential amino acid tryptophan. Here, we demonstrated that 5-HT in mature adipocytes regulated energy expenditure and lipid metabolism. Tryptophan hydroxylase 1 (TPH1) is the rate-limiting enzyme during 5-HT synthesis in non-neural peripheral tissues. We generated adipose tissue-specific Tph1 knockout (Tph1 FKO) mice and adipose tissue-specific serotonin receptor 2A KO (Htr2a FKO) mice and analyzed their phenotypes during high-fat diet (HFD) induced obesity. Tph1 FKO mice fed HFD exhibited reduced lipid accumulation, increased thermogenesis, and resistance to obesity. In addition, Htr2a FKO mice fed HFD showed reduced lipid accumulation in white adipose tissue and resistance to obesity. These data suggest that the inhibition of serotonin signaling might be an effective strategy in obesity.", - "journal_title": "Endocrinology and metabolism (Seoul, Korea)", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/32615731/" - } - ], - "5410301d-afc6-4773-8e2c-272eb9079aa4": [ - { - "pub_id": "31672980", - "title": "A multi-omics digital research object for the genetics of sleep regulation.", - "authors": "Maxime Jan,Nastassia Gobet,Shanaz Diessler,Paul Franken,Ioannis Xenarios", - "abstract": "With the aim to uncover the molecular pathways underlying the regulation of sleep, we recently assembled an extensive and comprehensive systems genetics dataset interrogating a genetic reference population of mice at the levels of the genome, the brain and liver transcriptomes, the plasma metabolome, and the sleep-wake phenome. To facilitate a meaningful and efficient re-use of this public resource by others we designed, describe in detail, and made available a Digital Research Object (DRO), embedding data, documentation, and analytics. We present and discuss both the advantages and limitations of our multi-modal resource and analytic pipeline. The reproducibility of the results was tested by a bioinformatician not implicated in the original project and the robustness of results was assessed by re-annotating genetic and transcriptome data from the mm9 to the mm10 mouse genome assembly.", - "journal_title": "Scientific data", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/31672980/" - } - ], - "cb76344a-9307-4a44-b6b2-455b728bb249": [ - { - "pub_id": "29335692", - "title": "Marine natural products.", - "authors": "John W Blunt,Anthony R Carroll,Brent R Copp,Rohan A Davis,Robert A Keyzers,Mich\u00e8le R Prinsep", - "abstract": "Covering: 2016. Previous review: Nat. Prod. Rep., 2017, 34, 235-294This review covers the literature published in 2016 for marine natural products (MNPs), with 757 citations (643 for the period January to December 2016) referring to compounds isolated from marine microorganisms and phytoplankton, green, brown and red algae, sponges, cnidarians, bryozoans, molluscs, tunicates, echinoderms, mangroves and other intertidal plants and microorganisms. The emphasis is on new compounds (1277 in 432 papers for 2016), together with the relevant biological activities, source organisms and country of origin. Reviews, biosynthetic studies, first syntheses, and syntheses that led to the revision of structures or stereochemistries, have been included.", - "journal_title": "Natural product reports", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/29335692/" - } - ], - "44aca4d8-cd8b-4243-a79f-02a3884604c6": [ - { - "pub_id": "27933539", - "title": "Systems Genetics Analysis of Iron and Its Regulation in Brain and Periphery.", - "authors": "Byron C Jones,Leslie C Jellen", - "abstract": "In this contribution, we demonstrate the utility of the systems genetics-systems biology approach to the study of iron regulation while employing a comprehensive database. We describe our work in iron regulation in the brain and periphery under normal iron and iron-restricted dietary conditions in the BXD family of recombinant inbred mouse strains. Using multiple measures, we showed wide variation among the strains in the effect of being fed an iron-restricted diet for 100 days in every measure from brain and from the periphery. All data were entered into GeneNetwork ( www.genenetwork.org ), a database that contains genotypic, phenotypic, and gene expression data (Rosen et al., Methods Mol Biol 401:287-303, 2007). Using this resource, we were able to ask the following four questions concerning possible candidate genes underlying our measures: (1) what is the range of response for each of the measures? (2) Does the pattern of variability show continuous (additive genetic) or discrete (Mendelian) distribution across strains? (3) Are there genetic markers that are associated with the variability in the measures? (4) Are there genes in near the markers that contain associated allelic differences, and whose expression is related to the variability in the measures? Other questions that we could address include: (5) what is the association among the measures between the sexes? (6) What is the association among the measures, e.g., is liver iron status under the diets related to brain iron? (7) What is the relationship between our measures and other phenotypic parameters-i.e., is there an association between our brain iron measures and neurochemical phenotypes extant in the database? And finally, (8) are there gene networks that underlie single or combined measures?", - "journal_title": "Methods in molecular biology (Clifton, N.J.)", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/27933539/" - } - ], - "5a56fa6d-9e77-4b95-a836-04d0fa31ee2c": [ - { - "pub_id": "27206819", - "title": "2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: The Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC)Developed with the special contribution of the Heart Failure Association (HFA) of the ESC.", - "authors": "Piotr Ponikowski,Adriaan A Voors,Stefan D Anker,H\u00e9ctor Bueno,John G F Cleland,Andrew J S Coats,Volkmar Falk,Jos\u00e9 Ram\u00f3n Gonz\u00e1lez-Juanatey,Veli-Pekka Harjola,Ewa A Jankowska,Mariell Jessup,Cecilia Linde,Petros Nihoyannopoulos,John T Parissis,Burkert Pieske,Jillian P Riley,Giuseppe M C Rosano,Luis M Ruilope,Frank Ruschitzka,Frans H Rutten,Peter van der Meer, ", - "abstract": "", - "journal_title": "European heart journal", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/27206819/" - } - ], - "ecf7c695-3cea-4d3a-a3b2-b99240d30bdb": [ - { - "pub_id": "35024308", - "title": "Proteomics and metabolic phenotyping define principal roles for the aryl hydrocarbon receptor in mouse liver.", - "authors": "Jian Jin,Banrida Wahlang,Monika Thapa,Kimberly Z Head,Josiah E Hardesty,Sudhir Srivastava,Michael L Merchant,Shesh N Rai,Russell A Prough,Matthew C Cave", - "abstract": "Dioxin-like molecules have been associated with endocrine disruption and liver disease. To better understand aryl hydrocarbon receptor (AHR) biology, metabolic phenotyping and liver proteomics were performed in mice following ligand-activation or whole-body genetic ablation of this receptor. Male wild type (WT) and <i>Ahr</i> <sup>-/-</sup> mice (Taconic) were fed a control diet and exposed to 3,3',4,4',5-pentachlorobiphenyl (PCB126) (61\u00a0nmol/kg by gavage) or vehicle for two weeks. PCB126 increased expression of canonical AHR targets (<i>Cyp1a1</i> and <i>Cyp1a2</i>) in WT but not <i>Ahr</i> <sup>-/-</sup>. Knockouts had increased adiposity with decreased glucose tolerance; smaller livers with increased steatosis and perilipin-2; and paradoxically decreased blood lipids. PCB126 was associated with increased hepatic triglycerides in <i>Ahr</i> <sup>-/-</sup>. The liver proteome was impacted more so by <i>Ahr</i> <sup>-/-</sup> genotype than ligand-activation, but top gene ontology (GO) processes were similar. The PCB126-associated liver proteome was <i>Ahr</i>-dependent. <i>Ahr</i> principally regulated liver metabolism (<i>e</i>.<i>g</i>., lipids, xenobiotics, organic acids) and bioenergetics, but it also impacted liver endocrine response (<i>e</i>.<i>g</i>., the insulin receptor) and function, including the production of steroids, hepatokines, and pheromone binding proteins. These effects could have been indirectly mediated by interacting transcription factors or microRNAs. The biologic roles of the AHR and its ligands warrant more research in liver metabolic health and disease.", - "journal_title": "Acta pharmaceutica Sinica. B", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/35024308/" - } - ], - "7765b4ff-6e66-427c-b580-5e825c9f18f7": [ - { - "pub_id": "29211722", - "title": "Enhancing mitochondrial proteostasis reduces amyloid-\u03b2 proteotoxicity.", - "authors": "Vincenzo Sorrentino,Mario Romani,Laurent Mouchiroud,John S Beck,Hongbo Zhang,Davide D'Amico,Norman Moullan,Francesca Potenza,Adrien W Schmid,Sol\u00e8ne Rietsch,Scott E Counts,Johan Auwerx", - "abstract": "Alzheimer's disease is a common and devastating disease characterized by aggregation of the amyloid-\u03b2 peptide. However, we know relatively little about the underlying molecular mechanisms or how to treat patients with Alzheimer's disease. Here we provide bioinformatic and experimental evidence of a conserved mitochondrial stress response signature present in diseases involving amyloid-\u03b2 proteotoxicity in human, mouse and Caenorhabditis elegans that involves the mitochondrial unfolded protein response and mitophagy pathways. Using a worm model of amyloid-\u03b2 proteotoxicity, GMC101, we recapitulated mitochondrial features and confirmed that the induction of this mitochondrial stress response was essential for the maintenance of mitochondrial proteostasis and health. Notably, increasing mitochondrial proteostasis by pharmacologically and genetically targeting mitochondrial translation and mitophagy increases the fitness and lifespan of GMC101 worms and reduces amyloid aggregation in cells, worms and in transgenic mouse models of Alzheimer's disease. Our data support the relevance of enhancing mitochondrial proteostasis to delay amyloid-\u03b2 proteotoxic diseases, such as Alzheimer's disease.", - "journal_title": "Nature", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/29211722/" - } - ], - "a7863e20-daee-45db-941e-e7ae5976569d": [ - { - "pub_id": "28837622", - "title": "Lef1-dependent hypothalamic neurogenesis inhibits anxiety.", - "authors": "Yuanyuan Xie,Dan Kaufmann,Matthew J Moulton,Samin Panahi,John A Gaynes,Harrison N Watters,Dingxi Zhou,Hai-Hui Xue,Camille M Fung,Edward M Levine,Anthea Letsou,K C Brennan,Richard I Dorsky", - "abstract": "While innate behaviors are conserved throughout the animal kingdom, it is unknown whether common signaling pathways regulate the development of neuronal populations mediating these behaviors in diverse organisms. Here, we demonstrate that the Wnt/\u00df-catenin effector Lef1 is required for the differentiation of anxiolytic hypothalamic neurons in zebrafish and mice, although the identity of Lef1-dependent genes and neurons differ between these 2 species. We further show that zebrafish and Drosophila have common Lef1-dependent gene expression in their respective neuroendocrine organs, consistent with a conserved pathway that has diverged in the mouse. Finally, orthologs of Lef1-dependent genes from both zebrafish and mouse show highly correlated hypothalamic expression in marmosets and humans, suggesting co-regulation of 2 parallel anxiolytic pathways in primates. These findings demonstrate that during evolution, a transcription factor can act through multiple mechanisms to generate a common behavioral output, and that Lef1 regulates circuit development that is fundamentally important for mediating anxiety in a wide variety of animal species.", - "journal_title": "PLoS biology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/28837622/" - } - ], - "158883bf-a56d-48bd-939b-8c081ff52e8c": [ - { - "pub_id": "29960114", - "title": "Interaction between leucine and palmitate catabolism in 3T3-L1 adipocytes and primary adipocytes from control and obese rats.", - "authors": "Daniela Salinas-Rubio,Armando R Tovar,Iv\u00e1n Torre-Villalvazo,Omar Granados-Portillo,Nimbe Torres,Jos\u00e9 Pedraza-Chaverri,Lilia G Noriega", - "abstract": "Metabolic profiling studies have highlighted increases in the plasma free fatty acid (FFA) and branched-chain amino acid (BCAA) concentrations, which are hallmarks of the obese and insulin-resistant phenotype. However, little is known about how the increase of the BCAA concentration modifies the metabolic fate of FFA, and vice versa, in adipocytes. Therefore, we incubated differentiated 3T3-L1 adipocytes or primary adipocytes from rats fed a control or a high-fat diet with: (1) 0, 250, 500 and 1000 \u03bcM of leucine and determined the oxidation and incorporation of [1-<sup>14</sup>C]-palmitate into lipids or proteins or (2) 0, 250, 500 or 1000 \u03bcM of palmitate and evaluated the oxidation and incorporation of [U-<sup>14</sup>C]-leucine into lipids or proteins. Leucine decreased palmitate oxidation and increased its incorporation into the lipid fraction in adipocytes; the latter was reduced in adipocytes from obese rats. However, palmitate increased leucine oxidation in adipocytes as well as reduced leucine incorporation into the protein and lipid fractions in adipocytes from obese rats. These results demonstrate that leucine modifies the metabolic fate of palmitate, and vice versa, in adipocytes and that the metabolic interaction between leucine and palmitate catabolism is altered in adipocytes from obese rats.", - "journal_title": "The Journal of nutritional biochemistry", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/29960114/" - } - ], - "ae4fff82-4b74-4dff-bff2-6cf4bfaa06e4": [ - { - "pub_id": "30598166", - "title": "Human-Disease Phenotype Map Derived from PheWAS across 38,682 Individuals.", - "authors": "Anurag Verma,Lisa Bang,Jason E Miller,Yanfei Zhang,Ming Ta Michael Lee,Yu Zhang,Marta Byrska-Bishop,David J Carey,Marylyn D Ritchie,Sarah A Pendergrass,Dokyoon Kim, ", - "abstract": "Phenome-wide association studies (PheWASs) have been a useful tool for testing associations between genetic variations and multiple complex traits or diagnoses. Linking PheWAS-based associations between phenotypes and a variant or a genomic region into a network provides a new way to investigate cross-phenotype associations, and it might broaden the understanding of genetic architecture that exists between diagnoses, genes, and pleiotropy. We created a network of associations from one of the largest PheWASs on electronic health record (EHR)-derived phenotypes across 38,682 unrelated samples from the Geisinger's biobank; the samples were genotyped through the DiscovEHR project. We computed associations between 632,574 common variants and 541 diagnosis codes. Using these associations, we constructed a \"disease-disease\" network (DDN) wherein pairs of diseases were connected on the basis of shared associations with a given genetic variant. The DDN provides a landscape of intra-connections within the same disease classes, as well as inter-connections across disease classes. We identified clusters of diseases with known biological connections, such as autoimmune disorders (type 1 diabetes, rheumatoid arthritis, and multiple sclerosis) and cardiovascular disorders. Previously unreported relationships between multiple diseases were identified on the basis of genetic associations as well. The network approach applied in this study can be used to uncover interactions between diseases as a result of their shared, potentially pleiotropic SNPs. Additionally, this approach might advance clinical research and even clinical practice by accelerating our understanding of disease mechanisms on the basis of similar underlying genetic associations.", - "journal_title": "American journal of human genetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/30598166/" - } - ], - "f0373711-c50a-4272-84cb-a642925be2fe": [ - { - "pub_id": "30541014", - "title": "Silencing the ACAT1 Gene in Human SH-SY5Y Neuroblastoma Cells Inhibits the Expression of Cyclo-Oxygenase 2 (COX2) and Reduces \u03b2-Amyloid-Induced Toxicity Due to Activation of Protein Kinase C (PKC) and ERK.", - "authors": "Ying Chen,Lu Zhu,Lei Ji,Ying Yang,Lu Lu,Xiaodong Wang,Guomim Zhou", - "abstract": "BACKGROUND Acyl-coenzymeA: cholesterol acyltransferase (ACAT) 1, a key enzyme converting excess free cholesterol to cholesterol esters, has been demonstrated to be associated with the pathogenesis of Alzheimer disease (AD). However, the mechanism underlying the protective role of ACAT1 blockage in AD progression remains elusive. MATERIAL AND METHODS Human neuroblastoma SH-SY5Y cells were treated for 24 h with increasing concentrations of aggregated A\u03b2\u2082\u2085\u208b\u2083\u2085 (5, 15, 25, and 45 \u03bcmol) with or without the ACAT1 siRNA pretreatment. Cell viability analysis was measured by CCK-8 assay. The genome-wide correlation between ACAT1 and all other probe sets was measured by the Pearson correlation coefficient (r). Western blotting was used to detect the ACAT1 protein expression in the hippocampus of APP/PSN transgenic AD mice. The mRNA level for each target was analyzed by qPCR. Western blotting was used to detect the ACAT1, cyclo-oxygenase-2 (Cox2), Calcium voltage-gated channel subunits (CACNAs), and ERK/PKC proteins in SH-SY5Y cells with or without the ACAT1 siRNA pretreatment in the presence of A\u03b2\u2082\u2085\u208b\u2083\u2085. RESULTS The expression of ACAT1 was significantly increased in the hippocampus of APP/PSN mice, and also showed an increasing trend when SH-SY5Y cells were exposed to A\u03b2\u2082\u2085\u208b\u2083\u2085. Silencing ACAT1 significantly attenuated A\u03b2-induced cytotoxicity and cell apoptosis in SH-SY5Y cells. The genome-wide correlation analysis showed that Ptgs2 had the most significant correlation with Acat1 in the hippocampus of BXD RI mice. We further determined the regulatory effect of ACAT1 on COX2 expression by silencing or over-expressing ACAT1 in SH-SY5Y cells and found that silencing ACAT1 played a protective role in AD progression by regulating CACNAs and PKC/ERK signaling cascades. CONCLUSIONS Silencing ACAT1 attenuates A\u03b2\u2082\u2085\u208b\u2083\u2085-induced cytotoxicity and cell apoptosis in SH-SY5Y cells, which may due to the synergistic effect of ACAT1 and COX2 through PKC/ERK pathways.", - "journal_title": "Medical science monitor : international medical journal of experimental and clinical research", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/30541014/" - } - ], - "4049da4d-c7cf-4e30-9a21-c77609fad23d": [ - { - "pub_id": "31586406", - "title": "YEASTRACT+: a portal for cross-species comparative genomics of transcription regulation in yeasts.", - "authors": "Pedro T Monteiro,Jorge Oliveira,Pedro Pais,Miguel Antunes,Margarida Palma,Mafalda Cavalheiro,M\u00f3nica Galocha,Cl\u00e1udia P Godinho,Lu\u00eds C Martins,Nuno Bourbon,Marta N Mota,Ricardo A Ribeiro,Romeu Viana,Isabel S\u00e1-Correia,Miguel C Teixeira", - "abstract": "The YEASTRACT+ information system (http://YEASTRACT-PLUS.org/) is a wide-scope tool for the analysis and prediction of transcription regulatory associations at the gene and genomic levels in yeasts of biotechnological or human health relevance. YEASTRACT+ is a new portal that integrates the previously existing YEASTRACT (http://www.yeastract.com/) and PathoYeastract (http://pathoyeastract.org/) databases and introduces the NCYeastract (Non-Conventional Yeastract) database (http://ncyeastract.org/), focused on the so-called non-conventional yeasts. The information in the YEASTRACT database, focused on Saccharomyces cerevisiae, was updated. PathoYeastract was extended to include two additional pathogenic yeast species: Candida parapsilosis and Candida tropicalis. Furthermore, the NCYeastract database was created, including five biotechnologically relevant yeast species: Zygosaccharomyces baillii, Kluyveromyces lactis, Kluyveromyces marxianus, Yarrowia lipolytica and Komagataella phaffii. The YEASTRACT+ portal gathers 289 706 unique documented regulatory associations between transcription factors (TF) and target genes and 420 DNA binding sites, considering 247 TFs from 10 yeast species. YEASTRACT+ continues to make available tools for the prediction of the TFs involved in the regulation of gene/genomic expression. In this release, these tools were upgraded to enable predictions based on orthologous regulatory associations described for other yeast species, including two new tools for cross-species transcription regulation comparison, based on multi-species promoter and TF regulatory network analyses.", - "journal_title": "Nucleic acids research", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/31586406/" - } - ], - "d3d67989-3ee6-4956-84a6-d0b48bb421bc": [ - { - "pub_id": "30294635", - "title": "Data sets of eQTL loci, correlation analysis, and overlapped genes among gene sets that their expression levels are closely related to genes of Vegf family.", - "authors": "Jinglin Cui,Jing Li,Hang Lu,Hong Yu,Dongmei Wei,Yan Jiao,Monica M Jablonski,Weikuan Gu,Hong Chen", - "abstract": "This data is generated from the analysis of similarities and differences in gene expression levels and pathways among genes (VegfA, VegfB, VegfC, and Pgf) in Vegf family using whole genome expression data generated from normal retina of eighty strains of mice. The results have been published in doi:10.1016/j.exer.2018.06.024 (Cui et al., 2018) [1]. Fig. 1 shows the expression quantitative trait loci (eQTL) that regulate the expression level of each gene in the Vegf family. The other three figure show the overlapped genes among the top 500 genes that their expression levels are most closely correlated to each of the Vegf genes. The four tables contain the information of top 50 genes that their expression levels are most closely correlated to each of the Vegf genes, and the correlation of the top 50 genes from one gene to the other genes in the Vegf family.", - "journal_title": "Data in brief", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/30294635/" - } - ], - "9497cd3a-8b36-46d3-be18-d9a6f4c36a27": [ - { - "pub_id": "27838001", - "title": "The allostatic impact of chronic ethanol on gene expression: A genetic analysis of chronic intermittent ethanol treatment in the BXD cohort.", - "authors": "Andrew D van der Vaart,Jennifer T Wolstenholme,Maren L Smith,Guy M Harris,Marcelo F Lopez,Aaron R Wolen,Howard C Becker,Robert W Williams,Michael F Miles", - "abstract": "The transition from acute to chronic ethanol exposure leads to lasting behavioral and physiological changes such as increased consumption, dependence, and withdrawal. Changes in brain gene expression are hypothesized to underlie these adaptive responses to ethanol. Previous studies on acute ethanol identified genetic variation in brain gene expression networks and behavioral responses to ethanol across the BXD panel of recombinant inbred mice. In this work, we have performed the first joint genetic and genomic analysis of transcriptome shifts in response to chronic intermittent ethanol (CIE) by vapor chamber exposure in a BXD cohort. CIE treatment is known to produce significant and sustained changes in ethanol consumption with repeated cycles of ethanol vapor. Using Affymetrix microarray analysis of prefrontal cortex (PFC) and nucleus accumbens (NAC) RNA, we compared CIE expression responses to those seen following acute ethanol treatment, and to voluntary ethanol consumption. Gene expression changes in PFC and NAC after CIE overlapped significantly across brain regions and with previously published expression following acute ethanol. Genes highly modulated by CIE were enriched for specific biological processes including synaptic transmission, neuron ensheathment, intracellular signaling, and neuronal projection development. Expression quantitative trait locus (eQTL) analyses identified genomic loci associated with ethanol-induced transcriptional changes with largely distinct loci identified between brain regions. Correlating CIE-regulated genes to ethanol consumption data identified specific genes highly associated with variation in the increase in drinking seen with repeated cycles of CIE. In particular, multiple myelin-related genes were identified. Furthermore, genetic variance in or near dynamin3 (Dnm3) on Chr1 at \u223c164\u00a0Mb may have a major regulatory role in CIE-responsive gene expression. Dnm3 expression correlates significantly with ethanol consumption, is contained in a highly ranked functional group of CIE-regulated genes in the NAC, and has a cis-eQTL within a genomic region linked with multiple CIE-responsive genes.", - "journal_title": "Alcohol (Fayetteville, N.Y.)", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/27838001/" - } - ], - "7d866915-9d92-4401-8340-ffdef457debe": [ - { - "pub_id": "27284200", - "title": "Systems proteomics of liver mitochondria function.", - "authors": "Evan G Williams,Yibo Wu,Pooja Jha,S\u00e9bastien Dubuis,Peter Blattmann,Carmen A Argmann,Sander M Houten,Tiffany Amariuta,Witold Wolski,Nicola Zamboni,Ruedi Aebersold,Johan Auwerx", - "abstract": "Recent improvements in quantitative proteomics approaches, including Sequential Window Acquisition of all Theoretical Mass Spectra (SWATH-MS), permit reproducible large-scale protein measurements across diverse cohorts. Together with genomics, transcriptomics, and other technologies, transomic data sets can be generated that permit detailed analyses across broad molecular interaction networks. Here, we examine mitochondrial links to liver metabolism through the genome, transcriptome, proteome, and metabolome of 386 individuals in the BXD mouse reference population. Several links were validated between genetic variants toward transcripts, proteins, metabolites, and phenotypes. Among these, sequence variants in Cox7a2l alter its protein's activity, which in turn leads to downstream differences in mitochondrial supercomplex formation. This data set demonstrates that the proteome can now be quantified comprehensively, serving as a key complement to transcriptomics, genomics, and metabolomics--a combination moving us forward in complex trait analysis.", - "journal_title": "Science (New York, N.Y.)", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/27284200/" - } - ], - "6c545f35-f036-4e5f-8eed-19a8b048001b": [ - { - "pub_id": "33844961", - "title": "Commonalities of optic nerve injury and glaucoma-induced neurodegeneration: Insights from transcriptome-wide studies.", - "authors": "Jiaxing Wang,Felix L Struebing,Eldon E Geisert", - "abstract": "Glaucoma is a collection of diseases that lead to an irreversible vision loss due to damage of retinal ganglion cells (RGCs). Although the underlying events leading to RGC death are not fully understood, recent research efforts are beginning to define the genetic changes that play a critical role in the initiation and progression of glaucomatous injury and RGC death. Several genetic and experimental animal models have been developed to mimic glaucomatous neurodegeneration. These models differ in many respects but all result in the loss of RGCs. Assessing transcriptional changes across different models could provide a more complete perspective on the molecular drivers of RGC degeneration. For the past several decades, changes in the retinal transcriptome during neurodegeneration process were defined using microarray methods, RNA sequencing and now single cell RNA sequencing. It is understood that these methods have strengths and weaknesses due to technical differences and variations in the analytical tools used. In this review, we focus on the use of transcriptome-wide expression profiling of the changes occurring as RGCs are lost across different glaucoma models. Commonalities of optic nerve crush and glaucoma-induced neurodegeneration are identified and discussed.", - "journal_title": "Experimental eye research", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/33844961/" - } - ], - "746d211e-4a1a-4e6e-8404-3301767c363d": [ - { - "pub_id": "31754022", - "title": "Identifying gene function and module connections by the integration of multispecies expression compendia.", - "authors": "Hao Li,Daria Rukina,Fabrice P A David,Terytty Yang Li,Chang-Myung Oh,Arwen W Gao,Elena Katsyuba,Maroun Bou Sleiman,Andrea Komljenovic,Qingyao Huang,Robert W Williams,Marc Robinson-Rechavi,Kristina Schoonjans,Stephan Morgenthaler,Johan Auwerx", - "abstract": "The functions of many eukaryotic genes are still poorly understood. Here, we developed and validated a new method, termed GeneBridge, which is based on two linked approaches to impute gene function and bridge genes with biological processes. First, <u>G</u>ene-<u>M</u>odule <u>A</u>ssociation <u>D</u>etermination (G-MAD) allows the annotation of gene function. Second, <u>M</u>odule-<u>M</u>odule <u>A</u>ssociation <u>D</u>etermination (M-MAD) allows predicting connectivity among modules. We applied the GeneBridge tools to large-scale multispecies expression compendia-1700 data sets with over 300,000 samples from human, mouse, rat, fly, worm, and yeast-collected in this study. G-MAD identifies novel functions of genes-for example, <i>DDT</i> in mitochondrial respiration and <i>WDFY4</i> in T cell activation-and also suggests novel components for modules, such as for cholesterol biosynthesis. By applying G-MAD on data sets from respective tissues, tissue-specific functions of genes were identified-for instance, the roles of <i>EHHADH</i> in liver and kidney, as well as <i>SLC6A1</i> in brain and liver. Using M-MAD, we identified a list of module-module associations, such as those between mitochondria and proteasome, mitochondria and histone demethylation, as well as ribosomes and lipid biosynthesis. The GeneBridge tools together with the expression compendia are available as an open resource, which will facilitate the identification of connections linking genes, modules, phenotypes, and diseases.", - "journal_title": "Genome research", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/31754022/" - } - ], - "4edf9e5c-915d-4e38-b48f-2a0b82132bd0": [ - { - "pub_id": "27933532", - "title": "Precise Network Modeling of Systems Genetics Data Using the Bayesian Network Webserver.", - "authors": "Jesse D Ziebarth,Yan Cui", - "abstract": "The Bayesian Network Webserver (BNW, http://compbio.uthsc.edu/BNW ) is an integrated platform for Bayesian network modeling of biological datasets. It provides a web-based network modeling environment that seamlessly integrates advanced algorithms for probabilistic causal modeling and reasoning with Bayesian networks. BNW is designed for precise modeling of relatively small networks that contain less than 20 nodes. The structure learning algorithms used by BNW guarantee the discovery of the best (most probable) network structure given the data. To facilitate network modeling across multiple biological levels, BNW provides a very flexible interface that allows users to assign network nodes into different tiers and define the relationships between and within the tiers. This function is particularly useful for modeling systems genetics datasets that often consist of multiscalar heterogeneous genotype-to-phenotype data. BNW enables users to, within seconds or minutes, go from having a simply formatted input file containing a dataset to using a network model to make predictions about the interactions between variables and the potential effects of experimental interventions. In this chapter, we will introduce the functions of BNW and show how to model systems genetics datasets with BNW.", - "journal_title": "Methods in molecular biology (Clifton, N.J.)", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/27933532/" - } - ], - "91b62c02-3993-4d6e-bfb1-b2630326f078": [ - { - "pub_id": "35470554", - "title": "Extreme phenotypic diversity in operant response to intravenous cocaine or saline infusion in the hybrid mouse diversity panel.", - "authors": "Jared R Bagley,Arshad H Khan,Desmond J Smith,James D Jentsch", - "abstract": "Cocaine self-administration is a complexly determined trait, with a substantial proportion of individual differences being determined by genetic variation. However, the relevant genetic variants that drive heritable differences in cocaine use remain undiscovered. Cocaine intravenous self-administration (IVSA) procedures in laboratory animals provide opportunities to prospectively investigate neurogenetic influences on the acquisition of voluntary cocaine use. Here, we provide information on cocaine (or saline-as a control) IVSA in 84 members of the hybrid mouse diversity panel (HMDP), an array of genetically distinct classical or recombinant inbred strains. We found cocaine IVSA to be substantially heritable in this population, with strain-level intake ranging for near 0 to >25\u2009mg/kg/session. Though saline IVSA was also found to be heritable, a modest genetic correlation between cocaine and saline IVSA indicates that operant responding for the cocaine reinforcer was influenced, at least in part, by unique genetic variants. Genome-wide association studies (GWAS) of infusions earned in cocaine and saline groups revealed significant quantitative trait loci (QTL) on Chromosomes 3 and 14 for cocaine, but not saline, IVSA. Positional candidates were further prioritized through use of bulk RNA sequencing data that revealed genes with cis-eQTL and genetic correlation to number of infusions. Additionally, these data identify reference strains with extreme cocaine IVSA phenotypes, revealing them as polygenic models of risk and resilience to cocaine reinforcement. This work is part of an ongoing effort to characterize genetic variation that moderates cocaine IVSA that may, in turn, provide a more comprehensive understanding of cocaine risk genetics and neurobiology.", - "journal_title": "Addiction biology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/35470554/" - } - ], - "a4508fb3-c66b-4526-b2a2-a327505d085a": [ - { - "pub_id": "35844806", - "title": "Targeting Ferroptosis as a Novel Approach to Alleviate Aortic Dissection.", - "authors": "Na Li,Xin Yi,Yi He,Bo Huo,Yue Chen,Zihao Zhang,Qunhui Wang,Yi Li,Xiaoxuan Zhong,Rui Li,Xue-Hai Zhu,Zemin Fang,Xiang Wei,Ding-Sheng Jiang", - "abstract": "A variety of programmed cell death types have been shown to participate in the loss of smooth muscle cells (SMCs) during the development of aortic dissection (AD), but it is still largely unclear whether ferroptosis is involved in the development of AD. In the present study, we found that the expression of key ferroptosis regulatory proteins, solute carrier family 7 member 11 (SLC7A11), ferroptosis suppressor protein 1 (FSP1) and glutathione peroxidase 4 (GPX4) were downregulated in aortas of Stanford type A AD (TAAD) patients, and liproxstatin-1, a specific inhibitor of ferroptosis, obviously abolished the \u03b2-aminopropionitrile (BAPN)-induced development and rupture of AD in mice. Furthermore, the expression of methyltransferase-like 3 (METTL3), a major methyltransferase of RNA m<sup>6</sup>A, was remarkably upregulated in the aortas of TAAD patients, and the protein levels of METTL3 were negatively correlated with SLC7A11 and FSP1 levels in human aortas. Overexpression of METTL3 in human aortic SMCs (HASMCs) inhibited, while METTL3 knockdown promoted SLC7A11 and FSP1 expression. More importantly, overexpression of METTL3 facilitated imidazole ketone erastin- and cystine deprivation-induced ferroptosis, while knockdown of METTL3 repressed ferroptosis of HASMCs. Overexpression of either SLC7A11 or FSP1 largely abrogated the effect of METTL3 on HASMC ferroptosis. Therefore, we have revealed that ferroptosis is a critical cause of AD in both humans and mice and that METTL3 promotes ferroptosis of HASMCs by inhibiting the expression of SLC7A11 and FSP1. Thus, targeting ferroptosis or m<sup>6</sup>A RNA methylation is a potential novel strategy for the treatment of AD.", - "journal_title": "International journal of biological sciences", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/35844806/" - } - ], - "f6abed2a-3182-46be-aae6-97d99f08e73e": [ - { - "pub_id": "31634382", - "title": "Diet modulates cecum bacterial diversity and physiological phenotypes across the BXD mouse genetic reference population.", - "authors": "Maria Elisa Perez-Munoz,Autumn M McKnite,Evan G Williams,Johan Auwerx,Robert W Williams,Daniel A Peterson,Daniel C Ciobanu", - "abstract": "The BXD family has become one of the preeminent genetic reference populations to understand the genetic and environmental control of phenotypic variation. Here we evaluate the responses to different levels of fat in the diet using both chow diet (CD, 13-18% fat) and a high-fat diet (HFD, 45-60% fat). We studied cohorts of BXD strains, both inbred parents C57BL/6J and DBA/2J (commonly known as B6 and D2, respectively), as well as B6D2 and D2B6 reciprocal F1 hybrids. The comparative impact of genetic and dietary factors was analyzed by profiling a range of phenotypes, most prominently their cecum bacterial composition. The parents of the BXDs and F1 hybrids express limited differences in terms of weight and body fat gain on CD. In contrast, the strain differences on HFD are substantial for percent body fat, with DBA/2J accumulating 12.5% more fat than C57BL/6J (P < 0.0001). The F1 hybrids born to DBA/2J dams (D2B6F1) have 10.6% more body fat (P < 0.001) than those born to C57BL/6J dams. Sequence analysis of the cecum microbiota reveals important differences in bacterial composition among BXD family members with a substantial shift in composition caused by HFD. Relative to CD, the HFD induces a decline in diversity at the phylum level with a substantial increase in Firmicutes (+13.8%) and a reduction in Actinobacteria (-7.9%). In the majority of BXD strains, the HFD also increases cecal sIgA (P < 0.0001)-an important component of the adaptive immunity response against microbial pathogens. Host genetics modulates variation in cecum bacterial composition at the genus level in CD, with significant quantitative trait loci (QTLs) for Oscillibacter mapped to Chr 3 (18.7-19.2 Mb, LRS = 21.4) and for Bifidobacterium mapped to Chr 6 (89.21-89.37 Mb, LRS = 19.4). Introduction of HFD served as an environmental suppressor of these QTLs due to a reduction in the contribution of both genera (P < 0.001). Relations among liver metabolites and cecum bacterial composition were predominant in CD cohort, but these correlations do not persist following the shift to HFD. Overall, these findings demonstrate the important impact of environmental/dietary manipulation on the relationships between host genetics, gastrointestinal bacterial composition, immunological parameters, and metabolites-knowledge that will help in the understanding of the causal sources of metabolic disorders.", - "journal_title": "PloS one", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/31634382/" - } - ], - "58cc5d33-4104-416a-9bd5-72c9b7d96b2e": [ - { - "pub_id": "29421330", - "title": "Genomic loci modulating retinal ganglion cell death following elevated IOP in the mouse.", - "authors": "Felix L Struebing,Rebecca King,Ying Li,Jessica N Cooke Bailey, ,Janey L Wiggs,Eldon E Geisert", - "abstract": "The present study was designed to identify genomic loci modulating the susceptibility of retinal ganglion cells (RGC) to elevated intraocular pressure (IOP) in the BXD recombinant inbred mouse strain set. IOP was elevated by injecting magnetic microspheres into the anterior chamber and blocking the trabecular meshwork using a handheld magnet to impede drainage. The IOP was then measured over the next 21 days. Only animals with IOP greater than 25\u202fmmHg for two consecutive days or an IOP above 30\u202fmmHg on a single day after microsphere-injection were used in this study. On day 21, mice were sacrificed and the optic nerve was processed for histology. Axons were counted for both the injected and the control eye in 49 BXD strains, totaling 181 normal counts and 191 counts associated with elevated IOP. The axon loss for each strain was calculated and the data were entered into genenetwork.org. The average number of normal axons in the optic nerve across all strains was 54,788\u202f\u00b1\u202f16% (SD), which dropped to 49,545\u202f\u00b1\u202f20% in animals with artificially elevated IOP. Interval mapping demonstrated a relatively similar genome-wide map for both conditions with a suggestive Quantitative Trait Locus (QTL) on proximal Chromosome 3. When the relative axon loss was used to generate a genome-wide interval map, we identified one significant QTL (p\u202f<\u202f0.05) on Chromosome 18 between 53.6 and 57\u202fMb. Within this region, the best candidate gene for modulating axon loss was Aldh7a1. Immunohistochemistry demonstrated ALDH7A1 expression in mouse RGCs. ALDH7A1 variants were not significantly associated with glaucoma in the NEIGHBORHOOD GWAS dataset, but this enzyme was identified as part of the butanoate pathway previously associated with glaucoma risk. Our results suggest that genomic background influences susceptibility to RGC degeneration and death in an inducible glaucoma model.", - "journal_title": "Experimental eye research", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/29421330/" - } - ], - "fe558be3-948c-4475-abbc-eb1ea36ff756": [ - { - "pub_id": "30252437", - "title": "Understanding Central Nervous System Effects of Deliriant Hallucinogenic Drugs through Experimental Animal Models.", - "authors": "Andrey D Volgin,Oleg A Yakovlev,Konstantin A Demin,Polina A Alekseeva,Evan J Kyzar,Christopher Collins,David E Nichols,Allan V Kalueff", - "abstract": "Hallucinogenic drugs potently alter human behavior and have a millennia-long history of use for medicinal and religious purposes. Interest is rapidly growing in their potential as CNS modulators and therapeutic agents for brain conditions. Antimuscarinic cholinergic drugs, such as atropine and scopolamine, induce characteristic hyperactivity and dream-like hallucinations and form a separate group of hallucinogens known as \"deliriants\". Although atropine and scopolamine are relatively well-studied drugs in cholinergic physiology, deliriants represent the least-studied class of hallucinogens in terms of their behavioral and neurological phenotypes. As such, novel approaches and new model organisms are needed to investigate the CNS effects of these compounds. Here, we comprehensively evaluate the preclinical effects of deliriant hallucinogens in various animal models, their mechanisms of action, and potential interplay with other signaling pathways. We also parallel experimental and clinical findings on deliriant agents and outline future directions of translational research in this field.", - "journal_title": "ACS chemical neuroscience", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/30252437/" - } - ], - "2b7de368-bca5-49a5-b5d1-3eafa3844021": [ - { - "pub_id": "33225719", - "title": "ChREBP downregulates SNAT2 amino acid transporter expression through interactions with SMRT in response to a high-carbohydrate diet.", - "authors": "Laura Vel\u00e1zquez-Villegas,Lilia G Noriega,Adriana M L\u00f3pez-Barradas,Sandra Tobon-Cornejo,Ana Luisa M\u00e9ndez-Garc\u00eda,Armando R Tovar,Nimbe Torres,Victor M Ortiz-Ortega", - "abstract": "Carbohydrate responsive element-binding protein (ChREBP) has been identified as a primary transcription factor that maintains energy homeostasis through transcriptional regulation of glycolytic, lipogenic, and gluconeogenic enzymes in response to a high-carbohydrate diet. Amino acids are important substrates for gluconeogenesis, but nevertheless, knowledge is lacking about whether this transcription factor regulates genes involved in the transport or use of these metabolites. Here, we demonstrate that ChREBP represses the expression of the amino acid transporter sodium-coupled neutral amino acid transporter 2 (SNAT2) in response to a high-sucrose diet in rats by binding to a carbohydrate response element (ChoRE) site located -160\u2009bp upstream of the transcriptional start site in the SNAT2 promoter region. Additionally, immunoprecipitation assays revealed that ChREBP and silencing mediator of retinoic acid and thyroid hormone receptor (SMRT) interact with each other, as part of the complex that repress SNAT2 expression. The interaction between these proteins was confirmed by an in vivo chromatin immunoprecipitation assay. These findings suggest that glucogenic amino acid uptake by the liver is controlled by ChREBP through the repression of SNAT2 expression in rats consuming a high-carbohydrate diet.<b>NEW & NOTEWORTHY</b> This study highlights the key role of carbohydrate responsive element-binding protein (ChREBP) in the fine-tuned regulation between glucose and amino acid metabolism in the liver via regulation of the amino acid transporter sodium-coupled neutral amino acid transporter 2 (SNAT2) expression after the consumption of a high-carbohydrate diet. ChREBP binds to a carbohydrate response element (ChoRE) site in the SNAT2 promoter region and recruits silencing mediator of retinoic acid and thyroid hormone receptor (SMRT) corepressor to reduce SNAT2 transcription. This study revealed that ChREBP prevents the uptake of glucogenic amino acids upon the consumption of a high-carbohydrate diet.", - "journal_title": "American journal of physiology. Endocrinology and metabolism", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/33225719/" - } - ], - "87b8410d-4032-41e3-9924-8922056ed610": [ - { - "pub_id": "35351712", - "title": "Association of serum cardiac troponin I and severity of coronary stenosis in patients with varied renal functions: a retrospective cohort study.", - "authors": "Qian Zhang,Yong-Fei Wang,Xiao Hu,Ya-Jun Tan,Cui Gao,Jianxiao Chen,Fei Han,Jianghua Chen,Yi Yang", - "abstract": "Recent studies showed cardiac troponin I (cTnI) might be a non-invasive biomarker to estimate the severity of coronary stenosis. However, serum cTnI is also found associated with renal function. The study objective is to analyse the association of serum cTnI and severity of coronary stenosis in patients with varied renal functions. A retrospective cohort study. The First Affiliated Hospital, College of Medicine, Zhejiang University in Hangzhou, China. A total of 6487 subjects who underwent elective coronary angiography between January 2017 to June 2020 were involved in this study. Severity of coronary stenosis was divided into three degrees based on Gensini score, mild coronary stenosis, moderate coronary stenosis and severe coronary stenosis. By using ordinal logistic regression, serum cTnI was associated with severity of coronary stenosis (OR=1.14, p<0.05). By construction and comparison of two models for predicting severity of coronary stenosis, the addition of cTnI significantly improved the predictive ability of the model. Differences between areas under the curves were 0.03, 0.03, 0.03, 0.12 (all p<0.05). Net reclassification improvements were 0.08, 0.05, 0.05, 0.35, respectively, in varied renal functions. Compared with the participants with normal renal function and without hypertroponinaemia, groups of participants with hypertroponinaemia showed higher ORs. ORs were 3.52, 4.20, 4.45, 6.00, respectively, as renal function decreased (all p<0.05). In this cohort of patients with stable coronary artery disease and varied renal functions, cTnI was intensely associated with severity of coronary stenosis which based on Gensini score. The presentation of hypertroponinaemia in patients with impaired renal function always indicates a higher risk of severe coronary stenosis.", - "journal_title": "BMJ open", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/35351712/" - } - ], - "88dc3b00-055d-45f4-bdcb-1e7320770faf": [ - { - "pub_id": "32035127", - "title": "Identification of novel genetic variants associated with cardiorespiratory fitness.", - "authors": "Anja Bye,Marie Klevjer,Einar Ryeng,Gustavo Jose Justo da Silva,Jose Bianco Nascimento Moreira,Dorthe Stensvold,Ulrik Wisl\u00f8ff", - "abstract": "Low maximal oxygen uptake (VO<sub>2max</sub>) is a strong and independent risk factor for all-cause and cardiovascular disease (CVD) mortality. For other CVD risk factors, numerous genetic association studies have been performed, revealing promising risk markers and new therapeutic targets. However, large genomic association studies on VO<sub>2max</sub> are still lacking, despite the fact that VO<sub>2max</sub> has a large genetic component. We performed a genetic association study on 123.545 single-nucleotide polymorphisms (SNPs) and directly measured VO<sub>2max</sub> in 3470 individuals (exploration cohort). Candidate SNPs from the exploration cohort were analyzed in a validation cohort of 718 individuals, in addition to 7 wild-card SNPs. Sub-analyses were performed for each gender. Validated SNPs were used to create a genetic score for VO<sub>2max</sub>. In silico analyses and genotype-phenotype databases were used to predict physiological function of the SNPs. In the exploration cohort, 41 SNPs were associated with VO<sub>2max</sub> (p\u00a0<\u00a05.0\u00a0\u2217\u00a010<sup>-4</sup>). Six of the candidate SNPs were associated with VO<sub>2max</sub> also in the validation cohort, in addition to three wild-card SNPs (p\u00a0<\u00a00.05, in men, women or both). The cumulative number of high-VO<sub>2max</sub><sub>-</sub>SNPs correlated negatively with CVD risk factors, e.g. waist-circumference, visceral fat, fat %, cholesterol levels and BMI. In silico analysis indicated that several of the VO<sub>2max</sub>-SNPs influence gene expression in adipose tissue, skeletal muscle and heart. We discovered and validated new SNPs associated with VO<sub>2max</sub> and proposed possible links between VO<sub>2max</sub> and CVD. Studies combining several large cohorts with directly measured VO<sub>2max</sub> are needed to identify more SNPs associated with this phenotype.", - "journal_title": "Progress in cardiovascular diseases", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/32035127/" - } - ], - "c24fda05-46ed-4f50-9d20-e00f32ae956e": [ - { - "pub_id": "29025058", - "title": "Cohort Profile: Genetics of Diabetes Audit and Research in Tayside Scotland (GoDARTS).", - "authors": "Harry L H\u00e9bert,Bridget Shepherd,Keith Milburn,Abirami Veluchamy,Weihua Meng,Fiona Carr,Louise A Donnelly,Roger Tavendale,Graham Leese,Helen M Colhoun,Ellie Dow,Andrew D Morris,Alexander S Doney,Chim C Lang,Ewan R Pearson,Blair H Smith,Colin N A Palmer", - "abstract": "", - "journal_title": "International journal of epidemiology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/29025058/" - } - ], - "8fefe9b8-fa89-46ed-a8aa-69f2bb6bfa41": [ - { - "pub_id": "29566793", - "title": "Genome-wide Analyses Identify KIF5A as a Novel ALS Gene.", - "authors": "Aude Nicolas,Kevin P Kenna,Alan E Renton,Nicola Ticozzi,Faraz Faghri,Ruth Chia,Janice A Dominov,Brendan J Kenna,Mike A Nalls,Pamela Keagle,Alberto M Rivera,Wouter van Rheenen,Natalie A Murphy,Joke J F A van Vugt,Joshua T Geiger,Rick A Van der Spek,Hannah A Pliner, Shankaracharya,Bradley N Smith,Giuseppe Marangi,Simon D Topp,Yevgeniya Abramzon,Athina Soragia Gkazi,John D Eicher,Aoife Kenna, ,Gabriele Mora,Andrea Calvo,Letizia Mazzini,Nilo Riva,Jessica Mandrioli,Claudia Caponnetto,Stefania Battistini,Paolo Volanti,Vincenzo La Bella,Francesca L Conforti,Giuseppe Borghero,Sonia Messina,Isabella L Simone,Francesca Trojsi,Fabrizio Salvi,Francesco O Logullo,Sandra D'Alfonso,Lucia Corrado,Margherita Capasso,Luigi Ferrucci, ,Cristiane de Araujo Martins Moreno,Sitharthan Kamalakaran,David B Goldstein, ,Aaron D Gitler,Tim Harris,Richard M Myers, ,Hemali Phatnani,Rajeeva Lochan Musunuri,Uday Shankar Evani,Avinash Abhyankar,Michael C Zody, ,Julia Kaye,Steven Finkbeiner,Stacia K Wyman,Alex LeNail,Leandro Lima,Ernest Fraenkel,Clive N Svendsen,Leslie M Thompson,Jennifer E Van Eyk,James D Berry,Timothy M Miller,Stephen J Kolb,Merit Cudkowicz,Emily Baxi, ,Michael Benatar,J Paul Taylor,Evadnie Rampersaud,Gang Wu,Joanne Wuu, ,Giuseppe Lauria,Federico Verde,Isabella Fogh,Cinzia Tiloca,Giacomo P Comi,Gianni Sorar\u00f9,Cristina Cereda, ,Philippe Corcia,Hannu Laaksovirta,Liisa Myllykangas,Lilja Jansson,Miko Valori,John Ealing,Hisham Hamdalla,Sara Rollinson,Stuart Pickering-Brown,Richard W Orrell,Katie C Sidle,Andrea Malaspina,John Hardy,Andrew B Singleton,Janel O Johnson,Sampath Arepalli,Peter C Sapp,Diane McKenna-Yasek,Meraida Polak,Seneshaw Asress,Safa Al-Sarraj,Andrew King,Claire Troakes,Caroline Vance,Jacqueline de Belleroche,Frank Baas,Anneloor L M A Ten Asbroek,Jos\u00e9 Luis Mu\u00f1oz-Blanco,Dena G Hernandez,Jinhui Ding,J Raphael Gibbs,Sonja W Scholz,Mary Kay Floeter,Roy H Campbell,Francesco Landi,Robert Bowser,Stefan M Pulst,John M Ravits,Daniel J L MacGowan,Janine Kirby,Erik P Pioro,Roger Pamphlett,James Broach,Glenn Gerhard,Travis L Dunckley,Christopher B Brady,Neil W Kowall,Juan C Troncoso,Isabelle Le Ber,Kevin Mouzat,Serge Lumbroso,Terry D Heiman-Patterson,Freya Kamel,Ludo Van Den Bosch,Robert H Baloh,Tim M Strom,Thomas Meitinger,Aleksey Shatunov,Kristel R Van Eijk,Mamede de Carvalho,Maarten Kooyman,Bas Middelkoop,Matthieu Moisse,Russell L McLaughlin,Michael A Van Es,Markus Weber,Kevin B Boylan,Marka Van Blitterswijk,Rosa Rademakers,Karen E Morrison,A Nazli Basak,Jes\u00fas S Mora,Vivian E Drory,Pamela J Shaw,Martin R Turner,Kevin Talbot,Orla Hardiman,Kelly L Williams,Jennifer A Fifita,Garth A Nicholson,Ian P Blair,Guy A Rouleau,Jes\u00fas Esteban-P\u00e9rez,Alberto Garc\u00eda-Redondo,Ammar Al-Chalabi, ,Ekaterina Rogaeva,Lorne Zinman,Lyle W Ostrow,Nicholas J Maragakis,Jeffrey D Rothstein,Zachary Simmons,Johnathan Cooper-Knock,Alexis Brice,Stephen A Goutman,Eva L Feldman,Summer B Gibson,Franco Taroni,Antonia Ratti,Cinzia Gellera,Philip Van Damme,Wim Robberecht,Pietro Fratta,Mario Sabatelli,Christian Lunetta,Albert C Ludolph,Peter M Andersen,Jochen H Weishaupt,William Camu,John Q Trojanowski,Vivianna M Van Deerlin,Robert H Brown,Leonard H van den Berg,Jan H Veldink,Matthew B Harms,Jonathan D Glass,David J Stone,Pentti Tienari,Vincenzo Silani,Adriano Chi\u00f2,Christopher E Shaw,Bryan J Traynor,John E Landers", - "abstract": "To identify novel genes associated with ALS, we undertook two lines of investigation. We carried out a genome-wide association study comparing 20,806 ALS cases and 59,804 controls. Independently, we performed a rare variant burden analysis comparing 1,138 index familial ALS cases and 19,494 controls. Through both approaches, we identified kinesin family member 5A (KIF5A) as a novel gene associated with ALS. Interestingly, mutations predominantly in the N-terminal motor domain of KIF5A are causative for two neurodegenerative diseases: hereditary spastic paraplegia (SPG10) and Charcot-Marie-Tooth type 2 (CMT2). In contrast, ALS-associated mutations are primarily located at the C-terminal cargo-binding tail domain and patients harboring loss-of-function mutations displayed an extended survival relative to typical ALS cases. Taken together, these results broaden the phenotype spectrum resulting from mutations in KIF5A and strengthen the role of cytoskeletal defects in the pathogenesis of ALS.", - "journal_title": "Neuron", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/29566793/" - } - ], - "b314fea7-0af5-4f4c-b163-a4c6f129098d": [ - { - "pub_id": "34831199", - "title": "Integrative Analyses Reveal <i>Tstd1</i> as a Potential Modulator of HDL Cholesterol and Mitochondrial Function in Mice.", - "authors": "Adi Zheng,Hao Li,Zhihui Feng,Jiankang Liu", - "abstract": "High-density lipoprotein (HDL) cholesterol levels are closely associated with human health and diseases. To identify genes modulating plasma HDL levels, we integrated HDL measurements and multi-omics data collected from diverse mouse cohorts and combined a list of systems genetics methods, including quantitative trait loci (QTL) mapping analysis, mediation analysis, transcriptome-wide association analysis (TWAS), and correlation analysis. We confirmed a significant and conserved QTL for plasma HDL on chromosome 1 and identified that <i>Tstd1</i> liver transcript correlates with plasma HDL in several independent mouse cohorts, suggesting <i>Tstd1</i> may be a potential modulator of plasma HDL levels. Correlation analysis using over 70 transcriptomics datasets in humans and mice revealed consistent correlations between <i>Tstd1</i> and genes known to be involved in cholesterol and HDL regulation. Consistent with strong enrichment in gene sets related to cholesterol and lipoproteins in the liver, mouse strains with high <i>Tstd1</i> exhibited higher plasma levels of HDL, total cholesterol and other lipid markers. GeneBridge using large-scale expression datasets identified conserved and positive associations between <i>TSTD1/Tstd1</i> and mitochondrial pathways, as well as cholesterol and lipid pathways in human, mouse and rat. In summary, we identified <i>Tstd1</i> as a new modulator of plasma HDL and mitochondrial function through integrative systems analyses, and proposed a new mechanism of HDL modulation and a potential therapeutic target for relevant diseases. This study highlights the value of such integrative approaches in revealing molecular mechanisms of complex traits or diseases.", - "journal_title": "Cells", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/34831199/" - } - ], - "6e5525a1-476c-4668-833e-e32bdf437ac8": [ - { - "pub_id": "31593271", - "title": "Effect of a Hospital-Initiated Program Combining Transitional Care and Long-term Self-management Support on Outcomes of Patients Hospitalized With Chronic Obstructive Pulmonary Disease: A Randomized Clinical Trial.", - "authors": "Hanan Aboumatar,Mohammad Naqibuddin,Suna Chung,Hina Chaudhry,Samuel W Kim,Jamia Saunders,Lee Bone,Ayse P Gurses,Amy Knowlton,Peter Pronovost,Nirupama Putcha,Cynthia Rand,Debra Roter,Carol Sylvester,Carol Thompson,Jennifer L Wolff,Judith Hibbard,Robert A Wise", - "abstract": "Patients hospitalized for chronic obstructive pulmonary disease (COPD) exacerbations have high rehospitalization rates and reduced quality of life. To evaluate whether a hospital-initiated program that combined transition and long-term self-management support for patients hospitalized due to COPD and their family caregivers can improve outcomes. Single-site randomized clinical trial conducted in Baltimore, Maryland, with 240 participants. Participants were patients hospitalized due to COPD, randomized to intervention or usual care, and followed up for 6 months after hospital discharge. Enrollment occurred from March 2015 to May 2016; follow-up ended in December 2016. The intervention (n\u2009=\u2009120) involved a comprehensive 3-month program to help patients and their family caregivers with long-term self-management of COPD. It was delivered by nurses with special training on supporting patients with COPD using standardized tools. Usual care (n\u2009=\u2009120) included transition support for 30 days after discharge to ensure adherence to discharge plan and connection to outpatient care. The primary outcome was number of COPD-related acute care events (hospitalizations and emergency department visits) per participant at 6 months. The co-primary outcome was change in participants' health-related quality of life measured by the St George's Respiratory Questionnaire (SGRQ) at 6 months after discharge (score, 0 [best] to 100 [worst]; 4-point difference is clinically meaningful). Among 240 patients who were randomized (mean [SD] age, 64.9 [9.8] years; 61.7% women), 203 (85%) completed the study. The mean (SD) baseline SGRQ score was 62.3 (18.8) in the intervention group and 63.6 (17.4) in the usual care group. The mean number of COPD-related acute care events per participant at 6 months was 1.40 (95% CI, 1.01-1.79) in the intervention group vs 0.72 (95% CI, 0.45-0.97) in the usual care group (difference, 0.68 [95% CI, 0.22-1.15]; P\u2009=\u2009.004). The mean change in participants' SGRQ total score at 6 months was 2.81 in the intervention group and -2.69 in the usual care group (adjusted difference, 5.18 [95% CI, -2.15 to 12.51]; P\u2009=\u2009.11). During the study period, there were 15 deaths (intervention: 8; usual care: 7) and 339 hospitalizations (intervention: 202; usual care: 137). In a single-site randomized clinical trial of patients hospitalized due to COPD, a 3-month program that combined transition and long-term self-management support resulted in significantly greater COPD-related hospitalizations and emergency department visits, without improvement in quality of life. Further research is needed to determine reasons for this unanticipated finding. ClinicalTrials.gov Identifier: NCT02036294.", - "journal_title": "JAMA", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/31593271/" - } - ], - "f041550e-5f2d-430e-8f46-15ebea6ca496": [ - { - "pub_id": "28398643", - "title": "Systems Genetic Analysis in GeneNetwork.org.", - "authors": "Clarissa C Parker,Price E Dickson,Vivek M Philip,Mary Thomas,Elissa J Chesler", - "abstract": "Genome-wide association studies (GWAS) have emerged as a powerful tool to identify alleles and molecular pathways that influence susceptibility to psychiatric disorders and other diseases. Forward genetics using mouse mapping populations allows for a complementary approach that provides rigorous genetic and environmental control. In this unit, we describe techniques and tools that reduce the technical burden traditionally associated with genetic mapping in mice and enhance their translational utility to human psychiatric disorders. We provide guidance on choosing the appropriate mapping population, discuss the importance of phenotype, and offer detailed instructions on using the Web-based resource GeneNetwork to aid neuroscientists in better understanding the mechanisms through which genes influence behavior. We believe that the continued development of mouse mapping populations, genetic tools, bioinformatics resources, and statistical methodologies should remain a parallel strategy by which to investigate the genetic and environmental underpinnings of psychiatric disorders and other diseases in humans. \u00a9 2017 by John Wiley & Sons, Inc.", - "journal_title": "Current protocols in neuroscience", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/28398643/" - } - ], - "2418ad89-9f7f-4f6f-b27b-a153c7a52d96": [ - { - "pub_id": "36537573", - "title": "Neurog2 regulates Isl1 to modulate horizontal cell number.", - "authors": "Patrick W Keeley,Pooja S Patel,Matthew S Ryu,Benjamin E Reese", - "abstract": "The population sizes of different retinal cell types vary between different strains of mice, and that variation can be mapped to genomic loci in order to identify its polygenic origin. In some cases, controlling genes act independently, whereas in other instances, they exhibit epistasis. Here, we identify an epistatic interaction revealed through the mapping of quantitative trait loci from a panel of recombinant inbred strains of mice. The population of retinal horizontal cells exhibits a twofold variation in number, mapping to quantitative trait loci on chromosomes 3 and 13, where these loci are shown to interact epistatically. We identify a prospective genetic interaction underlying this, mediated by the bHLH transcription factor Neurog2, at the chromosome 3 locus, functioning to repress the LIM homeodomain transcription factor Isl1, at the chromosome 13 locus. Using single and double conditional knockout mice, we confirm the countervailing actions of each gene, and validate in vitro a crucial role for two single nucleotide polymorphisms in the 5'UTR of Isl1, one of which yields a novel E-box, mediating the repressive action of Neurog2.", - "journal_title": "Development (Cambridge, England)", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/36537573/" - } - ], - "fa8bba46-ce94-439a-a676-35187a3abcbf": [ - { - "pub_id": "27933523", - "title": "Integrative Functional Genomics for Systems Genetics in GeneWeaver.org.", - "authors": "Jason A Bubier,Michael A Langston,Erich J Baker,Elissa J Chesler", - "abstract": "The abundance of existing functional genomics studies permits an integrative approach to interpreting and resolving the results of diverse systems genetics studies. However, a major challenge lies in assembling and harmonizing heterogeneous data sets across species for facile comparison to the positional candidate genes and coexpression networks that come from systems genetic studies. GeneWeaver is an online database and suite of tools at www.geneweaver.org that allows for fast aggregation and analysis of gene set-centric data. GeneWeaver contains curated experimental data together with resource-level data such as GO annotations, MP annotations, and KEGG pathways, along with persistent stores of user entered data sets. These can be entered directly into GeneWeaver or transferred from widely used resources such as GeneNetwork.org. Data are analyzed using statistical tools and advanced graph algorithms to discover new relations, prioritize candidate genes, and generate function hypotheses. Here we use GeneWeaver to find genes common to multiple gene sets, prioritize candidate genes from a quantitative trait locus, and characterize a set of differentially expressed genes. Coupling a large multispecies repository curated and empirical functional genomics data to fast computational tools allows for the rapid integrative analysis of heterogeneous data for interpreting and extrapolating systems genetics results.", - "journal_title": "Methods in molecular biology (Clifton, N.J.)", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/27933523/" - } - ], - "d685bfad-fa39-4755-80d5-df87c710431f": [ - { - "pub_id": "31629034", - "title": "Low-dose alcohol ameliorated homocysteine-induced anxiety-related behavior via attenuating oxidative stress in mice.", - "authors": "Jie Cheng,Fan Li,Xiaoming Sun,Shuqin Liu,Lina Chen,Feng Tian,Zhenghang Zhao,Hao Hu,Xiaogang Li", - "abstract": "Recent studies showed that homocysteine (Hcy) levels were obviously elevated in patients with anxiety, furthermore, oxidative stress and inflammation were closely linked with Hcy-related damage. Despite alcohol exposure has differential effects on different forms of anxiety, the role of alcohol on anxiety-related behavior induced by high Hcy levels is still not entirely clear. The present study investigated the protective potential of low-dose alcohol against homocysteine-induced anxiety-related behavior and explored the possible underlying mechanisms. Mice were administered intragastrically with methionine (2.0\u202fg/kg/day) or alcohol (0.6\u202fg/kg/day). After 21 days of administration, the anxiety-related behavior was evaluated through open field (OF) and elevated plus maze (EPM) tests, and the variations of oxidative stress and inflammation levels were measured. The results of OF and EPM tests showed that the anxiety-related behavior in mice was prevented by alcohol treatment. Alcohol lowered the elevated serum Hcy levels and alleviated the damage of hippocampal tissues in hyperhomocysteinemia (HHcy) mice. Meanwhile, the superoxide dismutase (SOD) activity of the hippocampal tissues enhanced, and the malondialdehyde (MDA) concentration of the hippocampal tissues and the serum interleukin-1\u03b2 (IL-1\u03b2) level decreased. In addition, after administering alcohol, the increase of superoxide dismutase 1 (SOD1), heme oxygenase 1 (HO-1) protein expression and the decrease of IL-1\u03b2 protein expression were also detected in HHcy mice hippocampal tissues. Taken together, low-dose alcohol significantly ameliorated the Hcy-induced anxiety-related behavior in mice, which might be related to SOD1 and HO-1 upregulation and IL-1\u03b2 downregulation.", - "journal_title": "Neuroscience letters", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/31629034/" - } - ], - "56b668c7-f98e-49bd-ad50-00065465c8aa": [ - { - "pub_id": "36241774", - "title": "Leptin receptor co-expression gene network moderates the effect of early life adversity on eating behavior in children.", - "authors": "Randriely Merscher Sobreira de Lima,Barbara Barth,Danusa Mar Arcego,Euclides Jos\u00e9 de Mendon\u00e7a Filho,Sachin Patel,Zihan Wang,Irina Pokhvisneva,Carine Parent,Robert D Levitan,Michael S Kobor,Ana Paula Santana de Vasconcellos Bittencourt,Michael J Meaney,Carla Dalmaz,Patr\u00edcia Pelufo Silveira", - "abstract": "Leptin influences eating behavior. Exposure to early adversity is associated with eating behaviour disorders and metabolic syndrome, but the role of the leptin receptor on this relationship is poorly explored. We investigated whether individual differences in brain region specific leptin receptor (LepR) gene networks could moderate the effects of early adversity on eating behavior and metabolism. We created an expression-based polygenic risk score (ePRS) reflecting variations in the function of LepR gene network in prefrontal cortex and hypothalamus to investigate the interactions between a cumulative index of postnatal adversity on eating behavior in two independent birth cohorts (MAVAN and GUSTO). To explore whether variations in the prefrontal cortex or hypothalamic genetic scores could be associated with metabolic measurements, we also assessed the relationship between LepR-ePRS and fasting blood glucose and leptin levels in a third independent cohort (ALSPAC). We identified significant interaction effects between postnatal adversity and prefrontal-based LepR-ePRS on the Child Eating Behavior Questionnaire scores. In MAVAN, we observed a significant interaction effect on food enjoyment at 48 months (\u03b2\u2009=\u200961.58, p\u2009=\u20090.015) and 72 months (\u03b2\u2009=\u200997.78, p\u2009=\u20090.001); food responsiveness at 48 months (\u03b2\u2009=\u200983.79, p\u2009=\u20090.009) satiety at 48 months (\u03b2\u2009=\u2009-43.63, p\u2009=\u20090.047). Similar results were observed in the GUSTO cohort, with a significant interaction effect on food enjoyment (\u03b2\u2009=\u200930.48, p\u2009=\u20090.006) food fussiness score (\u03b2\u2009=\u2009-24.07, p\u2009=\u20090.02) and satiety score at 60 months (\u03b2\u2009=\u2009-17.00, p\u2009=\u20090.037). No effects were found when focusing on the\u00a0hypothalamus-based LepR-ePRS on eating behavior in MAVAN and GUSTO cohorts, and there was no\u00a0effect of hypothalamus and prefrontal cortex based ePRSs on metabolic measures in ALSPAC. Our study indicated that exposure to postnatal adversity interacts with prefrontal cortex LepR-ePRS to moderate eating behavior, suggesting a neurobiological mechanism associated with the development of eating behavior problems in response to early adversity. The knowledge of these mechanisms may guide the understanding of eating patterns associated with risk for obesity in response to fluctuations in stress exposure early in life.", - "journal_title": "Communications biology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/36241774/" - } - ], - "0951ba9d-bb8f-424b-b63f-16d94cb7166c": [ - { - "pub_id": "31679460", - "title": "RNA-binding protein ZFP36/TTP protects against ferroptosis by regulating autophagy signaling pathway in hepatic stellate cells.", - "authors": "Zili Zhang,Mei Guo,Yujia Li,Min Shen,Desong Kong,Jiangjuan Shao,Hai Ding,Shanzhong Tan,Anping Chen,Feng Zhang,Shizhong Zheng", - "abstract": "Ferroptosis is a recently discovered form of programmed cell death, but its regulatory mechanisms remain poorly understood. Here, we show that the RNA-binding protein ZFP36/TTP (ZFP36 ring finger protein) plays a crucial role in regulating ferroptosis in hepatic stellate cells (HSCs). Upon exposure to ferroptosis-inducing compounds, the ubiquitin ligase FBXW7/CDC4 (F-box and WD repeat domain containing 7) decreased ZFP36 protein expression by recognizing SFSGLPS motif. <i>FBXW7</i> plasmid contributed to classical ferroptotic events, whereas <i>ZFP36</i> plasmid impaired <i>FBXW7</i> plasmid-induced HSC ferroptosis. Interestingly, <i>ZFP36</i> plasmid inhibited macroautophagy/autophagy activation by destabilizing ATG16L1 (autophagy related 16 like 1) mRNA. <i>ATG16L1</i> plasmid eliminated the inhibitory action of <i>ZFP36</i> plasmid on ferroptosis, and <i>FBXW7</i> plasmid enhanced the effect of <i>ATG16L1</i> plasmid on autophagy. Importantly, <i>ZFP36</i> plasmid promoted <i>ATG16L1</i> mRNA decay via binding to the AU-rich elements (AREs) within the 3'-untranslated region. The internal mutation of the ARE region abrogated the ZFP36-mediated <i>ATG16L1</i> mRNA instability, and prevented <i>ZFP36</i> plasmid-mediated ferroptosis resistance. In mice, treatment with erastin and sorafenib alleviated murine liver fibrosis by inducing HSC ferroptosis. HSC-specific overexpression of <i>Zfp36</i> impaired erastin- or sorafenib-induced HSC ferroptosis. Noteworthy, we analyzed the effect of sorafenib on HSC ferroptosis in fibrotic patients with hepatocellular carcinoma receiving sorafenib monotherapy. Attractively, sorafenib monotherapy led to ZFP36 downregulation, ferritinophagy activation, and ferroptosis induction in human HSCs. Overall, these results revealed novel molecular mechanisms and signaling pathways of ferroptosis, and also identified ZFP36-autophagy-dependent ferroptosis as a potential target for the treatment of liver fibrosis. ARE: AU-rich elements; ATG: autophagy related; BECN1: beclin 1; CHX: cycloheximide; COL1A1: collagen type I alpha 1 chain; ELAVL1/HuR: ELAV like RNA binding protein 1; FBXW7/CDC4: F-box and WD repeat domain containing 7; FN1: fibronectin 1; FTH1: ferritin heavy chain 1; GPX4/PHGPx: glutathione peroxidase 4; GSH: glutathione; HCC: hepatocellular carcinoma; HSC: hepatic stellate cell; LSEC: liver sinusoidal endothelial cell; MAP1LC3A: microtubule associated protein 1 light chain 3 alpha; MDA: malondialdehyde; NCOA4: nuclear receptor coactivator 4; PTGS2/COX2: prostaglandin-endoperoxide synthase 2; RBP: RNA-binding protein; ROS: reactive oxygen species; SLC7A11/xCT: solute carrier family 7 member 11; SQSTM1/p62: sequestosome 1; TNF: tumor necrosis factor; TP53/p53: tumor protein p53; UTR: untranslated region; ZFP36/TTP: ZFP36 ring finger protein.", - "journal_title": "Autophagy", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/31679460/" - } - ], - "ee04d190-5b08-4b82-ad80-00287373b0a0": [ - { - "pub_id": "31920576", - "title": "A Cross-Species Systems Genetics Analysis Links APBB1IP as a Candidate for Schizophrenia and Prepulse Inhibition.", - "authors": "David G Ashbrook,Stephanie Cahill,Reinmar Hager", - "abstract": "<b>Background</b>: Prepulse inhibition (PPI) of the startle response is a highly conserved form of sensorimotor gating, disruption of which is found in schizophrenia patients and their unaffected first-degree relatives. PPI can be measured in many species, and shows considerable phenotypic variation between and within rodent models. This makes PPI a useful endophenotype. Genome-wide association studies (GWAS) have been carried out to identify genetic variants underlying schizophrenia, and these suggest that schizophrenia is highly polygenic. GWAS have been unable to account for the high heritability of schizophrenia seen in family studies, partly because of the low power of GWAS due to multiple comparisons. By contrast, complementary mouse model linkage studies often have high statistical power to detect variants for behavioral traits but lower resolution, producing loci that include tens or hundreds of genes. To capitalize on the advantages of both GWAS and genetic mouse models, our study uses a cross-species approach to identify novel genes associated with PPI regulation, which thus may contribute to the PPI deficits seen in schizophrenia. <b>Results</b>: Using experimental data from the recombinant inbred (RI) mouse panel BXD, we identified two significant loci affecting PPI. These genomic regions contain genetic variants which influence PPI in mice and are therefore candidates that may be influencing aspects of schizophrenia in humans. We next investigated these regions in whole-genome data from the Psychiatric Genomics Consortium (PGC) schizophrenia GWAS and identify one novel candidate gene (<i>ABPP1IP</i>) that was significantly associated with PPI in mice and risk of schizophrenia in humans. A systems genetics approach demonstrates that <i>APBB1IP</i> coexpresses with several other genes related to schizophrenia in several brain regions. Gene coexpression and enrichment analysis shows clear links between <i>APBB1IP</i> and the immune system. <b>Conclusion</b>: The combination of human GWAS and mouse quantitative trait loci (QTL) from some of the largest study systems available has enabled us to identify a novel gene, <i>APBB1IP</i>, which influences schizophrenia in humans and PPI in mice.", - "journal_title": "Frontiers in behavioral neuroscience", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/31920576/" - } - ], - "1e65fbdd-8146-4543-8907-9f929fae72a8": [ - { - "pub_id": "29348476", - "title": "Animal models of obesity and diabetes mellitus.", - "authors": "Maximilian Kleinert,Christoffer Clemmensen,Susanna M Hofmann,Mary C Moore,Simone Renner,Stephen C Woods,Peter Huypens,Johannes Beckers,Martin Hrabe de Angelis,Annette Sch\u00fcrmann,Mostafa Bakhti,Martin Klingenspor,Mark Heiman,Alan D Cherrington,Michael Ristow,Heiko Lickert,Eckhard Wolf,Peter J Havel,Timo D M\u00fcller,Matthias H Tsch\u00f6p", - "abstract": "More than one-third of the worldwide population is overweight or obese and therefore at risk of developing type 2 diabetes mellitus. In order to mitigate this pandemic, safer and more potent therapeutics are urgently required. This necessitates the continued use of animal models to discover, validate and optimize novel therapeutics for their safe use in humans. In order to improve the transition from bench to bedside, researchers must not only carefully select the appropriate model but also draw the right conclusions. In this Review, we consolidate the key information on the currently available animal models of obesity and diabetes and highlight the advantages, limitations and important caveats of each of these models.", - "journal_title": "Nature reviews. Endocrinology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/29348476/" - } - ], - "e8a26549-f13b-4c3f-97b1-a33bcc8baa80": [ - { - "pub_id": "31164799", - "title": "Genetic Factors Mediate the Impact of Chronic Stress and Subsequent Response to Novel Acute Stress.", - "authors": "Elena E Terenina,Sonia Cavigelli,Pierre Mormede,Wenyuan Zhao,Cory Parks,Lu Lu,Byron C Jones,Megan K Mulligan", - "abstract": "Individual differences in physiological and biobehavioral adaptation to chronic stress are important predictors of health and fitness; genetic differences play an important role in this adaptation. To identify these differences we measured the biometric, neuroendocrine, and transcriptional response to stress among inbred mouse strains with varying degrees of genetic similarity, C57BL/6J (B), C57BL/6NJ (N), and DBA/2J (D). The B and D strains are highly genetically diverse whereas the B and N substrains are highly similar. Strain differences in hypothalamic-pituitary-adrenal (HPA) axis cross-sensitization were determined by plasma corticosterone (CORT) levels and hippocampal gene expression following 7-weeks of chronic mild stress (CMS) or normal housing (NH) and subsequent exposure to novel acute restraint. Fecal CORT metabolites and body and organ weights were also measured. All strains exposed to CMS had reduced heart weights, whereas body weight gain was attenuated only in B and N strains. Acute stress alone produced larger plasma CORT responses in the D and N strains compared to the B strain. CMS paired with acute stress produced cross-sensitization of the CORT response in the N strain. The N strain also had the largest number of hippocampal transcripts with up-regulated expression in response to stress. In contrast, the D strain had the largest number of transcripts with down-regulated expression following CMS and acute stress. In summary, we observed differential responses to CMS at both the physiological and molecular level among genetically diverse strains, indicating that genetic factors drive individual differences in experience-dependent regulation of the stress response.", - "journal_title": "Frontiers in neuroscience", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/31164799/" - } - ], - "a98d7249-5433-47b6-be74-2efbe581e0cb": [ - { - "pub_id": "28515850", - "title": "Dissection of Z-disc myopalladin gene network involved in the development of restrictive cardiomyopathy using system genetics approach.", - "authors": "Qingqing Gu,Uzmee Mendsaikhan,Zaza Khuchua,Byron C Jones,Lu Lu,Jeffrey A Towbin,Biao Xu,Enkhsaikhan Purevjav", - "abstract": "To investigate the regulation of Myopalladin (<i>Mypn</i>) and identify its gene network involved in restrictive cardiomyopathy (RCM). Gene expression values were measured in the heart of a large family of BXD recombinant inbred (RI) mice derived from C57BL/6J and DBA/2J. The proteomics data were collected from <i>Mypn</i> knock-in and knock-out mice. Expression quantitative trait locus (eQTL) mapping methods and gene enrichment analysis were used to identify <i>Mypn</i> regulation, gene pathway and co-expression networks. A wide range of variation was found in expression of <i>Mypn</i> among BXD strains. We identified upstream genetic loci at chromosome 1 and 5 that modulate the expression of <i>Mypn</i>. Candidate genes within these loci include <i>Ncoa2</i>, <i>Vcpip1</i>, <i>Sgk3</i>, and <i>Lgi2</i>. We also identified 15 sarcomeric genes interacting with <i>Mypn</i> and constructed the gene network. Two novel members of this network (<i>Syne1</i> and <i>Myom1</i>) have been confirmed at the protein level. Several members in this network are already known to relate to cardiomyopathy with some novel genes candidates that could be involved in RCM. Using systematic genetics approach, we constructed <i>Mypn</i> co-expression networks that define the biological process categories within which similarly regulated genes function. Through this strategy we have found several novel genes that interact with <i>Mypn</i> that may play an important role in the development of RCM.", - "journal_title": "World journal of cardiology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/28515850/" - } - ], - "a144ec66-3723-4a2c-a7ce-78b5ed66364b": [ - { - "pub_id": "28571877", - "title": "Shaping vulnerability to addiction - the contribution of behavior, neural circuits and molecular mechanisms.", - "authors": "Gabor Egervari,Roberto Ciccocioppo,J David Jentsch,Yasmin L Hurd", - "abstract": "Substance use disorders continue to impose increasing medical, financial and emotional burdens on society in the form of morbidity and overdose, family disintegration, loss of employment and crime, while advances in prevention and treatment options remain limited. Importantly, not all individuals exposed to abused substances effectively develop the disease. Genetic factors play a significant role in determining addiction vulnerability and interactions between innate predisposition, environmental factors and personal experiences are also critical. Thus, understanding individual differences that contribute to the initiation of substance use as well as on long-term maladaptations driving compulsive drug use and relapse propensity is of critical importance to reduce this devastating disorder. In this paper, we discuss current topics in the field of addiction regarding individual vulnerability related to behavioral endophenotypes, neural circuits, as well as genetics and epigenetic mechanisms. Expanded knowledge of these factors is of importance to improve and personalize prevention and treatment interventions in the future.", - "journal_title": "Neuroscience and biobehavioral reviews", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/28571877/" - } - ], - "16cf4a95-88bc-405c-9959-ff758dd57b8c": [ - { - "pub_id": "29674951", - "title": "Integrating Genetic and Gene Co-expression Analysis Identifies Gene Networks Involved in Alcohol and Stress Responses.", - "authors": "Jie Luo,Pei Xu,Peijian Cao,Hongjian Wan,Xiaonan Lv,Shengchun Xu,Gangjun Wang,Melloni N Cook,Byron C Jones,Lu Lu,Xusheng Wang", - "abstract": "Although the link between stress and alcohol is well recognized, the underlying mechanisms of how they interplay at the molecular level remain unclear. The purpose of this study is to identify molecular networks underlying the effects of alcohol and stress responses, as well as their interaction on anxiety behaviors in the hippocampus of mice using a systems genetics approach. Here, we applied a gene co-expression network approach to transcriptomes of 41 BXD mouse strains under four conditions: stress, alcohol, stress-induced alcohol and control. The co-expression analysis identified 14 modules and characterized four expression patterns across the four conditions. The four expression patterns include up-regulation in no restraint stress and given an ethanol injection (NOE) but restoration in restraint stress followed by an ethanol injection (RSE; pattern 1), down-regulation in NOE but rescue in RSE (pattern 2), up-regulation in both restraint stress followed by a saline injection (RSS) and NOE, and further amplification in RSE (pattern 3), and up-regulation in RSS but reduction in both NOE and RSE (pattern 4). We further identified four functional subnetworks by superimposing protein-protein interactions (PPIs) to the 14 co-expression modules, including \u03b3-aminobutyric acid receptor (GABA) signaling, glutamate signaling, neuropeptide signaling, cAMP-dependent signaling. We further performed module specificity analysis to identify modules that are specific to stress, alcohol, or stress-induced alcohol responses. Finally, we conducted causality analysis to link genetic variation to these identified modules, and anxiety behaviors after stress and alcohol treatments. This study underscores the importance of integrative analysis and offers new insights into the molecular networks underlying stress and alcohol responses.", - "journal_title": "Frontiers in molecular neuroscience", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/29674951/" - } - ], - "8cf9bdbe-c528-4b4f-b9c6-7af49d680a92": [ - { - "pub_id": "31406845", - "title": "A theoretical framework for interaction of nursing discipline with genetics and genomics.", - "authors": "Jiale Hu,Leilei Yu,Shokoufeh Modanloo,Yiyan Zhou,Yan Yang", - "abstract": "Since the completion of the Human Genome Project, health science has been strongly influenced by the advances in genetics and genomics. However, the progress of embracing genetics and genomics into nursing discipline is limited. One of the main barriers is lack of understanding on the relevancy of genetics and genomics to nursing discipline. This paper aims to synthesize and develop a theoretical framework for the interaction of nursing discipline with genetics and genomics. Through content analysis and constant comparative method, a theoretical framework was developed from synthesis of the studies regarding nursing and genetics/genomics indexed in multiple English and Chinese databases. Four main theoretical statements were constructed in the framework: 1) There are three ways to show how genetics and genomics can influence nursing discipline: a new specialty, new technologies and a new lens; 2) The significant contribution of nursing discipline to genetics and genomics lies in how nurses could focus on the association between human responses and genes and how nurses could advocate for their clients in the genetic and genomic era; 3) A paradigm shift occurs after a constant interaction of nursing discipline with genetics and genomics; 4) Implementation strategies could be used to facilitate the integration of genetics and genomics to nursing discipline and advance the paradigm shift. The framework will help to understand the relationship between nursing discipline and genetics and genomics and implicate the future studies integrating genetics and genomic science into nursing discipline.", - "journal_title": "International journal of nursing sciences", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/31406845/" - } - ], - "5812bd82-0c95-4386-8110-bfc45ca337ff": [ - { - "pub_id": "15781756", - "title": "Metabolic syndrome: a comprehensive perspective based on interactions between obesity, diabetes, and inflammation.", - "authors": "Paresh Dandona,Ahmad Aljada,Ajay Chaudhuri,Priya Mohanty,Rajesh Garg", - "abstract": "", - "journal_title": "Circulation", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/15781756/" - } - ], - "2174033d-08a1-4cc8-a260-1414373a25a8": [ - { - "pub_id": "29892901", - "title": "Deciphering signature of selection affecting beef quality traits in Angus cattle.", - "authors": "Mengistie Taye,Joon Yoon,Tadelle Dessie,Seoae Cho,Sung Jong Oh,Hak-Kyo Lee,Heebal Kim", - "abstract": "Artificial selection towards a desired phenotype/trait has modified the genomes of livestock dramatically that generated breeds that greatly differ in morphology, production and environmental adaptation traits. Angus cattle are among the famous cattle breeds developed for superior beef quality. This paper aimed at exploring genomic regions under selection in Angus cattle that are associated with meat quality traits and other associated phenotypes. The whole genome of 10 Angus cattle was compared with 11 Hanwoo (A-H) and 9 Jersey (A-J) cattle breeds using a cross-population composite likelihood ratio (XP-CLR) statistical method. The top 1% of the empirical distribution was taken as significant and annotated using UMD3.1. As a result, 255 and 210 genes were revealed under selection from A-H and A-J comparisons, respectively. The WebGestalt gene ontology analysis resulted in sixteen (A-H) and five (A-J) significantly enriched KEGG pathways. Several pathways associated with meat quality traits (insulin signaling, type II diabetes mellitus pathway, focal adhesion pathway, and ECM-receptor interaction), and feeding efficiency (olfactory transduction, tight junction, and metabolic pathways) were enriched. Genes affecting beef quality traits (e.g., FABP3, FTO, DGAT2, ACS, ACAA2, CPE, TNNI1), stature and body size (e.g., PLAG1, LYN, CHCHD7, RPS20), fertility and dystocia (e.g., ESR1, RPS20, PPP2R1A, GHRL, PLAG1), feeding efficiency (e.g., PIK3CD, DNAJC28, DNAJC3, GHRL, PLAG1), coat color (e.g., MC1-R) and genetic disorders (e.g., ITGB6, PLAG1) were found to be under positive selection in Angus cattle. The study identified genes and pathways that are related to meat quality traits and other phenotypes of Angus cattle. The findings in this study, after validation using additional or independent dataset, will provide useful information for the study of Angus cattle in particular and beef cattle in general.", - "journal_title": "Genes & genomics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/29892901/" - } - ], - "d9564b3c-efac-42ae-8e15-bf962c0a7a3c": [ - { - "pub_id": "28688048", - "title": "Susceptibility background for type 2 diabetes in eleven Mexican Indigenous populations: HNF4A gene analysis.", - "authors": "M A Granados-Silvestre,M G Ortiz-L\u00f3pez,J Granados,S Canizales-Quinteros,Rosenda I Pe\u00f1aloza-Espinosa,C Lechuga,V Acu\u00f1a-Alonzo,K S\u00e1nchez-Pozos,M Menjivar", - "abstract": "The genetic risk of developing type 2 diabetes (T2D) increases in parallel with the proportion of Native American ancestry. Mestizo Mexicans have a 70% Native Amerindian genetic background. The T130I polymorphism in the HNF4A gene has been associated with early-onset T2D in mestizo Mexicans. Thus, the aim of the present study was to evaluate the frequency and relationship of the T130I variant in the HNF4A gene with risk factors for developing T2D in eleven indigenous groups from Mexico. In two groups, all exons of the HNF4A gene were directly sequenced; in the remaining the T130I polymorphism was analyzed by restriction fragment length polymorphism. Ancestry informative markers were assessed to confirm the Amerindian component. An additional analysis of EHH was carried out. Interestingly, HNF4A gene screening revealed only the presence of the T130I polymorphism. The range frequency of the risk allele (T) in the indigenous groups was from 2.7 to 16%. Genotypic frequencies (T130I/I130I) were higher and significantly different from those of all of the populations included in the HapMap Project (P\u00a0<\u00a00.005). EHH scores suggest a positive selection for T130I polymorphism. Metabolic traits indicate a relationship between the T130I/I130I genotypes with high triglyceride concentrations in the indigenous groups (P\u00a0<\u00a00.005). These results strongly suggest that the high frequency of the T130I polymorphism and its biological relationship with dysfunction in lipid metabolism in Mexican indigenous groups is a risk factor for the developing of T2D in Mexicans.", - "journal_title": "Molecular genetics and genomics : MGG", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/28688048/" - } - ], - "66d544c8-d67c-45a0-8a88-e8196b94da8d": [ - { - "pub_id": "29432124", - "title": "<i>CDKN2A/B</i> T2D Genome-Wide Association Study Risk SNPs Impact Locus Gene Expression and Proliferation in Human Islets.", - "authors": "Yahui Kong,Rohit B Sharma,Socheata Ly,Rachel E Stamateris,William M Jesdale,Laura C Alonso", - "abstract": "Genome-wide association studies link the <i>CDKN2A/B</i> locus with type 2 diabetes (T2D) risk, but mechanisms increasing risk remain unknown. The <i>CDKN2A/B</i> locus encodes cell cycle inhibitors <i>p14</i>, <i>p15</i>, and <i>p16</i>; <i>MTAP</i>; and <i>ANRIL</i>, a long noncoding RNA. The goal of this study was to determine whether <i>CDKN2A/B</i> T2D risk SNPs impact locus gene expression, insulin secretion, or \u03b2-cell proliferation in human islets. Islets from donors without diabetes (<i>n</i> = 95) were tested for SNP genotype (rs10811661, rs2383208, rs564398, and rs10757283), gene expression (<i>p14</i>, <i>p15</i>, <i>p16</i>, <i>MTAP</i>, <i>ANRIL</i>, <i>PCNA</i>, <i>KI67</i>, and <i>CCND2</i>), insulin secretion (<i>n</i> = 61), and \u03b2-cell proliferation (<i>n</i> = 47). Intriguingly, locus genes were coregulated in islets in two physically overlapping cassettes: <i>p14</i>-<i>p16-ANRIL</i>, which increased with age, and <i>MTAP</i>-<i>p15</i>, which did not. Risk alleles at rs10811661 and rs2383208 were differentially associated with expression of <i>ANRIL</i>, but not <i>p14</i>, <i>p15, p16</i>, or <i>MTAP</i>, in age-dependent fashion, such that younger homozygous risk donors had higher <i>ANRIL</i> expression, equivalent to older donor levels. We identified several risk SNP combinations that may impact locus gene expression, suggesting possible mechanisms by which SNPs impact locus biology. Risk allele carriers at <i>ANRIL</i> coding SNP rs564398 had reduced \u03b2-cell proliferation index. In conclusion, <i>CDKN2A/B</i> locus SNPs may impact T2D risk by modulating islet gene expression and \u03b2-cell proliferation.", - "journal_title": "Diabetes", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/29432124/" - } - ], - "0e19bd5a-a6fa-4c02-b55f-14931725faee": [ - { - "pub_id": "23719380", - "title": "Gut metagenome in European women with normal, impaired and diabetic glucose control.", - "authors": "Fredrik H Karlsson,Valentina Tremaroli,Intawat Nookaew,G\u00f6ran Bergstr\u00f6m,Carl Johan Behre,Bj\u00f6rn Fagerberg,Jens Nielsen,Fredrik B\u00e4ckhed", - "abstract": "Type 2 diabetes (T2D) is a result of complex gene-environment interactions, and several risk factors have been identified, including age, family history, diet, sedentary lifestyle and obesity. Statistical models that combine known risk factors for T2D can partly identify individuals at high risk of developing the disease. However, these studies have so far indicated that human genetics contributes little to the models, whereas socio-demographic and environmental factors have greater influence. Recent evidence suggests the importance of the gut microbiota as an environmental factor, and an altered gut microbiota has been linked to metabolic diseases including obesity, diabetes and cardiovascular disease. Here we use shotgun sequencing to characterize the faecal metagenome of 145 European women with normal, impaired or diabetic glucose control. We observe compositional and functional alterations in the metagenomes of women with T2D, and develop a mathematical model based on metagenomic profiles that identified T2D with high accuracy. We applied this model to women with impaired glucose tolerance, and show that it can identify women who have a diabetes-like metabolism. Furthermore, glucose control and medication were unlikely to have major confounding effects. We also applied our model to a recently described Chinese cohort and show that the discriminant metagenomic markers for T2D differ between the European and Chinese cohorts. Therefore, metagenomic predictive tools for T2D should be specific for the age and geographical location of the populations studied.", - "journal_title": "Nature", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/23719380/" - } - ], - "af4c6e19-fafe-4178-a9eb-213991f344d6": [ - { - "pub_id": "29199021", - "title": "An Integrated Systems Genetics and Omics Toolkit to Probe Gene Function.", - "authors": "Hao Li,Xu Wang,Daria Rukina,Qingyao Huang,Tao Lin,Vincenzo Sorrentino,Hongbo Zhang,Maroun Bou Sleiman,Danny Arends,Aaron McDaid,Peiling Luan,Naveed Ziari,Laura A Vel\u00e1zquez-Villegas,Karim Gariani,Zoltan Kutalik,Kristina Schoonjans,Richard A Radcliffe,Pjotr Prins,Stephan Morgenthaler,Robert W Williams,Johan Auwerx", - "abstract": "Identifying genetic and environmental factors that impact complex traits and common diseases is a high biomedical priority. Here, we developed, validated, and implemented a series of multi-layered systems approaches, including (expression-based) phenome-wide association, transcriptome-/proteome-wide association, and (reverse-) mediation analysis, in an open-access web server (systems-genetics.org) to expedite the systems dissection of gene function. We applied these approaches to multi-omics datasets from the BXD mouse genetic reference population, and identified and validated associations between genes and clinical and molecular phenotypes, including previously unreported links between Rpl26 and body weight, and Cpt1a and lipid\u00a0metabolism. Furthermore, through mediation and reverse-mediation analysis we established regulatory relations between genes, such as the co-regulation of BCKDHA and BCKDHB protein levels, and identified targets of transcription factors E2F6, ZFP277, and ZKSCAN1. Our multifaceted toolkit enabled the identification of gene-gene and gene-phenotype links that are robust and that translate well across populations and species, and can be universally applied to any populations with multi-omics datasets.", - "journal_title": "Cell systems", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/29199021/" - } - ], - "33c07906-39ca-4241-a50c-ddc6e0ca5fd3": [ - { - "pub_id": "29176626", - "title": "Systems genetics identifies a role for Cacna2d1 regulation in elevated intraocular pressure and glaucoma susceptibility.", - "authors": "Sumana R Chintalapudi,Doaa Maria,Xiang Di Wang,Jessica N Cooke Bailey, , ,Pirro G Hysi,Janey L Wiggs,Robert W Williams,Monica M Jablonski", - "abstract": "Glaucoma is a multi-factorial blinding disease in which genetic factors play an important role. Elevated intraocular pressure is a highly heritable risk factor for primary open angle glaucoma and currently the only target for glaucoma therapy. Our study helps to better understand underlying genetic and molecular mechanisms that regulate intraocular pressure, and identifies a new candidate gene, Cacna2d1, that modulates intraocular pressure and a promising therapeutic, pregabalin, which binds to CACNA2D1 protein and lowers intraocular pressure significantly. Because our study utilizes a genetically diverse population of mice with known sequence variants, we are able to determine that the intraocular pressure-lowering effect of pregabalin is dependent on the Cacna2d1 haplotype. Using human genome-wide association study (GWAS) data, evidence for association of a CACNA2D1 single-nucleotide polymorphism and primary open angle glaucoma is found. Importantly, these results demonstrate that our systems genetics approach represents an efficient method to identify genetic variation that can guide the selection of therapeutic targets.", - "journal_title": "Nature communications", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/29176626/" - } - ], - "29d9fa5b-7b6e-4b59-899a-5e47bf657370": [ - { - "pub_id": "30221471", - "title": "Systems genetics of sensation seeking.", - "authors": "Price E Dickson,Tyler A Roy,Kathryn A McNaughton,Troy D Wilcox,Padam Kumar,Elissa J Chesler", - "abstract": "Sensation seeking is a multifaceted, heritable trait which predicts the development of substance use and abuse in humans; similar phenomena have been observed in rodents. Genetic correlations among sensation seeking and substance use indicate shared biological mechanisms, but the genes and networks underlying these relationships remain elusive. Here, we used a systems genetics approach in the BXD recombinant inbred mouse panel to identify shared genetic mechanisms underlying substance use and preference for sensory stimuli, an intermediate phenotype of sensation seeking. Using the operant sensation seeking (OSS) paradigm, we quantified preference for sensory stimuli in 120 male and 127 female mice from 62 BXD strains and the C57BL/6J and DBA/2J founder strains. We used relative preference for the active and inactive levers to dissociate preference for sensory stimuli from locomotion and exploration phenotypes. We identified genomic regions on chromosome 4 (155.236-155.742\u2009Mb) and chromosome 13 (72.969-89.423\u2009Mb) associated with distinct behavioral components of OSS. Using publicly available behavioral data and mRNA expression data from brain regions involved in reward processing, we identified (a) genes within these behavioral QTL exhibiting genome-wide significant cis-eQTL and (b) genetic correlations among OSS phenotypes, ethanol phenotypes and mRNA expression. From these analyses, we nominated positional candidates for behavioral QTL associated with distinct OSS phenotypes including Gnb1 and Mef2c. Genetic covariation of Gnb1 expression, preference for sensory stimuli and multiple ethanol phenotypes suggest that heritable variation in Gnb1 expression in reward circuitry partially underlies the widely reported relationship between sensation seeking and substance use.", - "journal_title": "Genes, brain, and behavior", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/30221471/" - } - ], - "8d6b4c71-c766-4009-85c0-dbe0b5d3f39f": [ - { - "pub_id": "32294413", - "title": "A Multi-Omics Perspective of Quantitative Trait Loci in Precision Medicine.", - "authors": "Youqiong Ye,Zhao Zhang,Yaoming Liu,Lixia Diao,Leng Han", - "abstract": "Quantitative trait loci (QTL) analysis is an important approach to investigate the effects of genetic variants identified through an increasing number of large-scale, multidimensional 'omics data sets. In this 'big data' era, the research community has identified a significant number of molecular QTLs (molQTLs) and increased our understanding of their effects. Herein, we review multiple categories of molQTLs, including those associated with transcriptome, post-transcriptional regulation, epigenetics, proteomics, metabolomics, and the microbiome. We summarize approaches to identify molQTLs and to infer their causal effects. We further discuss the integrative analysis of molQTLs through a multi-omics perspective. Our review highlights future opportunities to better understand the functional significance of genetic variants and to utilize the discovery of molQTLs in precision medicine.", - "journal_title": "Trends in genetics : TIG", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/32294413/" - } - ], - "1b7b2ec6-5cf3-41c5-a5a0-06de2bf7212e": [ - { - "pub_id": "32483258", - "title": "Skeletal muscle enhancer interactions identify genes controlling whole-body metabolism.", - "authors": "Kristine Williams,Lars R Ingerslev,Jette Bork-Jensen,Martin Wohlwend,Ann Normann Hansen,Lewin Small,Rasmus Ribel-Madsen,Arne Astrup,Oluf Pedersen,Johan Auwerx,Christopher T Workman,Niels Grarup,Torben Hansen,Romain Barr\u00e8s", - "abstract": "Obesity and type 2 diabetes (T2D) are metabolic disorders influenced by lifestyle and genetic factors that are characterized by insulin resistance in skeletal muscle, a prominent site of glucose disposal. Numerous genetic variants have been associated with obesity and T2D, of which the majority are located in non-coding DNA regions. This suggests that most variants mediate their effect by altering the activity of gene-regulatory elements, including enhancers. Here, we map skeletal muscle genomic enhancer elements that are dynamically regulated after exposure to the free fatty acid palmitate or the inflammatory cytokine TNF\u03b1. By overlapping enhancer positions with the location of disease-associated genetic variants, and resolving long-range chromatin interactions between enhancers and gene promoters, we identify target genes involved in metabolic dysfunction in skeletal muscle. The majority of these genes also associate with altered whole-body metabolic phenotypes in the murine BXD genetic reference population. Thus, our combined genomic investigations identified genes that are involved in skeletal muscle metabolism.", - "journal_title": "Nature communications", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/32483258/" - } - ], - "2c7924d6-99d9-4b94-b855-72cbff6c199d": [ - { - "pub_id": "31228159", - "title": "Networking in Biology: The Hybrid Rat Diversity Panel.", - "authors": "Boris Tabakoff,Harry Smith,Lauren A Vanderlinden,Paula L Hoffman,Laura M Saba", - "abstract": "One of the most fruitful resources for systems genetic studies of nonhuman mammals is a panel of inbred strains that exhibits significant genetic diversity between strains but genetic stability (isogenicity) within strains. These characteristics allow for fine mapping of complex phenotypes (QTLs) and provide statistical power to identify loci which contribute nominally to the phenotype. This type of resource also allows the planning and performance of investigations using the same genetic backgrounds over several generations of the test animals. Often, rats are preferred over mice for physiologic and behavioral studies because of their larger size and more distinguishable anatomy (particularly for their central nervous system). The Hybrid Rat Diversity Panel (HRDP) is a panel of inbred rat strains, which combines two recombinant inbred panels (the HXB/BXH, 30 strains; the LEXF/FXLE, 34 strains and 35 more strains of inbred rats which were selected for genetic diversity, based on their fully sequenced genomes and/or thorough genotyping). The genetic diversity and statistical power of this panel for mapping studies rivals or surpasses currently available panels in mouse. The genetic stability of this panel makes it particularly suitable for collection of high-throughput omics data as relevant technology becomes available for engaging in truly integrative systems biology. The PhenoGen website ( http://phenogen.org ) is the repository for the initial transcriptome data, making the raw data, the processed data, and the analysis results, e.g., organ-specific protein coding and noncoding transcripts, isoform analysis, expression quantitative trait loci, and co-expression networks, available to the research public. The data sets and tools being developed will complement current efforts to analyze the human transcriptome and its genetic controls (the Genotype-Tissue Expression Project (GTEx)) and allow for dissection of genetic networks that predispose to particular phenotypes and gene-by-environment interactions that are difficult or even impossible to study in humans. The HRDP is an essential population for exploring truly integrative systems genetics.", - "journal_title": "Methods in molecular biology (Clifton, N.J.)", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/31228159/" - } - ], - "8cc4b750-4d64-4d36-8ed8-c8eb72d56990": [ - { - "pub_id": "31467227", - "title": "Association of Leukemia Target Genes <i>Tet2, Bcl2</i>, and <i>Slc23a2</i> in Vitamin C Pathways.", - "authors": "Jing Li,Wenqi Zhang,Weidong Liu,Jarrett Rong,Yuhan Chen,Weikuan Gu,Wei Zhang", - "abstract": "Vitamin C has been used in combination with several target genes in the treatment of leukemia. Tet methylcytosine dioxygenase (Tet2), B-cell lymphoma 2 (Bcl2), and solute carrier family 23 member 2 (Slc23a2) are the major target genes in the treatment of leukemia and are relevant to vitamin C. Using whole-genome expression profiles from mouse livers, the expression quantitative trait locus (eQTL), correlation matrix, and gene network graph were constructed with probes from each of these three genes and with their relative genes. The function of key genes was examined by their pathways and reported information. The results indicated that although direct correlations among their expression levels were not strong, alternative connecting pathways were discovered. By comparing the expression levels of one probe with known sequences from each of the three genes, we identified several key genes, induced myeloid leukemia cell differentiation protein (Mcl1), far upstream element-binding protein 1 (Fubp1), and tumor protein D52-like 2 (Tpd52l2), which play important roles in acute lymphocytic leukemia and acute myelocytic leukemia. In conclusion, Alternative pathways and key genes that connect Tet2, Bcl2, and Slc23a2 for their therapeutic applications with vitamin C were identified.", - "journal_title": "Cancer genomics & proteomics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/31467227/" - } - ], - "54147a26-a71a-4e11-8f95-334df4bac365": [ - { - "pub_id": "30261172", - "title": "Genetic differences in the behavioral organization of binge eating, conditioned food reward, and compulsive-like eating in C57BL/6J and DBA/2J strains.", - "authors": "Richard K Babbs,Julia C Kelliher,Julia L Scotellaro,Kimberly P Luttik,Megan K Mulligan,Camron D Bryant", - "abstract": "Binge eating (BE) is a heritable symptom of eating disorders associated with anxiety, depression, malnutrition, and obesity. Genetic analysis of BE could facilitate therapeutic discovery. We used an intermittent, limited access BE paradigm involving sweetened palatable food (PF) to examine genetic differences in BE, conditioned food reward, and compulsive-like eating between C57BL/6J (B6J) and DBA/2J (D2J) inbred mouse strains. D2J mice showed a robust escalation in intake and conditioned place preference for the PF-paired side. D2J mice also showed a unique style of compulsive-like eating in the light/dark conflict test where they rapidly hoarded and consumed PF in the preferred unlit environment. BE and compulsive-like eating exhibited narrow-sense heritability estimates between 56 and 73%. To gain insight into the genetic basis, we phenotyped and genotyped a small cohort of 133 B6J \u00d7 D2J-F<sub>2</sub> mice at the peak location of three quantitative trait loci (QTL) previously identified in F<sub>2</sub> mice for sweet taste (chromosome 4: 156\u202fMb), bitter taste (chromosome 6: 133\u202fMb) and behavioral sensitivity to drugs of abuse (chromosome 11: 50\u202fMb). The D2J allele on chromosome 6 was associated with greater PF intake on training days and greater compulsive-like PF intake, but only in males, suggesting that decreased bitter taste may increase BE in males. The D2J allele on chromosome 11 was associated with an increase in final PF intake and slope of escalation across days. Future studies employing larger crosses and genetic reference panels comprising B6J and D2J alleles will identify causal genes and neurobiological mechanisms.", - "journal_title": "Physiology & behavior", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/30261172/" - } - ], - "e091d263-6ffc-4ff0-bd1d-2a0c757b0f74": [ - { - "pub_id": "34454100", - "title": "Prefrontal cortex VAMP1 gene network moderates the effect of the early environment on cognitive flexibility in children.", - "authors": "Carla Dalmaz,Barbara Barth,Irina Pokhvisneva,Zihan Wang,Sachin Patel,Jorge A Quillfeldt,Euclides J Mendon\u00e7a Filho,Randriely Merscher Sobreira de Lima,Danusa M Arcego,Roberto Britto Sassi,Geoffrey B C Hall,Michael S Kobor,Michael J Meaney,Patr\u00edcia P Silveira", - "abstract": "During development, genetic and environmental factors interact to modify specific phenotypes. Both in humans and in animal models, early adversities influence cognitive flexibility, an important brain function related to behavioral adaptation to variations in the environment. Abnormalities in cognitive functions are related to changes in synaptic connectivity in the prefrontal cortex (PFC), and altered levels of synaptic proteins. We investigated if individual variations in the expression of a network of genes co-expressed with the synaptic protein VAMP1 in the prefrontal cortex moderate the effect of early environmental quality on the performance of children in cognitive flexibility tasks. Genes overexpressed in early childhood and co-expressed with the VAMP1 gene in the PFC were selected for study. SNPs from these genes (post-clumping) were compiled in an expression-based polygenic score (PFC-ePRS-VAMP1). We evaluated cognitive performance of the 4\u00a0years-old children in two cohorts using similar cognitive flexibility tasks. In the first cohort (MAVAN) we utilized two CANTAB tasks: (a) the Intra-/Extra-dimensional Set Shift (IED) task, and (b) the Spatial Working Memory (SWM) task. In the second cohort, GUSTO, we used the Dimensional Change Card Sort (DCCS) task. The results show that in 4\u00a0years-old children, the PFC-ePRS-VAMP1 network moderates responsiveness to the effects of early adversities on the performance in attentional flexibility tests. The same result was observed for a spatial working memory task. Compared to attentional flexibility, reversal learning showed opposite effects of the environment, as moderated by the ePRS. A parallel ICA analysis was performed to identify relationships between whole-brain voxel based gray matter density and SNPs that comprise the PFC-ePRS-VAMP1. The early environment predicts differences in gray matter content in regions such as prefrontal and temporal cortices, significantly associated with a genetic component related to Wnt signaling pathways. Our data suggest that a network of genes co-expressed with VAMP1 in the PFC moderates the influence of early environment on cognitive function in children.", - "journal_title": "Neurobiology of learning and memory", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/34454100/" - } - ], - "1907b52f-515b-447c-b7b3-0e37bf1ce8b7": [ - { - "pub_id": "29957968", - "title": "Legal and Ethical Aspects of Pain Management.", - "authors": "Marko Juki\u0107,Livia Puljak", - "abstract": "In this manuscript we presented legal and ethical aspects of pain management. Pain is a global public health problem because the burden of acute and chronic pain is considerable and is continuously increasing. It has been postulated that pain management is a fundamental human right, and that health systems are obliged to ensure universal access to pain management services. The suggestion that pain management is a right was fuelled by ample evidence about inadequate treatment of pain. Undertreatment and underprescribing in the context of pain can potentially have serious legal consequences, including charges about negligence, elder abuse, manslaughter and euthanasia. Multiple international declarations by professional societies have outlined pain management as a core ethical duty in medicine. Therefore, healthcare professionals need to be aware of multiple facets of pain-related ethics, including appraisal of patient's decision-making capacity. The worldwide opioid crisis also calls for careful consideration of specific ethical issues. Finally, healthcare workers need to be aware of the the risks associated with promoting pain management as a human right because patients and their caretakers can mistakenly perceive that they have right to total analgesia. Patients do have the right to pain management, but patient rights have limits, which may interfere with other competing rights, and also rights of their physicians. Treatment of pain must be medically, ethically and economically justified. Healthcare workers have an obligation to continuously improve their knowledge about pain management, including medical, legal and ethical aspects of pain.", - "journal_title": "Acta medica academica", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/29957968/" - } - ], - "f38b812e-89b2-42f5-ba20-ce5fcf0c5faa": [ - { - "pub_id": "20624279", - "title": "Copy number variation at leptin receptor gene locus associated with metabolic traits and the risk of type 2 diabetes mellitus.", - "authors": "Jae-Pil Jeon,Sung-Mi Shim,Hye-Young Nam,Gil-Mi Ryu,Eun-Jung Hong,Hyung-Lae Kim,Bok-Ghee Han", - "abstract": "Recent efforts have been made to link complex human traits and disease susceptibility to DNA copy numbers. The leptin receptor (LEPR) has been implicated in obesity and diabetes. Mutations and genetic variations of LEPR gene have been discovered in rodents and humans. However, the association of DNA copy number variations at the LEPR gene locus with human complex diseases has not been reported. In an attempt to study DNA copy number variations associated with metabolic traits and type 2 diabetes mellitus (T2DM), we targeted the LEPR gene locus in DNA copy number analyses. We identified DNA copy number variations at the LEPR gene locus among a Korean population using genome-wide SNP chip data, and then quantified copy numbers of the E2 DNA sequence in the first two exons overlapped between LEPR and LEPROT genes by the quantitative multiplex PCR of short fluorescent fragment (QMPSF) method. Among the non-diabetic subjects (n = 1,067), lower E2 DNA copy numbers were associated with higher fasting glucose levels in men (p = 1.24 x 10(-7)) and women (p = 9.45 x 10(-5)), as well as higher total cholesterol levels in men (p = 9.96 x 10(-7)). In addition, the significant association between lower E2 DNA copy numbers and lower level of postprandial 2 hr insulin was evident only in non-diabetic women, whereas some obesity-related phenotypes and total cholesterol level exhibited significant associations only in non-diabetic men. Logistic regression analysis indicated that lower E2 DNA copy numbers were associated with T2DM (odds ratio, 1.92; 95% CI, 1.26-2.96; p < 0.003) in our nested case-control study. Interestingly, the E2 DNA copy number exhibited a negative correlation with LEPR gene expression, but a positive correlation with LEPROT gene expression. This work suggests that a structural variation at the LEPR gene locus is functionally associated with complex metabolic traits and the risk of T2DM.", - "journal_title": "BMC genomics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/20624279/" - } - ], - "526dec47-a420-4f2f-90d1-f1074dcfea33": [ - { - "pub_id": "29502958", - "title": "AQR is a novel type 2 diabetes-associated gene that regulates signaling pathways critical for glucose metabolism.", - "authors": "Chun Song,Han Yan,Hanming Wang,Yan Zhang,Huiqing Cao,Yiqi Wan,Lingbao Kong,Shenghan Chen,Hong Xu,Bingxing Pan,Jin Zhang,Guohuang Fan,Hongbo Xin,Zicai Liang,Weiping Jia,Xiao-Li Tian", - "abstract": "Type 2 diabetes mellitus (T2DM) is a common metabolic disease influenced by both genetic and environmental factors. In this study, we performed an in-house genotyping and meta-analysis study using three independent GWAS datasets of T2DM and found that rs3743121, located 1 kb downstream of AQR, was a novel susceptibility SNP associated with T2DM. The risk allele C of rs3743121 was correlated with the increased expression of AQR in white blood cells, similar to that observed in T2DM models. The knockdown of AQR in HepG2 facilitated the glucose uptake, decreased the expression level of PCK2, increased the phosphorylation of GSK-3\u03b2, and restored the insulin sensitivity. Furthermore, the suppression of AQR inhibited the mTOR pathway and the protein ubiquitination process. Our study suggests that AQR is a novel type 2 diabetes-associated gene that regulates signaling pathways critical for glucose metabolism.", - "journal_title": "Journal of genetics and genomics = Yi chuan xue bao", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/29502958/" - } - ], - "64a4b18e-dc3c-439b-96bb-5ea79f693fd6": [ - { - "pub_id": "35755401", - "title": "A Framework for Promoting Diversity, Equity, and Inclusion in Genetics and Genomics Research.", - "authors": "Timothy R Rebbeck,John F P Bridges,Jennifer W Mack,Stacy W Gray,Jeffrey M Trent,Suzanne George,Norah L Crossnohere,Electra D Paskett,Corrie A Painter,Nikhil Wagle,Miria Kano,Patricia Nez Henderson,Jeffrey A Henderson,Shiraz I Mishra,Cheryl L Willman,Andrew L Sussman", - "abstract": "Research into the genetic and genomic (\"genomics\") foundations of disease is central to our understanding of disease prevention, early detection, diagnostic accuracy, and therapeutic intervention. Inequitable participation in genomics research by historically excluded populations limits the ability to translate genomic knowledge to achieve health equity and ensure that findings are generalizable to diverse populations. We propose a novel framework for promoting diversity, equity, and inclusion in genomics research. Building on principles of community-based participatory research and collective impact frameworks, the framework can guide our understanding of the social, cultural, health system, policy, community, and individual contexts in which engagement and genomics research are being done. Our framework highlights the involvement of a multistakeholder team, including the participants and communities to be engaged, to ensure robust methods for recruitment, retention, return of genomic results, quality of engagement, follow-up, and monitoring of participants. The proposed engagement framework will guide investigators in optimizing equitable representation in research and enhancing the rigor of genomics investigation.", - "journal_title": "JAMA health forum", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/35755401/" - } - ], - "0369cb1b-dfa7-4f81-b791-efefcfad2ea8": [ - { - "pub_id": "29207974", - "title": "Spectrum of mutations in monogenic diabetes genes identified from high-throughput DNA sequencing of 6888 individuals.", - "authors": "Vikas Bansal,Johann Gassenhuber,Tierney Phillips,Glenn Oliveira,Rebecca Harbaugh,Nikki Villarasa,Eric J Topol,Thomas Seufferlein,Bernhard O Boehm", - "abstract": "Diagnosis of monogenic as well as atypical forms of diabetes mellitus has important clinical implications for their specific diagnosis, prognosis, and targeted treatment. Single gene mutations that affect beta-cell function represent 1-2% of all cases of diabetes. However, phenotypic heterogeneity and lack of family history of diabetes can limit the diagnosis of monogenic forms of diabetes. Next-generation sequencing technologies provide an excellent opportunity to screen large numbers of individuals with a diagnosis of diabetes for mutations in disease-associated genes. We utilized a targeted sequencing approach using the Illumina HiSeq to perform a case-control sequencing study of 22 monogenic diabetes genes in 4016 individuals with type 2 diabetes (including 1346 individuals diagnosed before the age of 40 years) and 2872 controls. We analyzed protein-coding variants identified from the sequence data and compared the frequencies of pathogenic variants (protein-truncating variants and missense variants) between the cases and controls. A total of 40 individuals with diabetes (1.8% of early onset sub-group and 0.6% of adult onset sub-group) were carriers of known pathogenic missense variants in the GCK, HNF1A, HNF4A, ABCC8, and INS genes. In addition, heterozygous protein truncating mutations were detected in the GCK, HNF1A, and HNF1B genes in seven individuals with diabetes. Rare missense mutations in the GCK gene were significantly over-represented in individuals with diabetes (0.5% carrier frequency) compared to controls (0.035%). One individual with early onset diabetes was homozygous for a rare pathogenic missense variant in the WFS1 gene but did not have the additional phenotypes associated with Wolfram syndrome. Targeted sequencing of genes linked with monogenic diabetes can identify disease-relevant mutations in individuals diagnosed with type 2 diabetes not suspected of having monogenic forms of the disease. Our data suggests that GCK-MODY frequently masquerades as classical type 2 diabetes. The results confirm that MODY is under-diagnosed, particularly in individuals presenting with early onset diabetes and clinically labeled as type 2 diabetes; thus, sequencing of all monogenic diabetes genes should be routinely considered in such individuals. Genetic information can provide a specific diagnosis, inform disease prognosis and may help to better stratify treatment plans.", - "journal_title": "BMC medicine", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/29207974/" - } - ], - "9fb37fb6-88b5-4819-87e1-78b0f93e2932": [ - { - "pub_id": "27913849", - "title": "Targeted next-generation sequencing reveals MODY in up to 6.5% of antibody-negative diabetes cases listed in the Norwegian Childhood Diabetes Registry.", - "authors": "Bente B Johansson,Henrik U Irgens,Janne Molnes,Pawe\u0142 Sztromwasser,Ingvild Aukrust,Petur B Juliusson,Oddmund S\u00f8vik,Shawn Levy,Torild Skrivarhaug,Geir Joner,Anders Molven,Stefan Johansson,P\u00e5l R Nj\u00f8lstad", - "abstract": "MODY can be wrongly diagnosed as type 1 diabetes in children. We aimed to find the prevalence of MODY in a nationwide population-based registry of childhood diabetes. Using next-generation sequencing, we screened the HNF1A, HNF4A, HNF1B, GCK and INS genes in all 469 children (12.1%) negative for both GAD and IA-2 autoantibodies and 469 antibody-positive matched controls selected from the Norwegian Childhood Diabetes Registry (3882 children). Variants were classified using clinical diagnostic criteria for pathogenicity ranging from class 1 (neutral) to class 5 (pathogenic). We identified 58 rare exonic and splice variants in cases and controls. Among antibody-negative patients, 6.5% had genetic variants of classes 3-5 (vs 2.4% in controls; p\u2009=\u20090.002). For the stricter classification (classes 4 and 5), the corresponding number was 4.1% (vs 0.2% in controls; p\u2009=\u20091.6\u2009\u00d7\u200910<sup>-5</sup>). HNF1A showed the strongest enrichment of class 3-5 variants, with 3.9% among antibody-negative patients (vs 0.4% in controls; p\u2009=\u20090.0002). Antibody-negative carriers of variants in class 3 had a similar phenotype to those carrying variants in classes 4 and 5. This is the first study screening for MODY in all antibody-negative children in a nationwide population-based registry. Our results suggest that the prevalence of MODY in antibody-negative childhood diabetes may reach 6.5%. One-third of these MODY cases had not been recognised by clinicians. Since a precise diagnosis is important for treatment and genetic counselling, molecular screening of all antibody-negative children should be considered in routine diagnostics.", - "journal_title": "Diabetologia", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/27913849/" - } - ], - "efc6d914-13a6-488d-9cd2-db9d25202833": [ - { - "pub_id": "36440584", - "title": "NLRP3 Inflammasome Activation Through Heart-Brain Interaction Initiates Cardiac Inflammation and Hypertrophy During Pressure Overload.", - "authors": "Yasutomi Higashikuni,Wenhao Liu,Genri Numata,Kimie Tanaka,Daiju Fukuda,Yu Tanaka,Yoichiro Hirata,Teruhiko Imamura,Eiki Takimoto,Issei Komuro,Masataka Sata", - "abstract": "Mechanical stress on the heart, such as high blood pressure, initiates inflammation and causes hypertrophic heart disease. However, the regulatory mechanism of inflammation and its role in the stressed heart remain unclear. IL-1\u03b2 (interleukin-1\u03b2) is a proinflammatory cytokine that causes cardiac hypertrophy and heart failure. Here, we show that neural signals activate the NLRP3 (nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing 3) inflammasome for IL-1\u03b2 production to induce adaptive hypertrophy in the stressed heart. C57BL/6 mice, knockout mouse strains for NLRP3 and P2RX7 (P2X purinoceptor 7), and adrenergic neuron-specific knockout mice for SLC17A9, a secretory vesicle protein responsible for the storage and release of ATP, were used for analysis. Pressure overload was induced by transverse aortic constriction. Various animal models were used, including pharmacological treatment with apyrase, lipopolysaccharide, 2'(3')-<i>O</i>-(4-benzoylbenzoyl)-ATP, MCC950, anti-IL-1\u03b2 antibodies, clonidine, pseudoephedrine, isoproterenol, and bisoprolol, left stellate ganglionectomy, and ablation of cardiac afferent nerves with capsaicin. Cardiac function and morphology, gene expression, myocardial IL-1\u03b2 and caspase-1 activity, and extracellular ATP level were assessed. In vitro experiments were performed using primary cardiomyocytes and fibroblasts from rat neonates and human microvascular endothelial cell line. Cell surface area and proliferation were assessed. Genetic disruption of NLRP3 resulted in significant loss of IL-1\u03b2 production, cardiac hypertrophy, and contractile function during pressure overload. A bone marrow transplantation experiment revealed an essential role of NLRP3 in cardiac nonimmune cells in myocardial IL-1\u03b2 production and cardiac phenotype. Pharmacological depletion of extracellular ATP or genetic disruption of the P2X7 receptor suppressed myocardial NLRP3 inflammasome activity during pressure overload, indicating an important role of ATP/P2X7 axis in cardiac inflammation and hypertrophy. Extracellular ATP induced hypertrophic changes of cardiac cells in an NLRP3- and IL-1\u03b2-dependent manner in vitro. Manipulation of the sympathetic nervous system suggested sympathetic efferent nerves as the main source of extracellular ATP. Depletion of ATP release from sympathetic efferent nerves, ablation of cardiac afferent nerves, or a lipophilic \u03b2-blocker reduced cardiac extracellular ATP level, and inhibited NLRP3 inflammasome activation, IL-1\u03b2 production, and adaptive cardiac hypertrophy during pressure overload. Cardiac inflammation and hypertrophy are regulated by heart-brain interaction. Controlling neural signals might be important for the treatment of hypertensive heart disease.", - "journal_title": "Circulation", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/36440584/" - } - ], - "a63e5457-c23a-4429-8a17-e230c3c80053": [ - { - "pub_id": "29370175", - "title": "Genomic locus modulating corneal thickness in the mouse identifies POU6F2 as a potential risk of developing glaucoma.", - "authors": "Rebecca King,Felix L Struebing,Ying Li,Jiaxing Wang,Allison Ashley Koch,Jessica N Cooke Bailey,Puya Gharahkhani, , ,Stuart MacGregor,R Rand Allingham,Michael A Hauser,Janey L Wiggs,Eldon E Geisert", - "abstract": "Central corneal thickness (CCT) is one of the most heritable ocular traits and it is also a phenotypic risk factor for primary open angle glaucoma (POAG). The present study uses the BXD Recombinant Inbred (RI) strains to identify novel quantitative trait loci (QTLs) modulating CCT in the mouse with the potential of identifying a molecular link between CCT and risk of developing POAG. The BXD RI strain set was used to define mammalian genomic loci modulating CCT, with a total of 818 corneas measured from 61 BXD RI strains (between 60-100 days of age). The mice were anesthetized and the eyes were positioned in front of the lens of the Phoenix Micron IV Image-Guided OCT system or the Bioptigen OCT system. CCT data for each strain was averaged and used to QTLs modulating this phenotype using the bioinformatics tools on GeneNetwork (www.genenetwork.org). The candidate genes and genomic loci identified in the mouse were then directly compared with the summary data from a human POAG genome wide association study (NEIGHBORHOOD) to determine if any genomic elements modulating mouse CCT are also risk factors for POAG.This analysis revealed one significant QTL on Chr 13 and a suggestive QTL on Chr 7. The significant locus on Chr 13 (13 to 19 Mb) was examined further to define candidate genes modulating this eye phenotype. For the Chr 13 QTL in the mouse, only one gene in the region (Pou6f2) contained nonsynonymous SNPs. Of these five nonsynonymous SNPs in Pou6f2, two resulted in changes in the amino acid proline which could result in altered secondary structure affecting protein function. The 7 Mb region under the mouse Chr 13 peak distributes over 2 chromosomes in the human: Chr 1 and Chr 7. These genomic loci were examined in the NEIGHBORHOOD database to determine if they are potential risk factors for human glaucoma identified using meta-data from human GWAS. The top 50 hits all resided within one gene (POU6F2), with the highest significance level of p = 10-6 for SNP rs76319873. POU6F2 is found in retinal ganglion cells and in corneal limbal stem cells. To test the effect of POU6F2 on CCT we examined the corneas of a Pou6f2-null mice and the corneas were thinner than those of wild-type littermates. In addition, these POU6F2 RGCs die early in the DBA/2J model of glaucoma than most RGCs. Using a mouse genetic reference panel, we identified a transcription factor, Pou6f2, that modulates CCT in the mouse. POU6F2 is also found in a subset of retinal ganglion cells and these RGCs are sensitive to injury.", - "journal_title": "PLoS genetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/29370175/" - } - ], - "fc19faa4-77b2-4883-9529-8ed898b59a61": [ - { - "pub_id": "34875419", - "title": "Chilling tolerance in rice: Past and present.", - "authors": "Junhua Li,Zeyong Zhang,Kang Chong,Yunyuan Xu", - "abstract": "Rice is generally sensitive to chilling stress, which seriously affects growth and yield. Since early in the last century, considerable efforts have been made to understand the physiological and molecular mechanisms underlying the response to chilling stress and improve rice chilling tolerance. Here, we review the research trends and advances in this field. The phenotypic and biochemical changes caused by cold stress and the physiological explanations are briefly summarized. Using published data from the past 20 years, we reviewed the past progress and important techniques in the identification of quantitative trait loci (QTL), novel genes, and cellular pathways involved in rice chilling tolerance. The advent of novel technologies has significantly advanced studies of cold tolerance, and the characterization of QTLs, key genes, and molecular modules have sped up molecular design breeding for cold tolerance in rice varieties. In addition to gene function studies based on overexpression or artificially generated mutants, elucidating natural allelic variation in specific backgrounds is emerging as a novel approach for the study of cold tolerance in rice, and the superior alleles identified using this approach can directly facilitate breeding.", - "journal_title": "Journal of plant physiology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/34875419/" - } - ], - "1dd221c6-72a9-4c5c-9061-5f2819178e62": [ - { - "pub_id": "33797169", - "title": "Systems genetic analysis of nicotine withdrawal deficits in hippocampus-dependent learning.", - "authors": "Lisa R Goldberg,Munir Gunes Kutlu,Dana Zeid,Laurel R Seemiller,Thomas J Gould", - "abstract": "Cognitive deficits, such as disrupted learning, are a major symptom of nicotine withdrawal. These deficits are heritable, yet their genetic basis is largely unknown. Our lab has developed a mouse model of nicotine withdrawal deficits in learning, using chronic nicotine exposure via osmotic minipumps and fear conditioning. Here, we utilized the BXD genetic reference panel to identify genetic variants underlying nicotine withdrawal deficits in learning. Male and female mice (n = 6-11 per sex per strain, 31 strains) received either chronic saline or nicotine (6.3 mg/kg per day for 12\u2009days), and were then tested for hippocampus-dependent learning deficits using contextual fear conditioning. Quantitative trait locus (QTL) mapping analyses using GeneNetwork identified a significant QTL on Chromosome 4 (82.13\u2009Mb, LRS = 20.03, p\u2009<\u20090.05). Publicly available hippocampal gene expression data were used to identify eight positional candidates (Snacpc3, Mysm1, Rps6, Plaa, Lurap1l, Slc24a2, Hacd4, Ptprd) that overlapped with our behavioral QTL and correlated with our behavioral data. Overall, this study demonstrates that genetic factors impact cognitive deficits during nicotine withdrawal in the BXD recombinant inbred panel and identifies candidate genes for future research.", - "journal_title": "Genes, brain, and behavior", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/33797169/" - } - ], - "1867a302-3886-4b76-9124-31440e17cbd9": [ - { - "pub_id": "30619460", - "title": "Different Effect of <i>Sox11</i> in Retinal Ganglion Cells Survival and Axon Regeneration.", - "authors": "Ying Li,Felix L Struebing,Jiaxing Wang,Rebecca King,Eldon E Geisert", - "abstract": "<b>Purpose:</b> The present study examines the role of <i>Sox11</i> in the initial response of retinal ganglion cells (RGCs) to axon damage and in optic nerve regeneration in mouse. <b>Methods:</b> Markers of retinal injury were identified using the normal retina database and optic nerve crush (ONC) database on GeneNetwork<sup>2</sup> (www.genenetwork.org). One gene, <i>Sox11</i>, was highly upregulated following ONC. We examined the role of this transcription factor, <i>Sox11</i>, following ONC and optic nerve regeneration in mice. <i>In situ</i> hybridization was performed using the Affymetrix 2-plex Quantigene View RNA <i>In Situ</i> Hybridization Tissue Assay System. <i>Sox11</i> was partially knocked out by intravitreal injection of AAV2-CMV-Cre-GFP in <i>Sox11</i> <sup>f/f</sup> mice. Optic nerve regeneration model used <i>Pten</i> knockdown. Mice were perfused and the retinas and optic nerves were dissected and examined for RGC survival and axon growth. <b>Results:</b> <i>Sox11</i> was dramatically upregulated in the retina following ONC injury. The level of <i>Sox11</i> message increased by approximately eightfold 2 days after ONC. <i>In situ</i> hybridization demonstrated low-level <i>Sox11</i> message in RGCs and cells in the inner nuclear layer in the normal retina as well as a profound increase in <i>Sox11</i> message within the ganglion cells following ONC. In <i>Sox11</i> <sup>f/f</sup> retinas, partially knocking out <i>Sox11</i> significantly increased RGC survival after ONC as compared to the AAV2-CMV-GFP control group; however, it had little effect on the ability of axon regeneration. Combinatorial downregulation of both <i>Sox11</i> and <i>Pten</i> resulted in a significant increase in RGC survival as compared to <i>Pten</i> knockdown only. When <i>Pten</i> was knocked down there was a remarkable increase in the number and the length of regenerating axons. Partially knocking out <i>Sox11</i> in combination with <i>Pten</i> deletion resulted in a fewer regenerating axons. <b>Conclusion:</b> Taken together, these data demonstrate that <i>Sox11</i> is involved in the initial response of the retina to injury, playing a role in the early attempts of axon regeneration and neuronal survival. Downregulation of <i>Sox11</i> aids in RGC survival following injury of optic nerve axons, while a partial knockout of <i>Sox11</i> negates the axon regeneration stimulated by <i>Pten</i> knockdown.", - "journal_title": "Frontiers in genetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/30619460/" - } - ], - "ea036684-619d-4b82-9242-c0b220f2d8df": [ - { - "pub_id": "32877673", - "title": "Cross-Species Analyses Identify Dlgap2 as a Regulator of Age-Related Cognitive Decline and Alzheimer's Dementia.", - "authors": "Andrew R Ouellette,Sarah M Neuner,Logan Dumitrescu,Laura C Anderson,Daniel M Gatti,Emily R Mahoney,Jason A Bubier,Gary Churchill,Luanne Peters,Matthew J Huentelman,Jeremy H Herskowitz,Hyun-Sik Yang,Alexandra N Smith,Christiane Reitz,Brian W Kunkle,Charles C White,Philip L De Jager,Julie A Schneider,David A Bennett,Nicholas T Seyfried, ,Elissa J Chesler,Niran Hadad,Timothy J Hohman,Catherine C Kaczorowski", - "abstract": "Genetic mechanisms underlying age-related cognitive decline and dementia remain poorly understood. Here, we take advantage of the Diversity Outbred mouse population to utilize quantitative trait loci mapping and identify Dlgap2 as a positional candidate responsible for modifying working memory decline. To evaluate the translational relevance of this finding, we utilize longitudinal cognitive measures from human patients, RNA expression from post-mortem brain tissue, data from a genome-wide association study (GWAS) of Alzheimer's dementia (AD), and GWAS results in African Americans. We find an association between Dlgap2 and AD phenotypes at the variant, gene and protein expression, and methylation levels. Lower cortical DLGAP2 expression is observed in AD and is associated with more plaques and tangles at autopsy and faster cognitive decline. Results will inform future studies aimed at investigating the cross-species role of Dlgap2 in regulating cognitive decline and highlight the benefit of using genetically diverse mice to prioritize novel candidates.", - "journal_title": "Cell reports", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/32877673/" - } - ], - "f7ea05c2-8ca9-4795-b8b5-3ac31bb10a70": [ - { - "pub_id": "32454514", - "title": "When research goes wrong: the importance of clinical trials methodology.", - "authors": "Eleanor J Molloy,Cynthia F Bearer", - "abstract": "", - "journal_title": "Pediatric research", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/32454514/" - } - ], - "16f3eea1-c5f6-4948-83cc-2efa10437a11": [ - { - "pub_id": "28575045", - "title": "The effect of alcohol on the differential expression of cluster of differentiation 14 gene, associated pathways, and genetic network.", - "authors": "Diana X Zhou,Yinghong Zhao,Jessica A Baker,Qingqing Gu,Kristin M Hamre,Junming Yue,Byron C Jones,Melloni N Cook,Lu Lu", - "abstract": "Alcohol consumption affects human health in part by compromising the immune system. In this study, we examined the expression of the Cd14 (cluster of differentiation 14) gene, which is involved in the immune system through a proinflammatory cascade. Expression was evaluated in BXD mice treated with saline or acute 1.8 g/kg i.p. ethanol (12.5% v/v). Hippocampal gene expression data were generated to examine differential expression and to perform systems genetics analyses. The Cd14 gene expression showed significant changes among the BXD strains after ethanol treatment, and eQTL mapping revealed that Cd14 is a cis-regulated gene. We also identified eighteen ethanol-related phenotypes correlated with Cd14 expression related to either ethanol responses or ethanol consumption. Pathway analysis was performed to identify possible biological pathways involved in the response to ethanol and Cd14. We also constructed a genetic network for Cd14 using the top 20 correlated genes and present several genes possibly involved in Cd14 and ethanol responses based on differential gene expression. In conclusion, we found Cd14, along with several other genes and pathways, to be involved in ethanol responses in the hippocampus, such as increased susceptibility to lipopolysaccharides and neuroinflammation.", - "journal_title": "PloS one", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/28575045/" - } - ], - "06a8d056-096c-41aa-8159-4fe4a2de1d5e": [ - { - "pub_id": "31034606", - "title": "Impact of Genetic Variation on Stress-Related Ethanol Consumption.", - "authors": "Megan K Mulligan,Lu Lu,Sonia A Cavigelli,Pierre Morm\u00e8de,Elena Terenina,Wenyuan Zhao,Robert W Williams,Byron C Jones", - "abstract": "The effect of stress on alcohol consumption in humans is highly variable, and the underlying processes are not yet understood. Attempts to model a positive relationship between stress and increased ethanol (EtOH) consumption in animals have been only modestly successful. Our hypothesis is that individual differences in stress effects on EtOH consumption are mediated by genetics. We measured alcohol consumption, using the drinking-in-the-dark (DID) paradigm in females from 2 inbred mouse strains, C57BL/6J (B6) and DBA/2J (D2), and 35 of their inbred progeny (the BXD family). A control group was maintained in normal housing and a stress group was exposed to chronic mild stress (CMS), consisting of unpredictable stressors over 7\u00a0weeks. These included predator, social, and environmental perturbations. Alcohol intake was measured over 16\u00a0weeks in both groups during baseline (preceding 5-week period), CMS (intervening 7-week period), and post-CMS (final 4-week period). We detected a strong effect of CMS on alcohol intake. A few strains demonstrated CMS-related increased alcohol consumption; however, most showed decreased intake. We identified 1 nearly significant quantitative trait locus on chromosome 5 that contains the neuronal nitric oxide synthase gene (Nos1). The expression of Nos1 is frequently changed following alcohol exposure, and variants in this gene segregating among the BXD population may modulate alcohol intake in response to stress. The results we present here represent the first study to combine chronic stress and alcohol consumption in a genetic reference population of mice. Differences in susceptibility to the effects of stressful environments vis-\u00e0-vis alcohol use disorders would suggest that the differences have at least some basis in genetic constitution. We have also nominated a likely candidate gene underlying the large individual differences in effects of stress on alcohol consumption.", - "journal_title": "Alcoholism, clinical and experimental research", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/31034606/" - } - ], - "dcc71b11-5668-4274-9f35-d9b7f01695a2": [ - { - "pub_id": "30576700", - "title": "Offspring genetic effects on maternal care.", - "authors": "Harry G Potter,David G Ashbrook,Reinmar Hager", - "abstract": "Parental care is found widely across animal taxa and is manifest in a range of behaviours from basic provisioning in cockroaches to highly complex behaviours seen in mammals. The evolution of parental care is viewed as the outcome of an evolutionary cost/benefit trade-off between investing in current and future offspring, leading to the selection of traits in offspring that influence parental behaviour. Thus, level and quality of parental care are affected by both parental and offspring genetic differences that directly and indirectly influence parental care behaviour. While significant research effort has gone into understanding how parental genomes affect parental, and mostly maternal, behaviour, few studies have investigated how offspring genomes affect parental care. In this review, we bring together recent findings across different fields focussing on the mechanism and genetics of offspring effects on maternal care in mammals.", - "journal_title": "Frontiers in neuroendocrinology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/30576700/" - } - ], - "9c77964b-6adf-4557-b53c-58dcbb83f86b": [ - { - "pub_id": "31785241", - "title": "Tlr4 participates in the responses of markers of apoptosis, inflammation, and ER stress to different acute exercise intensities in mice hearts.", - "authors": "Larissa G de Vicente,Ana P Pinto,Vitor R Mu\u00f1oz,Rafael L Rovina,Alisson L da Rocha,Rafael C Gaspar,Lilian E C M da Silva,Fernando M Simabuco,Fabiani G Frantz,Jos\u00e9 R Pauli,Leandro P de Moura,Dennys E Cintra,Eduardo R Ropelle,Adelino S R da Silva", - "abstract": "Toll-like receptor 4 (Tlr4) is recognized due to its role in the immune response. Also, this protein can participate in the signaling pathway of events triggered by physical exercise such as apoptosis, inflammation, and endoplasmic reticulum (ER) stress. The main objective of this study was to evaluate the role of Tlr4 in the markers of these events in the myocardium of mice submitted to acute physical exercise (APE) protocols at different intensities. Echocardiogram, RT-qPCR, and immunoblotting technique were used to evaluate the left ventricle of wild-type (WT) and Tlr4 knockout (Tlr4 KO) submitted to APE protocols at 45, 60, and 75% of their maximal velocity. Also, we performed the bioinformatics analysis to establish the connection of heart mRNA levels of Tlr4 with heart genes of inflammation and ER stress of several isogenic strains of BXD mice. Under basal conditions, the Tlr4 deletion diminished the performance, and expression of inflammation and ER stress genes in the left ventricle, but increased the serum levels of CK, Il-17, and Tnf-alpha. Under the same exercise conditions, the Tlr4 deletion reduced the glycemia, serum levels of CK, Il-17, and Tnf-alpha, as well as genes and/or proteins related to apoptosis, inflammation and ER stress in the left ventricle, but increased the levels of CK-mb and LDH, as well as other genes related to apoptosis, inflammation, and ER stress in the left ventricle. Altogether, the current findings highlighted the effects of different acute exercise intensities were attenuated in the heart of Tlr4 KO mice.", - "journal_title": "Life sciences", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/31785241/" - } - ], - "ed937e0a-1b83-4400-9bb3-d61ef714a797": [ - { - "pub_id": "32470469", - "title": "Identifying modifier genes for hypertrophic cardiomyopathy.", - "authors": "Yuanjian Chen,Fuyi Xu,Undral Munkhsaikhan,Charlie Boyle,Theresa Borcky,Wenyuan Zhao,Enkhsaikhan Purevjav,Jeffrey A Towbin,Fang Liao,Robert W Williams,Syamal K Bhattacharya,Lu Lu,Yao Sun", - "abstract": "Hypertrophic cardiomyopathy (HCM) severity greatly varies among patients even with the same HCM gene mutations. This variation is largely regulated by modifier gene(s), which, however, remain largely unknown. The current study is aimed to identify modifier genes using BXD strains, a large murine genetic reference population (GRP) derived from crosses between C57BL/6\u00a0J (B6) and D2 DBA/2\u00a0J (D2) mice. D2 mice natualy carrythe genetic basis and phenotypes of HCM. Myocardial hypertrophy, the major phenotype of HCM, was determined by cardiomyocyte size on cardiac sections in 30 BXD strains, and their parental B6 and D2 strains and morphometric analysis was performed. Quantitative Trait Locus (QTL) mapping for cardiomyocyte sizes was conducted with WebQTL in GeneNetwork. Correlation of cardiomyocyte size and cardiac gene expression in BXDs accessed from GeneNetwork were evaluated. QTL candidate genes associated with cardiomyocyte sizes were prioritized based on the score system. Cardiomyocyte size varied significantly among BXD strains. Interval mapping on cardiomyocyte size data showed a significant QTL on chromosome (Chr) 2 at 66-\u00a073.5\u00a0Mb and a suggestive QTL on Chr 5 at 20.9-39.7\u00a0Mb. Further score system revealed a high QTL score for Xirp2 in Chr 2. Xirp2 encodes xin actin-binding repeat containing 2, which is highly expressed in cardiac tissue and associate with cardiomyopathy and heart failure. In Chr5 QTL, Nos3, encoding nitric oxide synthase 3, received the highest score, which is significantly correlated with cardiomyocyte size. These results indicate that Xirp2 and Nos3 serve as novel candidate modifier genes for myocardial hypertrophy in HCM. These candidate genes will be validated in our future studies.", - "journal_title": "Journal of molecular and cellular cardiology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/32470469/" - } - ], - "4cd75ea5-5e5a-44b7-95f7-93c9c9086a1e": [ - { - "pub_id": "30681412", - "title": "Different genetic mechanisms mediate spontaneous versus UVR-induced malignant melanoma.", - "authors": "Blake Ferguson,Herlina Y Handoko,Pamela Mukhopadhyay,Arash Chitsazan,Lois Balmer,Grant Morahan,Graeme J Walker", - "abstract": "Genetic variation conferring resistance and susceptibility to carcinogen-induced tumorigenesis is frequently studied in mice. We have now turned this idea to melanoma using the collaborative cross (CC), a resource of mouse strains designed to discover genes for complex diseases. We studied melanoma-prone transgenic progeny across seventy CC genetic backgrounds. We mapped a strong quantitative trait locus for rapid onset spontaneous melanoma onset to <i>Prkdc</i>, a gene involved in detection and repair of DNA damage. In contrast, rapid onset UVR-induced melanoma was linked to the ribosomal subunit gene <i>Rrp15</i>. Ribosome biogenesis was upregulated in skin shortly after UVR exposure. Mechanistically, variation in the 'usual suspects' by which UVR may exacerbate melanoma, defective DNA repair, melanocyte proliferation, or inflammatory cell infiltration, did not explain melanoma susceptibility or resistance across the CC. Instead, events occurring soon after exposure, such as dysregulation of ribosome function, which alters many aspects of cellular metabolism, may be important.", - "journal_title": "eLife", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/30681412/" - } - ], - "90a19d89-daac-4de9-8213-d3047b1e4b65": [ - { - "pub_id": "33529666", - "title": "Characterizing modifier genes of cardiac fibrosis phenotype in hypertrophic cardiomyopathy.", - "authors": "Fuyi Xu,Yuanjian Chen,Kaitlin A Tillman,Yan Cui,Robert W Williams,Syamal K Bhattacharya,Lu Lu,Yao Sun", - "abstract": "Clinical phenotypes of hypertrophic cardiomyopathy (HCM) vary greatly even among patients with the same gene mutations. This variability is largely regulated by unidentified modifier loci. The purpose of the study is to identify modifier genes for cardiac fibrosis-a major phenotype of HCM-using the BXD family, a murine cohort. The relative severity of cardiac fibrosis was estimated by quantitation of cardiac collagen volume fraction (CCVF) across 66 members of the BXD family. Quantitative trait locus (QTL) mapping for cardiac fibrosis was done using GeneNetwork. Candidate modifier loci and genes associated with fibrosis were prioritized based on an explicit scoring system. Networks of correlation between fibrosis and cardiac transcriptomes were evaluated to generate causal models of disease susceptibility. CCVF levels varied greatly within this family. Interval mapping identified a significant CCVF-related QTL on chromosome (Chr) 2 in males, and a significant QTL on Chr 4\u00a0Mb in females. The scoring system highlighted two strong candidate genes in the Chr 2 locus-Nek6 and Nr6a1. Both genes are highly expressed in the heart. Cardiac Nek6 mRNA levels are significantly correlated with CCVF. Nipsnap3b and Fktn are lead candidate genes for the Chr 4 locus, and both are also highly expressed in heart. Cardiac Nipsnap3b gene expression correlates well with CCVF. Our study demonstrated that candidate modifier genes of cardiac fibrosis phenotype in HCM are different in males and females. Nek6 and Nr6a1 are strong candidates in males, while Nipsnap3b and Fktn are top candidates in females.", - "journal_title": "International journal of cardiology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/33529666/" - } - ], - "3f5f72cd-f06f-4b4b-8868-c5317d3734d2": [ - { - "pub_id": "28266114", - "title": "Interaction of lifestyle, behaviour or systemic diseases with dental caries and periodontal diseases: consensus report of group 2 of the joint EFP/ORCA workshop on the boundaries between caries and periodontal diseases.", - "authors": "Iain L C Chapple,Philippe Bouchard,Maria Grazia Cagetti,Guglielmo Campus,Maria-Clotilde Carra,Fabio Cocco,Luigi Nibali,Philippe Hujoel,Marja L Laine,Peter Lingstrom,David J Manton,Eduardo Montero,Nigel Pitts,H\u00e9l\u00e8ne Rang\u00e9,Nadine Schlueter,Wim Teughels,Svante Twetman,Cor Van Loveren,Fridus Van der Weijden,Alexandre R Vieira,Andreas G Schulte", - "abstract": "Periodontal diseases and dental caries are the most common diseases of humans and the main cause of tooth loss. Both diseases can lead to nutritional compromise and negative impacts upon self-esteem and quality of life. As complex chronic diseases, they share common risk factors, such as a requirement for a pathogenic plaque biofilm, yet they exhibit distinct pathophysiologies. Multiple exposures contribute to their causal pathways, and susceptibility involves risk factors that are inherited (e.g. genetic variants), and those that are acquired (e.g. socio-economic factors, biofilm load or composition, smoking, carbohydrate intake). Identification of these factors is crucial in the prevention of both diseases as well as in their management. To systematically appraise the scientific literature to identify potential risk factors for caries and periodontal diseases. One systematic review (genetic risk factors), one narrative review (role of diet and nutrition) and reference documentation for modifiable acquired risk factors common to both disease groups, formed the basis of the report. There is moderately strong evidence for a genetic contribution to periodontal diseases and caries susceptibility, with an attributable risk estimated to be up to 50%. The genetics literature for periodontal disease is more substantial than for caries and genes associated with chronic periodontitis are the vitamin D receptor (VDR), Fc gamma receptor IIA (Fc-\u03b3RIIA) and Interleukin 10 (IL10) genes. For caries, genes involved in enamel formation (AMELX, AMBN, ENAM, TUFT, MMP20, and KLK4), salivary characteristics (AQP5), immune regulation and dietary preferences had the largest impact. No common genetic variants were found. Fermentable carbohydrates (sugars and starches) were the most relevant common dietary risk factor for both diseases, but associated mechanisms differed. In caries, the fermentation process leads to acid production and the generation of biofilm components such as Glucans. In periodontitis, glycaemia drives oxidative stress and advanced glycation end-products may also trigger a hyper inflammatory state. Micronutrient deficiencies, such as for vitamin C, vitamin D or vitamin B12, may be related to the onset and progression of both diseases. Functional foods or probiotics could be helpful in caries prevention and periodontal disease management, although evidence is limited and biological mechanisms not fully elucidated. Hyposalivation, rheumatoid arthritis, smoking/tobacco use, undiagnosed or sub-optimally controlled diabetes and obesity are common acquired risk factors for both caries and periodontal diseases.", - "journal_title": "Journal of clinical periodontology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/28266114/" - } - ], - "078821a0-5fd5-4685-84a6-822a0da040ea": [ - { - "pub_id": "16699517", - "title": "A genome-wide association study of nonsynonymous SNPs identifies a type 1 diabetes locus in the interferon-induced helicase (IFIH1) region.", - "authors": "Deborah J Smyth,Jason D Cooper,Rebecca Bailey,Sarah Field,Oliver Burren,Luc J Smink,Cristian Guja,Constantin Ionescu-Tirgoviste,Barry Widmer,David B Dunger,David A Savage,Neil M Walker,David G Clayton,John A Todd", - "abstract": "In this study we report convincing statistical support for a sixth type 1 diabetes (T1D) locus in the innate immunity viral RNA receptor gene region IFIH1 (also known as mda-5 or Helicard) on chromosome 2q24.3. We found the association in an interim analysis of a genome-wide nonsynonymous SNP (nsSNP) scan, and we validated it in a case-control collection and replicated it in an independent family collection. In 4,253 cases, 5,842 controls and 2,134 parent-child trio genotypes, the risk ratio for the minor allele of the nsSNP rs1990760 A --> G (A946T) was 0.86 (95% confidence interval = 0.82-0.90) at P = 1.42 x 10(-10).", - "journal_title": "Nature genetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/16699517/" - } - ], - "aac62bce-e0ed-48c1-b78e-845144597089": [ - { - "pub_id": "28861277", - "title": "Long read reference genome-free reconstruction of a full-length transcriptome from <i>Astragalus membranaceus</i> reveals transcript variants involved in bioactive compound biosynthesis.", - "authors": "Jun Li,Yuka Harata-Lee,Matthew D Denton,Qianjin Feng,Judith R Rathjen,Zhipeng Qu,David L Adelson", - "abstract": "<i>Astragalus membranaceus,</i> also known as Huangqi in China, is one of the most widely used medicinal herbs in Traditional Chinese Medicine. Traditional Chinese Medicine formulations from <i>Astragalus membranaceus</i> have been used to treat a wide range of illnesses, such as cardiovascular disease, type 2 diabetes, nephritis and cancers. Pharmacological studies have shown that immunomodulating, anti-hyperglycemic, anti-inflammatory, antioxidant and antiviral activities exist in the extract of <i>Astragalus membranaceus</i>. Therefore, characterising the biosynthesis of bioactive compounds in <i>Astragalus membranaceus</i>, such as Astragalosides, Calycosin and Calycosin-7-O-\u03b2-d-glucoside, is of particular importance for further genetic studies of <i>Astragalus membranaceus</i>. In this study, we reconstructed the <i>Astragalus membranaceus</i> full-length transcriptomes from leaf and root tissues using PacBio Iso-Seq long reads. We identified 27 975 and 22 343 full-length unique transcript models in each tissue respectively. Compared with previous studies that used short read sequencing, our reconstructed transcripts are longer, and are more likely to be full-length and include numerous transcript variants. Moreover, we also re-characterised and identified potential transcript variants of genes involved in Astragalosides, Calycosin and Calycosin-7-O-\u03b2-d-glucoside biosynthesis. In conclusion, our study provides a practical pipeline to characterise the full-length transcriptome for species without a reference genome and a useful genomic resource for exploring the biosynthesis of active compounds in <i>Astragalus membranaceus</i>.", - "journal_title": "Cell discovery", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/28861277/" - } - ], - "91d6996a-319d-461e-ae78-3c64a70832cc": [ - { - "pub_id": "30297969", - "title": "Fine-mapping type 2 diabetes loci to single-variant resolution using high-density imputation and islet-specific epigenome maps.", - "authors": "Anubha Mahajan,Daniel Taliun,Matthias Thurner,Neil R Robertson,Jason M Torres,N William Rayner,Anthony J Payne,Valgerdur Steinthorsdottir,Robert A Scott,Niels Grarup,James P Cook,Ellen M Schmidt,Matthias Wuttke,Chlo\u00e9 Sarnowski,Reedik M\u00e4gi,Jana Nano,Christian Gieger,Stella Trompet,C\u00e9cile Lecoeur,Michael H Preuss,Bram Peter Prins,Xiuqing Guo,Lawrence F Bielak,Jennifer E Below,Donald W Bowden,John Campbell Chambers,Young Jin Kim,Maggie C Y Ng,Lauren E Petty,Xueling Sim,Weihua Zhang,Amanda J Bennett,Jette Bork-Jensen,Chad M Brummett,Micka\u00ebl Canouil,Kai-Uwe Ec Kardt,Krista Fischer,Sharon L R Kardia,Florian Kronenberg,Kristi L\u00e4ll,Ching-Ti Liu,Adam E Locke,Jian'an Luan,Ioanna Ntalla,Vibe Nylander,Sebastian Sch\u00f6nherr,Claudia Schurmann,Lo\u00efc Yengo,Erwin P Bottinger,Ivan Brandslund,Cramer Christensen,George Dedoussis,Jose C Florez,Ian Ford,Oscar H Franco,Timothy M Frayling,Vilmantas Giedraitis,Sophie Hackinger,Andrew T Hattersley,Christian Herder,M Arfan Ikram,Martin Ingelsson,Marit E J\u00f8rgensen,Torben J\u00f8rgensen,Jennifer Kriebel,Johanna Kuusisto,Symen Ligthart,Cecilia M Lindgren,Allan Linneberg,Valeriya Lyssenko,Vasiliki Mamakou,Thomas Meitinger,Karen L Mohlke,Andrew D Morris,Girish Nadkarni,James S Pankow,Annette Peters,Naveed Sattar,Alena Stan\u010d\u00e1kov\u00e1,Konstantin Strauch,Kent D Taylor,Barbara Thorand,Gudmar Thorleifsson,Unnur Thorsteinsdottir,Jaakko Tuomilehto,Daniel R Witte,Jos\u00e9e Dupuis,Patricia A Peyser,Eleftheria Zeggini,Ruth J F Loos,Philippe Froguel,Erik Ingelsson,Lars Lind,Leif Groop,Markku Laakso,Francis S Collins,J Wouter Jukema,Colin N A Palmer,Harald Grallert,Andres Metspalu,Abbas Dehghan,Anna K\u00f6ttgen,Goncalo R Abecasis,James B Meigs,Jerome I Rotter,Jonathan Marchini,Oluf Pedersen,Torben Hansen,Claudia Langenberg,Nicholas J Wareham,Kari Stefansson,Anna L Gloyn,Andrew P Morris,Michael Boehnke,Mark I McCarthy", - "abstract": "We expanded GWAS discovery for type 2 diabetes (T2D) by combining data from 898,130 European-descent individuals (9% cases), after imputation to high-density reference panels. With these data, we (i) extend the inventory of T2D-risk variants (243 loci, 135 newly implicated in T2D predisposition, comprising 403 distinct association signals); (ii) enrich discovery of lower-frequency risk alleles (80 index variants with minor allele frequency <5%, 14 with estimated allelic odds ratio >2); (iii) substantially improve fine-mapping of causal variants (at 51 signals, one variant accounted for >80% posterior probability of association (PPA)); (iv) extend fine-mapping through integration of tissue-specific epigenomic information (islet regulatory annotations extend the number of variants with PPA >80% to 73); (v) highlight validated therapeutic targets (18 genes with associations attributable to coding variants); and (vi) demonstrate enhanced potential for clinical translation (genome-wide chip heritability explains 18% of T2D risk; individuals in the extremes of a T2D polygenic risk score differ more than ninefold in prevalence).", - "journal_title": "Nature genetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/30297969/" - } - ], - "f3d226b6-665f-478f-943b-adc17aab7ce9": [ - { - "pub_id": "31104364", - "title": "Cognitive and behavioral improvement in adults with fragile X syndrome treated with metformin-two cases.", - "authors": "Dragana Protic,Elber Y Aydin,Flora Tassone,Maria M Tan,Randi J Hagerman,Andrea Schneider", - "abstract": "The majority of individuals with fragile X syndrome (FXS) have intellectual disability, behavioral problems, autism, and language deficits. IQ typically declines with age in boys with the full mutation. The results of preclinical studies demonstrated that metformin, a biguanide used to treat type 2 diabetes, rescues multiple phenotypes of FXS in both Drosophila and mouse models. Preliminary studies of patients with FXS demonstrated improvements in behavior. Here, we present two cases of individuals who have been treated with metformin clinically for one year. Both patients demonstrated significant cognitive and behavioral improvements. They also improved eating habits and normalization of their weight percentiles. Metformin may be a candidate drug for treatment of several types of symptoms in individuals with FXS.", - "journal_title": "Molecular genetics & genomic medicine", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/31104364/" - } - ], - "fea5b928-83dd-4c4d-8f03-297865d583e3": [ - { - "pub_id": "30874305", - "title": "Discovery of early life stress interacting and sex-specific quantitative trait loci impacting cocaine responsiveness.", - "authors": "Jared R Bagley,Karen K Szumlinski,Tod E Kippin", - "abstract": "Addiction vulnerability involves complex gene X environment interactions leading to a pathological response to drugs. Identification of the genes involved in these interactions is an important step in understanding the underlying neurobiology and rarely have such analyses examined sex-specific influences. To dissect this interaction, we examined the impact of prenatal stress (PNS) on cocaine responsiveness in male and female mice of the BXD recombinant inbred panel. BXD strains were subjected to timed mating and assigned to PNS or control groups. PNS dams were subjected to restraint stress (1-hr restraint, three times daily) starting between embryonic day (E) 11 and 14 and continued until parturition. Adult male and female, control and PNS offspring were tested for locomotor response to initial and repeated cocaine injections (sensitization) as well as cocaine-induced conditioned place preference (CPP). Strain, PNS, and sex interacted to modulate initial and sensitized cocaine-induced locomotion, as well as CPP. Moreover, a quantitative trait locus (QTL) interacting with PNS regulating initial locomotor response to cocaine (chromosome X, 37.91 to 50.95\u00a0Mb) was identified. Also PNS-independent, female-specific QTLs regulating CPP (chromosome 11, 65.50 to 81.31\u00a0Mb) and sensitized cocaine-induced locomotion (chromosome 16, 95.79 to 98.32\u00a0Mb) were identified. Publicly available mRNA expression data were utilized to identify cis-eQTL and transcript covariation with the behavioural phenotype to prioritize candidate genes; including Aifm1. These QTL encompass genes that may moderate genetic susceptibility to PNS and interact with sex to determine adult responsiveness to cocaine and addiction vulnerability. This article is part of a themed section on The Importance of Sex Differences in Pharmacology Research. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.21/issuetoc.", - "journal_title": "British journal of pharmacology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/30874305/" - } - ], - "516cc395-4e7c-4371-9444-24edb56a7233": [ - { - "pub_id": "28696432", - "title": "Cross-disorder risk gene CACNA1C differentially modulates susceptibility to psychiatric disorders during development and adulthood.", - "authors": "N Dedic,M L P\u00f6hlmann,J S Richter,D Mehta,D Czamara,M W Metzger,J Dine,B T Bedenk,J Hartmann,K V Wagner,A Jurik,L M Almli,A Lori,S Moosmang,F Hofmann,C T Wotjak,G Rammes,M Eder,A Chen,K J Ressler,W Wurst,M V Schmidt,E B Binder,J M Deussing", - "abstract": "Single-nucleotide polymorphisms (SNPs) in CACNA1C, the \u03b11C subunit of the voltage-gated L-type calcium channel Ca<sub>v</sub>1.2, rank among the most consistent and replicable genetics findings in psychiatry and have been associated with schizophrenia, bipolar disorder and major depression. However, genetic variants of complex diseases often only confer a marginal increase in disease risk, which is additionally influenced by the environment. Here we show that embryonic deletion of Cacna1c in forebrain glutamatergic neurons promotes the manifestation of endophenotypes related to psychiatric disorders including cognitive decline, impaired synaptic plasticity, reduced sociability, hyperactivity and increased anxiety. Additional analyses revealed that depletion of Cacna1c during embryonic development also increases the susceptibility to chronic stress, which suggest that Ca<sub>v</sub>1.2 interacts with the environment to shape disease vulnerability. Remarkably, this was not observed when Cacna1c was deleted in glutamatergic neurons during adulthood, where the later deletion even improved cognitive flexibility, strengthened synaptic plasticity and induced stress resilience. In a parallel gene \u00d7 environment design in humans, we additionally demonstrate that SNPs in CACNA1C significantly interact with adverse life events to alter the risk to develop symptoms of psychiatric disorders. Overall, our results further validate Cacna1c as a cross-disorder risk gene in mice and humans, and additionally suggest a differential role for Ca<sub>v</sub>1.2 during development and adulthood in shaping cognition, sociability, emotional behavior and stress susceptibility. This may prompt the consideration for pharmacological manipulation of Ca<sub>v</sub>1.2 in neuropsychiatric disorders with developmental and/or stress-related origins.", - "journal_title": "Molecular psychiatry", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/28696432/" - } - ], - "5a6808e5-fc6c-47ae-9fca-8fed42cab3df": [ - { - "pub_id": "34567285", - "title": "Therapy Strategy of CD47 in Diffuse Large B-Cell Lymphoma (DLBCL).", - "authors": "Wenqi Zhang,Yanfeng Fan,Meng Li,Linqi Yang,Zhenya Zhang,Lihong Liu", - "abstract": "At present, the use of the common chemotherapy regimen CHOP/R-CHOP for diffuse large B-cell lymphoma (DLBCL) has some shortcomings, especially for relapsed and refractory DLBCL. CD47 is now considered as a prominent target in cancer therapies, and CD47 blockade mainly inhibits the CD47-SIRP<i>\u03b1</i> axis to prevent tumor immune escape. Here, we evaluated the effects of the latest CD47 antibodies reported and the correlations of closely related genes with CD47 in this disease. In the future, therapeutic strategies for DLBCL will focus on multitarget antibody combined treatment and multigene joint attacks.", - "journal_title": "Disease markers", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/34567285/" - } - ], - "ce2c68bf-878d-460c-8d9b-d45ce3034ef7": [ - { - "pub_id": "34552269", - "title": "Gene-by-environment modulation of lifespan and weight gain in the murine BXD family.", - "authors": "Suheeta Roy,Maroun Bou Sleiman,Pooja Jha,Jesse F Ingels,Casey J Chapman,Melinda S McCarty,Jesse D Ziebarth,Michael Hook,Anna Sun,Wenyuan Zhao,Jinsong Huang,Sarah M Neuner,Lynda A Wilmott,Thomas M Shapaker,Arthur G Centeno,David G Ashbrook,Megan K Mulligan,Catherine C Kaczorowski,Liza Makowski,Yan Cui,Robert W Read,Richard A Miller,Khyobeni Mozhui,Evan G Williams,Saunak Sen,Lu Lu,Johan Auwerx,Robert W Williams", - "abstract": "How lifespan and body weight vary as a function of diet and genetic differences is not well understood. Here we quantify the impact of differences in diet on lifespan in a genetically diverse family of female mice, split into matched isogenic cohorts fed a low-fat chow diet (CD, n\u2009=\u2009663) or a high-fat diet (HFD, n\u2009=\u2009685). We further generate key metabolic data in a parallel cohort euthanized at four time points. HFD feeding shortens lifespan by 12%: equivalent to a decade in humans. Initial body weight and early weight gains account for longevity differences of roughly 4-6\u2009days per gram. At 500\u2009days, animals on a HFD typically gain four times as much weight as control, but variation in weight gain does not correlate with lifespan. Classic serum metabolites, often regarded as health biomarkers, are not necessarily strong predictors of longevity. Our data indicate that responses to a HFD are substantially modulated by gene-by-environment interactions, highlighting the importance of genetic variation in making accurate individualized dietary recommendations.", - "journal_title": "Nature metabolism", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/34552269/" - } - ], - "88f640f5-8c18-4d4b-be58-e6c4c8accce7": [ - { - "pub_id": "32131477", - "title": "Modeling the Genetic Basis of Individual Differences in Susceptibility to Gulf War Illness.", - "authors": "Byron C Jones,Diane B Miller,Lu Lu,Wenyuan Zhao,David G Ashbrook,Fuyi Xu,Megan K Mulligan,Robert W Williams,Daming Zhuang,Carolina Torres-Rojas,James P O'Callaghan", - "abstract": "Between 25% and 30% of the nearly one million military personnel who participated in the 1991 Persian Gulf War became ill with chronic symptoms ranging from gastrointestinal to nervous system dysfunction. This disorder is now referred to as Gulf War Illness (GWI) and the underlying pathophysiology has been linked to exposure-based neuroinflammation caused by organophosphorous (OP) compounds coupled with high circulating glucocorticoids. In a mouse model of GWI we developed, corticosterone was shown to act synergistically with an OP (diisopropylflurophosphate) to dramatically increase proinflammatory cytokine gene expression in the brain. Because not all Gulf War participants became sick, the question arises as to whether differential genetic constitution might underlie individual differences in susceptibility. To address this question of genetic liability, we tested the impact of OP and glucocorticoid exposure in a genetic reference population of 30 inbred mouse strains. We also studied both sexes. The results showed wide differences among strains and overall that females were less sensitive to the combined treatment than males. Furthermore, we identified one OP-glucocorticoid locus and nominated a candidate gene-<i>Spon1</i>-that may underlie the marked differences in response.", - "journal_title": "Brain sciences", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/32131477/" - } - ], - "e43dfc29-b1b5-4a0e-be56-660c90e012cc": [ - { - "pub_id": "30854227", - "title": "Variable outcomes of human heart attack recapitulated in genetically diverse mice.", - "authors": "Ekaterina Salimova,Kristen J Nowak,Ana C Estrada,Milena B Furtado,Elyshia McNamara,Quang Nguyen,Lois Balmer,Christoph Preuss,Jeffrey W Holmes,Mirana Ramialison,Grant Morahan,Nadia A Rosenthal", - "abstract": "Clinical variation in patient responses to myocardial infarction (MI) has been difficult to model in laboratory animals. To assess the genetic basis of variation in outcomes after heart attack, we characterized responses to acute MI in the Collaborative Cross (CC), a multi-parental panel of genetically diverse mouse strains. Striking differences in post-MI functional, morphological, and myocardial scar features were detected across 32 CC founder and recombinant inbred strains. Transcriptomic analyses revealed a plausible link between increased intrinsic cardiac oxidative phosphorylation levels and MI-induced heart failure. The emergence of significant quantitative trait loci for several post-MI traits indicates that utilizing CC strains is a valid approach for gene network discovery in cardiovascular disease, enabling more accurate clinical risk assessment and prediction.", - "journal_title": "NPJ Regenerative medicine", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/30854227/" - } - ], - "5be82617-a00b-414d-9058-bfbdb2974f43": [ - { - "pub_id": "29101900", - "title": "Glutaredoxin-2 controls cardiac mitochondrial dynamics and energetics in mice, and protects against human cardiac pathologies.", - "authors": "Georges N Kanaan,Bianca Ichim,Lara Gharibeh,Wael Maharsy,David A Patten,Jian Ying Xuan,Arkadiy Reunov,Philip Marshall,John Veinot,Keir Menzies,Mona Nemer,Mary-Ellen Harper", - "abstract": "Glutaredoxin 2 (GRX2), a mitochondrial glutathione-dependent oxidoreductase, is central to glutathione homeostasis and mitochondrial redox, which is crucial in highly metabolic tissues like the heart. Previous research showed that absence of Grx2, leads to impaired mitochondrial complex I function, hypertension and cardiac hypertrophy in mice but the impact on mitochondrial structure and function in intact cardiomyocytes and in humans has not been explored. We hypothesized that Grx2 controls cardiac mitochondrial dynamics and function in cellular and mouse models, and that low expression is associated with human cardiac dysfunction. Here we show that Grx2 absence impairs mitochondrial fusion, ultrastructure and energetics in primary cardiomyocytes and cardiac tissue. Moreover, provision of the glutathione precursor, N-acetylcysteine (NAC) to Grx2-/- mice did not restore glutathione redox or prevent impairments. Using genetic and histopathological data from the human Genotype-Tissue Expression consortium we demonstrate that low GRX2 is associated with fibrosis, hypertrophy, and infarct in the left ventricle. Altogether, GRX2 is important in the control of cardiac mitochondrial structure and function, and protects against human cardiac pathologies.", - "journal_title": "Redox biology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/29101900/" - } - ], - "5b5a5f8d-149d-4504-99b8-f3374dadee54": [ - { - "pub_id": "36756365", - "title": "Rate of tau propagation is a heritable disease trait in genetically diverse mouse strains.", - "authors": "Lindsay A Welikovitch,Simon Dujardin,Amy R Dunn,Analiese R Fernandes,Anita Khasnavis,Lori B Chibnik,Catherine C Kaczorowski,Bradley T Hyman", - "abstract": "The speed and scope of cognitive deterioration in Alzheimer's disease is highly associated with the advancement of tau neurofibrillary lesions across brain networks. We tested whether the rate of tau propagation is a heritable disease trait in a large, well-characterized cohort of genetically divergent mouse strains. Using an AAV-based model system, P301L-mutant human tau (hTau) was introduced into the entorhinal cortex of mice derived from 18 distinct lines. The extent of tau propagation was measured by distinguishing hTau-producing cells from neurons that were recipients of tau transfer. Heritability calculation revealed that 43% of the variability in tau spread was due to genetic variants segregating across background strains. Strain differences in glial markers were also observed, but did not correlate with tau propagation. Identifying unique genetic variants that influence the progression of pathological tau may uncover novel molecular targets to prevent or slow the pace of tau spread and cognitive decline.", - "journal_title": "iScience", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/36756365/" - } - ], - "0d181969-5716-4b92-9e7e-d9789dcb05ed": [ - { - "pub_id": "29947923", - "title": "Genetic variants of gestational diabetes mellitus: a study of 112 SNPs among 8722 women in two independent populations.", - "authors": "Ming Ding,Jorge Chavarro,Sjurdur Olsen,Yuan Lin,Sylvia H Ley,Wei Bao,Shristi Rawal,Louise G Grunnet,Anne Cathrine B Thuesen,James L Mills,Edwina Yeung,Stefanie N Hinkle,Wei Zhang,Allan Vaag,Aiyi Liu,Frank B Hu,Cuilin Zhang", - "abstract": "Gestational diabetes mellitus (GDM) is a common complication of pregnancy that has substantial short- and long-term adverse health implications for women and their children. However, large-scale studies on genetic risk loci for GDM remain sparse. We conducted a case-control study among 2636 women with GDM and 6086 non-GDM control women from the Nurses' Health Study II and the Danish National Birth Cohort. A total of 112 susceptibility genetic variants confirmed by genome-wide association studies for type 2 diabetes were selected and measured. A weighted genetic risk score (GRS) was created based on variants that were significantly associated with risk of GDM after correcting for the false discovery rate. For the first time, we identified eight variants associated with GDM, namely rs7957197 (HNF1A), rs10814916 (GLIS3), rs3802177 (SLC30A8), rs9379084 (RREB1), rs34872471 (TCF7L2), rs7903146 (TCF7L2), rs11787792 (GPSM1) and rs7041847 (GLIS3). In addition, we confirmed three variants, rs10830963 (MTNR1B), rs1387153 (MTNR1B) and rs4506565 (TCF7L2), that had previously been significantly associated with GDM risk. Furthermore, compared with participants in the first (lowest) quartile of weighted GRS based on these 11 SNPs, the ORs for GDM were 1.07 (95% CI 0.93, 1.22), 1.23 (95% CI 1.07, 1.41) and 1.53 (95% CI 1.34, 1.74) for participants in the second, third and fourth (highest) quartiles, respectively. The significant positive associations between the weighted GRS and risk of GDM persisted across most of the strata of major risk factors for GDM, including family history of type 2 diabetes, smoking status, BMI and age. In this large-scale case-control study with women from two independent populations, eight novel GDM SNPs were identified. These findings offer the potential to improve our understanding of the aetiology of GDM, and particularly of biological mechanisms related to beta cell function.", - "journal_title": "Diabetologia", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/29947923/" - } - ], - "15687ed3-8ed6-400c-bef7-746b7c1a47c7": [ - { - "pub_id": "28708479", - "title": "The essential role of exercise in the management of type 2 diabetes.", - "authors": "John P Kirwan,Jessica Sacks,Stephan Nieuwoudt", - "abstract": "Exercise is typically one of the first management strategies advised for patients newly diagnosed with type 2 diabetes. Together with diet and behavior modification, exercise is an essential component of all diabetes and obesity prevention and lifestyle intervention programs. Exercise training, whether aerobic or resistance training or a combination, facilitates improved glucose regulation. High-intensity interval training is also effective and has the added benefit of being very time-efficient. While the efficacy, scalability, and affordability of exercise for the prevention and management of type 2 diabetes are well established, sustainability of exercise recommendations for patients remains elusive.", - "journal_title": "Cleveland Clinic journal of medicine", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/28708479/" - } - ], - "07fe0af5-b67c-47f0-91dd-7dd226fa4de8": [ - { - "pub_id": "30133189", - "title": "Approaches to carrier testing and results disclosure in translational genomics research: The clinical sequencing exploratory research consortium experience.", - "authors": "Kathryn M Porter,Tia L Kauffman,Barbara A Koenig,Katie L Lewis,Heidi L Rehm,Carolyn Sue Richards,Natasha T Strande,Holly K Tabor,Susan M Wolf,Yaping Yang,Laura M Amendola,Danielle R Azzariti,Jonathan S Berg,Katie Bergstrom,Leslie G Biesecker,Sawona Biswas,Kevin M Bowling,Wendy K Chung,Ellen W Clayton,Laura K Conlin,Gregory M Cooper,Matthew C Dulik,Levi A Garraway,Arezou A Ghazani,Robert C Green,Susan M Hiatt,Seema M Jamal,Gail P Jarvik,Katrina A B Goddard,Benjamin S Wilfond, ", - "abstract": "Clinical genome and exome sequencing (CGES) is primarily used to address specific clinical concerns by detecting risk of future disease, clarifying diagnosis, or directing treatment. Additionally, CGES makes possible the disclosure of autosomal recessive and X-linked carrier results as additional secondary findings, and research about the impact of carrier results disclosure in this context is needed. Representatives from 11 projects in the clinical sequencing exploratory research (CSER) consortium collected data from their projects using a structured survey. The survey focused on project characteristics, which variants were offered and/or disclosed to participants as carrier results, methods for carrier results disclosure, and project-specific outcomes. We recorded quantitative responses and report descriptive statistics with the aim of describing the variability in approaches to disclosing carrier results in translational genomics research projects. The proportion of participants with carrier results was related to the number of genes included, ranging from 3% (three genes) to 92% (4,600 genes). Between one and seven results were disclosed to those participants who received any positive result. Most projects offered participants choices about whether to receive some or all of the carrier results. There were a range of approaches to communicate results, and many projects used separate approaches for disclosing positive and negative results. Future translational genomics research projects will need to make decisions regarding whether and how to disclose carrier results. The CSER consortium experience identifies approaches that balance potential participant interest while limiting impact on project resources.", - "journal_title": "Molecular genetics & genomic medicine", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/30133189/" - } - ], - "f53cd4d6-2d42-47e1-b58f-5bf8f2d65ef5": [ - { - "pub_id": "28646223", - "title": "Regular exercise participation improves genomic stability in diabetic patients: an exploratory study to analyse telomere length and DNA damage.", - "authors": "Ivan Dimauro,Antonella Sgura,Monica Pittaluga,Fiorenza Magi,Cristina Fantini,Rosa Mancinelli,Antonio Sgadari,Stefania Fulle,Daniela Caporossi", - "abstract": "Physical activity has been demonstrated to be effective in the prevention and treatment of different chronic conditions, including type 2 diabetes (T2D). In particular, several studies highlighted how the beneficial effects of physical activity may be related to the stability of the DNA molecule, such as longer telomeric ends. Here we analyze the effect of exercise training on telomere length, spontaneous and H<sub>2</sub>O<sub>2</sub>-induced DNA damage, as well as the apoptosis level in leukocytes from untrained or trained T2D patients vs. age-matched control subjects (CS) (57-66 years). Moreover, expression analysis of selected genes belonging to DNA repair systems, cell cycle control, antioxidant and defence systems was performed. Subjects that participated in a regular exercise program showed a longer telomere sequence than untrained counterparts. Moreover, ex vivo treatment of leukocytes with H<sub>2</sub>O<sub>2</sub> highlighted that: (1) oxidative DNA damage induced similar telomere attrition in all groups; (2) in T2D subjects, physical activity seemed to prevent a significant increase of genomic oxidative DNA damage induced by chronic exposure to pro-oxidant stimulus, and (3) decreased the sensitivity of leukocytes to apoptosis. Finally, the gene expression analysis in T2D subjects suggested an adaptive response to prolonged exercise training that improved the response of specific genes.", - "journal_title": "Scientific reports", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/28646223/" - } - ], - "c87ea109-ad9a-4406-bfcf-8f56223a4da5": [ - { - "pub_id": "22520940", - "title": "Apolipoprotein E gene polymorphism: effects on plasma lipids and risk of type 2 diabetes and coronary artery disease.", - "authors": "Rajesh Chaudhary,Atip Likidlilid,Thavatchai Peerapatdit,Damras Tresukosol,Sorachai Srisuma,Suphachai Ratanamaneechat,Charn Sriratanasathavorn", - "abstract": "The most common apolipoprotein E (apoE) gene polymorphism has been found to influence plasma lipid concentration and its correlation with coronary artery disease (CAD) has been extensively investigated in the last decade. It is, however, unclear whether apoE gene polymorphism is also associated with increased risk of type 2 diabetes mellitus (T2DM). The knowledge of this study may provide the primary prevention for T2DM and CAD development before its initiation and progression. Therefore, this study was carried out to determine the association between apoE gene polymorphism and T2DM with and without CAD and its role in lipid metabolism. The case-control study was carried out on a total of 451 samples including 149 normal control subjects, 155 subjects with T2DM, and 147 subjects with T2DM complicated with CAD. The apoE gene polymorphism was tested by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Univariable and multivariable logistic regression analyses were used to identify the possible risks of T2DM and CAD. A significantly increased frequency of E3/E4 genotype was observed only in T2DM with CAD group (p = 0.0004), whereas the \u03b54 allele was significantly higher in both T2DM (p = 0.047) and T2DM with CAD (p = 0.009) as compared with controls. E3/E4 genotype was also the independent risk in developing CAD after adjusting with established risk factors with adjusted odds ratio (OR) 2.52 (95%CI 1.28-4.97, p = 0.008). The independent predictor of individuals carrying \u03b54 allele still remained significantly associated with both CAD (adjusted OR 2.32, 95%CI 1.17-4.61, p = 0.016) and T2DM (adjusted OR 2.04, 95%CI 1.07-3.86, p = 0.029). After simultaneously examining the joint association of E3/E4 genotype combined with either obesity or smoking the risk increased to approximately 5-fold in T2DM (adjusted OR 4.93, 95%CI 1.74-13.98, p = 0.003) and 10-fold in CAD (adjusted OR 10.48, 95%CI 3.56-30.79, p < 0.0001). The association between apoE genotypes on plasma lipid levels was compared between E3/E3 as a reference and E4-bearing genotypes. E4-bearing genotypes showed lower HDL-C and higher VLDL-C and TG, whereas other values of plasma lipid concentrations showed no significant difference. These results indicate that \u03b54 allele has influence on lipid profiles and is associated with the development of both T2DM with and without CAD, and furthermore, it increased the risk among the subjects with obesity and/or smoking, the conditions associated with high oxidative stress.", - "journal_title": "Cardiovascular diabetology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/22520940/" - } - ], - "dbe5a781-3561-48cb-9f63-cfb4f3246434": [ - { - "pub_id": "32961889", - "title": "Genetic Variation in CNS Myelination and Functional Brain Connectivity in Recombinant Inbred Mice.", - "authors": "Andrea Goudriaan,Maarten Loos,Sabine Spijker,August B Smit,Mark H G Verheijen", - "abstract": "Myelination greatly increases the speed of action potential propagation of neurons, thereby enhancing the efficacy of inter-neuronal communication and hence, potentially, optimizing the brain's signal processing capability. The impact of genetic variation on the extent of axonal myelination and its consequences for brain functioning remain to be determined. Here we investigated this question using a genetic reference panel (GRP) of mouse BXD recombinant inbred (RI) strains, which partly model genetic diversity as observed in human populations, and which show substantial genetic differences in a variety of behaviors, including learning, memory and anxiety. We found coherent differences in the expression of myelin genes in brain tissue of RI strains of the BXD panel, with the largest differences in the hippocampus. The parental C57BL/6J (C57) and DBA/2J (DBA) strains were on opposite ends of the expression spectrum, with C57 showing higher myelin transcript expression compared with DBA. Our experiments showed accompanying differences between C57 and DBA in myelin protein composition, total myelin content, and white matter conduction velocity. Finally, the hippocampal myelin gene expression of the BXD strains correlated significantly with behavioral traits involving anxiety and/or activity. Taken together, our data indicate that genetic variation in myelin gene expression translates to differences observed in myelination, axonal conduction speed, and possibly in anxiety/activity related behaviors.", - "journal_title": "Cells", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/32961889/" - } - ], - "a813bad6-3435-4e24-8e41-2ea6f046790a": [ - { - "pub_id": "33634081", - "title": "<i>Smarce1</i> and <i>Tensin 4</i> Are Putative Modulators of Corneoscleral Stiffness.", - "authors": "Elizabeth M Boazak,Rebecca King,Jiaxing Wang,Cassandra M Chu,Aaron M Toporek,Joseph M Sherwood,Darryl R Overby,Eldon E Geisert,C Ross Ethier", - "abstract": "The biomechanical properties of the cornea and sclera are important in the onset and progression of multiple ocular pathologies and vary substantially between individuals, yet the source of this variation remains unknown. Here we identify genes putatively regulating corneoscleral biomechanical tissue properties by conducting high-fidelity ocular compliance measurements across the BXD recombinant inbred mouse set and performing quantitative trait analysis. We find seven cis-eQTLs and non-synonymous SNPs associating with ocular compliance, and show by RT-qPCR and immunolabeling that only two of the candidate genes, <i>Smarce1</i> and <i>Tns4</i>, showed significant expression in corneal and scleral tissues. Both have mechanistic potential to influence the development and/or regulation of tissue material properties. This work motivates further study of <i>Smarce1</i> and <i>Tns4</i> for their role(s) in ocular pathology involving the corneoscleral envelope as well as the development of novel mouse models of ocular pathophysiology, such as myopia and glaucoma.", - "journal_title": "Frontiers in bioengineering and biotechnology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/33634081/" - } - ], - "eff15911-d490-4f72-b336-ae2d826fdb93": [ - { - "pub_id": "35388223", - "title": "Brain charts for the human lifespan.", - "authors": "R A I Bethlehem,J Seidlitz,S R White,J W Vogel,K M Anderson,C Adamson,S Adler,G S Alexopoulos,E Anagnostou,A Areces-Gonzalez,D E Astle,B Auyeung,M Ayub,J Bae,G Ball,S Baron-Cohen,R Beare,S A Bedford,V Benegal,F Beyer,J Blangero,M Blesa C\u00e1bez,J P Boardman,M Borzage,J F Bosch-Bayard,N Bourke,V D Calhoun,M M Chakravarty,C Chen,C Chertavian,G Chetelat,Y S Chong,J H Cole,A Corvin,M Costantino,E Courchesne,F Crivello,V L Cropley,J Crosbie,N Crossley,M Delarue,R Delorme,S Desrivieres,G A Devenyi,M A Di Biase,R Dolan,K A Donald,G Donohoe,K Dunlop,A D Edwards,J T Elison,C T Ellis,J A Elman,L Eyler,D A Fair,E Feczko,P C Fletcher,P Fonagy,C E Franz,L Galan-Garcia,A Gholipour,J Giedd,J H Gilmore,D C Glahn,I M Goodyer,P E Grant,N A Groenewold,F M Gunning,R E Gur,R C Gur,C F Hammill,O Hansson,T Hedden,A Heinz,R N Henson,K Heuer,J Hoare,B Holla,A J Holmes,R Holt,H Huang,K Im,J Ipser,C R Jack,A P Jackowski,T Jia,K A Johnson,P B Jones,D T Jones,R S Kahn,H Karlsson,L Karlsson,R Kawashima,E A Kelley,S Kern,K W Kim,M G Kitzbichler,W S Kremen,F Lalonde,B Landeau,S Lee,J Lerch,J D Lewis,J Li,W Liao,C Liston,M V Lombardo,J Lv,C Lynch,T T Mallard,M Marcelis,R D Markello,S R Mathias,B Mazoyer,P McGuire,M J Meaney,A Mechelli,N Medic,B Misic,S E Morgan,D Mothersill,J Nigg,M Q W Ong,C Ortinau,R Ossenkoppele,M Ouyang,L Palaniyappan,L Paly,P M Pan,C Pantelis,M M Park,T Paus,Z Pausova,D Paz-Linares,A Pichet Binette,K Pierce,X Qian,J Qiu,A Qiu,A Raznahan,T Rittman,A Rodrigue,C K Rollins,R Romero-Garcia,L Ronan,M D Rosenberg,D H Rowitch,G A Salum,T D Satterthwaite,H L Schaare,R J Schachar,A P Schultz,G Schumann,M Sch\u00f6ll,D Sharp,R T Shinohara,I Skoog,C D Smyser,R A Sperling,D J Stein,A Stolicyn,J Suckling,G Sullivan,Y Taki,B Thyreau,R Toro,N Traut,K A Tsvetanov,N B Turk-Browne,J J Tuulari,C Tzourio,\u00c9 Vachon-Presseau,M J Valdes-Sosa,P A Valdes-Sosa,S L Valk,T van Amelsvoort,S N Vandekar,L Vasung,L W Victoria,S Villeneuve,A Villringer,P E V\u00e9rtes,K Wagstyl,Y S Wang,S K Warfield,V Warrier,E Westman,M L Westwater,H C Whalley,A V Witte,N Yang,B Yeo,H Yun,A Zalesky,H J Zar,A Zettergren,J H Zhou,H Ziauddeen,A Zugman,X N Zuo, , , , , , , , , , , , , , , , , , , , ,E T Bullmore,A F Alexander-Bloch", - "abstract": "Over the past few decades, neuroimaging has become a ubiquitous tool in basic research and clinical studies of the human brain. However, no reference standards currently exist to quantify individual differences in neuroimaging metrics over time, in contrast to growth charts for anthropometric traits such as height and weight<sup>1</sup>. Here we assemble an interactive open resource to benchmark brain morphology derived from any current or future sample of MRI data ( http://www.brainchart.io/ ). With the goal of basing these reference charts on the largest and most inclusive dataset available, acknowledging limitations due to known biases of MRI studies relative to the diversity of the global population, we aggregated 123,984 MRI scans, across more than 100 primary studies, from 101,457 human participants between 115 days post-conception to 100 years of age. MRI metrics were quantified by centile scores, relative to non-linear trajectories<sup>2</sup> of brain structural changes, and rates of change, over the lifespan. Brain charts identified previously unreported neurodevelopmental milestones<sup>3</sup>, showed high stability of individuals across longitudinal assessments, and demonstrated robustness to technical and methodological differences between primary studies. Centile scores showed increased heritability compared with non-centiled MRI phenotypes, and provided a standardized measure of atypical brain structure that revealed patterns of neuroanatomical variation across neurological and psychiatric disorders. In summary, brain charts are an essential step towards robust quantification of individual variation benchmarked to normative trajectories in multiple, commonly used neuroimaging phenotypes.", - "journal_title": "Nature", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/35388223/" - } - ], - "93ef3283-7711-4d49-923c-c8fc3afd4209": [ - { - "pub_id": "32294219", - "title": "Systems Genetics and Systems Biology Analysis of Paraquat Neurotoxicity in BXD Recombinant Inbred Mice.", - "authors": "Carolina Torres-Rojas,Daming Zhuang,Paola Jimenez-Carrion,Isabel Silva,James P O'Callaghan,Lu Lu,Wenyuan Zhao,Megan K Mulligan,Robert W Williams,Byron C Jones", - "abstract": "Paraquat (PQ) is an herbicide used in many countries, including the United States. It is also implicated as a risk factor for sporadic Parkinson's disease, especially in those living in agricultural areas and drinking well water. Studies linking PQ to sporadic Parkinson's disease are not consistent however and there appears to be interindividual differential susceptibility. One likely reason is genetically based differential susceptibility to paraquat neurotoxicity in subpopulations. To address this issue, we tested the effects of paraquat in a genetic reference population of mice (the BXD recombinant inbred strain family). In our earlier work, we showed that in genetically susceptible mice, paraquat increases iron in the ventral midbrain, the area containing the substantia nigra. Our hypothesis is that genetic variability contributes to diverse PQ-related susceptibility and iron concentration. To test this hypothesis, we treated male mice from 28 to 39 BXD strains plus the parental strains with 1 of 3 doses of paraquat, 1, 5, and 10\u2009mg/kg 3 times on a weekly basis. At the end of the treatment period, we analyzed the ventral midbrain for concentrations of iron, copper, and zinc, also we measured the concentration of paraquat in cerebellum, and proinflammatory cytokines in serum and cerebellum. The effect on paraquat-treated mice with 5\u2009mg/kg and principal component analysis of iron showed suggestive quantitative trait loci on chromosome 5. Overall, our results suggest that gene Prkag2 and related networks may serve as potential targets against paraquat toxicity and demonstrate the utility of genetically diverse mouse models for the study of complex human toxicity.", - "journal_title": "Toxicological sciences : an official journal of the Society of Toxicology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/32294219/" - } - ], - "0ba1ad53-88df-4c3b-96fb-7d4e257704d9": [ - { - "pub_id": "31274109", - "title": "<i>Taar1</i> gene variants have a causal role in methamphetamine intake and response and interact with <i>Oprm1</i>.", - "authors": "Alexandra M Stafford,Cheryl Reed,Harue Baba,Nicole Ar Walter,John Rk Mootz,Robert W Williams,Kim A Neve,Lev M Fedorov,Aaron J Janowsky,Tamara J Phillips", - "abstract": "We identified a locus on mouse chromosome 10 that accounts for 60% of the genetic variance in methamphetamine intake in mice selectively bred for high versus low methamphetamine consumption. We nominated the trace amine-associated receptor 1 gene, <i>Taar1</i>, as the strongest candidate and identified regulation of the mu-opioid receptor 1 gene, <i>Oprm1</i>, as another contributor. This study exploited CRISPR-Cas9 to test the causal role of <i>Taar1</i> in methamphetamine intake and a genetically-associated thermal response to methamphetamine. The methamphetamine-related traits were rescued, converting them to levels found in methamphetamine-avoiding animals. We used a family of recombinant inbred mouse strains for interval mapping and to examine independent and epistatic effects of <i>Taar1</i> and <i>Oprm1</i>. Both methamphetamine intake and the thermal response mapped to <i>Taar1</i> and the independent effect of <i>Taar1</i> was dependent on genotype at <i>Oprm1</i>. Our findings encourage investigation of the contribution of <i>Taar1</i> and <i>Oprm1</i> variants to human methamphetamine addiction.", - "journal_title": "eLife", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/31274109/" - } - ], - "7635a2fd-54a3-49e3-a0df-adbb97ff9613": [ - { - "pub_id": "34176056", - "title": "Genetic differences in ethanol consumption: effects on iron, copper, and zinc regulation in mouse hippocampus.", - "authors": "Byron C Jones,Keith M Erikson,Megan K Mulligan,Carolina Torres-Rojas,Wenyuan Zhao,Daming Zhuang,Lu Lu,Robert W Williams", - "abstract": "One common characteristic of neurodegenerative diseases is dysregulation of iron, usually with observed increases in its concentration in various regions. Heavy alcohol consumption is believed to contribute to such iron dysregulation in the brain with accompanying dementia. To examine this effect and related genetic-based individual differences in an animal model, we subjected female mice from 12 BXD recombinant inbred strains to 16\u00a0weeks of alcohol consumption using the drinking in the dark (DID) method. Daily consumption was recorded and at the end of 16\u00a0weeks hippocampus tissues harvested. Concentrations of iron, copper and zinc were measured using X-ray fluorescence technology. The results showed that, DID increased iron overall across all strains, ranging from 3 to 68%. Copper and Zinc both decreased, ranging from 0.4-42 and 5-35% respectively. Analysis of variance revealed significant strain by treatment interactions for all three metals. Additionally, in the DID group, we observed strain differences in reduction of hippocampus mass. These findings are particularly interesting to us because high alcohol consumption in humans has been associated with neurodegeneration and dementia related to disruption of iron regulation. The findings of alcohol consumption associated decreases in copper and zinc are novel. The role of copper regulation and neurological function related to alcohol consumption is as yet largely unexplored. The role of zinc is better known as a neuromodulator in the hippocampus and appears to be protective against neurological damage. It would seem then, that the alcohol-related decrease in zinc in the hippocampus would be of concern and warrants further study.", - "journal_title": "Biometals : an international journal on the role of metal ions in biology, biochemistry, and medicine", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/34176056/" - } - ], - "3da7c010-cd02-4d09-8d73-99b70bc6d81c": [ - { - "pub_id": "29469954", - "title": "Apremilast Alters Behavioral Responses to Ethanol in Mice: II. Increased Sedation, Intoxication, and Reduced Acute Functional Tolerance.", - "authors": "Yuri A Blednov,Adriana J Da Costa,R Adron Harris,Robert O Messing", - "abstract": "In our companion paper, we reported that the phosphodiesterase type 4 inhibitor apremilast reduced ethanol (EtOH) intake and preference in different drinking models in male and female C57BL/6J mice. In this study, we measured the effects of apremilast on other behaviors that are correlated with EtOH consumption. The effects of apremilast (20\u00a0mg/kg) on the following behaviors were studied in male and female C57BL/6J mice: locomotor response to a novel situation; EtOH- and lithium chloride (LiCl)-induced conditioned taste aversion (CTA) to saccharin; conditioned place preference (CPP) and conditioned place avoidance (CPA) to EtOH; severity of handling-induced convulsions after EtOH administration; EtOH-induced anxiolytic-like behavior in the elevated plus maze; duration of EtOH-induced loss of righting reflex (LORR); recovery from EtOH-induced motor impairment on the rotarod; and acute functional tolerance (AFT) to EtOH's ataxic effects. Apremilast did not change the acquisition of EtOH-induced CPP, severity of acute withdrawal from EtOH, or EtOH's anxiolytic-like effect. Apremilast did not alter the extinction of EtOH- or LiCl-induced CTA, but may interfere with acquisition of CTA to EtOH. Apremilast increased the acquisition of CPA to EtOH, reduced locomotor responses to a novel situation, and prolonged the duration of LORR and the recovery from acute motor incoordination induced by EtOH. The longer recovery from the ataxic effect may be attributed to reduced development of AFT to EtOH. Our results suggest that apremilast increases the duration of EtOH intoxication by reducing AFT. Apremilast also reduces some aspects of general reward and increases EtOH's aversive properties, which might also contribute to its ability to reduce EtOH drinking.", - "journal_title": "Alcoholism, clinical and experimental research", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/29469954/" - } - ], - "34184c8d-b167-4ae8-bfce-01e18d78fe41": [ - { - "pub_id": "29605608", - "title": "Genetic variations in key inflammatory cytokines exacerbates the risk of diabetic nephropathy by influencing the gene expression.", - "authors": "Iqra Hameed,Shariq R Masoodi,Perveez A Malik,Shahnaz A Mir,Khalid Ghazanfar,Bashir A Ganai", - "abstract": "Diabetic nephropathy is the single strongest predictor of mortality in patients with diabetes. The development of overt nephropathy involves important inter-individual variations, even after adjusting for potential confounding influences of modifiable and non-modifiable risk factors. Genome-wide transcriptome studies have reported the activation of inflammatory signaling pathways and there is mounting indication of the role of genetic factors. We screened nine genetic variations in three cytokine genes (TNF-\u03b1, IL-6 and IL-\u03b2) in 1326 unrelated subjects comprising of healthy controls (n\u202f=\u202f464), type 2 diabetics with nephropathy (DN, n\u202f=\u202f448) and type 2 diabetes without nephropathy (T2D, n\u202f=\u202f414) by sequence-specific amplification. Functional implication of SNPs was elucidated by correlation studies and relative gene expression using Realtime-Quantitative PCR (RT-qPCR). Individual SNP analysis showed highest association of IL-1\u03b2 rs16944-TT genotype (OR\u202f=\u202f3.51, 95%CI\u202f=\u202f2.36-5.21, P\u202f=\u202f0.001) and TNF-\u03b1 rs1800629-AA genotype (OR\u202f=\u202f2.75, 95% CI\u202f=\u202f1.64-4.59, P\u202f=\u202f0.001) with T2D and DN respectively. The haplotype frequency showed significant risk of seven combinations among T2D and four combinations among DN subjects. The highest risk of T2D and DN was associated with GGTGAGTTT (OR\u202f=\u202f4.25, 95%CI\u202f=\u202f3.3-14.20, P\u202f=\u202f0.0016) and GACGACCTT (OR\u202f=\u202f21.3, 95%CI\u202f=\u202f15.1-28.33, P\u202f=\u202f0.026) haplotypes respectively. Relative expression by RT-qPCR showed increased cytokine expression in cases as compared to controls. TNF-\u03b1 expression was increased by more than four-folds (n-fold\u202f=\u202f4.43\u202f\u00b1\u202f1.11) in DN. TNF-\u03b1, IL-6 and IL-1\u03b2 transcript levels were significantly modulated by promoter region SNPs. The present study implicates a strong association between cytokine TNF-\u03b1, IL-6 and IL-1\u03b2 gene promoter polymorphisms and modulation of transcript levels with susceptibility to nephropathy in diabetes subjects.", - "journal_title": "Gene", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/29605608/" - } - ], - "1b5c24ec-d9a8-421d-aea9-4ffd8ab3c571": [ - { - "pub_id": "29063962", - "title": "Association of PGC-1\u03b1 gene with type 2 diabetes in three unrelated endogamous groups of North-West India (Punjab): a case-control and meta-analysis study.", - "authors": "Rubina Sharma,Kawaljit Matharoo,Rohit Kapoor,A J S Bhanwer", - "abstract": "PGC-1\u03b1 (Peroxisome proliferator-activated receptor gamma, coactivator 1 alpha) plays a key role in glucose homeostasis inside liver and muscle. The impact of six polymorphisms of PGC-1\u03b1 with Type 2 Diabetes (T2D) susceptibility was evaluated on 1125 samples comprising of 554 T2D cases and 571 controls among three endogamous groups (Bania, Brahmin and Jat Sikh) of North-West India (Punjab). Single-locus analysis showed a significant differential pattern of genetic association of PGC-1\u03b1 among studied groups emphasizing the role of ethnicity towards disease susceptibility. Haplotypes G-A-G-G-C-C in Bania group; G-G-G-G-C-A in Brahmin; G-A-A-G-T-C, G-G-G-G-T-C in Jat Sikh groups conferred ~\u2009two to fivefold increased T2D risk. Intriguingly, the haplotype combination G-A-G-G-C-C provided T2D risk in Banias whereas it played a protective role in Brahmins reflecting the role of ethnic heterogeneity. In the secondary structure prediction of mRNA, slight free energy change along with structural changes was observed between the wild and variant allele of rs3736265, rs8192678 and rs2970847 loci. Meta-analyses conducted on rs8192678 and rs2970847 variants illustrated the overall effect of minor alleles providing a higher risk for the T2D development. Divergence in genetic variants and haplotype combinations associated with T2D risk among studied groups is inferred from the present dataset, which strongly highlights the combinatorial effect of diverse ethnic background of the population under study with genetics towards susceptibility to complex diseases like T2D.", - "journal_title": "Molecular genetics and genomics : MGG", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/29063962/" - } - ], - "8f6c3be4-4598-4ae2-a7a8-8ea5a7a52794": [ - { - "pub_id": "18698414", - "title": "Improved elucidation of biological processes linked to diabetic nephropathy by single probe-based microarray data analysis.", - "authors": "Clemens D Cohen,Maja T Lindenmeyer,Felix Eichinger,Alexander Hahn,Martin Seifert,Anton G Moll,Holger Schmid,Eva Kiss,Elisabeth Gr\u00f6ne,Hermann-Josef Gr\u00f6ne,Matthias Kretzler,Thomas Werner,Peter J Nelson", - "abstract": "Diabetic nephropathy (DN) is a complex and chronic metabolic disease that evolves into a progressive fibrosing renal disorder. Effective transcriptomic profiling of slowly evolving disease processes such as DN can be problematic. The changes that occur are often subtle and can escape detection by conventional oligonucleotide DNA array analyses. We examined microdissected human renal tissue with or without DN using Affymetrix oligonucleotide microarrays (HG-U133A) by standard Robust Multi-array Analysis (RMA). Subsequent gene ontology analysis by Database for Annotation, Visualization and Integrated Discovery (DAVID) showed limited detection of biological processes previously identified as central mechanisms in the development of DN (e.g. inflammation and angiogenesis). This apparent lack of sensitivity may be associated with the gene-oriented averaging of oligonucleotide probe signals, as this includes signals from cross-hybridizing probes and gene annotation that is based on out of date genomic data. We then examined the same CEL file data using a different methodology to determine how well it could correlate transcriptomic data with observed biology. ChipInspector (CI) is based on single probe analysis and de novo gene annotation that bypasses probe set definitions. Both methods, RMA and CI, used at default settings yielded comparable numbers of differentially regulated genes. However, when verified by RT-PCR, the single probe based analysis demonstrated reduced background noise with enhanced sensitivity and fewer false positives. Using a single probe based analysis approach with de novo gene annotation allowed an improved representation of the biological processes linked to the development and progression of DN. The improved analysis was exemplified by the detection of Wnt signaling pathway activation in DN, a process not previously reported to be involved in this disease.", - "journal_title": "PloS one", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/18698414/" - } - ], - "2ee22ab1-6a66-4144-998e-0dee028c0f26": [ - { - "pub_id": "12404098", - "title": "Cardiovascular and diabetes mortality determined by nutrition during parents' and grandparents' slow growth period.", - "authors": "G Kaati,L O Bygren,S Edvinsson", - "abstract": "Overfeeding and overeating in families are traditions that are often transferred from generation to generation. Irrespective of these family traditions, food availability might lead to overfeeding, in its turn leading to metabolic adaptations. Apart from selection, could these adaptations to the social environment have transgenerational effects? This study will attempt to answer the following question: Can overeating during a child's slow growth period (SGP), before their prepubertal peak in growth velocity influence descendants' risk of death from cardiovascular disease and diabetes? Data were collected by following three cohorts born in 1890, 1905 and 1920 in Overkalix parish in northern Sweden up until death or 1995. The parents' or grandparents' access to food during their SGP was determined by referring to historical data on harvests and food prices, records of local community meetings and general historical facts. If food was not readily available during the father's slow growth period, then cardiovascular disease mortality of the proband was low. Diabetes mortality increased if the paternal grandfather was exposed to a surfeit of food during his slow growth period. (Odds Ratio 4.1, 95% confidence interval 1.33-12.93, P=0.01). Selection bias seemed to be unlikely. A nutrition-linked mechanism through the male line seems to have influenced the risk for cardiovascular and diabetes mellitus mortality.", - "journal_title": "European journal of human genetics : EJHG", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/12404098/" - } - ], - "ee21529b-bf7d-49ec-a21e-c52c9c7ff7e1": [ - { - "pub_id": "28222533", - "title": "Type 1 Diabetes Mellitus and Cognitive Impairments: A Systematic Review.", - "authors": "Wei Li,Edgar Huang,Sujuan Gao", - "abstract": "Type 1 diabetes mellitus (T1DM) is a major subtype of diabetes and is usually diagnosed at a young age with insulin deficiency. The life expectancy of T1DM patients has increased substantially in comparison with that three decades ago due to the availability of exogenous insulin, though it is still shorter than that of healthy people. However, the relation remains unclear between T1DM and dementia as an aging-related disease. We conducted a systematic review of existing literature on T1DM and cognition impairments by carrying out searches in electronic databases Medline, EMBASE, and Google Scholar. We restricted our review to studies involving only human subjects and excluded studies on type 2 diabetes mellitus or non-classified diabetes. A meta-analysis was first performed on the relationship between T1DM and cognitive changes in youths and adults respectively. Then the review focused on the cognitive complications of T1DM and their relation with the characteristics of T1DM, glycemic control, diabetic complications, comorbidities, and others. First, age at onset, disease duration, and glycemic dysregulation were delineated for their association with cognitive changes. Then diabetic ketoacidosis, angiopathy, and neuropathy were examined as diabetic complications for their involvement in cognitive impairments. Lastly, body mass index and blood pressure were discussed for their relations with the cognitive changes. Future studies are needed to elucidate the pathogenesis of T1DM-related cognitive impairments or dementia.", - "journal_title": "Journal of Alzheimer's disease : JAD", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/28222533/" - } - ], - "34a57416-2154-45dc-9e75-f928db77ad86": [ - { - "pub_id": "30871457", - "title": "Evaluation of Sirtuin-3 probe quality and co-expressed genes using literature cohesion.", - "authors": "Sujoy Roy,Kazi I Zaman,Robert W Williams,Ramin Homayouni", - "abstract": "Gene co-expression studies can provide important insights into molecular and cellular signaling pathways. The GeneNetwork database is a unique resource for co-expression analysis using data from a variety of tissues across genetically distinct inbred mice. However, extraction of biologically meaningful co-expressed gene sets is challenging due to variability in microarray platforms, probe quality, normalization methods, and confounding biological factors. In this study, we tested whether literature derived functional cohesion could be used as an objective metric in lieu of 'ground truth' to evaluate the quality of probes and microarray datasets. We examined Sirtuin-3 (Sirt3) co-expressed gene sets extracted from either liver or brain tissues of BXD recombinant inbred mice in the GeneNetwork database. Depending on the microarray platform, there were as many as 26 probes that targeted different regions of Sirt3 primary transcript. Co-expressed gene sets (ranging from 100-1000 genes) associated with each Sirt3 probe were evaluated using the previously developed literature-derived cohesion p-value (LPv) and benchmarked against 'gold standards' derived from proteomic studies or Gene Ontology classifications. We found that the maximal F-measure was obtained at an average window size of 535 genes. Using set size of 500 genes, the Pearson correlations between LPv and F-measure as well as between LPv and mitochondrial gene enrichment p-values were 0.90 and 0.93, respectively. Importantly, we found that the LPv approach can distinguish high quality Sirt3 probes. Analysis of the most functionally cohesive Sirt3 co-expressed gene set revealed core metabolic pathways that were shared between hippocampus and liver as well as distinct pathways which were unique to each tissue. These results are consistent with other studies that suggest Sirt3 is a key metabolic regulator and has distinct functions in energy-producing vs. energy-demanding tissues. Our results provide proof-of-concept that literature cohesion analysis is useful for evaluating the quality of probes and microarray datasets, particularly when experimentally derived gold standards are unavailable. Our approach would enable researchers to rapidly identify biologically meaningful co-expressed gene sets and facilitate discovery from high throughput genomic data.", - "journal_title": "BMC bioinformatics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/30871457/" - } - ], - "0c6c0977-2cf9-4bbf-bc31-fe025f008089": [ - { - "pub_id": "34326545", - "title": "Variably methylated retrotransposons are refractory to a range of environmental perturbations.", - "authors": "Tessa M Bertozzi,Jessica L Becker,Georgina E T Blake,Amita Bansal,Duy K Nguyen,Denise S Fernandez-Twinn,Susan E Ozanne,Marisa S Bartolomei,Rebecca A Simmons,Erica D Watson,Anne C Ferguson-Smith", - "abstract": "The agouti viable yellow (A<sup>vy</sup>) allele is an insertional mutation in the mouse genome caused by a variably methylated intracisternal A particle (VM-IAP) retrotransposon. A<sup>vy</sup> expressivity is sensitive to a range of early-life chemical exposures and nutritional interventions, suggesting that environmental perturbations can have long-lasting effects on the methylome. However, the extent to which VM-IAP elements are environmentally labile with phenotypic implications is unknown. Using a recently identified repertoire of VM-IAPs, we assessed the epigenetic effects of different environmental contexts. A longitudinal aging analysis indicated that VM-IAPs are stable across the murine lifespan, with only small increases in DNA methylation detected for a subset of loci. No significant effects were observed after maternal exposure to the endocrine disruptor bisphenol A, an obesogenic diet or methyl donor supplementation. A genetic mouse model of abnormal folate metabolism exhibited shifted VM-IAP methylation levels and altered VM-IAP-associated gene expression, yet these effects are likely largely driven by differential targeting by polymorphic KRAB zinc finger proteins. We conclude that epigenetic variability at retrotransposons is not predictive of environmental susceptibility.", - "journal_title": "Nature genetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/34326545/" - } - ], - "3f27c6b7-2180-418d-abe8-088f6d69c0fe": [ - { - "pub_id": "32742255", - "title": "Discovery of a Role for <i>Rab3b</i> in Habituation and Cocaine Induced Locomotor Activation in Mice Using Heterogeneous Functional Genomic Analysis.", - "authors": "Jason A Bubier,Vivek M Philip,Price E Dickson,Guy Mittleman,Elissa J Chesler", - "abstract": "Substance use disorders are prevalent and present a tremendous societal cost but the mechanisms underlying addiction behavior are poorly understood and few biological treatments exist. One strategy to identify novel molecular mechanisms of addiction is through functional genomic experimentation. However, results from individual experiments are often noisy. To address this problem, the convergent analysis of multiple genomic experiments can discern signal from these studies. In the present study, we examine genetic loci that modulate the locomotor response to cocaine identified in the recombinant inbred (BXD RI) genetic reference population. We then applied the GeneWeaver software system for heterogeneous functional genomic analysis to integrate and aggregate multiple studies of addiction genomics, resulting in the identification of <i>Rab3b</i> as a functional correlate of the locomotor response to cocaine in rodents. This gene encodes a member of the RAB family of Ras-like GTPases known to be involved in trafficking of secretory and endocytic vesicles in eukaryotic cells. The convergent evidence for a role of <i>Rab3b</i> includes co-occurrence in previously published genetic mapping studies of cocaine related behaviors; methamphetamine response and cocaine- and amphetamine-regulated transcript prepropeptide (<i>Cartpt</i>) transcript abundance; evidence related to other addictive substances; density of polymorphisms; and its expression pattern in reward pathways. To evaluate this finding, we examined the effect of RAB3 complex perturbation in cocaine response. B6;129-<i>Rab3b<sup>tm1Sud</sup> Rab3c<sup>tm1sud</sup> Rab3d<sup>tm1sud</sup></i> triple null mice (<i>Rab3bcd</i> <sup>-/-</sup>) exhibited significant deficits in habituation, and increased acute and repeated cocaine responses. This previously unidentified mechanism of the behavioral predisposition and response to cocaine is an example of many that can be identified and validated using aggregate genomic studies.", - "journal_title": "Frontiers in neuroscience", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/32742255/" - } - ], - "75813bc2-f0b5-400c-92d7-0958df97a04f": [ - { - "pub_id": "29357292", - "title": "Reproducibility and replicability of rodent phenotyping in preclinical studies.", - "authors": "Neri Kafkafi,Joseph Agassi,Elissa J Chesler,John C Crabbe,Wim E Crusio,David Eilam,Robert Gerlai,Ilan Golani,Alex Gomez-Marin,Ruth Heller,Fuad Iraqi,Iman Jaljuli,Natasha A Karp,Hugh Morgan,George Nicholson,Donald W Pfaff,S Helene Richter,Philip B Stark,Oliver Stiedl,Victoria Stodden,Lisa M Tarantino,Valter Tucci,William Valdar,Robert W Williams,Hanno W\u00fcrbel,Yoav Benjamini", - "abstract": "The scientific community is increasingly concerned with the proportion of published \"discoveries\" that are not replicated in subsequent studies. The field of rodent behavioral phenotyping was one of the first to raise this concern, and to relate it to other methodological issues: the complex interaction between genotype and environment; the definitions of behavioral constructs; and the use of laboratory mice and rats as model species for investigating human health and disease mechanisms. In January 2015, researchers from various disciplines gathered at Tel Aviv University to discuss these issues. The general consensus was that the issue is prevalent and of concern, and should be addressed at the statistical, methodological and policy levels, but is not so severe as to call into question the validity and the usefulness of model organisms as a whole. Well-organized community efforts, coupled with improved data and metadata sharing, have a key role in identifying specific problems and promoting effective solutions. Replicability is closely related to validity, may affect generalizability and translation of findings, and has important ethical implications.", - "journal_title": "Neuroscience and biobehavioral reviews", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/29357292/" - } - ], - "23320305-5766-48e6-8d89-fd252e47cbac": [ - { - "pub_id": "30769143", - "title": "Exploring the involvement of Tac2 in the mouse hippocampal stress response through gene networking.", - "authors": "Mike Hook,Fuyi Xu,Elena Terenina,Wenyuan Zhao,Athena Starlard-Davenport,Pierre Mormede,Byron C Jones,Megan K Mulligan,Lu Lu", - "abstract": "Tachykinin 2 (Tac2) is expressed in a number of areas throughout the brain, including the hippocampus. However, knowledge about its function has been only well explored in the hypothalamus in the context of reproductive health. In this study, we identified and validated increased hippocampal Tac2 mRNA expression in response to chronic mild stress in mice. Expression quantitative trait locus (eQTL) analysis showed Tac2 is cis-regulated in the hippocampus. Using a systems genetics approach, we constructed a Tac2 co-expression network to better understand the relationship between Tac2 and the hippocampal stress response. Our network identified 69 total genes associated with Tac2, several of which encode major neuropeptides involved in hippocampal stress signaling as well as critical genes for producing neural plasticity, indicating that Tac2 is involved in these processes. Pathway analysis for the member of Tac2 gene network revealed a strong connection between Tac2 and neuroactive ligand-receptor interaction, calcium signaling pathway, as well as cardiac muscle contraction. In addition, we also identified 46 stress-related phenotypes, specifically fear conditioning response, that were significantly correlated with Tac2 expression. Our results provide evidence for Tac2 as a strong candidate gene who likely plays a role in hippocampal stress processing and neural plasticity.", - "journal_title": "Gene", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/30769143/" - } - ], - "1705b972-f675-44ef-8294-c4f9d3040cd5": [ - { - "pub_id": "32045820", - "title": "Pex3 is involved in the genetic regulation of Nr3c2 expression in the amygdala of mice.", - "authors": "Rixin Cai,Xuelei Tao,Ying Chen,Athena Starlard-Davenport,Byron C Jones,Melloni N Cook,Lu Lu", - "abstract": "The mineralocorticoid receptor (Nr3c2) has received increased attention as an important stress-related gene. Here, we sought to uncover candidate genes regulating the expression of Nr3c2. Using a genetical genomics approach, we identified a significant trans-regulated expression quantitative trait locus (eQTL) at Chromosome 10 for Nr3c2 expression in the amygdala of BXD RI strains. We then examined genes upstream of the eQTL to identify likely regulatory candidates of Nr3c2 expression. Pex3 (peroxisomal) expression was highly correlated with that of Nr3c2, had a significant cis-regulated eQTL that mapped to the Nr3c2 eQTL region and thus emerged as the most likely regulatory candidate of Nr3c2 expression. In vitro studies showed that silencing of Pex3 by siRNA decreased Nr3c2 expression in HEK293T and SHSY5 cell lines while overexpression increased Nr3c2 expression. A relationship between the expression of these two genes was further supported by our observations that expression levels of Pex3 and Nr3c2 decreased in the amygdala of mice exposed to chronic unpredictable stress. Our findings provide insight into the genetic regulation of Nr3c2 expression and suggest a new role for Pex3 in stress responses. Future characterization of Pex3's role in the regulation of Nr3c2 expression and the pathways involved may lead to a better understanding of stress responses and risk for stress-related pathology.", - "journal_title": "Psychiatry research", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/32045820/" - } - ], - "f1944f5d-cbf0-4204-bf38-52750d782dfd": [ - { - "pub_id": "29775679", - "title": "Identification and validation of midbrain Kcnq4 regulation of heavy alcohol consumption in rodents.", - "authors": "Natalie S McGuier,Jennifer A Rinker,Reginald Cannady,Diana B Fulmer,Sara R Jones,Michaela Hoffman,Patrick J Mulholland", - "abstract": "Currently available pharmacotherapies for treating alcohol use disorder (AUD) suffer from deleterious side effects and are not efficacious in diverse populations. Clinical and preclinical studies provide evidence that the Kcnq family of genes that encode K<sub>V</sub>7 channels influence alcohol intake and dependence. K<sub>V</sub>7 channels are a class of slowly activating voltage-dependent K<sup>+</sup> channels that regulate neuronal excitability. Studies indicate that the K<sub>V</sub>7 channel positive modulator retigabine can decrease dopaminergic neuron firing, alter dopamine (DA) release, and reduce alcohol intake in heavy drinking rodents. Given the critical nature of ventral tegmental area (VTA) DA to the addiction process and predominant expression of Kcnq4 in DA neurons, we investigated the role of midbrain Kcnq genes and K<sub>V</sub>7 channels in the VTA of genetically diverse mice and long-term heavy drinking rats, respectively. Integrative bioinformatics analysis identified negative correlations between midbrain Kcnq4 expression and alcohol intake and seeking behaviors. Kcnq4 expression levels were also correlated with dopaminergic-related phenotypes in BXD strains, and Kcnq4 was present in support intervals for alcohol sensitivity and alcohol withdrawal severity QTLs in rodents. Pharmacological validation studies revealed that VTA K<sub>V</sub>7 channels regulate excessive alcohol intake in rats with a high-drinking phenotype. Administration of a novel and selective K<sub>V</sub>7.2/4 channel positive modulator also reduced alcohol drinking in rats. Together, these findings indicate that midbrain Kcnq4 expression regulates alcohol-related behaviors in genetically diverse mice and provide evidence that K<sub>V</sub>7.4 channels are a critical mediator of excessive alcohol drinking.", - "journal_title": "Neuropharmacology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/29775679/" - } - ], - "08aeb508-32df-4632-ad96-814e4e6f63e1": [ - { - "pub_id": "29280852", - "title": "Bivariate Genome-Wide Association Study of Depressive Symptoms With Type 2 Diabetes and Quantitative Glycemic Traits.", - "authors": "Kadri Haljas,Azmeraw T Amare,Behrooz Z Alizadeh,Yi-Hsiang Hsu,Thomas Mosley,Anne Newman,Joanne Murabito,Henning Tiemeier,Toshiko Tanaka,Cornelia van Duijn,Jingzhong Ding,David J Llewellyn,David A Bennett,Antonio Terracciano,Lenore Launer,Karl-Heinz Ladwig,Marylin C Cornelis,Alexander Teumer,Hans Grabe,Sharon L R Kardia,Erin B Ware,Jennifer A Smith,Harold Snieder,Johan G Eriksson,Leif Groop,Katri R\u00e4ikk\u00f6nen,Jari Lahti", - "abstract": "Shared genetic background may explain phenotypic associations between depression and Type 2 diabetes (T2D). We aimed to study, on a genome-wide level, if genetic correlation and pleiotropic loci exist between depressive symptoms and T2D or glycemic traits. We estimated single-nucleotide polymorphism (SNP)-based heritability and analyzed genetic correlation between depressive symptoms and T2D and glycemic traits with the linkage disequilibrium score regression by combining summary statistics of previously conducted meta-analyses for depressive symptoms by CHARGE consortium (N = 51,258), T2D by DIAGRAM consortium (N = 34,840 patients and 114,981 controls), fasting glucose, fasting insulin, and homeostatic model assessment of \u03b2-cell function and insulin resistance by MAGIC consortium (N = 58,074). Finally, we investigated pleiotropic loci using a bivariate genome-wide association study approach with summary statistics from genome-wide association study meta-analyses and reported loci with genome-wide significant bivariate association p value (p < 5 \u00d7 10). Biological annotation and function of significant pleiotropic SNPs were assessed in several databases. The SNP-based heritability ranged from 0.04 to 0.10 in each individual trait. In the linkage disequilibrium score regression analyses, depressive symptoms showed no significant genetic correlation with T2D or glycemic traits (p > 0.37). However, we identified pleiotropic genetic variations for depressive symptoms and T2D (in the IGF2BP2, CDKAL1, CDKN2B-AS, and PLEKHA1 genes), and fasting glucose (in the MADD, CDKN2B-AS, PEX16, and MTNR1B genes). We found no significant overall genetic correlations between depressive symptoms, T2D, or glycemic traits suggesting major differences in underlying biology of these traits. However, several potential pleiotropic loci were identified between depressive symptoms, T2D, and fasting glucose, suggesting that previously established phenotypic associations may be partly explained by genetic variation in these specific loci.", - "journal_title": "Psychosomatic medicine", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/29280852/" - } - ], - "aa5b5723-1b81-4d27-8514-55665819be80": [ - { - "pub_id": "28325553", - "title": "Metabolomics through the lens of precision cardiovascular medicine.", - "authors": "Sin Man Lam,Yuan Wang,Bowen Li,Jie Du,Guanghou Shui", - "abstract": "Metabolomics, which targets at the extensive characterization and quantitation of global metabolites from both endogenous and exogenous sources, has emerged as a novel technological avenue to advance the field of precision medicine principally driven by genomics-oriented approaches. In particular, metabolomics has revealed the cardinal roles that the environment exerts in driving the progression of major diseases threatening public health. Herein, the existent and potential applications of metabolomics in two key areas of precision cardiovascular medicine will be critically discussed: 1) the use of metabolomics in unveiling novel disease biomarkers and pathological pathways; 2) the contribution of metabolomics in cardiovascular drug development. Major issues concerning the statistical handling of big data generated by metabolomics, as well as its interpretation, will be briefly addressed. Finally, the need for integration of various omics branches and adopting a multi-omics approach to precision medicine will be discussed.", - "journal_title": "Journal of genetics and genomics = Yi chuan xue bao", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/28325553/" - } - ], - "90eca621-c5fb-46c7-830b-40f0faa1b5a2": [ - { - "pub_id": "29739359", - "title": "Genome-wide association studies for diabetic macular edema and proliferative diabetic retinopathy.", - "authors": "Patricia S Graham,Georgia Kaidonis,Sotoodeh Abhary,Mark C Gillies,Mark Daniell,Rohan W Essex,John H Chang,Stewart R Lake,Bishwanath Pal,Alicia J Jenkins,Alex W Hewitt,Ecosse L Lamoureux,Philip G Hykin,Nikolai Petrovsky,Matthew A Brown,Jamie E Craig,Kathryn P Burdon", - "abstract": "Diabetic macular edema (DME) and proliferative diabetic retinopathy (PDR) are sight-threatening complications of diabetes mellitus and leading causes of adult-onset blindness worldwide. Genetic risk factors for diabetic retinopathy (DR) have been described previously, but have been difficult to replicate between studies, which have often used composite phenotypes and been conducted in different populations. This study aims to identify genetic risk factors for DME and PDR as separate complications in Australians of European descent with type 2 diabetes. Caucasian Australians with type 2 diabetes were evaluated in a genome-wide association study (GWAS) to compare 270 DME cases and 176 PDR cases with 435 non-retinopathy controls. All participants were genotyped by SNP array and after data cleaning, cases were compared to controls using logistic regression adjusting for relevant covariates. The top ranked SNP for DME was rs1990145 (p\u2009=\u20094.10\u2009\u00d7\u200910<sup>-\u20096</sup>, OR\u2009=\u20092.02 95%CI [1.50, 2.72]) on chromosome 2. The top-ranked SNP for PDR was rs918519 (p\u2009=\u20093.87\u2009\u00d7\u200910<sup>-\u20096</sup>, OR\u2009=\u20090.35 95%CI [0.22, 0.54]) on chromosome 5. A trend towards association was also detected at two SNPs reported in the only other reported GWAS of DR in Caucasians; rs12267418 near MALRD1 (p\u2009=\u20090.008) in the DME cohort and rs16999051 in the diabetes gene PCSK2 (p\u2009=\u20090.007) in the PDR cohort. This study has identified loci of interest for DME and PDR, two common ocular complications of diabetes. These findings require replication in other Caucasian cohorts with type 2 diabetes and larger cohorts will be required to identify genetic loci with statistical confidence. There is considerable overlap in the patient cohorts with each retinopathy subtype, complicating the search for genes that contribute to PDR and DME biology.", - "journal_title": "BMC medical genetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/29739359/" - } - ], - "cf4b0a35-aaad-4a91-96eb-ab0256ac32ce": [ - { - "pub_id": "28974674", - "title": "Insights into beta cell regeneration for diabetes via integration of molecular landscapes in human insulinomas.", - "authors": "Huan Wang,Aaron Bender,Peng Wang,Esra Karakose,William B Inabnet,Steven K Libutti,Andrew Arnold,Luca Lambertini,Micheal Stang,Herbert Chen,Yumi Kasai,Milind Mahajan,Yayoi Kinoshita,Gustavo Fernandez-Ranvier,Thomas C Becker,Karen K Takane,Laura A Walker,Shira Saul,Rong Chen,Donald K Scott,Jorge Ferrer,Yevgeniy Antipin,Michael Donovan,Andrew V Uzilov,Boris Reva,Eric E Schadt,Bojan Losic,Carmen Argmann,Andrew F Stewart", - "abstract": "Although diabetes results in part from a deficiency of normal pancreatic beta cells, inducing human beta cells to regenerate is difficult. Reasoning that insulinomas hold the \"genomic recipe\" for beta cell expansion, we surveyed 38 human insulinomas to obtain insights into therapeutic pathways for beta cell regeneration. An integrative analysis of whole-exome and RNA-sequencing data was employed to extensively characterize the genomic and molecular landscape of insulinomas relative to normal beta cells. Here, we show at the pathway level that the majority of the insulinomas display mutations, copy number variants and/or dysregulation of epigenetic modifying genes, most prominently in the polycomb and trithorax families. Importantly, these processes are coupled to co-expression network modules associated with cell proliferation, revealing candidates for inducing beta cell regeneration. Validation of key computational predictions supports the concept that understanding the molecular complexity of insulinoma may be a valuable approach to diabetes drug discovery.Diabetes results in part from a deficiency of functional pancreatic beta cells. Here, the authors study the genomic and epigenetic landscapes of human insulinomas to gain insight into possible pathways for therapeutic beta cell regeneration, highlighting epigenetic genes and pathways.", - "journal_title": "Nature communications", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/28974674/" - } - ], - "d70e16cb-b617-4674-91d3-81beecc170b5": [ - { - "pub_id": "31238105", - "title": "Strain differences in maternal neuroendocrine and behavioral responses to stress and the relation to offspring cocaine responsiveness.", - "authors": "Jared R Bagley,Julia Adams,Rachel V Bozadjian,Lana Bubalo,Tod E Kippin", - "abstract": "Early life stress exposure, including prenatal stress (PNS), influences subsequent risk for many disorders, including substance abuse, and these effects interact with genetic factors to determine risk for disease. We previously demonstrated gene X environmental interactions across the BXD recombinant inbred mouse strain panel and their progenitor strains in PNS modulation of cocaine-induced reward and locomotion. Critical to dissecting genetic interactions with PNS is consideration of the modes of stress transmission to the offspring. Both maternal neuroendocrine responses during stress and subsequent maternal-offspring interactions following stress may serve as transmission modes for PNS-induced changes in cocaine responsiveness. Therefore, we characterized the maternal stress response by measuring restraint stress-induced plasma corticosterone (CORT) during gestation as well as effects of restraint stress on dam-pup contact in the first 10 postnatal days in BXD and progenitor mouse strains. Restraint stress interacted with strain to affect plasma CORT levels and dam-pup contact, indicating heritable variation of the maternal stress response. Furthermore, strain-level variance in maternal stress response correlated to the impact on cocaine response exhibited by adult offspring. These findings implicate multiple modes of maternal stress response in alterations of offspring drug responsiveness and indicate that assessment of maternal endocrine and behavioral responses during early life can be utilized to dissect the complex intersection of maternal factors, the response of the offspring and genetics.", - "journal_title": "International journal of developmental neuroscience : the official journal of the International Society for Developmental Neuroscience", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/31238105/" - } - ], - "095da902-d92c-44ab-a5c3-43a143d502bb": [ - { - "pub_id": "38085098", - "title": "Using encrypted genotypes and phenotypes for collaborative genomic analyses to maintain data confidentiality.", - "authors": "Tianjing Zhao,Fangyi Wang,Richard Mott,Jack Dekkers,Hao Cheng", - "abstract": "To adhere to and capitalize on the benefits of the FAIR (findable, accessible, interoperable, and reusable) principles in agricultural genome-to-phenome studies, it is crucial to address privacy and intellectual property issues that prevent sharing and reuse of data in research and industry. Direct sharing of genotype and phenotype data is often prohibited due to intellectual property and privacy concerns. Thus, there is a pressing need for encryption methods that obscure confidential aspects of the data, without affecting the outcomes of certain statistical analyses. A homomorphic encryption method for genotypes and phenotypes (HEGP) has been proposed for single-marker regression in genome-wide association studies (GWAS) using linear mixed models with Gaussian errors. This methodology permits frequentist likelihood-based parameter estimation and inference. In this paper, we extend HEGP to broader applications in genome-to-phenome analyses. We show that HEGP is suited to commonly used linear mixed models for genetic analyses of quantitative traits including genomic best linear unbiased prediction (GBLUP) and ridge-regression best linear unbiased prediction (RR-BLUP), as well as Bayesian variable selection methods (e.g. those in Bayesian Alphabet), for genetic parameter estimation, genomic prediction, and GWAS. By advancing the capabilities of HEGP, we offer researchers and industry professionals a secure and efficient approach for collaborative genomic analyses while preserving data confidentiality.", - "journal_title": "Genetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/38085098/" - } - ], - "a5e25b91-4846-4a42-b9b4-838031ec19b7": [ - { - "pub_id": "34154043", - "title": "Expression of LONP1 Is High in Visceral Adipose Tissue in Obesity, and Is Associated with Glucose and Lipid Metabolism.", - "authors": "Ju Hee Lee,Saet-Byel Jung,Seong Eun Lee,Ji Eun Kim,Jung Tae Kim,Yea Eun Kang,Seul Gi Kang,Hyon-Seung Yi,Young Bok Ko,Ki Hwan Lee,Bon Jeong Ku,Minho Shong,Hyun Jin Kim", - "abstract": "The nature and role of the mitochondrial stress response in adipose tissue in relation to obesity are not yet known. To determine whether the mitochondrial unfolded protein response (UPRmt) in adipose tissue is associated with obesity in humans and rodents. Visceral adipose tissue (VAT) was obtained from 48 normoglycemic women who underwent surgery. Expression levels of mRNA and proteins were measured for mitochondrial chaperones, intrinsic proteases, and components of electron-transport chains. Furthermore, we systematically analyzed metabolic phenotypes with a large panel of isogenic BXD inbred mouse strains and Genotype-Tissue Expression (GTEx) data. In VAT, expression of mitochondrial chaperones and intrinsic proteases localized in inner and outer mitochondrial membranes was not associated with body mass index (BMI), except for the Lon protease homolog, mitochondrial, and the corresponding gene LONP1, which showed high-level expression in the VAT of overweight or obese individuals. Expression of LONP1 in VAT positively correlated with BMI. Analysis of the GTEx database revealed that elevation of LONP1 expression is associated with enhancement of genes involved in glucose and lipid metabolism in VAT. Mice with higher Lonp1 expression in adipose tissue had better systemic glucose metabolism than mice with lower Lonp1 expression. Expression of mitochondrial LONP1, which is involved in the mitochondrial quality control stress response, was elevated in the VAT of obese individuals. In a bioinformatics analysis, high LONP1 expression in VAT was associated with enhanced glucose and lipid metabolism.", - "journal_title": "Endocrinology and metabolism (Seoul, Korea)", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/34154043/" - } - ], - "66baf01d-e081-4034-b7ec-03592eac90a7": [ - { - "pub_id": "32922257", - "title": "Exploring the Role of Chemokine Receptor 6 (<i>Ccr6</i>) in the BXD Mouse Model of Gulf War Illness.", - "authors": "Jun Gao,Fuyi Xu,Athena Starlard-Davenport,Diane B Miller,James P O'Callaghan,Byron C Jones,Lu Lu", - "abstract": "Gulf War illness (GWI) is a chronic and multi-symptomatic disorder with persistent neuroimmune symptomatology. Chemokine receptor 6 (CCR6) has been shown to be involved in several inflammation disorders in humans. However, the causative relationship between <i>CCR6</i> and neuroinflammation in GWI has not yet been investigated. By using RNA-seq data of prefrontal cortex (PFC) from 31 C57BL/6J X DBA/2J (BXD) recombinant inbred (RI) mouse strains and their parental strains under three chemical treatment groups - saline control (CTL), diisopropylfluorophosphate (DFP), and corticosterone combined with diisopropylfluorophosphate (CORT+DFP), we identified <i>Ccr6</i> as a candidate gene underlying individual differences in susceptibility to GWI. The <i>Ccr6</i> gene is <i>cis</i>-regulated and its expression is significantly correlated with CORT+DFP treatment. Its mean transcript abundance in PFC of BXD mice decreased 1.6-fold (<i>p</i> < 0.0001) in the CORT+DFP group. The response of <i>Ccr6</i> to CORT+DFP is also significantly different (<i>p</i> < 0.0001) between the parental strains, suggesting <i>Ccr6</i> is affected by both host genetic background and chemical treatments. Pearson product-moment correlation analysis revealed 1473 <i>Ccr6</i>-correlated genes (<i>p</i> < 0.05). Enrichment of these genes was seen in the immune, inflammation, cytokine, and neurological related categories. In addition, we also found five central nervous system-related phenotypes and fecal corticosterone concentration have significant correlation (<i>p</i> < 0.05) with expression of <i>Ccr6</i> in the PFC. We further established a protein-protein interaction subnetwork for the <i>Ccr6-</i>correlated genes, which provides an insight on the interaction of G protein-coupled receptors, kallikrein-kinin system and neuroactive ligand-receptors. This analysis likely defines the heterogeneity and complexity of GWI. Therefore, our results suggest that <i>Ccr6</i> is one of promising GWI biomarkers.", - "journal_title": "Frontiers in neuroscience", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/32922257/" - } - ], - "c7baf2cb-4b8a-4701-9977-95e81b8df4cb": [ - { - "pub_id": "30246031", - "title": "Sex Differences in Correlation with Gene Expression Levels between <i>Ifi200</i> Family Genes and Four Sets of Immune Disease-Relevant Genes.", - "authors": "Yanhong Cao,Lishi Wang,Cong-Yi Wang,Jicheng Ye,Ying Wang,Tiantian Li,Franklin Garcia-Godoy,Dianjun Sun,Weikuan Gu,Arnold E Postlethwaite", - "abstract": "The HIN-200 family genes in humans have been linked to several autoimmune diseases-particularly to systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA). Recently, its human counterpart gene cluster, the <i>Ifi200</i> family in mice, has been linked to spontaneous arthritis disease (SAD). However, many immune-mediated diseases (including RA and SLE) show gender difference. Understanding whether or not and how these genes play a role in sex difference in immune-mediated diseases is essential for diagnosis/treatment. This study takes advantage of the whole genome gene expression profiles of recombinant inbred (RI) strain populations from female and male mice to analyze potential sex differences in a variety of genes in disease pathways. Expression levels and regulatory QTL of <i>Ifi200</i> family genes between female and male mice were first examined in a large mouse population, including RI strains derived from C57BL/6J, DBA/2J (BXD), and classic inbred strains. Sex similarities and differences were then analyzed for correlations with gene expression levels between genes in the <i>Ifi200</i> family and four selected gene sets: known immune <i>Ifi200</i> pathway-related genes, lupus-relevant genes, osteoarthritis- (OA-) and RA-relevant genes, and sex hormone-related genes. The expression level of <i>Ifi202b</i> showed the most sex difference in correlation with known immune-related genes (the <i>P</i> value for <i>Ifi202b</i> is 0.0004). <i>Ifi202b</i> also showed gender difference in correlation with selected sex hormone genes, with a <i>P</i> value of 0.0243. When comparing coexpression levels between <i>Ifi200</i> genes and lupus-relevant genes, <i>Ifi203</i> and <i>Ifi205</i> showed significant sex difference (<i>P</i> values: 0.0303 and 0.002, resp.). Furthermore, several key genes (e.g., <i>Csf1r</i>, <i>Ifnb1</i>, <i>IL-20</i>, <i>IL-22</i>, <i>IL-24</i>, <i>Jhdm1d</i>, <i>Csf1r</i>, <i>Ifnb1</i>, <i>IL-20</i>, <i>IL-22</i>, <i>IL-24</i>, and <i>Tgfb2</i> that regulate sex differences in immune diseases) were discovered. Different genes in the <i>Ifi200</i> family play different roles in sex difference among dissimilar pathways of these four gene groups.", - "journal_title": "Journal of immunology research", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/30246031/" - } - ], - "721eafff-b103-4ad4-a1b4-340942951440": [ - { - "pub_id": "34867157", - "title": "Hippocampal Transcriptome-Wide Association Study Reveals Correlations Between Impaired Glutamatergic Synapse Pathway and Age-Related Hearing Loss in BXD-Recombinant Inbred Mice.", - "authors": "Tingzhi Deng,Jingjing Li,Jian Liu,Fuyi Xu,Xiaoya Liu,Jia Mi,Jonas Bergquist,Helen Wang,Chunhua Yang,Lu Lu,Xicheng Song,Cuifang Yao,Geng Tian,Qing Yin Zheng", - "abstract": "Age-related hearing loss (ARHL) is associated with cognitive dysfunction; however, the detailed underlying mechanisms remain unclear. The aim of this study is to investigate the potential underlying mechanism with a system genetics approach. A transcriptome-wide association study was performed on aged (12-32 months old) BXD mice strains. The hippocampus gene expression was obtained from 56 BXD strains, and the hearing acuity was assessed from 54 BXD strains. Further correlation analysis identified a total of 1,435 hearing-related genes in the hippocampus (<i>p</i> < 0.05). Pathway analysis of these genes indicated that the impaired glutamatergic synapse pathway is involved in ARHL (<i>p</i> = 0.0038). Further gene co-expression analysis showed that the expression level of glutamine synthetase (<i>Gls</i>), which is significantly correlated with ARHL (<i>n</i> = 26, <i>r</i> = -0.46, <i>p</i> = 0.0193), is a crucial regulator in glutamatergic synapse pathway and associated with learning and memory behavior. In this study, we present the first systematic evaluation of hippocampus gene expression pattern associated with ARHL, learning, and memory behavior. Our results provide novel potential molecular mechanisms involved in ARHL and cognitive dysfunction association.", - "journal_title": "Frontiers in neuroscience", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/34867157/" - } - ], - "41fc22ce-f0dc-4d81-a2b5-14c563c7c767": [ - { - "pub_id": "36590920", - "title": "Transcriptome-wide association study reveals cholesterol metabolism gene Lpl is a key regulator of cognitive dysfunction.", - "authors": "Wei Hu,Jian Liu,Yaorui Hu,Qingling Xu,Tingzhi Deng,Mengna Wei,Lu Lu,Jia Mi,Jonas Bergquist,Fuyi Xu,Geng Tian", - "abstract": "Cholesterol metabolism in the brain plays a crucial role in normal physiological function, and its aberrations are associated with cognitive dysfunction. The present study aimed to determine which cholesterol-related genes play a vital role in cognitive dysfunction and to dissect its underlying molecular mechanisms using a systems genetics approach in the BXD mice family. We first systematically analyzed the association of expression of 280 hippocampal genes related to cholesterol metabolism with cognition-related traits and identified lipoprotein lipase (Lpl) as a critical regulator. This was further confirmed by phenome-wide association studies that indicate Lpl associated with hippocampus volume residuals and anxiety-related traits. By performing expression quantitative trait locus mapping, we demonstrate that <i>Lpl</i> is strongly <i>cis-</i>regulated in the BXD hippocampus. We also identified \u223c3,300 genes significantly (<i>p</i> < 0.05) correlated with the <i>Lpl</i> expression. Those genes are mainly involved in the regulation of neuron-related traits through the MAPK signaling pathway, axon guidance, synaptic vesicle cycle, and NF-kappa B signaling pathway. Furthermore, a protein-protein interaction network analysis identified several direct interactors of Lpl, including Rab3a, Akt1, Igf1, Crp, and Lrp1, which indicates that Lpl involves in the regulation of cognitive dysfunction through Rab3a-mediated synaptic vesicle cycle and Akt1/Igf1/Crp/Lrp1-mediated MAPK signaling pathway. Our findings demonstrate the importance of the Lpl, among the cholesterol-related genes, in regulating cognitive dysfunction and highlighting the potential signaling pathways, which may serve as novel therapeutic targets for the treatment of cognitive dysfunction.", - "journal_title": "Frontiers in molecular neuroscience", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/36590920/" - } - ], - "52990c69-609c-448e-9f2c-36e1655ca6db": [ - { - "pub_id": "36099916", - "title": "Integrative systems analysis identifies genetic and dietary modulators of bile acid homeostasis.", - "authors": "Hao Li,Alessia Perino,Qingyao Huang,Giacomo V G Von Alvensleben,Amir Banaei-Esfahani,Laura A Velazquez-Villegas,Karim Gariani,Melanie Korbelius,Maroun Bou Sleiman,J\u00e9romine Imbach,Yu Sun,Xiaoxu Li,Alexis Bachmann,Ludger J E Goeminne,Hector Gallart-Ayala,Evan G Williams,Julijana Ivanisevic,Johan Auwerx,Kristina Schoonjans", - "abstract": "Bile acids (BAs) are complex and incompletely understood enterohepatic-derived hormones that control whole-body metabolism. Here, we profiled postprandial BAs in the liver, feces, and plasma of 360 chow- or high-fat-diet-fed BXD male mice and demonstrated that both genetics and diet strongly influence BA abundance, composition, and correlation with metabolic traits. Through an integrated systems approach, we mapped hundreds of quantitative trait loci that modulate BAs and identified both known and unknown regulators of BA homeostasis. In particular, we discovered carboxylesterase 1c (Ces1c) as a genetic determinant of plasma tauroursodeoxycholic acid (TUDCA), a BA species with established disease-preventing actions. The association between Ces1c and plasma TUDCA was validated using data from independent mouse cohorts and a Ces1c knockout mouse model. Collectively, our data are a unique resource to dissect the physiological importance of BAs as determinants of metabolic traits, as underscored by the identification of CES1C as a master regulator of plasma TUDCA levels.", - "journal_title": "Cell metabolism", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/36099916/" - } - ], - "8e257b8d-c5c9-4c9b-9b4a-3987c18188da": [ - { - "pub_id": "35816897", - "title": "Appraising the causal role of smoking in multiple diseases: A systematic review and meta-analysis of Mendelian randomization studies.", - "authors": "Susanna C Larsson,Stephen Burgess", - "abstract": "The causal association between cigarette smoking and several diseases remains equivocal. The purpose of this study was to appraise the causal role of smoking in a wide range of diseases by summarizing the evidence from Mendelian randomization (MR) studies. MR studies on genetic liability to smoking initiation or lifetime smoking (composite of smoking initiation, heaviness, duration, and cessation) in relation to circulatory system, digestive system, nervous system, musculoskeletal system, endocrine, metabolic, and eye diseases, and neoplasms published until February 15, 2022, were identified in PubMed. De novo MR analyses were performed using summary statistics data from genome-wide association studies. Meta-analysis was applied to combine study-specific estimates. Meta-analyses of findings of 29 published MR studies and 123 de novo MR analyses of 57 distinct primary outcomes showed that genetic liability to smoking (smoking initiation or lifetime smoking) was associated with increased risk of 13 circulatory system diseases, several digestive system diseases (including diverticular, gallstone, gastroesophageal reflux, and Crohn's disease, acute pancreatitis, and periodontitis), epilepsy, certain musculoskeletal system diseases (including fracture, osteoarthritis, and rheumatoid arthritis), endocrine (polycystic ovary syndrome), metabolic (type 2 diabetes) and eye diseases (including age-related macular degeneration and senile cataract) as well as cancers of the lung, head and neck, esophagus, pancreas, bladder, kidney, cervix, and ovaries, and myeloid leukemia. Smoking liability was associated with decreased risk of Parkinson's disease and prostate cancer. This study found robust evidence that cigarette smoking causes a wide range of diseases. This work was supported by research grants from the Swedish Cancer Society (Cancerfonden), the Swedish Heart Lung Foundation (Hj\u00e4rt-Lungfonden, 20210351), the Swedish Research Council for Health, Working Life and Welfare (Forte, 2018-00123), and the Swedish Research Council (Vetenskapsr\u00e5det, 2019-00977). Stephen Burgess is supported by Sir Henry Dale Fellowship jointly funded by the Wellcome Trust and the Royal Society (204623/Z/16/Z) and the National Institute for Health Research Cambridge Biomedical Research Centre (BRC-1215-20014). The views expressed are those of the authors and not necessarily those of the National Institute for Health Research or the Department of Health and Social Care.", - "journal_title": "EBioMedicine", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/35816897/" - } - ], - "afe6a42e-2c8b-4cfd-9334-157d1b9d15b6": [ - { - "pub_id": "30022099", - "title": "Cognitive decline and dementia in diabetes mellitus: mechanisms and clinical implications.", - "authors": "Geert Jan Biessels,Florin Despa", - "abstract": "Cognitive dysfunction is increasingly recognized as an important comorbidity of diabetes mellitus. Different stages of diabetes-associated cognitive dysfunction exist, each with different cognitive features, affected age groups and prognoses and probably with different underlying mechanisms. Relatively subtle, slowly progressive cognitive decrements occur in all age groups. More severe stages, particularly mild cognitive impairment and dementia, with progressive deficits, occur primarily in older individuals (>65 years of age). Patients in the latter group are the most relevant for patient management and are the focus of this Review. Here, we review the evolving insights from studies on risk factors, brain imaging and neuropathology, which provide important clues on mechanisms of both the subtle cognitive decrements and the more severe stages of cognitive dysfunction. In the majority of patients, the cognitive phenotype is probably defined by multiple aetiologies. Although both the risk of clinically diagnosed Alzheimer disease and that of vascular dementia is increased in association with diabetes, the cerebral burden of the prototypical pathologies of Alzheimer disease (such as neurofibrillary tangles and neuritic plaques) is not. A major challenge for researchers is to pinpoint from the spectrum of diabetes-related disease processes those that affect the brain and contribute to development of dementia beyond the pathologies of Alzheimer disease. Observations from experimental models can help to meet that challenge, but this requires further improving the synergy between experimental and clinical scientists. The development of targeted treatment and preventive strategies will therefore depend on these translational efforts.", - "journal_title": "Nature reviews. Endocrinology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/30022099/" - } - ], - "2f39f55f-2604-49d4-9589-0e1403b84d7a": [ - { - "pub_id": "31560378", - "title": "Global, Regional, and National Cancer Incidence, Mortality, Years of Life Lost, Years Lived With Disability, and Disability-Adjusted Life-Years for 29 Cancer Groups, 1990 to 2017: A Systematic Analysis for the Global Burden of Disease Study.", - "authors": " ,Christina Fitzmaurice,Degu Abate,Naghmeh Abbasi,Hedayat Abbastabar,Foad Abd-Allah,Omar Abdel-Rahman,Ahmed Abdelalim,Amir Abdoli,Ibrahim Abdollahpour,Abdishakur S M Abdulle,Nebiyu Dereje Abebe,Haftom Niguse Abraha,Laith Jamal Abu-Raddad,Ahmed Abualhasan,Isaac Akinkunmi Adedeji,Shailesh M Advani,Mohsen Afarideh,Mahdi Afshari,Mohammad Aghaali,Dominic Agius,Sutapa Agrawal,Ayat Ahmadi,Elham Ahmadian,Ehsan Ahmadpour,Muktar Beshir Ahmed,Mohammad Esmaeil Akbari,Tomi Akinyemiju,Ziyad Al-Aly,Assim M AlAbdulKader,Fares Alahdab,Tahiya Alam,Genet Melak Alamene,Birhan Tamene T Alemnew,Kefyalew Addis Alene,Cyrus Alinia,Vahid Alipour,Syed Mohamed Aljunid,Fatemeh Allah Bakeshei,Majid Abdulrahman Hamad Almadi,Amir Almasi-Hashiani,Ubai Alsharif,Shirina Alsowaidi,Nelson Alvis-Guzman,Erfan Amini,Saeed Amini,Yaw Ampem Amoako,Zohreh Anbari,Nahla Hamed Anber,Catalina Liliana Andrei,Mina Anjomshoa,Fereshteh Ansari,Ansariadi Ansariadi,Seth Christopher Yaw Appiah,Morteza Arab-Zozani,Jalal Arabloo,Zohreh Arefi,Olatunde Aremu,Habtamu Abera Areri,Al Artaman,Hamid Asayesh,Ephrem Tsegay Asfaw,Alebachew Fasil Ashagre,Reza Assadi,Bahar Ataeinia,Hagos Tasew Atalay,Zerihun Ataro,Suleman Atique,Marcel Ausloos,Leticia Avila-Burgos,Euripide F G A Avokpaho,Ashish Awasthi,Nefsu Awoke,Beatriz Paulina Ayala Quintanilla,Martin Amogre Ayanore,Henok Tadesse Ayele,Ebrahim Babaee,Umar Bacha,Alaa Badawi,Mojtaba Bagherzadeh,Eleni Bagli,Senthilkumar Balakrishnan,Abbas Balouchi,Till Winfried B\u00e4rnighausen,Robert J Battista,Masoud Behzadifar,Meysam Behzadifar,Bayu Begashaw Bekele,Yared Belete Belay,Yaschilal Muche Belayneh,Kathleen Kim Sachiko Berfield,Adugnaw Berhane,Eduardo Bernabe,Mircea Beuran,Nickhill Bhakta,Krittika Bhattacharyya,Belete Biadgo,Ali Bijani,Muhammad Shahdaat Bin Sayeed,Charles Birungi,Catherine Bisignano,Helen Bitew,Tone Bj\u00f8rge,Archie Bleyer,Kassawmar Angaw Bogale,Hunduma Amensisa Bojia,Antonio M Borz\u00ec,Cristina Bosetti,Ibrahim R Bou-Orm,Hermann Brenner,Jerry D Brewer,Andrey Nikolaevich Briko,Nikolay Ivanovich Briko,Maria Teresa Bustamante-Teixeira,Zahid A Butt,Giulia Carreras,Juan J Carrero,F\u00e9lix Carvalho,Clara Castro,Franz Castro,Ferr\u00e1n Catal\u00e1-L\u00f3pez,Ester Cerin,Yazan Chaiah,Wagaye Fentahun Chanie,Vijay Kumar Chattu,Pankaj Chaturvedi,Neelima Singh Chauhan,Mohammad Chehrazi,Peggy Pei-Chia Chiang,Tesfaye Yitna Chichiabellu,Onyema Greg Chido-Amajuoyi,Odgerel Chimed-Ochir,Jee-Young J Choi,Devasahayam J Christopher,Dinh-Toi Chu,Maria-Magdalena Constantin,Vera M Costa,Emanuele Crocetti,Christopher Stephen Crowe,Maria Paula Curado,Saad M A Dahlawi,Giovanni Damiani,Amira Hamed Darwish,Ahmad Daryani,Jos\u00e9 das Neves,Feleke Mekonnen Demeke,Asmamaw Bizuneh Demis,Birhanu Wondimeneh Demissie,Gebre Teklemariam Demoz,Edgar Denova-Guti\u00e9rrez,Afshin Derakhshani,Kalkidan Solomon Deribe,Rupak Desai,Beruk Berhanu Desalegn,Melaku Desta,Subhojit Dey,Samath Dhamminda Dharmaratne,Meghnath Dhimal,Daniel Diaz,Mesfin Tadese Tadese Dinberu,Shirin Djalalinia,David Teye Doku,Thomas M Drake,Manisha Dubey,Eleonora Dubljanin,Eyasu Ejeta Duken,Hedyeh Ebrahimi,Andem Effiong,Aziz Eftekhari,Iman El Sayed,Maysaa El Sayed Zaki,Shaimaa I El-Jaafary,Ziad El-Khatib,Demelash Abewa Elemineh,Hajer Elkout,Richard G Ellenbogen,Aisha Elsharkawy,Mohammad Hassan Emamian,Daniel Adane Endalew,Aman Yesuf Endries,Babak Eshrati,Ibtihal Fadhil,Vahid Fallah Omrani,Mahbobeh Faramarzi,Mahdieh Abbasalizad Farhangi,Andrea Farioli,Farshad Farzadfar,Netsanet Fentahun,Eduarda Fernandes,Garumma Tolu Feyissa,Irina Filip,Florian Fischer,James L Fisher,Lisa M Force,Masoud Foroutan,Marisa Freitas,Takeshi Fukumoto,Neal D Futran,Silvano Gallus,Fortune Gbetoho Gankpe,Reta Tsegaye Gayesa,Tsegaye Tewelde Gebrehiwot,Gebreamlak Gebremedhn Gebremeskel,Getnet Azeze Gedefaw,Belayneh K Gelaw,Birhanu Geta,Sefonias Getachew,Kebede Embaye Gezae,Mansour Ghafourifard,Alireza Ghajar,Ahmad Ghashghaee,Asadollah Gholamian,Paramjit Singh Gill,Themba T G Ginindza,Alem Girmay,Muluken Gizaw,Ricardo Santiago Gomez,Sameer Vali Gopalani,Giuseppe Gorini,B\u00e1rbara Niegia Garcia Goulart,Ayman Grada,Maximiliano Ribeiro Guerra,Andre Luiz Sena Guimaraes,Prakash C Gupta,Rahul Gupta,Kishor Hadkhale,Arvin Haj-Mirzaian,Arya Haj-Mirzaian,Randah R Hamadeh,Samer Hamidi,Lolemo Kelbiso Hanfore,Josep Maria Haro,Milad Hasankhani,Amir Hasanzadeh,Hamid Yimam Hassen,Roderick J Hay,Simon I Hay,Andualem Henok,Nathaniel J Henry,Claudiu Herteliu,Hagos D Hidru,Chi Linh Hoang,Michael K Hole,Praveen Hoogar,Nobuyuki Horita,H Dean Hosgood,Mostafa Hosseini,Mehdi Hosseinzadeh,Mihaela Hostiuc,Sorin Hostiuc,Mowafa Househ,Mohammedaman Mama Hussen,Bogdan Ileanu,Milena D Ilic,Kaire Innos,Seyed Sina Naghibi Irvani,Kufre Robert Iseh,Sheikh Mohammed Shariful Islam,Farhad Islami,Nader Jafari Balalami,Morteza Jafarinia,Leila Jahangiry,Mohammad Ali Jahani,Nader Jahanmehr,Mihajlo Jakovljevic,Spencer L James,Mehdi Javanbakht,Sudha Jayaraman,Sun Ha Jee,Ensiyeh Jenabi,Ravi Prakash Jha,Jost B Jonas,Jitendra Jonnagaddala,Tamas Joo,Suresh Banayya Jungari,Mikk J\u00fcrisson,Ali Kabir,Farin Kamangar,Andr\u00e9 Karch,Narges Karimi,Ansar Karimian,Amir Kasaeian,Gebremicheal Gebreslassie Kasahun,Belete Kassa,Tesfaye Dessale Kassa,Mesfin Wudu Kassaw,Anil Kaul,Peter Njenga Keiyoro,Abraham Getachew Kelbore,Amene Abebe Kerbo,Yousef Saleh Khader,Maryam Khalilarjmandi,Ejaz Ahmad Khan,Gulfaraz Khan,Young-Ho Khang,Khaled Khatab,Amir Khater,Maryam Khayamzadeh,Maryam Khazaee-Pool,Salman Khazaei,Abdullah T Khoja,Mohammad Hossein Khosravi,Jagdish Khubchandani,Neda Kianipour,Daniel Kim,Yun Jin Kim,Adnan Kisa,Sezer Kisa,Katarzyna Kissimova-Skarbek,Hamidreza Komaki,Ai Koyanagi,Kristopher J Krohn,Burcu Kucuk Bicer,Nuworza Kugbey,Vivek Kumar,Desmond Kuupiel,Carlo La Vecchia,Deepesh P Lad,Eyasu Alem Lake,Ayenew Molla Lakew,Dharmesh Kumar Lal,Faris Hasan Lami,Qing Lan,Savita Lasrado,Paolo Lauriola,Jeffrey V Lazarus,James Leigh,Cheru Tesema Leshargie,Yu Liao,Miteku Andualem Limenih,Stefan Listl,Alan D Lopez,Platon D Lopukhov,Raimundas Lunevicius,Mohammed Madadin,Sameh Magdeldin,Hassan Magdy Abd El Razek,Azeem Majeed,Afshin Maleki,Reza Malekzadeh,Ali Manafi,Navid Manafi,Wondimu Ayele Manamo,Morteza Mansourian,Mohammad Ali Mansournia,Lorenzo Giovanni Mantovani,Saman Maroufizadeh,Santi Martini S Martini,Tivani Phosa Mashamba-Thompson,Benjamin Ballard Massenburg,Motswadi Titus Maswabi,Manu Raj Mathur,Colm McAlinden,Martin McKee,Hailemariam Abiy Alemu Meheretu,Ravi Mehrotra,Varshil Mehta,Toni Meier,Yohannes A Melaku,Gebrekiros Gebremichael Meles,Hagazi Gebre Meles,Addisu Melese,Mulugeta Melku,Peter T N Memiah,Walter Mendoza,Ritesh G Menezes,Shahin Merat,Tuomo J Meretoja,Tomislav Mestrovic,Bartosz Miazgowski,Tomasz Miazgowski,Kebadnew Mulatu M Mihretie,Ted R Miller,Edward J Mills,Seyed Mostafa Mir,Hamed Mirzaei,Hamid Reza Mirzaei,Rashmi Mishra,Babak Moazen,Dara K Mohammad,Karzan Abdulmuhsin Mohammad,Yousef Mohammad,Aso Mohammad Darwesh,Abolfazl Mohammadbeigi,Hiwa Mohammadi,Moslem Mohammadi,Mahdi Mohammadian,Abdollah Mohammadian-Hafshejani,Milad Mohammadoo-Khorasani,Reza Mohammadpourhodki,Ammas Siraj Mohammed,Jemal Abdu Mohammed,Shafiu Mohammed,Farnam Mohebi,Ali H Mokdad,Lorenzo Monasta,Yoshan Moodley,Mahmood Moosazadeh,Maryam Moossavi,Ghobad Moradi,Mohammad Moradi-Joo,Maziar Moradi-Lakeh,Farhad Moradpour,Lidia Morawska,Joana Morgado-da-Costa,Naho Morisaki,Shane Douglas Morrison,Abbas Mosapour,Seyyed Meysam Mousavi,Achenef Asmamaw Muche,Oumer Sada S Muhammed,Jonah Musa,Ashraf F Nabhan,Mehdi Naderi,Ahamarshan Jayaraman Nagarajan,Gabriele Nagel,Azin Nahvijou,Gurudatta Naik,Farid Najafi,Luigi Naldi,Hae Sung Nam,Naser Nasiri,Javad Nazari,Ionut Negoi,Subas Neupane,Polly A Newcomb,Haruna Asura Nggada,Josephine W Ngunjiri,Cuong Tat Nguyen,Leila Nikniaz,Dina Nur Anggraini Ningrum,Yirga Legesse Nirayo,Molly R Nixon,Chukwudi A Nnaji,Marzieh Nojomi,Shirin Nosratnejad,Malihe Nourollahpour Shiadeh,Mohammed Suleiman Obsa,Richard Ofori-Asenso,Felix Akpojene Ogbo,In-Hwan Oh,Andrew T Olagunju,Tinuke O Olagunju,Mojisola Morenike Oluwasanu,Abidemi E Omonisi,Obinna E Onwujekwe,Anu Mary Oommen,Eyal Oren,Doris D V Ortega-Altamirano,Erika Ota,Stanislav S Otstavnov,Mayowa Ojo Owolabi,Mahesh P A,Jagadish Rao Padubidri,Smita Pakhale,Amir H Pakpour,Adrian Pana,Eun-Kee Park,Hadi Parsian,Tahereh Pashaei,Shanti Patel,Snehal T Patil,Alyssa Pennini,David M Pereira,Cristiano Piccinelli,Julian David Pillay,Majid Pirestani,Farhad Pishgar,Maarten J Postma,Hadi Pourjafar,Farshad Pourmalek,Akram Pourshams,Swayam Prakash,Narayan Prasad,Mostafa Qorbani,Mohammad Rabiee,Navid Rabiee,Amir Radfar,Alireza Rafiei,Fakher Rahim,Mahdi Rahimi,Muhammad Aziz Rahman,Fatemeh Rajati,Saleem M Rana,Samira Raoofi,Goura Kishor Rath,David Laith Rawaf,Salman Rawaf,Robert C Reiner,Andre M N Renzaho,Nima Rezaei,Aziz Rezapour,Ana Isabel Ribeiro,Daniela Ribeiro,Luca Ronfani,Elias Merdassa Roro,Gholamreza Roshandel,Ali Rostami,Ragy Safwat Saad,Parisa Sabbagh,Siamak Sabour,Basema Saddik,Saeid Safiri,Amirhossein Sahebkar,Mohammad Reza Salahshoor,Farkhonde Salehi,Hosni Salem,Marwa Rashad Salem,Hamideh Salimzadeh,Joshua A Salomon,Abdallah M Samy,Juan Sanabria,Milena M Santric Milicevic,Benn Sartorius,Arash Sarveazad,Brijesh Sathian,Maheswar Satpathy,Miloje Savic,Monika Sawhney,Mehdi Sayyah,Ione J C Schneider,Ben Sch\u00f6ttker,Mario Sekerija,Sadaf G Sepanlou,Masood Sepehrimanesh,Seyedmojtaba Seyedmousavi,Faramarz Shaahmadi,Hosein Shabaninejad,Mohammad Shahbaz,Masood Ali Shaikh,Amir Shamshirian,Morteza Shamsizadeh,Heidar Sharafi,Zeinab Sharafi,Mehdi Sharif,Ali Sharifi,Hamid Sharifi,Rajesh Sharma,Aziz Sheikh,Reza Shirkoohi,Sharvari Rahul Shukla,Si Si,Soraya Siabani,Diego Augusto Santos Silva,Dayane Gabriele Alves Silveira,Ambrish Singh,Jasvinder A Singh,Solomon Sisay,Freddy Sitas,Eug\u00e8ne Sobngwi,Moslem Soofi,Joan B Soriano,Vasiliki Stathopoulou,Mu'awiyyah Babale Sufiyan,Rafael Tabar\u00e9s-Seisdedos,Takahiro Tabuchi,Ken Takahashi,Omid Reza Tamtaji,Mohammed Rasoul Tarawneh,Segen Gebremeskel Tassew,Parvaneh Taymoori,Arash Tehrani-Banihashemi,Mohamad-Hani Temsah,Omar Temsah,Berhe Etsay Tesfay,Fisaha Haile Tesfay,Manaye Yihune Teshale,Gizachew Assefa Tessema,Subash Thapa,Kenean Getaneh Tlaye,Roman Topor-Madry,Marcos Roberto Tovani-Palone,Eugenio Traini,Bach Xuan Tran,Khanh Bao Tran,Afewerki Gebremeskel Tsadik,Irfan Ullah,Olalekan A Uthman,Marco Vacante,Maryam Vaezi,Patricia Varona P\u00e9rez,Yousef Veisani,Simone Vidale,Francesco S Violante,Vasily Vlassov,Stein Emil Vollset,Theo Vos,Kia Vosoughi,Giang Thu Vu,Isidora S Vujcic,Henry Wabinga,Tesfahun Mulatu Wachamo,Fasil Shiferaw Wagnew,Yasir Waheed,Fitsum Weldegebreal,Girmay Teklay Weldesamuel,Tissa Wijeratne,Dawit Zewdu Wondafrash,Tewodros Eshete Wonde,Adam Belay Wondmieneh,Hailemariam Mekonnen Workie,Rajaram Yadav,Abbas Yadegar,Ali Yadollahpour,Mehdi Yaseri,Vahid Yazdi-Feyzabadi,Alex Yeshaneh,Mohammed Ahmed Yimam,Ebrahim M Yimer,Engida Yisma,Naohiro Yonemoto,Mustafa Z Younis,Bahman Yousefi,Mahmoud Yousefifard,Chuanhua Yu,Erfan Zabeh,Vesna Zadnik,Telma Zahirian Moghadam,Zoubida Zaidi,Mohammad Zamani,Hamed Zandian,Alireza Zangeneh,Leila Zaki,Kazem Zendehdel,Zerihun Menlkalew Zenebe,Taye Abuhay Zewale,Arash Ziapour,Sanjay Zodpey,Christopher J L Murray", - "abstract": "Cancer and other noncommunicable diseases (NCDs) are now widely recognized as a threat to global development. The latest United Nations high-level meeting on NCDs reaffirmed this observation and also highlighted the slow progress in meeting the 2011 Political Declaration on the Prevention and Control of Noncommunicable Diseases and the third Sustainable Development Goal. Lack of situational analyses, priority setting, and budgeting have been identified as major obstacles in achieving these goals. All of these have in common that they require information on the local cancer epidemiology. The Global Burden of Disease (GBD) study is uniquely poised to provide these crucial data. To describe cancer burden for 29 cancer groups in 195 countries from 1990 through 2017 to provide data needed for cancer control planning. We used the GBD study estimation methods to describe cancer incidence, mortality, years lived with disability, years of life lost, and disability-adjusted life-years (DALYs). Results are presented at the national level as well as by Socio-demographic Index (SDI), a composite indicator of income, educational attainment, and total fertility rate. We also analyzed the influence of the epidemiological vs the demographic transition on cancer incidence. In 2017, there were 24.5 million incident cancer cases worldwide (16.8 million without nonmelanoma skin cancer [NMSC]) and 9.6 million cancer deaths. The majority of cancer DALYs came from years of life lost (97%), and only 3% came from years lived with disability. The odds of developing cancer were the lowest in the low SDI quintile (1 in 7) and the highest in the high SDI quintile (1 in 2) for both sexes. In 2017, the most common incident cancers in men were NMSC (4.3 million incident cases); tracheal, bronchus, and lung (TBL) cancer (1.5 million incident cases); and prostate cancer (1.3 million incident cases). The most common causes of cancer deaths and DALYs for men were TBL cancer (1.3 million deaths and 28.4 million DALYs), liver cancer (572\u202f000 deaths and 15.2 million DALYs), and stomach cancer (542\u202f000 deaths and 12.2 million DALYs). For women in 2017, the most common incident cancers were NMSC (3.3 million incident cases), breast cancer (1.9 million incident cases), and colorectal cancer (819\u202f000 incident cases). The leading causes of cancer deaths and DALYs for women were breast cancer (601\u202f000 deaths and 17.4 million DALYs), TBL cancer (596\u202f000 deaths and 12.6 million DALYs), and colorectal cancer (414\u202f000 deaths and 8.3 million DALYs). The national epidemiological profiles of cancer burden in the GBD study show large heterogeneities, which are a reflection of different exposures to risk factors, economic settings, lifestyles, and access to care and screening. The GBD study can be used by policy makers and other stakeholders to develop and improve national and local cancer control in order to achieve the global targets and improve equity in cancer care.", - "journal_title": "JAMA oncology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/31560378/" - } - ], - "af76add5-194c-49cc-9cd1-84d95884885b": [ - { - "pub_id": "34241569", - "title": "A functional genomic approach to identify reference genes for human pancreatic beta cell real-time quantitative RT-PCR analysis.", - "authors": "Maria In\u00eas Alvelos,Florian Szymczak,\u00c2ngela Castela,Sandra Mar\u00edn-Ca\u00f1as,Bianca Marmontel de Souza,Ioannis Gkantounas,Maikel Colli,Federica Fantuzzi,Cristina Cosentino,Mariana Igoillo-Esteve,Lorella Marselli,Piero Marchetti,Miriam Cnop,D\u00e9cio L Eizirik", - "abstract": "Exposure of human pancreatic beta cells to pro-inflammatory cytokines or metabolic stressors is used to model events related to type 1 and type 2 diabetes, respectively. Quantitative real-time PCR is commonly used to quantify changes in gene expression. The selection of the most adequate reference gene(s) for gene expression normalization is an important pre-requisite to obtain accurate and reliable results. There are no universally applicable reference genes, and the human beta cell expression of commonly used reference genes can be altered by different stressors. Here we aimed to identify the most stably expressed genes in human beta cells to normalize quantitative real-time PCR gene expression.We used comprehensive RNA-sequencing data from the human pancreatic beta cell line EndoC-\u03b2H1, human islets exposed to cytokines or the free fatty acid palmitate in order to identify the most stably expressed genes. Genes were filtered based on their level of significance (adjusted <i>P</i>-value >0.05), fold-change (|fold-change| <1.5) and a coefficient of variation <10%. Candidate reference genes were validated by quantitative real-time PCR in independent samples.We identified a total of 264 genes stably expressed in EndoC-\u03b2H1 cells and human islets following cytokines - or palmitate-induced stress, displaying a low coefficient of variation. Validation by quantitative real-time PCR of the top five genes <i>ARF1, CWC15, RAB7A, SIAH1</i> and <i>VAPA</i> corroborated their expression stability under most of the tested conditions. Further validation in independent samples indicated that the geometric mean of <i>ACTB</i> and <i>VAPA</i> expression can be used as a reliable normalizing factor in human beta cells.", - "journal_title": "Islets", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/34241569/" - } - ], - "cdef5df7-ea47-4fbd-be84-37046d9042ce": [ - { - "pub_id": "29385592", - "title": "Communication of cancer-related genetic and genomic information: A landscape analysis of reviews.", - "authors": "Emily B Peterson,Wen-Ying Sylvia Chou,Anna Gaysynsky,Melinda Krakow,Ashley Elrick,Muin J Khoury,Kimberly A Kaphingst", - "abstract": "Cancer-related genetic and genomic testing (CGT) is changing cancer care by personalizing care options, leading to an era of precision medicine. Advances in and increased use of CGT add complexity to clinical communication. This landscape analysis assessed published reviews of communication issues related to CGT and discusses implications for practice and behavioral research. A comprehensive electronic literature search was conducted of peer-reviewed literature reviews on studies related to CGT communication published between January 2010 and January 2017, resulting in a final sample of 24 reviews. Reviews were categorized, with overlaps, into four domains across the genetic testing communication continuum. Reviews on CGT-related knowledge, attitudes, and perceptions (n = 8) found that despite substantial public interest, their knowledge and awareness remains low. Providers also reported insufficient knowledge and overall caution, particularly regarding direct-to-consumer (DTC) genetic testing. Reviews of decision-making about CGT and test uptake (n = 8) identified individual, interpersonal, and systems-level barriers to uptake. Reviews of patient-provider CGT communication (n = 8) revealed limited communication and little empirical research on outcomes of communication or efforts at improving clinical and family communication. There were mixed findings in reviews (n = 15) on the psychological and behavioral impact of CGT, and DTC testing particularly had little effect on behaviors. Taken together, there is very little extant research in CGT in minority and underserved communities. In order for scientific advances in CGT to translate into equitable, patient-centered care, behavioral research, including health literacy and communication, plays critical roles.", - "journal_title": "Translational behavioral medicine", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/29385592/" - } - ], - "5d3cb4d8-eb7c-40ce-bda5-d2347d64c4fc": [ - { - "pub_id": "30945019", - "title": "Heterogeneous impact of type 2 diabetes mellitus-related genetic variants on gestational glycemic traits: review and future research needs.", - "authors": "Shasha Liu,Yunqiang Liu,Shunyao Liao", - "abstract": "Gestational glucose homeostasis influences mother's metabolic health, pregnancy outcomes, fetal development and offspring growth. To understand the genetic roles in pregnant glucose metabolism and genetic predisposition for gestational diabetes (GDM), we reviewed the recent literature up to Jan, 2018 and evaluated the influence of T2DM-related genetic variants on gestational glycemic traits and glucose tolerance. A total of 140 variants of 89 genes were integrated. Their associations with glycemic traits in and outside pregnancy were compared. The genetic circumstances underlying glucose metabolism exhibit a similarity between pregnant and non-pregnant populations. While, not all of the T2DM-associated genetic variants are related to pregnant glucose tolerance, such as genes involved in fasting insulin/C-peptide regulation. Some genetic variants may have distinct effects on gestational glucose homeostasis. And certain genes may be particularly involved in this process via specific mechanisms, such as HKDC1, MTNR1B, BACE2, genes encoding cell cycle regulators, adipocyte regulators, inflammatory factors and hepatic factors related to gestational glucose sensing and insulin signaling. However, it is currently difficult to evaluate these associations with quantitative synthesis due to inadequate data, different analytical methods, varied measurements for glycemic traits, controversies in diagnosis of GDM, and unknown ethnicity- and/or sex-related influences on pregnant maternal metabolism. In conclusion, different genetic associations with glycemic traits may exist between pregnant and non-pregnant conditions. Comprehensive research on specific genetic regulation in gestation is necessary.", - "journal_title": "Molecular genetics and genomics : MGG", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/30945019/" - } - ], - "f8605b9d-94b1-47dd-a5a9-3e14452dff24": [ - { - "pub_id": "30178632", - "title": "A genome-wide association study suggests new evidence for an association of the NADPH Oxidase 4 (NOX4) gene with severe diabetic retinopathy in type 2 diabetes.", - "authors": "Weihua Meng,Kaanan P Shah,Samuela Pollack,Iiro Toppila,Harry L Hebert,Mark I McCarthy,Leif Groop,Emma Ahlqvist,Valeriya Lyssenko,Elisabet Agardh,Mark Daniell,Georgia Kaidonis,Jamie E Craig,Paul Mitchell,Gerald Liew,Annette Kifley,Jie Jin Wang,Mark W Christiansen,Richard A Jensen,Alan Penman,Heather A Hancock,Ching J Chen,Adolfo Correa,Jane Z Kuo,Xiaohui Li,Yii-der I Chen,Jerome I Rotter,Ronald Klein,Barbara Klein,Tien Y Wong,Andrew D Morris,Alexander S F Doney,Helen M Colhoun,Alkes L Price,Kathryn P Burdon,Per-Henrik Groop,Niina Sandholm,Michael A Grassi,Lucia Sobrin,Colin N A Palmer, ", - "abstract": "Diabetic retinopathy is the most common eye complication in patients with diabetes. The purpose of this study is to identify genetic factors contributing to severe diabetic retinopathy. A genome-wide association approach was applied. In the Genetics of Diabetes Audit and Research in Tayside Scotland (GoDARTS) datasets, cases of severe diabetic retinopathy were defined as type 2 diabetic patients who were ever graded as having severe background retinopathy (Level R3) or proliferative retinopathy (Level R4) in at least one eye according to the Scottish Diabetic Retinopathy Grading Scheme\u00a0or who were once treated by laser photocoagulation. Controls were diabetic individuals whose longitudinal retinopathy screening records were either normal (Level R0) or only with mild background retinopathy (Level R1) in both eyes. Significant Single Nucleotide Polymorphisms (SNPs) were taken forward for meta-analysis using multiple Caucasian cohorts. Five hundred and sixty cases of type 2 diabetes with severe diabetic retinopathy and 4,106 controls were identified in the GoDARTS cohort. We revealed that rs3913535 in the NADPH Oxidase 4 (NOX4) gene reached a p value of 4.05\u00a0\u00d7\u00a010<sup>-9</sup> . Two nearby SNPs, rs10765219 and rs11018670 also showed promising p values (p values\u00a0=\u00a07.41\u00a0\u00d7\u00a010<sup>-8</sup> and 1.23\u00a0\u00d7\u00a010<sup>-8</sup> , respectively). In the meta-analysis using multiple Caucasian cohorts (excluding GoDARTS), rs10765219 and rs11018670 showed associations for diabetic retinopathy (p\u00a0=\u00a00.003 and 0.007, respectively), while the p value of rs3913535 was not significant (p\u00a0=\u00a00.429). This genome-wide association study of severe diabetic retinopathy suggests new evidence for the involvement of the NOX4 gene.", - "journal_title": "Acta ophthalmologica", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/30178632/" - } - ], - "118cf2e9-f789-48a4-bf8d-a018af45fd31": [ - { - "pub_id": "18401556", - "title": "Endothelial nitric oxide synthase gene haplotypes and diabetic nephropathy among Asian Indians.", - "authors": "Tarunveer Singh Ahluwalia,Monica Ahuja,Taranjit Singh Rai,Harbir Singh Kohli,Kamal Sud,Anil Bhansali,Madhu Khullar", - "abstract": "Endothelial dysfunction plays a key role in the pathogenesis of diabetic vascular disease, including diabetic nephropathy. Endothelial-derived nitric oxide synthase (eNOS) gene polymorphisms affect eNOS activity and are associated with endothelial dysfunction. We evaluated the association of the constitutive endothelial nitric oxide synthase gene (eNOS) polymorphisms with type 2 diabetic nephropathy. We genotyped three polymorphisms of eNOS (Two SNPs: -786T > C, 894G > T and one 27-bp repeat polymorphism in Intron 4 (27VNTR)) in type 2 diabetic nephropathy patients (cases: n = 195) and type 2 diabetic without nephropathy (controls: n = 255), using validated PCR-RFLP assays. We measured serum NO levels in these subjects and examined its correlation with diabetic nephropathy and eNOS genotypes. The frequency of CC (-786T > C), TT (894G > T) and aa genotypes (27VNTR) were significantly higher in diabetic nephropathy patients as compared to the diabetes without nephropathy group (CC: P = 0.003, TT: P = 0.03, aa: P < 0.0001). These mutant genotypes were found to be associated with higher risk of nephropathy (-786T > C: OR: 5.5, 95%CI: 1.53-19.79; 894G > T: OR: 1.8, 95%CI: 1.03-3.16; Intron 4: OR: 6.23, 95%CI: 2.23-16.31). Haplotype with all the wild alleles (T-b-G) was found to be associated with a decreased risk of nephropathy (OR: 0.68, P = 0.005) and haplotype with all mutant alleles (C-a-T) was associated with higher risk of diabetic nephropathy as compared to diabetes without nephropathy group (OR: 2.6, P = 0.14). No significant linkage disequilibria were observed among the variants in this case-control study. The serum NO levels were observed to be significantly (P < 0.05) lower in mutant allele carriers ('C' allele of T-786C SNP and/or 'T' allele of G894T SNP) as compared with the wild-type allele carriers (-786T and/or 894G) within each of the subject groups (with and without nephropathy). These results suggest that the eNOS gene locus is associated with diabetic nephropathy and the functional polymorphisms (-786T > C & 894G > T) might lead to a decreased expression of eNOS gene.", - "journal_title": "Molecular and cellular biochemistry", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/18401556/" - } - ], - "23157342-c7ff-490a-b810-e93fdb9bc4f9": [ - { - "pub_id": "32174956", - "title": "Systems Genetics of Optic Nerve Axon Necrosis During Glaucoma.", - "authors": "Andrew B Stiemke,Eric Sah,Raven N Simpson,Lu Lu,Robert W Williams,Monica M Jablonski", - "abstract": "In this study, we identify genomic regions that modulate the number of necrotic axons in optic nerves of a family of mice, some of which have severe glaucoma, and define a set of high priority positional candidate genes that modulate retinal ganglion cell (RGC) axonal degeneration. A large cohort of the BXD family were aged to greater than 13 months of age. Optic nerves from 74 strains and the DBA/2J (D2) parent were harvested, sectioned, and stained with p-phenylenediamine. Numbers of necrotic axons per optic nerve cross-section were counted from 1 to 10 replicates per genotype. Strain means and standard errors were uploaded into GeneNetwork 2 for mapping and systems genetics analyses (Trait 18614). The number of necrotic axons per nerve ranged from only a few hundred to more than 4,000. Using conventional interval mapping as well as linear mixed model mapping, we identified a single locus on chromosome 12 between 109 and 112.5 Mb with a likelihood ratio statistic (LRS) of ~18.5 (<i>p</i> genome-wide ~0.1). Axon necrosis is not linked to locations of major known glaucoma genes in this family, including <i>Gpnmb</i>, <i>Tyrp1, Cdh11, Pou6f2,</i> and <i>Cacna2d1</i>. This indicates that although these genes contribute to pigmentary dispersion or elevated IOP, none directly modulates axon necrosis. Of 156 positional candidates, eight genes-<i>CDC42 binding protein kinase beta</i> (<i>Cdc42bpb</i>); <i>eukaryotic translation initiation factor 5</i> (<i>Eif5</i>); <i>BCL2-associated athanogene 5</i> (<i>Bag5</i>); <i>apoptogenic 1, mitochondrial</i> (<i>Apopt1</i>); <i>kinesin light chain 1</i> (<i>Klc1</i>); <i>X-ray repair cross complementing 3</i> (<i>Xrcc3</i>); <i>protein phosphatase 1, regulatory subunit 13B</i> (<i>Ppp1r13b</i>); and <i>transmembrane protein 17</i>9 (<i>Tmem179</i>)-passed stringent criteria and are high priority candidates. Several candidates are linked to mitochondria and/or axons, strengthening their plausible role as modulators of ON necrosis. Additional studies are required to validate and/or eliminate plausible candidates. Surprisingly, IOP and ON necrosis are inversely correlated across the BXD family in mice >13 months of age and these two traits share few genes among their top ocular and retinal correlates. These data suggest that the two traits are independently modulated or that a more complex and multifaceted approach is required to reveal their association.", - "journal_title": "Frontiers in genetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/32174956/" - } - ], - "af6d5068-d4e5-4ac0-98fc-4185da16bb0f": [ - { - "pub_id": "29729633", - "title": "Thrombospondin-4 mediates cardiovascular remodelling in angiotensin II-induced hypertension.", - "authors": "Teresa Palao,Lejla Medzikovic,Catarina Rippe,Shaynah Wanga,Claudia Al-Mardini,Angela van Weert,Judith de Vos,Nicole N van der Wel,Henk A van Veen,Ed T van Bavel,Karl Sw\u00e4rd,Vivian de Waard,Erik Ntp Bakker", - "abstract": "Thrombospondin 4 (TSP-4) expression is induced in the heart and vasculature under pathological conditions, including myocardial infarction, myocardial pressure overload, and hypertension. TSP-4 is linked to remodelling processes, where it may affect extracellular matrix protein organization. In previous work, we studied the role of TSP-4 in small arteries during hypertension using Ang II-treated Thrombospondin 4 knockout (Thbs4<sup>-/-</sup>) mice. We reported increased heart weight, as well as the occurrence of aortic aneurysms in the Ang II-treated Thbs4<sup>-/-</sup> animals. In the present study, we further characterized the hearts and aortas from these animals. Hypertrophy of cardiomyocytes, together with perivascular fibrosis and inflammation was observed in the Ang II-treated Thbs4<sup>-/-</sup> hearts. In the aortas, an increase in the aortic wall cross-sectional area (CSA) and wall thickness of the Ang II-treated Thbs4<sup>-/-</sup> mice was found. More detailed investigation of the Ang II-treated Thbs4<sup>-/-</sup> aortas also revealed the appearance of aortic dissections in the outer medial layer of the arteries, as well as pronounced inflammation. No differences were found in several other extracellular matrix-related parameters, such as number of elastin breaks or stress-strain relationships. However, at the ultrastructural level, collagen fibers showed alterations in diameter in the media and adventitia of the Ang II-treated Thbs4<sup>-/-</sup> mice, in the area prone to dissection. In conclusion, we identified TSP-4 as an important protein in the development of cardiac hypertrophy and aortic dissections in Ang II-induced hypertension.", - "journal_title": "Cardiovascular pathology : the official journal of the Society for Cardiovascular Pathology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/29729633/" - } - ], - "a7f40b8e-5da0-43f5-a8dd-acbab8735211": [ - { - "pub_id": "30642763", - "title": "The RNA-Binding Protein PUM2 Impairs Mitochondrial Dynamics and Mitophagy During Aging.", - "authors": "Davide D'Amico,Adrienne Mottis,Francesca Potenza,Vincenzo Sorrentino,Hao Li,Mario Romani,Vera Lemos,Kristina Schoonjans,Nicola Zamboni,Graham Knott,Bernard L Schneider,Johan Auwerx", - "abstract": "Little information is available about how post-transcriptional mechanisms regulate the aging process. Here, we show that the RNA-binding protein Pumilio2 (PUM2), which is a translation repressor, is induced upon aging and acts as a negative regulator of lifespan and mitochondrial homeostasis. Multi-omics and cross-species analyses of PUM2 function show that it inhibits the translation of the mRNA encoding for the mitochondrial fission factor (Mff), thereby impairing mitochondrial fission and mitophagy. This\u00a0mechanism is conserved in C.\u00a0elegans by the PUM2\u00a0ortholog PUF-8. puf-8 knock-down in old nematodes and Pum2 CRISPR/Cas9-mediated knockout in the\u00a0muscles of elderly mice enhances mitochondrial fission and mitophagy in both models, hence improving mitochondrial quality control and tissue homeostasis. Our data reveal how a PUM2-mediated layer of post-transcriptional regulation links altered Mff translation to mitochondrial dynamics and mitophagy, thereby mediating age-related mitochondrial dysfunctions.", - "journal_title": "Molecular cell", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/30642763/" - } - ], - "7a5c1a3b-4bb2-4834-ba6f-4f36f12f57e0": [ - { - "pub_id": "15383460", - "title": "Mapping of genes that control the antibody response to human factor IX in mice.", - "authors": "Jay N Lozier,Nahid Tayebi,Pei Zhang", - "abstract": "We tested the hypothesis that the antibody response to human factor IX in mice is controlled by genetic factors, especially histocompatibility antigens. Seven inbred mouse strains were immunized against human factor IX by adenoviral gene transfer or serial injections of human factor IX protein. A/J mice had the highest antibody response and 2 C57 mouse strains had the lowest response. We used the adenovirus vector to immunize 26 recombinant inbred mouse strains (AXB and BXA) derived from A/J and C57BL/6J mice and observed highly significant linkage (logarithmic odds [LOD] scores approximately 4.8) for the polymorphic D17Mit62 marker that is 1 centimorgan ( approximately 300 000 base pair [bp]) from the mouse major histocompatibility complex (MHC) locus (H-2). Experiments in mice with chimeric MHC genes indicated that class IaK or class II H-2 (or both) genes were critical, but other genes contributed to the antibody response. Polymorphic markers from chromosomes 1 and 10 that are near important immunoregulatory genes such as interleukin 10 and the interferon-gamma gene show suggestive linkage (LOD scores of approximately 2.3-2.6) to the factor IX antibody response. This study confirms the hypothesis that H-2 (and other) genes control factor IX antibody development in mice and suggests their potential importance for factor IX antibody development in humans with hemophilia B.", - "journal_title": "Blood", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/15383460/" - } - ], - "52769f14-9d64-49a9-80ec-c41e500d8384": [ - { - "pub_id": "32587610", - "title": "An Age-Related Hearing Protection Locus on Chromosome 16 of BXD Strain Mice.", - "authors": "Qing Yin Zheng,Lihong Kui,Fuyi Xu,Tihua Zheng,Bo Li,Melinda McCarty,Zehua Sun,Aizheng Zhang,Luying Liu,Athena Starlard-Davenport,Ruben Stepanyan,Bo Hua Hu,Lu Lu", - "abstract": "Inbred mouse models are widely used to study age-related hearing loss (AHL). Many genes associated with AHL have been mapped in a variety of strains. However, little is known about gene variants that have the converse function-protective genes that confer strong resistance to hearing loss. Previously, we reported that C57BL/6J (B6) and DBA/2J (D2) strains share a common hearing loss allele in <i>Cdh23</i>. The cadherin 23 (<i>Cdh23</i>) gene is a key contributor to early-onset hearing loss in humans. In this study, we tested hearing across a large family of 54 BXD strains generated from B6 to D2 crosses. Five of 54 strains maintain the normal threshold (20\u2009dB SPL) even at 2 years old-an age at which both parental strains are essentially deaf. Further analyses revealed an age-related hearing protection (<i>ahp</i>) locus on chromosome 16 (Chr 16) at 57~76\u2009Mb with a maximum LOD of 5.7. A small number of BXD strains at 2 years with good hearing correspond roughly to the percentage of humans who have good hearing at 90 years old. Further studies to define candidate genes in the <i>ahp</i> locus and related molecular mechanisms involved in age-related resilience or resistance to AHL are warranted.", - "journal_title": "Neural plasticity", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/32587610/" - } - ], - "bab65477-76ce-4506-bec8-589f1793e8af": [ - { - "pub_id": "15485132", - "title": "Role of genetic factors in the etiopathogenesis of cerebrovascular accidents: from an animal model to the human disease.", - "authors": "Speranza Rubattu,Rosita Stanzione,Bruna Gigante,Massimo Volpe", - "abstract": "1. The present work summarizes current knowledge on the genetic susceptibility to stroke, a complex cardiovascular phenotypic trait due to both gene/environment and gene/ gene interactions. 2. Evidence for the existence of genes directly contributing to stroke occurrence was first obtained in the animal model of the stroke-prone (sp) spontaneously hypertensive rat (SHR) through a linkage analysis approach in F2 segregating hybrid populations. In fact, several Quantitative Trait Loci (QTLs) were detected in different chromosomes of the rat. Candidate genes were identified (ANP, BNP, Adrenomedullin) and subsequently analyzed to obtain information on the fine disease mechanisms possibly dependent from specific sequence mutations. 3. The most important achievement was represented by the fact that the gene encoding ANP appeared to play a role in the disease of both rats and humans, thus providing a suggestive parallelism between the animal model and the human cerebrovascular disease. A more extensive analysis is required to identify the potential pathogenic role of genetic factors involved in human stroke.", - "journal_title": "Cellular and molecular neurobiology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/15485132/" - } - ], - "dfebf2a5-8553-41f9-af2d-f781778d1342": [ - { - "pub_id": "32691494", - "title": "Growth differentiation factor 15 protects against the aging-mediated systemic inflammatory response in humans and mice.", - "authors": "Ji Sun Moon,Ludger J E Goeminne,Jung Tae Kim,Jing Wen Tian,Seok-Hwan Kim,Ha Thi Nga,Seul Gi Kang,Baeki E Kang,Jin-Seok Byun,Young-Sun Lee,Jae-Han Jeon,Minho Shong,Johan Auwerx,Dongryeol Ryu,Hyon-Seung Yi", - "abstract": "Mitochondrial dysfunction is associated with aging-mediated inflammatory responses, leading to metabolic deterioration, development of insulin resistance, and type 2 diabetes. Growth differentiation factor 15 (GDF15) is an important mitokine generated in response to mitochondrial stress and dysfunction; however, the implications of GDF15 to the aging process are poorly understood in mammals. In this study, we identified a link between mitochondrial stress-induced GDF15 production and protection from tissue inflammation on aging in humans and mice. We observed an increase in serum levels and hepatic expression of GDF15 as well as pro-inflammatory cytokines in elderly subjects. Circulating levels of cell-free mitochondrial DNA were significantly higher in elderly subjects with elevated serum levels of GDF15. In the BXD mouse reference population, mice with metabolic impairments and shorter survival were found to exhibit higher hepatic Gdf15 expression. Mendelian randomization links reduced GDF15 expression in human blood to increased body weight and inflammation. GDF15 deficiency promotes tissue inflammation by increasing the activation of resident immune cells in metabolic organs, such as in the liver and adipose tissues of 20-month-old mice. Aging also results in more severe liver injury and hepatic fat deposition in Gdf15-deficient mice. Although GDF15 is not required for Th17 cell differentiation and IL-17 production in Th17 cells, GDF15 contributes to regulatory T-cell-mediated suppression of conventional T-cell activation and inflammatory cytokines. Taken together, these data reveal that GDF15 is indispensable for attenuating aging-mediated local and systemic inflammation, thereby maintaining glucose homeostasis and insulin sensitivity in humans and mice.", - "journal_title": "Aging cell", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/32691494/" - } - ], - "6daf89f2-caee-4128-a1a0-61a5c2d37b48": [ - { - "pub_id": "34834564", - "title": "<i>Ace2</i> and <i>Tmprss2</i> Expressions Are Regulated by <i>Dhx32</i> and Influence the Gastrointestinal Symptoms Caused by SARS-CoV-2.", - "authors": "Fuyi Xu,Jun Gao,Buyan-Ochir Orgil,Akhilesh Kumar Bajpai,Qingqing Gu,Enkhsaikhan Purevjav,Athena S Davenport,Kui Li,Jeffrey A Towbin,Dennis D Black,Joseph F Pierre,Lu Lu", - "abstract": "Studies showed that the gastrointestinal (GI) tract is one of the most important pathways for SARS-CoV-2 infection and coronavirus disease 2019 (COVID-19). As SARS-CoV-2 cellular entry depends on the ACE2 receptor and TMPRSS2 priming of the spike protein, it is important to understand the molecular mechanisms through which these two proteins and their cognate transcripts interact and influence the pathogenesis of COVID-19. In this study, we quantified the expression, associations, genetic modulators, and molecular pathways for <i>Tmprss2</i> and <i>Ace2</i> mRNA expressions in GI tissues using a systems genetics approach and the expanded family of highly diverse BXD mouse strains. The results showed that both <i>Tmprss2</i> and <i>Ace2</i> are highly expressed in GI tissues with significant covariation. We identified a significant expression quantitative trait locus on chromosome 7 that controls the expression of both <i>Tmprss2</i> and <i>Ace2</i>. <i>Dhx32</i> was found to be the strongest candidate in this interval. Co-expression network analysis demonstrated that both <i>Tmprss2</i> and <i>Ace2</i> were located at the same module that is significantly associated with other GI-related traits. Protein-protein interaction analysis indicated that hub genes in this module are linked to circadian rhythms. Collectively, our data suggested that genes with circadian rhythms of expression may have an impact on COVID-19 disease, with implications related to the timing and treatment of COVID-19.", - "journal_title": "Journal of personalized medicine", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/34834564/" - } - ], - "bbfc7f30-2854-454a-87d7-39ebfd78673f": [ - { - "pub_id": "35887687", - "title": "Potential Similarities in Sex Difference in Key Genes and Their Expression, Network, EQTL and Pathways between COVID-19 and Chronic Kidney Disease Based on Mouse Model.", - "authors": "Zhuo Yu,Jingyu Zhan,Wei Dong,Lu Lu,Monica M Jablonski,Lotfi Aleya,Jingyu Chen,Peiqing Zhang,Hong Chen,Weikuan Gu", - "abstract": "COVID-19 and chronic kidney disease (CKD) share similarity in sex bias and key genes in the disease pathway of sex difference. We investigated the sex difference of molecular pathways of four key players of these two diseases using an existing large set of whole genome expression profiles from the kidneys of female and male mouse models. Our data show that there is little to no correlation at the whole genome expression level between female and male mice among these four genes. There are considerable sex differences among genes in upstream regulation, <i>Ace2</i> complex interaction, and downstream pathways. Snap25 and Plcb4 may play important roles in the regulation of the expression level of <i>Adam17</i>, <i>Tmprss2</i>, and <i>Cd146</i> in females. In males, Adh4 is a candidate gene for the regulation of <i>Adam17</i>, while Asl, Auts2, and Rabger1 are candidates for <i>Tmprss2</i>. Within the <i>Ace2</i> complex, <i>Cd146</i> directly influences the expression level of <i>Adam17</i> and <i>Ace2</i> in the female, while in the male Adam potentially has a stronger influence on <i>Ace2</i> than that of <i>Tmprss2</i>. Among the top 100 most related genes, only one or two genes from four key genes and 11 from the control B-Actin were found to be the same between sexes. Among the top 10 sets of genes in the downstream pathway of <i>Ace2</i>, only two sets are the same between the sexes. We concluded that these known key genes and novel genes in CKD may play significant roles in the sex difference in the CKD and COVID-19 disease pathways.", - "journal_title": "Journal of personalized medicine", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/35887687/" - } - ], - "6482f94f-bb32-458a-bbd8-2d164efba104": [ - { - "pub_id": "31017905", - "title": "Cross-species alcohol dependence-associated gene networks: Co-analysis of mouse brain gene expression and human genome-wide association data.", - "authors": "Kristin M Mignogna,Silviu A Bacanu,Brien P Riley,Aaron R Wolen,Michael F Miles", - "abstract": "Genome-wide association studies on alcohol dependence, by themselves, have yet to account for the estimated heritability of the disorder and provide incomplete mechanistic understanding of this complex trait. Integrating brain ethanol-responsive gene expression networks from model organisms with human genetic data on alcohol dependence could aid in identifying dependence-associated genes and functional networks in which they are involved. This study used a modification of the Edge-Weighted Dense Module Searching for genome-wide association studies (EW-dmGWAS) approach to co-analyze whole-genome gene expression data from ethanol-exposed mouse brain tissue, human protein-protein interaction databases and alcohol dependence-related genome-wide association studies. Results revealed novel ethanol-responsive and alcohol dependence-associated gene networks in prefrontal cortex, nucleus accumbens, and ventral tegmental area. Three of these networks were overrepresented with genome-wide association signals from an independent dataset. These networks were significantly overrepresented for gene ontology categories involving several mechanisms, including actin filament-based activity, transcript regulation, Wnt and Syndecan-mediated signaling, and ubiquitination. Together, these studies provide novel insight for brain mechanisms contributing to alcohol dependence.", - "journal_title": "PloS one", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/31017905/" - } - ], - "3b1fe8ff-a6c5-4f0b-b824-9a854297f6f0": [ - { - "pub_id": "15660159", - "title": "A golden age of brain exploration.", - "authors": "Virginia Gewin", - "abstract": "The Allen Brain Atlas of gene expression in the mouse brain is poised to serve as an outstanding resource to neuroscience", - "journal_title": "PLoS biology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/15660159/" - } - ], - "8e5b5131-2de8-4a9a-800b-721b4643582f": [ - { - "pub_id": "30984232", - "title": "Identification of a Functional Non-coding Variant in the GABA <sub><i>A</i></sub> Receptor \u03b12 Subunit of the C57BL/6J Mouse Reference Genome: Major Implications for Neuroscience Research.", - "authors": "Megan K Mulligan,Timothy Abreo,Sarah M Neuner,Cory Parks,Christine E Watkins,M Trevor Houseal,Thomas M Shapaker,Michael Hook,Haiyan Tan,Xusheng Wang,Jesse Ingels,Junmin Peng,Lu Lu,Catherine C Kaczorowski,Camron D Bryant,Gregg E Homanics,Robert W Williams", - "abstract": "GABA type-A (GABA-A) receptors containing the \u03b12 subunit (GABRA2) are expressed in most brain regions and are critical in modulating inhibitory synaptic function. Genetic variation at the <i>GABRA2</i> locus has been implicated in epilepsy, affective and psychiatric disorders, alcoholism and drug abuse. <i>Gabra2</i> expression varies as a function of genotype and is modulated by sequence variants in several brain structures and populations, including F2 crosses originating from C57BL/6J (B6J) and the BXD recombinant inbred family derived from B6J and DBA/2J. Here we demonstrate a global reduction of GABRA2 brain protein and mRNA in the B6J strain relative to other inbred strains, and identify and validate the causal mutation in B6J. The mutation is a single base pair deletion located in an intron adjacent to a splice acceptor site that only occurs in the B6J reference genome. The deletion became fixed in B6J between 1976 and 1991 and is now pervasive in many engineered lines, BXD strains generated after 1991, the Collaborative Cross, and the majority of consomic lines. Repair of the deletion using CRISPR-<i>Cas9</i>-mediated gene editing on a B6J genetic background completely restored brain levels of GABRA2 protein and mRNA. Comparison of transcript expression in hippocampus, cortex, and striatum between B6J and repaired genotypes revealed alterations in GABA-A receptor subunit expression, especially in striatum. These results suggest that naturally occurring variation in GABRA2 levels between B6J and other substrains or inbred strains may also explain strain differences in anxiety-like or alcohol and drug response traits related to striatal function. Characterization of the B6J private mutation in the <i>Gabra2</i> gene is of critical importance to molecular genetic studies in neurobiological research because this strain is widely used to generate genetically engineered mice and murine genetic populations, and is the most widely utilized strain for evaluation of anxiety-like, depression-like, pain, epilepsy, and drug response traits that may be partly modulated by GABRA2 function.", - "journal_title": "Frontiers in genetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/30984232/" - } - ], - "a763df30-51d0-49a7-ab12-8e5eca84d963": [ - { - "pub_id": "29149120", - "title": "Genomics Education: Knowledge of Nurses Across the Profession and Integration Into Practice.", - "authors": "Lisa B Aiello", - "abstract": "Since the completion of the Human Genome Project in 2003, the implications of genetics and genomics for health and illness have become clearer. All nurses, at all levels and across all specialties, must have a basic understanding of genetics and genomics to provide appropriate care. \u2029. This article provides an overview of the integration of genetics and genomics into nursing education, as well as continued barriers to nursing knowledge of genetics and genomics.\u2029. A literature review was conducted using CINAHL\u00ae, PubMed, ProQuest, and Google Scholar. Databases were reviewed for literature published from January 1962 to November 2017.\u2029. Although genetic and genomic education has been integrated into undergraduate and graduate nursing curricula, a gap exists in this knowledge among student nurses, practicing nurses, and nursing faculty.", - "journal_title": "Clinical journal of oncology nursing", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/29149120/" - } - ], - "faf00b06-9a8a-4a7f-9cf5-a0c7d99e1922": [ - { - "pub_id": "15688072", - "title": "Data integration: challenges for drug discovery.", - "authors": "David B Searls", - "abstract": "The effective integration of data and knowledge from many disparate sources will be crucial to future drug discovery. Data integration is a key element of conducting scientific investigations with modern platform technologies, managing increasingly complex discovery portfolios and processes, and fully realizing economies of scale in large enterprises. However, viewing data integration as simply an 'IT problem' underestimates the novel and serious scientific and management challenges it embodies - challenges that could require significant methodological and even cultural changes in our approach to data.", - "journal_title": "Nature reviews. Drug discovery", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/15688072/" - } - ], - "41ab0b16-b3f5-47b2-9058-abd3c4f4f662": [ - { - "pub_id": "15711545", - "title": "Complex trait analysis of gene expression uncovers polygenic and pleiotropic networks that modulate nervous system function.", - "authors": "Elissa J Chesler,Lu Lu,Siming Shou,Yanhua Qu,Jing Gu,Jintao Wang,Hui Chen Hsu,John D Mountz,Nicole E Baldwin,Michael A Langston,David W Threadgill,Kenneth F Manly,Robert W Williams", - "abstract": "Patterns of gene expression in the central nervous system are highly variable and heritable. This genetic variation among normal individuals leads to considerable structural, functional and behavioral differences. We devised a general approach to dissect genetic networks systematically across biological scale, from base pairs to behavior, using a reference population of recombinant inbred strains. We profiled gene expression using Affymetrix oligonucleotide arrays in the BXD recombinant inbred strains, for which we have extensive SNP and haplotype data. We integrated a complementary database comprising 25 years of legacy phenotypic data on these strains. Covariance among gene expression and pharmacological and behavioral traits is often highly significant, corroborates known functional relations and is often generated by common quantitative trait loci. We found that a small number of major-effect quantitative trait loci jointly modulated large sets of transcripts and classical neural phenotypes in patterns specific to each tissue. We developed new analytic and graph theoretical approaches to study shared genetic modulation of networks of traits using gene sets involved in neural synapse function as an example. We built these tools into an open web resource called WebQTL that can be used to test a broad array of hypotheses.", - "journal_title": "Nature genetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/15711545/" - } - ], - "ec5d7978-2efe-4cba-9b7e-4dddd63cc24c": [ - { - "pub_id": "19936100", - "title": "Genomic loci modulating the retinal transcriptome in wound healing.", - "authors": "F\u00e9lix R V\u00e1zquez-Chona,Lu Lu,Robert W Williams,Eldon E Geisert", - "abstract": "The present study predicts and tests genetic networks that modulate gene expression during the retinal wound-healing response. Upstream modulators and target genes were defined using meta-analysis and bioinformatic approaches. Quantitative trait loci (QTLs) for retinal acute phase genes (Vazquez-Chona et al. 2005) were defined using QTL analysis of CNS gene expression (Chesler et al. 2005). Candidate modulators were defined using computational analysis of gene and motif sequences. The effect of candidate genes on wound healing was tested using animal models of gene expression. A network of early wound-healing genes is modulated by a locus on chromosome 12. The genetic background of the locus altered the wound-healing response of the retina. The C57BL/6 allele conferred enhanced expression of neuronal marker Thy1 and heat-shock-like crystallins, whereas the DBA/2J allele correlated with greater levels of the classic marker of retinal stress, glial fibrillary acidic protein (GFAP). Id2 and Lpin1 are candidate upstream modulators as they strongly correlated with the segregation of DBA/2J and C57BL/6 alleles, and their dosage levels correlated with the enhanced expression of survival genes (Thy1 and crystallin genes). We defined a genetic network associated with the retinal acute injury response. Using genetic linkage analysis of natural transcript variation, we identified regulatory loci and can didate modulators that control transcript levels of acute phase genes. Our results support the convergence of gene expression profiling, QTL analysis, and bioinformatics as a rational approach to discover molecular pathways controlling retinal wound healing.", - "journal_title": "Gene regulation and systems biology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/19936100/" - } - ], - "3bae277a-538d-4ae7-9d57-62a254d02515": [ - { - "pub_id": "15938754", - "title": "Haplotypes at the Tas2r locus on distal chromosome 6 vary with quinine taste sensitivity in inbred mice.", - "authors": "Theodore M Nelson,Steven D Munger,John D Boughter", - "abstract": "The detection of bitter-tasting compounds by the gustatory system is thought to alert animals to the presence of potentially toxic food. Some, if not all, bitter stimuli activate specific taste receptors, the T2Rs, which are expressed in subsets of taste receptor cells on the tongue and palate. However, there is evidence for both receptor-dependent and -independent transduction mechanisms for a number of bitter stimuli, including quinine hydrochloride (QHCl) and denatonium benzoate (DB). We used brief-access behavioral taste testing of BXD/Ty recombinant inbred (RI) mouse strains to map the major quantitative trait locus (QTL) for taste sensitivity to QHCl. This QTL is restricted to a ~5 Mb interval on chromosome 6 that includes 24 genes encoding T2Rs (Tas2rs). Tas2rs at this locus display in total 307 coding region single nucleotide polymorphisms (SNPs) between the two BXD/Ty RI parental strains, C57BL/6J (quinine-sensitive) and DBA/2J (quinine insensitive); approximately 50% of these mutations are silent. Individual RI lines contain exclusively either C57BL/6J or DBA/2J Tas2r alleles at this locus, and RI lines containing C57BL/6J Tas2r alleles are more sensitive to QHCl than are lines containing DBA/2J alleles. Thus, the entire Tas2r cluster comprises a large haplotype that correlates with quinine taster status. These studies, the first using a taste-salient assay to map the major QTL for quinine taste, indicate that a T2R-dependent transduction cascade is responsible for the majority of strain variance in quinine taste sensitivity. Furthermore, the large number of polymorphisms within coding exons of the Tas2r cluster, coupled with evidence that inbred strains exhibit largely similar bitter taste phenotypes, suggest that T2R receptors are quite tolerant to variation.", - "journal_title": "BMC genetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/15938754/" - } - ], - "09d8b848-6c07-43d7-980f-eb1c8933091d": [ - { - "pub_id": "15922957", - "title": "Genetic analysis of the antibody response to AAV2 and factor IX.", - "authors": "Huang-Ge Zhang,Katherine A High,Qi Wu,PingAr Yang,Alex Schlachterman,Shaohua Yu,Nengjun Yi,Hui-Chen Hsu,John D Mountz", - "abstract": "We have analyzed the antibody response against either AAV2 or canine F.IX (cF.IX) in parental C57BL/6 (B6) and DBA/2 (D2) and 18 strains of B6 x D2 (BXD) recombinant inbred (RI) strains of mice after iv administration of AAV2-(ApoE)4/hAAT-cF.IX. There was a higher anti-AAV2 capsid response in B6 compared to D2 mice, with IgG2b being the major isotype separating the high and low responders in these two strains. In contrast, the antibody response to cF.IX was lower than the response to the AAV2 capsid and was limited to the IgG1 isotype in both strains. Genetic linkage analysis of the IgG2b anti-AAV2 antibody response in BXD RI strains revealed a significant locus at D4Mit164 (29 cM, LRS=15.3) and two suggestive loci at D6Mit16 (30.5 cM, LRS=11.2) and D17Mit187 (47.4 cM, LRS=13.1). Genetic linkage analysis of the IgG1 anti-cF.IX antibody response revealed a suggestive locus at D1Mit218 (67 cM, LRS=14.1). Significant epistatic interaction was found between two loci (D8Mit45 and D16Mit47; LOD=6.54) for anti-AAV2 and two other loci (D5Mit348 and D15Mit161; LOD=7.66) for anti-cF.IX. These results indicate that multiple genetic loci independently regulate the isotype-specific antibody response to the AAV2 capsid and the cF.IX transgene.", - "journal_title": "Molecular therapy : the journal of the American Society of Gene Therapy", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/15922957/" - } - ], - "ab1a324f-3c9c-4b41-bb1d-5d5ca216a001": [ - { - "pub_id": "16330321", - "title": "Mouse phenogenomics: the fast track to \"systems metabolism\".", - "authors": "Carmen A Argmann,Pierre Chambon,Johan Auwerx", - "abstract": "With the completion of the many genomes, genetics is positioned to meet physiology. In this review, we summarize the coming of \"systems metabolism\" in mammals through the use of the mouse, as a model system to study metabolism. Building on mouse genetics with increasingly sophisticated clinical and molecular phenotyping strategies has enabled scientists to now tackle complex biomedical questions, such as those related to the pathogenesis of the common metabolic disorders. The ultimate goal of such strategies will be to mimic human metabolism with the click of a mouse.", - "journal_title": "Cell metabolism", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/16330321/" - } - ], - "a402d4b4-d3a5-4809-b68c-932c6885e9f3": [ - { - "pub_id": "16380229", - "title": "Type 2 autoimmune hepatitis murine model: the influence of genetic background in disease development.", - "authors": "Pascal Lapierre,Kathie B\u00e9land,Idriss Djilali-Saiah,Fernando Alvarez", - "abstract": "Genetic predisposition is recognized as an important factor for the development of autoimmune hepatitis (AIH). To assess the potential contribution of MHC and non-MHC genes, type 2 AIH was reproduced in three mice strains, taking advantage of their different genetic makeup with regard to MHC and non-MHC genes. Mice (C57BL/6, 129/Sv and BALB/c) were DNA vaccinated with a pCMV-CTLA4-CYP2D6-FTCD plasmid coding for the extracellular region of CTLA-4 and for the antigenic region of the CYP2D6 and FTCD, and with pCMV-IL12. ALT and total IgG levels, liver histology, FACS analysis and liver T-cell cytotoxicity assays were monitored up to 8 months post-injection. C57BL/6 mice showed elevated serum ALT levels, autoantibodies, antigen-specific cytotoxic T-cells and lobular and periportal inflammatory infiltrate. The 129/Sv mice showed slightly elevated ALT levels, sparse liver lobular infiltrate and cytotoxic T-cells. The BALB/c mice showed no liver inflammation. All mice had elevated total serum IgG levels. This murine model of type 2 AIH shows that MHC and non-MHC genes contribute to the susceptibility to autoimmune hepatitis. The understanding of the genetic determinants implicated in AIH development will be a major advance in the study of its pathogenesis and could lead to a better diagnostic approach and preventive strategies.", - "journal_title": "Journal of autoimmunity", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/16380229/" - } - ], - "56304081-0426-453f-b77b-ca2ef02a125f": [ - { - "pub_id": "16239464", - "title": "Systems biology. Less is more in modeling large genetic networks.", - "authors": "Stefan Bornholdt", - "abstract": "", - "journal_title": "Science (New York, N.Y.)", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/16239464/" - } - ], - "e3339afd-cf6d-4972-8e7a-d94e692ec630": [ - { - "pub_id": "15585274", - "title": "An investigation on the physicochemical properties of chitosan/DNA polyelectrolyte complexes.", - "authors": "Wenguang Liu,Shujun Sun,Zhiqiang Cao,Xin Zhang,Kangde Yao,William W Lu,K D K Luk", - "abstract": "In this work, to eliminate the effect of the hydrophobicity of N-acetyl groups in chitosan on the interaction between chitosan and DNA, a water soluble chitosan with molecular weight of 5000 and deacetylated degree of 99% was selected to complex with DNA at varied charged ratios. The physicochemical properties of chitoplexes were investigated by means of FTIR, circular dichroism (CD), static fluorescence spectroscopy, and atomic force microscopy (AFM). The results indicated that upon interacting with chitosan, the DNA molecules saved a B conformation, and the binding affinity of chitosan to DNA was dependent on pH of media. At pH 5.5, highly charged chitosan had a strong binding affinity with DNA; whereas in pH 12.0 medium, only weak interactions existed. The CD spectra of Hoechst 33258 competitive displacement revealed that chitosan was partially bound to the minor groove of DNA. The morphology of chitosan/DNA complexes was strongly dependent upon the charge ratios. At charge ratio (+/-) of 1:4, not all DNA could be entrapped in the complex; at ratio of 8:1, the spherical complexes with mean size of nanoscale were formed without free DNA, but no typical toroid patterns were observed, which might stem from the strong compact of DNA caused by highly charged chitosan. It was supposed that the strong interaction of chitosan with DNA possibly prevented gene unpacking from chitosan vector, consequently restraining gene expression in nucleus.", - "journal_title": "Biomaterials", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/15585274/" - } - ], - "d0d6c5d6-36c6-45f1-9107-cef95df83bb3": [ - { - "pub_id": "15552964", - "title": "[Approach to depressogenic genes from genetic analyses of animal models].", - "authors": "Takeo Yoshikawa", - "abstract": "Human depression or mood disorder is defined as a complex disease, making positional cloning of susceptibility genes a formidable task. We have undertaken genetic analyses of three different animal models for depression, comparing our results with advanced database resources. We first performed quantitative trait loci (QTL) analysis on two mouse models of \"despair\", namely, the forced swim test (FST) and tail suspension test (TST), and detected multiple chromosomal loci that control immobility time in these tests. Since one QTL detected on mouse chromosome 11 harbors the GABA A receptor subunit genes, we tested these genes for association in human mood disorder patients. We obtained significant associations of the alpha 1 and alpha 6 subunit genes with the disease, particularly in females. This result was striking, because we had previously detected an epistatic interaction between mouse chromosomes 11 and X that regulates immobility time in these animals. Next, we performed genome-wide expression analyses using a rat model of depression, learned helplessness (LH). We found that in the frontal cortex of LH rats, a disease implicated region, the LIM kinase 1 gene (Limk 1) showed greatest alteration, in this case down-regulation. By combining data from the QTL analysis of FST/TST and DNA microarray analysis of mouse frontal cortex, we identified adenylyl cyclase-associated CAP protein 1 (Cap 1) as another candidate gene for depression susceptibility. Both Limk 1 and Cap 1 are key players in the modulation of actin G-F conversion. In summary, our current study using animal models suggests disturbances of GABAergic neurotransmission and actin turnover as potential pathophysiologies for mood disorder.", - "journal_title": "Seishin shinkeigaku zasshi = Psychiatria et neurologia Japonica", - "languages": [ - "jpn" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/15552964/" - } - ], - "80eb54fe-0d83-4300-9fba-e17ce5d1e5b4": [ - { - "pub_id": "16226337", - "title": "Bioinformatics toolbox for narrowing rodent quantitative trait loci.", - "authors": "Keith DiPetrillo,Xiaosong Wang,Ioannis M Stylianou,Beverly Paigen", - "abstract": "Quantitative trait locus (QTL) analysis is a powerful method for localizing disease genes, but identifying the causal gene remains difficult. Rodent models of disease facilitate QTL gene identification, and causal genes underlying rodent QTL are often associated with the corresponding human diseases. Recently developed bioinformatics methods, including comparative genomics, combined cross analysis, interval-specific and genome-wide haplotype analysis, followed by sequence and expression analysis, each facilitated by public databases, provide new tools for narrowing rodent QTLs. Here we discuss each tool, illustrate its application and generate a bioinformatics strategy for narrowing QTLs. Combining these bioinformatics tools with classical experimental methods should accelerate QTL gene identification.", - "journal_title": "Trends in genetics : TIG", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/16226337/" - } - ], - "5043c845-5d0d-4821-992b-ee5fa043c046": [ - { - "pub_id": "15953654", - "title": "Gene array profiling of large hypothalamic CNS regions in lactating and randomly cycling virgin mice.", - "authors": "Stephen C Gammie,Nina S Hasen,Tarif A Awad,Anthony P Auger,Heather M Jessen,Jules B Panksepp,Anne M Bronikowski", - "abstract": "A dramatic example of neuronal and physiological plasticity in adult mammals occurs during the transition from a non-maternal to a maternal, lactating state. In this study, we compared gene expression within a large continuous region of the CNS involved in maternal behaviors (hypothalamus, preoptic regions, and nucleus accumbens) between lactating (L) (postpartum Day 7) and randomly cycling virgin (V) outbred mice. Using high-density oligonucleotide arrays representing 11,904 genes, two statistical algorithms were used to identify significant differences in gene expression: robust multiarray (P < 0.001) (n = 92 genes) and significance analysis of microarrays using a 10% false discover rate (n = 114 genes). 27 common genes were identified as significant using both techniques. A subset of genes (n = 5) were selected and examined by real-time PCR. Our findings were consistent with previous published work. For example, neuropeptide Y (NPY) and proenkephalin were elevated in L mice, whereas POMC was decreased. Increased levels of NPY Y2 receptor and polo-like kinase and decreased levels of endothelin receptor type b in L mice are examples of novel gene expression changes not previously identified. Expression differences occurred in broad classes. Together, our findings provide possible new material on gene expression changes that may support maternal behaviors. The advantages and drawbacks of sampling large CNS regions using arrays are discussed.", - "journal_title": "Brain research. Molecular brain research", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/15953654/" - } - ], - "a6924cbc-a767-49f8-b06e-4725ba2a6198": [ - { - "pub_id": "17849199", - "title": "Genes, environment, and dyslexia. The 2005 Norman Geschwind Memorial Lecture.", - "authors": "Richard K Olson", - "abstract": "This article presents an overview of some methods and results from our continuing studies of genetic and environmental influences on dyslexia, and on individual differences across the normal range that have been conducted over the past 25 years in the Colorado Learning Disabilities Research Center (CLDRC) and in related projects. CLDRC investigators compare the similarities of identical twin pairs who share all their genes and fraternal twins who share half their segregating genes to assess the balance of genetic, shared family environment, and nonshared environment influences on dyslexia and on individual differences across the normal range. We have learned that among the children we have studied in Colorado, group deficits in reading (dyslexia) and individual differences in reading across the normal range are primarily due to genetic influences, and these genetic influences are often shared with some of the same genetic influences on deficits and individual differences in language and ADHD. We have also learned from our molecular-genetic linkage studies that there are regions on several chromosomes likely to contain genes that influence dyslexia. Several specific genes within these regions have been tentatively identified through molecular-genetic association analyses, but much more research is needed to understand the pathways among specific genes, regions of noncoding DNA that regulate the activity of those genes, the brain, and dyslexia. I conclude with a discussion of our research on individual differences in early reading development, on the role of early learning constraints in dyslexia, and on how genetic influences are expressed through their interaction and correlation with the environment.", - "journal_title": "Annals of dyslexia", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/17849199/" - } - ], - "a3b95558-785a-4338-a7d4-798edd26995b": [ - { - "pub_id": "15895553", - "title": "The Anp32 family of proteins containing leucine-rich repeats.", - "authors": "Antoni Matilla,Martin Radrizzani", - "abstract": "Herein we describe the characteristic features of the Anp32 family represented by the cerebellar leucine-rich repeat protein (Lanp) and the cerebellar developmental-regulated protein 1 (Cpd1). The Anp32 family consists of 32 evolutionarily-conserved proteins and is included within the superfamily of leucine-rich repeat (LRR) proteins characterized by the presence of tandem arrays of a LRR, a structural motif implicated in the mediation of protein-protein interactions. We describe three novel human Anp32 proteins, reveal the evolutionary relationships of the members of the Anp32 family, provide insights into their biochemical and structural properties, and review their macromolecular interactions, substrate specificities, tissue distribution/expression patterns, and physiological and pathological roles. Recent findings indicate a conserved role of members of the Anp32 family during evolution in the modulation of cell signalling and transduction of gene expression to regulate the morphology and dynamics of the cytoskeleton, cell adhesion, neural development or cerebellar morphogenesis.", - "journal_title": "Cerebellum (London, England)", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/15895553/" - } - ], - "bbf4a07f-b30d-4bd6-ba32-16ad470231b1": [ - { - "pub_id": "15613385", - "title": "Methodological aspects of the genetic dissection of gene expression.", - "authors": "O Carlborg,D J De Koning,K F Manly,E Chesler,R W Williams,C S Haley", - "abstract": "Dissection of the genetics underlying gene expression utilizes techniques from microarray analyses as well as quantitative trait loci (QTL) mapping. Available QLT mapping methods are not tailored for the highly automated analyses required to deal with the thousand of gene transcripts encountered in the mapping of QTL affecting gene expression (sometimes referred to as eQTL). This report focuses on the adaptation of QTL mapping methodology to perform automated mapping of QTL affecting gene expression. The analyses of expression data on > 12,000 gene transcripts in BXD recombinant inbred mice found, on average, 629 QTL exceeding the genome-wide 5% threshold. Using additional information on trait repeatabilities and QTL location, 168 of these were classified as 'high confidence' QTL. Current sample sizes of genetical genomics studies make it possible to detect a reasonable number of QTL using simple genetic models, but considerably larger studies are needed to evaluate more complex genetic models. After extensive analyses of real data and additional simulated data (altogether > 300,000 genome scans) we make the following recommendations for detection of QTL for gene expression: (1) For populations with an unbalanced number of replicates on each genotype, weighted least squares should be preferred above ordinary least squares. Weights can be based on repeatability of the trait and the number of replicates. (2) A genome scan based on multiple marker information but analysing only at marker locations is a good approximation to a full interval mapping procedure. (3) Significance testing should be based on empirical genome-wide significance thresholds that are derived for each trait separately. (4) The significant QTL can be separated into high and low confidence QTL using a false discovery rate that incorporates prior information such as transcript repeatabilities and co-localization of gene-transcripts and QTL. (5) Including observations on the founder lines in the QTL analysis should be avoided as it inflates the test statistic and increases the Type I error. (6) To increase the computational efficiency of the study, use of parallel computing is advised. These recommendations are summarized in a possible strategy for mapping of QTL in a least squares framework. The software used for this study is available on request from the authors.", - "journal_title": "Bioinformatics (Oxford, England)", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/15613385/" - } - ], - "83072278-19ab-4b08-9892-6dec72d766d6": [ - { - "pub_id": "16284411", - "title": "The impact of neuroinformatics.", - "authors": "David N Kennedy", - "abstract": "", - "journal_title": "Neuroinformatics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/16284411/" - } - ], - "c2efeeee-f71a-4292-8240-80a4518f820d": [ - { - "pub_id": "16085706", - "title": "Using progenitor strain information to identify quantitative trait nucleotides in outbred mice.", - "authors": "B Yalcin,J Flint,R Mott", - "abstract": "We have developed a fast and economical strategy for dissecting the genetic architecture of quantitative trait loci at a molecular level. The method uses two pieces of information: mapping data from crosses that involve more than two inbred strains and sequence variants in the progenitor strains within the interval containing a quantitative trait locus (QTL). By testing whether the strain distribution pattern in the progenitor strains is consistent with the observed genetic effect of the QTL we can assign a probability that any sequence variant is a quantitative trait nucleotide (QTN). It is not necessary to genotype the animals except at a skeleton of markers; the genotypes at all other polymorphisms are estimated by a multipoint analysis. We apply the method to a 4.8-Mb region on mouse chromosome 1 that contains a QTL influencing anxiety segregating in a heterogeneous stock and show that, under the assumption that a single QTN is present and lies in a region conserved between the human and mouse genomes, it is possible to reduce the number of variants likely to be the quantitative trait nucleotide from many thousands to <20.", - "journal_title": "Genetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/16085706/" - } - ], - "6f44583d-c019-4a89-8779-784d8c3894d8": [ - { - "pub_id": "16261418", - "title": "Genetics of body weight in the LXS recombinant inbred mouse strains.", - "authors": "Beth Bennett,Phyllis J Carosone-Link,Lu Lu,Elissa J Chesler,Thomas E Johnson", - "abstract": "This is the first phenotypic analysis of 75 new recombinant inbred (RI) strains derived from ILS and ISS progenitors. We analyzed body weight in two independent cohorts of female mice at various ages and in males at 60 days. Body weight is a complex trait which has been mapped in numerous crosses in rodents. The LXS RI strains displayed a large range of weights, transgressing those of the inbred progenitors, supporting the utility of this large panel for mapping traits not selected in the progenitors. Numerous QTLs for body weight mapped in single- and multilocus scans. We assessed replication between these and previously reported QTLs based on overlapping confidence intervals of published QTLs for body weight at 60 days and used meta-analyses to determine combined p values for three QTL regions located on Chromosomes 4, 5, and 11. Strain distribution patterns of microsatellite marker genotypes, weight, and other phenotypes are available on WebQTL (http://www.webqtl.org/search.html ) and allow genetic mapping of any heritable quantitative phenotype measured in these strains. We report one such analysis, correlating brain and body weights. Large reference panels of RI strains, such as the LXS, are invaluable for identifying genetic correlations, GXE (Gene X Environment) interactions, and replicating previously identified QTLs.", - "journal_title": "Mammalian genome : official journal of the International Mammalian Genome Society", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/16261418/" - } - ], - "3cafb9e7-b3d9-4e8e-a727-da79282d2b14": [ - { - "pub_id": "16240411", - "title": "Applications of gene targeting technology to mental retardation and developmental disability research.", - "authors": "Aurea F Pimenta,Pat Levitt", - "abstract": "The human and mouse genome projects elucidated the sequence and position map of innumerous genes expressed in the central nervous system (CNS), advancing our ability to manipulate these sequences and create models to investigate regulation of gene expression and function. In this article, we reviewed gene targeting methodologies with emphasis on applications to CNS development and neurodevelopmental disorders.", - "journal_title": "Mental retardation and developmental disabilities research reviews", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/16240411/" - } - ], - "903e9615-c329-48be-9547-386a00f2dd94": [ - { - "pub_id": "19875164", - "title": "Diabetes in Asia.", - "authors": "Ambady Ramachandran,Ronald Ching Wan Ma,Chamukuttan Snehalatha", - "abstract": "Prevalence of type 2 diabetes has rapidly increased in native and migrant Asian populations. Diabetes develops at a younger age in Asian populations than in white populations, hence the morbidity and mortality associated with the disease and its complications are also common in young Asian people. The young age of these populations and the high rates of cardiovascular risk factors seen in Asian people substantially increase lifetime risk of cardiovascular disease. Several distinctive features are apparent in pathogenetic factors for diabetes and their thresholds in Asian populations. The economic burden due to diabetes at personal, societal, and national levels is huge. National strategies to raise public awareness about the disease and to improve standard of care and implementation of programmes for primary prevention are urgently needed.", - "journal_title": "Lancet (London, England)", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/19875164/" - } - ], - "ddb46b49-97a2-4d06-951b-9fcab8278599": [ - { - "pub_id": "15705776", - "title": "Genetic analysis of the hypothalamic corticotropin-releasing factor system.", - "authors": "Steven J Garlow,Ericka Boone,Wei Li,Michael J Owens,Charles B Nemeroff", - "abstract": "The goal of this study was to use BxD recombinant inbred mice to search for genes that control the hypothalamic corticotrophin-releasing factor (CRF) system. The specific phenotype that was measured was abundance of transcripts that encode CRF, CRF receptor (Crf-R1), CRF binding protein, and arginine vasopressin (AVP) in total hypothalamic RNA. The strain distribution patterns for the transcript abundances for each target were continuously distributed, consistent with these being quantitative traits. Marker regression and interval mapping revealed associations with quantitative trait loci (QTL) for CRF transcript abundance on chromosome 1 (at 89.2 cM), chromosome 12 (between 54-58 cM), and chromosome 13 (between 26-30 cM); for Crf-R1 transcript abundance on chromosome 7 (at 1.5 cM), chromosome 12 (at 37 cM), and chromosome X (at 30 cM); for CRF binding protein transcript abundance on chromosome 7 (at 48.5 cM), chromosome 8 (at 65 cM), and chromosome 12 (at 19 cM); and for AVP transcript abundance on chromosome 7 (at 1 cM), chromosome 12 (at 13 cM), and chromosome 13 (at 45 cM). The transcript abundance QTL were not linked to their respective structural genes. Interval mapping on chromosome 7 reveals substantial overlap between QTL that control AVP and Crf-R1 transcript abundance and on chromosome 12 for QTL that control CRF and Crf-R1, which may indicate loci that coordinate regulation of the CRF system. There are QTL for all four targets on chromosome 12. There are a number of neurodevelopmental genes in very close proximity to the transcript abundance QTL that are potential candidate genes.", - "journal_title": "Endocrinology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/15705776/" - } - ], - "60e08224-f0e8-409c-b00a-b9e7358d3548": [ - { - "pub_id": "16205357", - "title": "Cerebellar gene expression profiling and eQTL analysis in inbred mouse strains selected for ethanol sensitivity.", - "authors": "Erik J MacLaren,James M Sikela", - "abstract": "Inbred Long-Sleep (ILS) and Inbred Short-Sleep (ISS) mice exhibit striking differences in a number of alcohol and drug related behaviors. This study examined the expression levels of more than 39,000 transcripts in these strains in the cerebellum, a major target of ethanol's actions in the CNS, to find differentially expressed (DE) candidate genes for these phenotypes. Genes that were differentially expressed between the strains were identified using oligonucleotide arrays as well as complimentary DNA arrays. Sequence alignment was used to locate DE genes in the mouse genome assembly. In silico expression QTL (eQTL) mapping was used to identify chromosomal regions likely to control the transcription level of DE genes, and the EASE program identified overrepresented functional themes. The genomic region immediately upstream of the cyclase associated protein homolog 1 (Cap1) gene was directly sequenced from PCR products. Nearly 300 genes were identified as differentially expressed between the cerebella of ILS and ISS. These genes and their corresponding eQTLs map to genomic regions linked to several phenotypes that differ between the ILS and ISS strains, including ethanol preference and cocaine-induced locomotor activation on Chromosomes 4 and 7 respectively. Eight genes were cross-platform validated, four of which are more highly expressed in ILS cerebellum. Three SNPs, one of which disrupts a predicted Sp1 binding site, were found in the upstream region of Cap1, a strong candidate for influencing ethanol phenotypes. Many of these DE genes are candidates to influence ethanol and drug regulated phenotypes because they either map to ethanol related QTLs in the genome or are linked to them through eQTL mapping. Genes involved in calcium ion binding and transcriptional regulation are overrepresented and therefore these gene classes may influence ethanol behaviors in mice and humans.", - "journal_title": "Alcoholism, clinical and experimental research", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/16205357/" - } - ], - "a7aa1a3e-4681-4596-b9d0-384dbb260857": [ - { - "pub_id": "16475030", - "title": "Metastasis predictive signature profiles pre-exist in normal tissues.", - "authors": "Haiyan Yang,Nigel Crawford,Luanne Lukes,Richard Finney,Mindy Lancaster,Kent W Hunter", - "abstract": "Previous studies from our laboratory have demonstrated that metastatic propensity is significantly influenced by the genetic background upon which tumors arise. We have also established that human gene expression profiles predictive of metastasis are not only present in mouse tumors with both high and low metastatic capacity, but also correlate with genetic background. These results suggest that human metastasis-predictive gene expression signatures may be significantly driven by genetic background, rather than acquired somatic mutations. To test this hypothesis, gene expression profiling was performed on inbred mouse strains with significantly different metastatic efficiencies. Analysis of previously described human metastasis signature gene expression patterns in normal tissues permitted accurate categorization of high or low metastatic mouse genotypes. Furthermore, prospective identification of animals at high risk of metastasis was achieved by using mass spectrometry to characterize salivary peptide polymorphisms in a genetically heterogeneous population. These results strongly support the role of constitutional genetic variation in modulation of metastatic efficiency and suggest that predictive signature profiles could be developed from normal tissues in humans. The ability to identify those individuals at high risk of disseminated disease at the time of clinical manifestation of a primary cancer could have a significant impact on cancer management.", - "journal_title": "Clinical & experimental metastasis", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/16475030/" - } - ], - "62a4ee72-b305-4027-be68-1c156fb7adbe": [ - { - "pub_id": "15940293", - "title": "Genetic tests of biologic systems in affective disorders.", - "authors": "E Hattori,C Liu,H Zhu,E S Gershon", - "abstract": "To liberate candidate gene analyses from criticisms of inexhaustiveness of examination of specific candidate genes, or incompleteness in the choice of candidate genes to study for specific neurobiological pathways, study of sizeable sets of genes pertinent to each putative pathophysiological pathway is required. For many years, genes have been tested in a 'one by one' manner for association with major affective disorders, primarily bipolar illness. However, it is conceivable that not individual genes but abnormalities in several genes within a system or in several neuronal, neural, or hormonal systems are implicated in the functional hypotheses for etiology of affective disorders. Compilation of candidate genes for entire pathways is a challenge, but can reasonably be carried out for the major affective disorders as discussed here. We present here five groupings of genes implicated by neuropharmacological and other evidence, which suggest 252 candidate genes worth examining. Inexhaustiveness of gene interrogation would apply to many studies in which only one polymorphism per gene is analyzed. In contrast to whole-genome association studies, a study of a limited number of candidate genes can readily exploit information on genomic sequence variations obtained from databases and/or resequencing, and has an advantage of not having the complication of an extremely stringent statistical criterion for association.", - "journal_title": "Molecular psychiatry", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/15940293/" - } - ], - "7ab1ee39-84b7-4def-91d6-5d79c4d46598": [ - { - "pub_id": "15967025", - "title": "Inbred mouse strains C57BL/6J and DBA/2J vary in sensitivity to a subset of bitter stimuli.", - "authors": "John D Boughter,Sandeep Raghow,Theodore M Nelson,Steven D Munger", - "abstract": "Common inbred mouse strains are genotypically diverse, but it is still poorly understood how this diversity relates to specific differences in behavior. To identify quantitative trait genes that influence taste behavior differences, it is critical to utilize assays that exclusively measure the contribution of orosensory cues. With a few exceptions, previous characterizations of behavioral taste sensitivity in inbred mouse strains have generally measured consumption, which can be confounded by post-ingestive effects. Here, we used a taste-salient brief-access procedure to measure taste sensitivity to eight stimuli characterized as bitter or aversive in C57BL/6J (B6) and DBA/2J (D2) mice. B6 mice were more sensitive than D2 mice to a subset of bitter stimuli, including quinine hydrochloride (QHCl), 6-n-propylthiouracil (PROP), and MgCl2. D2 mice were more sensitive than B6 mice to the bitter stimulus raffinose undecaacetate (RUA). These strains did not differ in sensitivity to cycloheximide (CYX), denatonium benzoate (DB), KCl or HCl. B6-D2 taste sensitivity differences indicate that differences in consumption of QHCl, PROP, MgCl2 and RUA are based on immediate orosensory cues, not post-ingestive effects. The absence of a strain difference for CYX suggests that polymorphisms in a T2R-type taste receptor shown to be differentially sensitive to CYX in vitro are unlikely to differentially contribute to the CYX behavioral response in vivo. The results of these studies point to the utility of these common mouse strains and their associated resources for investigation into the genetic mechanisms of taste.", - "journal_title": "BMC genetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/15967025/" - } - ], - "54881d38-e18b-41a8-90d5-b1f990859811": [ - { - "pub_id": "16288200", - "title": "Genetic networks controlling retinal injury.", - "authors": "Felix R Vazquez-Chona,Amna N Khan,Chun K Chan,Anthony N Moore,Pramod K Dash,M Rosario Hernandez,Lu Lu,Elissa J Chesler,Kenneth F Manly,Robert W Williams,Eldon E Geisert", - "abstract": "The present study defines genomic loci underlying coordinate changes in gene expression following retinal injury. A group of acute phase genes expressed in diverse nervous system tissues was defined by combining microarray results from injury studies from rat retina, brain, and spinal cord. Genomic loci regulating the brain expression of acute phase genes were identified using a panel of BXD recombinant inbred (RI) mouse strains. Candidate upstream regulators within a locus were defined using single nucleotide polymorphism databases and promoter motif databases. The acute phase response of rat retina, brain, and spinal cord was dominated by transcription factors. Three genomic loci control transcript expression of acute phase genes in brains of BXD RI mouse strains. One locus was identified on chromosome 12 and was highly correlated with the expression of classic acute phase genes. Within the locus we identified the inhibitor of DNA binding 2 (Id2) as a candidate upstream regulator. Id2 was upregulated as an acute phase transcript in injury models of rat retina, brain, and spinal cord. We defined a group of transcriptional changes associated with the retinal acute injury response. Using genetic linkage analysis of natural transcript variation, we identified regulatory loci and candidate regulators that control transcript levels of acute phase genes.", - "journal_title": "Molecular vision", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/16288200/" - } - ], - "eee1f302-d85d-4445-8845-772c46ed7821": [ - { - "pub_id": "30355154", - "title": "Clinical Metagenomic Next-Generation Sequencing for Pathogen Detection.", - "authors": "Wei Gu,Steve Miller,Charles Y Chiu", - "abstract": "Nearly all infectious agents contain DNA or RNA genomes, making sequencing an attractive approach for pathogen detection. The cost of high-throughput or next-generation sequencing has been reduced by several orders of magnitude since its advent in 2004, and it has emerged as an enabling technological platform for the detection and taxonomic characterization of microorganisms in clinical samples from patients. This review focuses on the application of untargeted metagenomic next-generation sequencing to the clinical diagnosis of infectious diseases, particularly in areas in which conventional diagnostic approaches have limitations. The review covers ( a) next-generation sequencing technologies and common platforms, ( b) next-generation sequencing assay workflows in the clinical microbiology laboratory, ( c) bioinformatics analysis of metagenomic next-generation sequencing data, ( d) validation and use of metagenomic next-generation sequencing for diagnosing infectious diseases, and ( e) significant case reports and studies in this area. Next-generation sequencing is a new technology that has the promise to enhance our ability to diagnose, interrogate, and track infectious diseases.", - "journal_title": "Annual review of pathology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/30355154/" - } - ], - "159bdc9a-8d2f-4ada-81b4-2184cb385820": [ - { - "pub_id": "16416085", - "title": "Meeting report for the 4th annual Complex Trait Consortium meeting: from QTLs to systems genetics.", - "authors": "David W Threadgill", - "abstract": "The fourth annual meeting of the Complex Trait Consortium (CTC) was held in Groningen, the Netherlands on June 26-29, 2005. This meeting, which set a new attendance record, followed three previous and highly successful meetings. The focus at this meeting was on continued resource development and the exiting new field of systems genetics, the integration and anchoring of multi-dimensional data-types to underlying genetic variation. A new aspect at the meeting was the three-minute, 'come see my poster' presentations that generated significant interaction at the poster sessions. If the 2005 meeting is an indicator of things to come, future meetings promise to offer even more exciting research efforts to integrate high-throughput biological measurements with genetic variation to unravel the mechanisms responsible for inter-individual variation.", - "journal_title": "Mammalian genome : official journal of the International Mammalian Genome Society", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/16416085/" - } - ], - "8dad24f7-b658-44fa-af65-6f33db69c15a": [ - { - "pub_id": "15683449", - "title": "Genetic segregation of spontaneous erosive arthritis and generalized autoimmune disease in the BXD2 recombinant inbred strain of mice.", - "authors": "J D Mountz,P Yang,Q Wu,J Zhou,A Tousson,A Fitzgerald,J Allen,X Wang,S Cartner,W E Grizzle,N Yi,L Lu,R W Williams,H-C Hsu", - "abstract": "The BXD2 strain of mice is one of approximately 80 BXD recombinant inbred (RI) mouse strains derived from an intercross between C57BL/6J (B6) and DBA/2J (D2) strains. We have discovered that adult BXD2 mice spontaneously develop generalized autoimmune disease, including glomerulonephritis (GN), increased serum titres of rheumatoid factor (RF) and anti-DNA antibody, and a spontaneous erosive arthritis characterized by mononuclear cell infiltration, synovial hyperplasia, and bone and cartilage erosion. The features of lupus and arthritis developed by the BXD2 mice segregate in F2 mice generated by crossing BXD2 mice with the parental B6 and D2 strains. Genetic linkage analysis of the serum levels of anti-DNA and RF by using the BXD RI strains shows that the serum titers of anti-DNA and RF were influenced by a genetic locus on mouse chromosome (Chr) 2 near the marker D2Mit412 (78 cm, 163 Mb) and on Chr 4 near D4Mit146 (53.6 cm, 109 Mb), respectively. Both loci are close to the B-cell hyperactivity, lupus or GN susceptibility loci that have been identified previously. The results of our study suggest that the BXD2 strain of mice is a novel model for complex autoimmune disease that will be useful in identifying the mechanisms critical for the immunopathogenesis and genetic segregation of lupus and erosive arthritis.", - "journal_title": "Scandinavian journal of immunology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/15683449/" - } - ], - "2dfc2b82-b8eb-4e73-957a-0ea8a4401a84": [ - { - "pub_id": "16174757", - "title": "Genetic deletion of Cdc42GAP reveals a role of Cdc42 in erythropoiesis and hematopoietic stem/progenitor cell survival, adhesion, and engraftment.", - "authors": "Lei Wang,Linda Yang,Marie-Dominique Filippi,David A Williams,Yi Zheng", - "abstract": "Rho family GTPases are key signal transducers in cell regulation. Although a body of literature has implicated the Rho family members Rac1 and Rac2 in multiple hematopoietic-cell functions, the role of Cdc42 in hematopoiesis remains unclear. Here we have examined the hematopoietic properties and the hematopoietic stem/progenitor cell (HSP) functions of gene-targeted mice carrying null alleles of cdc42gap, a negative regulator of Cdc42. The Cdc42GAP-/- fetal liver and bone marrow cells showed a 3-fold increase in Cdc42 activity but normal Rac and RhoA activities, indicating that Cdc42GAP knockout resulted in a gain of Cdc42 activity in the hematopoietic tissues. Cdc42GAP-/- mice were anemic. The cellularity of fetal liver and bone marrow, the number and composition percentage of HSPs, and the erythroid blast-forming unit and colony-forming unit (BFU-E/CFU-E) activities were significantly reduced in the homozygous mice. The decrease in HSP number was associated with increased apoptosis of the Cdc42GAP-/- HSPs and the activation of JNK-mediated apoptotic machinery. Moreover, homozygous HSPs showed impaired cortical F-actin assembly, deficiency in adhesion and migration, and defective engraftment. These results provide evidence that Cdc42 activity is important for erythropoiesis and for multiple HSP functions, including survival, adhesion, and engraftment.", - "journal_title": "Blood", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/16174757/" - } - ], - "8244e2c7-d48d-4a2a-bd89-339e6d580d12": [ - { - "pub_id": "16118460", - "title": "Genetic studies to identify hepatic fibrosis genes and SNPs in human populations.", - "authors": "Christopher Paul Day", - "abstract": "Increasing evidence suggests that non-sex-linked genetic factors play a role in determining both susceptibility to, and progression of, liver fibrosis. The elucidation of these factors will have many potential benefits in the management of patients with chronic liver disease. A variety of approaches can be used to look for genetic factors playing a role in liver fibrosis. In the future, genome-wide single nucleotide polymorphism (SNP) scanning of cases and controls may become feasible; however, to date, studies have relied on candidate-gene, case-control, allele-association methodology. This section will focus on the design and interpretation of case-control association studies in liver disease using non-alcoholic fatty liver disease (NAFLD) to illustrate the key issues and potential pitfalls of this approach.", - "journal_title": "Methods in molecular medicine", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/16118460/" - } - ], - "0c732155-1349-41d1-9f72-fa98cb6f1466": [ - { - "pub_id": "16054724", - "title": "Cationic lipid saturation influences intracellular delivery of encapsulated nucleic acids.", - "authors": "James Heyes,Lorne Palmer,Kaz Bremner,Ian MacLachlan", - "abstract": "An analogous series of cationic lipids (1,2-distearyloxy-N,N-dimethyl-3-aminopropane (DSDMA), 1,2-dioleyloxy-N,N-dimethyl-3-aminopropane (DODMA), 1,2-dilinoleyloxy-N,N-dimethyl-3-aminopropane (DLinDMA) and 1,2-dilinolenyloxy-N,N-dimethyl-3-aminopropane (DLenDMA)) possessing 0, 1, 2 or 3 double bonds per alkyl chain respectively, was synthesized to determine the correlation between lipid saturation, fusogenicity and efficiency of intracellular nucleic acid delivery. 31P-NMR analysis suggests that as saturation increases, from 2 to 0 double bonds, lamellar (L(alpha)) to reversed hexagonal (H(II)) phase transition temperature increases, indicating decreasing fusogenicity. This trend is largely reflected by the efficiency of gene silencing observed in vitro when the lipids are formulated as Stable Nucleic Acid Lipid Particles (SNALPs) encapsulating small inhibitory RNA (siRNA). Uptake experiments suggest that despite their lower gene silencing efficiency, the less fusogenic particles are more readily internalized by cells. Microscopic visualization of fluorescently labelled siRNA uptake was supported by quantitative data acquired using radiolabelled preparations. Since electrostatic binding is a precursor to uptake, the pKa of each cationic lipid was determined. The results support a transfection model in which endosomal release, mediated by fusion with the endosomal membrane, results in cytoplasmic translocation of the nucleic acid payload.", - "journal_title": "Journal of controlled release : official journal of the Controlled Release Society", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/16054724/" - } - ], - "2f6601d5-3f89-478e-9015-b45ea2daaf20": [ - { - "pub_id": "15790857", - "title": "Noise propagation in gene networks.", - "authors": "Juan M Pedraza,Alexander van Oudenaarden", - "abstract": "Accurately predicting noise propagation in gene networks is crucial for understanding signal fidelity in natural networks and designing noise-tolerant gene circuits. To quantify how noise propagates through gene networks, we measured expression correlations between genes in single cells. We found that noise in a gene was determined by its intrinsic fluctuations, transmitted noise from upstream genes, and global noise affecting all genes. A model was developed that explains the complex behavior exhibited by the correlations and reveals the dominant noise sources. The model successfully predicts the correlations as the network is systematically perturbed. This approach provides a step toward understanding and manipulating noise propagation in more complex gene networks.", - "journal_title": "Science (New York, N.Y.)", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/15790857/" - } - ], - "36a721f2-6f53-4574-b4cb-4e631c680a99": [ - { - "pub_id": "32702710", - "title": "Calmodulin-binding transcription activator (CAMTA) genes family: Genome-wide survey and phylogenetic analysis in flax (Linum usitatissimum).", - "authors": "Essa Ali,Mohammad Ammar Raza,Ming Cai,Nazim Hussain,Ahmad Naeem Shahzad,Mubshar Hussain,Murtaza Ali,Syed Asad Hussain Bukhari,Peilong Sun", - "abstract": "Flax (Linum usitatissimum) is a member of family linaceae with annual growth habit. It is included among those crops which were domesticated very early and has been used in development related studies as a model plant. In plants, Calmodulin-binding transcription activators (CAMTAs) comprise a unique set of Calmodulin-binding proteins. To elucidate the transport mechanism of secondary metabolites in flax, a genome-based study on these transporters was performed. The current investigation identified nine CAMTAs proteins, classified into three categories during phylogenetic analysis. Each group had significant evolutionary role as illustrated by the conservation of gene structures, protein domains and motif organizations over the distinctive phylogenetic classes. GO annotation suggested a link to sequence-specific DNA and protein binding, response to low temperature and transcription regulation by RNA polymerase II. The existence of different hormonal and stress responsive cis-regulatory elements in promotor region may directly correlate with the variation of their transcripts. MicroRNA target analysis revealed that various groups of miRNA families targeted the LuCAMTAs genes. Identification of CAMTA genes, miRNA studies and phylogenetic analysis may open avenues to uncover the underlying functional mechanism of this important family of genes in flax.", - "journal_title": "PloS one", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/32702710/" - } - ], - "6d926b1e-e103-4efd-b566-3440be33d947": [ - { - "pub_id": "23675545", - "title": "Bayesian geostatistical modeling of leishmaniasis incidence in Brazil.", - "authors": "Dimitrios-Alexios Karagiannis-Voules,Ronaldo G C Scholte,Luiz H Guimar\u00e3es,J\u00fcrg Utzinger,Penelope Vounatsou", - "abstract": "Leishmaniasis is endemic in 98 countries with an estimated 350 million people at risk and approximately 2 million cases annually. Brazil is one of the most severely affected countries. We applied Bayesian geostatistical negative binomial models to analyze reported incidence data of cutaneous and visceral leishmaniasis in Brazil covering a 10-year period (2001-2010). Particular emphasis was placed on spatial and temporal patterns. The models were fitted using integrated nested Laplace approximations to perform fast approximate Bayesian inference. Bayesian variable selection was employed to determine the most important climatic, environmental, and socioeconomic predictors of cutaneous and visceral leishmaniasis. For both types of leishmaniasis, precipitation and socioeconomic proxies were identified as important risk factors. The predicted number of cases in 2010 were 30,189 (standard deviation [SD]: 7,676) for cutaneous leishmaniasis and 4,889 (SD: 288) for visceral leishmaniasis. Our risk maps predicted the highest numbers of infected people in the states of Minas Gerais and Par\u00e1 for visceral and cutaneous leishmaniasis, respectively. Our spatially explicit, high-resolution incidence maps identified priority areas where leishmaniasis control efforts should be targeted with the ultimate goal to reduce disease incidence.", - "journal_title": "PLoS neglected tropical diseases", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/23675545/" - } - ], - "9a5c3e73-8270-400f-8a2d-4f36b757188c": [ - { - "pub_id": "16573589", - "title": "DNA microarray and proteomic strategies for understanding alcohol action.", - "authors": "James M Sikela,Erik J Maclaren,Young Kim,Anis Karimpour-Fard,Wei-Wen Cai,Jonathan Pollack,Robert Hitzemann,John Belknap,Shannon McWeeney,Robnet T Kerns,Chris Downing,Thomas E Johnson,Kathleen J Grant,Boris Tabakoff,Paula Hoffman,Christine C Wu,Michael F Miles", - "abstract": "This article summarizes the proceedings of a symposium presented at the 2005 annual meeting of the Research Society on Alcoholism in Santa Barbara, California. The organizer was James M. Sikela, and he and Michael F. Miles were chairs. The presentations were (1) Genomewide Surveys of Gene Copy Number Variation in Human and Mouse: Implications for the Genetics of Alcohol Action, by James M. Sikela; (2) Regional Differences in the Regulation of Brain Gene Expression: Relevance to the Detection of Genes Associated with Alcohol-Related Traits, by Robert Hitzemann; (3) Identification of Ethanol Quantitative Trait Loci Candidate Genes by Expression Profiling in Inbred Long Sleep/Inbred Short Sleep Congenic Mice, by Robnet T. Kerns; and (4) Quantitative Proteomic Analysis of AC7-Modified Mice, by Kathleen J. Grant.", - "journal_title": "Alcoholism, clinical and experimental research", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/16573589/" - } - ], - "cd7061ee-0596-4c33-abb9-d9fd6888d0aa": [ - { - "pub_id": "19179283", - "title": "Functional coding variation in recombinant inbred mouse lines reveals multiple serotonin transporter-associated phenotypes.", - "authors": "Ana M D Carneiro,David C Airey,Brent Thompson,Chong-Bin Zhu,Lu Lu,Elissa J Chesler,Keith M Erikson,Randy D Blakely", - "abstract": "The human serotonin (5-hydroxytryptamine, 5-HT) transporter (hSERT, SLC6A4) figures prominently in the etiology and treatment of many prevalent neurobehavioral disorders including anxiety, alcoholism, depression, autism, and obsessive-compulsive disorder (OCD). Here, we use naturally occurring polymorphisms in recombinant inbred (RI) lines to identify multiple phenotypes associated with altered SERT function. The widely used mouse strain C57BL/6J, harbors a SERT haplotype defined by 2 nonsynonymous coding variants [Gly-39 and Lys-152 (GK)]. At these positions, many other mouse lines, including DBA/2J, encode, respectively, Glu-39 and Arg-152 (ER haplotype), amino acids found also in hSERT. Ex vivo synaptosomal 5-HT transport studies revealed reduced uptake associated with the GK variant, a finding confirmed by in vitro heterologous expression studies. Experimental and in silico approaches using RI lines (C57BL/6J x DBA/2J = BXD) identify multiple anatomical, biochemical, and behavioral phenotypes specifically impacted by GK/ER variation. Among our findings are several traits associated with alcohol consumption and multiple traits associated with dopamine signaling. Further bioinformatic analysis of BXD phenotypes, combined with biochemical evaluation of SERT knockout mice, nominates SERT-dependent 5-HT signaling as a major determinant of midbrain iron homeostasis that, in turn, dictates iron-regulated DA phenotypes. Our studies provide an example of the power of coordinated in vitro, in vivo, and in silico approaches using mouse RI lines to elucidate and quantify the system-level impact of gene variation.", - "journal_title": "Proceedings of the National Academy of Sciences of the United States of America", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/19179283/" - } - ], - "4a34fec8-ff56-4ec0-b51c-c21c130e53dd": [ - { - "pub_id": "16607234", - "title": "Critical care of the bariatric patient.", - "authors": "Fredric M Pieracci,Philip S Barie,Alfons Pomp", - "abstract": "To synthesize the current literature on care of obese, critically ill, and bariatric surgical patients. A MEDLINE/PubMed search from 1966 to August 2005 was conducted using the search terms obesity, bariatric surgery, and critical illness, and a search of the Cochrane Library was also conducted. An increase in both the prevalence of obesity and the number of bariatric procedures performed has resulted in an increased number of obese and, specifically, bariatric surgical patients who require intensive care unit care. Obesity is a chronic inflammatory state with resultant effects on immune, metabolic, respiratory, cardiovascular, gastrointestinal, hematologic, and renal function. Principles of care of the critically ill obese patient are reviewed and then applied to critically ill bariatric surgical patients. Pharmacotherapy, vascular access, and the presentation and management of both pressure-induced rhabdomyolysis and anastomotic failure after bariatric surgery are also reviewed. Obesity causes a range of pathologic effects on all major organ systems. Knowledge of these effects and issues specific to the intensive care unit care of bariatric patients can help to predict and manage complications in this population.", - "journal_title": "Critical care medicine", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/16607234/" - } - ], - "23dcf284-7c19-4335-91e1-50c3b85e6bad": [ - { - "pub_id": "17112314", - "title": "An integrative genomic approach to uncover molecular mechanisms of prokaryotic traits.", - "authors": "Yang Liu,Jianrong Li,Lee Sam,Chern-Sing Goh,Mark Gerstein,Yves A Lussier", - "abstract": "With mounting availability of genomic and phenotypic databases, data integration and mining become increasingly challenging. While efforts have been put forward to analyze prokaryotic phenotypes, current computational technologies either lack high throughput capacity for genomic scale analysis, or are limited in their capability to integrate and mine data across different scales of biology. Consequently, simultaneous analysis of associations among genomes, phenotypes, and gene functions is prohibited. Here, we developed a high throughput computational approach, and demonstrated for the first time the feasibility of integrating large quantities of prokaryotic phenotypes along with genomic datasets for mining across multiple scales of biology (protein domains, pathways, molecular functions, and cellular processes). Applying this method over 59 fully sequenced prokaryotic species, we identified genetic basis and molecular mechanisms underlying the phenotypes in bacteria. We identified 3,711 significant correlations between 1,499 distinct Pfam and 63 phenotypes, with 2,650 correlations and 1,061 anti-correlations. Manual evaluation of a random sample of these significant correlations showed a minimal precision of 30% (95% confidence interval: 20%-42%; n = 50). We stratified the most significant 478 predictions and subjected 100 to manual evaluation, of which 60 were corroborated in the literature. We furthermore unveiled 10 significant correlations between phenotypes and KEGG pathways, eight of which were corroborated in the evaluation, and 309 significant correlations between phenotypes and 166 GO concepts evaluated using a random sample (minimal precision = 72%; 95% confidence interval: 60%-80%; n = 50). Additionally, we conducted a novel large-scale phenomic visualization analysis to provide insight into the modular nature of common molecular mechanisms spanning multiple biological scales and reused by related phenotypes (metaphenotypes). We propose that this method elucidates which classes of molecular mechanisms are associated with phenotypes or metaphenotypes and holds promise in facilitating a computable systems biology approach to genomic and biomedical research.", - "journal_title": "PLoS computational biology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/17112314/" - } - ], - "b1a1282d-421f-494a-b9df-5c3c9e1e2540": [ - { - "pub_id": "28708780", - "title": "Syndesmotic Ankle Fractures.", - "authors": "James D Michelson,Michael Wright,Michael Blankstein", - "abstract": "The diagnosis and treatment of syndesmotic ankle fractures is controversial. This systematic review was performed to clarify the current understanding addressing several clinical questions that arise in the treatment of such injuries. The English language literature was searched using PubMed, EMBASE, and Web of Science. The search terms were \"syndesmosis\" or \"syndesmotic\" in combination with the terms \"ankle fracture\" or \"fracture.\" The included dates were between 1967 and July 2015. Inclusion criteria were number of patients >20, patient age \u226518 years, follow-up \u22651 year, ankle fracture classification was reported, criteria for surgery was reported, technique of surgery was reported, and a validated outcome measure was used. Studies limited to biomechanical or imaging investigations were excluded. Information was abstracted using a standardized template, which encompassed the inclusion criteria together with the study type, postoperative regimen, and complications. Study quality was evaluated using the modified CONSORT statement and Coleman criteria. Study bias was assessed, and methodological quality was rated. Any difference in ratings was resolved by consensus. None. The overall quality of the studies was poor. The number or placement of syndesmotic screws or the breakage of trans-syndesmotic screws postoperatively had no adverse effect on outcomes (both with moderate strength of evidence). The use of alternative fixation devices (bioabsorbable and endobutton) had poor strength of evidence, as did the opinion that nondisplaced, unstable by stress test, syndesmotic injuries required fixation. There are insufficient data that link subtle rotational syndesmotic malreduction to clinical outcomes. Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence.", - "journal_title": "Journal of orthopaedic trauma", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/28708780/" - } - ], - "cb3f9967-9762-4a9b-96cb-0acccdc316d2": [ - { - "pub_id": "14634638", - "title": "The nature and identification of quantitative trait loci: a community's view.", - "authors": "Oduola Abiola,Joe M Angel,Philip Avner,Alexander A Bachmanov,John K Belknap,Beth Bennett,Elizabeth P Blankenhorn,David A Blizard,Valerie Bolivar,Gundrun A Brockmann,Kari J Buck,Jean-Francoise Bureau,William L Casley,Elissa J Chesler,James M Cheverud,Gary A Churchill,Melloni Cook,John C Crabbe,Wim E Crusio,Ariel Darvasi,Gerald de Haan,Peter Dermant,R W Doerge,Rosemary W Elliot,Charles R Farber,Lorraine Flaherty,Jonathan Flint,Howard Gershenfeld,John P Gibson,Jing Gu,Weikuan Gu,Heinz Himmelbauer,Robert Hitzemann,Hui-Chen Hsu,Kent Hunter,Fuad F Iraqi,Ritsert C Jansen,Thomas E Johnson,Byron C Jones,Gerd Kempermann,Frank Lammert,Lu Lu,Kenneth F Manly,Douglas B Matthews,Juan F Medrano,Margarete Mehrabian,Guy Mittlemann,Beverly A Mock,Jeffrey S Mogil,Xavier Montagutelli,Grant Morahan,John D Mountz,Hiroki Nagase,Richard S Nowakowski,Bruce F O'Hara,Alexander V Osadchuk,Beverly Paigen,Abraham A Palmer,Jeremy L Peirce,Daniel Pomp,Michael Rosemann,Glenn D Rosen,Leonard C Schalkwyk,Ze'ev Seltzer,Stephen Settle,Kazuhiro Shimomura,Siming Shou,James M Sikela,Linda D Siracusa,Jimmy L Spearow,Cory Teuscher,David W Threadgill,Linda A Toth,Ayo A Toye,Csaba Vadasz,Gary Van Zant,Edward Wakeland,Robert W Williams,Huang-Ge Zhang,Fei Zou, ", - "abstract": "This white paper by eighty members of the Complex Trait Consortium presents a community's view on the approaches and statistical analyses that are needed for the identification of genetic loci that determine quantitative traits. Quantitative trait loci (QTLs) can be identified in several ways, but is there a definitive test of whether a candidate locus actually corresponds to a specific QTL?", - "journal_title": "Nature reviews. Genetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/14634638/" - } - ], - "ef7565ef-c6e5-44e4-9628-43fa58f49826": [ - { - "pub_id": "12736193", - "title": "Genetic Models in Applied Physiology. HXB/BXH rat recombinant inbred strain platform: a newly enhanced tool for cardiovascular, behavioral, and developmental genetics and genomics.", - "authors": "Morton P Printz,Martin Jirout,Rebecca Jaworski,Adamu Alemayehu,Vladimir Kren", - "abstract": "This review deals with the largest set of rat recombinant inbred (RI) strains and summarizes past and recent accomplishments with this platform for genetic mapping and analyses of divergent and complex traits. This strain, derived by crossing the spontaneously hypertensive rat, SHR/Ola, with a Brown Norway congenic, BN-Lx, carrying polydactyly-luxate syndrome, is referred to as HXB/BXH. The RI strain set has been used for linkage and association studies to identify quantitative trait loci for numerous cardiovascular phenotypes, including arterial pressure, stress-elicited heart rate, and pressor response, and metabolic traits, including insulin resistance, dyslipidemia and glucose handling, and left ventricular hypertrophy. The strain's utility has been enhanced with development of a new framework marker-based map and strain distribution patterns of polymorphic markers. Quantitative trait loci for behavioral traits mapped include loci for startle motor response and habituation, anxiety and locomotion traits associated with elevated plus maze, and conditioned taste aversion. The polydactyly-luxate syndrome Lx mutation has allowed the study of alleles important to limb development and malformation phenotypes as well as teratogens. The RI strains have guided development of numerous congenic strains to test locus assignments and to study the effect of genetic background. Although these strains were originally developed to aid in studies of rat genetic hypertension and morphogenetic abnormalities, this rodent platform has been shown to be equally powerful for a wide spectrum of traits and endophenotypes. These strains provide a ready and available vehicle for many physiological and pharmacological studies.", - "journal_title": "Journal of applied physiology (Bethesda, Md. : 1985)", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/12736193/" - } - ], - "8bac5167-f777-4abe-a221-16dd818fc2c2": [ - { - "pub_id": "15897714", - "title": "The syntaxin binding protein 1 gene (Stxbp1) is a candidate for an ethanol preference drinking locus on mouse chromosome 2.", - "authors": "Christoph Fehr,Renee L Shirley,John C Crabbe,John K Belknap,Kari J Buck,Tamara J Phillips", - "abstract": "We previously mapped a quantitative trait locus (QTL) for ethanol preference drinking to mouse chromosome 2 (mapped with high confidence, LOD = 15.5, p = 3 x 10(-16)). The specific gene(s) in the QTL interval responsible for phenotypic variation in ethanol preference drinking has not been identified. In the current study, we investigated the association of the syntaxin binding protein 1 gene (Stxbp1) with ethanol preference drinking and other ethanol traits using a panel of B6 x D2 (BXD) recombinant inbred (RI) strains derived from the C57BL/6J (B6) and DBA/2J (D2) inbred mouse strains. Confirmation analyses for ethanol consumption and withdrawal were performed using a large B6D2 F2 cross, short-term selected lines derived from the B6 and D2 progenitor strains, and standard inbred strains. BXD RI strain analysis detected provisional associations between Stxbp1 molecular variants and ethanol consumption, as well as severity of acute ethanol withdrawal, ethanol-conditioned taste aversion, and ethanol-induced hypothermia. Confirmation analyses using three independent genetic models supported the involvement of Stxbp1 in ethanol preference drinking but not in ethanol withdrawal. Stxbp1 encodes a Sec1/Munc18-type protein essential for vesicular neurotransmitter release. The present study provides supporting evidence for the involvement of Stxbp1 in ethanol preference drinking.", - "journal_title": "Alcoholism, clinical and experimental research", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/15897714/" - } - ], - "d2749f7d-2943-4c3e-ae5a-ac3999aad956": [ - { - "pub_id": "16048786", - "title": "Regression-based quantitative trait loci mapping: robust, efficient and effective.", - "authors": "Sara A Knott", - "abstract": "Regression has always been an important tool for quantitative geneticists. The use of maximum likelihood (ML) has been advocated for the detection of quantitative trait loci (QTL) through linkage with molecular markers, and this approach can be very effective. However, linear regression models have also been proposed which perform similarly to ML, while retaining the many beneficial features of regression and, hence, can be more tractable and versatile than ML in some circumstances. Here, the use of linear regression to detect QTL in structured outbred populations is reviewed and its perceived shortfalls are revisited. It is argued that the approach is valuable now and will remain so in the future.", - "journal_title": "Philosophical transactions of the Royal Society of London. Series B, Biological sciences", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/16048786/" - } - ], - "4439ac39-e421-482f-9aa9-9ad11fa641c1": [ - { - "pub_id": "15711544", - "title": "Integrated transcriptional profiling and linkage analysis for identification of genes underlying disease.", - "authors": "Norbert Hubner,Caroline A Wallace,Heike Zimdahl,Enrico Petretto,Herbert Schulz,Fiona Maciver,Michael Mueller,Oliver Hummel,Jan Monti,Vaclav Zidek,Alena Musilova,Vladimir Kren,Helen Causton,Laurence Game,Gabriele Born,Sabine Schmidt,Anita M\u00fcller,Stuart A Cook,Theodore W Kurtz,John Whittaker,Michal Pravenec,Timothy J Aitman", - "abstract": "Integration of genome-wide expression profiling with linkage analysis is a new approach to identifying genes underlying complex traits. We applied this approach to the regulation of gene expression in the BXH/HXB panel of rat recombinant inbred strains, one of the largest available rodent recombinant inbred panels and a leading resource for genetic analysis of the highly prevalent metabolic syndrome. In two tissues important to the pathogenesis of the metabolic syndrome, we mapped cis- and trans-regulatory control elements for expression of thousands of genes across the genome. Many of the most highly linked expression quantitative trait loci are regulated in cis, are inherited essentially as monogenic traits and are good candidate genes for previously mapped physiological quantitative trait loci in the rat. By comparative mapping we generated a data set of 73 candidate genes for hypertension that merit testing in human populations. Mining of this publicly available data set is expected to lead to new insights into the genes and regulatory pathways underlying the extensive range of metabolic and cardiovascular disease phenotypes that segregate in these recombinant inbred strains.", - "journal_title": "Nature genetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/15711544/" - } - ], - "d1f04d58-2589-4183-aee4-569820dae052": [ - { - "pub_id": "37701759", - "title": "The claustrum and consciousness: An update.", - "authors": "Yin Siang Liaw,George J Augustine", - "abstract": "The seminal paper of Crick and Koch (2005) proposed that the claustrum, an enigmatic and thin grey matter structure that lies beside the insular cortex, may be involved in the processing of consciousness. As a result, this otherwise obscure structure has received ever-increasing interest in the search for neural correlates of consciousness. Here we review theories of consciousness and discuss the possible relationship between the claustrum and consciousness. We review relevant experimental evidence collected since the Crick and Koch (2005) paper and consider whether these findings support or contradict their hypothesis. We also explore how future experimental work can be designed to clarify how consciousness emerges from neural activity and to understand the role of the claustrum in consciousness.", - "journal_title": "International journal of clinical and health psychology : IJCHP", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/37701759/" - } - ], - "bd9f534c-92a2-48e8-8a6c-9ed24806604e": [ - { - "pub_id": "7811158", - "title": "Functioning and well-being outcomes of patients with depression compared with chronic general medical illnesses.", - "authors": "R D Hays,K B Wells,C D Sherbourne,W Rogers,K Spritzer", - "abstract": "Cross-sectional studies have found that depression is uniquely associated with limitations in well-being and functioning that were equal to or greater than those of chronic general medical conditions such as diabetes and arthritis. However, whether these relative limitations persist over time is not known. We conducted a 2-year observational study of 1790 adult outpatients with depression, diabetes, hypertension, recent myocardial infarction, and/or congestive heart failure. Change in functional status and well-being was compared for depressed patients vs patients with chronic general medical illnesses, controlling statistically for medical comorbidity, sociodemographics, system, and specialty of care. Over 2 years of follow-up, limitations in functioning and well-being improved somewhat for depressed patients; even so, at the end of 2 years, these limitations were similar to or worse than those attributed to chronic medical illnesses. Similar patterns were observed for depressed patients in the mental health specialty sector and those in the general medical sector, but the patients in the mental health specialty sector improved more. More severely depressed patients improved more in functioning, but even initially depressed patients without depressive disorder had substantial persistent limitations. Depressed patients have substantial and long-lasting decrements in multiple domains of functioning and well-being that equal or exceed those of patients with chronic medical illnesses.", - "journal_title": "Archives of general psychiatry", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/7811158/" - } - ], - "8ad08cb7-949d-44ee-bc4a-5a1b4d0da501": [ - { - "pub_id": "8989248", - "title": "CTLA4 alanine-17 confers genetic susceptibility to Graves' disease and to type 1 diabetes mellitus.", - "authors": "H Donner,H Rau,P G Walfish,J Braun,T Siegmund,R Finke,J Herwig,K H Usadel,K Badenhoop", - "abstract": "The genetic susceptibility to Graves' disease and type 1 (insulin-dependent) diabetes mellitus is conferred by genes in the human leukocyte antigen region on the short arm of chromosome 6, but several other genes are presumed to determine disease susceptibility. Among those candidate genes is the cytotoxic T lymphocyte antigen 4 (CTLA4) located on chromosome 2q33 in man. We investigated the distribution of the CTLA4 exon 1 polymorphism (49 A/G) in Graves' disease and IDDM. This dimorphism at codon 17 results in an amino acid exchange (Thr/Ala) in the leader peptide of the expressed protein and was analyzed by PCR, single strand conformation polymorphism, and restriction fragment length polymorphism analysis in 305 patients with Graves' disease, 293 patients with IDDM, and 325 controls. Patients with Graves' disease had significantly more Ala alleles than controls, both as homozygotes (21% vs. 13%) and as heterozygotes (53% vs. 46%), and less Thr as homozygotes (26% vs. 42%; P < 2 x 10(-4). The phenotypic frequency of Ala-positive patients (73%) was significantly higher than of controls (58%; P = 10(-4); relative risk = 2). Patients with IDDM also had significantly more Ala alleles as homozygotes (19%) or heterozygotes (50%; P = 0.01). In conclusion, an alanine at codon 17 of CTLA4 is associated with genetic susceptibility to Graves' disease as well as to IDDM.", - "journal_title": "The Journal of clinical endocrinology and metabolism", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/8989248/" - } - ], - "21f4f4d2-8f80-4da2-a0f9-77be35da52d5": [ - { - "pub_id": "30865571", - "title": "Nutrigenetics, epigenetics and gestational diabetes: consequences in mother and child.", - "authors": "Marica Franzago,Federica Fraticelli,Liborio Stuppia,Ester Vitacolonna", - "abstract": "Gestational Diabetes Mellitus (GDM) is the most common metabolic condition during pregnancy and may result in short- and long-term complications for both mother and offspring. The complexity of phenotypic outcomes seems influenced by genetic susceptibility, nutrient-gene interactions and lifestyle interacting with clinical factors. There is strong evidence that not only the adverse genetic background but also the epigenetic modifications in response to nutritional and environmental factors could influence the maternal hyperglycemia in pregnancy and the foetal metabolic programming. In this view, the correlation between epigenetic modifications and their transgenerational effects represents a very interesting field of study. The present review gives insight into the role of gene variants and their interactions with nutrients in GDM. In addition, we provide an overview of the epigenetic changes and their role in the maternal-foetal transmission of chronic diseases. Overall, the knowledge of epigenetic modifications induced by an adverse intrauterine and perinatal environment could shed light on the potential pathophysiological mechanisms of long-term disease development in the offspring and provide useful tools for their prevention.", - "journal_title": "Epigenetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/30865571/" - } - ], - "6b7c6ac7-208d-4942-af31-cc3c37252751": [ - { - "pub_id": "20043853", - "title": "Prioritizing genes for follow-up from genome wide association studies using information on gene expression in tissues relevant for type 2 diabetes mellitus.", - "authors": "Hemang Parikh,Valeriya Lyssenko,Leif C Groop", - "abstract": "Genome-wide association studies (GWAS) have emerged as a powerful approach for identifying susceptibility loci associated with polygenetic diseases such as type 2 diabetes mellitus (T2DM). However, it is still a daunting task to prioritize single nucleotide polymorphisms (SNPs) from GWAS for further replication in different population. Several recent studies have shown that genetic variation often affects gene-expression at proximal (cis) as well as distal (trans) genomic locations by different mechanisms such as altering rate of transcription or splicing or transcript stability. To prioritize SNPs from GWAS, we combined results from two GWAS related to T2DM, the Diabetes Genetics Initiative (DGI) and the Wellcome Trust Case Control Consortium (WTCCC), with genome-wide expression data from pancreas, adipose tissue, liver and skeletal muscle of individuals with or without T2DM or animal models thereof to identify T2DM susceptibility loci. We identified 1,170 SNPs associated with T2DM with P < 0.05 in both GWAS and 243 genes that were located in the vicinity of these SNPs. Out of these 243 genes, we identified 115 differentially expressed in publicly available gene expression profiling data. Notably five of them, IGF2BP2, KCNJ11, NOTCH2, TCF7L2 and TSPAN8, have subsequently been shown to be associated with T2DM in different populations. To provide further validation of our approach, we reversed the approach and started with 26 known SNPs associated with T2DM and related traits. We could show that 12 (57%) (HHEX, HNF1B, IGF2BP2, IRS1, KCNJ11, KCNQ1, NOTCH2, PPARG, TCF7L2, THADA, TSPAN8 and WFS1) out of 21 genes located in vicinity of these SNPs were showing aberrant expression in T2DM from the gene expression profiling studies. Utilizing of gene expression profiling data from different tissues of individuals with or without T2DM or animal models thereof is a powerful tool for prioritizing SNPs from WGAS for further replication studies.", - "journal_title": "BMC medical genomics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/20043853/" - } - ], - "9de4364a-3da5-4a76-a68c-cddba815af1c": [ - { - "pub_id": "19426526", - "title": "The genetic control of neocortex volume and covariation with neocortical gene expression in mice.", - "authors": "Shiv M Gaglani,Lu Lu,Robert W Williams,Glenn D Rosen", - "abstract": "The size of the cerebral cortex varies widely within human populations, and a large portion of this variance is modulated by genetic factors. The discovery and characterization of these genes and their variants can contribute to an understanding of individual differences in brain development, behavior, and disease susceptibility. Here we use unbiased stereological techniques to map quantitative trait loci (QTLs) that modulate the volume of neocortex. We estimated volumes bilaterally in an expanded set of BXD recombinant inbred strains (n = 56 strains and 223 animals) taken from the Mouse Brain Library http://www.mbl.org. We generated matched microarray data for the cerebral cortex in the same large panel of strains and in parental neonates to efficiently nominate and evaluate candidate genes. Volume of the neocortex varies widely, and is a heritable trait. Genome-wide mapping of this trait revealed two QTLs--one on chromosome (Chr) 6 at 88 +/- 5 Mb and another at Chr 11 (41 +/- 8 Mb). We generated both neonatal and adult neocortical gene expression databases using microarray technology. Using these databases in combination with other bioinformatic tools we have identified positional candidates on these QTL intervals. This study is the first to use the expanded set of BXD strains to map neocortical volume, and we found that normal variation of this trait is, at least in part, genetically modulated. These results provide a baseline from which to assess the genetic contribution to regional variation in neocortical volume, as well as other neuroanatomic phenotypes that may contribute to variation in regional volume, such as proliferation, death, and number and packing density of neurons.", - "journal_title": "BMC neuroscience", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/19426526/" - } - ], - "90e2b0b3-8948-4794-a454-de0204e06bb4": [ - { - "pub_id": "24032284", - "title": "Genomic damage in patients with type-2 diabetes mellitus.", - "authors": "D N Binici,A Karaman,M Co\u015fkun,A Uyanik O\u011flu,F U\u00e7ar", - "abstract": "DNA damage seems to play a role in the pathogenesis of type-2 diabetes mellitus (DM2) and its complications. Several in vitro assays have been used to measure the DNA damage. In the present study, we aimed to investigate the frequency of sister chromatid exchange (SCE) and micronuclei (MN) in DM2 patients compared with healthy controls. SCE and MN tests were carried out with the blood-cell cultures from 50 DM2 patients and 30 healthy, age- and sex-matched control subjects. The mean age of the DM2 patients was 58.12 +/- 13.39 years, with a mean duration of the diabetes of 5.40 +/- 4.32 years. The mean level of HbAlc of the DM2 patients was 8.93 +/- 2.56. Patients with DM2 showed a higher frequency of SCE compared with controls (7.11 +/- 1.14 and 4.96 +/- 0.92, p < 0.001). Furthermore, the SCE frequency was positively correlated with the plasma HbA1c level (p < 0.05), but there was no significant correlation between the duration of diabetes and SCE. On the other hand, our result showed a MN frequency significant increase in DM2 patients (3.45 +/- 1.01 per 1000 cells) relative to that of the control group (1.79 +/- 0.67 per 1000 cells) (p < 0.001), but there was no significant correlation between the duration of diabetes, HbA1c and MN. In conclusion, these results suggest that DM2 is a condition with genomic instability characterized by an increased level of SCE and MN. Hyperglycemia-induced oxidative stress may be the underlying factor of the increased SCE and MN frequency.", - "journal_title": "Genetic counseling (Geneva, Switzerland)", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/24032284/" - } - ], - "e622ade6-f276-4309-a7a0-831276d169ec": [ - { - "pub_id": "15161765", - "title": "Interaction and association analysis of a type 1 diabetes susceptibility locus on chromosome 5q11-q13 and the 7q32 chromosomal region in Scandinavian families.", - "authors": "Pernilla Holm,Berit Rydlander,Holger Luthman,Ingrid Kockum, ", - "abstract": "We have previously reported suggestive linkage to chromosome 5p13-q13 in type 1 diabetic families. ISL1, a transcription factor involved in pancreas development, maps to this region. Sequencing of the ISL1 gene in patients and control subjects identified seven single nucleotide polymorphisms (SNPs) and one microsatellite in noncoding regions. Four haplotypes formed by six of these SNPs and one microsatellite were associated with type 1 diabetes in Swedish families (P < 0.04). To identify possible interactions with the 5q11-q13 region, we applied pathway-restricted linkage analysis by analyzing for effects from regions encoding other transcription factors that are active during pancreas development and maintenance of insulin production. Linkage analysis allowing for interaction between 5q11-q13 and 7q32 resulted in an increase of logarithm of odds from 2.2 to 5.3. This increase was estimated to correspond to a P value <0.0016 using permutation. The transcription factor PAX4 is located at 7q32 and participates downstream of ISL1 in the transcription factor cascade critical to beta-cell development. Association with type 1 diabetes was also observed using the transmission disequilibrium test for two haplotypes at the PAX4 locus (P < 0.05). We conclude that pathway-restricted linkage analysis assists in the identification of possible gene-gene interactions and that 5q11-q13 and 7q32 together constitute a significant susceptibility factor for type 1 diabetes.", - "journal_title": "Diabetes", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/15161765/" - } - ], - "263ebf41-8033-4dd7-90ff-de0c1df22eb5": [ - { - "pub_id": "21983784", - "title": "Deep resequencing of GWAS loci identifies independent rare variants associated with inflammatory bowel disease.", - "authors": "Manuel A Rivas,M\u00e9lissa Beaudoin,Agnes Gardet,Christine Stevens,Yashoda Sharma,Clarence K Zhang,Gabrielle Boucher,Stephan Ripke,David Ellinghaus,Noel Burtt,Tim Fennell,Andrew Kirby,Anna Latiano,Philippe Goyette,Todd Green,Jonas Halfvarson,Talin Haritunians,Joshua M Korn,Finny Kuruvilla,Caroline Lagac\u00e9,Benjamin Neale,Ken Sin Lo,Phil Schumm,Leif T\u00f6rkvist, , , ,Marla C Dubinsky,Steven R Brant,Mark S Silverberg,Richard H Duerr,David Altshuler,Stacey Gabriel,Guillaume Lettre,Andre Franke,Mauro D'Amato,Dermot P B McGovern,Judy H Cho,John D Rioux,Ramnik J Xavier,Mark J Daly", - "abstract": "More than 1,000 susceptibility loci have been identified through genome-wide association studies (GWAS) of common variants; however, the specific genes and full allelic spectrum of causal variants underlying these findings have not yet been defined. Here we used pooled next-generation sequencing to study 56 genes from regions associated with Crohn's disease in 350 cases and 350 controls. Through follow-up genotyping of 70 rare and low-frequency protein-altering variants in nine independent case-control series (16,054 Crohn's disease cases, 12,153 ulcerative colitis cases and 17,575 healthy controls), we identified four additional independent risk factors in NOD2, two additional protective variants in IL23R, a highly significant association with a protective splice variant in CARD9 (P < 1 \u00d7 10(-16), odds ratio \u2248 0.29) and additional associations with coding variants in IL18RAP, CUL2, C1orf106, PTPN22 and MUC19. We extend the results of successful GWAS by identifying new, rare and probably functional variants that could aid functional experiments and predictive models.", - "journal_title": "Nature genetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/21983784/" - } - ], - "36167b9b-8d77-47d4-b094-42f6795c9113": [ - { - "pub_id": "32440765", - "title": "Prospective avenues for human population genomics and disease mapping in southern Africa.", - "authors": "Yolandi Swart,Gerald van Eeden,Anel Sparks,Caitlin Uren,Marlo M\u00f6ller", - "abstract": "Population substructure within human populations is globally evident and a well-known confounding factor in many genetic studies. In contrast, admixture mapping exploits population stratification to detect genotype-phenotype correlations in admixed populations. Southern Africa has untapped potential for disease mapping of ancestry-specific disease risk alleles due to the distinct genetic diversity in its populations compared to other populations worldwide. This diversity contributes to a number of phenotypes, including ancestry-specific disease risk and response to pathogens. Although the 1000 Genomes Project significantly improved our understanding of genetic variation globally, southern African populations are still severely underrepresented in biomedical and human genetic studies due to insufficient large-scale publicly available data. In addition to a lack of genetic data in public repositories, existing software, algorithms and resources used for imputation and phasing of genotypic data (amongst others) are largely ineffective for populations with a complex genetic architecture such as that seen in southern Africa. This review article, therefore, aims to summarise the current limitations of conducting genetic studies on populations with a complex genetic architecture to identify potential areas for further research and development.", - "journal_title": "Molecular genetics and genomics : MGG", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/32440765/" - } - ], - "e66846a6-1546-481b-baae-a55fc524c8af": [ - { - "pub_id": "15496194", - "title": "Diabetic nephropathy: Linking histology, cell biology, and genetics.", - "authors": "Sharon Adler", - "abstract": "", - "journal_title": "Kidney international", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/15496194/" - } - ], - "a2df7722-9091-4c02-896d-cbdedc30a4ce": [ - { - "pub_id": "28302740", - "title": "Genetics and Genomics of Congenital Heart Disease.", - "authors": "Samir Zaidi,Martina Brueckner", - "abstract": "Congenital heart disease is the most common birth defect, and because of major advances in medical and surgical management, there are now more adults living with congenital heart disease (CHD) than children. Until recently, the cause of the majority of CHD was unknown. Advances in genomic technologies have discovered the genetic causes of a significant fraction of CHD, while at the same time pointing to remarkable complexity in CHD genetics. This review will focus on the evidence for genetic causes underlying CHD and discuss data supporting both monogenic and complex genetic mechanisms underlying CHD. The discoveries from CHD genetic studies draw attention to biological pathways that simultaneously open the door to a better understanding of cardiac development and affect clinical care of patients with CHD. Finally, we address clinical genetic evaluation of patients and families affected by CHD.", - "journal_title": "Circulation research", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/28302740/" - } - ], - "27e14ff3-b5a5-4f60-80a2-eaa2ab53e991": [ - { - "pub_id": "19008955", - "title": "Dissection of a QTL hotspot on mouse distal chromosome 1 that modulates neurobehavioral phenotypes and gene expression.", - "authors": "Khyobeni Mozhui,Daniel C Ciobanu,Thomas Schikorski,Xusheng Wang,Lu Lu,Robert W Williams", - "abstract": "A remarkably diverse set of traits maps to a region on mouse distal chromosome 1 (Chr 1) that corresponds to human Chr 1q21-q23. This region is highly enriched in quantitative trait loci (QTLs) that control neural and behavioral phenotypes, including motor behavior, escape latency, emotionality, seizure susceptibility (Szs1), and responses to ethanol, caffeine, pentobarbital, and haloperidol. This region also controls the expression of a remarkably large number of genes, including genes that are associated with some of the classical traits that map to distal Chr 1 (e.g., seizure susceptibility). Here, we ask whether this QTL-rich region on Chr 1 (Qrr1) consists of a single master locus or a mixture of linked, but functionally unrelated, QTLs. To answer this question and to evaluate candidate genes, we generated and analyzed several gene expression, haplotype, and sequence datasets. We exploited six complementary mouse crosses, and combed through 18 expression datasets to determine class membership of genes modulated by Qrr1. Qrr1 can be broadly divided into a proximal part (Qrr1p) and a distal part (Qrr1d), each associated with the expression of distinct subsets of genes. Qrr1d controls RNA metabolism and protein synthesis, including the expression of approximately 20 aminoacyl-tRNA synthetases. Qrr1d contains a tRNA cluster, and this is a functionally pertinent candidate for the tRNA synthetases. Rgs7 and Fmn2 are other strong candidates in Qrr1d. FMN2 protein has pronounced expression in neurons, including in the dendrites, and deletion of Fmn2 had a strong effect on the expression of few genes modulated by Qrr1d. Our analysis revealed a highly complex gene expression regulatory interval in Qrr1, composed of multiple loci modulating the expression of functionally cognate sets of genes.", - "journal_title": "PLoS genetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/19008955/" - } - ], - "ceab3d6d-62ca-459a-9a97-02a16d4dd193": [ - { - "pub_id": "36626356", - "title": "Healthy lifestyle behaviors, mediating biomarkers, and risk of microvascular complications among individuals with type 2 diabetes: A cohort study.", - "authors": "Tingting Geng,Kai Zhu,Qi Lu,Zhenzhen Wan,Xue Chen,Liegang Liu,An Pan,Gang Liu", - "abstract": "The influence of overall lifestyle behaviors on diabetic microvascular complications remains unknown. In addition, the potential mediating biomarkers underlying the association is unclear. This study aimed to examine the associations of the combined lifestyle factors with risks of total and individual microvascular complications among patients with type 2 diabetes (T2D) and to explore the potential mediation effects of metabolic biomarkers. This retrospective cohort study included 15,104 patients with T2D free of macro- and microvascular complications at baseline (2006 to 2010) from the UK Biobank. Healthy lifestyle behaviors included noncurrent smoking, recommended waist circumference, regular physical activity, healthy diet, and moderate alcohol drinking. Outcomes were ascertained using electronic health records. Over a median of 8.1 years of follow-up, 1,296 cases of the composite microvascular complications occurred, including 558 diabetic retinopathy, 625 diabetic kidney disease, and 315 diabetic neuropathy, with some patients having 2 or 3 microvascular complications simultaneously. After multivariable adjustment for sociodemographic characteristics, history of hypertension, glycemic control, and medication histories, the hazard ratios (95% confidence intervals (CIs)) for the participants adhering 4 to 5 low-risk lifestyle behaviors versus 0 to 1 were 0.65 (0.46, 0.91) for diabetic retinopathy, 0.43 (0.30, 0.61) for diabetic kidney disease, 0.46 (0.29, 0.74) for diabetic neuropathy, and 0.54 (0.43, 0.68) for the composite outcome (all Ps-trend \u22640.01). Further, the population-attributable fraction (95% CIs) of diabetic microvascular complications for poor adherence to the overall healthy lifestyle (<4 low-risk factors) ranged from 25.3% (10.0%, 39.4%) to 39.0% (17.7%, 56.8%). In addition, albumin, HDL-C, triglycerides, apolipoprotein A, C-reactive protein, and HbA1c collectively explained 23.20% (12.70%, 38.50%) of the associations between overall lifestyle behaviors and total diabetic microvascular complications. The key limitation of the current analysis was the potential underreporting of microvascular complications because the cases were identified via electronic health records. Adherence to overall healthy lifestyle behaviors was associated with a significantly lower risk of microvascular complications in patients with T2D, and the favorable associations were partially mediated through improving biomarkers of glycemic control, systemic inflammation, liver function, and lipid profile.", - "journal_title": "PLoS medicine", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/36626356/" - } - ], - "9ce1bc1f-3bbb-4acb-bc4f-a939315a509b": [ - { - "pub_id": "19853688", - "title": "Rationale and design of the Duke Electrophysiology Genetic and Genomic Studies (EPGEN) biorepository.", - "authors": "Jason I Koontz,Daniel Haithcock,Valerie Cumbea,Anthony Waldron,Kristie Stricker,Amy Hughes,Kent Nilsson,Albert Sun,Jonathan P Piccini,William E Kraus,Geoffrey S Pitt,Svati H Shah,Patrick Hranitzky", - "abstract": "Disturbances in cardiac rhythm can lead to significant morbidity and mortality. Many arrhythmias are known to have a heritable component, but the degree to which genetic variation contributes to disease risk and morbidity is poorly understood. The EPGEN is a prospective single-center repository that archives DNA, RNA, and protein samples obtained at the time of an electrophysiologic evaluation or intervention. To identify genes and molecular variants that are associated with risk for arrhythmic phenotypes, EPGEN uses unbiased genomic screening; candidate gene analysis; and both unbiased and targeted transcript, protein, and metabolite profiling. To date, EPGEN has successfully enrolled >1,500 subjects. The median age of the study population is 62.9 years; 35% of the subjects are female and 21% are black. To this point, the study population has been composed of patients who had undergone defibrillator (implantable cardioverter-defibrillator or cardiac resynchronization therapy defibrillator) implantation (45%), electrophysiology studies or ablation procedures (35%), and pacemaker implantation or other procedures (20%). The cohort has a high prevalence of comorbidities, including diabetes (33%), hypertension (73%), chronic kidney disease (26%), and peripheral vascular disease (13%). We have established a biorepository and clinical database composed of patients with electrophysiologic diseases. EPGEN will seek to (1) improve risk stratification, (2) elucidate mechanisms of arrhythmogenesis, and (3) identify novel pharmacologic targets for the treatment of heart rhythm disorders.", - "journal_title": "American heart journal", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/19853688/" - } - ], - "4d7f8d18-ddcf-4afc-8412-64f530ba7333": [ - { - "pub_id": "29368431", - "title": "Experience with genomic sequencing in pediatric patients with congenital cardiac defects in a large community hospital.", - "authors": "Natalie S Hauser,Benjamin D Solomon,Thierry Vilboux,Alina Khromykh,Rajiv Baveja,Dale L Bodian", - "abstract": "Congenital cardiac defects, whether isolated or as part of a larger syndrome, are the most common type of human birth defect occurring on average in about 1% of live births depending on the malformation. As there is an expanding understanding of the underlying molecular mechanisms by which a cardiac defect may occur, there is a need to assess the current rates of diagnosis of cardiac defects by molecular sequencing in a clinical setting. In this report, we evaluated 34 neonatal and pediatric patients born with a cardiac defect and their parents using exomized preexisting whole genome sequencing (WGS) data to model clinically available exon-based tests. Overall, we identified candidate variants in previously reported cardiac-related genes in 35% (12/34) of the probands. These include clearly pathogenic variants in two of 34 patients (6%) and variants of uncertain significance in relevant genes in 10 patients (26%), of these latter 10, 2 segregated with clinically apparent findings in the family trios. These findings suggest that with current knowledge of the proteins underlying CHD, genomic sequencing can identify the underlying genetic etiology in certain patients; however, this technology currently does not have a high enough yield to be of routine clinical use in the screening of pediatric congenital cardiac defects.", - "journal_title": "Molecular genetics & genomic medicine", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/29368431/" - } - ], - "37c22adb-2b45-4a15-a05b-dfcec0fb17ca": [ - { - "pub_id": "21150313", - "title": "DNA methylation profiling identifies epigenetic differences between diabetes patients with ESRD and diabetes patients without nephropathy.", - "authors": "Carmen Sapienza,Jean Lee,Jasmine Powell,Oluwatoyin Erinle,Faahud Yafai,James Reichert,Elias S Siraj,Michael Madaio", - "abstract": "We identified potential epigenetic biomarkers for chronic kidney disease progression by comparing site-specific DNA methylation levels in more than 14,000 genes between African American and Hispanic diabetes patients with end stage renal disease (ESRD) and diabetes patients without nephropathy. We identified 187 genes that are differentially methylated between the two groups on at least two CpG sites in each gene in DNA extracted from saliva. Of the 187 genes whose mean methylation levels differed between the two groups, 39 genes, or closely related gene family members, have been reported to be involved in kidney development or diabetic nephropathy, per se, or have been associated with dialysis-induced changes in gene expression in peripheral blood cells. The fact that such a substantial fraction (21%) of the 187 candidate genes have been implicated previously through genome association or transcription profiling studies suggests strongly that the DNA methylation differences we observe are associated with disease predisposition and/or treatment. The fact that these nephropathy and/or dialysis-associated differences between patients were identified in DNA extracted from saliva offers proof-of-principle that inter-individual epigenetic differences may prove useful as predictive biomarkers of disease susceptibility.", - "journal_title": "Epigenetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/21150313/" - } - ], - "792e547d-5b91-49ba-b9e3-0d6727c1d483": [ - { - "pub_id": "20353613", - "title": "Integration of microRNA changes in vivo identifies novel molecular features of muscle insulin resistance in type 2 diabetes.", - "authors": "Iain J Gallagher,Camilla Scheele,Pernille Keller,Anders R Nielsen,Judit Remenyi,Christian P Fischer,Karim Roder,John Babraj,Claes Wahlestedt,Gyorgy Hutvagner,Bente K Pedersen,James A Timmons", - "abstract": "Skeletal muscle insulin resistance (IR) is considered a critical component of type II diabetes, yet to date IR has evaded characterization at the global gene expression level in humans. MicroRNAs (miRNAs) are considered fine-scale rheostats of protein-coding gene product abundance. The relative importance and mode of action of miRNAs in human complex diseases remains to be fully elucidated. We produce a global map of coding and non-coding RNAs in human muscle IR with the aim of identifying novel disease biomarkers. We profiled >47,000 mRNA sequences and >500 human miRNAs using gene-chips and 118 subjects (n = 71 patients versus n = 47 controls). A tissue-specific gene-ranking system was developed to stratify thousands of miRNA target-genes, removing false positives, yielding a weighted inhibitor score, which integrated the net impact of both up- and down-regulated miRNAs. Both informatic and protein detection validation was used to verify the predictions of in vivo changes. The muscle mRNA transcriptome is invariant with respect to insulin or glucose homeostasis. In contrast, a third of miRNAs detected in muscle were altered in disease (n = 62), many changing prior to the onset of clinical diabetes. The novel ranking metric identified six canonical pathways with proven links to metabolic disease while the control data demonstrated no enrichment. The Benjamini-Hochberg adjusted Gene Ontology profile of the highest ranked targets was metabolic (P < 7.4 x 10-8), post-translational modification (P < 9.7 x 10-5) and developmental (P < 1.3 x 10-6) processes. Protein profiling of six development-related genes validated the predictions. Brain-derived neurotrophic factor protein was detectable only in muscle satellite cells and was increased in diabetes patients compared with controls, consistent with the observation that global miRNA changes were opposite from those found during myogenic differentiation. We provide evidence that IR in humans may be related to coordinated changes in multiple microRNAs, which act to target relevant signaling pathways. It would appear that miRNAs can produce marked changes in target protein abundance in vivo by working in a combinatorial manner. Thus, miRNA detection represents a new molecular biomarker strategy for insulin resistance, where micrograms of patient material is needed to monitor efficacy during drug or life-style interventions.", - "journal_title": "Genome medicine", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/20353613/" - } - ], - "4443620a-33a8-42d3-a193-54d6adbb48c5": [ - { - "pub_id": "16670152", - "title": "Behavioral, physiological, and molecular differences in response to dietary restriction in three inbred mouse strains.", - "authors": "Cigdem Gelegen,David A Collier,Iain C Campbell,Hugo Oppelaar,Martien J H Kas", - "abstract": "Food restriction paradigms are widely used in animal studies to investigate systems involved in energy regulation. We have observed behavioral, physiological, and molecular differences in response to food restriction in three inbred mouse strains, C57BL/6J, A/J, and DBA/2J. These are the progenitors of chromosome substitution and recombinant inbred mouse strains used for mapping complex traits. DBA/2J and A/J mice increased their locomotor activity during food restriction, and both displayed a decrease in body temperature, but the decrease was significantly larger in DBA/2J compared with A/J mice. C57BL/6J mice did not increase their locomotor activity and displayed a large decrease in their body temperature. The large decline in body temperature during food restriction in DBA/2J and C57BL/6J strains was associated with a robust reduction in plasma leptin levels. DBA/2J mice showed a marked decrease in white and brown adipose tissue masses and an upregulation of the antithermogenic hypothalamic neuropeptide Y Y(1) receptor. In contrast, A/J mice showed a reduction in body temperature to a lesser extent that may be explained by downregulation of the thermogenic melanocortin 3 receptor and by behavioral thermoregulation as a consequence of their increased locomotor activity. These data indicate that genetic background is an important parameter in controlling an animal's adaptation strategy in response to food restriction. Therefore, mouse genetic mapping populations based on these progenitor lines are highly valuable for investigating mechanisms underlying strain-dependent differences in behavioral physiology that are seen during reduced food availability.", - "journal_title": "American journal of physiology. Endocrinology and metabolism", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/16670152/" - } - ], - "831b5b65-0767-4a8f-ac18-306a14e95185": [ - { - "pub_id": "23046601", - "title": "RNA interference of gonadotropin-inhibitory hormone gene induces aggressive and sexual behaviors in birds.", - "authors": "Takayoshi Ubuka,Takanobu Mizuno,Yujiro Fukuda,George E Bentley,John C Wingfield,Kazuyoshi Tsutsui", - "abstract": "Gonadotropin-inhibitory hormone (GnIH) was originally identified in the Japanese quail as a hypothalamic neuropeptide inhibitor of pituitary gonadotropin synthesis and release. GnIH neuronal fibers not only terminate in the median eminence to control anterior pituitary function but also extend widely in the brain, suggesting multiple roles in the regulation of behavior. To identify the role of GnIH neurons in the regulation of behavior, we tested the effect of RNA interference (RNAi) of the GnIH gene on aggressive and sexual behaviors of white-crowned sparrows and Japanese quail. Administration of small interfering RNA against GnIH precursor mRNA (GnIH siRNA) into the third ventricle of white-crowned sparrows reduced resting time, spontaneous production of complex vocalizations, and stimulated brief agonistic vocalizations. These behaviors resembled those of breeding birds during territorial defense. Central administration of GnIH siRNA induced aggressive and sexual behaviors and GnIH administration suppressed GnIH RNAi induced aggressive and sexual behaviors in the male quail. In summary, GnIH may function as a central nervous system suppressor of social interaction, thus playing an important role in the control of reproductive behavior, general aggression and territorial defense.", - "journal_title": "General and comparative endocrinology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/23046601/" - } - ], - "b87bb1b6-8f39-4e64-ab9b-db07b1d91867": [ - { - "pub_id": "28226201", - "title": "Genomewide Association Study of Alcohol Dependence Identifies Risk Loci Altering Ethanol-Response Behaviors in Model Organisms.", - "authors": "Amy E Adkins,Laura M Hack,Tim B Bigdeli,Vernell S Williamson,G Omari McMichael,Mohammed Mamdani,Alexis C Edwards,Fazil Aliev,Robin F Chan,Poonam Bhandari,Richard C Raabe,Joseph T Alaimo,GinaMari G Blackwell,Arden Moscati,Ryan S Poland,Benjamin Rood,Diana G Patterson,Dermot Walsh, ,John B Whitfield,Gu Zhu,Grant W Montgomery,Anjali K Henders,Nicholas G Martin,Andrew C Heath,Pamela A F Madden,Josef Frank,Monika Ridinger,Norbert Wodarz,Michael Soyka,Peter Zill,Marcus Ising,Markus M N\u00f6then,Falk Kiefer,Marcella Rietschel, ,Joel Gelernter,Richard Sherva,Ryan Koesterer,Laura Almasy,Hongyu Zhao,Henry R Kranzler,Lindsay A Farrer,Brion S Maher,Carol A Prescott,Danielle M Dick,Silviu A Bacanu,Laura D Mathies,Andrew G Davies,Vladimir I Vladimirov,Mike Grotewiel,M Scott Bowers,Jill C Bettinger,Bradley T Webb,Michael F Miles,Kenneth S Kendler,Brien P Riley", - "abstract": "Alcohol dependence (AD) shows evidence for genetic liability, but genes influencing risk remain largely unidentified. We conducted a genomewide association study in 706 related AD cases and 1,748 unscreened population controls from Ireland. We sought replication in 15,496 samples of European descent. We used model organisms (MOs) to assess the role of orthologous genes in ethanol (EtOH)-response behaviors. We tested 1 primate-specific gene for expression differences in case/control postmortem brain tissue. We detected significant association in COL6A3 and suggestive association in 2 previously implicated loci, KLF12 and RYR3. None of these signals are significant in replication. A suggestive signal in the long noncoding RNA LOC339975 is significant in case:control meta-analysis, but not in a population sample. Knockdown of a COL6A3 ortholog in Caenorhabditis elegans reduced EtOH sensitivity. Col6a3 expression correlated with handling-induced convulsions in mice. Loss of function of the KLF12 ortholog in C.\u00a0elegans impaired development of acute functional tolerance (AFT). Klf12 expression correlated with locomotor activation following EtOH injection in mice. Loss of function of the RYR3 ortholog reduced EtOH sensitivity in C.\u00a0elegans and rapid tolerance in Drosophila. The ryanodine receptor antagonist dantrolene reduced motivation to self-administer EtOH in rats. Expression of LOC339975 does not differ between cases and controls but is reduced in carriers of the associated rs11726136 allele in nucleus accumbens (NAc). We detect association between AD and COL6A3, KLF12, RYR3, and LOC339975. Despite nonreplication of COL6A3, KLF12, and RYR3 signals, orthologs of these genes influence behavioral response to EtOH in MOs, suggesting potential involvement in human EtOH response and AD liability. The associated LOC339975 allele may influence gene expression in human NAc. Although the functions of long noncoding RNAs are poorly understood, there is mounting evidence implicating these genes in multiple brain functions and disorders.", - "journal_title": "Alcoholism, clinical and experimental research", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/28226201/" - } - ], - "843c0ab9-0a56-49f7-9be0-681b386cbbc5": [ - { - "pub_id": "16251990", - "title": "Laboratory models of alcoholism: treatment target identification and insight into mechanisms.", - "authors": "David M Lovinger,John C Crabbe", - "abstract": "Laboratory models, including animal tissues and live animals, have proven useful for discovery of molecular targets of alcohol action as well as for characterization of genetic and environmental factors that influence alcohol's neural actions. Here we consider strengths and weaknesses of laboratory models used in alcohol research and analyze the limitations of using animals to model a complex human disease. We describe targets for the neural actions of alcohol, and we review studies in which animal models were used to examine excessive alcohol drinking and to discover genes that may contribute to risk for alcoholism. Despite some limitations of the laboratory models used in alcohol research, these experimental approaches are likely to contribute to the development of new therapies for alcohol abuse and alcoholism.", - "journal_title": "Nature neuroscience", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/16251990/" - } - ], - "9292f4ab-191e-4e8f-af39-68099158fd32": [ - { - "pub_id": "20031921", - "title": "Analysis of natural allelic variation controlling Arabidopsis thaliana seed germinability in response to cold and dark: identification of three major quantitative trait loci.", - "authors": "Ping-Hong Meng,Audrey Macquet,Olivier Loudet,Annie Marion-Poll,Helen M North", - "abstract": "Light and temperature are key external factors in the control of Arabidopsis thaliana seed germination and dormancy mechanisms. Perception and response to these stimuli have to ensure that seedling emergence and growth occur at the most advantageous time for correct establishment. Analysis of over 300 Arabidopsis accessions identified 14, from 12 different geographical locations, that were able to germinate to greater than 20% at 6 degrees C in the dark. This natural variation was exploited to identify genetic loci responsible for cold-tolerant, dark germination. A quantitative trait loci approach was used on recombinant inbred line progeny of a cross between Bay-0 and Shahdara. Six distinct quantitative trait loci were identified, three of which were major loci, each responsible for 17-25% of the phenotypic variability in this trait. Parental phenotypes indicated that the majority of the cold-tolerant, dark-germination characteristics are related to light responses. Validation of the three major loci using heterogeneous inbred families confirmed the feasibility of fine mapping and cloning the genes at the quantitative trait loci responsible for cold-tolerant, dark germination.", - "journal_title": "Molecular plant", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/20031921/" - } - ], - "57a3fa09-8f10-49fe-99f7-04add25c1804": [ - { - "pub_id": "15569717", - "title": "Alcohol and gene expression in the central nervous system.", - "authors": "Travis J Worst,Kent E Vrana", - "abstract": "To describe recent research focusing on the analysis of gene and protein expression relevant to understanding ethanol consumption, dependence and effects, in order to identify common themes. A selective literature search was used to collate the relevant data. Over 160 genes have been individually assessed before or after ethanol administration, as well as in genetically selected lines. Techniques for studying gene expression include northern blots, differential display, real time reverse transcriptase-polymerase chain reaction (RT-PCR) and in situ hybridization. More recently, high throughput functional genomic technology, such as DNA microarrays, has been used to examine gene expression. Recent gene expression analyses have dramatically increased the number of candidate genes (nine array papers have illuminated 600 novel gene transcripts that may contribute to alcohol abuse and alcoholism). Although functional genomic experiments (transcriptome analysis) have failed to identify a single alcoholism gene, they have illuminated important pathways and gene products that may contribute to the risk of alcohol abuse and alcoholism.", - "journal_title": "Alcohol and alcoholism (Oxford, Oxfordshire)", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/15569717/" - } - ], - "b58ddaa8-9d41-4dc5-97d7-aca64de3685b": [ - { - "pub_id": "19370154", - "title": "In silico whole genome association scan for murine prepulse inhibition.", - "authors": "Bradley Todd Webb,Joseph L McClay,Cristina Vargas-Irwin,Timothy P York,Edwin J C G van den Oord", - "abstract": "The complex trait of prepulse inhibition (PPI) is a sensory gating measure related to schizophrenia and can be measured in mice. Large-scale public repositories of inbred mouse strain genotypes and phenotypes such as PPI can be used to detect Quantitative Trait Loci (QTLs) in silico. However, the method has been criticized for issues including insufficient number of strains, not controlling for false discoveries, the complex haplotype structure of inbred mice, and failing to account for genotypic and phenotypic subgroups. We have implemented a method that addresses these issues by incorporating phylogenetic analyses, multilevel regression with mixed effects, and false discovery rate (FDR) control. A genome-wide scan for PPI was conducted using over 17,000 single nucleotide polymorphisms (SNPs) in 37 strains phenotyped. Eighty-nine SNPs were significant at a false discovery rate (FDR) of 5%. After accounting for long-range linkage disequilibrium, we found 3 independent QTLs located on murine chromosomes 1 and 13. One of the PPI positives corresponds to a region of human chromosome 6p which includes DTNBP1, a gene implicated in schizophrenia. Another region includes the gene Tsn which alters PPI when knocked out. These genes also appear to have correlated expression with PPI. These results support the usefulness of using an improved in silico mapping method to identify QTLs for complex traits such as PPI which can be then be used for to help identify loci influencing schizophrenia in humans.", - "journal_title": "PloS one", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/19370154/" - } - ], - "fee26613-3228-4e76-80a5-db316980c43c": [ - { - "pub_id": "24923803", - "title": "Identification of a QTL in Mus musculus for alcohol preference, withdrawal, and Ap3m2 expression using integrative functional genomics and precision genetics.", - "authors": "Jason A Bubier,Jeremy J Jay,Christopher L Baker,Susan E Bergeson,Hiroshi Ohno,Pamela Metten,John C Crabbe,Elissa J Chesler", - "abstract": "Extensive genetic and genomic studies of the relationship between alcohol drinking preference and withdrawal severity have been performed using animal models. Data from multiple such publications and public data resources have been incorporated in the GeneWeaver database with >60,000 gene sets including 285 alcohol withdrawal and preference-related gene sets. Among these are evidence for positional candidates regulating these behaviors in overlapping quantitative trait loci (QTL) mapped in distinct mouse populations. Combinatorial integration of functional genomics experimental results revealed a single QTL positional candidate gene in one of the loci common to both preference and withdrawal. Functional validation studies in Ap3m2 knockout mice confirmed these relationships. Genetic validation involves confirming the existence of segregating polymorphisms that could account for the phenotypic effect. By exploiting recent advances in mouse genotyping, sequence, epigenetics, and phylogeny resources, we confirmed that Ap3m2 resides in an appropriately segregating genomic region. We have demonstrated genetic and alcohol-induced regulation of Ap3m2 expression. Although sequence analysis revealed no polymorphisms in the Ap3m2-coding region that could account for all phenotypic differences, there are several upstream SNPs that could. We have identified one of these to be an H3K4me3 site that exhibits strain differences in methylation. Thus, by making cross-species functional genomics readily computable we identified a common QTL candidate for two related bio-behavioral processes via functional evidence and demonstrate sufficiency of the genetic locus as a source of variation underlying two traits.", - "journal_title": "Genetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/24923803/" - } - ], - "80a77e9d-0d80-4548-9253-c14b8bb5cff7": [ - { - "pub_id": "24814482", - "title": "Pharmacological Inhibition of poly(ADP-ribose) polymerases improves fitness and mitochondrial function in skeletal muscle.", - "authors": "Eija Pirinen,Carles Cant\u00f3,Young Suk Jo,Laia Morato,Hongbo Zhang,Keir J Menzies,Evan G Williams,Laurent Mouchiroud,Norman Moullan,Carolina Hagberg,Wei Li,Silvie Timmers,Ralph Imhof,Jef Verbeek,Aurora Pujol,Barbara van Loon,Carlo Viscomi,Massimo Zeviani,Patrick Schrauwen,Anthony A Sauve,Kristina Schoonjans,Johan Auwerx", - "abstract": "We previously demonstrated that the deletion of the poly(ADP-ribose)polymerase (Parp)-1 gene in mice enhances oxidative metabolism, thereby protecting against diet-induced obesity. However, the therapeutic use of PARP inhibitors to enhance mitochondrial function remains to be explored. Here, we show tight negative correlation between Parp-1 expression and energy expenditure in heterogeneous mouse populations, indicating that variations in PARP-1 activity have an impact on metabolic homeostasis. Notably, these genetic correlations can be translated into pharmacological applications. Long-term treatment with PARP inhibitors enhances fitness in mice by increasing the abundance of mitochondrial respiratory complexes and boosting mitochondrial respiratory capacity. Furthermore, PARP inhibitors reverse mitochondrial defects in primary myotubes of obese humans and attenuate genetic defects of mitochondrial metabolism in human fibroblasts and C. elegans. Overall, our work validates in worm, mouse, and human models that PARP inhibition may be used to treat both genetic and acquired muscle dysfunction linked to defective mitochondrial function.", - "journal_title": "Cell metabolism", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/24814482/" - } - ], - "d3dae048-6a34-4ab5-9c47-4f11da232b97": [ - { - "pub_id": "19107586", - "title": "Studies on Syntaxin 12 and alcohol preference involving C57BL/6J and DBA/2J strains of mice.", - "authors": "J Weng,M N Symons,S M Singh", - "abstract": "C57BL/6J and DBA/2J inbred mouse strains have been extensively studied for the genetic dissection of alcohol-related phenotypes. We have previously found Syntaxin 12 to be associated with alcohol preference in C57BL/6J and DBA/2J due to its strain-specific and ethanol responsive expression in the male brain. In the current study, we combined genetic and expression analyses to assess the segregation of Syntaxin 12 c.*1370G>A polymorphism with its strain-specific expression and alcohol preference in an F (2) population (N = 427) derived from C57BL/6J and DBA/2J strains. Syntaxin 12 c.*1370G>A polymorphism was found to segregate with alcohol preference in the B6D2F2 population and a correlation was identified between Syntaxin 12 expression and alcohol preference in the selected B6D2F2 males (r = -0.473, r (2) = 0.22). We followed up our analysis in the BXD RI lines using resources from WebQTL and the Mouse Phenome Database. Our study detected significant associations of Syntaxin 12 molecular variants with its level of expression and alcohol preference in B6D2F2 males. Overall, our findings support a role for Syntaxin 12 as a potential contributor to alcohol preference in mice.", - "journal_title": "Behavior genetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/19107586/" - } - ], - "32338b01-15af-4ec9-9bc4-e9c58b53068e": [ - { - "pub_id": "26357913", - "title": "Genetic properties of the MAGIC maize population: a new platform for high definition QTL mapping in Zea mays.", - "authors": "Matteo Dell'Acqua,Daniel M Gatti,Giorgio Pea,Federica Cattonaro,Frederik Coppens,Gabriele Magris,Aye L Hlaing,Htay H Aung,Hilde Nelissen,Joke Baute,Elisabetta Frascaroli,Gary A Churchill,Dirk Inz\u00e9,Michele Morgante,Mario Enrico P\u00e8", - "abstract": "Maize (Zea mays) is a globally produced crop with broad genetic and phenotypic variation. New tools that improve our understanding of the genetic basis of quantitative traits are needed to guide predictive crop breeding. We have produced the first balanced multi-parental population in maize, a tool that provides high diversity and dense recombination events to allow routine quantitative trait loci (QTL) mapping in maize. We produced 1,636 MAGIC maize recombinant inbred lines derived from eight genetically diverse founder lines. The characterization of 529 MAGIC maize lines shows that the population is a balanced, evenly differentiated mosaic of the eight founders, with mapping power and resolution strengthened by high minor allele frequencies and a fast decay of linkage disequilibrium. We show how MAGIC maize may find strong candidate genes by incorporating genome sequencing and transcriptomics data. We discuss three QTL for grain yield and three for flowering time, reporting candidate genes. Power simulations show that subsets of MAGIC maize might achieve high-power and high-definition QTL mapping. We demonstrate MAGIC maize's value in identifying the genetic bases of complex traits of agronomic relevance. The design of MAGIC maize allows the accumulation of sequencing and transcriptomics layers to guide the identification of candidate genes for a number of maize traits at different developmental stages. The characterization of the full MAGIC maize population will lead to higher power and definition in QTL mapping, and lay the basis for improved understanding of maize phenotypes, heterosis included. MAGIC maize is available to researchers.", - "journal_title": "Genome biology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/26357913/" - } - ], - "5964906e-b016-4a60-b043-db826b438048": [ - { - "pub_id": "18185497", - "title": "Variation in mouse basolateral amygdala volume is associated with differences in stress reactivity and fear learning.", - "authors": "Rebecca J Yang,Khyobeni Mozhui,Rose-Marie Karlsson,Heather A Cameron,Robert W Williams,Andrew Holmes", - "abstract": "A wealth of research identifies the amygdala as a key brain region mediating negative affect, and implicates amygdala dysfunction in the pathophysiology of anxiety disorders. Although there is a strong genetic component to anxiety disorders such as posttraumatic stress disorder (PTSD) there remains debate about whether abnormalities in amygdala function predispose to these disorders. In the present study, groups of C57BL/6 x DBA/2 (B x D) recombinant inbred strains of mice were selected for differences in volume of the basolateral amygdala complex (BLA). Strains with relatively small, medium, or large BLA volumes were compared for Pavlovian fear learning and memory, anxiety-related behaviors, depression-related behavior, and glucocorticoid responses to stress. Strains with relatively small BLA exhibited stronger conditioned fear responses to both auditory tone and contextual stimuli, as compared to groups with larger BLA. The small BLA group also showed significantly greater corticosterone responses to stress than the larger BLA groups. BLA volume did not predict clear differences in measures of anxiety-like behavior or depression-related behavior, other than greater locomotor inhibition to novelty in strains with smaller BLA. Neither striatal, hippocampal nor cerebellar volumes correlated significantly with any behavioral measure. The present data demonstrate a phenotype of enhanced fear conditioning and exaggerated glucocorticoid responses to stress associated with small BLA volume. This profile is reminiscent of the increased fear processing and stress reactivity that is associated with amygdala excitability and reduced amygdala volume in humans carrying loss of function polymorphisms in the serotonin transporter and monoamine oxidase A genes. Our study provides a unique example of how natural variation in amygdala volume associates with specific fear- and stress-related phenotypes in rodents, and further supports the role of amygdala dysfunction in anxiety disorders such as PTSD.", - "journal_title": "Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/18185497/" - } - ], - "ebb49f39-ee30-4b32-959d-305276fd589e": [ - { - "pub_id": "26018251", - "title": "An Islet-Targeted Genome-Wide Association Scan Identifies Novel Genes Implicated in Cytokine-Mediated Islet Stress in Type 2 Diabetes.", - "authors": "Poonam R Sharma,Aaron J Mackey,Eden A Dejene,James W Ramadan,Carl D Langefeld,Nicholette D Palmer,Kent D Taylor,Lynne E Wagenknecht,Richard M Watanabe,Stephen S Rich,Craig S Nunemaker", - "abstract": "Genome-wide association studies in human type 2 diabetes (T2D) have renewed interest in the pancreatic islet as a contributor to T2D risk. Chronic low-grade inflammation resulting from obesity is a risk factor for T2D and a possible trigger of \u03b2-cell failure. In this study, microarray data were collected from mouse islets after overnight treatment with cytokines at concentrations consistent with the chronic low-grade inflammation in T2D. Genes with a cytokine-induced change of >2-fold were then examined for associations between single nucleotide polymorphisms and the acute insulin response to glucose (AIRg) using data from the Genetics Underlying Diabetes in Hispanics (GUARDIAN) Consortium. Significant evidence of association was found between AIRg and single nucleotide polymorphisms in Arap3 (5q31.3), F13a1 (6p25.3), Klhl6 (3q27.1), Nid1 (1q42.3), Pamr1 (11p13), Ripk2 (8q21.3), and Steap4 (7q21.12). To assess the potential relevance to islet function, mouse islets were exposed to conditions modeling low-grade inflammation, mitochondrial stress, endoplasmic reticulum (ER) stress, glucotoxicity, and lipotoxicity. RT-PCR revealed that one or more forms of stress significantly altered expression levels of all genes except Arap3. Thapsigargin-induced ER stress up-regulated both Pamr1 and Klhl6. Three genes confirmed microarray predictions of significant cytokine sensitivity: F13a1 was down-regulated 3.3-fold by cytokines, Ripk2 was up-regulated 1.5- to 3-fold by all stressors, and Steap4 was profoundly cytokine sensitive (167-fold up-regulation). Three genes were thus closely associated with low-grade inflammation in murine islets and also with a marker for islet function (AIRg) in a diabetes-prone human population. This islet-targeted genome-wide association scan identified several previously unrecognized candidate genes related to islet dysfunction during the development of T2D.", - "journal_title": "Endocrinology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/26018251/" - } - ], - "bb86d287-d3b8-43cf-9fa6-bece9d3059c8": [ - { - "pub_id": "32499647", - "title": "Identification of type 2 diabetes loci in 433,540 East Asian individuals.", - "authors": "Cassandra N Spracklen,Momoko Horikoshi,Young Jin Kim,Kuang Lin,Fiona Bragg,Sanghoon Moon,Ken Suzuki,Claudia H T Tam,Yasuharu Tabara,Soo-Heon Kwak,Fumihiko Takeuchi,Jirong Long,Victor J Y Lim,Jin-Fang Chai,Chien-Hsiun Chen,Masahiro Nakatochi,Jie Yao,Hyeok Sun Choi,Apoorva K Iyengar,Hannah J Perrin,Sarah M Brotman,Martijn van de Bunt,Anna L Gloyn,Jennifer E Below,Michael Boehnke,Donald W Bowden,John C Chambers,Anubha Mahajan,Mark I McCarthy,Maggie C Y Ng,Lauren E Petty,Weihua Zhang,Andrew P Morris,Linda S Adair,Masato Akiyama,Zheng Bian,Juliana C N Chan,Li-Ching Chang,Miao-Li Chee,Yii-Der Ida Chen,Yuan-Tsong Chen,Zhengming Chen,Lee-Ming Chuang,Shufa Du,Penny Gordon-Larsen,Myron Gross,Xiuqing Guo,Yu Guo,Sohee Han,Annie-Green Howard,Wei Huang,Yi-Jen Hung,Mi Yeong Hwang,Chii-Min Hwu,Sahoko Ichihara,Masato Isono,Hye-Mi Jang,Guozhi Jiang,Jost B Jonas,Yoichiro Kamatani,Tomohiro Katsuya,Takahisa Kawaguchi,Chiea-Chuen Khor,Katsuhiko Kohara,Myung-Shik Lee,Nanette R Lee,Liming Li,Jianjun Liu,Andrea O Luk,Jun Lv,Yukinori Okada,Mark A Pereira,Charumathi Sabanayagam,Jinxiu Shi,Dong Mun Shin,Wing Yee So,Atsushi Takahashi,Brian Tomlinson,Fuu-Jen Tsai,Rob M van Dam,Yong-Bing Xiang,Ken Yamamoto,Toshimasa Yamauchi,Kyungheon Yoon,Canqing Yu,Jian-Min Yuan,Liang Zhang,Wei Zheng,Michiya Igase,Yoon Shin Cho,Jerome I Rotter,Ya-Xing Wang,Wayne H H Sheu,Mitsuhiro Yokota,Jer-Yuarn Wu,Ching-Yu Cheng,Tien-Yin Wong,Xiao-Ou Shu,Norihiro Kato,Kyong-Soo Park,E-Shyong Tai,Fumihiko Matsuda,Woon-Puay Koh,Ronald C W Ma,Shiro Maeda,Iona Y Millwood,Juyoung Lee,Takashi Kadowaki,Robin G Walters,Bong-Jo Kim,Karen L Mohlke,Xueling Sim", - "abstract": "Meta-analyses of genome-wide association studies (GWAS) have identified more than 240 loci that are associated with type 2 diabetes (T2D)<sup>1,2</sup>; however, most of these loci have been identified in analyses of individuals with European ancestry. Here, to examine T2D risk in East Asian individuals, we carried out a meta-analysis of GWAS data from 77,418 individuals with T2D and 356,122 healthy control individuals. In the main analysis, we identified 301 distinct association signals at 183 loci, and across T2D association models with and without consideration of body mass index and sex, we identified 61 loci that are newly implicated in predisposition to T2D. Common variants associated with T2D in both East Asian and European populations exhibited strongly correlated effect sizes. Previously undescribed associations include signals in or near GDAP1, PTF1A, SIX3, ALDH2, a microRNA cluster, and genes that affect the differentiation of muscle and adipose cells<sup>3</sup>. At another locus, expression quantitative trait loci at two overlapping T2D signals affect two genes-NKX6-3 and ANK1-in different tissues<sup>4-6</sup>. Association studies in diverse populations identify additional loci and elucidate disease-associated genes, biology, and pathways.", - "journal_title": "Nature", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/32499647/" - } - ], - "df542302-18b9-43c2-a421-cba1dba0b3be": [ - { - "pub_id": "23710470", - "title": "Animal models of GWAS-identified type 2 diabetes genes.", - "authors": "Gabriela da Silva Xavier,Elisa A Bellomo,James A McGinty,Paul M French,Guy A Rutter", - "abstract": "More than 65 loci, encoding up to 500 different genes, have been implicated by genome-wide association studies (GWAS) as conferring an increased risk of developing type 2 diabetes (T2D). Whilst mouse models have in the past been central to understanding the mechanisms through which more penetrant risk genes for T2D, for example, those responsible for neonatal or maturity-onset diabetes of the young, only a few of those identified by GWAS, notably TCF7L2 and ZnT8/SLC30A8, have to date been examined in mouse models. We discuss here the animal models available for the latter genes and provide perspectives for future, higher throughput approaches towards efficiently mining the information provided by human genetics.", - "journal_title": "Journal of diabetes research", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/23710470/" - } - ], - "7ca1b7d0-cbae-4c68-b8e8-610435d84f9f": [ - { - "pub_id": "23840826", - "title": "Congenic mice provide evidence for a genetic locus that modulates spontaneous arthritis caused by deficiency of IL-1RA.", - "authors": "Yanhong Cao,Xiaoyun Liu,Nan Deng,Yan Jiao,Yonghui Ma,Karen A Hasty,John M Stuart,Weikuan Gu", - "abstract": "To understand the role of genetic factors involved in the development of spontaneous arthritis in mice deficient in IL-1 receptor antagonist protein (IL_1RA), we have identified a genomic region containing a major quantitative trait locus (QTL) for this disease. The QTL is on chromosome 1 and appears to be the strongest genetic region regulating arthritis. To confirm the importance of the QTL and to identify potential candidate genes within it, we conducted speed congenic breeding to transfer the QTL region from DBA/1 mice that are resistant to spontaneous arthritis into BALB/c(-/-) which are susceptible. Genetic markers along every chromosome were used to assist in the selection of progeny in each generation to backcross to BALB/c(-/-). By the 6th generation we determined that all of the chromosomes in the progeny were of BALB/c origin with the exception of portions of chromosome 1. At this stage we intercrossed selected mice to produce homozygous strains containing the genomic background of BALB/c(-/-) except for the QTL region on chromosome 1, which was from DBA/1. We were able to establish two congenic strains with overlapping DBA/1 DNA segments. These strains were observed for the development of spontaneous arthritis. Both congenic strains were relatively resistant to spontaneous arthritis and had delayed onset and reduced severity of disease. The gene/s that regulates this major QTL would appear to be located in the region of the QTL that is shared by both strains. The common transferred region is between D1Mit110 and D1Mit209 on chromosome 1. We evaluated this region for candidate genes and have identified a limited number of candidates. Confirmation of the identity and precise role of the candidates will require additional study.", - "journal_title": "PloS one", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/23840826/" - } - ], - "e2799196-122f-4b4f-a2a6-68adf24a236f": [ - { - "pub_id": "18594913", - "title": "Using hippocampal microRNA expression differences between mouse inbred strains to characterise miRNA function.", - "authors": "Michael J Parsons,Christina H Grimm,Jose L Paya-Cano,Karen Sugden,Wilfried Nietfeld,Hans Lehrach,Leonard C Schalkwyk", - "abstract": "Micro-RNAs (miRNAs) are short, single-stranded, noncoding RNAs that are involved in the regulation of protein-coding genes at the level of messenger RNA (mRNA). They are involved in the regulation of numerous traits, including developmental timing, apoptosis, immune function, and neuronal development. To better understand how the expression of the miRNAs themselves is regulated, we looked for miRNA expression differences among four mouse inbred strains, A/J, BALB/cJ, C57BL/6J, and DBA/2J, in one tissue, the hippocampus. A total of 166 miRNA RT-PCR assays were used to screen RNA pools for each strain. Twenty miRNA species that were markedly different between strains were further investigated using eight individual samples per strain, and 11 miRNAs showed significant differences across strains (p < 0.05). This is the first observation of miRNA expression differences across inbred mice strains. We conducted an in silico correlation analysis of the expression of these differentially expressed miRNAs with phenotype data and mRNA expression to better characterise the effects of these miRNAs on both phenotype and the regulation of mRNA expression. This approach has allowed us to nominate miRNAs that have potential roles in anxiety, exploration, and learning and memory.", - "journal_title": "Mammalian genome : official journal of the International Mammalian Genome Society", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/18594913/" - } - ], - "a67372ac-02b7-41c4-bb55-5152444c5479": [ - { - "pub_id": "16772024", - "title": "Gene expression profiling in the striatum of inbred mouse strains with distinct opioid-related phenotypes.", - "authors": "Michal Korostynski,Dorota Kaminska-Chowaniec,Marcin Piechota,Ryszard Przewlocki", - "abstract": "Mouse strains with a contrasting response to morphine provide a unique model for studying the genetically determined diversity of sensitivity to opioid reward, tolerance and dependence. Four inbred strains selected for this study exhibit the most distinct opioid-related phenotypes. C57BL/6J and DBA/2J mice show remarkable differences in morphine-induced antinociception, self-administration and locomotor activity. 129P3/J mice display low morphine tolerance and dependence in contrast to high sensitivity to precipitated withdrawal observed in SWR/J and C57BL/6J strains. In this study, we attempted to investigate the relationships between genetic background and basal gene expression profile in the striatum, a brain region involved in the mechanism of opioid action. Gene expression was studied by Affymetrix Mouse Genome 430v2.0 arrays with probes for over 39.000 transcripts. Analysis of variance with the control for false discovery rate (q < 0.01) revealed inter-strain variation in the expression of ~3% of the analyzed transcripts. A combination of three methods of array pre-processing was used to compile a list of ranked transcripts covered by 1528 probe-sets significantly different between the mouse strains under comparison. Using Gene Ontology analysis, over-represented patterns of genes associated with cytoskeleton and involved in synaptic transmission were identified. Differential expression of several genes with relevant neurobiological function (e.g. GABA-A receptor alpha subunits) was validated by quantitative RT-PCR. Analysis of correlations between gene expression and behavioural data revealed connection between the level of mRNA for K homology domain containing, RNA binding, signal transduction associated 1 (Khdrbs1) and ATPase Na+/K+ alpha2 subunit (Atp1a2) with morphine self-administration and analgesic effects, respectively. Finally, the examination of transcript structure demonstrated a possible inter-strain variability of expressed mRNA forms as for example the catechol-O-methyltransferase (Comt) gene. The presented study led to the recognition of differences in the gene expression that may account for distinct phenotypes. Moreover, results indicate strong contribution of genetic background to differences in gene transcription in the mouse striatum. The genes identified in this work constitute promising candidates for further animal studies and for translational genetic studies in the field of addictive and analgesic properties of opioids.", - "journal_title": "BMC genomics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/16772024/" - } - ], - "d74b9d37-258f-440c-afdd-cb3ed7c14f34": [ - { - "pub_id": "35706766", - "title": "The GLM framework of the Lee-Carter model: a multi-country study.", - "authors": "Shafiqah Azman,Dharini Pathmanathan", - "abstract": "The Lee-Carter model is a well-known model in modeling mortality. We aim to compare three probability models (Poisson, negative binomial and binomial) based on the Generalized Linear Model (GLM) framework of the Lee-Carter model. These models are applied to mortality data for 10 selected countries (Japan, United States, United Kingdom, Australia, Sweden, Spain, Belgium, Canada, Netherlands and Bulgaria) and the fit of these models is assessed using the deviance statistics and standardized residuals against fitted value plot. Among these three models, the negative binomial Lee-Carter model gave the best fit based on the deviance statistics and estimates of the log of deaths.", - "journal_title": "Journal of applied statistics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/35706766/" - } - ], - "bc76d2f5-204c-4883-84eb-371b666dc877": [ - { - "pub_id": "2690958", - "title": "Amylin and the amylin gene: structure, function and relationship to islet amyloid and to diabetes mellitus.", - "authors": "G J Cooper,A J Day,A C Willis,A N Roberts,K B Reid,B Leighton", - "abstract": "Amylin, the major peptide component of the islet amyloid commonly found in the pancreases of patients with type 2 (non-insulin-dependent) diabetes mellitus (NIDDM), is a recently discovered islet polypeptide. This peptide has many structural and functional features suggesting that it is a novel hormone, which may control carbohydrate metabolism in partnership with insulin and other glucoregulatory factors. Amylin is synthesised in, and probably secreted from, the beta-cells of the islets of Langerhans, where it has recently been immunolocalised to secretory granules. DNA cloning studies indicate that in the human and the rat, amylin is generated from a precursor, preproamylin, which displays a typical signal peptide followed by a small prohormone-like sequence containing the amylin sequence. The presence of the signal peptide suggests that amylin is secreted and plays a physiological role. Amylin is probably generated by proteolytic processing similar to that for proinsulin and other islet prohormones. The human amylin gene encodes the complete polypeptide precursor in two exons which are separated by an intron of approx. 5 kb, and is located on chromosome 12. Amylin is a potent modulator of glycogen synthesis and glucose uptake in skeletal muscle, and is capable of inducing an insulin-resistant state in this tissue in vitro, and perhaps also in the liver in vivo. In normal metabolism, amylin could act in concert with insulin as a signal for the body to switch the site of carbohydrate disposal from glycogen to longer-term stores in adipose tissue, by making skeletal muscle relatively insulin-resistant, whilst at the same time leaving rates of insulin-stimulated carbohydrate metabolism in adipose tissue unaltered. Several lines of evidence now implicate elevated amylin levels in the pathogenic mechanisms underlying NIDDM, and suggest to us that the obesity which frequently accompanies this syndrome is a result of, rather than a risk factor for, NIDDM. Following the beta-cell destruction which occurs in type 1 (insulin-dependent) diabetes mellitus (IDDM), it is probable that amylin secretion disappears in addition to that of insulin. As patients with insulin-treated IDDM frequently experience problems with hypoglycaemia, and as amylin acts to modulate the action of insulin in various tissues, it is possible that amylin deficiency may contribute to morbidity in insulin-treated IDDM, perhaps through the loss of a natural damping mechanism which guards against hypoglycaemia under conditions of normal physiology.", - "journal_title": "Biochimica et biophysica acta", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/2690958/" - } - ], - "71446078-8694-4c94-a2aa-28369903d470": [ - { - "pub_id": "35301183", - "title": "Physical activity as a protective factor for dementia and Alzheimer's disease: systematic review, meta-analysis and quality assessment of cohort and case-control studies.", - "authors": "Paula Iso-Markku,Urho M Kujala,Keegan Knittle,Juho Polet,Eero Vuoksimaa,Katja Waller", - "abstract": "Physical activity (PA) is associated with a decreased incidence of dementia, but much of the evidence comes from short follow-ups prone to reverse causation. This meta-analysis investigates the effect of study length on the association. A systematic review and meta-analysis. Pooled effect sizes, dose-response analysis and funnel plots were used to synthesise the results. CINAHL (last search 19 October 2021), PsycInfo, Scopus, PubMed, Web of Science (21 October 2021) and SPORTDiscus (26 October 2021). Studies of adults with a prospective follow-up of at least 1\u2009year, a valid cognitive measure or cohort in mid-life at baseline and an estimate of the association between baseline PA and follow-up all-cause dementia, Alzheimer's disease or vascular dementia were included (n=58). PA was associated with a decreased risk of all-cause dementia (pooled relative risk 0.80, 95% CI 0.77 to 0.84, n=257\u2009983), Alzheimer's disease (0.86, 95% CI 0.80 to 0.93, n=128\u2009261) and vascular dementia (0.79, 95% CI 0.66 to 0.95, n=33 870), even in longer follow-ups (\u226520 years) for all-cause dementia and Alzheimer's disease. Neither baseline age, follow-up length nor study quality significantly moderated the associations. Dose-response meta-analyses revealed significant linear, spline and quadratic trends within estimates for all-cause dementia incidence, but only a significant spline trend for Alzheimer's disease. Funnel plots showed possible publication bias for all-cause dementia and Alzheimer's disease. PA was associated with lower incidence of all-cause dementia and Alzheimer's disease, even in longer follow-ups, supporting PA as a modifiable protective lifestyle factor, even after reducing the effects of reverse causation.", - "journal_title": "British journal of sports medicine", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/35301183/" - } - ], - "3aee857e-2d58-4b93-b8f7-dcefafc6ee6a": [ - { - "pub_id": "1644240", - "title": "A genetic marker at the glucokinase gene locus for type 2 (non-insulin-dependent) diabetes mellitus in Mauritian Creoles.", - "authors": "K C Chiu,M A Province,G K Dowse,P Z Zimmet,G Wagner,S Serjeantson,M A Permutt", - "abstract": "The prevalence of Type 2 (non-insulin-dependent) diabetes mellitus is high in Mauritius, a multiethnic island nation in the southwestern Indian Ocean. Evaluation of candidate genes in the different ethnic groups represents a means of assessing the genetic component. As glucokinase is known to be a key regulator of glucose homeostasis in liver and pancreatic Beta-cells, the human gene was isolated and a dinucleotide repeat (CA)n marker was identified at this locus. A polymerase chain reaction assay was developed, and alleles differing in size were observed in individuals, according to the number of repeats in the amplified fragment. Eighty-five Creoles and 63 Indians of known glucose tolerance status were typed by amplification of genomic DNA for this dinucleotide (CA)n repeat marker. Four different alleles were observed including Z, the most common allele, and Z + 2, Z + 4, and Z + 10, which differed from Z by 2, 4, and 10 nucleotides respectively. In Mauritian Creoles, the frequency of the Z + 2 allele was greater in Type 2 diabetic subjects than in control subjects (23.8% vs 8.9%, p = 0.008), and the frequency of the Z allele was lower in Type 2 diabetic subjects (60% vs 75.6%, p = 0.03). Analysis with univariate logistic regression models indicated that the Z + 2 allele had the highest odds ratio, 3.08 (95% confidence interval 1.14-8.35, p = 0.0416), among the other risk factors (age, sex, body mass index, and waist/hip ratio). The multivariate odds ratio for Type 2 diabetes was 2.88 (95% confidence interval 0.98-8.50, p = 0.0551).(ABSTRACT TRUNCATED AT 250 WORDS)", - "journal_title": "Diabetologia", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/1644240/" - } - ], - "20771d36-aa57-46ad-b3c6-80f5b038ba43": [ - { - "pub_id": "350680", - "title": "Obese and diabetes: two mutant genes causing diabetes-obesity syndromes in mice.", - "authors": "D L Coleman", - "abstract": "", - "journal_title": "Diabetologia", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/350680/" - } - ], - "da483ef5-232a-4589-af18-f01d33cc77ec": [ - { - "pub_id": "3511099", - "title": "Diabetes due to secretion of a structurally abnormal insulin (insulin Wakayama). Clinical and functional characteristics of [LeuA3] insulin.", - "authors": "K Nanjo,T Sanke,M Miyano,K Okai,R Sowa,M Kondo,S Nishimura,K Iwo,K Miyamura,B D Given", - "abstract": "We have identified a non-insulin-dependent diabetic patient with fasting hyperinsulinemia (90 microU/ml), an elevated insulin:C-peptide molar ratio (1.68; normal, 0.05-0.20), normal insulin counterregulatory hormone levels, and an adequate response to exogenously administered insulin. Insulin-binding antibodies were absent from serum, erythrocyte insulin receptor binding was normal, and greater than 90% of circulating immunoreactive insulin coeluted with 125I-labeled insulin on gel filtration. The patient's insulin diluted in parallel with a human standard in the insulin radioimmunoassay, confirming close molecular similarity. The patient's insulin was purified from serum and shown to possess both reduced binding and ability to stimulate glucose uptake and oxidation in vitro. Analysis of the patient's insulin by high-performance liquid chromatography (HPLC) revealed two products: 7.3% of insulin immunoreactivity coeluted with the human standard, while the remaining 92.7% eluted as a single peak with increased hydrophobicity. Family studies confirmed the presence of hyperinsulinemia in four of five relatives in three generations, with secretion of an abnormal insulin documented by HPLC in the three tested. Leukocyte DNA was harvested from the propositus and the insulin gene cloned. One allele was normal, but the other displayed a thymine for guanine substitution at nucleotide position 1298 from the putative cap site, resulting in a leucine for valine substitution at position 3 of the insulin A chain. Insulin Wakayama is therefore identified as [LeuA3] insulin.", - "journal_title": "The Journal of clinical investigation", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/3511099/" - } - ], - "1ee7ac81-6f9e-4840-b8ca-a4a299dc4a31": [ - { - "pub_id": "8447318", - "title": "Transmission test for linkage disequilibrium: the insulin gene region and insulin-dependent diabetes mellitus (IDDM).", - "authors": "R S Spielman,R E McGinnis,W J Ewens", - "abstract": "A population association has consistently been observed between insulin-dependent diabetes mellitus (IDDM) and the \"class 1\" alleles of the region of tandem-repeat DNA (5' flanking polymorphism [5'FP]) adjacent to the insulin gene on chromosome 11p. This finding suggests that the insulin gene region contains a gene or genes contributing to IDDM susceptibility. However, several studies that have sought to show linkage with IDDM by testing for cosegregation in affected sib pairs have failed to find evidence for linkage. As means for identifying genes for complex diseases, both the association and the affected-sib-pairs approaches have limitations. It is well known that population association between a disease and a genetic marker can arise as an artifact of population structure, even in the absence of linkage. On the other hand, linkage studies with modest numbers of affected sib pairs may fail to detect linkage, especially if there is linkage heterogeneity. We consider an alternative method to test for linkage with a genetic marker when population association has been found. Using data from families with at least one affected child, we evaluate the transmission of the associated marker allele from a heterozygous parent to an affected offspring. This approach has been used by several investigators, but the statistical properties of the method as a test for linkage have not been investigated. In the present paper we describe the statistical basis for this \"transmission test for linkage disequilibrium\" (transmission/disequilibrium test [TDT]). We then show the relationship of this test to tests of cosegregation that are based on the proportion of haplotypes or genes identical by descent in affected sibs. The TDT provides strong evidence for linkage between the 5'FP and susceptibility to IDDM. The conclusions from this analysis apply in general to the study of disease associations, where genetic markers are usually closely linked to candidate genes. When a disease is found to be associated with such a marker, the TDT may detect linkage even when haplotype-sharing tests do not.", - "journal_title": "American journal of human genetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/8447318/" - } - ], - "52b92796-0947-4d9b-aec8-791118996f78": [ - { - "pub_id": "1944595", - "title": "Insulin-IGF2 region on chromosome 11p encodes a gene implicated in HLA-DR4-dependent diabetes susceptibility.", - "authors": "C Julier,R N Hyer,J Davies,F Merlin,P Soularue,L Briant,G Cathelineau,I Deschamps,J I Rotter,P Froguel", - "abstract": "A class of alleles at the VNTR (variable number of tandem repeat) locus in the 5' region of the insulin gene (INS) on chromosome 11p is associated with increased risk of insulin-dependent diabetes mellitus (IDDM), but family studies have failed to demonstrate linkage. INS is thought to contribute to IDDM susceptibility but this view has been difficult to reconcile with the lack of linkage evidence. We thus investigated polymorphisms of INS and neighbouring loci in random diabetics, IDDM multiplex families and controls. HLA-DR4-positive diabetics showed an increased risk associated with common variants at polymorphic sites in a 19-kilobase segment spanned by the 5' INS VNTR and the third intron of the gene for insulin-like growth factor II (IGF2). As INS is the major candidate gene from this region, diabetic and control sequence were compared to identify all INS polymorphisms that could contribute to disease susceptibility. In multiplex families the IDDM-associated alleles were transmitted preferentially to HLA-DR4-positive diabetic offspring from heterozygous parents. The effect was strongest in paternal meioses, suggesting a possible role for maternal imprinting. Our results strongly support the existence of a gene or genes affecting HLA-DR4 IDDM susceptibility which is located in a 19-kilobase region of INS-IGF2. Our results also suggest new ways to map susceptibility loci in other common diseases.", - "journal_title": "Nature", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/1944595/" - } - ], - "120e8112-ef4f-4e8a-9178-df95b8727f40": [ - { - "pub_id": "3057885", - "title": "Genetic heterogeneity, modes of inheritance, and risk estimates for a joint study of Caucasians with insulin-dependent diabetes mellitus.", - "authors": "G Thomson,W P Robinson,M K Kuhner,S Joe,M J MacDonald,J L Gottschall,J Barbosa,S S Rich,J Bertrams,M P Baur", - "abstract": "From 11 studies, a total of 1,792 Caucasian probands with insulin-dependent diabetes mellitus (IDDM) are analyzed. Antigen genotype frequencies in patients, transmission from affected parents to affected children, and the relative frequencies of HLA-DR3 and -DR4 homozygous patients all indicate that DR3 predisposes in a \"recessive\"-like and DR4 in a \"dominant\"-like or \"intermediate\" fashion, after allowing for the DR3/DR4 synergistic effect. Removal of DR3 and DR4 reveals an overall protective effect of DR2, predisposing effects of DR1 and DRw8, and a slight protective effect of DR5 and a predisposing effect of DRw6. Analysis of affected-parent-to-affected-child data indicates that a subset of DR2 may predispose. The non-DR3, non-DR4 antigens are not independently associated with DR3 and DR4; the largest effect is a deficiency of DR2, followed by excesses of DR1, DRw8, and DRw6, in DR4 individuals, as compared with DR3 individuals. HLA-B locus distributions on patient haplotypes indicate that only subsets of both DR3 and DR4 are predisposing. The presence or absence of Asp at position 57 of the DQ beta gene, recently implicated in IDDM predisposition, is not by itself sufficient to explain the inheritance of IDDM. At a minimum, the distinguishing features of the DR3-associated and DR4-associated predisposition remain to be identified at the molecular level. Risk estimates for sibs of probands are calculated based on an overall sibling risk of 6%; estimates for those sharing two, one, or zero haplotypes are 12.9%, 4.5%, and 1.8%, respectively. Risk estimates subdivided by the DR type of the proband are also calculated, the highest being 19.2% for sibs sharing two haplotypes with a DR3/DR4 proband.", - "journal_title": "American journal of human genetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/3057885/" - } - ], - "8a65c2b0-9989-4218-acdb-cc5a782b1d65": [ - { - "pub_id": "1990836", - "title": "High-resolution linkage mapping for susceptibility genes in human polygenic disease: insulin-dependent diabetes mellitus and chromosome 11q.", - "authors": "R N Hyer,C Julier,J D Buckley,M Trucco,J Rotter,R Spielman,A Barnett,S Bain,C Boitard,I Deschamps", - "abstract": "Insulin-dependent diabetes mellitus (IDDM) has a complex pattern of genetic inheritance. In addition to genes mapping to the major histocompatibility complex (MHC), several lines of evidence point to the existence of other genetic susceptibility factors. Recent studies of the nonobese diabetic mouse (NOD) model of IDDM have suggested the presence, on mouse chromosome 9, of a susceptibility gene linked to the locus encoding the T-cell antigen, Thy-1. A region on human chromosome 11q is syntenic to this region on mouse chromosome 9. We have used a set of polymorphic DNA markers from chromosome 11q to investigate this region for linkage to a susceptibility gene in 81 multiplex diabetic pedigrees. The data were investigated by maximization of lod scores over genetic models and by multiple-locus affected-sib-pair analysis. We were able to exclude the presence of a susceptibility gene (location scores less than -2) throughout greater than 90% of the chromosome 11q homology region, under the assumption that the susceptibility factor would cause greater than 50% of affected sib pairs to share two alleles identical by descent. Theoretical estimates of the power to map susceptibility genes with a high-resolution map of linked markers in a candidate region were made, using HLA as a model locus. This result illustrates the feasibility that IDDM linkage studies using mapped sets of polymorphic DNA markers have, both for other areas of the genome in IDDM and for other polygenic diseases. The analytic approaches introduced here will be useful for affected-sib-pair studies of other complex phenotypes.", - "journal_title": "American journal of human genetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/1990836/" - } - ], - "29ac42a6-62bc-4143-aabe-d169539e7fff": [ - { - "pub_id": "7909524", - "title": "Genetic predisposition to diabetic nephropathy. Evidence for a role of the angiotensin I--converting enzyme gene.", - "authors": "A Doria,J H Warram,A S Krolewski", - "abstract": "In search of genetic determinants of susceptibility to diabetic nephropathy, we examined the association between DNA sequence differences at the locus of angiotensin I-converting enzyme (ACE) and renal complications in 151 insulin-dependent diabetes mellitus (IDDM) patients with a diabetes duration of 16-21 years. This nested case-control study included 77 normoalbuminuric control subjects (albumin excretion rate < 30 micrograms/min) and 74 cases with evidence of nephropathy ranging from microalbuminuria to overt proteinuria. DNA from each of these patients was genotyped at the ACE locus by a three-allele restriction fragment-melting polymorphism (RFMP) (Dde I), which we described recently, and a two-allele insertion/deletion recognized as an Xba I restriction fragment-length polymorphism, which has been shown by other investigators to be associated with serum levels of ACE and with risk of myocardial infarction. The least common allele of the Dde I RFMP was significantly more frequent among cases with nephropathy than among normoalbuminuric control subjects (12.8 vs. 4.5%, P < 0.05). The deletion in the ACE gene was also more frequent in case than in control subjects (56.1 vs. 47.4%), but the difference was not statistically significant (P < 0.25) with this sample size. To determine the independence of these associations, the two polymorphisms were analyzed jointly to identify Xba I/Dde I haplotypes. As might be expected, carriers of the Xba I/Dde I '+ =' haplotype had a fourfold risk of developing diabetic nephropathy (odds ratio [OR] 4.0, 95% confidence interval [CI] 1.5-11.0). However, this did not explain all of the excess Xba I '+' allele among cases.(ABSTRACT TRUNCATED AT 250 WORDS)", - "journal_title": "Diabetes", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/7909524/" - } - ], - "045bb226-6aa5-42d4-b27a-b4ab640dd144": [ - { - "pub_id": "6363172", - "title": "A polymorphic locus near the human insulin gene is associated with insulin-dependent diabetes mellitus.", - "authors": "G I Bell,S Horita,J H Karam", - "abstract": "A polymorphic region flanking the human insulin gene on the short arm of chromosome 11, the insulin-gene-linked DNA polymorphism, can be described as a locus with at least three classes of alleles: a common small \"class 1\" allele averaging 570 base pairs, a rare intermediate \"class 2\" allele of about 1320 base pairs, and a large \"class 3\" allele averaging 2470 base pairs in size. We have determined the genotype at this locus of 393 unrelated diabetic and nondiabetic individuals. Differences were observed in the genotypic and allelic frequencies between groups of different races. Asians [17 nondiabetic, 2 with insulin-dependent diabetes mellitus (IDDM), and 8 with non-insulin-dependent diabetes mellitus (NIDDM)] exhibited the least variation in the size of this locus and 98% of the alleles in this group were class 1. A group of American blacks (32 nondiabetic, 5 with IDDM, and 40 with NIDDM) exhibited considerable variation in the size of this locus, and about 22% of the individuals examined had a genotype that included a rare class 2 allele. In neither of these two racial groups were the genotypic or allelic frequencies different between the nondiabetic and diabetic segments of these groups. However, in a group of Caucasians (83 nondiabetic, 113 with IDDM, and 76 with NIDDM), there was a significantly higher frequency of class 1 alleles and genotypes containing two class 1 alleles in the diabetic patients compared with nondiabetic controls.(ABSTRACT TRUNCATED AT 250 WORDS)", - "journal_title": "Diabetes", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/6363172/" - } - ], - "5c47eab4-1731-4e56-a04f-077aa6646ea9": [ - { - "pub_id": "15492844", - "title": "Human FOX gene family (Review).", - "authors": "Masuko Katoh,Masaru Katoh", - "abstract": "Human Forkhead-box (FOX) gene family consists of at least 43 members, including FOXA1, FOXA2, FOXA3, FOXB1, FOXC1, FOXC2, FOXD1, FOXD2, FOXD3, FOXD4, FOXD5 (FOXD4L1), FOXD6 (FOXD4L3), FOXE1, FOXE2, FOXE3, FOXF1, FOXF2, FOXG1 (FOXG1B), FOXH1, FOXI1, FOXJ1, FOXJ2, FOXJ3, FOXK1, FOXK2, FOXL1, FOXL2, FOXM1, FOXN1, FOXN2 (HTLF), FOXN3 (CHES1), FOXN4, FOXN5 (FOXR1), FOXN6 (FOXR2), FOXO1 (FOXO1A), FOXO2 (FOXO6), FOXO3 (FOXO3A), FOXO4 (MLLT7), FOXP1, FOXP2, FOXP3, FOXP4, and FOXQ1. FOXE3-FOXD2 (1p33), FOXQ1-FOXF2-FOXC1 (6p25.3), and FOXF1-FOXC2-FOXL1 (16q24.1) loci are FOX gene clusters within the human genome. Members of FOX subfamilies A-G, I-L and Q were grouped into class 1 FOX proteins, while members of FOX subfamilies H and M-P were grouped into class 2 FOX proteins. C-terminal basic region within the FOX domain was the common feature of class 1 FOX proteins. FOXH1 and FOXO1 mRNAs are expressed in human embryonic stem (ES) cells. FOXC1, FOXC2, FOXE1, FOXE3, FOXL2, FOXN1, FOXP2 and FOXP3 genes are mutated in human congenital disorders. FOXA1 gene is amplified and over-expressed in esophageal and lung cancer. FOXM1 gene is up-regulated in pancreatic cancer and basal cell carcinoma due to the transcriptional regulation by Sonic Hedgehog (SHH) pathway. FOXO1 gene is fused to PAX3 or PAX7 genes in rhabdomyosarcoma. FOXO3 and FOXO4 genes are fused to MLL gene in hematological malignancies. Deregulation of FOX family genes leads to congenital disorders, diabetes mellitus, or carcinogenesis. Expression profiles, genetic alterations and epigenetic changes of FOX family genes as well as binding proteins and target genes of FOX family transcription factors should be comprehensively investigated to develop novel therapeutics and preventives for human diseases.", - "journal_title": "International journal of oncology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/15492844/" - } - ], - "633a55dc-244d-42e2-942b-8046b2391ef0": [ - { - "pub_id": "17903298", - "title": "Genome-wide association with diabetes-related traits in the Framingham Heart Study.", - "authors": "James B Meigs,Alisa K Manning,Caroline S Fox,Jose C Florez,Chunyu Liu,L Adrienne Cupples,Jos\u00e9e Dupuis", - "abstract": "Susceptibility to type 2 diabetes may be conferred by genetic variants having modest effects on risk. Genome-wide fixed marker arrays offer a novel approach to detect these variants. We used the Affymetrix 100K SNP array in 1,087 Framingham Offspring Study family members to examine genetic associations with three diabetes-related quantitative glucose traits (fasting plasma glucose (FPG), hemoglobin A1c, 28-yr time-averaged FPG (tFPG)), three insulin traits (fasting insulin, HOMA-insulin resistance, and 0-120 min insulin sensitivity index); and with risk for diabetes. We used additive generalized estimating equations (GEE) and family-based association test (FBAT) models to test associations of SNP genotypes with sex-age-age2-adjusted residual trait values, and Cox survival models to test incident diabetes. We found 415 SNPs associated (at p < 0.001) with at least one of the six quantitative traits in GEE, 242 in FBAT (18 overlapped with GEE for 639 non-overlapping SNPs), and 128 associated with incident diabetes (31 overlapped with the 639) giving 736 non-overlapping SNPs. Of these 736 SNPs, 439 were within 60 kb of a known gene. Additionally, 53 SNPs (of which 42 had r2 < 0.80 with each other) had p < 0.01 for incident diabetes AND (all 3 glucose traits OR all 3 insulin traits, OR 2 glucose traits and 2 insulin traits); of these, 36 overlapped with the 736 other SNPs. Of 100K SNPs, one (rs7100927) was in moderate LD (r2 = 0.50) with TCF7L2 (rs7903146), and was associated with risk of diabetes (Cox p-value 0.007, additive hazard ratio for diabetes = 1.56) and with tFPG (GEE p-value 0.03). There were no common (MAF > 1%) 100K SNPs in LD (r2 > 0.05) with ABCC8 A1369S (rs757110), KCNJ11 E23K (rs5219), or SNPs in CAPN10 or HNFa. PPARG P12A (rs1801282) was not significantly associated with diabetes or related traits. Framingham 100K SNP data is a resource for association tests of known and novel genes with diabetes and related traits posted at http://www.ncbi.nlm.nih.gov/projects/gap/cgi-bin/study.cgi?id=phs000007 webcite. Framingham 100K data replicate the TCF7L2 association with diabetes.", - "journal_title": "BMC medical genetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/17903298/" - } - ], - "40cc7eee-9d31-4a82-83a8-bd8b160c844b": [ - { - "pub_id": "14636289", - "title": "Genome-wide screen in obese pedigrees with type 2 diabetes mellitus from a defined Dutch population.", - "authors": "J H van Tilburg,L A Sandkuijl,L Franke,E Strengman,P L Pearson,T W van Haeften,C Wijmenga", - "abstract": "A genome scan was performed in obese type 2 diabetes mellitus pedigrees to identify susceptibility loci involved in obesity-driven type 2 diabetes mellitus. We studied the 20% most obese diabetes pedigrees from a confined Dutch population from around the town of Breda. Previously we, and others, have already shown that a susceptibility locus influencing obesity in diabetes may reside on chromosome 18p11. We now report evidence to also suggest linkage for type 2 diabetes in these obese pedigrees on chromosome regions 11p (genome-wide P-value </= 0.061) and 12q (genome-wide P-value </= 0.029), thereby confirming previous findings from corresponding regions. The linkage found in the Breda Cohort of type 2 diabetes patients is influenced by obesity. This supports the notion that a genetic predisposition to obesity is probably intertwined with a genetic predisposition to type 2 diabetes. Further efforts should address the question of how, on a genetic level, these two factors interact.", - "journal_title": "European journal of clinical investigation", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/14636289/" - } - ], - "3c0d6ddb-72a5-49d6-b2b7-035f116f1ebb": [ - { - "pub_id": "17890495", - "title": "Meta-analysis of genome-wide linkage studies in BMI and obesity.", - "authors": "Catherine L Saunders,Benedetta D Chiodini,Pak Sham,Cathryn M Lewis,Victor Abkevich,Adebowale A Adeyemo,Mariza de Andrade,Rector Arya,Gerald S Berenson,John Blangero,Michael Boehnke,Ingrid B Borecki,Yvon C Chagnon,Wei Chen,Anthony G Comuzzie,Hong-Wen Deng,Ravindranath Duggirala,Mary F Feitosa,Philippe Froguel,Robert L Hanson,Johannes Hebebrand,Patricia Huezo-Dias,Ahmed H Kissebah,Weidong Li,Amy Luke,Lisa J Martin,Matthew Nash,Miina Ohman,Lyle J Palmer,Leena Peltonen,Markus Perola,R Arlen Price,Susan Redline,Sathanur R Srinivasan,Michael P Stern,Steven Stone,Heather Stringham,Stephen Turner,Cisca Wijmenga,David A Collier", - "abstract": "The objective was to provide an overall assessment of genetic linkage data of BMI and BMI-defined obesity using a nonparametric genome scan meta-analysis. We identified 37 published studies containing data on over 31,000 individuals from more than >10,000 families and obtained genome-wide logarithm of the odds (LOD) scores, non-parametric linkage (NPL) scores, or maximum likelihood scores (MLS). BMI was analyzed in a pooled set of all studies, as a subgroup of 10 studies that used BMI-defined obesity, and for subgroups ascertained through type 2 diabetes, hypertension, or subjects of European ancestry. Bins at chromosome 13q13.2- q33.1, 12q23-q24.3 achieved suggestive evidence of linkage to BMI in the pooled analysis and samples ascertained for hypertension. Nominal evidence of linkage to these regions and suggestive evidence for 11q13.3-22.3 were also observed for BMI-defined obesity. The FTO obesity gene locus at 16q12.2 also showed nominal evidence for linkage. However, overall distribution of summed rank p values <0.05 is not different from that expected by chance. The strongest evidence was obtained in the families ascertained for hypertension at 9q31.1-qter and 12p11.21-q23 (p < 0.01). Despite having substantial statistical power, we did not unequivocally implicate specific loci for BMI or obesity. This may be because genes influencing adiposity are of very small effect, with substantial genetic heterogeneity and variable dependence on environmental factors. However, the observation that the FTO gene maps to one of the highest ranking bins for obesity is interesting and, while not a validation of this approach, indicates that other potential loci identified in this study should be investigated further.", - "journal_title": "Obesity (Silver Spring, Md.)", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/17890495/" - } - ], - "d0af1efd-db27-42e5-b934-ed15b79484e8": [ - { - "pub_id": "11607785", - "title": "NFkappaB polymorphisms and susceptibility to type 1 diabetes.", - "authors": "D M Hegazy,D A O'Reilly,B M Yang,A D Hodgkinson,B A Millward,A G Demaine", - "abstract": "Nuclear factor kappa B (NFkappaB) is an important transcription factor that is involved in the response to oxidative stress and inflammation. Recent studies suggest that it may be involved in the development of diabetic microvascular complications. A highly polymorphic (CA) dinucleotide repeat microsatellite has been identified in the regulatory region of the NFkappaB gene. The aim of this study was to investigate whether this polymorphic region was associated with susceptibility to type 1 diabetes, or its late complications. Genomic DNA was extracted from the peripheral blood of 217 patients with type 1 diabetes mellitus (T1DM) and 111 normal healthy controls. In our population 18 alleles (A1-A18) were identified. There was a highly significant decrease in the frequency of allele 146 bp (A14) in type 1 diabetes (0.03) compared with the normal controls (0.28) (chi(2) = 79.8, Pc = 0.00001). In contrast, the frequency of the allele 138 bp (A10) was significantly increased in patients with type 1 diabetes (0.17) compared with the normal controls (0.02) (chi(2) = 32.8, P < 0.00000). These results demonstrate that the NFkappaB gene may play a role in the susceptibility to type 1 diabetes: individuals with the A10 allele may be more likely to develop diabetes compared with the A14 allele.", - "journal_title": "Genes and immunity", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/11607785/" - } - ], - "3714bf5e-c32f-4815-86bc-36b2b8d97341": [ - { - "pub_id": "22929610", - "title": "Angiotensin-converting enzyme inhibitor/angiotensin II receptor blockers and pneumonia risk among stroke patients.", - "authors": "Chia-Lin Liu,Wen-Yi Shau,Chi-Shin Wu,Mei-Shu Lai", - "abstract": "To investigate the effect of angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers on pneumonia hospitalization in patients with stroke history in Taiwan. We conducted a case-crossover study using the National Health Insurance Research Database in Taiwan during the period from 1998 to 2007. Patients who had stroke history and were subsequently admitted for pneumonia were enrolled for analysis. The status of exposure to angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers 1-30 days prior to admission (case period) was compared to that during 91-120 days and 181-210 days before admission (control periods) for each patient. Conditional logistic regression was used to estimate the odds ratio (OR) and 95% confidence interval (95% CI) for the association between pneumonia and use of angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers. In this study, 13\u200a832 patients with incident pneumonia from the stroke patient population were enrolled. After adjustment for time-varying confounding factors, angiotensin-converting enzyme inhibitor use was associated with a decreased pneumonia risk (OR 0.70; 95% CI 0.68-0.87) and a significant dose-response relationship (P \u200a<\u200a 0.01). The pneumonia risk associated with angiotensin II receptor blockers use was not significant (OR 1.02; 95% CI 0.87-1.19). Our study revealed a significant protective effect with dose-response relationship of angiotensin-converting enzyme inhibitor use on hospitalization for pneumonia among stroke patients. Further studies to confirm the protective effect of angiotensin-converting enzyme inhibitor use on pneumonia risk are warranted.", - "journal_title": "Journal of hypertension", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/22929610/" - } - ], - "9ac94855-0005-41fc-bdab-035926679476": [ - { - "pub_id": "19237574", - "title": "Antidiabetic drug metformin (GlucophageR) increases biogenesis of Alzheimer's amyloid peptides via up-regulating BACE1 transcription.", - "authors": "Yaomin Chen,Kun Zhou,Ruishan Wang,Yun Liu,Young-Don Kwak,Tao Ma,Robert C Thompson,Yongbo Zhao,Layton Smith,Laura Gasparini,Zhijun Luo,Huaxi Xu,Francesca-Fang Liao", - "abstract": "Epidemiological, clinical and experimental evidence suggests a link between type 2 diabetes and Alzheimer's disease (AD). Insulin modulates metabolism of beta-amyloid precursor protein (APP) in neurons, decreasing the intracellular accumulation of beta-amyloid (Abeta) peptides, which are pivotal in AD pathogenesis. The present study investigates whether the widely prescribed insulin-sensitizing drug, metformin (Glucophage(R)), affects APP metabolism and Abeta generation in various cell models. We demonstrate that metformin, at doses that lead to activation of the AMP-activated protein kinase (AMPK), significantly increases the generation of both intracellular and extracellular Abeta species. Furthermore, the effect of metformin on Abeta generation is mediated by transcriptional up-regulation of beta-secretase (BACE1), which results in an elevated protein level and increased enzymatic activity. Unlike insulin, metformin exerts no effect on Abeta degradation. In addition, we found that glucose deprivation and various tyrphostins, known inhibitors of insulin-like growth factors/insulin receptor tyrosine kinases, do not modulate the effect of metformin on Abeta. Finally, inhibition of AMP-activated protein kinase (AMPK) by the pharmacological inhibitor Compound C largely suppresses metformin's effect on Abeta generation and BACE1 transcription, suggesting an AMPK-dependent mechanism. Although insulin and metformin display opposing effects on Abeta generation, in combined use, metformin enhances insulin's effect in reducing Abeta levels. Our findings suggest a potentially harmful consequence of this widely prescribed antidiabetic drug when used as a monotherapy in elderly diabetic patients.", - "journal_title": "Proceedings of the National Academy of Sciences of the United States of America", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/19237574/" - } - ], - "5bda696a-af28-4fe7-96c6-7b184428c59e": [ - { - "pub_id": "19741265", - "title": "Genetics and genomics of chronic obstructive pulmonary disease.", - "authors": "Edwin K Silverman,Avrum Spira,Peter D Par\u00e9", - "abstract": "Chronic obstructive pulmonary disease (COPD) fulfills criteria for a complex genetic disease in which environmental factors interact with multiple polymorphic genes to influence susceptibility. Finding the genes that influence susceptibility can be approached in hypothesis testing or unbiased study designs. In candidate gene association studies, genetic variation in, and/or levels of, expression of genes known or suspected to be involved in the pathogenesis of COPD are compared in affected and unaffected individuals. Although this approach is useful it is limited by our present knowledge of disease pathophysiology. Genomewide studies of gene expression and of genetic variation are now possible and are not constrained by our limited knowledge. Although both of these unbiased approaches are in their infancy, they have already provided exciting new avenues for future investigation and potentially now approaches to risk prediction and therapy.", - "journal_title": "Proceedings of the American Thoracic Society", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/19741265/" - } - ], - "39e48ed7-91ac-4062-b394-22606abe7e58": [ - { - "pub_id": "19727952", - "title": "Obesity and genetics regulate microRNAs in islets, liver, and adipose of diabetic mice.", - "authors": "Enpeng Zhao,Mark P Keller,Mary E Rabaglia,Angie T Oler,Donnie S Stapleton,Kathryn L Schueler,Elias Chaibub Neto,Jee Young Moon,Ping Wang,I-Ming Wang,Pek Yee Lum,Irena Ivanovska,Michele Cleary,Danielle Greenawalt,John Tsang,Youn Jeong Choi,Robert Kleinhanz,Jin Shang,Yun-Ping Zhou,Andrew D Howard,Bei B Zhang,Christina Kendziorski,Nancy A Thornberry,Brian S Yandell,Eric E Schadt,Alan D Attie", - "abstract": "Type 2 diabetes results from severe insulin resistance coupled with a failure of b cells to compensate by secreting sufficient insulin. Multiple genetic loci are involved in the development of diabetes, although the effect of each gene on diabetes susceptibility is thought to be small. MicroRNAs (miRNAs) are noncoding 19-22-nucleotide RNA molecules that potentially regulate the expression of thousands of genes. To understand the relationship between miRNA regulation and obesity-induced diabetes, we quantitatively profiled approximately 220 miRNAs in pancreatic islets, adipose tissue, and liver from diabetes-resistant (B6) and diabetes-susceptible (BTBR) mice. More than half of the miRNAs profiled were expressed in all three tissues, with many miRNAs in each tissue showing significant changes in response to genetic obesity. Furthermore, several miRNAs in each tissue were differentially responsive to obesity in B6 versus BTBR mice, suggesting that they may be involved in the pathogenesis of diabetes. In liver there were approximately 40 miRNAs that were downregulated in response to obesity in B6 but not BTBR mice, indicating that genetic differences between the mouse strains play a critical role in miRNA regulation. In order to elucidate the genetic architecture of hepatic miRNA expression, we measured the expression of miRNAs in genetically obese F2 mice. Approximately 10% of the miRNAs measured showed significant linkage (miR-eQTLs), identifying loci that control miRNA abundance. Understanding the influence that obesity and genetics exert on the regulation of miRNA expression will reveal the role miRNAs play in the context of obesity-induced type 2 diabetes.", - "journal_title": "Mammalian genome : official journal of the International Mammalian Genome Society", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/19727952/" - } - ], - "caed4af0-165d-4ec4-b3c3-0f1eb2a56db2": [ - { - "pub_id": "15793260", - "title": "Genetic analysis of HNF4A polymorphisms in Caucasian-American type 2 diabetes.", - "authors": "Allison M Bagwell,Jennifer L Bento,Josyf C Mychaleckyj,Barry I Freedman,Carl D Langefeld,Donald W Bowden", - "abstract": "Hepatocyte nuclear factor 4alpha (HNF4A), the gene for the maturity-onset diabetes of the young type 1 monogenic form of type 2 diabetes, is within the type 2 diabetes-linked region on chromosome 20q12-q13.1 and, consequently, is a positional candidate gene for type 2 diabetes in the general population. Previous studies have identified only a few rare coding mutations. However, recent studies suggest that single nucleotide polymorphisms (SNPs) located near the P2 (beta-cell) promoter of HNF4A are associated with diabetes susceptibility. In this study, we evaluated 23 SNPs spanning 111 kb including the HNF4A gene for association with type 2 diabetes in a collection of Caucasian type 2 diabetic patients with end-stage renal disease (n = 300) and control subjects (n = 310). None of the individual SNPs were associated with type 2 diabetes in this collection of case subjects (P values ranging from 0.06 to 0.99). However, haplotype analysis identifies significant differences between haplotype frequencies in type 2 diabetic case and control subjects (P = 0.013 to P < 0.001), with two uncommon \"risk\" haplotypes (2.4 and 2.2% of chromosomes) and two uncommon \"protective\" haplotypes (7.1 and 5.0% of chromosomes) accounting for the evidence of association. Our results suggest that type 2 diabetes linked to 20q12-13 is a heterogeneous disease in which different populations may have different type 2 diabetes susceptibility loci.", - "journal_title": "Diabetes", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/15793260/" - } - ], - "069a62e0-e56a-46ab-9f93-c13a76a79989": [ - { - "pub_id": "27429334", - "title": "Increasing importance of genetics in nursing.", - "authors": "Deborah Jacks Camak", - "abstract": "To examine the empirical literature related to the incorporation of genetic research and genetic competency needed by the nurse in practice. Literature review. This article will explore published research within the past seven years of 2008-2015 that address the need for the increased incorporation of genetic content in nursing practice in addition to the need for the nurse to effectively screen the patient at risk of a genetic disorder. This literature review specifically focuses on the inadequacy of nurses in addressing genomic health compromise and serving as advocates for patients and families facing genetic disorders. A review of the literature published from 2008 to 2015 related to the incorporation of genetics in nursing practice and the role of the nurse as a patient advocate for families facing genetic disorders with resulting genomic health compromise. The research exposes the lack of adequate preparation of nurses to incorporate and utilize the recent advances in genomic healthcare. Practicing nurses lack understating and skill in the application of genetics and genomic technologies to patient care. The nursing profession, including nursing academia, need to enhance the integration of genetic and genomic content into nursing curriculum and practice. Practicing nurses are inadequately prepared to apply genetic advancements in screening at risk patients and addressing the needs of the patient or family facing a genomic health compromise.", - "journal_title": "Nurse education today", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/27429334/" - } - ], - "0e30f24a-4b61-4e4e-bbbe-22b87d4946ff": [ - { - "pub_id": "11756346", - "title": "SNP43 of CAPN10 and the risk of type 2 Diabetes in African-Americans: the Atherosclerosis Risk in Communities Study.", - "authors": "Michael J Garant,W H Linda Kao,Frederick Brancati,Josef Coresh,Tejal M Rami,Craig L Hanis,Eric Boerwinkle,Alan R Shuldiner, ", - "abstract": "Recently, an A-to-G variant in intron 3 (SNP43) of the calcium-activated neutral protease 10 gene (CAPN10) was identified as a possible type 2 diabetes susceptibility gene through positional cloning in Mexican-Americans. We conducted cross-sectional and prospective studies to evaluate the relation between SNP43 and type 2 diabetes and related traits in middle-aged African-American participants of the Atherosclerosis Risk in Communities Study, a population-based longitudinal study. At baseline, 269 prevalent diabetes cases and 1,159 nondiabetic control subjects were studied. Those with the G/G genotype were more likely to have diabetes than those with the A/G or A/A genotype (odds ratio [OR] 1.41, 95% CI 1.00-1.99, P = 0.05). In the prospective study, 166 of the control subjects developed incident diabetes over 9 years of follow-up. The incidence of diabetes for individuals with the G/G genotype did not differ significantly from those with at least one copy of the A allele (23.3 vs. 19.5 per 1,000 person years, P = 0.29). Pooling prevalent and incident diabetic cases together, individuals with the G/G genotype were approximately 40% more likely to have diabetes than those without (OR 1.38, 95% CI 1.04-1.83, P = 0.03). Because of the high frequency of the G allele (0.88), approximately 25% of the susceptibility to type 2 diabetes in African-Americans may be attributed to the G/G genotype at SNP43 of CAPN10, although most of the subjects with the G/G genotype did not develop diabetes over the 9 years of follow-up. We conclude from this large prospective study that the G allele of SNP43 of CAPN10 or another allele or gene that is in linkage disequilibrium with it increases susceptibility to type 2 diabetes in African-Americans.", - "journal_title": "Diabetes", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/11756346/" - } - ], - "df7c135a-056e-4385-a49c-d33a2c56fedc": [ - { - "pub_id": "15543146", - "title": "Mutations in PTF1A cause pancreatic and cerebellar agenesis.", - "authors": "Gabrielle S Sellick,Karen T Barker,Irene Stolte-Dijkstra,Christina Fleischmann,Richard J Coleman,Christine Garrett,Anna L Gloyn,Emma L Edghill,Andrew T Hattersley,Peter K Wellauer,Graham Goodwin,Richard S Houlston", - "abstract": "Individuals with permanent neonatal diabetes mellitus usually present within the first three months of life and require insulin treatment. We recently identified a locus on chromosome 10p13-p12.1 involved in permanent neonatal diabetes mellitus associated with pancreatic and cerebellar agenesis in a genome-wide linkage search of a consanguineous Pakistani family. Here we report the further linkage analysis of this family and a second family of Northern European descent segregating an identical phenotype. Positional cloning identified the mutations 705insG and C886T in the gene PTF1A, encoding pancreas transcription factor 1alpha, as disease-causing sequence changes. Both mutations cause truncation of the expressed PTF1A protein C-terminal to the basic-helix-loop-helix domain. Reporter-gene studies using a minimal PTF1A deletion mutant indicate that the deleted region defines a new domain that is crucial for the function of this protein. PTF1A is known to have a role in mammalian pancreatic development, and the clinical phenotype of the affected individuals implicated the protein as a key regulator of cerebellar neurogenesis. The essential role of PTF1A in normal cerebellar development was confirmed by detailed neuropathological analysis of Ptf1a(-/-) mice.", - "journal_title": "Nature genetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/15543146/" - } - ], - "f7871728-d790-4bbe-9aee-4ba40a30e5c9": [ - { - "pub_id": "17065357", - "title": "Analysis of 14 candidate genes for diabetic nephropathy on chromosome 3q in European populations: strongest evidence for association with a variant in the promoter region of the adiponectin gene.", - "authors": "Nathalie Vionnet,David Tregou\u00ebt,Gbenga Kazeem,Ivo Gut,Per-Henrik Groop,Lise Tarnow,Hans-Henrik Parving,Samy Hadjadj,Carol Forsblom,Martin Farrall,Dominique Gauguier,Roger Cox,Fumihiko Matsuda,Simon Heath,Alexandre Th\u00e9vard,Rachel Rousseau,Fran\u00e7ois Cambien,Michel Marre,Mark Lathrop", - "abstract": "Linkage studies have mapped loci for diabetic nephropathy and associated phenotypes on chromosome 3q. We studied 14 plausible candidate genes in the linkage region because of their potential role in vascular complications. In a large-scale study of patients from Denmark, Finland, and France who have type 1 diabetes, 1,057 case and 1,127 control subjects, as well as 532 trios, were investigated for association with diabetic nephropathy. We analyzed 69 haplotype-tagging single nucleotide polymorphisms and nonsynonymous variants that were identified by sequencing. Polymorphisms in three genes, glucose transporter 2 (SLC2A2), kininogen (KNG1), and adiponectin (ADIPOQ), showed nominal association with diabetic nephropathy in single-point analysis. The T-allele of SLC2A2_16459CT was associated with a decreased risk of diabetic nephropathy (odds ratio 0.79 [95% CI 0.66-0.96], P = 0.016), whereas the T-allele of KNG_7965CT and the A-allele of ADIPOQ_prom2GA were associated with increased risk of nephropathy (1.17 [1.03-1.32], P = 0.016; 1.46 [1.11-1.93], P = 0.006, respectively). Analyses of the transmission disequilibrium test showed similar trends only for ADIPOQ_prom2GA with the overtransmission of the A-allele to patients with diabetic nephropathy (1.52 [0.86-2.66], P = NS) and of the G-allele to patients without diabetic nephropathy (0.50 [0.27-0.92], P = 0.026). The overall significance for this variant (nominal P = 0.011) suggests that ADIPOQ might be involved in the development of diabetic nephropathy.", - "journal_title": "Diabetes", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/17065357/" - } - ], - "c28536b5-703d-4b79-beee-3d38fa55d188": [ - { - "pub_id": "9039882", - "title": "A prospective study of risk factors for pulmonary embolism in women.", - "authors": "S Z Goldhaber,F Grodstein,M J Stampfer,J E Manson,G A Colditz,F E Speizer,W C Willett,C H Hennekens", - "abstract": "To investigate risk factors for pulmonary embolism in women. Prospective study based on biennial, mailed questionnaires. Nurses' Health Study with 16 years of follow-up from 1976 to 1992. A group of 112822 women aged 30 to 55 years in 1976, free from diagnosed cardiovascular disease or cancer at baseline. Overall, there were 1619770 person-years of follow-up. Based on self-report and medical records, we documented 280 cases of pulmonary embolism, of which 125 were primary (no identified antecedent cancer, trauma, surgery, or immobilization). Information on height, weight, cigarette smoking, hypertension, diabetes, and hypercholesterolemia was collected by questionnaire. In multivariate analysis, obesity, cigarette smoking, and hypertension were independent predictors of pulmonary embolism. Specifically, obese women (body mass index > or = 29.0 kg/m2) had an increased risk of primary pulmonary embolism (multivariate relative risk=2.9; 95% confidence interval [CI], 1.5-5.4). Heavy cigarette smokers also had an increased risk of primary pulmonary embolism. The relative risk (RR) of primary pulmonary embolism was 1.9 (95% CI, 0.9-3.7) for women currently smoking 25 to 34 cigarettes per day and 3.3 (95% CI, 1.7-6.5) for those smoking 35 cigarettes or more daily as compared with never smokers. Hypertension, even after adjustment for body mass index, was also associated with an increased risk of primary pulmonary embolism (RR=1.9; 95% CI, 1.2-2.8). High serum cholesterol levels (RR=1.1; 95% CI, 0.62-1.8) and diabetes (RR=0.7; 95% CI, 0.3-1.9) did not appear to be related to primary pulmonary embolism. These prospective data indicate that obesity, cigarette smoking, and hypertension are associated with increased risk of pulmonary embolism in women. Control of these risk factors will decrease risks of pulmonary embolism as well as coronary heart disease.", - "journal_title": "JAMA", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/9039882/" - } - ], - "63b39d8d-f3cd-43b8-bb43-51c9ae039d00": [ - { - "pub_id": "17603485", - "title": "Two variants on chromosome 17 confer prostate cancer risk, and the one in TCF2 protects against type 2 diabetes.", - "authors": "Julius Gudmundsson,Patrick Sulem,Valgerdur Steinthorsdottir,Jon T Bergthorsson,Gudmar Thorleifsson,Andrei Manolescu,Thorunn Rafnar,Daniel Gudbjartsson,Bjarni A Agnarsson,Adam Baker,Asgeir Sigurdsson,Kristrun R Benediktsdottir,Margret Jakobsdottir,Thorarinn Blondal,Simon N Stacey,Agnar Helgason,Steinunn Gunnarsdottir,Adalheidur Olafsdottir,Kari T Kristinsson,Birgitta Birgisdottir,Shyamali Ghosh,Steinunn Thorlacius,Dana Magnusdottir,Gerdur Stefansdottir,Kristleifur Kristjansson,Yu Bagger,Robert L Wilensky,Muredach P Reilly,Andrew D Morris,Charlotte H Kimber,Adebowale Adeyemo,Yuanxiu Chen,Jie Zhou,Wing-Yee So,Peter C Y Tong,Maggie C Y Ng,Torben Hansen,Gitte Andersen,Knut Borch-Johnsen,Torben Jorgensen,Alejandro Tres,Fernando Fuertes,Manuel Ruiz-Echarri,Laura Asin,Berta Saez,Erica van Boven,Siem Klaver,Dorine W Swinkels,Katja K Aben,Theresa Graif,John Cashy,Brian K Suarez,Onco van Vierssen Trip,Michael L Frigge,Carole Ober,Marten H Hofker,Cisca Wijmenga,Claus Christiansen,Daniel J Rader,Colin N A Palmer,Charles Rotimi,Juliana C N Chan,Oluf Pedersen,Gunnar Sigurdsson,Rafn Benediktsson,Eirikur Jonsson,Gudmundur V Einarsson,Jose I Mayordomo,William J Catalona,Lambertus A Kiemeney,Rosa B Barkardottir,Jeffrey R Gulcher,Unnur Thorsteinsdottir,Augustine Kong,Kari Stefansson", - "abstract": "We performed a genome-wide association scan to search for sequence variants conferring risk of prostate cancer using 1,501 Icelandic men with prostate cancer and 11,290 controls. Follow-up studies involving three additional case-control groups replicated an association of two variants on chromosome 17 with the disease. These two variants, 33 Mb apart, fall within a region previously implicated by family-based linkage studies on prostate cancer. The risks conferred by these variants are moderate individually (allele odds ratio of about 1.20), but because they are common, their joint population attributable risk is substantial. One of the variants is in TCF2 (HNF1beta), a gene known to be mutated in individuals with maturity-onset diabetes of the young type 5. Results from eight case-control groups, including one West African and one Chinese, demonstrate that this variant confers protection against type 2 diabetes.", - "journal_title": "Nature genetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/17603485/" - } - ], - "92297a96-fe67-4841-aa08-7556c4e10cf8": [ - { - "pub_id": "18794854", - "title": "MYH9 is associated with nondiabetic end-stage renal disease in African Americans.", - "authors": "W H Linda Kao,Michael J Klag,Lucy A Meoni,David Reich,Yvette Berthier-Schaad,Man Li,Josef Coresh,Nick Patterson,Arti Tandon,Neil R Powe,Nancy E Fink,John H Sadler,Matthew R Weir,Hanna E Abboud,Sharon G Adler,Jasmin Divers,Sudha K Iyengar,Barry I Freedman,Paul L Kimmel,William C Knowler,Orly F Kohn,Kristopher Kramp,David J Leehey,Susanne B Nicholas,Madeleine V Pahl,Jeffrey R Schelling,John R Sedor,Denyse Thornley-Brown,Cheryl A Winkler,Michael W Smith,Rulan S Parekh, ", - "abstract": "As end-stage renal disease (ESRD) has a four times higher incidence in African Americans compared to European Americans, we hypothesized that susceptibility alleles for ESRD have a higher frequency in the West African than the European gene pool. We carried out a genome-wide admixture scan in 1,372 ESRD cases and 806 controls and found a highly significant association between excess African ancestry and nondiabetic ESRD (lod score = 5.70) but not diabetic ESRD (lod = 0.47) on chromosome 22q12. Each copy of the European ancestral allele conferred a relative risk of 0.50 (95% CI = 0.39-0.63) compared to African ancestry. Multiple common SNPs (allele frequencies ranging from 0.2 to 0.6) in the gene encoding nonmuscle myosin heavy chain type II isoform A (MYH9) were associated with two to four times greater risk of nondiabetic ESRD and accounted for a large proportion of the excess risk of ESRD observed in African compared to European Americans.", - "journal_title": "Nature genetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/18794854/" - } - ], - "d978c09f-53e0-4a69-bfa6-e15537f32ffb": [ - { - "pub_id": "29219149", - "title": "Global aetiology and epidemiology of type 2 diabetes mellitus and its complications.", - "authors": "Yan Zheng,Sylvia H Ley,Frank B Hu", - "abstract": "Globally, the number of people with diabetes mellitus has quadrupled in the past three decades, and diabetes mellitus is the ninth major cause of death. About 1 in 11 adults worldwide now have diabetes mellitus, 90% of whom have type 2 diabetes mellitus (T2DM). Asia is a major area of the rapidly emerging T2DM global epidemic, with China and India the top two epicentres. Although genetic predisposition partly determines individual susceptibility to T2DM, an unhealthy diet and a sedentary lifestyle are important drivers of the current global epidemic; early developmental factors (such as intrauterine exposures) also have a role in susceptibility to T2DM later in life. Many cases of T2DM could be prevented with lifestyle changes, including maintaining a healthy body weight, consuming a healthy diet, staying physically active, not smoking and drinking alcohol in moderation. Most patients with T2DM have at least one complication, and cardiovascular complications are the leading cause of morbidity and mortality in these patients. This Review provides an updated view of the global epidemiology of T2DM, as well as dietary, lifestyle and other risk factors for T2DM and its complications.", - "journal_title": "Nature reviews. Endocrinology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/29219149/" - } - ], - "e9620bff-9687-4e0c-87d2-99a6138c4e11": [ - { - "pub_id": "18464045", - "title": "The environmental genome project: reference polymorphisms for drug metabolism genes and genome-wide association studies.", - "authors": "Mark J Rieder,Robert J Livingston,Ian B Stanaway,Deborah A Nickerson", - "abstract": "The Environmental Genome Project (EGP) has generated a comprehensive resource of commonly occurring single nucleotide polymorphisms (SNPs) in more than six hundred environmental response genes, including a number of drug metabolism genes. The gene-oriented sequence variation discovery carried out by the EGP is complementary to the HapMap and enables genome-wide association studies (GWAS) that survey a large portion of the known common variation. For GWAS focused on drug metabolism genes and phenotypes, it is important to know the proportion of common SNPs covered by the commercially available high-throughput genotyping chips. Herein, we review a subset of Phase I cytochrome P450 genes studied by the EGP, approaches to GWAS, and the sensitivity of available genotyping platforms to capture common sequence variation in this subset of drug metabolism genes.", - "journal_title": "Drug metabolism reviews", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/18464045/" - } - ], - "84e3d477-2d6e-4d5b-9861-e53e45b5d081": [ - { - "pub_id": "7795649", - "title": "A gene for maturity onset diabetes of the young (MODY) maps to chromosome 12q.", - "authors": "M Vaxillaire,V Boccio,A Philippi,C Vigouroux,J Terwilliger,P Passa,J S Beckmann,G Velho,G M Lathrop,P Froguel", - "abstract": "Maturity-onset diabetes of the young (MODY) is a subtype of non-insulin dependent diabetes mellitus, with early age of onset. MODY is genetically heterogeneous, associated with glucokinase mutations and a locus on chromosome 20q; in about 50% of cases, its genetic background is unknown. We have studied 12 families in which MODY is unlinked to either glucokinase or chromosome 20q markers, and find significant evidence for linkage with microsatellite markers on chromosome 12q, most likely within a 7 centimogran interval bracketed by D12S86 and D12S342. The disease was estimated to be linked to this chromosome region in approximately 50% of families in a heterogeneity analysis. These MODY patients exhibit major hyperglycaemia with a severe insulin secretory defect, suggesting that the causal gene is implicated in pancreatic beta-cell function.", - "journal_title": "Nature genetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/7795649/" - } - ], - "76ae2f09-af4d-422a-b939-625f0fe4ae1c": [ - { - "pub_id": "29862628", - "title": "Sex as a determinant of type 1 diabetes at diagnosis.", - "authors": "Maaret Turtinen,Taina H\u00e4rk\u00f6nen,Anna Parkkola,Jorma Ilonen,Mikael Knip, ", - "abstract": "The present study tested the hypothesis that girls have a more aggressive disease process than boys at the diagnosis of type 1 diabetes (T1D). Demographic and clinical characteristics, the humoral autoantibody profile, and the genetic risk assessed by the presence of human leukocyte antigen DR-DQ haplotypes were analyzed in terms of sex in 4993 children and adolescents diagnosed with T1D between January 2003 and December 2016. A clear male preponderance (56.6%) was observed in our cohort and boys were significantly older than girls at clinical diagnosis (mean 8.3 vs 7.7\u2009years, P\u2009<\u2009.001). Age-adjusted analyses showed a poorer metabolic decompensation in girls than boys at diagnosis. Boys tested more often positive for autoantibodies against insulin autoantibodies (P\u2009=\u2009.008), islet antigen-2 autoantibodies (P\u2009=\u2009.033), and zinc transporter 8 autoantibodies (P\u2009=\u2009.027), whereas girls had a higher frequency of glutamic acid decarboxylase autoantibodies (GADA) (P\u2009<\u2009.001) and higher GADA (P\u2009<\u2009.001) and islet cell antibody titers (P\u2009=\u2009.001). We did not find any significant differences in the genetic risk profile between girls and boys. Our data show that the metabolic derangement is more severe in girls already at diagnosis of T1D and this finding is independent of age. The immunologic aggressiveness of the disease is more variable as the predominance of different autoantibodies varies between sexes with a higher frequency of GADA in girls, while the 3 other biochemical autoantibodies were more common in boys.", - "journal_title": "Pediatric diabetes", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/29862628/" - } - ], - "42083d88-b55c-47cd-bf6c-3e0ef2741177": [ - { - "pub_id": "19208173", - "title": "Comparison of automated candidate gene prediction systems using genes implicated in type 2 diabetes by genome-wide association studies.", - "authors": "Erdahl T Teber,Jason Y Liu,Sara Ballouz,Diane Fatkin,Merridee A Wouters", - "abstract": "Automated candidate gene prediction systems allow geneticists to hone in on disease genes more rapidly by identifying the most probable candidate genes linked to the disease phenotypes under investigation. Here we assessed the ability of eight different candidate gene prediction systems to predict disease genes in intervals previously associated with type 2 diabetes by benchmarking their performance against genes implicated by recent genome-wide association studies. Using a search space of 9556 genes, all but one of the systems pruned the genome in favour of genes associated with moderate to highly significant SNPs. Of the 11 genes associated with highly significant SNPs identified by the genome-wide association studies, eight were flagged as likely candidates by at least one of the prediction systems. A list of candidates produced by a previous consensus approach did not match any of the genes implicated by 706 moderate to highly significant SNPs flagged by the genome-wide association studies. We prioritized genes associated with medium significance SNPs. The study appraises the relative success of several candidate gene prediction systems against independent genetic data. Even when confronted with challengingly large intervals, the candidate gene prediction systems can successfully select likely disease genes. Furthermore, they can be used to filter statistically less-well-supported genetic data to select more likely candidates. We suggest consensus approaches fail because they penalize novel predictions made from independent underlying databases. To realize their full potential further work needs to be done on prioritization and annotation of genes.", - "journal_title": "BMC bioinformatics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/19208173/" - } - ], - "1ef9a72d-b9ef-4955-a351-fca0175da3d1": [ - { - "pub_id": "7912209", - "title": "Isolation of the human LIM/homeodomain gene islet-1 and identification of a simple sequence repeat polymorphism [corrected].", - "authors": "Y Tanizawa,A C Riggs,S Dagogo-Jack,M Vaxillaire,P Froguel,L Liu,H Donis-Keller,M A Permutt", - "abstract": "The islet-1 (Isl-1) gene encodes a protein that binds to the enhancer region of the insulin gene. Isl-1 is a member of the LIM/homeodomain family of transcription factors. Because insulin deficiency, either relative or absolute, is a cardinal feature of non-insulin-dependent diabetes mellitus (NIDDM), this study addressed the question of whether mutations in genes that regulate insulin production could be involved. Rat Isl-1 was the first insulin enhancer binding protein to be isolated, and, in this study, the rat gene was used to isolate a partial human islet Isl-1 cDNA and subsequently to isolate genomic clones. A simple sequence repeat was found in the Isl-1 gene, and polymerase chain reaction amplification of this region of genomic DNA revealed 12 alleles in St. Louis African-Americans (het = 0.87), 14 alleles in black Nigerians (het = 0.89), 8 alleles in Japanese (het = 0.69), and 8 alleles in Caucasians (het = 0.81). Genetic linkage analysis uniquely placed Isl-1 on chromosome 5q (D5S395[12.8 cM]Isl-1 [11.6 cM]D5S407). The simple sequence repeat polymorphism at the Isl-1 locus was used to evaluate mutations in this gene as a possible contributor to the pathogenesis of NIDDM. Allelic frequencies did not differ between patients with NIDDM (n = 165) and nondiabetic control subjects (n = 163) in two black populations (St. Louis African-Americans and Nigerians). Linkage analyses in 15 nonglucokinase maturity-onset diabetes of the young pedigrees indicated that linkage could be rejected (LOD score < -3.0) over a distance of 15 cM.(ABSTRACT TRUNCATED AT 250 WORDS)", - "journal_title": "Diabetes", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/7912209/" - } - ], - "81820057-eea4-456f-ba0f-ee2021794574": [ - { - "pub_id": "11246890", - "title": "A gene conferring susceptibility to type 2 diabetes in conjunction with obesity is located on chromosome 18p11.", - "authors": "A Parker,J Meyer,S Lewitzky,J S Rennich,G Chan,J D Thomas,M Orho-Melander,M Lehtovirta,C Forsblom,A Hyrkk\u00f6,M Carlsson,C Lindgren,L C Groop", - "abstract": "Genome-wide nonparametric linkage analysis of 480 sib-pairs affected with type 2 diabetes revealed linkage to a previously unreported susceptibility locus on chromosome 18p11. This result improved with stringent subphenotyping using age- and sex-adjusted BMI, ultimately reaching a logarithm of odds of 3.82 (allele sharing 0.6654) at a point between markers D18S976 and D18S391 when the most obese 20% of the sample was analyzed. Several genes on chromosome 18 have been suggested as metabolic disease candidates, but none of these colocalize with our linkage result. We conclude that our results provide support for the presence of a currently uncharacterized gene on chromosome 18p, certain alleles of which confer increased susceptibility to type 2 diabetes in conjunction with obesity. We additionally observed moderate evidence for linkage to chromosome 1, near marker D1S3462; chromosome 4, near marker D4S2361; chromosome 5, near marker D5S1505; and chromosome 17, near marker D17S1301.", - "journal_title": "Diabetes", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/11246890/" - } - ], - "c8c58fdf-06e3-4da4-a920-d5bcbcd18289": [ - { - "pub_id": "11246891", - "title": "A genome scan for type 2 diabetes susceptibility loci in a genetically isolated population.", - "authors": "M A Permutt,J C Wasson,B K Suarez,J Lin,J Thomas,J Meyer,S Lewitzky,J S Rennich,A Parker,L DuPrat,S Maruti,S Chayen,B Glaser", - "abstract": "A total of 896 individuals of Ashkenazi Jewish descent were ascertained in Israel from 267 multiplex families, including 472 sib-pairs affected with type 2 diabetes. A genome-wide scan with average marker spacing of 9.5 cM revealed five regions on four chromosomes (4q, 8q, 14q, and 20q) that exhibited nominal evidence for linkage (P < 0.05). The highest observed nonparametric linkage Z score was 2.41 (equivalent to a logarithm of odds score of 1.26) at marker D4S1501. A maximal signal, with a Z score of 2.05, was observed on chromosome 20 near marker D20S195, and another on 20p near marker D20S103 (Z 1.80). A single marker on chromosome 8 (D8S593) and two adjacent markers on chromosome 14 (D14S749 and D14S605) also attained evidence of linkage. To explore the hypothesis that the signals on chromosomes 4 and 20 are differentially attributable to variation in BMI or age of onset, an ordered subset analysis was conducted. This analysis revealed that only when the families were ranked by BMI (in increasing order) did a subset attain nominal significance, and only for chromosome 4. The findings reported here lend credence to the hypothesis, now supported by four studies of Caucasian populations and most recently by a combined analysis of 1,852 pedigrees, that a type 2 diabetes susceptibility locus resides on chromosome 20q. This population, because of its unique genetic attributes, may facilitate identification of this and other genes contributing to type 2 diabetes.", - "journal_title": "Diabetes", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/11246891/" - } - ], - "2a71b781-89fe-4055-bbb1-15aa226e1e3a": [ - { - "pub_id": "15161769", - "title": "Genome-wide scan for type 2 diabetes loci in Hong Kong Chinese and confirmation of a susceptibility locus on chromosome 1q21-q25.", - "authors": "Maggie C Y Ng,Wing-Yee So,Nancy J Cox,Vincent K L Lam,Clive S Cockram,Julian A J H Critchley,Graeme I Bell,Juliana C N Chan", - "abstract": "We conducted an autosomal genome scan to map loci for type 2 diabetes in a Hong Kong Chinese population. We studied 64 families, segregating type 2 diabetes, of which 57 had at least one member with an age at diagnosis of </=40 years. These families included a total of 126 affected sibpairs and 4 other affected relative pairs. Nonparametric linkage analysis revealed seven regions showing nominal evidence for linkage with type 2 diabetes (logarithm of odds [LOD] >0.59, P(pointwise) < 0.05): chromosome 1 at 173.9 cM (LOD = 3.09), chromosome 3 at 26.3 cM (LOD = 1.27), chromosome 4 at 135.3 cM (LOD = 2.63), chromosome 5 at 139.3 cM (LOD = 0.84), chromosome 6 at 178.9 cM (LOD = 1.91), chromosome 12 at 48.7 cM (LOD = 1.99), and chromosome 18 at 28.1 cM (LOD = 1.00). Simulation studies showed genome-wide significant evidence for linkage of the chromosome 1 region (P(genome-wide) = 0.036). We have confirmed the results of previous studies for the presence of a susceptibility locus on chromosome 1q21-q25 (173.9 cM) and suggest the locations of other loci that may contribute to the development of type 2 diabetes in Hong Kong Chinese.", - "journal_title": "Diabetes", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/15161769/" - } - ], - "19289b03-85fc-4e34-bbda-f0a9f1048d4c": [ - { - "pub_id": "15024687", - "title": "Novel analytical methods applied to type 1 diabetes genome-scan data.", - "authors": "Flemming Pociot,Allan E Karlsen,Claus B Pedersen,Mogens Aalund,J\u00f8rn Nerup, ", - "abstract": "Complex traits like type 1 diabetes mellitus (T1DM) are generally taken to be under the influence of multiple genes interacting with each other to confer disease susceptibility and/or protection. Although novel methods are being developed, analyses of whole-genome scans are most often performed with multipoint methods that work under the assumption that multiple trait loci are unrelated to each other; that is, most models specify the effect of only one locus at a time. We have applied a novel approach, which includes decision-tree construction and artificial neural networks, to the analysis of T1DM genome-scan data. We demonstrate that this approach (1) allows identification of all major susceptibility loci identified by nonparametric linkage analysis, (2) identifies a number of novel regions as well as combinations of markers with predictive value for T1DM, and (3) may be useful in characterizing markers in linkage disequilibrium with protective-gene variants. Furthermore, the approach outlined here permits combined analyses of genetic-marker data and information on environmental and clinical covariates.", - "journal_title": "American journal of human genetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/15024687/" - } - ], - "15ecd7e9-45d5-48f7-bc0a-54f3d882fd4f": [ - { - "pub_id": "8181666", - "title": "Obesity, diabetes, and neoplasia in yellow A(vy)/- mice: ectopic expression of the agouti gene.", - "authors": "T T Yen,A M Gill,L G Frigeri,G S Barsh,G L Wolff", - "abstract": "The viable yellow A(vy) mutation results in a mottled yellow mouse that is obese, slightly larger than its nonyellow sibs, and more susceptible to tumor formation in those tissues sensitized by the strain genome. The mutation exhibits variable expressivity resulting in a continuum of coat color phenotypes, from clear yellow to pseudoagouti. The mouse agouti protein is a paracrine signaling molecule that induces hair follicle melanocytes to switch from the synthesis of black pigment to yellow pigment. Molecular cloning studies indicate that the obesity and growth effects of the A(vy) mutation result from ectopic expression of the normal agouti gene product. This review seeks to summarize the current state of knowledge regarding the obesity, stimulation of somatic growth, and enhancement of tumor formation caused by the A(vy) mutation, and to interpret these pleiotropic effects in terms of the normal function of the agouti protein.", - "journal_title": "FASEB journal : official publication of the Federation of American Societies for Experimental Biology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/8181666/" - } - ], - "08d420b0-d726-4eba-aae6-85b288cf8fa6": [ - { - "pub_id": "15616037", - "title": "Genetic linkage and association of the growth hormone secretagogue receptor (ghrelin receptor) gene in human obesity.", - "authors": "Andrea Baessler,Michael J Hasinoff,Marcus Fischer,Wibke Reinhard,Gabriele E Sonnenberg,Michael Olivier,Jeanette Erdmann,Heribert Schunkert,Angela Doering,Howard J Jacob,Anthony G Comuzzie,Ahmed H Kissebah,Anne E Kwitek", - "abstract": "The growth hormone secretagogue receptor (GHSR) (ghrelin receptor) plays an important role in the regulation of food intake and energy homeostasis. The GHSR gene lies on human chromosome 3q26 within a quantitative trait locus strongly linked to multiple phenotypes related to obesity and the metabolic syndrome. Because the biological function and location of the GHSR gene make it an excellent candidate gene, we tested the relation between common single nucleotide polymorphisms (SNPs) in the GHSR gene and human obesity. We performed a comprehensive analysis of SNPs, linkage disequilibrium (LD), and haplotype structure across the entire GHSR gene region (99.3 kb) in 178 pedigrees with multiple obese members (DNA of 1,095 Caucasians) and in an independent sample of the general population (MONICA Augsburg left ventricular hypertrophy substudy; DNA of 1,418 Caucasians). The LD analysis revealed a disequilibrium block consisting of five SNPs, consistent in both study cohorts. We found linkage among all five SNPs, their haplotypes, and BMI. Further, we found suggestive evidence for transmission disequilibrium for the minor SNP alleles (P < 0.05) and the two most common haplotypes with the obesity affection status (\"susceptible\" P = 0.025, \"nonsusceptible\" P = 0.045) in the family cohort using the family-based association test program. Replication of these findings in the general population resulted in stronger evidence for an association of the SNPs (best P = 0.00001) and haplotypes with the disease (\"susceptible\" P = 0.002, \"nonsusceptible\" P = 0.002). To our knowledge, these data are the first to demonstrate linkage and association of SNPs and haplotypes within the GHSR gene region and human obesity. This linkage, together with significant transmission disequilibrium in families and replication of this association in an independent population, provides evidence that common SNPs and haplotypes within the GHSR region are involved in the pathogenesis of human obesity.", - "journal_title": "Diabetes", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/15616037/" - } - ], - "678fb0b1-d0b4-410e-8764-348ec93b1e1b": [ - { - "pub_id": "34609116", - "title": "Genetic associated complications of type 2 diabetes mellitus.", - "authors": "Yee H Wong,Shen H Wong,Xiao T Wong,Qiao Y Yap,Khar Y Yip,Liang Z Wong,Dinesh K Chellappan,Subrat K Bhattamisra,Mayuren Candasamy", - "abstract": "According to the International Diabetes Federation, the number of adults (age of 20-79) being diagnosed with diabetes mellitus (DM) have increased from 285 million in year 2009 to 463 million in year 2019 which comprises of 95% type 2 DM patient (T2DM). Research have claimed that genetic predisposition could be one of the factors causing T2DM complications. In addition, T2DM complications cause an incremental risk to mortality. Therefore, this article aims to discuss some complications of T2DM in and their genetic association. The complications that are discussed in this article are diabetic nephropathy, diabetes induced cardiovascular disease, diabetic neuropathy, diabetic foot ulcer (DFU) and Alzheimer's disease (AD). According to the information obtained, genes associated with diabetic nephropathy (DN) are gene GABRR1 and ELMO1 that cause injury to glomerular. Replication of genes FRMD3, CARS and MYO16/IRS2 shown to have link with DN. The increase of gene THBS2, NGAL, PIP, TRAF6 polymorphism, ICAM-1 encoded for rs5498 polymorphism and C667T increase susceptibility towards DN in T2DM patient. Genes associated with cardiovascular diseases are adiponectin gene (ACRP30) and apolipoprotein E (APOE) polymorphism gene with \u03be2 allele. Haptoglobin (Hp) 1-1 genotype and mitochondria superoxide dismutase 2 (SOD2) plays a role in cardiovascular events. As for genes related to diabetic neuropathy, janus kinase (JAK), mutation of SCN9A and TRPA1 gene and destruction of miRNA contribute to pathogenesis of diabetic neuropathy among T2DM patients. Expression of cytokine IL-6, IL-10, miR-146a are found to cause diabetic neuropathy. Besides, A1a16Va1 gene polymorphism, an oxidative stress influence was found as one of the gene factors. Diabetic retinopathy (DR) is believed to have association with monocyte chemoattractant protein-1 (MCP-1) and insulin-like growth factor 1 (IGF1). Over-expression of gene ENPP1, IL-6 pro-inflammatory cytokine, ARHGAP22's protein rs3844492 polymorphism and TLR4 heterozygous genotype are contributing to significant pathophysiological process causing DR, while research found increases level of UCP1 gene protects retina cells from oxidative stress. DFU is manifested by slowing in re-epithelialization of keratinocyte, persistence wound inflammation and healing impairment. Re-epithelialization disturbance was caused by E2F3 gene, reduction of Tacl gene encoded substance P causing persistence inflammation while expression of MMp-9 polymorphism contributes to healing impairment. A decrease in HIF-1a gene expression leads to increased risk of pathogenesis, while downregulation of TLR2 increases severity of wound in DFU patients. SNPs alleles has been shown to have significant association between the genetic dispositions of T<inf>2</inf>DM and AD. The progression of AD can be due to the change in DNA methylation of CLOCK gene, followed with worsening of AD by APOE4 gene due to dyslipidemia condition in T2DM patients. Insulin resistance is also a factor that contributes to pathogenesis of AD.", - "journal_title": "Panminerva medica", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/34609116/" - } - ], - "b8654f66-66ad-41c8-8578-b8fd00fffaec": [ - { - "pub_id": "12771549", - "title": "Single nucleotide polymorphism haplotypes in the cholesteryl-ester transfer protein (CETP) gene and lipid phenotypes.", - "authors": "Anja Bauerfeind,Hans Knoblauch,Herbert Schuster,Friedrich C Luft,Jens G Reich", - "abstract": "We studied the association between high (HDL) and low-density (LDL) cholesterol concentrations and family-derived haplotypes based on six common SNPs in the cholesteryl-ester transfer protein (CETP) gene. We based our analysis on 201 founders from families recruited throughout Germany. The analysis revealed one subhaplotype block with complete, pairwise, linkage disequilibrium between 5 SNPs located in the promoter and intron 1. The sixth SNP was the well known 1405V polymorphism in exon 14, close to the 3' end of the gene. Four haplotypes accounted for 86% of the entire sample. We found that haplotype associations with HDL, LDL, and the LDL/HDL ratio were more robust than associations with individual SNPs. Moreover, the associations were robust for men, but not for women. Our data suggest an interaction between gender and genetic variation within the CETP gene.", - "journal_title": "Human heredity", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/12771549/" - } - ], - "286480ca-0d7f-4a93-952b-2cf57292104d": [ - { - "pub_id": "17213368", - "title": "Metabolic and genomic dissection of diabetes in the Cohen rat.", - "authors": "Chana Yagil,Ronit Barkalifa,Marina Sapojnikov,Alexander Wechsler,David Ben-Dor,Sarah Weksler-Zangen,Nurit Kaiser,Itamar Raz,Yoram Yagil", - "abstract": "We investigated the metabolic and genetic basis of diabetes in the Cohen Diabetic rat, a model of diet-induced diabetes, as a means to identify the molecular mechanisms involved. By altering individual components in the diabetogenic diet, we established that the dietary susceptibility that leads to the development of diabetes in this model is directly related to the high casein and low copper content in chow. The development of diabetes is accompanied by depletion of the acini from the exocrine pancreas and replacement with fat cells, while the appearance of the islets of Langerhans remains intact. With reversion back from diabetogenic to regular diet, the diabetic phenotype disappears but the histological changes in the exocrine pancreas prevail. Using positional cloning, we detected a major quantitative trait locus (QTL) on rat chromosome 4 with a chromosomal span of 4.9 cM, and two additional loci on chromosomes 7 and X. A screen for genes within that QTL in the rat and in the syntenic regions in mouse and man revealed only 23 candidate genes. Notable among these genes is Ica1, which has been causally associated with diabetes and bovine casein. We conclude that the development of diabetes in our model is dependent upon high casein and low copper in diet, that it is accompanied by histomorphological changes in the exocrine but not endocrine pancreas, that it is reversible, and that it is associated with a major QTL on chromosome 4 in which we detected Ica1, a high priority candidate gene.", - "journal_title": "Physiological genomics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/17213368/" - } - ], - "64d87c52-1185-4080-8d06-134c32dae5fd": [ - { - "pub_id": "19486824", - "title": "Philosophical and ethical issues at the forefront of neuroscience and genetics: an overview for psychiatrists.", - "authors": "Jinger G Hoop,Ryan Spellecy", - "abstract": "This review has touched upon some of the major ethical issues surrounding emerging technologies in neuroscience and genetics. Although at first glance these issues may seem somewhat peripheral to the clinical practice of psychiatry, we suggest that they may have unanticipated effects upon the care of patients with mental illness. Certainly, the philosophical issues surrounding free will are of tremendous consequence to persons who commit crimes while suffering severe symptoms of mental illness. In addition, the opening up of a lucrative new \"enhancement\" market for the sale of new therapies could divert commercial resources away from the development of therapies for mental illness, although it is also possible that some enhancements will have secondary benefits as treatments for disease. Social acceptance of enhancement therapies could have a beneficial, normalizing effect on public attitudes toward those who receive mental health treatment. On the other hand, a moral backlash against enhancements as \"quick fixes\" that deprive individuals of authenticity could have a secondary effect of increasing the stigma of mental health treatment. For all of these reasons, it has become increasingly important for psychiatrists to be informed about and active participants in the public conversation about neuroethics. Psychiatric patients appear to have much at stake in these ethical debates, and psychiatrists have valuable expertise to offer as professionals with intimate knowledge of the human mind, its limitations, and its potential.", - "journal_title": "The Psychiatric clinics of North America", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/19486824/" - } - ], - "c6c3ce6b-4b97-49ad-8935-b9e02c5552b5": [ - { - "pub_id": "12480795", - "title": "Omega-3 fatty acids in inflammation and autoimmune diseases.", - "authors": "Artemis P Simopoulos", - "abstract": "Among the fatty acids, it is the omega-3 polyunsaturated fatty acids (PUFA) which possess the most potent immunomodulatory activities, and among the omega-3 PUFA, those from fish oil-eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA)--are more biologically potent than alpha-linolenic acid (ALA). Some of the effects of omega-3 PUFA are brought about by modulation of the amount and types of eicosanoids made, and other effects are elicited by eicosanoid-independent mechanisms, including actions upon intracellular signaling pathways, transcription factor activity and gene expression. Animal experiments and clinical intervention studies indicate that omega-3 fatty acids have anti-inflammatory properties and, therefore, might be useful in the management of inflammatory and autoimmune diseases. Coronary heart disease, major depression, aging and cancer are characterized by an increased level of interleukin 1 (IL-1), a proinflammatory cytokine. Similarly, arthritis, Crohn's disease, ulcerative colitis and lupus erythematosis are autoimmune diseases characterized by a high level of IL-1 and the proinflammatory leukotriene LTB(4) produced by omega-6 fatty acids. There have been a number of clinical trials assessing the benefits of dietary supplementation with fish oils in several inflammatory and autoimmune diseases in humans, including rheumatoid arthritis, Crohn's disease, ulcerative colitis, psoriasis, lupus erythematosus, multiple sclerosis and migraine headaches. Many of the placebo-controlled trials of fish oil in chronic inflammatory diseases reveal significant benefit, including decreased disease activity and a lowered use of anti-inflammatory drugs.", - "journal_title": "Journal of the American College of Nutrition", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/12480795/" - } - ], - "0f184e31-6a20-451f-b588-d4711d0a09ef": [ - { - "pub_id": "9285775", - "title": "A susceptibility locus for early-onset non-insulin dependent (type 2) diabetes mellitus maps to chromosome 20q, proximal to the phosphoenolpyruvate carboxykinase gene.", - "authors": "H Zouali,E H Hani,A Philippi,N Vionnet,J S Beckmann,F Demenais,P Froguel", - "abstract": "Several candidate genes for non-insulin-dependent diabetes mellitus (NIDDM) map on chromosome 20, including the phosphoenolpyruvate carboxykinase gene (PCK1) and one of the maturity onset diabetes of the young genes (MODY1). Thus, we have investigated the entire long arm of chromosome 20. Linkage analyses were conducted in a total sample of 148 NIDDM families (301 NIDDM sib pairs) and in a subset of 42 early onset NIDDM families, where genetic components are likely to play a more important role (55 NIDDM sib pairs diagnosed at or before 45 years of age), using 10 highly polymorphic markers with an average map density of 7.5 cM. Using affected sib pair methods (two-point linkage and multipoint linkage analyses), significant results were obtained with the 20q13 region, in the vicinity of the PCK1 locus, only in the subset of 55 early onset NIDDM sib pairs (multipoint MLS = 2.74, P = 0.0004; MLS = 2.34, P = 0.0009 when using a conservative weighting procedure). Moreover, another region spanning the ribophorin II (RPNII, phospholipase C (PLC1) and adenosine deaminase (ADA) loci suggested linkage with NIDDM (multipoint MLS of 1.81 in all NIDDM sib pairs, P = 0.003; MLS = 1.31, P = 0.012 when using a conservative weighting procedure). Whereas our study suggests the location of a susceptibility locus for early onset NIDDM in the PCK1 gene region, further investigation in larger data sets is required to confirm these results and assess the role of other regions on chromosome 20q in human NIDDM.", - "journal_title": "Human molecular genetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/9285775/" - } - ], - "d86525a8-0a2f-44a8-b343-61a5df8d6e68": [ - { - "pub_id": "19465406", - "title": "Association of RASGRP1 with type 1 diabetes is revealed by combined follow-up of two genome-wide studies.", - "authors": "H Q Qu,S F A Grant,J P Bradfield,C Kim,E Frackelton,H Hakonarson,C Polychronakos", - "abstract": "The two genome-wide association studies published by us and by the Wellcome Trust Case-Control Consortium (WTCCC) revealed a number of novel loci, but neither had the statistical power to elucidate all of the genetic components of type 1 diabetes risk, a task for which larger effective sample sizes are needed. We analysed data from two sources: (1) The previously published second stage of our study, with a total sample size of the two stages consisting of 1046 Canadian case-parent trios and 538 multiplex families with 929 affected offspring from the Type 1 Diabetes Genetics Consortium (T1DGC); (2) the Rapid Response 2 (RR2) project of the T1DGC, which genotyped 4417 individuals from 1062 non-overlapping families, including 2059 affected individuals (mostly sibling pairs) for the 1536 markers with the highest statistical significance for type 1 diabetes in the WTCCC results. One locus, mapping to a linkage disequilibrium (LD) block at chr15q14, reached statistical significance by combining results from two markers (rs17574546 and rs7171171) in perfect LD with each other (r2 = 1). We obtained a joint p value of 1.3 x 10(-6), which exceeds by an order of magnitude the conservative threshold of 3.26 x 10(-5) obtained by correcting for the 1536 single nucleotide polymorphisms (SNPs) tested in our study. Meta-analysis with the original WTCCC genome-wide data produced a p value of 5.83 x 10(-9). A novel type 1 diabetes locus was discovered. It involves RASGRP1, a gene known to play a crucial role in thymocyte differentiation and T cell receptor (TCR) signalling by activating the Ras signalling pathway.", - "journal_title": "Journal of medical genetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/19465406/" - } - ], - "71172700-7bcc-42f5-9354-d8e9290e8743": [ - { - "pub_id": "15148141", - "title": "Diabetes mellitus and risk of Alzheimer disease and decline in cognitive function.", - "authors": "Zoe Arvanitakis,Robert S Wilson,Julia L Bienias,Denis A Evans,David A Bennett", - "abstract": "Few prospective studies have assessed diabetes mellitus as a risk factor for incident Alzheimer disease (AD) and decline in cognitive function. To evaluate the association of diabetes mellitus with risk of AD and change in different cognitive systems. Longitudinal cohort study. For up to 9 years, 824 older (those >55 years) Catholic nuns, priests, and brothers underwent detailed annual clinical evaluations. Clinically diagnosed AD and change in global and specific measures of cognitive function. Diabetes mellitus was present in 127 (15.4%) of the participants. During a mean of 5.5 years of observation, 151 persons developed AD. In a proportional hazards model adjusted for age, sex, and educational level, those with diabetes mellitus had a 65% increase in the risk of developing AD compared with those without diabetes mellitus (hazard ratio, 1.65; 95% confidence interval, 1.10-2.47). In random effects models, diabetes mellitus was associated with lower levels of global cognition, episodic memory, semantic memory, working memory, and visuospatial ability at baseline. Diabetes mellitus was associated with a 44% greater rate of decline in perceptual speed (P =.02), but not in other cognitive systems. Diabetes mellitus may be associated with an increased risk of developing AD and may affect cognitive systems differentially.", - "journal_title": "Archives of neurology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/15148141/" - } - ], - "9e513fea-5257-4887-9802-57d416f21dfc": [ - { - "pub_id": "17957226", - "title": "The impact of genetics and genomics on public health.", - "authors": "Angela Brand,Helmut Brand,Tobias Schulte in den B\u00e4umen", - "abstract": "Public health practice has to date concerned itself with environmental or social determinants of health and disease and has paid scant attention to genomic variations within the population. The advances brought about by genomics are changing these perceptions. In the long run, this knowledge will enable health promotion messages and disease prevention programmes to be specifically directed at susceptible individuals and families, or at subgroups of the population, based on their genomic risk profile. As the controversial discourse in science and health politics shows, the integration of genomics into public health research, policy and practice is one of the major challenges that our health-care system is currently facing.", - "journal_title": "European journal of human genetics : EJHG", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/17957226/" - } - ], - "ce87fc4c-0457-4e29-beb4-1c195e693cd1": [ - { - "pub_id": "19143813", - "title": "Confirmation of HLA class II independent type 1 diabetes associations in the major histocompatibility complex including HLA-B and HLA-A.", - "authors": "J M M Howson,N M Walker,D Clayton,J A Todd, ", - "abstract": "Until recently, human leucocyte antigen (HLA) class II-independent associations with type 1 diabetes (T1D) in the Major Histocompatibility Complex (MHC) region were not adequately characterized owing to insufficient map coverage, inadequate statistical approaches and strong linkage disequilibrium spanning the entire MHC. Here we test for HLA class II-independent associations in the MHC using fine mapping data generated by the Type 1 Diabetes Genetics Consortium (T1DGC). We have applied recursive partitioning to the modelling of the class II loci and used stepwise conditional logistic regression to test approximately 1534 loci between 29 and 34 Mb on chromosome 6p21, typed in 2240 affected sibpair (ASP) families. Preliminary analyses confirm that HLA-B (at 31.4 Mb), HLA-A (at 30.0 Mb) are associated with T1D independently of the class II genes HLA-DRB1 and HLA-DQB1 (P = 6.0 x 10(-17) and 8.8 x 10(-13), respectively). In addition, a second class II region of association containing the single-nucleotide polymorphism (SNP), rs439121, and the class II locus HLA-DPB1, was identified as a T1D susceptibility effect which is independent of HLA-DRB1, HLA-DQB1 and HLA-B (P = 9.2 x 10(-8)). A younger age-at-diagnosis of T1D was found for HLA-B*39 (P = 7.6 x 10(-6)), and HLA-B*38 was protective for T1D. These analyses in the T1DGC families replicate our results obtained previously in approximately 2000 cases and controls and 850 families. Taking both studies together, there is evidence for four T1D-associated regions at 30.0 Mb (HLA-A), 31.4 Mb (HLA-B), 32.5 Mb (rs9268831/HLA-DRA) and 33.2 Mb (rs439121/HLA-DPB1) that are independent of HLA-DRB1/HLA-DQB1. Neither study found evidence of independent associations at HLA-C, HLA-DQA1 loci nor in the UBD/MAS1L or ITPR3 gene regions. These studies show that to find true class II-independent effects, large, well-powered sample collections are required and be genotyped with a dense map of markers. In addition, a robust statistical methodology that fully models the class II effects is necessary. Recursive partitioning is a useful tool for modelling these multiallelic systems.", - "journal_title": "Diabetes, obesity & metabolism", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/19143813/" - } - ], - "c2e5d067-1f15-4f4e-8df5-19149e7ef22d": [ - { - "pub_id": "18212765", - "title": "Mechanisms of disease: genetic insights into the etiology of type 2 diabetes and obesity.", - "authors": "Cecilia M Lindgren,Mark I McCarthy", - "abstract": "Until recently, progress in identification of the genetic variants influencing predisposition to common forms of diabetes and obesity has been slow, a sharp contrast to the large number of genes implicated in rare monogenic forms of both conditions. Recent advances have transformed the situation, however, enabling researchers to undertake well-powered scans able to detect association signals across the entire genome. For type 2 diabetes, the six high-density genome-wide association studies so far performed have extended the number of loci harboring common variants implicated in diabetes susceptibility into double figures. One of these loci, mapping to the fat mass and obesity associated gene (FTO), influences diabetes risk through a primary effect on fat mass, making this the first common variant known to influence weight and individual risk of obesity. These findings offer two main avenues for clinical translation. First, the identification of new pathways involved in disease predisposition-for example, those influencing zinc transport and pancreatic islet regeneration in the case of type 2 diabetes-offers opportunities for development of novel therapeutic and preventative approaches. Second, with continuing efforts to identify additional genetic variants, it may become possible to use patterns of predisposition to tailor individual management of these conditions.", - "journal_title": "Nature clinical practice. Endocrinology & metabolism", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/18212765/" - } - ], - "278f8817-052c-4788-9687-d56c984cc516": [ - { - "pub_id": "11592815", - "title": "Sequence and functional analysis of GLUT10: a glucose transporter in the Type 2 diabetes-linked region of chromosome 20q12-13.1.", - "authors": "P A Dawson,J C Mychaleckyj,S C Fossey,S J Mihic,A L Craddock,D W Bowden", - "abstract": "We have carried out a detailed sequence and functional analysis of a novel human facilitative glucose transporter, designated GLUT10, located in the Type 2 diabetes-linked region of human chromosome 20q12-13.1. The GLUT10 gene is located between D20S888 and D20S891 and is encoded by 5 exons spanning 26.8 kb of genomic DNA. The human GLUT10 cDNA encodes a 541 amino acid protein that shares between 31 and 35% amino acid identity with human GLUT1-8. The predicted amino acid sequence of GLUT10 is nearly identical in length to the recently described GLUT9 homologue, but is longer than other known members of the GLUT family. In addition, we have cloned the mouse cDNA homolog of GLUT10 that encodes a 537 amino acid protein that shares 77.3% identity with human GLUT10. The amino acid sequence probably has 12 predicted transmembrane domains and shares characteristics of other mammalian glucose transporters. Human and mouse GLUT10 retain several sequence motifs characteristic of mammalian glucose transporters including VP497ETKG in the cytoplasmic C-terminus, G73R[K,R] between TMD2 and TMD3 (PROSITE PS00216), VD92RAGRR between TMD8 and TMD9 (PROSITE PS00216), Q242QLTG in TMD7, and tryptophan residues W430 (TMD10) and W454 (TMD11), that correspond to trytophan residues previously implicated in GLUT1 cytochalasin B binding and hexose transport. Neither human nor mouse GLUT10 retains the full P[E,D,N]SPR motif after Loop6 but instead is replaced with P186AG[T,A]. A PROSITE search also shows that GLUT10 has lost the SUGAR TRANSPORT 2 pattern (PS00217), a result of the substitution G113S in TMD4, while all other known human GLUTs retain the glycine and the pattern match. The significance of this substitution is unknown. Sites for N-linked glycosylation are predicted at N334ATG between TMD8 and TMD9 and N526STG in the cytoplasmic C-terminus. Northern hybridization analysis identified a single 4.4-kb transcript for GLUT10 in human heart, lung, brain, liver, skeletal muscle, pancreas, placenta, and kidney. By RT-PCR analysis, GLUT10 mRNA was also detected in fetal brain and liver. When expressed in Xenopus oocytes, human GLUT10 exhibited 2-deoxy-D-glucose transport with an apparent Km of approximately 0.3 mM. D-Glucose and D-galactose competed with 2-deoxy-D-glucose and transport was inhibited by phloretin. The gene localization and functional properties suggest a role for GLUT10 in glucose metabolism and Type 2 diabetes.", - "journal_title": "Molecular genetics and metabolism", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/11592815/" - } - ], - "44cfaebc-d9de-4d25-8991-4b17d524ac6e": [ - { - "pub_id": "9894356", - "title": "Type II diabetes, essential hypertension, and obesity as \"syndromes of impaired genetic homeostasis\": the \"thrifty genotype\" hypothesis enters the 21st century.", - "authors": "J V Neel,A B Weder,S Julius", - "abstract": "", - "journal_title": "Perspectives in biology and medicine", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/9894356/" - } - ], - "1b30ced3-9d09-4d3f-b46c-e67bf162c7a9": [ - { - "pub_id": "15942018", - "title": "Pathway analysis of coronary atherosclerosis.", - "authors": "Jennifer Y King,Rossella Ferrara,Raymond Tabibiazar,Joshua M Spin,Mary M Chen,Allan Kuchinsky,Aditya Vailaya,Robert Kincaid,Anya Tsalenko,David Xing-Fei Deng,Andrew Connolly,Peng Zhang,Eugene Yang,Clifton Watt,Zohar Yakhini,Amir Ben-Dor,Annette Adler,Laurakay Bruhn,Philip Tsao,Thomas Quertermous,Euan A Ashley", - "abstract": "Large-scale gene expression studies provide significant insight into genes differentially regulated in disease processes such as cancer. However, these investigations offer limited understanding of multisystem, multicellular diseases such as atherosclerosis. A systems biology approach that accounts for gene interactions, incorporates nontranscriptionally regulated genes, and integrates prior knowledge offers many advantages. We performed a comprehensive gene level assessment of coronary atherosclerosis using 51 coronary artery segments isolated from the explanted hearts of 22 cardiac transplant patients. After histological grading of vascular segments according to American Heart Association guidelines, isolated RNA was hybridized onto a customized 22-K oligonucleotide microarray, and significance analysis of microarrays and gene ontology analyses were performed to identify significant gene expression profiles. Our studies revealed that loss of differentiated smooth muscle cell gene expression is the primary expression signature of disease progression in atherosclerosis. Furthermore, we provide insight into the severe form of coronary artery disease associated with diabetes, reporting an overabundance of immune and inflammatory signals in diabetics. We present a novel approach to pathway development based on connectivity, determined by language parsing of the published literature, and ranking, determined by the significance of differentially regulated genes in the network. In doing this, we identify highly connected \"nexus\" genes that are attractive candidates for therapeutic targeting and followup studies. Our use of pathway techniques to study atherosclerosis as an integrated network of gene interactions expands on traditional microarray analysis methods and emphasizes the significant advantages of a systems-based approach to analyzing complex disease.", - "journal_title": "Physiological genomics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/15942018/" - } - ], - "9240ab9b-c5bb-4475-ad2b-111843cb146a": [ - { - "pub_id": "17632545", - "title": "A genome-wide association study identifies KIAA0350 as a type 1 diabetes gene.", - "authors": "Hakon Hakonarson,Struan F A Grant,Jonathan P Bradfield,Luc Marchand,Cecilia E Kim,Joseph T Glessner,Rosemarie Grabs,Tracy Casalunovo,Shayne P Taback,Edward C Frackelton,Margaret L Lawson,Luke J Robinson,Robert Skraban,Yang Lu,Rosetta M Chiavacci,Charles A Stanley,Susan E Kirsch,Eric F Rappaport,Jordan S Orange,Dimitri S Monos,Marcella Devoto,Hui-Qi Qu,Constantin Polychronakos", - "abstract": "Type 1 diabetes (T1D) in children results from autoimmune destruction of pancreatic beta cells, leading to insufficient production of insulin. A number of genetic determinants of T1D have already been established through candidate gene studies, primarily within the major histocompatibility complex but also within other loci. To identify new genetic factors that increase the risk of T1D, we performed a genome-wide association study in a large paediatric cohort of European descent. In addition to confirming previously identified loci, we found that T1D was significantly associated with variation within a 233-kb linkage disequilibrium block on chromosome 16p13. This region contains KIAA0350, the gene product of which is predicted to be a sugar-binding, C-type lectin. Three common non-coding variants of the gene (rs2903692, rs725613 and rs17673553) in strong linkage disequilibrium reached genome-wide significance for association with T1D. A subsequent transmission disequilibrium test replication study in an independent cohort confirmed the association. These results indicate that KIAA0350 might be involved in the pathogenesis of T1D and demonstrate the utility of the genome-wide association approach in the identification of previously unsuspected genetic determinants of complex traits.", - "journal_title": "Nature", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/17632545/" - } - ], - "fa72cb33-e1e4-49ea-a72e-dd851225ee0b": [ - { - "pub_id": "19020323", - "title": "Genotype score in addition to common risk factors for prediction of type 2 diabetes.", - "authors": "James B Meigs,Peter Shrader,Lisa M Sullivan,Jarred B McAteer,Caroline S Fox,Jos\u00e9e Dupuis,Alisa K Manning,Jose C Florez,Peter W F Wilson,Ralph B D'Agostino,L Adrienne Cupples", - "abstract": "Multiple genetic loci have been convincingly associated with the risk of type 2 diabetes mellitus. We tested the hypothesis that knowledge of these loci allows better prediction of risk than knowledge of common phenotypic risk factors alone. We genotyped single-nucleotide polymorphisms (SNPs) at 18 loci associated with diabetes in 2377 participants of the Framingham Offspring Study. We created a genotype score from the number of risk alleles and used logistic regression to generate C statistics indicating the extent to which the genotype score can discriminate the risk of diabetes when used alone and in addition to clinical risk factors. There were 255 new cases of diabetes during 28 years of follow-up. The mean (+/-SD) genotype score was 17.7+/-2.7 among subjects in whom diabetes developed and 17.1+/-2.6 among those in whom diabetes did not develop (P<0.001). The sex-adjusted odds ratio for diabetes was 1.12 per risk allele (95% confidence interval, 1.07 to 1.17). The C statistic was 0.534 without the genotype score and 0.581 with the score (P=0.01). In a model adjusted for sex and self-reported family history of diabetes, the C statistic was 0.595 without the genotype score and 0.615 with the score (P=0.11). In a model adjusted for age, sex, family history, body-mass index, fasting glucose level, systolic blood pressure, high-density lipoprotein cholesterol level, and triglyceride level, the C statistic was 0.900 without the genotype score and 0.901 with the score (P=0.49). The genotype score resulted in the appropriate risk reclassification of, at most, 4% of the subjects. A genotype score based on 18 risk alleles predicted new cases of diabetes in the community but provided only a slightly better prediction of risk than knowledge of common risk factors alone.", - "journal_title": "The New England journal of medicine", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/19020323/" - } - ], - "e9f3797e-89be-4c0a-b1dd-8b514779b324": [ - { - "pub_id": "10807873", - "title": "Allele-specific regulation of matrix metalloproteinase-12 gene activity is associated with coronary artery luminal dimensions in diabetic patients with manifest coronary artery disease.", - "authors": "S Jormsj\u00f6,S Ye,J Moritz,D H Walter,S Dimmeler,A M Zeiher,A Henney,A Hamsten,P Eriksson", - "abstract": "Both the processes of atherosclerosis and plaque rupture are indicated to be influenced by matrix metalloproteinase (MMP) activity. We therefore searched for common functional variation in the matrix metalloelastase (MMP-12) gene locus that may be implicated in coronary artery disease. Single-strand conformation polymorphism analysis of DNA from healthy individuals detected a common polymorphism within the MMP-12 gene promoter (an A-to-G substitution at position -82). The frequency of the G allele was 0. 19. The polymorphism influences the binding of the transcription factor activator protein-1 (AP-1) in electromobility shift assay. A higher binding affinity of AP-1 to the A allele was associated with higher MMP-12 promoter activity in vitro in transient transfection studies in U937 and murine lung macrophage (MALU) cells. Phorbol 12-myristate 13-acetate (PMA) and insulin, 2 known activators of AP-1, increased the binding of AP-1 to the MMP-12 promoter, with higher affinity for the A allele. In transfection experiments, both the A and the G alleles responded to insulin and PMA, the A allele showing higher promoter activity than the G allele. Furthermore, Western blot analysis demonstrated that insulin increased MMP-12 protein production. To analyze whether the -82 A/G polymorphism is associated with coronary artery disease, 367 consecutive patients who underwent percutaneous transluminal coronary angiography with stent implantation were genotyped. In patients (n=71) with diabetes, the A allele was associated with a smaller luminal diameter. In conclusion, a common functional polymorphism within the MMP-12 promoter influences coronary artery luminal dimensions in diabetic patients with manifest coronary artery disease.", - "journal_title": "Circulation research", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/10807873/" - } - ], - "ad90e0ba-7691-4d64-a64f-2416b2bd4eb0": [ - { - "pub_id": "17620046", - "title": "Recent development in pharmacogenomics: from candidate genes to genome-wide association studies.", - "authors": "Struan F A Grant,Hakon Hakonarson", - "abstract": "Genetic diversity, most notably through single nucleotide polymorphisms and copy-number variation, together with specific environmental exposures, contributes to both disease susceptibility and drug response variability. It has proved difficult to isolate disease genes that confer susceptibility to complex disorders, and as a consequence, even fewer genetic variants that influence clinical drug responsiveness have been uncovered. As such, the candidate gene approach has largely failed to deliver and, although the family-based linkage approach has certain theoretical advantages in dealing with common/complex disorders, progress has been slower than was hoped. More recently, genome-wide association studies have gained increasing popularity, as they enable scientists to robustly associate specific variants with the predisposition for complex disease, such as age-related macular degeneration, Type 2 diabetes, inflammatory bowel disease, obesity, autism and leukemia. This relatively new methodology has stirred new hope for the mapping of genes that regulate drug response related to these conditions. Collectively, these studies support the notion that modern high-throughput single nucleotide polymorphism genotyping technologies, when applied to large and comprehensively phenotyped patient cohorts, will readily reveal the most clinically relevant disease-modifying and drug response genes. This review addresses both recent advances in the genotyping field and highlights from genome-wide association studies, which have conclusively uncovered variants that underlie disease susceptibility and/or variability in drug response in common disorders.", - "journal_title": "Expert review of molecular diagnostics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/17620046/" - } - ], - "095b38c7-b0a8-4311-9f87-b506d90bd2a4": [ - { - "pub_id": "17434869", - "title": "A common variant in the FTO gene is associated with body mass index and predisposes to childhood and adult obesity.", - "authors": "Timothy M Frayling,Nicholas J Timpson,Michael N Weedon,Eleftheria Zeggini,Rachel M Freathy,Cecilia M Lindgren,John R B Perry,Katherine S Elliott,Hana Lango,Nigel W Rayner,Beverley Shields,Lorna W Harries,Jeffrey C Barrett,Sian Ellard,Christopher J Groves,Bridget Knight,Ann-Marie Patch,Andrew R Ness,Shah Ebrahim,Debbie A Lawlor,Susan M Ring,Yoav Ben-Shlomo,Marjo-Riitta Jarvelin,Ulla Sovio,Amanda J Bennett,David Melzer,Luigi Ferrucci,Ruth J F Loos,In\u00eas Barroso,Nicholas J Wareham,Fredrik Karpe,Katharine R Owen,Lon R Cardon,Mark Walker,Graham A Hitman,Colin N A Palmer,Alex S F Doney,Andrew D Morris,George Davey Smith,Andrew T Hattersley,Mark I McCarthy", - "abstract": "Obesity is a serious international health problem that increases the risk of several common diseases. The genetic factors predisposing to obesity are poorly understood. A genome-wide search for type 2 diabetes-susceptibility genes identified a common variant in the FTO (fat mass and obesity associated) gene that predisposes to diabetes through an effect on body mass index (BMI). An additive association of the variant with BMI was replicated in 13 cohorts with 38,759 participants. The 16% of adults who are homozygous for the risk allele weighed about 3 kilograms more and had 1.67-fold increased odds of obesity when compared with those not inheriting a risk allele. This association was observed from age 7 years upward and reflects a specific increase in fat mass.", - "journal_title": "Science (New York, N.Y.)", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/17434869/" - } - ], - "fcf8fb37-20cf-491c-96f8-04a5621812a2": [ - { - "pub_id": "18850179", - "title": "Sideways Glance: Genome wide association studies for type 2 diabetes mellitus.", - "authors": "Yula Sambuy", - "abstract": "", - "journal_title": "Genes & nutrition", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/18850179/" - } - ], - "3238f205-367c-40ce-9ebf-8c46bc48ed7a": [ - { - "pub_id": "16182581", - "title": "Genetic and genomic systems to study methylmalonic acidemia.", - "authors": "R J Chandler,C P Venditti", - "abstract": "Methylmalonic acidemia (MMAemia) is the biochemical hallmark of a group of genetic metabolic disorders that share a common defect in the ability to convert methylmalonyl-CoA into succinyl-CoA. This disorder is due to either a mutant methylmalonyl-CoA mutase apoenzyme or impaired synthesis of adenosylcobalamin, the cofactor for this enzyme. In this article, we will provide an overview of the pathways disrupted in these disorders, discuss the known metabolic blocks with a particular focus on molecular genetics, and review the use of selected model organisms to study features of methylmalonic acidemia.", - "journal_title": "Molecular genetics and metabolism", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/16182581/" - } - ], - "1396203b-cc03-475e-85ea-070e167d6ddd": [ - { - "pub_id": "10615960", - "title": "Analysis of parent-offspring trios provides evidence for linkage and association between the insulin gene and type 2 diabetes mediated exclusively through paternally transmitted class III variable number tandem repeat alleles.", - "authors": "S J Huxtable,P J Saker,L Haddad,M Walker,T M Frayling,J C Levy,G A Hitman,S O'Rahilly,A T Hattersley,M I McCarthy", - "abstract": "Variation at the variable number tandem repeat (VNTR) minisatellite 5' of the insulin gene (INS) is associated with several phenotypes, including type 1 diabetes, polycystic ovary syndrome, and birth weight. Case-control studies have suggested that class III VNTR alleles are also associated with type 2 diabetes, but results have been inconsistent and may reflect population stratification. To explore further the role of the INS-VNTR in type 2 diabetes susceptibility, we used family-based association methods in 155 parent-offspring trios from the British Diabetic Association-Warren Trios repository, each ascertained via a Europid proband with type 2 diabetes. Overall, there was no significant association between diabetes and the INS-VNTR genotype, with 65 of 119 heterozygous parents (55%) transmitting class III and 54 class I (P = 0.16, one-sided). However, whereas maternal transmissions followed Mendelian expectation, there was a marked excess of class III transmission from the 49 heterozygous fathers (34 [69%] vs. 15, P = 0.003 vs. 50% expectation, P = 0.003 vs. maternal transmission). These results confirm that variation within the TH-INS-IGF2 locus, most plausibly at the VNTR itself, influences type 2 diabetes susceptibility. By demonstrating that this effect is mediated exclusively by the paternally derived allele, these findings implicate imprinted genes in the pathogenesis of type 2 diabetes.", - "journal_title": "Diabetes", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/10615960/" - } - ], - "3c35547c-eb9b-470d-b74b-0f9a0529e965": [ - { - "pub_id": "19749172", - "title": "Pathomechanisms of type 2 diabetes genes.", - "authors": "Harald Staiger,Fausto Machicao,Andreas Fritsche,Hans-Ulrich H\u00e4ring", - "abstract": "Type 2 diabetes mellitus is a complex metabolic disease that is caused by insulin resistance and beta-cell dysfunction. Furthermore, type 2 diabetes has an evident genetic component and represents a polygenic disease. During the last decade, considerable progress was made in the identification of type 2 diabetes risk genes. This was crucially influenced by the development of affordable high-density single nucleotide polymorphism (SNP) arrays that prompted several successful genome-wide association scans in large case-control cohorts. Subsequent to the identification of type 2 diabetes risk SNPs, cohorts thoroughly phenotyped for prediabetic traits with elaborate in vivo methods allowed an initial characterization of the pathomechanisms of these SNPs. Although the underlying molecular mechanisms are still incompletely understood, a surprising result of these pathomechanistic investigations was that most of the risk SNPs affect beta-cell function. This favors a beta-cell-centric view on the genetics of type 2 diabetes. The aim of this review is to summarize the current knowledge about the type 2 diabetes risk genes and their variants' pathomechanisms.", - "journal_title": "Endocrine reviews", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/19749172/" - } - ], - "ce63119a-9a7b-4946-b1f5-bc8bfc4c10da": [ - { - "pub_id": "19035627", - "title": "Glossary of genetics/genomics terms: diabetes mellitus.", - "authors": "David Williamson,Anne Bardsley-Elliot", - "abstract": "Diabetes mellitus is recognized as one of the most significant public health problems in the world today. The World Health Organization (WHO) has estimated that worldwide some 3 million deaths per year are attributable to this disease, the majority of which are from type 2 diabetes. Moreover, the prevalence of type 2 diabetes specifically is steadily rising. According to a recent study from the US Centers for Disease Control and Prevention, the incidence of diagnosed diabetes in the US alone has nearly doubled over the last 10 years, and globally WHO estimates the prevalence worldwide to reach 366 million by the year 2030, more than double that of 2000.Genetic factors appear to play a role in determining an individual's risk of developing diabetes. It is hoped that genetic studies will ultimately identify key genetic elements that help determine susceptibility to diabetes, disease progression, and responsiveness to specific therapies, as well as help identify novel targets for future intervention. A substantial number of genetic loci, gene polymorphisms, and mutations have already been reported as having variable degrees of association with one or other type of diabetes (type 1, type 2, maturity onset diabetes of the young [MODY]), while others appear to be involved in response to antihyperglycemic agents. We have compiled the following glossary of genetic and genomic terms relating to diabetes, which we hope will prove a useful reference to researchers and clinicians with an interest in this disease. This is by no means an exhaustive list, but includes many of the genetic loci and variants that have been studied in association with diabetes.", - "journal_title": "Molecular diagnosis & therapy", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/19035627/" - } - ], - "e4a230f1-71f7-43da-a20c-6cd1fe3992ef": [ - { - "pub_id": "18454148", - "title": "Common variants near MC4R are associated with fat mass, weight and risk of obesity.", - "authors": "Ruth J F Loos,Cecilia M Lindgren,Shengxu Li,Eleanor Wheeler,Jing Hua Zhao,Inga Prokopenko,Michael Inouye,Rachel M Freathy,Antony P Attwood,Jacques S Beckmann,Sonja I Berndt, ,Kevin B Jacobs,Stephen J Chanock,Richard B Hayes,Sven Bergmann,Amanda J Bennett,Sheila A Bingham,Murielle Bochud,Morris Brown,St\u00e9phane Cauchi,John M Connell,Cyrus Cooper,George Davey Smith,Ian Day,Christian Dina,Subhajyoti De,Emmanouil T Dermitzakis,Alex S F Doney,Katherine S Elliott,Paul Elliott,David M Evans,I Sadaf Farooqi,Philippe Froguel,Jilur Ghori,Christopher J Groves,Rhian Gwilliam,David Hadley,Alistair S Hall,Andrew T Hattersley,Johannes Hebebrand,Iris M Heid, ,Claudia Lamina,Christian Gieger,Thomas Illig,Thomas Meitinger,H-Erich Wichmann,Blanca Herrera,Anke Hinney,Sarah E Hunt,Marjo-Riitta Jarvelin,Toby Johnson,Jennifer D M Jolley,Fredrik Karpe,Andrew Keniry,Kay-Tee Khaw,Robert N Luben,Massimo Mangino,Jonathan Marchini,Wendy L McArdle,Ralph McGinnis,David Meyre,Patricia B Munroe,Andrew D Morris,Andrew R Ness,Matthew J Neville,Alexandra C Nica,Ken K Ong,Stephen O'Rahilly,Katharine R Owen,Colin N A Palmer,Konstantinos Papadakis,Simon Potter,Anneli Pouta,Lu Qi, ,Joshua C Randall,Nigel W Rayner,Susan M Ring,Manjinder S Sandhu,Andr\u00e9 Scherag,Matthew A Sims,Kijoung Song,Nicole Soranzo,Elizabeth K Speliotes, ,Holly E Syddall,Sarah A Teichmann,Nicholas J Timpson,Jonathan H Tobias,Manuela Uda, ,Carla I Ganz Vogel,Chris Wallace,Dawn M Waterworth,Michael N Weedon, ,Cristen J Willer, , Wraight,Xin Yuan,Eleftheria Zeggini,Joel N Hirschhorn,David P Strachan,Willem H Ouwehand,Mark J Caulfield,Nilesh J Samani,Timothy M Frayling,Peter Vollenweider,Gerard Waeber,Vincent Mooser,Panos Deloukas,Mark I McCarthy,Nicholas J Wareham,In\u00eas Barroso,Kevin B Jacobs,Stephen J Chanock,Richard B Hayes,Claudia Lamina,Christian Gieger,Thomas Illig,Thomas Meitinger,H-Erich Wichmann,Peter Kraft,Susan E Hankinson,David J Hunter,Frank B Hu,Helen N Lyon,Benjamin F Voight,Martin Ridderstrale,Leif Groop,Paul Scheet,Serena Sanna,Goncalo R Abecasis,Giuseppe Albai,Ramaiah Nagaraja,David Schlessinger,Anne U Jackson,Jaakko Tuomilehto,Francis S Collins,Michael Boehnke,Karen L Mohlke", - "abstract": "To identify common variants influencing body mass index (BMI), we analyzed genome-wide association data from 16,876 individuals of European descent. After previously reported variants in FTO, the strongest association signal (rs17782313, P = 2.9 x 10(-6)) mapped 188 kb downstream of MC4R (melanocortin-4 receptor), mutations of which are the leading cause of monogenic severe childhood-onset obesity. We confirmed the BMI association in 60,352 adults (per-allele effect = 0.05 Z-score units; P = 2.8 x 10(-15)) and 5,988 children aged 7-11 (0.13 Z-score units; P = 1.5 x 10(-8)). In case-control analyses (n = 10,583), the odds for severe childhood obesity reached 1.30 (P = 8.0 x 10(-11)). Furthermore, we observed overtransmission of the risk allele to obese offspring in 660 families (P (pedigree disequilibrium test average; PDT-avg) = 2.4 x 10(-4)). The SNP location and patterns of phenotypic associations are consistent with effects mediated through altered MC4R function. Our findings establish that common variants near MC4R influence fat mass, weight and obesity risk at the population level and reinforce the need for large-scale data integration to identify variants influencing continuous biomedical traits.", - "journal_title": "Nature genetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/18454148/" - } - ], - "34f29ab8-f82a-4ed8-b42f-1a2280e21589": [ - { - "pub_id": "21167468", - "title": "GCTA: a tool for genome-wide complex trait analysis.", - "authors": "Jian Yang,S Hong Lee,Michael E Goddard,Peter M Visscher", - "abstract": "For most human complex diseases and traits, SNPs identified by genome-wide association studies (GWAS) explain only a small fraction of the heritability. Here we report a user-friendly software tool called genome-wide complex trait analysis (GCTA), which was developed based on a method we recently developed to address the \"missing heritability\" problem. GCTA estimates the variance explained by all the SNPs on a chromosome or on the whole genome for a complex trait rather than testing the association of any particular SNP to the trait. We introduce GCTA's five main functions: data management, estimation of the genetic relationships from SNPs, mixed linear model analysis of variance explained by the SNPs, estimation of the linkage disequilibrium structure, and GWAS simulation. We focus on the function of estimating the variance explained by all the SNPs on the X chromosome and testing the hypotheses of dosage compensation. The GCTA software is a versatile tool to estimate and partition complex trait variation with large GWAS data sets.", - "journal_title": "American journal of human genetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/21167468/" - } - ], - "e8018d14-937c-482b-b8ad-9a482abc418a": [ - { - "pub_id": "11306085", - "title": "Functional genomic studies of aldo-keto reductases.", - "authors": "J M Petrash,B S Murthy,M Young,K Morris,L Rikimaru,T A Griest,T Harter", - "abstract": "Aldose reductase (AR) is considered a potential mediator of diabetic complications and is a drug target for inhibitors of diabetic retinopathy and neuropathy in clinical trials. However, the physiological role of this enzyme still has not been established. Since effective inhibition of diabetic complications will require early intervention, it is important to delineate whether AR fulfills a physiological role that cannot be compensated by an alternate aldo-keto reductase. Functional genomics provides a variety of powerful new tools to probe the physiological roles of individual genes, especially those comprising gene families. Several eucaryotic genomes have been sequenced and annotated, including yeast, nematode and fly. To probe the function of AR, we have chosen to utilize the budding yeast Saccharomyces cerevisiae as a potential model system. Unlike Caenorhabditis elegans and D. melanogaster, yeast provides a more desirable system for our studies because its genome is manipulated more readily and is able to sustain multiple gene deletions in the presence of either drug or auxotrophic selectable markers. Using BLAST searches against the human AR gene sequence, we identified six genes in the complete S. cerevisiae genome with strong homology to AR. In all cases, amino acids thought to play important catalytic roles in human AR are conserved in the yeast AR-like genes. All six yeast AR-like open reading frames (ORFs) have been cloned into plasmid expression vectors. Substrate and AR inhibitor specificities have been surveyed on four of the enzyme forms to identify, which are the most functionally similar to human AR. Our data reveal that two of the enzymes (YDR368Wp and YHR104Wp) are notable for their similarity to human AR in terms of activity with aldoses and substituted aromatic aldehydes. Ongoing studies are aimed at characterizing the phenotypes of yeast strains containing single and multiple knockouts of the AR-like genes.", - "journal_title": "Chemico-biological interactions", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/11306085/" - } - ], - "1a93e25f-2a43-49e9-8450-03a57c93e613": [ - { - "pub_id": "18590522", - "title": "Meta-analysis approach identifies candidate genes and associated molecular networks for type-2 diabetes mellitus.", - "authors": "Axel Rasche,Hadi Al-Hasani,Ralf Herwig", - "abstract": "Multiple functional genomics data for complex human diseases have been published and made available by researchers worldwide. The main goal of these studies is the detailed analysis of a particular aspect of the disease. Complementary, meta-analysis approaches try to extract supersets of disease genes and interaction networks by integrating and combining these individual studies using statistical approaches. Here we report on a meta-analysis approach that integrates data of heterogeneous origin in the domain of type-2 diabetes mellitus (T2DM). Different data sources such as DNA microarrays and, complementing, qualitative data covering several human and mouse tissues are integrated and analyzed with a Bootstrap scoring approach in order to extract disease relevance of the genes. The purpose of the meta-analysis is two-fold: on the one hand it identifies a group of genes with overall disease relevance indicating common, tissue-independent processes related to the disease; on the other hand it identifies genes showing specific alterations with respect to a single study. Using a random sampling approach we computed a core set of 213 T2DM genes across multiple tissues in human and mouse, including well-known genes such as Pdk4, Adipoq, Scd, Pik3r1, Socs2 that monitor important hallmarks of T2DM, for example the strong relationship between obesity and insulin resistance, as well as a large fraction (128) of yet barely characterized novel candidate genes. Furthermore, we explored functional information and identified cellular networks associated with this core set of genes such as pathway information, protein-protein interactions and gene regulatory networks. Additionally, we set up a web interface in order to allow users to screen T2DM relevance for any - yet non-associated - gene. In our paper we have identified a core set of 213 T2DM candidate genes by a meta-analysis of existing data sources. We have explored the relation of these genes to disease relevant information and - using enrichment analysis - we have identified biological networks on different layers of cellular information such as signaling and metabolic pathways, gene regulatory networks and protein-protein interactions. The web interface is accessible via http://t2dm-geneminer.molgen.mpg.de.", - "journal_title": "BMC genomics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/18590522/" - } - ], - "af80affc-1032-4f72-928c-9502f1a1f5a2": [ - { - "pub_id": "7819154", - "title": "Prevention of insulitis and diabetes in beta 2-microglobulin-deficient non-obese diabetic mice.", - "authors": "T Sumida,M Furukawa,A Sakamoto,T Namekawa,T Maeda,M Zijlstra,I Iwamoto,T Koike,S Yoshida,H Tomioka", - "abstract": "beta 2-Microglobulin (beta 2m)-deficient non-obese diabetic (NOD) mice were established by crossing beta 2m-deficient 129/Sv mice with NOD mice, and used to examine the possible involvement of MHC class I molecules and CD8+ T cells in the development of insulitis and diabetes. In these mice, MHC class I molecules were not expressed, resulting in no generation of CD8+ T cells. None of eight lines of beta 2m-deficient NOD mice (-/-) established developed overt diabetes by 32 weeks, while control littermates (+/+) became diabetic by 22 weeks. histological studies showed no significant lymphocyte infiltration of the islets (insulitis score: 0.03 +/- 0.03) in any of the beta 2m-deficient NOD mice (-/-) compared with littermate NOD mice (+/+) with overt insulitis (1.42 +/- 0.28). These findings support the notion that the expression of MHC class I molecules and/or CD8+ T cells plays an essential role in the infiltration of CD4+ T cells in islets as well as the development of diabetes in NOD mice.", - "journal_title": "International immunology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/7819154/" - } - ], - "7432c2b7-6d20-4689-a12e-689211b3aa5a": [ - { - "pub_id": "11994901", - "title": "The search for type 2 diabetes susceptibility genes using whole-genome scans: an epidemiologist's perspective.", - "authors": "Michael P Stern", - "abstract": "Most whole-genome scan studies of type 2 diabetes have ascertained families on affected sibpairs. Although assuring enrollment of multiplex families, this strategy may lead to the enrollment of unrepresentative families, particularly in low-risk populations where relatively few diabetics have an affected sibling. In high-risk populations such as Hispanics and Native Americans, population-based ascertainment is often possible, since the high frequency of the disease favors enrollment of multiplex families even when they are not specifically sought. The results of the first generation of genome scan studies caused concern because of a perceived lack of reproducibility. More recently, however, a number of replications have emerged, specifically on chromosomes 1q, 2q, 3q, 9p, 10q, and 11q. The MODY 1 and 3 regions on chromosome 12q and 20q have also been replicated in multiple studies. The clinical features of diabetes in these latter families, however, suggest the common form of type 2 diabetes, rather than maturity-onset diabetes of the young (MODY). Also, diabetes in these families does not appear to be caused by the classical MODY mutations. Interestingly, functional variants of the MODY 4 gene (insulin promoter factor-1) have been associated with both MODY and the common form of type 2 diabetes. Currently available linkage studies implicate relatively broad chromosomal regions, and the challenge of narrowing these regions to facilitate gene discovery remains formidable. The linkages that have been replicated thus far provide good starting points to search for functional variants in type 2 diabetes susceptibility genes.", - "journal_title": "Diabetes/metabolism research and reviews", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/11994901/" - } - ], - "607a732d-9878-44b6-93ab-bcffe4284128": [ - { - "pub_id": "10343160", - "title": "Characterisation of the human central MHC gene, BAT1: genomic structure and expression.", - "authors": "R J Allcock,P Price,S Gaudieri,C Leelayuwat,C S Witt,R L Dawkins", - "abstract": "The BAT1 gene (D6S81E) encodes a member of the DEAD-box family of RNA-binding proteins, and lies in the central MHC. This region contains genes which affect susceptibility to immunopathological diseases. A 14-kb section of the human MHC containing the BAT1 gene and a further 5-kb telomeric of BAT1 was sequenced using DNA from individuals homozygous for HLA-A1, B8, DR3 and HLA- A1, B57, DR7. Analysis of our sequences and the previously reported human cDNA sequence showed that the expressed sequence of the 8.1 and 57.1 haplotypes is identical with only minor substitutions in the introns. Phylogenetic analysis suggests BAT1 may be a translation initiation factor. Screening of cells and tissues for BAT1 mRNA suggests an abundant member of a family of proteins expressed in multiple cell types, notably macrophages and hepatocytes. Expression was independent of MHC haplotype, consistent with the lack of sequence polymorphism.", - "journal_title": "Experimental and clinical immunogenetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/10343160/" - } - ], - "c77080f3-5fb8-4f3c-89f9-cabd3fd2bce1": [ - { - "pub_id": "19401414", - "title": "Confirmation of multiple risk Loci and genetic impacts by a genome-wide association study of type 2 diabetes in the Japanese population.", - "authors": "Fumihiko Takeuchi,Masakuni Serizawa,Ken Yamamoto,Tomomi Fujisawa,Eitaro Nakashima,Keizo Ohnaka,Hiroshi Ikegami,Takao Sugiyama,Tomohiro Katsuya,Makoto Miyagishi,Naoki Nakashima,Hajime Nawata,Jiro Nakamura,Suminori Kono,Ryoichi Takayanagi,Norihiro Kato", - "abstract": "To identify novel type 2 diabetes gene variants and confirm previously identified ones, a three-staged genome-wide association study was performed in the Japanese population. In the stage 1 scan, we genotyped 519 case and 503 control subjects with 482,625 single nucleotide polymorphism (SNP) markers; in the stage 2 panel comprising 1,110 case subjects and 1,014 control subjects, we assessed 1,456 SNPs (P < 0.0025, stage 1); additionally to direct genotyping, 964 healthy control subjects formed the in silico control panel. Along with genome-wide exploration, we aimed to replicate the disease association of 17 SNPs from 16 candidate loci previously identified in Europeans. The associated and/or replicated loci (23 SNPs; P < 7 x 10(-5) for genome-wide exploration and P < 0.05 for replication) were examined in the stage 3 panel comprising 4,000 case subjects and 12,569 population-based samples, from which 4,889 nondiabetic control subjects were preselected. The 12,569 subjects were used for overall risk assessment in the general population. Four loci-1 novel with suggestive evidence (PEPD on 19q13, P = 1.4 x 10(-5)) and three previously reported-were identified; the association of CDKAL1, CDKN2A/CDKN2B, and KCNQ1 were confirmed (P < 10(-19)). Moreover, significant associations were replicated in five other candidate loci: TCF7L2, IGF2BP2, SLC30A8, HHEX, and KCNJ11. There was substantial overlap of type 2 diabetes susceptibility genes between the two populations, whereas effect size and explained variance tended to be higher in the Japanese population. The strength of association was more prominent in the Japanese population than in Europeans for more than half of the confirmed type 2 diabetes loci.", - "journal_title": "Diabetes", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/19401414/" - } - ], - "42cc2118-f5b7-415e-9a42-212b80b0a3db": [ - { - "pub_id": "15135805", - "title": "Polymorphisms of chemokine and chemokine receptor genes in Type 1 diabetes mellitus and its complications.", - "authors": "B Yang,K Houlberg,A Millward,A Demaine", - "abstract": "Cytokines and chemokines have been implicated in the pathogenesis of Type 1 diabetes mellitus (T1DM) and its microvascular complications. Recently, genetic variants of monocyte chemotactic protein-1 (MCP-1), CC-chemokine receptor 2 (CCR2), CC-chemokine receptor 5 (CCR5) genes have been identified. The aim was to investigate whether genetic variants of the MCP-1 G(-2518)A, CCR2B 64I, CCR5 G(59029)A, and CCR5 Delta32 are associated with T1DM and its microvascular complications. Two hundred and sixty patients with T1DM with and without diabetic microvascular complications, and 104 normal controls were recruited for this study. Genotypes of the MCP-1 G(-2518)A, CCR2B 64I, CCR5 G(59029)A, and CCR5 delta32 were performed by polymerase chain reaction followed by digestion with appropriate restriction endonucleases. Frequencies of the MCP-1 A(-2518) allele (74.6% vs. 63.5%, p < 0.003) and A/A genotype (54.5% vs. 34.6%, p < 0.001, Pc = 0.002) were significantly higher in patients with T1DM compared with normal controls. CCR5 G(59029) was slightly increased in the patients with microvascular complications compared with the uncomplicated (21.4% vs. 10%, p < 0.03, Pc = ns). The frequency of haplotype G/G/W was slightly increased in the patients with diabetic complications compared to the uncomplicated (39.6% vs. 28.8%, p < 0.02, Pc = ns). These results suggest that polymorphisms of the MCP-1, CCR2 and CCR5 genes may be associated with T1DM and its complications.", - "journal_title": "Cytokine", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/15135805/" - } - ], - "c24330f7-9f82-404a-86d5-a16d814bb754": [ - { - "pub_id": "12874445", - "title": "Genomic strategies for diabetic nephropathy.", - "authors": "Katalin Susztak,Kumar Sharma,Mario Schiffer,Peter McCue,Emilio Ciccone,Erwin P B\u00f6ttinger", - "abstract": "Insight into the molecular mechanisms that underlie the origin and progression of diabetic nephropathy remains limited in part because conventional research tools have restricted investigators to focus on single genes or isolated pathways. Microarray technologies provide opportunities for evaluating genetic factors and environmental effects at a genomic scale during the pathogenesis of diabetic nephropathy. Despite the enormous power of the microarray technology, there are several pitfalls that need to be considered. This article discusses conceptual, practical, statistical, and logistical considerations for the use of microarrays in studies of experimental and human diabetic renal disease. New knowledge in this field will facilitate new approaches for molecular diagnosis and drug discovery.", - "journal_title": "Journal of the American Society of Nephrology : JASN", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/12874445/" - } - ], - "7d89c8f6-8741-4cc3-bdfb-e382dfb9c4c8": [ - { - "pub_id": "31986256", - "title": "Interpretation of risk loci from genome-wide association studies of Alzheimer's disease.", - "authors": "Shea J Andrews,Brian Fulton-Howard,Alison Goate", - "abstract": "Alzheimer's disease is a debilitating and highly heritable neurological condition. As such, genetic studies have sought to understand the genetic architecture of Alzheimer's disease since the 1990s, with successively larger genome-wide association studies (GWAS) and meta-analyses. These studies started with a small sample size of 1086 individuals in 2007, which was able to identify only the APOE locus. In 2013, the International Genomics of Alzheimer's Project (IGAP) did a meta-analysis of all existing GWAS using data from 74\u2008046 individuals, which stood as the largest Alzheimer's disease GWAS until 2018. This meta-analysis discovered 19 susceptibility loci for Alzheimer's disease in populations of European ancestry. Three new Alzheimer's disease GWAS published in 2018 and 2019, which used larger sample sizes and proxy phenotypes from biobanks, have substantially increased the number of known susceptibility loci in Alzheimer's disease to 40. The first, an updated GWAS from IGAP, included 94\u2008437 individuals and discovered 24 susceptibility loci. Although IGAP sought to increase sample size by recruiting additional clinical cases and controls, the two other studies used parental family history of Alzheimer's disease to define proxy cases and controls in the UK Biobank for a genome-wide association by proxy, which was meta-analysed with data from GWAS of clinical Alzheimer's disease to attain sample sizes of 388\u2008324 and 534\u2008403 individuals. These two studies identified 27 and 29 susceptibility loci, respectively. However, the three studies were not independent because of the large overlap in their participants, and interpretation can be challenging because different variants and genes were highlighted by each study, even in the same locus. Furthermore, neither the variant with the strongest Alzheimer's disease association nor the nearest gene are necessarily causal. This situation presents difficulties for experimental studies, drug development, and other future research. WHERE NEXT?: The ultimate goal of understanding the genetic architecture of Alzheimer's disease is to characterise novel biological pathways that underly Alzheimer's disease pathogenesis and to identify novel drug targets. GWAS have successfully contributed to the characterisation of the genetic architecture of Alzheimer's disease, with the identification of 40 susceptibility loci; however, this does not equate to the discovery of 40 Alzheimer's disease genes. To identify Alzheimer's disease genes, these loci need to be mapped to variants and genes through functional genomics studies that combine annotation of variants, gene expression, and gene-based or pathway-based analyses. Such studies are ongoing and have validated several genes at Alzheimer's disease loci, but greater sample sizes and cell-type specific data are needed to map all GWAS loci.", - "journal_title": "The Lancet. Neurology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/31986256/" - } - ], - "756b902b-cbc7-40e8-84a5-9372221d83a4": [ - { - "pub_id": "27885969", - "title": "36th International Symposium on Intensive Care and Emergency Medicine : Brussels, Belgium. 15-18 March 2016.", - "authors": "R. M. Bateman,M. D. Sharpe,J. E. Jagger,C. G. Ellis,J. Sol\u00e9-Viol\u00e1n,M. L\u00f3pez-Rodr\u00edguez,E. Herrera-Ramos,J. Ru\u00edz-Hern\u00e1ndez,L. Border\u00edas,J. Horcajada,N. Gonz\u00e1lez-Quevedo,O. Rajas,M. Briones,F. Rodr\u00edguez de Castro,C. Rodr\u00edguez Gallego,F. Esen,G. Orhun,P. Ergin Ozcan,E. Senturk,C. Ugur Yilmaz,N. Orhan,N. Arican,M. Kaya,M. Kucukerden,M. Giris,U. Akcan,S. Bilgic Gazioglu,E. Tuzun,R. Riff,O. Naamani,A. Douvdevani,R. Takegawa,H. Yoshida,T. Hirose,N. Yamamoto,H. Hagiya,M. Ojima,Y. Akeda,O. Tasaki,K. Tomono,T. Shimazu,S. Ono,T. Kubo,S. Suda,T. Ueno,T. Ikeda,T. Hirose,H. Ogura,H. Takahashi,M. Ojima,J. Kang,Y. Nakamura,T. Kojima,T. Shimazu,T. Ikeda,S. Suda,Y. Izutani,T. Ueno,S. Ono,T. Taniguchi,M. O,C. Dinter,J. Lotz,B. Eilers,C. Wissmann,R. Lott,M. M. Meili,P. S. Schuetz,H. Hawa,M. Sharshir,M. Aburageila,N. Salahuddin,V. Chantziara,S. Georgiou,A. Tsimogianni,P. Alexandropoulos,A. Vassi,F. Lagiou,M. Valta,G. Micha,E. Chinou,G. Michaloudis,A. Kodaira,T. Ikeda,S. Ono,T. Ueno,S. Suda,Y. Izutani,H. Imaizumi,M. V. De la Torre-Prados,A. Garcia-De la Torre,A. Enguix-Armada,A. Puerto-Morlan,V. Perez-Valero,A. Garcia-Alcantara,N. Bolton,J. Dudziak,S. Bonney,A. Tridente,P. Nee,G. Nicolaes,M. Wiewel,M. Schultz,K. Wildhagen,J. Horn,R. Schrijver,T. Van der Poll,C. Reutelingsperger,S. Pillai,G. Davies,G. Mills,R. Aubrey,K. Morris,P. Williams,P. Evans,E. G. Gayat,J. Struck,A. Cariou,N. Deye,B. Guidet,S. Jabert,J. Launay,M. Legrand,M. L\u00e9one,M. Resche-Rigon,E. Vicaut,A. Vieillard-Baron,A. Mebazaa,R. Arnold,M. Capan,A. Linder,P. Akesson,M. Popescu,D. Tomescu,C. L. Sprung,R. Calderon Morales,G. Munteanu,E. Orenbuch-Harroch,P. Levin,H. Kasdan,A. Reiter,T. Volker,Y. Himmel,Y. Cohen,J. Meissonnier,L. Girard,F. Rebeaud,I. Herrmann,B. Delwarde,E. Peronnet,E. Cerrato,F. Venet,A. Lepape,T. Rimmel\u00e9,G. Monneret,J. Textoris,N. Beloborodova,V. Moroz,A. Osipov,A. Bedova,Y. Sarshor,A. Pautova,A. Sergeev,E. Chernevskaya,J. Odermatt,R. Bolliger,L. Hersberger,M. Ottiger,M. Christ-Crain,B. Mueller,P. Schuetz,N. K. Sharma,A. K. Tashima,M. K. Brunialti,F. R. Machado,M. Assuncao,O. Rigato,R. Salomao,S. C. Cajander,G. Rasmussen,E. Tina,B. S\u00f6derquist,J. K\u00e4llman,K. Str\u00e5lin,A. L. Lange,J. S. Sund\u00e9n-Cullberg,A. M. Magnuson,O. H. Hultgren,G. Davies,S. Pillai,G. Mills,R. Aubrey,K. Morris,P. Williams,P. Evans,S. Pillai,G. Davies,G. Mills,R. Aubrey,K. Morris,P. Williams,P. Evans,S. Pillai,G. Davies,G. Mills,R. Aubrey,K. Morris,P. Williams,P. Evans,P. Van der Geest,M. Mohseni,J. Linssen,R. De Jonge,S. Duran,J. Groeneveld,R. Miller,B. K. Lopansri,L. C. McHugh,A. Seldon,J. P. Burke,J. Johnston,R. Reece-Anthony,A. Bond,A. Molokhia,C. Mcgrath,E. Nsutebu,P. Bank Pedersen,D. Pilsgaard Henriksen,S. Mikkelsen,A. Touborg Lassen,R. Tincu,C. Cobilinschi,D. Tomescu,Z. Ghiorghiu,R. Macovei,M. A. Wiewel,M. B. Harmon,L. A. Van Vught,B. P. Scicluna,A. J. Hoogendijk,J. Horn,A. H. Zwinderman,O. L. Cremer,M. J. Bonten,M. J. Schultz,T. Van der Poll,N. P. Juffermans,W. J. Wiersinga,G. Eren,Y. Tekdos,M. Dogan,O. Acicbe,E. Kaya,O. Hergunsel,S. Alsolamy,G. Ghamdi,L. Alswaidan,S. Alharbi,F. Alenezi,Y. Arabi,J. Heaton,A. Boyce,L. Nolan,J. Johnston,A. Dukoff-Gordon,A. Dean,A. Molokhia,T. Mann Ben Yehudah,C. Fleischmann,D. Thomas-Rueddel,C. Haas,U. Dennler,K. Reinhart,O. Suntornlohanakul,B. Khwannimit,F. Breckenridge,A. Puxty,P. Szturz,P. Folwarzcny,J. Svancara,R. Kula,P. Sevcik,L. Caneva,A. Casazza,E. Bellazzi,S. Marra,L. Pagani,M. Vetere,R. Vanzino,D. Ciprandi,R. Preda,R. Boschi,L. Carnevale,V. Lopez,M. Aguilar Arzapalo,L. Barradas,A. Escalante,J. Gongora,M. Cetina,B Adamik,D Jakubczyk,A K\u00fcbler,A. Radford,T. Lee,J. Singer,J. Boyd,D. Fineberg,M. Williams,J. Russell,E. Scarlatescu,D. Tomescu,G. Droc,S. Arama,M. M\u00fcller,M. Straat,S. S. Zeerleder,N. P. Juffermans,C. F. Fuchs,C. S. Scheer,S. W. Wauschkuhn,M. V. Vollmer,K. M. Meissner,S. K. Kuhn,K. H. Hahnenkamp,S. R. Rehberg,M. G. Gr\u00fcndling,N. Yamamoto,M. Ojima,S. Hamaguchi,T. Hirose,Y. Akeda,R. Takegawa,O. Tasaki,T. Shimazu,K. Tomono,E. G\u00f3mez-S\u00e1nchez,M. Heredia-Rodr\u00edguez,E. \u00c1lvarez-Fuente,M. Lorenzo-L\u00f3pez,E. G\u00f3mez-Pesquera,M. Arag\u00f3n-Camino,P. Liu-Zhu,A. S\u00e1nchez-L\u00f3pez,A. Hern\u00e1ndez-Lozano,M. T. Pel\u00e1ez-Jare\u00f1o,E. Tamayo,D. O. Thomas-R\u00fcddel,C. Fleischmann,C. Haas,U. Dennler,K. Reinhart,V. Adora,A. Kar,A. Chakraborty,S. Roy,A. Bandyopadhyay,M. Das,T. Mann Ben Yehudah,G. BenYehudah,M. Salim,N. Kumar,L. Arabi,T. Burger,P. Lephart,E. Toth-martin,C. Valencia,N. Hammami,S. Blot,J. L. Vincent,M. L. Lambert,J. Brunke,T. Riemann,I. Roschke,R. Tincu,C. Cobilinschi,D. Tomescu,Z. Ghiorghiu,R. Macovei,S. Nimitvilai,K. Jintanapramote,S. Jarupongprapa,D. Adukauskiene,D. Valanciene,G. Bose,V. Lostarakos,B. Carr,S. Khedher,A. Maaoui,A. Ezzamouri,M. Salem,J. Chen,D. R. Cranendonk,L. A. Van Vught,M. A. Wiewel,O. L. Cremer,J. Horn,M. J. Bonten,M. J. Schultz,T. Van der Poll,W. J. Wiersinga,M. Day,G. Penrice,K. Roy,P. Robertson,G. Godbole,B. Jones,M. Booth,L. Donaldson,Y. Kawano,H. Ishikura,H. Al-Dorzi,M. Almutairi,B. Alhamadi,A. Crizaldo Toledo,R. Khan,B. Al Raiy,Y. Arabi,H. Talaie,J. A. Van Oers,A. Harts,E. Nieuwkoop,P. Vos,Y. Boussarsar,F. Boutouta,S. Kamoun,I. Mezghani,S. Koubaji,A. Ben Souissi,A. Riahi,M. S. Mebazaa,E. Giamarellos-Bourboulis,N. Tziolos,C. Routsi,C. Katsenos,I. Tsangaris,I. Pneumatikos,G. Vlachogiannis,V. Theodorou,A. Prekates,E. Antypa,V. Koulouras,N. Kapravelos,C. Gogos,E. Antoniadou,K. Mandragos,A. Armaganidis,A. R. Robles Caballero,B. Civantos,J. C. Figueira,J. L\u00f3pez,A. Silva-Pinto,F. Ceia,A. Sarmento,L. Santos,G. Almekhlafi,Y. Sakr,H. Al-Dorzi,R. Khan,S. Baharoon,A. Aldawood,A. Matroud,J. Alchin,S. Al Johani,H. Balkhy,Y. Arabi,S. Alsolamy,S. Y. Yousif,B. O. Alotabi,A. S. Alsaawi,J. Ang,M. D. Curran,D. Enoch,V. Navapurkar,A. Morris,R. Sharvill,J. Astin,M. Heredia-Rodr\u00edguez,E. G\u00f3mez-S\u00e1nchez,M. T. Pel\u00e1ez-Jare\u00f1o,E. G\u00f3mez-Pesquera,M. Lorenzo-L\u00f3pez,P. Liu-Zhu,M. Arag\u00f3n-Camino,A. Hern\u00e1ndez-Lozano,A. S\u00e1nchez-L\u00f3pez,E. \u00c1lvarez-Fuente,E. Tamayo,J. Patel,C. Kruger,J. O\u2019Neal,H. Rhodes,J. Jancik,B. Fran\u00e7ois,P. F. Laterre,P. Eggimann,A. Torres,M. S\u00e1nchez,P. F. Dequin,G. L. Bassi,J. Chastre,H. S. Jafri,M. Ben Romdhane,Z. Douira,S. Kamoun,M. Bousselmi,A. Ben Souissi,Y. Boussarsar,A. Riahi,M. S. Mebazaa,A. Vakalos,V. Avramidis,T. H. Craven,G. Wojcik,K. Kefala,J. McCoubrey,J. Reilly,R. Paterson,D. Inverarity,I. Laurenson,T. S. Walsh,S. Mongodi,B. Bouhemad,A. Orlando,A. Stella,G. Via,G. Iotti,A. Braschi,F. Mojoli,M. Haliloglu,B. Bilgili,U. Kasapoglu,I. Sayan,M. S\u00fczer Aslan,A. Yalc\u0131n,I. Cinel,A. Vakalos,V. Avramidis,H. E. Ellis,K. Bauchmuller,D. Miller,A. Temple,J. Chastre,B. Fran\u00e7ois,A. Torres,C. E. Luyt,M. S\u00e1nchez,M. Singer,H. S. Jafri,Y. Nassar,M. S. Ayad,A. Trifi,S. Abdellatif,F. Daly,R. Nasri,S. Ben Lakhal,B. Bilgili,M. Haliloglu,F. Gul,I. Cinel,A. Kuzovlev,A. Shabanov,S. Polovnikov,V. Moroz,N. Kadrichu,T. Dang,K. Corkery,P. Challoner,G. Li Bassi,E. Aguilera,C. Chiurazzi,C. Travierso,A. Motos,L. Fernandez,R. Amaro,T. Senussi,F. Idone,J. Bobi,M. Rigol,A. Torres,C. J. Hodiamont,N. P. Juffermans,J. M. Janssen,C. S. Bouman,R. A. Math\u00f4t,M. D. De Jong,R. M. Van Hest,L. Payne,G. L. Fraser,B. Tudor,M. Lahner,G. Roth,C. Krenn,H. Talaie,P. Jault,J. Gabard,T. Leclerc,S. Jennes,Y. Que,A. Rousseau,F. Ravat,H. Al-Dorzi,A. Eissa,S. Al-Harbi,T. Aldabbagh,R. Khan,Y. Arabi,A. Trifi,S. Abdellatif.,F. Daly,R. Nasri,S. Ben Lakhal,F. Paramba,N. Purayil,V. Naushad,O. Mohammad,V. Negi,P. Chandra,A. Kleinsasser,M. R. Witrz,J. F. Buchner-Doeven,A. M. Tuip-de Boer,J. C. Goslings,N. P. Juffermans,M. Van Hezel,M. Straat,A Boing,R Van Bruggen,N Juffermans,D. Markopoulou,K. Venetsanou,V. Kaldis,D. Koutete,D. Chroni,I. Alamanos,L. Koch,J. Jancik,H. Rhodes,E. Walter,K. Maekawa,M. Hayakawa,S. Kushimoto,A. Shiraishi,H. Kato,J. Sasaki,H. Ogura,T. Matauoka,T. Uejima,N. Morimura,H. Ishikura,A. Hagiwara,M. Takeda,O. Tarabrin,S. Shcherbakow,D. Gavrychenko,G. Mazurenko,V. Ivanova,O. Chystikov,C. Plourde,J. Lessard,J. Chauny,R. Daoust,S. Shcherbakow,O. Tarabrin,D. Gavrychenko,G. Mazurenko,O. Chystikov,A. Vakalos,V. Avramidis,L. Kropman,L. In het Panhuis,J. Konings,D. Huskens,E. Schurgers,M. Roest,B. De Laat,M. Lance,M. Durila,P. Lukas,M. Astraverkhava,J. Jonas,I. Budnik,B. Shenkman,H. Hayami,Y. Koide,T. Goto,R. Iqbal,Y. Alhamdi,N. Venugopal,S. Abrams,C. Downey,C. H. Toh,I. D. Welters,V. B. Bombay,J. M. Chauny,R. D. Daoust,J. L. Lessard,M. M. Marquis,J. P. Paquet,K. Siemens,D. Sangaran,B. J. Hunt,A. Durward,A. Nyman,I. A. Murdoch,S. M. Tibby,F. Ampatzidou,D. Moisidou,E. Dalampini,M. Nastou,E. Vasilarou,V. Kalaizi,H. Chatzikostenoglou,G. Drossos,S. Spadaro,A. Fogagnolo,T. Fiore,A. Schiavi,V. Fontana,F. Taccone,C. Volta,E. Chochliourou,E. Volakli,A. Violaki,E. Samkinidou,G. Evlavis,V. Panagiotidou,M. Sdougka,R. Mothukuri,C. Battle,K. Guy,G. Mills,P. Evans,J. Wijesuriya,S. Keogh,A. Docherty,R. O\u2019Donnell,S. Brunskill,M. Trivella,C. Doree,L. Holst,M. Parker,M. Gregersen,J. Almeida,T. Walsh,S. Stanworth,S. Moravcova,J. Mansell,A. Rogers,R. A. Smith,C. Hamilton-Davies,A. Omar,M. Allam,O. Bilala,A. Kindawi,H. Ewila,F. Ampatzidou,D. Moisidou,M. Nastou,E. Dalampini,A. Malamas,E. Vasilarou,G. Drossos,G. Ferreira,J. Caldas,J. Fukushima,E. A. Osawa,E. Arita,L. Camara,S. Zeferino,J. Jardim,F. Gaioto,L. Dallan,F. B. Jatene,R. Kalil Filho,F. Galas,L. A. Hajjar,C. Mitaka,T. Ohnuma,T. Murayama,F. Kunimoto,M. Nagashima,T. Takei,M. Tomita,A. Omar,K. Mahmoud,S. Hanoura,S. Sudarsanan,P. Sivadasan,H. Othamn,Y. Shouman,R. Singh,A. Al Khulaifi,I. Mandel,S. Mikheev,I. Suhodolo,V. Kiselev,Y. Svirko,Y. Podoksenov,S. A. Jenkins,R. Griffin,M. S. Tovar Doncel,A. Lima,C. Aldecoa,C. Ince,A. Taha,A. Shafie,M. Mostafa,N. Syed,H. Hon,F. Righetti,E. Colombaroli,G. Castellano,F. Righetti,E. Colombaroli,M. Hravnak,L. C. Chen,A. D. Dubrawski,G. C. Clermont,M. R. Pinsky,S. Gonzalez,D. Macias,J. Acosta,P. Jimenez,A. Loza,A. Lesmes,F. Lucena,C. Leon,M. S. Tovar Doncel,C. Ince,C. Aldecoa,A. Lima,M. Bastide,J. Richecoeur,E. Frenoy,C. Lemaire,B. Sauneuf,F. Tamion,S. Nseir,D. Du Cheyron,H. Dupont,J. Maizel,M. Shaban,R. Kolko,N. Salahuddin,M. Sharshir,M. AbuRageila,A. AlHussain,P. Mercado,J. Maizel,L. Kontar,D. Titeca,F. Brazier,A. Riviere,M. Joris,T. Soupison,B. De Cagny,M. Slama,J. Wagner,A. K\u00f6rner,M. Kubik,S. Kluge,D. Reuter,B. Saugel,E. Colombaroli,F. Righetti,G. Castellano,T. Tran,D. De Bels,A. Cudia,M. Strachinaru,P. Ghottignies,J. Devriendt,C. Pierrakos,\u00d3. Mart\u00ednez Gonz\u00e1lez,R. Blancas,J. 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Belli,S. Busatti,G. Barettin,F. Candidi,F. Gargano,R. Barchetta,M. Falco,O. Demirkiran,M. Kosuk,S. Bozbay,V. Weber,J. Hartmann,S. Harm,I. Linsberger,T. Eichhorn,G. Valicek,G. Miestinger,C. Hoermann,S. Faenza,D. Ricci,E. Mancini,C. Gemelli,A. Cuoghi,S. Magnani,M. Atti,T. Laddomada,A. Doronzio,B. Balicco,M. C. Gruda,P. O\u2019Sullivan,V. P. Dan,T. Guliashvili,A. Scheirer,T. D. Golobish,V. J. Capponi,P. P. Chan,K. Kogelmann,M. Dr\u00fcner,D. Jarczak,F. Turani,A. B. Belli,S. M. Martni,V. C. Cotticelli,F. Mounajergi,R. Barchetta,S. Morimoto,H. Ishikura,I. Hussain,N. Salahuddin,A. Nadeem,K. Ghorab,K. Maghrabi,S. K. Kloesel,C. Goldfuss,A. Stieglitz,A. S. Stieglitz,L. Krstevska,G. Albuszies,M. Aguilar Arzapalo,L. Barradas,V. Lopez,A. Escalante,G. Jimmy,M. Cetina,J. Izawa,T. Iwami,S. Uchino,M. Takinami,T. Kitamura,T. Kawamura,J. G. Powell-Tuck,S. Crichton,M. Raimundo,L. Camporota,D. Wyncoll,M. Ostermann,A. Hana,H. R. De Geus,H. R. De Geus,A. Hana,M. Aydogdu,N. Boyaci,S. Yuksel,G. Gursel,A. B. Cayci Sivri,J. Meza-M\u00e1rquez,J. Nava-L\u00f3pez,R. Carrillo-Esper,A. Dardashti,A. Grubb,J. Maizel,M. Wetzstein,D. Titeca,L. Kontar,F. Brazier,B. De Cagny,A. Riviere,T. Soupison,M. Joris,M. Slama,E. Peters,H. Njimi,P. Pickkers,J. L. Vincent,M. Waraich,J. Doyle,T. Samuels,L. Forni,N. Desai,R. Baumber,P. Gunning,A. Sell,S. Lin,H. Torrence,M. O\u2019Dwyer,C. Kirwan,J. Prowle,T. Kim,M. E. O\u2019Connor,R. W. Hewson,C. J. Kirwan,R. M. Pearse,J. Prowle,S. Hanoura,A. Omar,H. Othamn,S. Sudarsanan,M. Allam,M. Maksoud,R. Singh,A. Al Khulaifi,M. E. O\u2019Connor,R. W. Hewson,C. J. Kirwan,R. M. Pearse,J. Prowle,O. Uzundere,D. Memis,M. \u00ddnal,A. Gultekin,N. Turan,M. A. Aydin,H. Basar,I. Sencan,A. Kapuagasi,M. Ozturk,Z. Uzundurukan,D. Gokmen,A. Ozcan,C. Kaymak,V. A. Artemenko,A. Budnyuk,R. Pugh,S. Bhandari,T. Mauri,C. Turrini,T. Langer,P. Taccone,C. A. Volta,C. Marenghi,L. Gattinoni,A. Pesenti,L. Sweeney,A. O\u2019Sullivan,P. Kelly,E. Mukeria,R. MacLoughlin,M. Pfeffer,J. T. Thomas,G. B. Bregman,G. K. Karp,E. K. Kishinevsky,D. S. Stavi,N. A. Adi,T. Poropat,R. Knafelj,E. Llopart,M. Batlle,C. De Haro,J. Mesquida,A. Artigas,D. Pavlovic,L. Lewerentz,A. Spassov,R. Schneider,S. De Smet,S. De Raedt,E. Derom,P Depuydt,S. Oeyen,D. Benoit,J. Decruyenaere,A. Gobatto,B. Besen,P. Tierno,L. Melro,P. Mendes,F. Cadamuro,M. Park,L. M. Malbouisson,B. C. Civantos,J. L. Lopez,A. Robles,J. Figueira,S. Yus,A. Garcia,A. Oglinda,G. Ciobanu,C. Oglinda,L. Schirca,T. Sertinean,V. Lupu,P. Kelly,A. O\u2019Sullivan,L. Sweeney,R. MacLoughlin,A. O\u2019Sullivan,P. Kelly,L. Sweeney,E. Mukeria,M. Wolny,R. MacLoughlin,A. Pagano,F. Numis,G. Visone,L. Saldamarco,T. Russo,G. Porta,F. Paladino,C. Bell,J. Liu,J. Debacker,C. Lee,E. Tamberg,V. Campbell,S. Mehta,A. Silva-Pinto,A. Sarmento,L. Santos,\u00dd. Kara,F. Y\u00fdld\u00fdr\u00fdm,A. Zerman,Z. G\u00fcll\u00fc,N. Boyac\u00fd,B. Basar\u00fdk Aydogan,\u00dc. Gayg\u00fds\u00fdz,K. G\u00f6nderen,G. Ar\u00fdk,M. Turkoglu,M. Aydogdu,G. Aygencel,Z. \u00dclger,G. Gursel,N. Boyac\u00fd,Z. Is\u00fdkdogan,\u00d6. \u00d6zdedeoglu,Z. G\u00fcll\u00fc,M. Badoglu,U. Gayg\u00fds\u00fdz,M. Aydogdu,G. Gursel,N. Kongpolprom,C. Sittipunt,A. Eden,Y. Kokhanovsky,S. Bursztein \u2013 De Myttenaere,R. Pizov,L. Neilans,N. MacIntyre,M. Radosevich,B. Wanta,V. Weber,T. Meyer,N. Smischney,D. Brown,D. Diedrich,A. Fuller,P. McLindon,K. Sim,M. Shoaeir,K. Noeam,A. Mahrous,R. Matsa,A. Ali,C. Dridi,S. Koubaji,S. Kamoun,F. Haddad,A. Ben Souissi,B. Laribi,A. Riahi,M. S. Mebazaa,A. P\u00e9rez-Calatayud,R. Carrillo-Esper,A. Zepeda-Mendoza,M. Diaz-Carrillo,E. Arch-Tirado,S. Carbognin,L. Pelacani,F. Zannoni,A. Agnoli,G. Gagliardi,R. Cho,A. Adams,S. Lunos,S. Ambur,R. Shapiro,M. Prekker,M. Thijssen,L. Janssen,N. Foudraine,C. J. Voscopoulos,J. Freeman,C. J. Voscopoulos,J. Freeman,E. George,C. J. Voscopoulos,D. Eversole,J. Freeman,E. George,S. Muttini,R. Bigi,G. Villani,N. Patroniti,G. Williams,C. J. Voscopoulos,J. Freeman,E George,A. Waldmann,S. B\u00f6hm,W. Windisch,S. Strassmann,C. Karagiannidis,A. Waldmann,S. B\u00f6hm,W. Windisch,S. Strassmann,C. Karagiannidis,C. K. Karagiannidis,A. W. Waldmann,S. B. B\u00f6hm,S. Strassmann,W. W. Windisch,P. Persson,S. Lundin,O. Stenqvist,G. Porta,F. Numis,C. S. Serra,A. P. Pagano,M. M. Masarone,L. R. Rinaldi,A. A. Amelia,M. F. Fascione,L. A. Adinolfi,E. R. Ruggiero,F. Asota,K. O\u2019Rourke,S. Ranjan,P. Morgan,J. W. DeBacker,E. Tamberg,L. O\u2019Neill,L. Munshi,L. Burry,E. Fan,S. Mehta,S. Poo,K. Mahendran,J. Fowles,C. Gerrard,A. Vuylsteke,R. Loveridge,C. Chaddock,S. Patel,V. Kakar,C. Willars,T. Hurst,C. Park,T. Best,A. Vercueil,G. Auzinger,A. Borgman,A. G. Proudfoot,E. Grins,K. E. Emiley,J. Schuitema,S. J. Fitch,G. Marco,J. Sturgill,M. G. Dickinson,M. Strueber,A. Khaghani,P. Wilton,S. M. Jovinge,C. Sampson,S. Harris-Fox,M. E. Cove,L. H. Vu,A. Sen,W. J. Federspiel,J. A. Kellum,C. Mazo Torre,J. Riera,S. Ramirez,B. Borgatta,L. Lagunes,J. Rello,A. K. Kuzovlev,V. Moroz,A. Goloubev,S. Polovnikov,S. Nenchuk,V. Karavana,C. Glynos,A. Asimakos,K. Pappas,C. Vrettou,M. Magkou,E. Ischaki,G. Stathopoulos,S. Zakynthinos,S. Spadaro,I. Kozhevnikova,F. Dalla Corte,S. Grasso,P. Casolari,G. Caramori,C. Volta,T. Andrianjafiarinoa,T. Randriamandrato,T. Rajaonera,S. El-Dash,E. L. V. Costa,M. R. Tucci,F Leleu,L Kontar,B. De Cagny,F. Brazier,D. Titeca,G. Bacari-Risal,J. Maizel,M. Amato,M. Slama,P. Mercado,J. Maizel,L. Kontar,D. Titeca,F. Brazier,A. Riviere,M. Joris,T. Soupison,B. De Cagny,S. El Dash,M. Slama, Remmington,A. Fischer,S. Squire,M. Boichat,H. Honzawa,H. Yasuda,T. Adati,S. Suzaki,M. Horibe,M. Sasaki,M. Sanui,R. Marinho,J. Daniel,H. Miranda,A. Marinho,K. Milinis,M. Cooper,G. R. Williams,E. McCarron,S. Simants,I. Patanwala,I. Welters,Y. Su,J. Fern\u00e1ndez Villanueva,R. Fern\u00e1ndez Garda,A. L\u00f3pez Lago,E. Rodr\u00edguez Ru\u00edz,R. Hern\u00e1ndez Vaquero,S. Tom\u00e9 Mart\u00ednez de Rituerto,E. Varo P\u00e9rez,N. Lefel,F. Schaap,D. Bergmans,S. Olde Damink,M. 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Van Assen,M. M. Admiraal,M. J. Van Putten,M. Tjepkema-Cloostermans,A. F. Van Rootselaar,J. Horn,M. Fallenius,M. B. Skrifvars,M. Reinikainen,S. Bendel,R. Raj,M. Abu-Habsa,C. Hymers,A. Borowska,H. Sivadhas,S. Sahiba,S. Perkins,J. Rubio,J. A. Rubio,R. Sierra,S. English,M. Chasse,A. Turgeon,F. Lauzier,D. Griesdale,A. Garland,D. Fergusson,R. Zarychanski,A. Tinmouth,C. Van Walraven,K. Montroy,J. Ziegler,R. Dupont Chouinard,R. Carignan,A. Dhaliwal,C. Lum,J. Sinclair,G. Pagliarello,L. McIntyre,S. English,M. Chasse,A. Turgeon,F. Lauzier,D. Griesdale,A. Garland,D. Fergusson,R. Zarychanski,A. Tinmouth,C. Van Walraven,K. Montroy,J. Ziegler,R. Dupont Chouinard,R. Carignan,A. Dhaliwal,C. Lum,J. Sinclair,G. Pagliarello,L. McIntyre,T. Groza,N. Moreau,D. Castanares-Zapatero,P. Hantson,M. Carbonara,F. Ortolano,T. Zoerle,S. Magnoni,S. Pifferi,V. Conte,N. Stocchetti,L. Carteron,T. Suys,C. Patet,H. Quintard,M. Oddo,J. A. Rubio,J. Rubio,R. Sierra,V. Spatenkova,E. Pokorna,P. Suchomel,N. Ebert,J. Jancik,H. Rhodes,T. Bylinski,C. Hawthorne,M. Shaw,I. Piper,J. Kinsella,A. K. Kink,I. R. R\u00e4tsep,A. Boutin,L. Moore,M. Chasse,R. Zarychanski,F. Lauzier,S. English,L. McIntyre,J. Lacroix,D. Griesdale,P. Lessard-Bonaventure,A. F. Turgeon,A. Boutin,L. Moore,R. Green,P. Lessard-Bonaventure,M. Erdogan,M. Butler,F. Lauzier,M. Chasse,S. English,L. McIntyre,R. Zarychanski,J. Lacroix,D. Griesdale,P. Desjardins,D. A. Fergusson,A. F. Turgeon,B. Goncalves,B. Vidal,C. Valdez,A. C. Rodrigues,L. Miguez,G. Moralez,T. Hong,A. Kutz,P. Hausfater,D. Amin,T. Struja,S. Haubitz,A. Huber,B. Mueller,P. Schuetz,T. Brown,J. Collinson,C. Pritchett,T. Slade,M. Le Guen,S. Hellings,R. Ramsaran,A. Alsheikhly,T. Abe,L. Kanapeckaite,M. Abu-Habsa,R. Bahl,M. Q. Russell,K. J. Real,M. Abu-Habsa,R. M. Lyon,N. P. Oveland,J. Penketh,M. Mcdonald,F. Kelly,M. Alfafi,S. Alsolamy,W. Almutairi,B. Alotaibi,A. E Van den Berg,Y. Schriel,L. Dawson,I. A. Meynaar,H. Talaie,D. Silva,S. Fernandes,J. Gouveia,J. Santos Silva,J. Foley,A. 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Mandeville,D. Stott,I. Guerreiro,H. Devine,P. MacTavish,J. McPeake,T. Quasim,J. Kinsella,M. Daniel,C. Goossens,M. B. Marques,S. Derde,S. Vander Perre,T. Dufour,S. E. Thiessen,F. G\u00fciza,T. Janssens,G. Hermans,I. Vanhorebeek,K. De Bock,G. Van den Berghe,L. Langouche,H. Devine,P. MacTavish,T. Quasim,J. Kinsella,M. Daniel,J. McPeake,B. Miles,S. Madden,H. Devine,M. Weiler,P. Marques,C. Rodrigues,M. Boeira,K. Brenner,C. Le\u00e3es,A. Machado,R. Townsend,J. Andrade,P. MacTavish,J. McPeake,H. Devine,J. Kinsella,M. Daniel,R. Kishore,C. Fenlon,T. Quasim,T. Fiks,A. Ruijter,M. Te Raa,P. Spronk,Y. S. Chiew,P. Docherty,J. Dickson,E. Moltchanova,C. Scarrot,C. Pretty,G. M. Shaw,J. G. Chase,T. Hall,W. C. Ngu,J. M. Jack,P. Morgan,B. Avard,A. Pavli,X. Gee,C. Bor,E. Akin Korhan,K. Demirag,M. Uyar,M. Shirazy,A. Fayed,S. Gupta,A. Kaushal,S. Dewan,A. Varma,E. Ghosh,L. Yang,L. Eshelman,B. Lord,E. Carlson,E. Helme,R. Broderick,S. Hadfield,R. Loveridge,J. Ramos,D. Forte,F. Yang,P. Hou,J. Dudziak,J. Feeney,K. Wilkinson,K. Bauchmuller,K. Shuker,M. Faulds,A. Raithatha,D. Bryden,L. England,N. Bolton,A. Tridente,K. Bauchmuller,K Shuker,A Tridente,M Faulds,A Matheson,J. Gaynor,D Bryden, ,J. Ramos,B. Peroni,R. Daglius-Dias,L. Miranda,C. Cohen,C. Carvalho,I. Velasco,D. Forte,J. M. Kelly,A. Neill,G. Rubenfeld,N. Masson,A. Min,E. Boezeman,J. Hofhuis,A. Hovingh,R. De Vries,P. Spronk,G. Cabral-Campello,I. Arag\u00e3o,T. Cardoso,M. Van Mol,M. Nijkamp,E. Kompanje,P. Ostrowski,A. Omar,K. Kiss,B. K\u00f6ves,V. Csernus,Z. Moln\u00e1r,Y. Hoydonckx,S. Vanwing,B. Stessel,A. Van Assche,L. Jamaer,J. Dubois,V. Medo,R. Galvez,J. P. Miranda,C. Stone,T. Wigmore,Y. Arunan,A. Wheeler,K. Bauchmuller,D. Bryden,Y. Wong,C. Poi,C. Gu,P. Molmy,N. Van Grunderbeeck,O. Nigeon,M. Lemyze,D. Thevenin,J. Mallat,J. Ramos,M. Correa,R. T. Carvalho,D. Forte,A. Fernandez,C. McBride,E. Koonthalloor,C. Walsh,A. Webber,M. Ashe,K. Smith,P. Jeanrenaud,A. Marudi,S. Baroni,F. Ragusa,E. Bertellini,E. A. Volakli,E. Chochliourou,M. Dimitriadou,A. Violaki,P. Mantzafleri,E. Samkinidou,O. Vrani,A. Arbouti,T. Varsami,M. Sdougka,J. A. Bollen,T. C. Van Smaalen,W. C. De Jongh,M. M. Ten Hoopen,D. Ysebaert,L. W. Van Heurn,W. N. Van Mook,K. Sim,A. Fuller,A. Roze des Ordons,P. Couillard,C. Doig,R. V. Van Keer,R. D. Deschepper,A. F. Francke,L. H. Huyghens,J. B. Bilsen,B. Nyamaizi,C. Dalrymple,A. Molokhia,A. Dobru,E. Marrinan,A. Ankuli,A. Molokhia,J. McPeake,R. Struthers,R. Crawford,H. Devine,P. Mactavish,T. Quasim,P. Morelli,M. Degiovanangelo,F. Lemos,V. MArtinez,F. Verga,J. Cabrera,G. Burghi,A. Rutten,S. Van Ieperen,S. De Geer,M. Van Vugt,E. Der Kinderen,A. Giannini,G Miccinesi,T Marchesi,E Prandi", - "abstract": "P001 - Sepsis impairs the capillary response within hypoxic capillaries and decreases erythrocyte oxygen-dependent ATP efflux R. M. Bateman, M. D. Sharpe, J. E. Jagger, C. G. Ellis P002 - Lower serum immunoglobulin G2 level does not predispose to severe flu. J. Sol\u00e9-Viol\u00e1n, M. L\u00f3pez-Rodr\u00edguez, E. Herrera-Ramos, J. Ru\u00edz-Hern\u00e1ndez, L. Border\u00edas, J. Horcajada, N. Gonz\u00e1lez-Quevedo, O. Rajas, M. Briones, F. Rodr\u00edguez de Castro, C. Rodr\u00edguez Gallego P003 - Brain protective effects of intravenous immunoglobulin through inhibition of complement activation and apoptosis in a rat model of sepsis F. Esen, G. Orhun, P. Ergin Ozcan, E. Senturk, C. Ugur Yilmaz, N. Orhan, N. Arican, M. Kaya, M. Kucukerden, M. Giris, U. Akcan, S. Bilgic Gazioglu, E. Tuzun P004 - Adenosine a1 receptor dysfunction is associated with leukopenia: A possible mechanism for sepsis-induced leukopenia R. Riff, O. Naamani, A. Douvdevani P005 - Analysis of neutrophil by hyper spectral imaging - A preliminary report R. Takegawa, H. Yoshida, T. Hirose, N. Yamamoto, H. Hagiya, M. Ojima, Y. Akeda, O. Tasaki, K. Tomono, T. Shimazu P006 - Chemiluminescent intensity assessed by eaa predicts the incidence of postoperative infectious complications following gastrointestinal surgery S. Ono, T. Kubo, S. Suda, T. Ueno, T. Ikeda P007 - Serial change of c1 inhibitor in patients with sepsis \u2013 A prospective observational study T. Hirose, H. Ogura, H. Takahashi, M. Ojima, J. Kang, Y. Nakamura, T. Kojima, T. Shimazu P008 - Comparison of bacteremia and sepsis on sepsis related biomarkers T. Ikeda, S. Suda, Y. Izutani, T. Ueno, S. Ono P009 - The changes of procalcitonin levels in critical patients with abdominal septic shock during blood purification T. Taniguchi, M. O P010 - Validation of a new sensitive point of care device for rapid measurement of procalcitonin C. Dinter, J. Lotz, B. Eilers, C. Wissmann, R. Lott P011 - Infection biomarkers in primary care patients with acute respiratory tract infections \u2013 Comparison of procalcitonin and C-reactive protein M. M. Meili, P. S. Schuetz P012 - Do we need a lower procalcitonin cut off? H. Hawa, M. Sharshir, M. Aburageila, N. Salahuddin P013 - The predictive role of C-reactive protein and procalcitonin biomarkers in central nervous system infections with extensively drug resistant bacteria V. Chantziara, S. Georgiou, A. Tsimogianni, P. Alexandropoulos, A. Vassi, F. Lagiou, M. Valta, G. Micha, E. Chinou, G. Michaloudis P014 - Changes in endotoxin activity assay and procalcitonin levels after direct hemoperfusion with polymyxin-b immobilized fiber A. Kodaira, T. Ikeda, S. Ono, T. Ueno, S. Suda, Y. Izutani, H. Imaizumi P015 - Diagnostic usefullness of combination biomarkers on ICU admission M. V. De la Torre-Prados, A. Garcia-De la Torre, A. Enguix-Armada, A. Puerto-Morlan, V. Perez-Valero, A. Garcia-Alcantara P016 - Platelet function analysis utilising the PFA-100 does not predict infection, bacteraemia, sepsis or outcome in critically ill patients N. Bolton, J. Dudziak, S. Bonney, A. Tridente, P. Nee P017 - Extracellular histone H3 levels are inversely correlated with antithrombin levels and platelet counts and are associated with mortality in sepsis patients G. Nicolaes, M. Wiewel, M. Schultz, K. Wildhagen, J. Horn, R. Schrijver, T. Van der Poll, C. Reutelingsperger P018 - Il-8: is this a more reliable biomarker for sepsis severity than CRP, Procalcitonin, E-selectin, IL-6 and TNF-[alpha] S. Pillai, G. Davies, G. Mills, R. Aubrey, K. Morris, P. Williams, P. Evans P019 - Relation between adrenomedullin and short-term outcome in ICU patients: Results from the frog ICU study E. G. Gayat, J. Struck, A. Cariou, N. Deye, B. Guidet, S. Jabert, J. Launay, M. Legrand, M. L\u00e9one, M. Resche-Rigon, E. Vicaut, A. Vieillard-Baron, A. Mebazaa P020 - Impact of disease severity assessment on performance of heparin-binding protein for the prediction of septic shock R. Arnold, M. Capan, A. Linder, P. Akesson P021 - Kinetics and prognostic value of presepsin (sCD14) in septic patients. A pilot study M. Popescu, D. Tomescu P022 - Comparison of CD64 levels performed by the facs and accellix systems C. L. Sprung, R. Calderon Morales, G. Munteanu, E. Orenbuch-Harroch, P. Levin, H. Kasdan, A. Reiter, T. Volker, Y. Himmel, Y. Cohen, J. Meissonnier P023 - Diagnosing sepsis in 5\u00a0minutes: Nanofluidic technology study with pancreatic-stone protein (PSP/ reg) L. Girard, F. Rebeaud P024 - How nanotechnology-based approaches could contribute to sepsis prevention, diagnosis and treatment I. Herrmann P025 - Il7r transcriptional expression analysis during septic shock B. Delwarde, E. Peronnet, E. Cerrato, F. Venet, A. Lepape, T. Rimmel\u00e9, G. Monneret, J. Textoris P026 - Disbalance of microbial metabolites of aromatic acids affects the severity in critically ill patients N. Beloborodova, V. Moroz, A. Osipov, A. Bedova, Y. Sarshor, A. Pautova, A. Sergeev, E. Chernevskaya P027 - Copeptin predicts 10-year all-cause mortality in community patients J. Odermatt, R. Bolliger, L. Hersberger, M. Ottiger, M. Christ-Crain, B. Mueller, P. Schuetz P028 - Identification of differential proteomic response in septic patients secondary to community and hospital acquired pneumonia N. K. Sharma, A. K. Tashima, M. K. Brunialti, F. R. Machado, M. Assuncao, O. Rigato, R. Salomao P029 - Monocyte HLA-DR expression in community-acquired bacteremic sepsis - dynamics associated to aetiology and prediction of secondary sepsis S. C. Cajander, G. Rasmussen, E. Tina, B. S\u00f6derquist, J. K\u00e4llman, K. Str\u00e5lin P030 - Soluble B- and T-lymphocyte attenuator: A possible prognostic marker in sepsis A. L. Lange, J. S. Sund\u00e9n-Cullberg, A. M. Magnuson, O. H. Hultgren P031 - Fractal dimension: A new biomarker for quantifying clot microstructure in patients across the sepsis spectrum G. Davies, S. Pillai, G. Mills, R. Aubrey, K. Morris, P. Williams, P. Evans P032 - Comparison between the new biomarker for coagulation, clot microstructure (Df) with rotational thromboelastometry (ROTEM) in patients across the sepsis spectrum S. Pillai, G. Davies, G. Mills, R. Aubrey, K. Morris, P. Williams, P. Evans P033 - Changes in fibrinolysis across the sepsis spectrum: The use of rotational thromboelastometry (ROTEM) lysis index (LI60) and D-Dimer concentration S. Pillai, G. Davies, G. Mills, R. Aubrey, K. Morris, P. Williams, P. Evans P034 - The intensive care infection score \u2013 a promising marker for the prediction of infection and its severity. P. Van der Geest, M. Mohseni, J. Linssen, R. De Jonge, S. Duran, J. Groeneveld P035 - Challenges in the clinical diagnosis of sepsis R. Miller III, B. K. Lopansri, L. C. McHugh, A. Seldon, J. P. Burke P036 - Does zero heat flux thermometry more accurately identify sepsis on intensive care? J. Johnston, R. Reece-Anthony, A. Bond, A. Molokhia P037 - Advancing quality (AQ) sepsis programme: Improving early identification & treatment of sepsis in North West England. C. Mcgrath, E. Nsutebu P038 - Prehospital transport of acute septic patients P. Bank Pedersen, D. Pilsgaard Henriksen, S. Mikkelsen, A. Touborg Lassen P039 - Vasodilatory plant extracts gel as an alternative treatment for fever in critically ill patients R. Tincu, C. Cobilinschi, D. Tomescu, Z. Ghiorghiu, R. Macovei P040 - Host response and outcome of hypothermic sepsis M. A. Wiewel, M. B. Harmon, L. A. Van Vught, B. P. Scicluna, A. J. Hoogendijk, J. Horn, A. H. Zwinderman, O. L. Cremer, M. J. Bonten, M. J. Schultz, T. Van der Poll, N. P. Juffermans, W. J. Wiersinga P041 - Septic shock alert over SIRS criteria has an impact on outcome but needs to be revised G. Eren, Y Tekdos, M. Dogan, O. Acicbe, E. Kaya, O. Hergunsel P042 - Association between previous prescription of \u03b2blockers and mortality rate among septic patients: A retrospective observational study S. Alsolamy, G. Ghamdi, L. Alswaidan, S. Alharbi, F. Alenezi, Y. Arabi P043 - Recognition and treatment of sepsis on labour ward\u2013 teaching & information resources can improve knowledge J. Heaton, A. Boyce, L. Nolan, J. Johnston, A. Dukoff-Gordon, A. Dean, A. Molokhia P044 - Culture negative sepsis in the ICU \u2013 what is unique to this patient population? T. Mann Ben Yehudah P045 - Organ dysfunction in severe sepsis patients identified in administrative data in Germany, 2007-2013 C. Fleischmann, D. Thomas-Rueddel, C. Haas, U. Dennler, K. Reinhart P046 - A comparison of residents\u2019 knowledge regarding; the Surviving Sepsis Campaign 2012 guideline O. Suntornlohanakul, B. Khwannimit P047 - Effectiveness of a septic shock bundle to improve outcomes in the ICU F. Breckenridge, A. Puxty P048 - Dose of norepinephrine in the first 24\u00a0hours as a parameter evaluating the effectiveness of treatment in patients with severe sepsis and septic shock P. Szturz, P. Folwarzcny, J. Svancara, R. Kula, P. Sevcik P049 - Norepinephrine or vasopressin\u2009+\u2009norepinephrine in septic shock. A retrospective series of 39 patients L. Caneva, A. Casazza, E. Bellazzi, S. Marra, L. Pagani, M. Vetere, R. Vanzino, D. Ciprandi, R. Preda, R. Boschi, L. Carnevale P050 - Methylene blue effectiveness as contributory treatment in patients with septic shock V. Lopez, M. Aguilar Arzapalo, L. Barradas, A. Escalante, J. Gongora, M. Cetina P051 - Coagulation disorders in patients with severe sepsis and DIC evaluated with thromboelastometry. B Adamik, D Jakubczyk, A K\u00fcbler P052 - Frequency and outcome of early sepsis-associated coagulopathy A. Radford, T. Lee, J. Singer, J. Boyd, D. Fineberg, M. Williams, J. Russell P053 - Assessment of coagulopathy in cancer patients with severe sepsis or septic shock. A case-control pilot study E. Scarlatescu, D. Tomescu, G. Droc, S. Arama P054 - Thromboelastometry in critically ill patients with disseminated intravascular coagulation M. M\u00fcller, M. Straat, S. S. Zeerleder, N. P. Juffermans P055 - Cessation of a preexisting chronic antiplatelet therapy is associated with increased mortality rates in severe sepsis and septic shock C. F. Fuchs, C. S. Scheer, S. W. Wauschkuhn, M. V. Vollmer, K. M. Meissner, S. K. Kuhn, K. H. Hahnenkamp, S. R. Rehberg, M. G. Gr\u00fcndling P056 - Neutrophil Extracellular Traps (NETs) production under hypoxic condition N. Yamamoto, M. Ojima, S. Hamaguchi, T. Hirose, Y. Akeda, R. Takegawa, O. Tasaki, T. Shimazu, K. Tomono P057 - Impact of ultraviolet air sterilizer in intensive care unit room, and clinical outcomes of patients E. G\u00f3mez-S\u00e1nchez, M. Heredia-Rodr\u00edguez, E. \u00c1lvarez-Fuente, M. Lorenzo-L\u00f3pez, E. G\u00f3mez-Pesquera, M. Arag\u00f3n-Camino, P. Liu-Zhu, A. S\u00e1nchez-L\u00f3pez, A. Hern\u00e1ndez-Lozano, M. T. Pel\u00e1ez-Jare\u00f1o, E. Tamayo P058 - Focus of infection in severe sepsis - comparison of administrative data and prospective cohorts from Germany D. O. Thomas-R\u00fcddel, C. Fleischmann, C. Haas, U. Dennler, K. Reinhart P059 - \u201cZero CLABSI\u201d \u2013 can we get there? Obstacles on the 4\u00a0year journey and our strategies to overcome them \u2013 experience from an Indian ICU V. Adora, A. Kar, A. Chakraborty, S. Roy, A. Bandyopadhyay, M. Das P060 - Novel molecular techniques to identify central venous catheter (CVC) associated blood stream infections (BSIs) T. Mann Ben Yehudah, G. Ben Yehudah, M. Salim, N. Kumar, L. Arabi, T. Burger, P. Lephart, E. Toth-martin P061 - Zero clabsi\u201d \u2013 can we get there? Obstacles on the 4\u00a0year journey and our strategies to overcome them \u2013 experience from an Indian ICU R. Rao, A. Kar, A. Chakraborty P062 - Prevention of central line-associated bloodstream infections in intensive care units: An international online survey C. Valencia, N. Hammami, S. Blot, J. L. Vincent, M. L. Lambert P063 - 30\u00a0days antimicrobial efficacy of non-leaching central venous catheters J. Brunke, T. Riemann, I. Roschke P064 - Efficacy of noble metal alloy-coated catheter in prevention of bacteriuria R. Tincu, C. Cobilinschi, D. Tomescu, Z. Ghiorghiu, R. Macovei P065 - Predicting bacteremic urinary tract infection in community setting: A prospective observational study S. Nimitvilai, K. Jintanapramote, S. Jarupongprapa P066 - Eight-year analysis of acinetobacter spp. monobacteremia in surgical and medical intensive care units at university hospital in Lithuania D. Adukauskiene, D. Valanciene P067 - Group A and group B streptococcal infections in intensive care unit \u2013 our experience in a tertiary centre G. Bose, V. Lostarakos, B. Carr P068 - Improved detection of spontaneous bacterial peritonitis by uritop\u2009+\u2009tm strip test and inoculation of blood culture bottles with ascitic fluid S. Khedher, A. Maaoui, A. Ezzamouri, M. Salem P069 - Increased risk of cellulitis in patients with congestive heart failure: a population based cohort study J. Chen P070 - Outcomes of severe cellulitis and necrotizing fasciitis in the critically ill D. R. Cranendonk, L. A. Van Vught, M. A. Wiewel, O. L. Cremer, J. Horn, M. J. Bonten, M. J. Schultz, T. Van der Poll, W. J. Wiersinga P071 - Botulism outbreak associated with people who inject drugs (PWIDs) in Scotland. M. Day, G. Penrice, K. Roy, P. Robertson, G. Godbole, B. Jones, M. Booth, L. Donaldson P072 - Surveillance of ESBL-producing enterobacteriaceae fecal carriers in the ICU Y. Kawano, H. Ishikura P073 - Prevalence of ESBL and carbapenemase producing uropathogens in a newly opened hospital in south India S. Sreevidya, N. Brahmananda Reddy, P. Muraray Govind, R. Pratheema, J. Devachandran Apollo Speciality Hospital - OMR, Chennai, India P074 - Prevalence, risk factors and outcomes of methicillin-resistant staphylococcus aureus nasal colonization in critically ill patients H. Al-Dorzi, M. Almutairi, B. Alhamadi, A. Crizaldo Toledo, R. Khan, B. Al Raiy, Y. Arabi P075 - Multidrug-resistant Acinetobacter baumannii infection in intensive care unit patients in a hospital with building construction: Is there an association? H. Talaie P076 - Multidrug-resistant organisms in a Dutch ICU J. A. Van Oers, A. Harts, E. Nieuwkoop, P. Vos P077 - Epidemiology and risk factors of ICU acquired infections caused by multidrug-resistant gram negative bacilli Y. Boussarsar, F. Boutouta, S. Kamoun, I. Mezghani, S. Koubaji, A. Ben Souissi, A. Riahi, M. S. Mebazaa P078 - Improving outcomes of severe infections by multidrug-resistant pathogens with polyclonal IgM-enriched immunoglobulins E. Giamarellos-Bourboulis, N. Tziolos, C. Routsi, C. Katsenos, I. Tsangaris, I. Pneumatikos, G. Vlachogiannis, V. Theodorou, A. Prekates, E. Antypa, V. Koulouras, N. Kapravelos, C. Gogos, E. Antoniadou, K. Mandragos, A. Armaganidis P079 - Must change the medical practice in ICU? A. R. Robles Caballero, B. Civantos, J. C. Figueira, J. L\u00f3pez P080 - Mediterranean spotted fever in an infectious diseases intensive care unit A. Silva-Pinto, F. Ceia, A. Sarmento, L. Santos P081 - Clinical features and outcomes of patients with Middle East respiratory syndrome requiring admission to a saudi intensive care unit: A retrospective analysis of 31 cases G. Almekhlafi, Y. Sakr P082 - The ICU response to a hospital outbreak of Middle East respiratory syndrome coronavirus infection H. Al-Dorzi, R. Khan, S. Baharoon, A. Aldawood, A. Matroud, J. Alchin, S. Al Johani, H. Balkhy, Y. Arabi P083 - Middle East respiratory syndrome: Surveillance data analysis S. Alsolamy, S. Y. Yousif, B. O. Alotabi, A. S. Alsaawi P085 - Use of Taqman array card molecular diagnostics in severe pneumonia: A case series J. Ang, MD Curran, D. Enoch, V. Navapurkar, A. Conway Morris P086 - \u2018BUNS\u2019: An investigation protocol improves the ICU management of pneumonia R. Sharvill, J. Astin P087 - Pneumonia in patients following secondary peritonitis: epidemiological features and impact on mortality M. Heredia-Rodr\u00edguez, E. G\u00f3mez-S\u00e1nchez, M. T. Pel\u00e1ez-Jare\u00f1o, E. G\u00f3mez-Pesquera, M. Lorenzo-L\u00f3pez, P. Liu-Zhu, M. Arag\u00f3n-Camino, A. Hern\u00e1ndez-Lozano, A. S\u00e1nchez-L\u00f3pez, E. \u00c1lvarez-Fuente, E. Tamayo P088 - The use of the \u201cCURB-65 score\u201d by emergency room clinicians in a large teaching hospital J. Patel, C. Kruger P089 - Incidence of community acquired pneumonia with viral infection in mechanically ventilated patients in the medical intensive care unit J. O\u2019Neal, H. Rhodes, J. Jancik P090 - The SAATELLITE Study: Prevention of S aureus Nosocomial Pneumonia (NP) with MEDI4893, a Human Monoclonal Antibody (mAb) Against S aureus B. Fran\u00e7ois, P. F. Laterre, P. Eggimann, A. Torres, M. S\u00e1nchez, P. F. Dequin, G. L. Bassi, J. Chastre, H. S. Jafri P091 - Risk factors and microbiological profile for nosocomial infections in trauma patients M. Ben Romdhane, Z. Douira, S. Kamoun, M. Bousselmi, A. Ben Souissi, Y. Boussarsar, A. Riahi, M.S. Mebazaa P092 - Correlation between percentages of ventilated patients developed vap and use of antimicrobial agents in ICU patients. A. Vakalos, V. Avramidis P093 - A comparison of two ventilator associated pneumonia surveillance techniques T. H. Craven, G. Wojcik, K. Kefala, J. McCoubrey, J. Reilly, R. Paterson, D. Inverarity, I. Laurenson, T. S. Walsh P094 - Lung ultrasound before and after fiberbronchoscopy - modifications may improve ventilator-associated pneumonia diagnosis S. Mongodi, B. Bouhemad, A. Orlando, A. Stella, G. Via, G. Iotti, A. Braschi, F. Mojoli P095 - Comparing the accuracy of predictors of mortality in ventilator-associated pneumonia M. Haliloglu, B. Bilgili, U. Kasapoglu, I. Sayan, M. S\u00fczer Aslan, A. Yalc\u0131n, I. Cinel P096 - Impact of pRBCs transfusion on percentage of ventilated patients developed VAP in ICU patients A. Vakalos, V. Avramidis P097 - The impact of a series of interventions on the rate of ventilator associated pneumonia in a large teaching hospital H. E. Ellis, K. Bauchmuller, D. Miller, A Temple P098 - The EVADE study: Prevention of Nosocomial Pneumonia (NP) caused by P aeruginosa with MEDI3902, a Novel Bispecific Monoclonal Antibody, against P aeruginosa virulence factors J. Chastre, B. Fran\u00e7ois, A. Torres, C. E. Luyt, M. S\u00e1nchez, M. Singer, H. S. Jafri P099 - Short-term inhaled colistin adjunctive therapy for ventilator-associated pneumonia Y. Nassar, M. S. Ayad P100 - Effect of aerosolised colistin on weaning from mechanical ventilation A. Trifi, S. Abdellatif, F. Daly, R. Nasri, S. Ben Lakhal P101 - Septic shock is an independent risk factor for colistin-induced severe acute kidney injury: a retrospective cohort study B. Bilgili, M. Haliloglu, F. Gul, I. Cinel P102 - Nosocomial pneumonia - emphasis on inhaled tobramycin A. Kuzovlev, A. Shabanov, S. Polovnikov, V. Moroz P103 - In vitro evaluation of amikacin inhale and commercial nebulizers in a mechanical ventilator N. Kadrichu, T. Dang, K. Corkery, P. Challoner P104 - The effects of nebulized amikacin/fosfomycin and systemic meropenem on severe amikacin-resistant meropenem-susceptible P.aeruginosa pneumonia G. Li Bassi, E. Aguilera, C. Chiurazzi, C. Travierso, A. Motos, L. Fernandez, R. Amaro, T. Senussi, F. Idone, J. Bobi, M. Rigol, A. Torres P105 - Optimization of gentamicin peak concentrations in critically ill patients C. J. Hodiamont, N. P. Juffermans, J. M. Janssen, C. S. Bouman, R. A. Math\u00f4t, M. D. De Jong, R. M. Van Hest P106 - Systematic review of cefepime induced neurotoxicity L. Payne, G. L. Fraser P107 - Unasyn\u00ae causes QT prolongation during treatment of intensive care patients B. Tudor, M. Lahner, G. Roth, C. Krenn P108 - Comparative study between teicoplanin and vancomycin in methicillin-resistant staphylococcus aureus (mrsa) infectious of toxicological intensive care unit (ticu) patients \u2013 Tehran, Iran H. Talaie P109 - Phage therapy against antimicrobial resistance, design of the first clinical study phagoburn P. Jault, J. Gabard, T. Leclerc, S. Jennes, Y. Que, A. Rousseau, F. Ravat P110 - Antibiotic dosing errors in critically ill patients with severe sepsis or septic shock H. Al-Dorzi, A. Eissa, S. Al-Harbi, T. Aldabbagh, R. Khan, Y. Arabi P111 - Does empiric antifungal therapy improve survival in septic critically ill patients? (immunocompromised excluded) A. Trifi, S. Abdellatif, F. Daly, R. Nasri, S. Ben Lakhal P112 - Neurocysticercosis-Qatar experience F. Paramba, N. Purayil, V. Naushad, O. Mohammad, V. Negi, P. Chandra P113 - Early indicators in acute haemorrhagic shock A. Kleinsasser P114 - Filtering of red blood cells reduces the inflammatory response of pulmonary cells in an in vitro model of mechanical ventilation M. R. Witrz, J. F. Buchner-Doeven, A. M. Tuip-de Boer, J. C. Goslings, N. P. Juffermans P115 - Microparticles from red blood cell transfusion induce a pro-coagulant and pro-inflammatory endothelial cell response M. Van Hezel, M. Straat, A Boing, R Van Bruggen, N Juffermans P116 - The contribution of cytokines on thrombosis development during hospitalization in ICU D. Markopoulou, K. Venetsanou, V. Kaldis, D. Koutete, D. Chroni, I. Alamanos P117 - Prophylactic enoxaparin dosing and adjustment through anti-xa monitoring in an inpatient burn unit L. Koch, J. Jancik, H. Rhodes, E. Walter P118 - Determination of optimal cut-off values of haemoglobin, platelet count and fibrinogen at 24\u00a0hours after injury associated with mortality in trauma patients K. Maekawa, M. Hayakawa, S. Kushimoto, A. Shiraishi, H. Kato, J. Sasaki, H. Ogura, T. Matauoka, T. Uejima, N. Morimura, H. Ishikura, A. Hagiwara, M. Takeda P119 - Trauma-induced coagulopathy - prothrombin complex concentrate vs fresh frozen plasma O. Tarabrin, S. Shcherbakow, D. Gavrychenko, G. Mazurenko, V. Ivanova, O. Chystikov P120 - First study to prove the superiority of prothrombin complex concentrates on mortality rate over fresh frozen plasma in patients with acute bleeding C. Plourde, J. Lessard, J. Chauny, R. Daoust P121 - Prothrombin complex concentrate vs fresh frozen plasma in obstetric massive bleeding S. Shcherbakow, O. Tarabrin, D. Gavrychenko, G. Mazurenko, O. Chystikov P122 - Impact of FFP transfusion on VAP in ICU patients A. Vakalos, V. Avramidis P123 - Preoperative platelet function test and the thrombin generation assay are predictive for blood loss after cardiac surgery L. Kropman, L. In het Panhuis, J. Konings, D. Huskens, E. Schurgers, M. Roest, B. De Laat, M. Lance P124 - Rotational thromboelastometry versus standard coagulation tests before surgical interventions M. Durila, P. Lukas, M. Astraverkhava, J. Jonas P125 - Correction of impaired clot quality and stability by fibrinogen and activated prothrombin complex concentrate in a model of severe thrombocytopenia I. Budnik, B. Shenkman P126 - Assessment of point-of-care prothrombin time analyzer as a monitor after cardiopulmonary bypass H. Hayami, Y. Koide, T. Goto P127 - Disseminated intravascular coagulation (dic) is underdiagnosed in critically ill patients: do we need d-dimer measurements? R. Iqbal, Y. Alhamdi, N. Venugopal, S. Abrams, C. Downey, C. H. Toh, I. D. Welters P128 - Validity of the age-adjusted d-dimer cutoff in patients with COPD B. Bombay, J. M. Chauny, R. D. Daoust, J. L. Lessard, M. M. Marquis, J. P. Paquet P129 - A scoping review of strategies for prevention and management of bleeding following paediatric cardiopulmonary bypass surgery K. Siemens, D. Sangaran, B. J. Hunt, A. Durward, A. Nyman, I. A. Murdoch, S. M. Tibby P130 - Nadir hemoglobulin during cardiopulmonary bypass: impact on postoperative morbidity and mortality F. Ampatzidou, D. Moisidou, E. Dalampini, M. Nastou, E. Vasilarou, V. Kalaizi, H. Chatzikostenoglou, G. Drossos P131 - Red blood cell transfusion do not influence the prognostic value of RDW in critically ill patients S. Spadaro, A. Fogagnolo, T. Fiore, A. Schiavi, V. Fontana, F. Taccone, C. Volta P132 - Reasons for admission in the paediatric intensive care unit and the need for blood and blood products transfusions E. Chochliourou, E. Volakli, A. Violaki, E. Samkinidou, G. Evlavis, V. Panagiotidou, M. Sdougka P133 - The implementation of a massive haemorrhage protocol (mhp) for the management of major trauma: a ten year, single-centre study R. Mothukuri, C. Battle, K. Guy, G. Mills, P. Evans P134 - An integrated major haemorrhage protocol for pre-hospital and retrieval medical teams J. Wijesuriya, S. Keogh P135 - The impact of transfusion thresholds on mortality and cardiovascular events in patients with cardiovascular disease (non-cardiac surgery): a systematic review and meta-analysis A. Docherty, R. O\u2019Donnell, S. Brunskill, M. Trivella, C. Doree, L. Holst, M. Parker, M. Gregersen, J. Almeida, T. Walsh, S. Stanworth P136 - The relationship between poor pre-operative immune status and outcome from cardiac surgery is specific to the peri-operative antigenic threat S. Moravcova, J. Mansell, A. Rogers, R. A. Smith, C. Hamilton-Davies P137 - Impact of simple clinical practice guidelines for reducing post-operative atrial fibrillation after cardiac surgery. A. Omar, M. Allam, O. Bilala, A. Kindawi, H. Ewila P138 - Dexamethasone administration during cardiopulmonary bypass has no beneficial effects on elective postoperative cardiac surgery patients F. Ampatzidou, D. Moisidou, M. Nastou, E. Dalampini, A. Malamas, E. Vasilarou, G. Drossos P139 - Intra-aortic balloon counterpulsation in patients undergoing cardiac surgery (IABCS): preliminary results G. Ferreira, J. Caldas, J. Fukushima, E. A. Osawa, E. Arita, L. Camara, S. Zeferino, J. Jardim, F. Gaioto, L. Dallan, F. B. Jatene, R. Kalil Filho, .F Galas, L. A. Hajjar P140 - Effects of low-dose atrial natriuretic peptide infusion on cardiac surgery-associated acute kidney injury C. Mitaka, T. Ohnuma, T. Murayama, F. Kunimoto, M. Nagashima, T. Takei, M. Tomita P141 - Acute kidney injury influence on high sensitive troponin measurements after cardiac surgery A. Omar, K. Mahmoud, S. Hanoura, S. Sudarsanan, P. Sivadasan, H. Othamn, Y. Shouman, R. Singh, A. Al Khulaifi P142 - Complex evaluation of endothelial dysfunction markers for prognosis of outcomes in patients undergoing cardiac surgery I. Mandel, S. Mikheev, I. Suhodolo, V. Kiselev, Y. Svirko, Y. Podoksenov P143 - New-onset atrial fibrillation in intensive care: incidence, management and outcome S. A. Jenkins, R. Griffin P144 - One single spot measurement of the sublingual microcirculation during acute pulmonary hypertension in a pig model of shock M. S. Tovar Doncel, A. Lima, C. Aldecoa, C. Ince P145 - Assessment of levosimendan as a therapeutic option to recruit the microcirculation in cardiogenic shock \u2013 initial experience in cardiac ICU A. Taha, A. Shafie, M. Mostafa, N. Syed, H. Hon P146 - Terlipressin vs. norepinephrine in the Potential Multiorgan Donor(PMD) F. Righetti, E. Colombaroli, G. Castellano P147 - Echocardiography in the potential heart donor exposed to substitution hormonotherapy F. Righetti, E. Colombaroli P148 - Machine learning can reduce rate of monitor alarms M. Hravnak, L. C. Chen, A. D. Dubrawski, G. C. Clermont, M. R. Pinsky P149 - Peripherally inserted central catheters placed in the ICU S. Gonzalez, D. Macias, J. Acosta, P. Jimenez, A. Loza, A. Lesmes, F. Lucena, C. Leon P150 - Recordings of abnormal central venous pressure waveform morphology during an episode of pulmonary hypertension in a porcine shock model M. S. Tovar Doncel, C. Ince, C. Aldecoa, A. Lima P151 - Ultrasound guided central venous access technique among French intensivists M. Bastide, J. Richecoeur, E. Frenoy, C. Lemaire, B. Sauneuf, F. Tamion, S. Nseir, D. Du Cheyron, H. Dupont, J. Maizel P152 - Predictive ability of the Pv-aCO2 gap in patients with shock M. Shaban, R. Kolko, N. Salahuddin, M. Sharshir, M. AbuRageila, A. AlHussain P153 - Comparison of echocardiography and pulmonary artery catheter measurements of hemodynamic parameters in critical ill patients P. Mercado, J. Maizel, L. Kontar, D. Titeca, F. Brazier, A. Riviere, M. Joris, T. Soupison, B. De Cagny, M. Slama P154 - The volume clamp method for noninvasive cardiac output measurement in postoperative cardiothoracic surgery patients: a comparison with intermittent pulmonary artery thermodilution J. Wagner, A. K\u00f6rner, M. Kubik, S. Kluge, D. Reuter, B. Saugel P155 - Hemodynamic monitoring in patients with septic shock (SS) \u2013 CPCCO (continuous pulse contour cardiac output) vs. TEE (transesophageal echocardiography) E. Colombaroli, F. Righetti, G. Castellano P156 - Cardiac output measurement with transthoracic echocardiography in critically ill patients: a pragmatic clinical study T. Tran, D. De Bels, A. Cudia, M. Strachinaru, P. Ghottignies, J. Devriendt, C. Pierrakos P157 - Left ventricular outflow tract velocity time integral correlates with stroke volume index in mechanically ventilated patients \u00d3. Mart\u00ednez Gonz\u00e1lez, R. Blancas, J. Luj\u00e1n, D. Ballesteros, C. Mart\u00ednez D\u00edaz, A. N\u00fa\u00f1ez, C. Mart\u00edn Parra, B. L\u00f3pez Matamala, M. Alonso Fern\u00e1ndez, M. Chana P158 - Transpulmonary thermodilution (TPTD) derived from femoral vs. jugular central venous catheter: validation of a previously published correction formula and a proprietary correction formula for global end-diastolic volume index (GEDVI) W. Huber, M. Eckmann, F. Elkmann, A. Gruber, I. Klein, R. M. Schmid, T. Lahmer P160 - Dynamic arterial elastance calculated with lidcoplus monitor does not predict changes in arterial pressure after a fluid challenge in postsurgical patients D. Bastoni, H. Aya, L. Toscani, L. Pigozzi, A. Rhodes, M. Cecconi P159 - Venous return driving pressure and resistance in acute blood volume changes P. W. Moller, S. Sondergaard, S. M. Jakob, J. Takala, D. Berger P160 - Dynamic arterial elastance calculated with lidcoplus monitor does not predict changes in arterial pressure after a fluid challenge in postsurgical patients D. Bastoni, H. Aya, L. Toscani, L. Pigozzi, A. Rhodes, M. Cecconi P161 - Analysis of duration of post-operative goal-directed therapy protocol C. Ostrowska, H. Aya, A. Abbas, J. Mellinghoff, C. Ryan, D. Dawson, A. Rhodes, M. Cecconi P162 - Hemodynamic optimization \u2013 back to square one? M. Cronhjort, O. Wall, E. Nyberg, R. Zeng, C. Svensen, J. M\u00e5rtensson, E. Joelsson-Alm P163 - Effectiveness of fluid thoracic content measurement by bioimpedance guiding intravascular volume optimization in patients with septic shock M. Aguilar Arzapalo, L. Barradas, V. Lopez, M. Cetina P164 - A systematic review on the role of internal jugular vein ultrasound measurements in assessment of volume status in critical shock patients N. Parenti, C. Palazzi, L. A. Amidei, F. B. Borrelli, S. C. Campanale, F. T. Tagliazucchi, G. S. Sedoni, D. L. Lucchesi, E. C. Carella, A. L Luciani P165 - Importance of recognizing dehydration in medical Intensive Care Unit M. Mackovic, N. Maric, M. Bakula P166 - Effect of volume for a fluid challenge in septic patients H. Aya, A. Rhodes, R. M. Grounds, N. Fletcher, M. Cecconi P167 - Fluid bolus practices in a large Australian intensive care unit B. Avard, P. Zhang P168 - Liberal late fluid management is associated with longer ventilation duration and worst outcome in severe trauma patients: a retrospective cohort of 294 patients M. Mezidi, J. Charbit, M. Ould-Chikh, P. Deras, C. Maury, O. Martinez, X. Capdevila P169 - Association of fluids and outcomes in emergency department patients hospitalized with community-acquired pneumonia P. Hou, W. Z. Linde-Zwirble, I. D. Douglas, N. S. Shapiro P170 - Association of positive fluid balance with poor outcome in medicosurgical ICU patients A. Ben Souissi, I. Mezghani, Y. Ben Aicha, S. Kamoun, B. Laribi, B. Jeribi, A. Riahi, M. S. Mebazaa P171 - Impact of fluid balance to organ dysfunction in critically ill patients C. Pereira, R. Marinho, R. Antunes, A. Marinho P172 - Volume bolus in ICU patients: do we need to balance our crystalloids? M. Crivits, M. Raes, J. Decruyenaere, E. Hoste P173 - The use of 6\u00a0% HES solution do not reduce total fluid requirement in the therapy of patients with burn shock V. Bagin, V. Rudnov, A. Savitsky, M. Astafyeva, I. Korobko, V. Vein P174 - Electron microscopic assessment of acute kidney injury in septic sheep resuscitated with crystalloids or different colloids T. Kampmeier , P. Arnemann, M. Hessler, A. Wald, K. Bockbreder, A. Morelli, H. Van Aken, S. Rehberg, C. Ertmer P175 - Alterations of conjunctival microcirculation in a sheep model of haemorrhagic shock and resuscitation with 0.9\u00a0% saline or balanced tetrastarch P. Arnemann, M. Hessler, T. Kampmeier, S. Rehberg, H. Van Aken, C. Ince, C. Ertmer P176 - A single centre nested pilot study investigating the effect of using 0.9\u00a0% saline or Plasma-Lyte 148 \u00ae as crystalloid fluid therapy on gastrointestinal feeding intolerance in mechanically ventilated patients receiving nasogastric enteral nutrition S. Reddy, M. Bailey, R. Beasley, R. Bellomo, D. Mackle, A. Psirides, P. Young P177 - A single centre nested pilot study investigating the effect on post-operative bleeding of using 0.9\u00a0% saline or Plasma-Lyte\u00ae 148 as crystalloid fluid therapy in adults in ICU after heart surgery S. Reddy, M. Bailey, R. Beasley, R. Bellomo, D. Mackle, P. Young P178 - Extreme hypernatremia and sepsis in a patient with Huntington\u2019s dementia: a conundrum in fluid management H. Venkatesh, S. Ramachandran, A. Basu, H. Nair P179 - Diagnosis and management of severe hypernatraemia in the critical care setting S. Egan, J. Bates P180 - Correlation between arterial blood gas and electrolyte disturbances during hospitalization and outcome in critically ill patients S. Oliveira, N. R. Rangel Neto, F. Q. Reis P181 - Missing the \u201cI\u201d in MUDPILES \u2013 a rare cause of high anion gap metabolic acidosis (HAGMA) C. P. Lee, X. L. Lin, C. Choong , K. M. Eu, W. Y. Sim , K. S. Tee, J. Pau , J. Abisheganaden P182 - Plasma NGAL and urinary output: potential parameters for early initiation of renal replacement therapy K. Maas, H. De Geus P183 - Renal replacement therapy for critically ill patients: an intermittent continuity E. Lafuente, R. Marinho, J. Moura, R. Antunes, A. Marinho P184 - A survey of practices related to renal replacement therapy in critically ill patients in the north of England. T. E. Doris, D. Monkhouse, T. Shipley, S. Kardasz, I Gonzalez P185 - High initiation creatinine associated with lower 28-day mortality in critically ill patients necessitating continuous renal replacement therapy S. Stads, A. J. Groeneveld P186 - The impact of Karnofsky performance scale on outcomes in acute kidney injury patients receiving renal replacement therapy on the intensive care unit I. Elsayed, N. Ward, A. Tridente, A. Raithatha P187 - Severe hypophosphatemia during citrate-anticoagulated CRRT A. Steuber, C. Pelletier, S. Schroeder, E. Michael, T. Slowinski, D. Kindgen-Milles P188 - Citrate regional anticoagulation for post dilution continuous renal replacement therapy S. Ghabina P189 - Citrate 18\u00a0mmol/l improves anticoagulation during RRT with adsorbing filters F. Turani, A. Belli, S. Busatti, G. Barettin, F. Candidi, F. Gargano, R. Barchetta, M. Falco P190 - Calcium gluconate instead of calcium chloride in citrate-anticoagulated CVVHD O. Demirkiran, M. Kosuk, S. Bozbay P191 - Enhanced clearance of interleukin-6 with continuous veno-venous haemodialysis (CVVHD) using Ultraflux EMiC2 vs. Ultraflux AV1000S V. Weber, J. Hartmann, S. Harm, I. Linsberger, T. Eichhorn, G. Valicek, G. Miestinger, C. Hoermann P192 - Removal of bilirubin with a new adsorbent system: in vitro kinetics S. Faenza, D. Ricci, E. Mancini, C. Gemelli, A. Cuoghi, S. Magnani, M. Atti P193 - Case series of patients with severe sepsis and septic shock treated with a new extracorporeal sorbent T. Laddomada, A. Doronzio, B. Balicco P194 - In vitro adsorption of a broad spectrum of inflammatory mediators with CytoSorb\u00ae hemoadsorbent polymer beads M. C. Gruda, P. O\u2019Sullivan, V. P. Dan, T. Guliashvili, A. Scheirer, T. D. Golobish, V. J. Capponi, P. P. Chan P195 - Observations in early vs. late use of cytosorb therapy in critically ill patients K. Kogelmann, M. Dr\u00fcner, D. Jarczak P196 - Oxiris membrane decreases endotoxin during rrt in septic patients with basal EAA\u2009>\u20090,6 F. Turani, A. B. Belli, S. M. Martni, V. C. Cotticelli, F. Mounajergi, R. Barchetta P197 - An observational prospective study on the onset of augmented renal clearance: the first report S. Morimoto, H. Ishikura P198 - An ultrasound- guided algorithm for the management of oliguria in severe sepsis I. Hussain, N. Salahuddin, A. Nadeem, K. Ghorab, K. Maghrabi P199 - Ultrasound in acute kidney injury (aki). First findings of farius, an education-programme in structural ultrasonography S. K. Kloesel, C. Goldfuss, A. Stieglitz, A. S. Stieglitz, L. Krstevska, G. Albuszies P200 - Effectiveness of renal angina index score predicting acute kidney injury on critically ill patients M. Aguilar Arzapalo, L. Barradas, V. Lopez, A. Escalante, G. Jimmy, M. Cetina P201 - Time length below blood pressure thresholds and progression of acute kidney injury in critically ill patients with or without sepsis: a retrospective, exploratory cohort study J. Izawa, T. Iwami, S. Uchino, M. Takinami, T. Kitamura, T. Kawamura P202 - Anaemia does not affect renal recovery in acute kidney injury J. G. Powell-Tuck, S. Crichton, M. Raimundo, L. Camporota, D. Wyncoll, M. Ostermann P203 - Estimated glomerular filtration rate based on serum creatinine: actual practice in Dutch ICU\u2019s A. Hana, H. R. De Geus P204 - Comparison of estimated glomerular filtration rate calculated by mdrd, ckd-epi-serum-creatinine and ckd-epi-cystatin-c in adult critically ill patients H. R. De Geus, A. Hana P205 - Early diagnosis of septic acute kidney injury in medical critical care patients with a urine cell cycle arrest marker: insulin like growth factor binding protein-7 (IGFBP-7) M. Aydogdu, N. Boyaci, S. Yuksel, G. Gursel, A. B. Cayci Sivri P206 - Urinary neutrophil gelatinase-associated lipocalin as early biomarker of severe acute kidney injury in intensive care J. Meza-M\u00e1rquez, J. Nava-L\u00f3pez, R. Carrillo-Esper P207 - Shrunken pore syndrome is associated with a sharp rise in mortality in patients undergoing elective coronary artery bypass grafting A. Dardashti, A. Grubb P208 - The biomarker nephrocheck\u2122 can discriminate the septic shock patients with an akin 1 or 2 acute renal failure who will not progress toward the akin 3 level J. Maizel, M. Wetzstein, D. Titeca, L. Kontar, F. Brazier, B. De Cagny, A. Riviere, T. Soupison, M. Joris, M. Slama P209 - A worldwide multicentre evaluation of acute kidney injury in septic and non-septic critically ill patients: the intensive care over nations (icon) audit E. Peters, H. Njimi, P. Pickkers, J. L. Vincent P210 - Does enhanced recovery after surgery reduce the incidence of acute kidney injury in those undergoing major gynae-oncological surgery? M. Waraich , J. Doyle, T. Samuels, L. Forni P211 - Identification of risk factors for the development of acute kidney injury after lower limb arthroplasty N. Desai, R. Baumber, P. Gunning, A. Sell P212 - Incidences and associations of acute kidney injury after major trauma S. Lin, H. Torrence, M. O\u2019Dwyer, C. Kirwan, J. Prowle P213 - Acute kidney injury of major trauma patients T Kim P214 - Trajectory of serum creatinine after major surgery and the diagnosis of acute kidney injury M. E. O\u2019Connor, R. W. Hewson, C. J. Kirwan, R. M. Pearse, J. Prowle P215 - Epidemiology of acute kidney injury after cardiac surgery. A single center retrospective study S. Hanoura , A. Omar, H. Othamn, S. Sudarsanan , M. Allam, M. Maksoud, R. Singh, A. Al Khulaifi P216 - Post-operative acute kidney injury after major non-cardiac surgery and its association with death in the following year M. E. O\u2019Connor, R. W. Hewson, C. J. Kirwan, R. M. Pearse, J. Prowle P217 - Factors affecting acute renal failure in intensive care unit and effect of these factors on mortality O. Uzundere, D. Memis , M. \u00ddnal, A. , N. Turan P218 - Results of the live kidney transplantations according to national data of turkish organ and tissue information system M. A. Aydin, H. Basar, I. Sencan, A. Kapuagasi, M. Ozturk, Z. Uzundurukan, D. Gokmen, A. Ozcan, C. Kaymak P219 - Anaesthesia procedure and intensive therapy in patients with neck phlegmon V. A. Artemenko, A. Budnyuk P220 - Nasal high flow oygen for acute respiratory failure: a systematic review R. Pugh , S. Bhandari P221 - Setting optimal flow rate during high flow nasal cannula support: preliminary results T. Mauri, C. Turrini, T. Langer, P. Taccone, C. A. Volta, C. Marenghi, L. Gattinoni, A. Pesenti P222 - Dose to dose consistency across two different gas flow rates using cystic fibrosis and normal adult breathing profiles during nasal high flow oxygen therapy L. Sweeney, A . O\u2019 Sullivan, P. Kelly, E. Mukeria, R. MacLoughlin P223 - Final results of an evaluation of airway medix closed suction system compared to a standard closed suction system M. Pfeffer, J. T. Thomas, G. B. Bregman, G. K. Karp, E. K. Kishinevsky, D. S. Stavi, N. A. Adi P224 - Different cuff materials and different leak tests - one size does not fit all T. Poropat, R. Knafelj P225 - Observational study on the value of the cuff-leak test and the onset of upper airway obstruction after extubation E. Llopart, M. Batlle, C. De Haro, J. Mesquida, A. Artigas P226 - A device for emergency transtracheal lung ventilation D. Pavlovic, L. Lewerentz, A. Spassov, R. Schneider P227 - Long-term outcome and health-related quality of life in patients discharged from the intensive care unit with a tracheostomy and with or without prolonged mechanical ventilation S. De Smet, S. De Raedt, E. Derom, P Depuydt, S. Oeyen, D. Benoit, J. Decruyenaere P228 - Ultrasound-guided percutaneous dilational tracheostomy versus bronchoscopy-guided percutaneous dilational tracheostomy in critically ill patients (trachus): a randomized clinical trial A. Gobatto, B. Bese, P. Tierno, L. Melro, P. Mendes, F. Cadamuro, M. Park, L. M. Malbouisson P229 - Is it safe to discharge patients with tracheostomy from the ICU to the ward? B. C. Civanto, J. L. Lopez, A. Robles, J. Figueira, S. Yus, A. Garcia P230 - The application of tracheostomy in children in ICU A. Oglinda, G. Ciobanu, C. Oglinda, L. Schirca, T. Sertinean, V. Lupu P231 - The impact of passive humidifiers on aerosol drug delivery during mechanical ventilation P. Kelly, A. O\u2019Sullivan, L. Sweeney, R. MacLoughlin P232 - Evaluation of vibrating mesh and jet nebuliser performance at two different attachment setups in line with a humidifier nebuliser system A. O\u2019Sullivan, P. Kelly, L. Sweeney, E. Mukeria, M. Wolny , R. MacLoughlin P233 - Psv-niv versus cpap in the treatment of acute cardiogenic pulmonary edema A. Pagano, F. Numis, G. Vison, L. Saldamarco, T. Russo, G. Porta, F. Paladino P234 - Noninvasive ventilation in patients with haematologic malignancy: a retrospective review C. Bell, J. Liu, J. Debacker, C. Lee, E. Tamberg, V. Campbell, S. Mehta P235 - Use of non-invasive ventilation in infectious diseases besides classical indications A. Silva-Pinto, A. Sarmento, L. 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Karagiannidis P256 - Validation of regional and global expiratory time constant measurement by electrical impedance tomography in ards and obstructive pulmonary diseases C. K. Karagiannidis, A. W. Waldmann, S. B. B\u00f6hm, S. Strassmann, W. W. Windisch P257 - Transpulmonary pressure in a model with elastic recoiling lung and expanding chest wall P. Persson, S. Lundin, O. Stenqvist P258 - Lactate in pleural and abdominal effusion G. Porta, F. Numis, C. S. Serra, A. P. Pagano, M. M. Masarone, L. R. Rinaldi, A. A. Amelia, M. F. Fascione, L. A. Adinolfi, E. R. Ruggiero P259 - Outcome of patients admitted to the intensive care with pulmonary fibrosis F. Asota, K. O\u2019Rourke, S. Ranjan, P. Morgan P260 - Sedation and analgesia practice in extra-corporeal membrane oxygenation (ECMO)-treated patients with acute respiratory distress syndrome (ARDS): a retrospective study J. W. DeBacker, E. Tamberg, L. O\u2019Neill, L. Munshi, L. Burry, E. Fan, S. Mehta P261 - Characteristics and outcomes of patients deemed not eligible when referred for veno-venous extracorporeal membrane oxygenation (vv-ECMO) S. Poo, K. Mahendran, J. Fowles, C. Gerrard, A. Vuylsteke P262 - The SAVE SMR for veno-arterial ECMO R. Loveridge, C. Chaddock, S. Patel, V. Kakar, C. Willars, T. Hurst, C. Park, T. Best, A. Vercueil, G. Auzinger P263 - A simplified score to predict early (48\u00a0h) mortality in patients being considered for VA-ECMO A. Borgman, A. G. Proudfoot, E. Grins, K. E. Emiley, J. Schuitema, S. J. Fitch, G. Marco, J. Sturgill, M. G. Dickinson, M. Strueber, A. Khaghani, P. Wilton, S. M. Jovinge P264 - Lung function six months post extra corporeal membrane oxygenation (ECMO) for severe acute respiratory failure in adult survivors C. Sampson, S. Harris-Fox P265 - Bicarbonate dialysis removes carbon dioxide in hypoventilated rodents. M. E. Cove, L. H. Vu, A. Sen, W. J. Federspiel, J. A. Kellum P266 - Procalcitonin as predictor of primary graft dysfunction and mortality in post-lung transplantation C. Mazo Torre, J. Riera, S. Ramirez, B. Borgatta, L. Lagunes, J. Rello P267 - New molecular biomarkers of acute respiratory distress syndrome in abdominal sepsis A. K. Kuzovlev, V. Moroz, A. Goloubev, S. Polovnikov, S. Nenchuk P268 - Tight junction\u2019s proteins claudin -5 and regulation by tnf in experimental murine lung injury model of ali/ards V. Karavana, C. Glynos, A. Asimakos, K. Pappas, C. Vrettou, M. Magkou, E. Ischaki, G. Stathopoulos, S. Zakynthinos P269 - Cell counts in endobronchial aspirate to assess airway inflammation in ARDS patients: a pilot study S. Spadaro, I. Kozhevnikova, F. Dalla Corte, S. Grasso, P. Casolari, G. Caramori, C. Volta P270 - Epidemiological and clinical profile of patients with acute respiratory distress syndrome in the surgical intensive care unit surgical, hospital JRA, Antananarivo T. Andrianjafiarinoa, T. Randriamandrato, T. Rajaonera P271 - Effect of high PEEP after recruitment maneuver on right ventricular function in ARDS. Is it good for the lung and for the heart? S. El-Dash, ELV Costa, MR Tucci, F Leleu, L Kontar, B. De Cagny, F. Brazier, D. Titeca, G. Bacari-Risal, J. Maizel, M. Amato, M. Slama P272 - Effect of recruitment maneuver on left ventricular systolic strain P. Mercado, J. Maizel, L. Kontar, D. Titeca, F. Brazier, A. Riviere, M. Joris, T. Soupison, B. De Cagny, S. El Dash, M. Slama P273 - Inhaled nitric oxide \u2013 is switching supplier cost effective? Remmington, A. Fischer, S. Squire, M. Boichat P274 - Epidemiological study of severe acute pancreatitis in Japan, comparison of the etiology and the patient outcomes on 1159 patients. H. Honzawa, H. Yasuda, T. Adati, S. Suzaki, M. Horibe, M. Sasaki, M. Sanui P275 - Extracorporeal liver support therapy. Experience in an intensive care unit R. Marinho, J. Daniel, H. Miranda, A. Marinho P276 - Accuracy of mortality prediction models in acute versus acute-on-chronic liver failure in the intensive care setting K. Milinis, M. Cooper, G. R. Williams, E. McCarron, S. Simants, I. Patanwala, I. Welters P277 - Risk of coronary artery disease in patients with chronic liver disease: a population based cohort study Y. Su P278 - 20\u00a0years of liver transplantation in Santiago de Compostela (Spain). Experience review J. Fern\u00e1ndez Villanueva, R. Fern\u00e1ndez Garda, A. L\u00f3pez Lago, E. Rodr\u00edguez Ru\u00edz, R. Hern\u00e1ndez Vaquero, S. Tom\u00e9 Mart\u00ednez de Rituerto, E. Varo P\u00e9rez P279 - Diarrhea is a risk factor for liver injury and may lead to intestinal failure associated liver disease in critical illness N. Lefel, F. Schaap, D. Bergmans, S. Olde Damink, M. Van de Poll P280 - Bowel care on the intensive care unit: constipation guideline compliance and complications K. Tizard, C. Lister, L. Poole P281 - Malnutrition assessed by phase angle determines outcomes in low risk cardiac surgery patients D. Ringaitiene, D. Gineityte, V. Vicka, I. Norkiene, J. Sipylaite P282 - Preoperative fasting times in an irish hospital A. O\u2019Loughlin, V. Maraj, J. Dowling P283 - Costs and final outcome of early x delayed feeding in a private Brazil ICU M. B. Velasco, D. M. Dalcomune, E. B. Dias, S. L. Fernandes P284 - Can ventilator derived energy expenditure measurements replace indirect calorimetry? T. Oshima, S. Graf, C. Heidegger, L. Genton, V. Karsegard, Y. Dupertuis, C. Pichard P285 - Revisiting the refeeding syndrome: results of a systematic review N. Friedli, Z. Stanga, B. Mueller, P. Schuetz P286 - Compliance with the new protocol for parenteral nutrition in our ICU L. Vandersteen, B. Stessel, S. Evers, A. Van Assche, L. Jamaer, J. Dubois P287 - Nutrition may be another treatment in the intensive care unit where less is more? R. Marinho, H. Castro, J. Moura, J. Valente, P. Martins, P. Casteloes, C. Magalhaes, S. Cabral, M. Santos, B. Oliveira, A. Salgueiro, A. Marinho P288 - Should we provide more protein to critically ill patients? R. Marinho, M. Santos, E. Lafuente, H. Castro, S. Cabral, J. Moura, P. Martins, B. Oliveira, A. Salgueiro, S. Duarte, S. Castro, M. Melo, P. Casteloes, A. Marinho P289 Protein provision in an adult intensive care unit S. Gray P290 - Prevalence and clinical outcomes of vitamin d deficiency in the medical critically ill patients in Songklanagarind hospital K. Maipang, R. Bhurayanontachai P291 - Vitamin d deficiency strongly predicts adverse medical outcome across different medical inpatient populations: results from a prospective study L. G. Gr\u00e4del, P. Sch\u00fctz P292 - Omega-3 fatty acids in patients undergoing cardiac surgery: a systematic review and meta-analysis P. Langlois, W. Manzanares P293 - Can 5-hydroxytriptophan prevent post-traumatic stress disorder in critically ill patients? R. Tincu, C. Cobilinschi, D. Tomescu, Z. Ghiorghiu, R. Macovei P294 - Parenteral selenium in the critically ill: an updated systematic review and meta-analysis W. Manzanares, P. Langlois, M. Lemieux, G. Elke, F. Bloos, K. Reinhart, D. Heyland P295 - Probiotics in the critically ill: an updated systematic review and meta-analysis P. Langlois, M. Lemieux, I. Aramendi, D. Heyland, W. Manzanares P296 - Diabetes with hyperglycemic crisis episodes may be associated with higher risk of pancreatic cancer: a population-based cohort study Y. Su P297 - Incidence of hypoglycemia in an intensive care unit depending on insulin protocol R. Marinho, N. Babo, A. Marinho P298 - Severity of the diseases is two-dimensionally correlated to blood glucose, including blood glucose variability, especially in moderately to severely ill patients with glucose intolerance. M. Hoshino, Y. Haraguchi, S. Kajiwara, T. Mitsuhashi, T. Tsubata, M. Aida P299 - A study of glycemic control by subcutaneous glargine injection transition from continuous regular insulin infusion in critically ill patients T. Rattanapraphat, R. Bhurayanontachai, C. Kongkamol, B. Khwannimit P300 - Glycemic control in Portuguese intensive care unit R. Marinho, M. Santos, H. Castro, E. Lafuente, A. Salgueiro, S. Cabral, P. Martins, J. Moura, B. Oliveira, M. Melo, B. Xavier, J. Valente, C. Magalhaes, P. Casteloes, A. Marinho P301 - Impact of hyperglycemia duration on the day of operation on short-term outcome of cardiac surgery patients D. Moisidou, F. Ampatzidou, C. Koutsogiannidis, M. Moschopoulou, G. Drossos P302 - Lactate levels in diabetic ketoacidosis patients at ICU admissions G. Taskin, M. \u00c7akir, AK G\u00fcler, A. Taskin, N. \u00d6cal, S. \u00d6zer, L. Yamanel P303 - Intensive care implications of merging heart attack centre units in London J. M. Wong, C. Fitton, S. Anwar, S. Stacey P304 - Special characteristics of in-hospital cardiac arrests M. Aggou, B. Fyntanidou, S. Patsatzakis, E. Oloktsidou, K. Lolakos, E. Papapostolou, V. Grosomanidis P305 - Clinical evaluation of ICU-admitted patients who were resuscitated in the general medicine ward S. Suda , T. Ikeda, S. Ono, T. Ueno, Y. Izutani P306 - Serious game evaluation of a one-hour training basic life support session for secondary school students: new tools for future bystanders S. Gaudry, V. Desailly, P. Pasquier, PB Brun, AT Tesnieres, JD Ricard, D. Dreyfuss, A. Mignon P307 - Public and clinical staff perceptions and knowledge of CPR compared to local and national data J. C White, A. Molokhia, A. Dean, A. Stilwell, G. Friedlaender P308 Dispatcher-assisted telephone cardiopulmonary resuscitation using a French-language compression-ventilation pediatric protocol M. Peters, S. Stipulante, A. Delfosse, AF Donneau, A. 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Spina P324 Factors associated with ventilator weaning after targeted temperature management for cardiac arrest patients in japan H. Tanaka, N. Otani, S. Ode, S. Ishimatsu P325 Differential activation of c-fos in paraventricular nuclei of the hypothalamus and thalamus of the rat following myocardial infarction J. Cho, J. B. Moon, C. W. Park, T. G. Ohk, M. C. Shin, M. H. Won P326 Monitoring of cTroponin I in patients with acute ischemic stroke - predictor of inhospital mortality S. Dakova, Z. Ramsheva, K. Ramshev P327 Hyperthermic preconditioning severely accelerates neuronal damage in the gerbil ischemic hippocampal dentate gyrus via decreasing sods expressions J. Cho, J. B. Moon, C. W. Park, T. G. Ohk, M. C. Shin P328 Failure in neuroprotection of remote limb ischemic post conditioning in the hippocampus of a gerbil model of transient cerebral ischemia J. Cho, J. B. Moon, C. W. Park, T. G. Ohk, M. C. Shin P329 Brain death and admission diagnosis in neurologic intensive care unit, a correlation? A Marudi, S Baroni, A Gaspari, E Bertellini P330 Brain magnetic resonance imaging findings in patients with septic shock G. Orhun, E. Senturk, P. E. Ozcan, S. Sencer, C. Ulusoy, E. Tuzun, F . Esen P331 Benefits of L-carnitine in valproic acid induced encephalopathy R. Tincu, C. Cobilinschi, D. Tomescu, Z. Ghiorghiu, R. Macovei P332Automatic analysis of EEG reactivity in comatose patients M. Van Assen, M. M. Admiraal, M. J. Van Putten, M. Tjepkema-Cloostermans, A. F. Van Rootselaar, J. Horn P333 Usefulness of common ICU severity scoring systems in predicting outcome after spontaneous intracerebral hemorrhage M. Fallenius, M. B. Skrifvars, M. Reinikainen, S. Bendel, R. Raj P334 Evalution of patients with suspected subarachnoid haemorrhage and negative ct imaging M. Abu-Habsa, C. Hymers, A. Borowska, H. Sivadhas, S. Sahiba, S. Perkins P335 Timing of endovascular and surgical treatment for aneurysmal subarachnoid haemorrhage: early but not so fast. J. Rubio, J. A. Rubio, R. Sierra P336 Red blood cell transfusion in aneurysmal subarachnoid hemorrhage \u2013 the Sahara cohort study S. English, M. Chasse, A. Turgeon, F. Lauzier, D. Griesdale, A. Garland, D. Fergusson, R. Zarychanski, A. Tinmouth, C. Van Walraven, K. Montroy, J. Ziegler, R. Dupont Chouinard, R. Carignan, A. Dhaliwal, C. Lum, J. Sinclair, G. Pagliarello, L. McIntyre P337 - Aneurysmal subarachnoid hemorrhage and anemia: a canadian multi-centre retrospective cohort study S. English, M. Chasse, A. Turgeon, F. Lauzier, D. Griesdale, A. Garland, D. Fergusson, R. Zarychanski, A. Tinmouth, C. Van Walraven, K. Montroy, J. Ziegler, R. Dupont Chouinard, R. Carignan, A. Dhaliwal, C. Lum, J. Sinclair, G. Pagliarello, L. McIntyre P338 - Does the neutrophil-to-lymphocyte (NLR) ratio predict symptomatic vasospasm or delayed cerebral ischemia (DCI) after aneurysmal subarachnoid haemorrhage (SAH)? T. Groza, N. Moreau, D. Castanares-Zapatero, P. Hantson P339 - ICU-acquired infections in aneurysmal subarachnoid hemorrhage patients: impact on ICU and hospital length of stay M. Carbonara , F. Ortolano, T. Zoerle, S. Magnoni, S. Pifferi, V. Conte, N. Stocchetti P340 - Cerebral metabolic effects of normobaric hyperoxia during the acute phase of aneurysmal subarachnoid hemorrhage L. Carteron, T. Suys, C. Patet, H. Quintard, M. Oddo P341 - Postoperative care for elective craniotomy: where is best done? J. A. Rubio, J. Rubio, R. Sierra P342 - 5-year follow-up of patients after transplantation of organs from donors from neurocritical care V. Spatenkova, E. Pokorna, P. Suchomel P343 - Evaluation of levetiracetam pharmacokinetics after severe traumatic brain injury in neurocritical care patients at a level one trauma center N. Ebert, J. Jancik, H. Rhodes P344 - Model based time series cluster analysis to determine unique patient states in traumatic brain injury T. Bylinski, C. Hawthorne, M. Shaw, I. Piper, J. Kinsella P345 - Brain compartment monitoring capabilities from ICP to BI (bioimpedance) during HS (hypertonic saline) administration. State of art simulation outcome depending on brain swelling type A. K. Kink , I. R. R\u00e4tsep P346 - Transfusion of red blood cells in patients with traumatic brain injury admitted to Canadian trauma health centers: a multicenter cohort study A. Boutin, L. Moore, M. Chasse, R. Zarychanski, F. Lauzier, S. English, L. McIntyre, J. Lacroix, D. Griesdale, P. Lessard-Bonaventure, A. F. Turgeon P347 - Hemoglobin thresholds and red blood cell transfusions in adult patients with moderate or severe traumatic brain injury: a retrospective cohort study A. Boutin, L. Moore, R. Green, P. Lessard-Bonaventure, M. Erdogan, M. Butler, F. Lauzier, M. Chasse, S. English, L. McIntyre, R. Zarychanski, J. Lacroix, D. Griesdale, P. Desjardins, D. A. Fergusson, A. F. Turgeon P348 - Characteristics of patients with gunshot wounds to the head - an observational Brazilian study B. Goncalves, B. Vidal, C. Valdez, A. C. Rodrigues, L. Miguez, G. Moralez P349 - Base excess as predictor for ICU admission and the injury severity in blunt trauma patients T. Hong P350 - Enhancement of usual emergency department care with proadrenomedullin to improve outcome prediction - Results from the multi-national, prospective, observational TRIAGE study A. Kutz, P. Hausfater, D. Amin, T. Struja, S. Haubitz, A. Huber, B. Mueller, P. Schuetz P351 - Developing an innovative emergency medicine point-of-care simulation programme T. Brown, J. Collinson, C. Pritchett, T. Slade P352 - The InSim program: an in situ simulation program for junior trainees in intensive care M. Le Guen, S. Hellings, R. Ramsaran P353 - Impact of excessive and inappropriate troponin testing in the emergency setting how good are we A. Alsheikhly P354 - The development of time tracking monitor at emergency department T. Abe P355 - Role of focussed echocardiography in emergency assessment of syncope L. Kanapeckaite, M. Abu-Habsa, R. Bahl P356 - Insertion of an open-ended 14-gauge catheter through the chest wall causes a significant pneumothorax in a self-ventilating swine model M. Q Russell, K. J. Real, M. Abu-Habsa , R. M. Lyon, N. P. Oveland P357 - Ez-io\u00ae intraosseous access teaching in the workplace using a mobile \u2018tea trolley\u2019 training method J. Penketh, M. Mcdonald, F. Kelly P358 - Black widow envenomation in Saudi Arabia: a prospective observational case series M. Alfafi, S. Alsolamy, W. Almutairi, B. Alotaibi P359 - Mechanical ventilation in patients with overdose not yet intubated on icu admission A. E. Van den Berg, Y. Schriel, L. Dawson, I. A. Meynaar P360 - Central nervous system depressants poisoning and ventilator associated pneumonia: an underrated risk factor in toxicological intensive care unit H. Talaie P361 - Acute barium intoxication treated with hemodiafiltration D. Silva, S. Fernandes, J. Gouveia, J. Santos Silva P362 - Major trauma presenting to the emergency department. the spectrum of cycling injuries in Ireland J. Foley, A. Kaskovagheorgescu, D. Evoy, J. Cronin, J. Ryan P363 - Burns from French military operations: a 14-year retrospective observational analysis. M. Huck, C. Hoffmann, J. Renner, P. Laitselart, N. Donat, A. Cirodde, J. V. Schaal, Y. Masson, A. Nau, T. Leclerc P364 - A comparison of mortality scores in burns patients on the intensive care unit. O. Howarth, K. Davenport, P. Jeanrenaud, S. Raftery P365 - Clasification of pain and its treatment and an intensive care rehabiliation clinic P. MacTavish, H. Devine, J. McPeake, M. Daniel, J. Kinsella, T. Quasim P366 - Pain management adequacy in critical care areas ,the process and the barriers perceived by critical care nurses S. Alrabiee, A. Alrashid , S. Alsolamy P367 - Pain assessment in critically ill adult patients: validation of the Turkish version of the critical-care pain observation tool O. Gundogan, C. Bor, E. Ak\u00fdn Korhan, K. Demirag , M. Uyar P368 - An audit of pain and sedation assessments in the intensive care unit: recommendations for clinical practice F. Frame, C. Ashton, L. Bergstrom Niska P369 - Impact of pharmaceutical care on treatment of pain and agitation in medical intensive care unit P. Dilokpattanamongkol, T. Suansanae, C. Suthisisang, S. Morakul, C. 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Bielka P377 - Hemodynamic effects of dexmedetomidine in a porcine model of septic shock Z. Aidoni, V. Grosomanidis, K. Kotzampassi, G. Stavrou, B. Fyntanidou, S. Patsatzakis, C. Skourtis P378 - Ketamine for analgosedation in severe hypoxic respiratory failure S. D. Lee, K. Williams, I. D. Weltes P379 - Madness from the moon? lunar cycle and the incidence of delirium on the intensive care unit S. Berhane, C. Arrowsmith, C. Peters, S. Robert P380 - Impaired dynamic cerebral autoregulation after coronary artery bypass grafting and association with postoperative delirium J. Caldas, R. B. Panerai, T. G. Robinson, L. Camara, G. Ferreira, E. Borg-Seng-Shu, M. De Lima Oliveira, N. C. Mian, L. Santos, R. Nogueira, S. P. Zeferino, M. Jacobsen Teixeira, F. Galas, L. A. Hajjar P381 - Risk factors predicting prolonged intensive care unit length of stay after major elective surgery. P. Killeen, M. McPhail, W. Bernal, J. Maggs, J. Wendon, T. Hughes P382 - Systemic inflammatory response syndrome criteria and hospital mortality prediction in a brazilian cohort of critically ill patients L. U. Taniguchi, E. M. Siqueira, J. M. Vieira Jr, L. C. Azevedo P383 - Evaluating the efficacy of a risk predictor panel in identifying patients at elevated risk of morbidity following emergency admission A. N. Ahmad, M. Abu-Habsa, R. Bahl, E. Helme, S. Hadfield, R. Loveridge P384 - A retrospective comparison of outcomes for elective surgical patients admitted post-operatively to the critical care unit or general ward J. Shak, C. Senver, R. Howard-Griffin P385 - Effect of obesity on mortality in surgical critically ill patients. P. Wacharasint, P. Fuengfoo, N. Sukcharoen, R. Rangsin P386 - The national early warning score (news) reliably improves adverse clinical outcome prediction in community-acquired pneumonia - results from a 6\u00a0year follow-up D. Sbiti-Rohr, P. Schuetz P387 - Clinical usefulness of the charlson\u00a1\u00afs weighted index of comorbidities _as prognostic factor in patients with prolonged acute mechanical ventilation H. Na, S. Song, S. Lee, E. Jeong, K. Lee P388 - Comparison of mortality prediction scoring systems in patients with cirrhosis admitted to general intensive care unit M. Cooper, K. Milinis, G. Williams, E. McCarron, S. Simants, I. Patanwala, I. D. Welters P389 - Impact of admission source and time of admission on outcome of pediatric intensive care patients: retrospective 15\u00a0years study E. Zoumpelouli, EA Volakli, V. Chrysohoidou, S. Georgiou, K. Charisopoulou, E. Kotzapanagiotou, V. Panagiotidou, K. Manavidou, Z. Stathi, M. Sdougka P390 - Heart rate variability and outcomes prediction in critical illness N. Salahuddin, B. AlGhamdi, Q. Marashly, K. Zaza, M. Sharshir, M. Khurshid, Z. Ali, M. Malgapo, M. Jamil, A. Shafquat, M. Shoukri, M. Hijazi P391 - The incidence and outcome of hyperlactatemia in the post anaesthesia care unit T. Abe, S. Uchino, M. Takinami P392 - Correlation between arterial blood gas disturbances and arterial lactate levels during hospitalization and outcome in critically septic patients N. R. Rangel Neto, S. Oliveira, F. Q. Reis, F. A. Rocha P393 - External validation of saps 3 and mpm iii scores in 48,816 patients from 72 brazilian icus G. Moralez, K. Ebecken, L. S. Rabello, M. F. Lima, R. Hatum, F. V. De Marco, A. Alves, J. E. Pinto, M. Godoy, P. E. Brasil, F. A. Bozza, J. I. Salluh, M. Soares P394 - The frailty penalty: pre-admission functional status confounds mortality prediction models in critically ill patients J. Krinsley, G. Kang P395 - \u2018sooner rather than later\u201d: how delayed discharge from critical care leads to increased out of hours discharges and subsequent increase in in-hospital mortality. J. Perry, H. Hines P396 - Identifying poor outcome patient groups in a resource-constrained critical care unit K. M. Wilkinson, C. Tordoff, B. Sloan, M. C. Bellamy P397 - Effects of icu weekend admission and discharge on mortality. E. Moreira, F. Verga, M. Barbato, G. Burghi P398 - Organizational factors, outcomes and resource use in 9,946 cancer patients admitted to 70 ICUs M Soares, U. V. Silva, L. C. Azevedo, A. P. Torelly, J. M. Kahn, D. C. Angus, M. F. Knibel, P. E. Brasil, F. A. Bozza, J. I. Salluh P399 - Evaluation of oncological critically ill patients, severity score and outcome compared to not oncological in a particular hospital cti. M. B. Velasco, D. M. Dalcomune P400 - Outcomes of patients admitted to a large uk critical care department with palliative oncological diagnoses R. Marshall, T. Gilpin, A. Tridente, A. Raithatha P401 - Predictors of mortality in febrile neutropenic patients with haematological malignancies admitted to an intensive care unit of a cancer center D. Mota, B. Loureiro, J. Dias, O. Afonso, F. Coelho, A. Martins, F. Faria P402 - Patients with hematologic malignancies requiring invasive mechanical ventilation: characteristics and predictors of mortality H. Al-Dorzi, H. Al Orainni , F. AlEid, H. Tlaygeh, A. Itani, A. Hejazi, Y. Arabi P403 - Patient-important outcomes in randomized controlled trials in critically ill patients: a systematic review S. Gaudry, J. Messika, J. D. Ricard, S. Guillo, B. Pasquet, E. Dubief, D. Dreyfuss, F. Tubach P404 - Alopecia in survivors of critical illness: a qualitative study C . Battle, K. James, P. Temblett P405 - The impact of mental health on icu admission L. Davies, C. Battle, C. Lynch P406 - Cognitive impairment 5\u00a0years after ICU discharge S. Pereira, S. Cavaco, J. Fernandes, I. Moreira, E. Almeida, F. Seabra Pereira, M. Malheiro, F. Cardoso, I. Arag\u00e3o, T. Cardoso P407 - Apache ii versus apache iv for octagenerians in medical icu M. Fister, R. Knafelj P408 - Outcomes of octagenarians in an indian icu P. Muraray Govind, N. Brahmananda Reddy, R. Pratheema, E. D. Arul, J. Devachandran P409 - Mortality and outcomes in elderly patients 80\u00a0years of age or older admitted to the icu M. B. Velasco , D. M. Dalcomune P410 - Octagenerians in medical icu - adding days to life or life to days? R. Knafelj, M. Fister P411 - The very elderly admitted to intensive care unit: outcomes and economic evaluation N. Chin-Yee, G. D\u2019Egidio, K. Thavorn, D. Heyland, K. Kyeremanteng P412 - The very elderly in intensive care: relationship between acuity of illness and long-term mortality A. G. Murchison, K. Swalwell, J. Mandeville, D. Stott P413 - Acquired weakness in an oncological intensive care unit I. Guerreiro P414 - Musculoskeletal problems in intensive care unit (ICU) patients post-discharge H. Devine, P. MacTavish, J. McPeake, T. Quasim, J. Kinsella, M. Daniel P415 - Premorbid obesity, but not nutrition, prevents critical illness-induced muscle wasting and weakness C. Goossens M. B. Marques, S. Derde, S. Vander Perre, T. Dufour, S. E. Thiessen, F. G\u00fciza, T. Janssens, G. Hermans, I. Vanhorebeek, K. De Bock, G. Van den Berghe, L. Langouche P416 - Physical outcome measures for critical care patients following intensive care unit (icu) discharge H. Devine, P. MacTavish, T. Quasim, J. Kinsella, M. Daniel, J. McPeake P417 - Improving active mobilisation in a general intensive care unit B. Miles , S. Madden, H. Devine P418 - Mobilization in patients on vasoactive drugs use \u2013 a pilot study. M. Weiler, P. Marques, C. Rodrigues, M. Boeira, K. Brenner, C. Le\u00e3es, A. Machado, R. Townsend, J. Andrade P419 - Pharmacy intervention at an intensive care rehabilitation clinic P. MacTavish, J. McPeake, H. Devine, J. Kinsella, M. Daniel, R. Kishore, C. Fenlon, T. Quasim P420 - Interactive gaming is feasible and potentially increases icu patients\u2019 motivation to be engaged in rehabilitation programs T. Fiks, A. Ruijter, M. Te Raa, P. Spronk P421 - Simulation-based design of a robust stopping rule to ensure patient safety Y. S. Chiew, P. Docherty, J. Dickson, E. Moltchanova, C. Scarrot, C. Pretty, G. M. Shaw, J. G. Chase P422 - Are daily blood tests on the intensive care unit necessary? T. Hall, W. C. Ngu, J. M. Jack, P. Morgan P423 - Measuring urine output in ward patients: is it helpful? B. Avard, A. Pavli, X. Gee P424 - The incidence of pressure ulcers in an adult mixed intensive care unit in turkey C . Bor, E. Akin Korhan, K. Demirag, M. Uyar P425 - Intensivist/patient ratios in closed ICUs in Alexandria, Egypt; an overview M. Shirazy, A. Fayed P426 - Eicu (electronic intensive care unit): impact on ALOS (average length of stay) in a developing country like India S. Gupta, A. Kaushal, S. Dewan, A. Varma P427 - Predicting deterioration in general ward using early deterioration indicator E. Ghosh, L. Yang, L. Eshelman, B. Lord, E. Carlson P428 - High impact enhanced critical care outreach - the imobile service: making a difference E. Helme, R. Broderick, S. Hadfield, R. Loveridge P429 - Impact of bed availability and cognitive load on intensive care unit (ICU) bed allocation: a vignette-based trial J. Ramos, D. Forte P430 - Characteristics of critically ill patients admitted through the emergency department F. Yang, P. Hou P431 - Admission to critical care: the quantification of functional reserve J. Dudziak, J. Feeney, K. Wilkinson, K. Bauchmuller, K. Shuker, M. Faulds, A. Raithatha, D. Bryden, L. England, N. Bolton, A. Tridente P432 - Admission to critical care: the importance of frailty K. Bauchmuller, K Shuker, A Tridente, M Faulds, A Matheson, J. Gaynor, D Bryden, S South Yorkshire Hospitals Research Collaboration P433 - Development of an instrument to aid triage decisions for intensive care unit admission J. Ramos, B. Peroni, R. Daglius-Dias, L. Miranda, C. Cohen, C. Carvalho, I . Velasco, D. Forte P434 - Using selective serotonin re-uptake inhibitors and serotonin-norepinephrine re-uptake inhibitors in critical care: a systematic review of the evidence for benefit or harm J. M. Kelly, A. Neill, G. Rubenfeld, N. Masson, A. Min P435 - Measuring adaptive coping of hospitalized patients with a severe medical condition:the sickness insight in coping questionnaire (sicq) E. Boezeman, J. Hofhuis , A. Hovingh, R. De Vries, P. Spronk P436 - Results of a national survey regarding intensive care medicine training G. Cabral-Campello, I. Arag\u00e3o, T. Cardoso P437 - Work engagement among healthcare professionals in the intensive care unit M. Van Mol, M. Nijkamp, E . Kompanje P438 - Empowering the intensive care practitioners. is it a burnout ameliorating intervention? P. Ostrowski, A. Omar P439 - Icu patients suffer from circadian rhythm desynchronisation K. Kiss , B. K\u00f6ves, V. Csernus, Z. Moln\u00e1r P440 - Noise reduction in the ICU: feasible ? Y. Hoydonckx, S. Vanwing, B. Stessel, A. Van Assche, L. Jamaer, J. Dubois P441 - Accidental removal of invasive devices in the critical patient into the bed-washing. does the presence of professional nurse modify his incidence? V. Medo, R. Galvez, J. P. Miranda P442 - Deprivation of liberty safeguards (dols): audit of compliance in a of a 16-bed specialist cancer critical care unit. C. Stone, T. Wigmore P443 - Use of a modified cristal score to predict futility of critical care in the elderly Y. Arunan, A. Wheeler, K. Bauchmuller, D. Bryden P444 - Improvement of Referral Rate to Palliative Care for Patients with Poor Prognosis in Neurosurgical Intensive Care Unit Y. Wong, C. Poi, C. 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Violaki, P. Mantzafleri, E. Samkinidou, O. Vrani, A. Arbouti, T. Varsami, M. Sdougka P452 - The potential impact of euthanasia on organ donation: analysis of data from belgium J. A. Bollen, T. C. Van Smaalen, W. C. De Jongh, M. M. Ten Hoopen, D. Ysebaert, L. W. Van Heurn, W. N. Van Mook P453 - Communication within an intensive care setting K. Sim, A. Fuller P454 - Development and implementation of a longitudinal communication curriculum for critical care medicine fellows A. Roze des Ordons, P. Couillard, C. Doig P455 - Staff-family conflict in a multi-ethnic intensive care unit R. V. Van Keer, R. D. Deschepper, A. F. Francke, L. H. Huyghens, J. B. Bilsen P456 - Does the source of admission to critical care affect family satisfaction? B. Nyamaizi, C. Dalrymple, A. Molokhia, A. Dobru P457 - A simple alternative to the family satisfaction survey (fs-icu) E. Marrinan, A. Ankuli, A. 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Giannini, G Miccinesi, T Marchesi, E Prandi", - "journal_title": "Critical care (London, England)", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/27885969/" - } - ], - "fece3616-2040-421d-9eae-1f6d8f71a871": [ - { - "pub_id": "20203603", - "title": "A human gut microbial gene catalogue established by metagenomic sequencing.", - "authors": "Junjie Qin,Ruiqiang Li,Jeroen Raes,Manimozhiyan Arumugam,Kristoffer Solvsten Burgdorf,Chaysavanh Manichanh,Trine Nielsen,Nicolas Pons,Florence Levenez,Takuji Yamada,Daniel R Mende,Junhua Li,Junming Xu,Shaochuan Li,Dongfang Li,Jianjun Cao,Bo Wang,Huiqing Liang,Huisong Zheng,Yinlong Xie,Julien Tap,Patricia Lepage,Marcelo Bertalan,Jean-Michel Batto,Torben Hansen,Denis Le Paslier,Allan Linneberg,H Bj\u00f8rn Nielsen,Eric Pelletier,Pierre Renault,Thomas Sicheritz-Ponten,Keith Turner,Hongmei Zhu,Chang Yu,Shengting Li,Min Jian,Yan Zhou,Yingrui Li,Xiuqing Zhang,Songgang Li,Nan Qin,Huanming Yang,Jian Wang,S\u00f8ren Brunak,Joel Dor\u00e9,Francisco Guarner,Karsten Kristiansen,Oluf Pedersen,Julian Parkhill,Jean Weissenbach, ,Peer Bork,S Dusko Ehrlich,Jun Wang", - "abstract": "To understand the impact of gut microbes on human health and well-being it is crucial to assess their genetic potential. Here we describe the Illumina-based metagenomic sequencing, assembly and characterization of 3.3 million non-redundant microbial genes, derived from 576.7 gigabases of sequence, from faecal samples of 124 European individuals. The gene set, approximately 150 times larger than the human gene complement, contains an overwhelming majority of the prevalent (more frequent) microbial genes of the cohort and probably includes a large proportion of the prevalent human intestinal microbial genes. The genes are largely shared among individuals of the cohort. Over 99% of the genes are bacterial, indicating that the entire cohort harbours between 1,000 and 1,150 prevalent bacterial species and each individual at least 160 such species, which are also largely shared. We define and describe the minimal gut metagenome and the minimal gut bacterial genome in terms of functions present in all individuals and most bacteria, respectively.", - "journal_title": "Nature", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/20203603/" - } - ], - "26a0247f-2c9a-4b7f-8a80-0b60721b69d5": [ - { - "pub_id": "9165217", - "title": "Association of diabetic neuropathy with Na/K ATPase gene polymorphism.", - "authors": "P Vague,D Dufayet,T Coste,C Moriscot,M F Jannot,D Raccah", - "abstract": "Diabetes mellitus induces a decrease in Na/K ATPase activity in man and animals, and this decrease plays a role in the development of diabetic neuropathy. Na/K ATPase is encoded by various genes, of which the ATP1 A1 gene is expressed predominantly in peripheral nerves and in erythrocytes. To investigate whether a polymorphism in the Na/K ATPase genes could explain the predisposition of some patients with insulin-dependent diabetes mellitus (IDDM) to develop polyneuropathy, a restriction fragment length polymorphism (RFLP) of the ATP1 A1 gene was studied together with erythrocyte Na/K ATPase activity in 81 Caucasian patients with more than 10 years' duration of IDDM. Associations with diabetic neuropathy, retinopathy and nephropathy were sought. Digestion of the first intron of the ATP1 A1 gene by the Bgl II restriction enzyme revealed a dimorphic allelism. Frequency of the restricted allele was 0.18 in this selected series (however, it was 0.10 in representative samples of IDDM patients and of normal subjects in our area). Mean erythrocyte Na/K ATPase activity was lower in diabetic patients than in 42 control subjects (292 +/- 10, vs 402 +/- 13 nmol Pi.mg protein-1.h-1, p < 0.0001) and was not related to HbA1c value or to diabetes duration. It was lower in the group of the 28 patients bearing the restricted allele (241 +/- 10 vs 319 +/- 11 nmol Pi.mg protein-1.h-1, p < 0.0001). Neuropathy was absent in 50 patients, mild in 15 and severe in 16. When classified accordingly the three groups of patients did not differ with respect to sex, age and duration of diabetes. The respective frequency of the restricted allele among the groups was 10, 73 and 81%, (p < 0.0001) and mean erythrocyte Na/K ATPase activity was respectively: 322 +/- 10.7 nmol Pi.mg protein-1.h-1, 268 +/- 15 and 229 +/- 17, (p < 0.001). A borderline association between renal status or retinal status and repartition of polymorphism and a borderline correlation between renal status and Na/K ATPase activity were found, but significance disappeared after checking for the presence or absence of neuropathy. IDDM patients bearing the ATP1 A1 variant detected by Bgl II RFLP are much more frequently affected by neuropathy (relative risk 6.5, with 95% CI 3.3-13). Identification of this risk factor may help to prevent this complication. It is suggested that the restricted allele is in linkage disequilibrium with a genomic mutation allowing diabetes to induce a greater impairment of Na/K ATPase activity which could in turn favour the development of neuropathy.", - "journal_title": "Diabetologia", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/9165217/" - } - ], - "e5f11232-0e76-4f32-86e8-5a5613feed39": [ - { - "pub_id": "16462940", - "title": "Genetic and genomic analysis of a fat mass trait with complex inheritance reveals marked sex specificity.", - "authors": "Susanna Wang,Nadir Yehya,Eric E Schadt,Hui Wang,Thomas A Drake,Aldons J Lusis", - "abstract": "The integration of expression profiling with linkage analysis has increasingly been used to identify genes underlying complex phenotypes. The effects of gender on the regulation of many physiological traits are well documented; however, \"genetical genomic\" analyses have not yet addressed the degree to which their conclusions are affected by sex. We constructed and densely genotyped a large F2 intercross derived from the inbred mouse strains C57BL/6J and C3H/HeJ on an apolipoprotein E null (ApoE-/-) background. This BXH.ApoE-/- population recapitulates several \"metabolic syndrome\" phenotypes. The cross consists of 334 animals of both sexes, allowing us to specifically test for the dependence of linkage on sex. We detected several thousand liver gene expression quantitative trait loci, a significant proportion of which are sex-biased. We used these analyses to dissect the genetics of gonadal fat mass, a complex trait with sex-specific regulation. We present evidence for a remarkably high degree of sex-dependence on both the cis and trans regulation of gene expression. We demonstrate how these analyses can be applied to the study of the genetics underlying gonadal fat mass, a complex trait showing significantly female-biased heritability. These data have implications on the potential effects of sex on the genetic regulation of other complex traits.", - "journal_title": "PLoS genetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/16462940/" - } - ], - "5a0bacfb-2d17-4c5b-be8c-4a998b07626e": [ - { - "pub_id": "11344238", - "title": "The N363S polymorphism of the glucocorticoid receptor: potential contribution to central obesity in men and lack of association with other risk factors for coronary heart disease and diabetes mellitus.", - "authors": "M G Dobson,C P Redfern,N Unwin,J U Weaver", - "abstract": "Considerable evidence suggests that diabetes mellitus and hypertension are influenced by genetic factors. Studies in humans have associated glucocorticoid receptor (GR) polymorphisms with high blood pressure, insulin sensitivity, body mass index, increased visceral fat, and variations in tissue-specific steroid sensitivity. The N363S polymorphism of the GR results in an asparagine to serine amino acid substitution in a modulatory region of the receptor. Phosphorylation of serine residues in this region has been shown to enhance transactivation of GR responsive genes. The aim of this study was to investigate the association between the 363S allele and risk factors for coronary heart disease and diabetes mellitus in a population of European origin living in the northeast of the United KINGDOM: Blood samples from 135 males and 240 females were characterized for 363 allele status. The overall frequency of the 363S allele was 3.0%, 23 heterozygotes (7 males and 16 females) but no 363S homozygotes were identified. The data show a significant association of the 363S allele with increased waist to hip ratio in males but not females. This allele was not associated with blood pressure, body mass index, serum cholesterol, triglycerides, low-density lipoprotein and high-density lipoprotein cholesterol levels, and glucose tolerance status. The results of this study suggest that this GR polymorphism may contribute to central obesity in men. Further studies are required to elucidate the properties of GR(363S) at a molecular level.", - "journal_title": "The Journal of clinical endocrinology and metabolism", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/11344238/" - } - ], - "5782c1a9-6ab1-4c66-b1e6-116ac6a0e50b": [ - { - "pub_id": "18952314", - "title": "Type 2 diabetes: new genes, new understanding.", - "authors": "Inga Prokopenko,Mark I McCarthy,Cecilia M Lindgren", - "abstract": "Over the past two years, there has been a spectacular change in the capacity to identify common genetic variants that contribute to predisposition to complex multifactorial phenotypes such as type 2 diabetes (T2D). The principal advance has been the ability to undertake surveys of genome-wide association in large study samples. Through these and related efforts, approximately 20 common variants are now robustly implicated in T2D susceptibility. Current developments, for example in high-throughput resequencing, should help to provide a more comprehensive view of T2D susceptibility in the near future. Although additional investigation is needed to define the causal variants within these novel T2D-susceptibility regions, to understand disease mechanisms and to effect clinical translation, these findings are already highlighting the predominant contribution of defects in pancreatic beta-cell function to the development of T2D.", - "journal_title": "Trends in genetics : TIG", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/18952314/" - } - ], - "4252d7ad-82de-480c-a801-9ed1c84fb968": [ - { - "pub_id": "16311214", - "title": "Peroxisome proliferator-activated receptor gamma and the regulation of adipocyte function: lessons from human genetic studies.", - "authors": "Mark Gurnell", - "abstract": "In recent years, the thiazolidinediones (e.g. rosiglitazone, pioglitazone) have emerged as an exciting novel class of therapeutic agent for the treatment of type 2 diabetes mellitus and the human metabolic syndrome. At first glance, the use of these high-affinity peroxisome proliferator-activated receptor gamma (PPARgamma) agonists, that promote adipogenesis, to treat a group of disorders that typically have their origins in obesity seems counter-intuitive. However, to view PPARgamma simply as a regulator of fat mass, and adipocytes themselves as passive vessels for energy storage, is to ignore an extensive body of data that speaks of the diverse roles of both this receptor and adipose tissue in the maintenance of normal metabolic homeostasis. This article highlights the important clinical and laboratory observations made in human subjects harbouring genetic variations in PPARgamma that have confirmed its pivotal role in the regulation of adipocyte endocrine function, and thus our metabolic response to the environment.", - "journal_title": "Best practice & research. Clinical endocrinology & metabolism", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/16311214/" - } - ], - "959e73bd-ac3b-437d-91b5-619b9d45aaca": [ - { - "pub_id": "18835935", - "title": "Genome-wide linkage scan in Gullah-speaking African American families with type 2 diabetes: the Sea Islands Genetic African American Registry (Project SuGAR).", - "authors": "Mich\u00e8le M Sale,Lingyi Lu,Ida J Spruill,Jyotika K Fernandes,Kerry H Lok,Jasmin Divers,Carl D Langefeld,W Timothy Garvey", - "abstract": "The Gullah-speaking African American population from the Sea Islands of South Carolina is characterized by a low degree of European admixture and high rates of type 2 diabetes and diabetic complications. Affected relative pairs with type 2 diabetes were recruited through the Sea Islands Genetic African American Registry (Project SuGAR). We conducted a genome-wide linkage scan, genotyping 5,974 single nucleotide polymorphisms in 471 affected subjects and 50 unaffected relatives from 197 pedigrees. Data were analyzed using a multipoint engine for rapid likelihood inference and ordered subsets analyses (OSAs) for age at type 2 diabetes diagnosis, waist circumference, waist-to-hip ratio, and BMI. We searched for heterogeneity and interactions using a conditional logistic regression likelihood approach. Linkage peaks on chromosome 14 at 123-124 cM were detected for type 2 diabetes (logarithm of odds [LOD] 2.10) and for the subset with later age at type 2 diabetes diagnosis (maximum LOD 4.05). Two linkage peaks on chromosome 7 were detected at 44-45 cM for type 2 diabetes (LOD 1.18) and at 78 cM for type 2 diabetes (LOD 1.64) and the subset with earlier age at type 2 diabetes diagnosis (maximum LOD 3.93). The chromosome 14 locus and a peak on 7p at 29.5 cM were identified as important in the multilocus model. Other regions that provided modest evidence for linkage included chromosome 1 at 167.5 cM (LOD 1.51) and chromosome 3 at 121.0 cM (LOD 1.61). This study revealed a novel type 2 diabetes locus in an African American population on 14q that appears to reduce age of disease onset and confirmed two loci on chromosome 7.", - "journal_title": "Diabetes", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/18835935/" - } - ], - "bad37687-51d8-4a3d-93f1-3a3e78e901e4": [ - { - "pub_id": "8790092", - "title": "Association of elevated serum lipid levels with retinal hard exudate in diabetic retinopathy. Early Treatment Diabetic Retinopathy Study (ETDRS) Report 22.", - "authors": "E Y Chew,M L Klein,F L Ferris,N A Remaley,R P Murphy,K Chantry,B J Hoogwerf,D Miller", - "abstract": "To evaluate the relationship between serum lipid levels, retinal hard exudate, and visual acuity in patients with diabetic retinopathy. Observational data from the Early Treatment Diabetic Retinopathy Study. Of the 3711 patients enrolled in the Early Treatment Diabetic Retinopathy Study, the first 2709 enrolled had serum lipid levels measured. Baseline fasting serum lipid levels, best-corrected visual acuity, and assessment of retinal thickening and hard exudate from stereoscopic macular photographs. Patients with elevated total serum cholesterol levels or serum low-density lipoprotein cholesterol levels at baseline were twice as likely to have retinal hard exudates as patients with normal levels. These patients were also at higher risk of developing hard exudate during the course of the study. The risk of losing visual acuity was associated with the extent of hard exudate even after adjusting for the extent of macular edema. These data demonstrate that elevated serum lipid levels are associated with an increased risk of retinal hard exudate in persons with diabetic retinopathy. Although retinal hard exudate usually accompanies diabetic macular edema, increasing amounts of exudate appear to be independently associated with an increased risk of visual impairment. Lowering elevated serum lipid levels has been shown to decrease the risk of cardiovascular morbidity. The observational data from the Early Treatment Diabetic Retinopathy Study suggest that lipid lowering may also decrease the risk of hard exudate formation and associated vision loss in patients with diabetic retinopathy. Preservation of vision may be an additional motivating factor for lowering serum lipid levels in persons with diabetic retinopathy and elevated serum lipid levels.", - "journal_title": "Archives of ophthalmology (Chicago, Ill. : 1960)", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/8790092/" - } - ], - "1a3856b6-260b-4980-b5be-548b6a0f556a": [ - { - "pub_id": "18612115", - "title": "Fetuin-A and incident diabetes mellitus in older persons.", - "authors": "Joachim H Ix,Christina L Wassel,Alka M Kanaya,Eric Vittinghoff,Karen C Johnson,Annemarie Koster,Jane A Cauley,Tamara B Harris,Steven R Cummings,Michael G Shlipak, ", - "abstract": "Fetuin-A is a hepatic secretory protein that binds the insulin receptor and inhibits insulin action in vitro. In prior cross-sectional studies in humans, higher fetuin-A levels were associated with insulin resistance. However, the longitudinal association of fetuin-A with incident type 2 diabetes mellitus is unknown. To determine whether fetuin-A levels are associated with incident diabetes in older persons. Observational study among 3075 well-functioning persons aged 70 to 79 years. In this case-cohort study, we retrospectively measured fetuin-A levels in baseline serum among 406 randomly selected participants without prevalent diabetes, and all participants who developed incident diabetes mellitus during a 6-year follow-up (to August 31, 2005). Incident diabetes mellitus. Incident diabetes developed in 135 participants (10.1 cases/1000 person-years). Participants with fetuin-A levels within the highest tertile (> 0.97 g/L) had an increased risk of incident diabetes (13.3 cases/1000 person-years) compared with participants in the lowest tertile (< or = 0.76 g/L) (6.5 cases/1000 person-years) in models adjusted for age, sex, race, waist circumference, body weight, physical activity, blood pressure level, fasting glucose level, high-density lipoprotein cholesterol concentration, triglyceride concentration, and C-reactive protein level (adjusted hazard ratio, 2.41; 95% confidence interval, 1.28-4.53; P = .007). The association was not affected by adipocytokine levels but was moderately attenuated by adjustment for visceral adiposity (adjusted hazard ratio of highest vs lowest tertile 1.72; 95% confidence interval, 0.98-3.05; P = .06). Among well-functioning older persons, serum fetuin-A is associated with incident diabetes, independent of other markers of insulin resistance.", - "journal_title": "JAMA", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/18612115/" - } - ], - "0f0c3b9e-4f25-4ed3-8fa1-77830bd51e96": [ - { - "pub_id": "11978629", - "title": "Genetic effects on age-dependent onset and islet cell autoantibody markers in type 1 diabetes.", - "authors": "Jinko Graham,William A Hagopian,Ingrid Kockum,Lou Sheng Li,Carani B Sanjeevi,Robert M Lowe,Jonathan B Schaefer,Marjan Zarghami,Heather L Day,Mona Landin-Olsson,Jerry P Palmer,Marta Janer-Villanueva,Leroy Hood,G\u00f6ran Sundkvist,Ake Lernmark,Norman Breslow,Gisela Dahlquist,G\u00f6ran Blohm\u00e9, , ", - "abstract": "Age-dependent associations between type 1 diabetes risk genes HLA, INS VNTR, and CTLA-4 and autoantibodies to GAD65 (GADAs), ICA512/IA-2, insulin, and islet cells were determined by logistic regression analysis in 971 incident patients with type 1 diabetes and 702 control subjects aged 0-34 years. GADAs were associated with HLA-DQ2 in young but not in older patients (P = 0.009). Autoantibodies to insulin were negatively associated with age (P < 0.0001) but positively associated with DQ8 (P = 0.03) and with INS VNTR (P = 0.04), supporting possible immune tolerance induction. ICA512/IA-2 were negatively associated with age (P < 0.0001) and with DQ2 (P < 0.0001) but positively associated with DQ8 (P = 0.04). Males were more likely than females to be negative for GADA (P < 0.0001), autoantibodies to islet cells (P = 0.04), and all four autoantibody markers (P = 0.004). The CTLA-4 3' end microsatellite marker was not associated with any of the autoantibodies. We conclude that age and genetic factors such as HLA-DQ and INS VNTR need to be combined with islet autoantibody markers when evaluating the risk for type 1 diabetes development.", - "journal_title": "Diabetes", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/11978629/" - } - ], - "632a479d-470e-487c-aec9-2224ac78f19c": [ - { - "pub_id": "7619101", - "title": "The Wisconsin Epidemiologic Study of diabetic retinopathy. XIV. Ten-year incidence and progression of diabetic retinopathy.", - "authors": "R Klein,B E Klein,S E Moss,K J Cruickshanks", - "abstract": "To examine the 10-year incidence and progression of diabetic retinopathy. Population-based incidence study. Seven hundred sixty-five insulin-taking diabetic persons diagnosed before age 30 years, 251 insulin-taking diabetic persons diagnosed at age 30 years or older, and 282 non-insulin-taking diabetic persons diagnosed at age 30 years or older who participated in baseline, 4-year, and 10-year follow-up examinations. The 10-year incidence of any retinopathy, progression of retinopathy, and progression to proliferative retinopathy were detected by masked grading of stereoscopic color fundus photographs using the modified Airlie House classification and the Early Treatment Diabetic Retinopathy Study severity scheme. The 10-year incidence of retinopathy (89%, 79%, and 67%), progression of retinopathy (76%, 69%, and 53%), and progression to proliferative retinopathy (30%, 24%, and 10%) were highest in the group diagnosed before age 30 years, intermediate in the insulin-taking group diagnosed at age 30 years or older, and lowest in the non-insulin-taking group, respectively. Increased risk of proliferative retinopathy was associated with more severe retinopathy at baseline. These data suggest relatively high 10-year rates of incidence and progression of retinopathy, and despite changes in the treatment of diabetes, there has been little change in the incidence and progression of diabetic retinopathy during the 10-year study period.", - "journal_title": "Archives of ophthalmology (Chicago, Ill. : 1960)", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/7619101/" - } - ], - "2eba20bf-94fe-4dd1-bed4-ade71dacd0d0": [ - { - "pub_id": "18252895", - "title": "HLA DR-DQ haplotypes and genotypes and type 1 diabetes risk: analysis of the type 1 diabetes genetics consortium families.", - "authors": "Henry Erlich,Ana Maria Valdes,Janelle Noble,Joyce A Carlson,Mike Varney,Pat Concannon,Josyf C Mychaleckyj,John A Todd,Persia Bonella,Anna Lisa Fear,Eva Lavant,Anthony Louey,Priscilla Moonsamy, ", - "abstract": "The Type 1 Diabetes Genetics Consortium has collected type 1 diabetic families worldwide for genetic analysis. The major genetic determinants of type 1 diabetes are alleles at the HLA-DRB1 and DQB1 loci, with both susceptible and protective DR-DQ haplotypes present in all human populations. The aim of this study is to estimate the risk conferred by specific DR-DQ haplotypes and genotypes. Six hundred and seven Caucasian families and 38 Asian families were typed at high resolution for the DRB1, DQA1, and DQB1 loci. The association analysis was performed by comparing the frequency of DR-DQ haplotypes among the chromosomes transmitted to an affected child with the frequency of chromosomes not transmitted to any affected child. A number of susceptible, neutral, and protective DR-DQ haplotypes have been identified, and a statistically significant hierarchy of type 1 diabetes risk has been established. The most susceptible haplotypes are the DRB1*0301-DQA1*0501-DQB1*0201 (odds ratio [OR] 3.64) and the DRB1*0405-DQA1*0301-DQB1*0302, DRB1*0401-DQA1*0301-DQB*0302, and DRB1*0402-DQA1*0301-DQB1*0302 haplotypes (ORs 11.37, 8.39, and 3.63), followed by the DRB1*0404-DQA1*0301-DQB1*0302 (OR 1.59) and the DRB1*0801-DQB1*0401-DQB1*0402 (OR 1.25) haplotypes. The most protective haplotypes are DRB1*1501-DQA1*0102-DQB1*0602 (OR 0.03), DRB1*1401-DQA1*0101-DQB1*0503 (OR 0.02), and DRB1*0701-DQA1*0201-DQB1*0303 (OR 0.02). Specific combinations of alleles at the DRB1, DQA1, and DQB1 loci determine the extent of haplotypic risk. The comparison of closely related DR-DQ haplotype pairs with different type 1 diabetes risks allowed identification of specific amino acid positions critical in determining disease susceptibility. These data also indicate that the risk associated with specific HLA haplotypes can be influenced by the genotype context and that the trans-complementing heterodimer encoded by DQA1*0501 and DQB1*0302 confers very high risk.", - "journal_title": "Diabetes", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/18252895/" - } - ], - "3675ae2a-18d5-4f2b-97e1-1827eddc0f6f": [ - { - "pub_id": "18711367", - "title": "Variants in KCNQ1 are associated with susceptibility to type 2 diabetes mellitus.", - "authors": "Kazuki Yasuda,Kazuaki Miyake,Yukio Horikawa,Kazuo Hara,Haruhiko Osawa,Hiroto Furuta,Yushi Hirota,Hiroyuki Mori,Anna Jonsson,Yoshifumi Sato,Kazuya Yamagata,Yoshinori Hinokio,He-Yao Wang,Toshihito Tanahashi,Naoto Nakamura,Yoshitomo Oka,Naoko Iwasaki,Yasuhiko Iwamoto,Yuichiro Yamada,Yutaka Seino,Hiroshi Maegawa,Atsunori Kashiwagi,Jun Takeda,Eiichi Maeda,Hyoung Doo Shin,Young Min Cho,Kyong Soo Park,Hong Kyu Lee,Maggie C Y Ng,Ronald C W Ma,Wing-Yee So,Juliana C N Chan,Valeriya Lyssenko,Tiinamaija Tuomi,Peter Nilsson,Leif Groop,Naoyuki Kamatani,Akihiro Sekine,Yusuke Nakamura,Ken Yamamoto,Teruhiko Yoshida,Katsushi Tokunaga,Mitsuo Itakura,Hideichi Makino,Kishio Nanjo,Takashi Kadowaki,Masato Kasuga", - "abstract": "We carried out a multistage genome-wide association study of type 2 diabetes mellitus in Japanese individuals, with a total of 1,612 cases and 1,424 controls and 100,000 SNPs. The most significant association was obtained with SNPs in KCNQ1, and dense mapping within the gene revealed that rs2237892 in intron 15 showed the lowest Pvalue (6.7 x 10(-13), odds ratio (OR) = 1.49). The association of KCNQ1 with type 2 diabetes was replicated in populations of Korean, Chinese and European ancestry as well as in two independent Japanese populations, and meta-analysis with a total of 19,930 individuals (9,569 cases and 10,361 controls) yielded a P value of 1.7 x 10(-42) (OR = 1.40; 95% CI = 1.34-1.47) for rs2237892. Among control subjects, the risk allele of this polymorphism was associated with impairment of insulin secretion according to the homeostasis model assessment of beta-cell function or the corrected insulin response. Our data thus implicate KCNQ1 as a diabetes susceptibility gene in groups of different ancestries.", - "journal_title": "Nature genetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/18711367/" - } - ], - "dfdd2573-3dba-45bb-9606-aa28f0405c99": [ - { - "pub_id": "16760222", - "title": "Isomers of the TCF1 gene encoding hepatocyte nuclear factor-1 alpha show differential expression in the pancreas and define the relationship between mutation position and clinical phenotype in monogenic diabetes.", - "authors": "Lorna W Harries,Sian Ellard,Amanda Stride,Noel G Morgan,Andrew T Hattersley", - "abstract": "The generation of multiple transcripts by mRNA processing has the potential to moderate differences in gene expression both between tissues and at different stages of development. Where gene function is compromised by mutation, the presence of multiple isoforms may influence the resulting phenotype. Heterozygous mutations in the transcription factor hepatocyte nuclear factor-1 alpha (HNF1A or TCF1 gene) result in early-onset diabetes as a result of pancreatic beta-cell dysfunction. We investigated the expression of the three alternatively processed isoforms of the HNF1A gene and their impact on the phenotype associated with mutations. Real-time PCR demonstrated variation in tissue expression of HNF1A isomers: HNF1A(A), with the lowest transactivation activity compared with the truncated isoforms HNF1A(B) and HNF1A(C), is the major isomer in liver (54%) and kidney (67%) but not in adult pancreas (24%) and islets (26%). However, in fetal pancreas HNF1A(A) is the major transcript (84%), which supports developmental regulation of isomer expression. We examined whether the isomers affected by the mutation altered the diabetes phenotype in 564 subjects with 123 mutations in HNF1A. Mutations that affected only isomer HNF1A(A) (exons 8-10) were diagnosed later (25.5 years) than mutations affecting all three isomers (exons 1-6) (18.0 years) (P=0.006). This first genotype/phenotype relationship described for patients with HNF1A mutations is explained by isomer structure and not by either mutation type or functional domain. We conclude that all three isomers may be critical for beta-cell function and could play a role in both the developing and mature beta cell.", - "journal_title": "Human molecular genetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/16760222/" - } - ], - "cbc03a11-fe9c-4b54-b290-bd24c1447607": [ - { - "pub_id": "17634522", - "title": "Summary of the American Heart Association's scientific statement on the relevance of genetics and genomics for prevention and treatment of cardiovascular disease.", - "authors": "Donna K Arnett, ", - "abstract": "", - "journal_title": "Arteriosclerosis, thrombosis, and vascular biology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/17634522/" - } - ], - "d9936dc6-ff6e-47a1-b89c-0138526ede6f": [ - { - "pub_id": "12943464", - "title": "Haplotypes and the systematic analysis of genetic variation in genes and genomes.", - "authors": "Margret R Hoehe", - "abstract": "Haplotypes have been used in various fields of genetics for a long time, in a variety of contexts, and for different purposes. Now, haplotype-based approaches to the analysis of candidate genes and genome-wide linkage disequilibrium (LD) mapping have gained center stage. It is time to explicitly distinguish the different concepts implied in the present haplotype approaches: haplotypes are not haplotypes, after all. The distinction of three different categories, ancestral, common haplotypes or haplotype blocks, gene-based haplotypes as complex genetic markers and gene-based functional haplotypes, is proposed. These categories serve as framework to review and analyze in particular the recent work suggesting evidence for a haplotype block structure of the human genome and the body of comparative sequencing studies addressing haplotype and LD structures at the gene level. Haplotype approaches will be evaluated along the dimensions preselection of variants versus complete DNA sequence information, role of LD and stages in the process of disease gene identification. Overall, the content of haplotypes is conceived as a function of available technologies to evaluate genetic variation and general advances in human genome research.", - "journal_title": "Pharmacogenomics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/12943464/" - } - ], - "b35f15cd-ed5d-4aae-a948-92c4f847c661": [ - { - "pub_id": "15458446", - "title": "A genome scan for diabetic nephropathy in African Americans.", - "authors": "Donald W Bowden,Carla J Colicigno,Carl D Langefeld,Mich\u00e8le M Sale,Adrienne Williams,Pamela J Anderson,Stephen S Rich,Barry I Freedman", - "abstract": "There is substantial evidence for a genetic contribution to diabetic nephropathy susceptibility in the African American population, but little is known about location or identity of susceptibility genes. DNA samples were collected from 206 type 2 diabetes (T2DM) and end-stage renal disease (ESRD)/nephropathy-affected sib pairs from 166 African American families (355 affected individuals). A genome scan was performed and data analyzed using nonparametric linkage regression (NPLR) analysis and ordered subsets analysis (OSA) methods. In initial NPLR analyses no logarithm of odds (LOD) scores >2.0 were observed. Four loci had LOD scores > or =1.0, with LOD = 1.43 at 29 cM on chromosome 7p the highest. NPLR analyses of multilocus interactions detected 6 loci (7p, 12p, 14q, 16p, 18q, and 21q) with LOD scores 1.15 to 1.63. NPLR analyses evaluating phenotypic interactions revealed multiple locations with evidence (P < 0.05) for interactions with age-at-onset of ESRD (9 loci), duration of diabetes before onset of ESRD (19 loci), and age-at-onset of diabetes (14 loci). Several loci identified by NPLR analyses were also identified using OSA. OSA revealed evidence for a nephropathy locus at 135 cM on chromosome 3 in an estimated 29% of the families (LOD = 4.55 in the optimal subset). Additional linkage evidence, LOD = 3.59, was observed on chromosome 7p (37% of the families, longer duration of diabetes prior to diagnosis of ESRD), and 18q (max. LOD = 3.72; 64% of the families, early diabetes diagnosis). The 7p linkage has been observed in a recent genome scan of African American type 2 diabetes. This first genome scan of diabetic nephropathy in African Americans reveals evidence for susceptibility loci on chromosomes 3q, 7p, and 18q. The 7p locus may represent a type 2 diabetes susceptibility locus.", - "journal_title": "Kidney international", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/15458446/" - } - ], - "43a455aa-e353-43ad-afc2-c6e0caaf180c": [ - { - "pub_id": "12493003", - "title": "Single nucleotide polymorphisms in innate immunity genes: abundant variation and potential role in complex human disease.", - "authors": "Ross Lazarus,Donata Vercelli,Lyle J Palmer,Walt J Klimecki,Edwin K Silverman,Brent Richter,Alberto Riva,Marco Ramoni,Fernando D Martinez,Scott T Weiss,David J Kwiatkowski", - "abstract": "Under selective pressure from infectious microorganisms, multicellular organisms have evolved immunological defense mechanisms, broadly categorized as innate or adaptive. Recent insights into the complex mechanisms of human innate immunity suggest that genetic variability in genes encoding its components may play a role in the development of asthma and related diseases. As part of a systematic assessment of genetic variability in innate immunity genes, we have thus far have examined 16 genes by resequencing 93 unrelated subjects from three ethnic samples (European American, African American and Hispanic American) and a sample of European American asthmatics. Approaches to discovering and understanding variation and the subsequent implementation of disease association studies are described and illustrated. Although highly conserved across a wide range of species, the innate immune genes we have sequenced demonstrate substantial interindividual variability predominantly in the form of single nucleotide polymorphisms (SNPs). Genetic variation in these genes may play a role in determining susceptibility to a range of common, chronic human diseases which have an inflammatory component. Differences in population history have produced distinctive patterns of SNP allele frequencies, linkage disequilibrium and haplotypes when ethnic groups are compared. These and other factors must be taken into account in the design and analysis of disease association studies.", - "journal_title": "Immunological reviews", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/12493003/" - } - ], - "b694f2dc-cee2-4eb7-b779-be963714486c": [ - { - "pub_id": "18614244", - "title": "The Biomaterialbank of the German Competence Network of Heart Failure (CNHF) is a valuable resource for biomedical and genetic research.", - "authors": "Maximilian G Posch,G\u00f6tz Gelbrich,Burkert Pieske,Elke Lehmkuhl,Christiane E Angermann,Stefan St\u00f6rk,Till Neumann,Hans-Dirk D\u00fcngen,Thomas Scheffold,Thomas M\u00fcller-Tasch,Bernhard Maisch,Mathias Rauchhaus,Rainer Dietz,Cemil Ozcelik, ", - "abstract": "Genetic research on heart failure (HF) requires large cohorts of well-phenotyped patients. The German Competence Network of Heart Failure (CNHF) organized a biobank in 2004 to supply the necessary infrastructure and standard operating procedures (SOPs) for a centralized collection of blood specimen. We centralized data and collected serum, plasma and DNA of well characterized HF subjects all over Germany. Different pseudonyms were created automatically to address data safety and other concerns about privacy. Thus far, we have collected 85,000 sample specimen from 9,500 prospectively evaluated patients with HF. Detailed medical data were prospectively acquired together with corresponding blood samples. In 2008 clinician-scientists can apply for access to the material. Our biobank represents a major facet of the CNHF and has already documented research and clinical utility.", - "journal_title": "International journal of cardiology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/18614244/" - } - ], - "ed1a5572-124a-4824-8b9c-5a540e5d6092": [ - { - "pub_id": "10779485", - "title": "Congenic mapping of the type 1 diabetes locus, Idd3, to a 780-kb region of mouse chromosome 3: identification of a candidate segment of ancestral DNA by haplotype mapping.", - "authors": "P A Lyons,N Armitage,F Argentina,P Denny,N J Hill,C J Lord,M B Wilusz,L B Peterson,L S Wicker,J A Todd", - "abstract": "Type 1 diabetes in the nonobese diabetic (NOD) mouse arises as a consequence of T cell-mediated destruction of the insulin-producing beta cells of the pancreas. Although little is known of the events that initiate and subsequently drive beta-cell destruction it is clear that the entire process is under complex genetic control. At present 19 loci have been mapped that influence the development of diabetes either at the level of initiation of insulitis or at the level of progression from insulitis to overt diabetes, or both. Previously, we have mapped one of these loci, Idd3, to a 0.35-cM interval on proximal mouse chromosome 3. In the present study we have narrowed the map position of this locus to an interval of 0.15 cM by a combination of novel congenic strains and an ancestral haplotype analysis approach. We have constructed a physical contig in bacterial artificial chromosome (BAC) clones across the minimal interval. Restriction mapping of the BAC contig placed the maximum size of the Idd3 interval at 780 kb between the markers D3Nds36 and D3Nds76. To refine further the Idd3 interval we developed a series of novel single nucleotide polymorphisms (SNPs) and carried out haplotype analysis on DNA from mouse strains known to carry either Idd3 susceptibility or protective alleles. This haplotype analysis identified a 145-kb segment of ancestral DNA between the microsatellite marker D3Nds6 and the SNP 81.3. One haplotype of this ancestral segment of DNA is found in mouse strains carrying an Idd3 susceptibility allele and another is found in mouse strains carrying an Idd3 protective allelle. Within the 780-kb congenically defined interval this 145-kb segment represents the most likely location for Idd3. The Il2 gene, which encodes the cytokine interleukin 2 (IL2), maps to this interval and is a strong candidate for Idd3. To investigate whether sequence variation exists in the promoter region of the Il2 gene, which might alter its expression, we sequenced the promoter region of the Il2 gene from mouse strains carrying either an Idd3 susceptibility or resistance allele. Two sequence variants were identified, neither of which fell in known regulatory elements within the Il2 promoter. In agreement with this observation steady-state Il2 mRNA levels showed no variation between susceptible and resistant mouse strains. These data suggest that the profound protection from diabetes seen in congenic mice carrying an Idd3 protective allele is unlikely to be due to differences in the level of expression of the Il2 gene. Instead, all of the current data support our hypothesis that Idd3 corresponds to amino acid variation at the amino terminus of Il2.", - "journal_title": "Genome research", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/10779485/" - } - ], - "0975edbc-0f57-495e-bc6d-f214e2d354d7": [ - { - "pub_id": "17947991", - "title": "Designing candidate gene and genome-wide case-control association studies.", - "authors": "Krina T Zondervan,Lon R Cardon", - "abstract": "This protocol describes how to appropriately design a genetic association case-control study, either focusing on a candidate gene (CG) or region or implementing a genome-wide approach. The steps described involve: (i) defining the case phenotype in adequate detail; (ii) checking the heritability of the disease in question; (iii) considering whether a population-based study is the appropriate design for the research question; (iv) the appropriate selection of controls; (v) sample size calculations and (vi) giving due consideration to whether it is a de novo or replication study. General guidelines are given, as well as specific examples of a CG and a genome-wide association study into type 2 diabetes. Software and websites used in this protocol include the International HapMap Consortium website, Genetic Power Calculator, CaT, and SNPSpD. Running each of the programs takes only a few seconds; the rate-limiting steps involve thinking through the designs and parameters in the disease models.", - "journal_title": "Nature protocols", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/17947991/" - } - ], - "2115ca11-44ee-4043-96ce-5347aba23a2d": [ - { - "pub_id": "15634032", - "title": "Pharmacokinetics and pharmacodynamics of systemically administered glucocorticoids.", - "authors": "David Czock,Frieder Keller,Franz Maximilian Rasche,Ulla H\u00e4ussler", - "abstract": "Glucocorticoids have pleiotropic effects that are used to treat diverse diseases such as asthma, rheumatoid arthritis, systemic lupus erythematosus and acute kidney transplant rejection. The most commonly used systemic glucocorticoids are hydrocortisone, prednisolone, methylprednisolone and dexamethasone. These glucocorticoids have good oral bioavailability and are eliminated mainly by hepatic metabolism and renal excretion of the metabolites. Plasma concentrations follow a biexponential pattern. Two-compartment models are used after intravenous administration, but one-compartment models are sufficient after oral administration.The effects of glucocorticoids are mediated by genomic and possibly nongenomic mechanisms. Genomic mechanisms include activation of the cytosolic glucocorticoid receptor that leads to activation or repression of protein synthesis, including cytokines, chemokines, inflammatory enzymes and adhesion molecules. Thus, inflammation and immune response mechanisms may be modified. Nongenomic mechanisms might play an additional role in glucocorticoid pulse therapy. Clinical efficacy depends on glucocorticoid pharmacokinetics and pharmacodynamics. Pharmacokinetic parameters such as the elimination half-life, and pharmacodynamic parameters such as the concentration producing the half-maximal effect, determine the duration and intensity of glucocorticoid effects. The special contribution of either of these can be distinguished with pharmacokinetic/pharmacodynamic analysis. We performed simulations with a pharmacokinetic/pharmacodynamic model using T helper cell counts and endogenous cortisol as biomarkers for the effects of methylprednisolone. These simulations suggest that the clinical efficacy of low-dose glucocorticoid regimens might be increased with twice-daily glucocorticoid administration.", - "journal_title": "Clinical pharmacokinetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/15634032/" - } - ], - "220633f9-c069-4085-a424-ef49dc9fa889": [ - { - "pub_id": "18221114", - "title": "Genotyping OLR1 gene: a genomic biomarker for cardiovascular diseases.", - "authors": "Lucia Vecchione,Elisa Gargiul,Paola Borgiani,Irene Predazzi,Ruggiero Mango,Francesco Romeo,Mauro Magnani,Giuseppe Novelli", - "abstract": "The human lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1), encoded by the OLR1 gene, is a scavenger receptor that has been implicated in the pathogenesis of atherosclerosis. LOX-1 activation is an important mechanism that contributes to plaque instability and subsequent development of acute coronary syndromes. Association studies have implicated OLR1 gene variants in myocardial infarction (MI) susceptibility. In particular, previously we demonstrated that intronic SNPs associated to susceptibility to myocardial infarction, regulate the expression of a new functional splicing isoform of the OLR1 gene, called LOXIN. The ratio OLR1/LOXIN mRNA is increased in subjects carrying the risk haplotype. On this basis, we developed a genetic kit named \"LOXIN test\" that allows the rapid identification of ORL1 genotypes and therefore establish the susceptibility risk to atherosclerosis and myocardial infarction. The recent patents related to OLR1, SNPs and LOXIN are also discussed in this article.", - "journal_title": "Recent patents on cardiovascular drug discovery", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/18221114/" - } - ], - "2420b221-94fa-40ac-8bfd-55e90d7c1c23": [ - { - "pub_id": "11423863", - "title": "The genetics of atopic dermatitis: strategies, candidate genes, and genome screens.", - "authors": "W O Cookson", - "abstract": "", - "journal_title": "Journal of the American Academy of Dermatology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/11423863/" - } - ], - "70667239-7e12-494f-a6dd-5b1d073b5a56": [ - { - "pub_id": "8816980", - "title": "IDDM2-VNTR-encoded susceptibility to type 1 diabetes: dominant protection and parental transmission of alleles of the insulin gene-linked minisatellite locus.", - "authors": "S T Bennett,A J Wilson,F Cucca,J Nerup,F Pociot,P A McKinney,A H Barnett,S C Bain,J A Todd", - "abstract": "IDDM2-encoded predisposition to type 1 diabetes has recently been mapped to the minisatellite or variable number of tandem repeat (VNTR) locus upstream of the insulin and insulin-like growth factor II genes on human chromosome 11p15.5. In a UK case-control study (n = 228 sporadic diabetics; n = 441 healthy controls), we show here that the genotype homozygous for VNTR class I alleles is predisposing to disease (RR = 2.68), and VNTR class III alleles are dominantly protective (RR = 0.37). In 722 diabetic families from the UK (n = 356), USA (n = 173), Denmark (n = 55) and Sardinia (n = 138), we have analysed the transmission of class I alleles to diabetic offspring from class I/III heterozygous parents. We confirm that in families from the USA, class I alleles are transmitted preferentially from fathers. However, in family data sets from the UK, Denmark and Sardinia, the reverse is true and maternal transmission is stronger. Furthermore, in the UK family data set, the difference between maternal and paternal transmissions is significant (P < 0.05). It is therefore unlikely that 'maternal imprinting' alone explains the parent-of-origin effects in IDDM2-encoded predisposition to type 1 diabetes, at least not in the UK. There is a relationship between VNTR class (allele length) and insulin gene expression, though some results from different studies are conflicting. In the human adult cadaveric pancreas, we confirm our preliminary results that class III alleles are associated with lower levels of insulin mRNA in vivo. Similar results have been obtained independently in human foetal pancreas samples. It is difficult to explain how these marginally lower levels of insulin expression could account for the observed VNTR class III-encoded protective effect. Perhaps the site of action of IDDM2, mediated by VNTR allelic variation, is not the pancreas but some other organ such as the thymus.", - "journal_title": "Journal of autoimmunity", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/8816980/" - } - ], - "0bcb68e6-4da3-457c-a68c-981b14d1ded8": [ - { - "pub_id": "19574059", - "title": "Genome-wide association studies in type 1 diabetes, inflammatory bowel disease and other immune-mediated disorders.", - "authors": "Hakon Hakonarson,Struan F A Grant", - "abstract": "Genome-wide association studies have delivered on the promise of uncovering genetic determinants of complex disease. In this review, we provide a summary of recent advances in the identification of multiple variants associated with autoimmune-mediated disorders; specifically type 1 diabetes and inflammatory bowel disease. Sixteen loci, all replicated in independent samples, have now been uncovered for type 1 diabetes and in excess of 40 for inflammatory bowel disease. The next steps are to identify the true causal variants underlying evidence of disease association and to leverage this information to improve diagnosis, prevention and cure of these diseases.", - "journal_title": "Seminars in immunology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/19574059/" - } - ], - "cacb086c-b42f-4cef-b4a2-4720a86fc6b5": [ - { - "pub_id": "20103712", - "title": "A genome-wide association study of treated A1C: a genetic needle in an environmental haystack?", - "authors": "Jose C Florez", - "abstract": "", - "journal_title": "Diabetes", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/20103712/" - } - ], - "1c2f4eb9-5880-418a-be08-4c33ec3a8889": [ - { - "pub_id": "18372903", - "title": "Meta-analysis of genome-wide association data and large-scale replication identifies additional susceptibility loci for type 2 diabetes.", - "authors": "Eleftheria Zeggini,Laura J Scott,Richa Saxena,Benjamin F Voight,Jonathan L Marchini,Tianle Hu,Paul I W de Bakker,Gon\u00e7alo R Abecasis,Peter Almgren,Gitte Andersen,Kristin Ardlie,Kristina Bengtsson Bostr\u00f6m,Richard N Bergman,Lori L Bonnycastle,Knut Borch-Johnsen,No\u00ebl P Burtt,Hong Chen,Peter S Chines,Mark J Daly,Parimal Deodhar,Chia-Jen Ding,Alex S F Doney,William L Duren,Katherine S Elliott,Michael R Erdos,Timothy M Frayling,Rachel M Freathy,Lauren Gianniny,Harald Grallert,Niels Grarup,Christopher J Groves,Candace Guiducci,Torben Hansen,Christian Herder,Graham A Hitman,Thomas E Hughes,Bo Isomaa,Anne U Jackson,Torben J\u00f8rgensen,Augustine Kong,Kari Kubalanza,Finny G Kuruvilla,Johanna Kuusisto,Claudia Langenberg,Hana Lango,Torsten Lauritzen,Yun Li,Cecilia M Lindgren,Valeriya Lyssenko,Amanda F Marvelle,Christa Meisinger,Kristian Midthjell,Karen L Mohlke,Mario A Morken,Andrew D Morris,Narisu Narisu,Peter Nilsson,Katharine R Owen,Colin N A Palmer,Felicity Payne,John R B Perry,Elin Pettersen,Carl Platou,Inga Prokopenko,Lu Qi,Li Qin,Nigel W Rayner,Matthew Rees,Jeffrey J Roix,Anelli Sandbaek,Beverley Shields,Marketa Sj\u00f6gren,Valgerdur Steinthorsdottir,Heather M Stringham,Amy J Swift,Gudmar Thorleifsson,Unnur Thorsteinsdottir,Nicholas J Timpson,Tiinamaija Tuomi,Jaakko Tuomilehto,Mark Walker,Richard M Watanabe,Michael N Weedon,Cristen J Willer, ,Thomas Illig,Kristian Hveem,Frank B Hu,Markku Laakso,Kari Stefansson,Oluf Pedersen,Nicholas J Wareham,In\u00eas Barroso,Andrew T Hattersley,Francis S Collins,Leif Groop,Mark I McCarthy,Michael Boehnke,David Altshuler", - "abstract": "Genome-wide association (GWA) studies have identified multiple loci at which common variants modestly but reproducibly influence risk of type 2 diabetes (T2D). Established associations to common and rare variants explain only a small proportion of the heritability of T2D. As previously published analyses had limited power to identify variants with modest effects, we carried out meta-analysis of three T2D GWA scans comprising 10,128 individuals of European descent and approximately 2.2 million SNPs (directly genotyped and imputed), followed by replication testing in an independent sample with an effective sample size of up to 53,975. We detected at least six previously unknown loci with robust evidence for association, including the JAZF1 (P = 5.0 x 10(-14)), CDC123-CAMK1D (P = 1.2 x 10(-10)), TSPAN8-LGR5 (P = 1.1 x 10(-9)), THADA (P = 1.1 x 10(-9)), ADAMTS9 (P = 1.2 x 10(-8)) and NOTCH2 (P = 4.1 x 10(-8)) gene regions. Our results illustrate the value of large discovery and follow-up samples for gaining further insights into the inherited basis of T2D.", - "journal_title": "Nature genetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/18372903/" - } - ], - "f8be7949-8fa0-4730-9143-caa6161bf463": [ - { - "pub_id": "16174701", - "title": "Realizing the promise of genomics in biomedical research.", - "authors": "Alan E Guttmacher,Francis S Collins", - "abstract": "", - "journal_title": "JAMA", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/16174701/" - } - ], - "0c892795-2bbf-4305-a7fb-e86b54f0d6df": [ - { - "pub_id": "15472205", - "title": "Significant association of the interleukin-6 gene polymorphisms C-174G and A-598G with type 2 diabetes.", - "authors": "T Illig,F Bongardt,A Sch\u00f6pfer,S M\u00fcller-Scholze,W Rathmann,W Koenig,B Thorand,C Vollmert,R Holle,H Kolb,C Herder, ", - "abstract": "Elevated blood concentrations of IL-6 have been shown to predict type 2 diabetes. Because the impact of IL-6 gene polymorphisms on diabetes status, parameters of the metabolic syndrome, and low-grade systemic inflammation has not been analyzed in a population-based study, we investigated the association of the IL-6 single nucleotide polymorphisms C-174G and A-598G on these parameters in 704 elderly participants of the Kooperative Gesundheitsforschung im Raum Augsburg/Cooperative Research in the Region of Augsburg (KORA) Survey 2000. Both -174G and -598G alleles were significantly associated with type 2 diabetes (-174G: odds ratio = 1.51, 95% confidence interval = 1.11-2.07, P = 0.0096; -598G: odds ratio = 1.56, 95% confidence interval = 1.13-2.15, P = 0.0069) but not with impaired glucose tolerance. In subgroup analyses, the association reached statistical significance in men and in leaner subjects (body mass index <or= 28.7 kg/m(2), i.e. study median) but not in women or more obese persons. Circulating IL-6 levels were not associated with the IL-6 polymorphisms, but significantly elevated levels of the chemokine monocyte chemoattractant protein-1/CC chemokine ligand 2 in carriers of the protective genotypes indicated an indirect effect of these single nucleotide polymorphisms on the innate immune system. Our findings confirm that immune gene polymorphisms can be considered as independent risk factors in the etiology of type 2 diabetes and suggest that their contribution may be indirect, by influencing the levels of other immune mediators like monocyte chemoattractant protein-1.", - "journal_title": "The Journal of clinical endocrinology and metabolism", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/15472205/" - } - ], - "5dbfad5b-73a3-4843-a230-1071adb296c4": [ - { - "pub_id": "18177782", - "title": "Recommended methods for determining responsiveness and minimally important differences for patient-reported outcomes.", - "authors": "Dennis Revicki,Ron D Hays,David Cella,Jeff Sloan", - "abstract": "The objective of this review is to summarize recommendations on methods for evaluating responsiveness and minimal important difference (MID) for patient-reported outcome (PRO) measures. We review, summarize, and integrate information on issues and methods for evaluating responsiveness and determining MID estimates for PRO measures. Recommendations are made on best-practice methods for evaluating responsiveness and MID. The MID for a PRO instrument is not an immutable characteristic, but may vary by population and context, and no one MID may be valid for all study applications. MID estimates should be based on multiple approaches and triangulation of methods. Anchor-based methods applying various relevant patient-rated, clinician-rated, and disease-specific variables provide primary and meaningful estimates of an instrument's MID. Results for the PRO measures from clinical trials can also provide insight into observed effects based on treatment comparisons and should be used to help determine MID. Distribution-based methods can support estimates from anchor-based approaches and can be used in situations where anchor-based estimates are unavailable. We recommend that the MID is based primarily on relevant patient-based and clinical anchors, with clinical trial experience used to further inform understanding of MID.", - "journal_title": "Journal of clinical epidemiology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/18177782/" - } - ], - "f9a2ab0b-4c01-4eae-97a2-e25fea69e1d5": [ - { - "pub_id": "17205963", - "title": "A leucine repeat in the carnosinase gene CNDP1 is associated with diabetic end-stage renal disease in European Americans.", - "authors": "Barry I Freedman,Pamela J Hicks,Michele M Sale,Eric D Pierson,Carl D Langefeld,Stephen S Rich,Jianzhao Xu,Caitrin McDonough,Bart Janssen,Benito A Yard,Fokko J van der Woude,Donald W Bowden", - "abstract": "Four linkage analyses have identified a region on chromosome 18q22-23 that appears to harbour a diabetic nephropathy (DN) susceptibility locus. A trinucleotide repeat sequence in exon 2 of the carnosinase gene (CNDP1) residing on 18q22.3 was subsequently associated with DN in European Caucasians and Arabs. We evaluated the role of the CNDP1 5 leucine/5 leucine (5-5) polymorphism (CNDP1 Mannheim) in diabetic end-stage renal disease (ESRD) susceptibility in 858 European Americans: 294 with type 2 DN-associated ESRD (DN-ESRD), 258 with diabetes mellitus (DM) lacking nephropathy and 306 healthy controls. Subjects with DM lacking nephropathy were significantly more likely to be homozygous for the 5-leucine repeat CNDP1 genotype (5-5), compared with those with DN-ESRD (P=0.02). Healthy controls were also more likely to be homozygous for the 5-5 genotype, compared with those with DN-ESRD (P=0.008). No significant difference in 5-5 genotype frequency was observed between healthy controls and DM cases without nephropathy (P=0.74). European Americans homozygous for the 5-5 leucine repeat polymorphism in the CNDP1 gene are at significantly reduced risk for developing diabetic ESRD. This replicates the CNDP1 gene association with DN that was initially detected in European Caucasians and in Arabs, and further demonstrates that the CNDP1 gene and carnosine pathway appear to play a role in susceptibility to DN.", - "journal_title": "Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/17205963/" - } - ], - "a49c4251-7a66-44f1-9f95-0d6e8191a2ad": [ - { - "pub_id": "17463249", - "title": "Replication of genome-wide association signals in UK samples reveals risk loci for type 2 diabetes.", - "authors": "Eleftheria Zeggini,Michael N Weedon,Cecilia M Lindgren,Timothy M Frayling,Katherine S Elliott,Hana Lango,Nicholas J Timpson,John R B Perry,Nigel W Rayner,Rachel M Freathy,Jeffrey C Barrett,Beverley Shields,Andrew P Morris,Sian Ellard,Christopher J Groves,Lorna W Harries,Jonathan L Marchini,Katharine R Owen,Beatrice Knight,Lon R Cardon,Mark Walker,Graham A Hitman,Andrew D Morris,Alex S F Doney, ,Mark I McCarthy,Andrew T Hattersley", - "abstract": "The molecular mechanisms involved in the development of type 2 diabetes are poorly understood. Starting from genome-wide genotype data for 1924 diabetic cases and 2938 population controls generated by the Wellcome Trust Case Control Consortium, we set out to detect replicated diabetes association signals through analysis of 3757 additional cases and 5346 controls and by integration of our findings with equivalent data from other international consortia. We detected diabetes susceptibility loci in and around the genes CDKAL1, CDKN2A/CDKN2B, and IGF2BP2 and confirmed the recently described associations at HHEX/IDE and SLC30A8. Our findings provide insight into the genetic architecture of type 2 diabetes, emphasizing the contribution of multiple variants of modest effect. The regions identified underscore the importance of pathways influencing pancreatic beta cell development and function in the etiology of type 2 diabetes.", - "journal_title": "Science (New York, N.Y.)", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/17463249/" - } - ], - "502cf764-8684-4949-bb2c-f68ba5a65a30": [ - { - "pub_id": "11812766", - "title": "Genetic variation in the gene encoding adiponectin is associated with an increased risk of type 2 diabetes in the Japanese population.", - "authors": "Kazuo Hara,Philippe Boutin,Yasumichi Mori,Kazuyuki Tobe,Christian Dina,Kazuki Yasuda,Toshimasa Yamauchi,Shuichi Otabe,Terumasa Okada,Kazuhiro Eto,Hiroko Kadowaki,Ryoko Hagura,Yasuo Akanuma,Yoshio Yazaki,Ryozo Nagai,Matsuo Taniyama,Koichi Matsubara,Madoka Yoda,Yasuko Nakano,Motowo Tomita,Satoshi Kimura,Chikako Ito,Philippe Froguel,Takashi Kadowaki", - "abstract": "An adipocyte-derived peptide, adiponectin (also known as GBP28), is decreased in subjects with type 2 diabetes. Recent genome-wide scans have mapped a diabetes susceptibility locus to chromosome 3q27, where the adiponectin gene (APM1) is located. Herein, we present evidence of an association between frequent single nucleotide polymorphisms at positions 45 and 276 in the adiponectin gene and type 2 diabetes (P = 0.003 and P = 0.002, respectively). Subjects with the G/G genotype at position 45 or the G/G genotype at position 276 had a significantly increased risk of type 2 diabetes (odds ratio 1.70 [95% CI 1.09-2.65] and 2.16 [1.22-3.95], respectively) compared with those having the T/T genotype at positions 45 and 276, respectively. In addition, the subjects with the G/G genotype at position 276 had a higher insulin resistance index than those with the T/T genotype (1.61 +/- 0.05 vs. 1.19 +/- 0.12, P = 0.001). The G allele at position 276 was linearly associated with lower plasma adiponectin levels (G/G: 10.4 +/- 0.85 microg/ml, G/T: 13.7 +/- 0.87 microg/ml, T/T: 16.6 +/- 2.24 microg/ml, P = 0.01) in subjects with higher BMIs. Based on these findings together with the observation that adiponectin improves insulin sensitivity in animal models, we conclude that the adiponectin gene may be a susceptibility gene for type 2 diabetes.", - "journal_title": "Diabetes", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/11812766/" - } - ], - "21368075-9e10-4260-b346-43b1029b3bf0": [ - { - "pub_id": "17353930", - "title": "Network-based prediction of protein function.", - "authors": "Roded Sharan,Igor Ulitsky,Ron Shamir", - "abstract": "Functional annotation of proteins is a fundamental problem in the post-genomic era. The recent availability of protein interaction networks for many model species has spurred on the development of computational methods for interpreting such data in order to elucidate protein function. In this review, we describe the current computational approaches for the task, including direct methods, which propagate functional information through the network, and module-assisted methods, which infer functional modules within the network and use those for the annotation task. Although a broad variety of interesting approaches has been developed, further progress in the field will depend on systematic evaluation of the methods and their dissemination in the biological community.", - "journal_title": "Molecular systems biology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/17353930/" - } - ], - "7ddaf43c-ab9f-4ecc-9754-b7deb57fec2f": [ - { - "pub_id": "11689339", - "title": "Genetics and genomics in infectious disease susceptibility.", - "authors": "J M Blackwell", - "abstract": "The past decade has witnessed a rapid transition from the first positional cloning of an infectious disease susceptibility gene (Slc11a1, also called Nramp1) in the mouse to genome-wide scans in human multicase families and the identification of potential disease-causing genes by simple inspection of the public human genome databases. Pathogen genome projects have facilitated multilocus sequence typing of pathogen isolates and studies of ecological fitness and virulence patterns in disease-causing isolates. Comparative sequence analysis of pathogen strains and functional genomics studies are now underway, hopefully providing new insight into infectious disease susceptibility.", - "journal_title": "Trends in molecular medicine", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/11689339/" - } - ], - "a551b815-1d9d-4dae-a194-8f77e317b506": [ - { - "pub_id": "21051460", - "title": "A recombination hotspot leads to sequence variability within a novel gene (AK005651) and contributes to type 1 diabetes susceptibility.", - "authors": "Iris K L Tan,Leanne Mackin,Nancy Wang,Anthony T Papenfuss,Colleen M Elso,Michelle P Ashton,Fiona Quirk,Belinda Phipson,Melanie Bahlo,Terence P Speed,Gordon K Smyth,Grant Morahan,Thomas C Brodnicki", - "abstract": "More than 25 loci have been linked to type 1 diabetes (T1D) in the nonobese diabetic (NOD) mouse, but identification of the underlying genes remains challenging. We describe here the positional cloning of a T1D susceptibility locus, Idd11, located on mouse chromosome 4. Sequence analysis of a series of congenic NOD mouse strains over a critical 6.9-kb interval in these mice and in 25 inbred strains identified several haplotypes, including a unique NOD haplotype, associated with varying levels of T1D susceptibility. Haplotype diversity within this interval between congenic NOD mouse strains was due to a recombination hotspot that generated four crossover breakpoints, including one with a complex conversion tract. The Idd11 haplotype and recombination hotspot are located within a predicted gene of unknown function, which exhibits decreased expression in relevant tissues of NOD mice. Notably, it was the recombination hotspot that aided our mapping of Idd11 and confirms that recombination hotspots can create genetic variation affecting a common polygenic disease. This finding has implications for human genetic association studies, which may be affected by the approximately 33,000 estimated hotspots in the genome.", - "journal_title": "Genome research", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/21051460/" - } - ], - "3ce10e4a-3ddc-4c7c-8897-84285ccfeedc": [ - { - "pub_id": "17126559", - "title": "A strategy to search for common obesity and type 2 diabetes genes.", - "authors": "Clara C Elbers,N Charlotte Onland-Moret,Lude Franke,Anne G Niehoff,Yvonne T van der Schouw,Cisca Wijmenga", - "abstract": "Worldwide, the incidence of type 2 diabetes is rising rapidly, mainly because of the increase in the incidence of obesity, which is an important risk factor for this condition. Both obesity and type 2 diabetes are complex genetic traits but they also share some nongenetic risk factors. Hence, it is tempting to speculate that the susceptibility to type 2 diabetes and obesity might also partly be due to shared genes. By comparing all of the published genome scans for type 2 diabetes and obesity, five overlapping chromosomal regions for both diseases (encompassing 612 candidate genes) have been identified. By analysing these five susceptibility loci for type 2 diabetes and obesity, using six freely available bioinformatics tools for disease gene identification, 27 functional candidate genes have been pinpointed that are involved in eating behaviour, metabolism and inflammation. These genes might reveal a molecular link between the two disorders.", - "journal_title": "Trends in endocrinology and metabolism: TEM", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/17126559/" - } - ], - "5293f814-f4a7-48e0-b4e5-b1f13fdc8516": [ - { - "pub_id": "11460565", - "title": "Insulin resistance: definition and consequences.", - "authors": "H E Lebovitz", - "abstract": "Insulin resistance is defined clinically as the inability of a known quantity of exogenous or endogenous insulin to increase glucose uptake and utilization in an individual as much as it does in a normal population. Insulin action is the consequence of insulin binding to its plasma membrane receptor and is transmitted through the cell by a series of protein-protein interactions. Two major cascades of protein-protein interactions mediate intracellular insulin action: one pathway is involved in regulating intermediary metabolism and the other plays a role in controlling growth processes and mitoses. The regulation of these two distinct pathways can be dissociated. Indeed, some data suggest that the pathway regulating intermediary metabolism is diminished in type 2 diabetes while that regulating growth processes and mitoses is normal.--Several mechanisms have been proposed as possible causes underlying the development of insulin resistance and the insulin resistance syndrome. These include: (1) genetic abnormalities of one or more proteins of the insulin action cascade (2) fetal malnutrition (3) increases in visceral adiposity. Insulin resistance occurs as part of a cluster of cardiovascular-metabolic abnormalities commonly referred to as \"The Insulin Resistance Syndrome\" or \"The Metabolic Syndrome\". This cluster of abnormalities may lead to the development of type 2 diabetes, accelerated atherosclerosis, hypertension or polycystic ovarian syndrome depending on the genetic background of the individual developing the insulin resistance.--In this context, we need to consider whether insulin resistance should be defined as a disease entity which needs to be diagnosed and treated with specific drugs to improve insulin action.", - "journal_title": "Experimental and clinical endocrinology & diabetes : official journal, German Society of Endocrinology [and] German Diabetes Association", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/11460565/" - } - ], - "ac1a803b-c559-430e-bc2c-acca9322e1fb": [ - { - "pub_id": "12540637", - "title": "Large-scale association studies of variants in genes encoding the pancreatic beta-cell KATP channel subunits Kir6.2 (KCNJ11) and SUR1 (ABCC8) confirm that the KCNJ11 E23K variant is associated with type 2 diabetes.", - "authors": "Anna L Gloyn,Michael N Weedon,Katharine R Owen,Martina J Turner,Bridget A Knight,Graham Hitman,Mark Walker,Jonathan C Levy,Mike Sampson,Stephanie Halford,Mark I McCarthy,Andrew T Hattersley,Timothy M Frayling", - "abstract": "The genes ABCC8 and KCNJ11, which encode the subunits sulfonylurea receptor 1 (SUR1) and inwardly rectifying potassium channel (Kir6.2) of the beta-cell ATP-sensitive potassium (K(ATP)) channel, control insulin secretion. Common polymorphisms in these genes (ABCC8 exon 16-3t/c, exon 18 T/C, KCNJ11 E23K) have been variably associated with type 2 diabetes, but no large ( approximately 2,000 subjects) case-control studies have been performed. We evaluated the role of these three variants by studying 2,486 U.K. subjects: 854 with type 2 diabetes, 1,182 population control subjects, and 150 parent-offspring type 2 diabetic trios. The E23K allele was associated with diabetes in the case-control study (odds ratio [OR] 1.18 [95% CI 1.04-1.34], P = 0.01) but did not show familial association with diabetes. Neither the exon 16 nor the exon 18 ABCC8 variants were associated with diabetes (1.04 [0.91-1.18], P = 0.57; 0.93 [0.71-1.23], P = 0.63, respectively). Meta-analysis of all case-control data showed that the E23K allele was associated with type 2 diabetes (K allele OR 1.23 [1.12-1.36], P = 0.000015; KK genotype 1.65 [1.34-2.02], P = 0.000002); but the ABCC8 variants were not associated. Our results confirm that E23K increases risk of type 2 diabetes and show that large-scale association studies are important for the identification of diabetes susceptibility alleles.", - "journal_title": "Diabetes", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/12540637/" - } - ], - "71627375-4ac8-491e-b83b-33c7d0e02572": [ - { - "pub_id": "16927413", - "title": "Glutathione S-transferase gene polymorphisms in Turkish patients with diabetes mellitus.", - "authors": "Serap Yalin,Rezan Hatungil,Lulufer Tamer,Nurcan Aras Ates,Nil Dogruer,Hatice Yildirim,Sevim Karakas,Ugur Atik", - "abstract": "Glutathione S-transferases (GSTs) are enzymes involved in the metabolism of many disease-causing electrophilic substrates and protect the cells against oxidative stress. In the present study, we investigated the GSTM1, GSTT1 and GSTP1 gene polymorphisms in diabetic patients and healthy individuals and searched whether polymorphisms in GST genes are associated with diabetes mellitus (DM) in the Turkish population. The study population consisted of 98 unrelated healthy individuals and 98 patients with DM. Genotyping of GSTM1, GSTT1 and GSTP1 genes was performed using real time polymerase chain reaction with a Light Cycler instrument. Patients had a higher frequency of the GSTM1 null genotype than the control group (Odds ratios, OR = 3.7; 95% confidence intervals, CI = 2.05-6.70). However, there was no significant difference in the frequencies of the GSTT1 and GSTP1 gene polymorphisms between the patients and control group. The combined analysis of these three GST genotypes showed a further DM risk increase (OR = 5.7, 95% CI = 1.51-31.07). This is the first study to determine the association of diabetes with GST gene polymorphism in the Turkish population. These results show that GSTM1 null genotype may play a significant role in the aetiopathogeneses of DM and the GSTM1 gene may be a useful marker in the prediction of DM susceptibility of the Turkish population.", - "journal_title": "Cell biochemistry and function", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/16927413/" - } - ], - "53ec015a-a33b-410f-a218-6d728814ded6": [ - { - "pub_id": "14718383", - "title": "A genomic perspective on protein tyrosine phosphatases: gene structure, pseudogenes, and genetic disease linkage.", - "authors": "Jannik N Andersen,Peter G Jansen,S\u00f8ren M Echwald,Ole H Mortensen,Toshiyuki Fukada,Robert Del Vecchio,Nicholas K Tonks,Niels Peter H M\u00f8ller", - "abstract": "The protein tyrosine phosphatases (PTPs) are now recognized as critical regulators of signal transduction under normal and pathophysiological conditions. In this analysis we have explored the sequence of the human genome to define the composition of the PTP family. Using public and proprietary sequence databases, we discovered one novel human PTP gene and defined chromosomal loci and exon structure of the additional 37 genes encoding known PTP transcripts. Direct orthologs were present in the mouse genome for all 38 human PTP genes. In addition, we identified 12 PTP pseudogenes unique to humans that have probably contaminated previous bioinformatics analysis of this gene family. PCR amplification and transcript sequencing indicate that some PTP pseudogenes are expressed, but their function (if any) is unknown. Furthermore, we analyzed the enhanced diversity generated by alternative splicing and provide predicted amino acid sequences for four human PTPs that are currently defined by fragments only. Finally, we correlated each PTP locus with genetic disease markers and identified 4 PTPs that map to known susceptibility loci for type 2 diabetes and 19 PTPs that map to regions frequently deleted in human cancers. We have made our analysis available at http://ptp.cshl.edu or http://science.novonordisk.com/ptp and we hope this resource will facilitate the functional characterization of these key enzymes.", - "journal_title": "FASEB journal : official publication of the Federation of American Societies for Experimental Biology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/14718383/" - } - ], - "f4a4466a-e930-472e-9d29-990cd6fe7e80": [ - { - "pub_id": "8879974", - "title": "ACE inhibitors and the kidney. A risk-benefit assessment.", - "authors": "G Navis,H J Faber,D de Zeeuw,P E de Jong", - "abstract": "ACE inhibitors effectively reduce systemic vascular resistance in patients with hypertension, heart failure or chronic renal disease. This antihypertensive efficacy probably accounts for an important part of their long term renoprotective effects in patients with diabetic and non-diabetic renal disease. The renal mechanisms underlying the renal adverse effects of ACE inhibitors--intrarenal efferent vasodilation with a consequent fall in filtration pressure--are held to be involved in their renoprotective effects as well. The fall in filtration pressure presumably contributes to the antiproteinuric effect as well as to long term renoprotection. The former is suggested by the positive correlation between the fall in filtration fraction and the reduction in proteinuria found during ACE inhibition. The latter is suggested by the correlation between the (slight) reduction in glomerular filtration rate at onset of therapy and a more favourable course of renal function in the long term. Such a fall in filtration rate at the onset of ACE inhibitor treatment is reversible after withdrawal, and can be considered the trade-off for long term renal protection in patients with diabetic and nondiabetic chronic renal disease. In conditions in which glomerular filtration is critically dependent on angiotensin II-mediated efferent vascular tone (such as a post-stenotic kidney, or patients with heart failure and severe depletion of circulating volume), ACE inhibition can induce acute renal failure, which is reversible after withdrawal of the drug. Systemic and renal haemodynamic effects of ACE inhibition, both beneficial and adverse, are potentiated by sodium depletion. Consequently, sodium repletion contributes to the restoration of renal function in patients with ACE inhibitor-induced acute renal failure. Our the other hand, co-treatment with diuretics and sodium restriction can improve therapeutic efficacy in patients in whom the therapeutic response of blood pressure or proteinuria is insufficient. Patients at the greatest risk for renal adverse effects (those with heart failure, diabetes mellitus and/or chronic renal failure) also can expect the greatest benefit. Therefore, ACE inhibitors should not be withheld in these patients, but dosages should be carefully titrated, with monitoring of renal function and serum potassium levels.", - "journal_title": "Drug safety", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/8879974/" - } - ], - "725a5276-7b03-4784-a13e-53b146cd4339": [ - { - "pub_id": "19641089", - "title": "Cis-regulatory mutations in human disease.", - "authors": "Douglas J Epstein", - "abstract": "Cis-acting regulatory sequences are required for the proper temporal and spatial control of gene expression. Variation in gene expression is highly heritable and a significant determinant of human disease susceptibility. The diversity of human genetic diseases attributed, in whole or in part, to mutations in non-coding regulatory sequences is on the rise. Improvements in genome-wide methods of associating genetic variation with human disease and predicting DNA with cis-regulatory potential are two of the major reasons for these recent advances. This review will highlight select examples from the literature that have successfully integrated genetic and genomic approaches to uncover the molecular basis by which cis-regulatory mutations alter gene expression and contribute to human disease. The fine mapping of disease-causing variants has led to the discovery of novel cis-acting regulatory elements that, in some instances, are located as far away as 1.5 Mb from the target gene. In other cases, the prior knowledge of the regulatory landscape surrounding the gene of interest aided in the selection of enhancers for mutation screening. The success of these studies should provide a framework for following up on the large number of genome-wide association studies that have identified common variants in non-coding regions of the genome that associate with increased risk of human diseases including, diabetes, autism, Crohn's, colorectal cancer, and asthma, to name a few.", - "journal_title": "Briefings in functional genomics & proteomics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/19641089/" - } - ], - "23509967-f787-4862-afce-bc8475f2d814": [ - { - "pub_id": "19264985", - "title": "Rare variants of IFIH1, a gene implicated in antiviral responses, protect against type 1 diabetes.", - "authors": "Sergey Nejentsev,Neil Walker,David Riches,Michael Egholm,John A Todd", - "abstract": "Genome-wide association studies (GWASs) are regularly used to map genomic regions contributing to common human diseases, but they often do not identify the precise causative genes and sequence variants. To identify causative type 1 diabetes (T1D) variants, we resequenced exons and splice sites of 10 candidate genes in pools of DNA from 480 patients and 480 controls and tested their disease association in over 30,000 participants. We discovered four rare variants that lowered T1D risk independently of each other (odds ratio = 0.51 to 0.74; P = 1.3 x 10(-3) to 2.1 x 10(-16)) in IFIH1 (interferon induced with helicase C domain 1), a gene located in a region previously associated with T1D by GWASs. These variants are predicted to alter the expression and structure of IFIH1 [MDA5 (melanoma differentiation-associated protein 5)], a cytoplasmic helicase that mediates induction of interferon response to viral RNA. This finding firmly establishes the role of IFIH1 in T1D and demonstrates that resequencing studies can pinpoint disease-causing genes in genomic regions initially identified by GWASs.", - "journal_title": "Science (New York, N.Y.)", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/19264985/" - } - ], - "d2441db2-4e0a-4119-aed9-1e275ddc7f9b": [ - { - "pub_id": "18344982", - "title": "Variations in DNA elucidate molecular networks that cause disease.", - "authors": "Yanqing Chen,Jun Zhu,Pek Yee Lum,Xia Yang,Shirly Pinto,Douglas J MacNeil,Chunsheng Zhang,John Lamb,Stephen Edwards,Solveig K Sieberts,Amy Leonardson,Lawrence W Castellini,Susanna Wang,Marie-France Champy,Bin Zhang,Valur Emilsson,Sudheer Doss,Anatole Ghazalpour,Steve Horvath,Thomas A Drake,Aldons J Lusis,Eric E Schadt", - "abstract": "Identifying variations in DNA that increase susceptibility to disease is one of the primary aims of genetic studies using a forward genetics approach. However, identification of disease-susceptibility genes by means of such studies provides limited functional information on how genes lead to disease. In fact, in most cases there is an absence of functional information altogether, preventing a definitive identification of the susceptibility gene or genes. Here we develop an alternative to the classic forward genetics approach for dissecting complex disease traits where, instead of identifying susceptibility genes directly affected by variations in DNA, we identify gene networks that are perturbed by susceptibility loci and that in turn lead to disease. Application of this method to liver and adipose gene expression data generated from a segregating mouse population results in the identification of a macrophage-enriched network supported as having a causal relationship with disease traits associated with metabolic syndrome. Three genes in this network, lipoprotein lipase (Lpl), lactamase beta (Lactb) and protein phosphatase 1-like (Ppm1l), are validated as previously unknown obesity genes, strengthening the association between this network and metabolic disease traits. Our analysis provides direct experimental support that complex traits such as obesity are emergent properties of molecular networks that are modulated by complex genetic loci and environmental factors.", - "journal_title": "Nature", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/18344982/" - } - ], - "d9df6ce7-31a9-4041-bff4-e9624815b61a": [ - { - "pub_id": "18162502", - "title": "PPARGC1A variation associated with DNA damage, diabetes, and cardiovascular diseases: the Boston Puerto Rican Health Study.", - "authors": "Chao-Qiang Lai,Katherine L Tucker,Laurence D Parnell,Xian Adiconis,Bibiana Garc\u00eda-Bailo,John Griffith,Mohsen Meydani,Jos\u00e9 M Ordov\u00e1s", - "abstract": "Individuals with type 2 diabetes exhibit higher DNA damage and increased risk of cardiovascular disease (CVD). However, mechanisms underlying the association between DNA damage and development of type 2 diabetes and CVD are not understood. We sought to link peroxisome proliferator-activated receptor-gamma coactivator-1 alpha (PPARGC1A), a master transcriptional regulator of mitochondrial oxidative phosphorylation and cellular energy metabolism, with DNA damage, type 2 diabetes, and CVD. We measured DNA damage as urinary 8-hydroxydeoxyguanosine (8-OHdG) concentration and examined the relationship between nine PPARGC1A genetic variants, DNA damage, type 2 diabetes, and self-reported CVD in 959 participants of the Boston Puerto Rican Health Study. With respect to urinary 8-OHdG, PPARGC1A variants showed significant association, and PPARGC1A haplotypes exhibited significant association after correction for multiple testing. Two independent PPARGC1A variants associated significantly with type 2 diabetes (odds ratios [ORs] 1.35 and 2.46; P = 0.045 and <0.001). Carriers of minor alleles of two other PPARGC1A variants, both in strong linkage disequilibrium and associated with lower DNA damage, showed lower prevalence of CVD (ORs 0.53 and 0.65; P = 0.030 and 0.175). Moreover, we found that physical activity correlated negatively with DNA damage. It is plausible that low physical activity combined with risk haplotyes contribute to the high prevalence of type 2 diabetes in this population. We propose that PPARGC1A influences development of type 2 diabetes and CVD via DNA damage. Increasing physical activity, which induces PPARGC1A expression, is a potential strategy to slow DNA damage, thereby decreasing the risk of CVD for individuals with type 2 diabetes.", - "journal_title": "Diabetes", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/18162502/" - } - ], - "a899062a-0d65-409c-8286-4f328b8a80e8": [ - { - "pub_id": "33938454", - "title": "Targeting the myostatin signaling pathway to treat muscle loss and metabolic dysfunction.", - "authors": "Se-Jin Lee", - "abstract": "Since the discovery of myostatin (MSTN; also known as GDF-8) as a critical regulator of skeletal muscle mass in 1997, there has been an extensive effort directed at understanding the cellular and physiological mechanisms underlying MSTN activity, with the long-term goal of developing strategies and agents capable of blocking MSTN signaling to treat patients with muscle loss. Considerable progress has been made in elucidating key components of this regulatory system, and in parallel with this effort has been the development of numerous biologics that have been tested in clinical trials for a wide range of indications, including muscular dystrophy, sporadic inclusion body myositis, spinal muscular atrophy, cachexia, muscle loss due to aging or following falls, obesity, and type 2 diabetes. Here, I review what is known about the MSTN regulatory system and the current state of efforts to target this pathway for clinical applications.", - "journal_title": "The Journal of clinical investigation", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/33938454/" - } - ], - "94a3eddb-6151-4319-b83a-6a0cfa8d1e49": [ - { - "pub_id": "12606533", - "title": "A genome-wide scan in families with maturity-onset diabetes of the young: evidence for further genetic heterogeneity.", - "authors": "Timothy M Frayling,Cecilia M Lindgren,Jean Claude Chevre,Stephan Menzel,Marie Wishart,Yamina Benmezroua,Alison Brown,Julie C Evans,Pamidghantam Subba Rao,Christian Dina,C\u00e9cile Lecoeur,Timo Kanninen,Peter Almgren,Michael P Bulman,Youxiang Wang,James Mills,Rosemarie Wright-Pascoe,Melanie M Mahtani,Francesco Prisco,Angels Costa,Ignacio Cognet,Torben Hansen,Oluf Pedersen,Sian Ellard,Tiinamaija Tuomi,Leif C Groop,Philippe Froguel,Andrew T Hattersley,Martine Vaxillaire", - "abstract": "Maturity-onset diabetes of the young (MODY) is a heterogeneous single gene disorder characterized by non-insulin-dependent diabetes, an early onset and autosomal dominant inheritance. Mutations in six genes have been shown to cause MODY. Approximately 15-20% of families fitting MODY criteria do not have mutations in any of the known genes. These families provide a rich resource for the identification of new MODY genes. This will potentially enable further dissection of clinical heterogeneity and bring new insights into mechanisms of beta-cell dysfunction. To facilitate the identification of novel MODY loci, we combined the results from three genome-wide scans on a total of 23 families fitting MODY criteria. We used both a strict parametric model of inheritance with heterogeneity and a model-free analysis. We did not identify any single novel locus but provided putative evidence for linkage to chromosomes 6 (nonparametric linkage [NPL]score 2.12 at 71 cM) and 10 (NPL score 1.88 at 169-175 cM), and to chromosomes 3 (heterogeneity LOD [HLOD] score 1.27 at 124 cM) and 5 (HLOD score 1.22 at 175 cM) in 14 more strictly defined families. Our results provide evidence for further heterogeneity in MODY.", - "journal_title": "Diabetes", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/12606533/" - } - ], - "e4eca0fc-d0bc-45fa-87e6-4958ebdf66f0": [ - { - "pub_id": "23404751", - "title": "Diagnosis and management of differentiated thyroid cancer using molecular biology.", - "authors": "Robert L Witt,Robert L Ferris,Edmund A Pribitkin,Steven I Sherman,David L Steward,Yuri E Nikiforov", - "abstract": "To define molecular biology in clinical practice for diagnosis, surgical management, and prognostication of differentiated thyroid cancer. Ovid Medline 2006-2012 Manuscripts with clinical correlates. Papillary thyroid carcinomas harbor point mutations of the BRAF and RAS genes or RET/PTC rearrangements, all of which activate the mitogen-activated protein kinase pathway. These mutually exclusive mutations are found in 70% of PTC. BRAF mutation is found in 45% of papillary thyroid cancer and is highly specific. Follicular carcinomas are known to harbor RAS mutation or PAX8/PPAR\u03b3 rearrangement. These mutations are also mutually exclusive and identified in 70% of follicular carcinomas. Molecular classifiers measure the expression of a large number of genes on a microarray chip providing a substantial negative predictive value pending further validation. 1) 20% to 30% of cytologically classified Follicular Neoplasms and Follicular Lesion of Undetermined Significance collectively are malignant on final pathology. Approximately 70% to 80% of thyroid lobectomies performed solely for diagnostic purposes are benign. Molecular alteration testing may reduce the number of unnecessary thyroid procedures, 2) may reduce the number of completion thyroidectomies, and 3) may lead to more individualized operative and postoperative management. Molecular testing for BRAF, RAS, RET/PTC, and PAX8/PPAR\u03b3 for follicular lesion of undetermined significance and follicular neoplasm improve specificity, whereas molecular classifiers may add negative predictive value to fine needle aspiration diagnosis.", - "journal_title": "The Laryngoscope", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/23404751/" - } - ], - "7bd7a98f-955a-4988-8981-a0ff7ab6f7df": [ - { - "pub_id": "17996556", - "title": "Future use of genomics in coronary artery disease.", - "authors": "Samir B Damani,Eric J Topol", - "abstract": "Coronary artery disease (CAD) remains the number one cause of death in industrialized countries despite our collective efforts to minimize attributable risk from known contributors to CAD such as hypertension, dyslipidemia, and smoking. In addition, clinical trials have consistently demonstrated a family history of coronary disease to be predictive for future cardiovascular events beyond that which would be explained by traditional risk factors. These findings support and have prompted widespread investigation into the genomic basis of CAD and myocardial infarction (MI). Recent advances in genotyping technology have allowed for easier identification and confirmation of susceptibility genes for complex traits across different cohorts via increased power of studies stemming from faster accrual of cases and control subjects and more precise genetic mapping. These technological advances have resulted in defining the genes contributing to a substantial or even majority of population-attributable risk for type 2 diabetes and age-related macular degeneration (AMD) cases. Similar progress in replicating novel susceptibility genes for CAD and specifically MI is now rapidly occurring, with a recent gene marker on chromosome 9p21 representing a highly significant and common variant susceptibility factor. With improved resequencing technology and better phenotypic characterization of our CAD cases and control subjects, we should achieve successes in gene identification and confirmation similar to diabetes and AMD, thereby allowing us to better quantify CAD risk earlier in life and institute more effective therapy reducing the individual propensity to develop CAD.", - "journal_title": "Journal of the American College of Cardiology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/17996556/" - } - ], - "915ee14c-df93-4482-966a-fbf3db2c11ea": [ - { - "pub_id": "15716906", - "title": "Genome-wide association studies for common diseases and complex traits.", - "authors": "Joel N Hirschhorn,Mark J Daly", - "abstract": "Genetic factors strongly affect susceptibility to common diseases and also influence disease-related quantitative traits. Identifying the relevant genes has been difficult, in part because each causal gene only makes a small contribution to overall heritability. Genetic association studies offer a potentially powerful approach for mapping causal genes with modest effects, but are limited because only a small number of genes can be studied at a time. Genome-wide association studies will soon become possible, and could open new frontiers in our understanding and treatment of disease. However, the execution and analysis of such studies will require great care.", - "journal_title": "Nature reviews. Genetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/15716906/" - } - ], - "81222665-0c3d-4088-b8d9-b26757be47b8": [ - { - "pub_id": "15761122", - "title": "Complement factor H polymorphism in age-related macular degeneration.", - "authors": "Robert J Klein,Caroline Zeiss,Emily Y Chew,Jen-Yue Tsai,Richard S Sackler,Chad Haynes,Alice K Henning,John Paul SanGiovanni,Shrikant M Mane,Susan T Mayne,Michael B Bracken,Frederick L Ferris,Jurg Ott,Colin Barnstable,Josephine Hoh", - "abstract": "Age-related macular degeneration (AMD) is a major cause of blindness in the elderly. We report a genome-wide screen of 96 cases and 50 controls for polymorphisms associated with AMD. Among 116,204 single-nucleotide polymorphisms genotyped, an intronic and common variant in the complement factor H gene (CFH) is strongly associated with AMD (nominal P value <10(-7)). In individuals homozygous for the risk allele, the likelihood of AMD is increased by a factor of 7.4 (95% confidence interval 2.9 to 19). Resequencing revealed a polymorphism in linkage disequilibrium with the risk allele representing a tyrosine-histidine change at amino acid 402. This polymorphism is in a region of CFH that binds heparin and C-reactive protein. The CFH gene is located on chromosome 1 in a region repeatedly linked to AMD in family-based studies.", - "journal_title": "Science (New York, N.Y.)", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/15761122/" - } - ], - "33c5de8c-7efc-41df-a540-22729d8b7d2c": [ - { - "pub_id": "19430480", - "title": "Genome-wide association study and meta-analysis find that over 40 loci affect risk of type 1 diabetes.", - "authors": "Jeffrey C Barrett,David G Clayton,Patrick Concannon,Beena Akolkar,Jason D Cooper,Henry A Erlich,C\u00e9cile Julier,Grant Morahan,J\u00f8rn Nerup,Concepcion Nierras,Vincent Plagnol,Flemming Pociot,Helen Schuilenburg,Deborah J Smyth,Helen Stevens,John A Todd,Neil M Walker,Stephen S Rich, ", - "abstract": "Type 1 diabetes (T1D) is a common autoimmune disorder that arises from the action of multiple genetic and environmental risk factors. We report the findings of a genome-wide association study of T1D, combined in a meta-analysis with two previously published studies. The total sample set included 7,514 cases and 9,045 reference samples. Forty-one distinct genomic locations provided evidence for association with T1D in the meta-analysis (P < 10(-6)). After excluding previously reported associations, we further tested 27 regions in an independent set of 4,267 cases, 4,463 controls and 2,319 affected sib-pair (ASP) families. Of these, 18 regions were replicated (P < 0.01; overall P < 5 \u00d7 10(-8)) and 4 additional regions provided nominal evidence of replication (P < 0.05). The many new candidate genes suggested by these results include IL10, IL19, IL20, GLIS3, CD69 and IL27.", - "journal_title": "Nature genetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/19430480/" - } - ], - "409b0b92-0a89-4a16-88d9-638af0f56b4e": [ - { - "pub_id": "18650507", - "title": "SLCO1B1 variants and statin-induced myopathy--a genomewide study.", - "authors": " ,E Link,S Parish,J Armitage,L Bowman,S Heath,F Matsuda,I Gut,M Lathrop,R Collins", - "abstract": "Lowering low-density lipoprotein cholesterol with statin therapy results in substantial reductions in cardiovascular events, and larger reductions in cholesterol may produce larger benefits. In rare cases, myopathy occurs in association with statin therapy, especially when the statins are administered at higher doses and with certain other medications. We carried out a genomewide association study using approximately 300,000 markers (and additional fine-mapping) in 85 subjects with definite or incipient myopathy and 90 controls, all of whom were taking 80 mg of simvastatin daily as part of a trial involving 12,000 participants. Replication was tested in a trial of 40 mg of simvastatin daily involving 20,000 participants. The genomewide scan yielded a single strong association of myopathy with the rs4363657 single-nucleotide polymorphism (SNP) located within SLCO1B1 on chromosome 12 (P=4x10(-9)). SLCO1B1 encodes the organic anion-transporting polypeptide OATP1B1, which has been shown to regulate the hepatic uptake of statins. The noncoding rs4363657 SNP was in nearly complete linkage disequilibrium with the nonsynonymous rs4149056 SNP (r(2)=0.97), which has been linked to statin metabolism. The prevalence of the rs4149056 C allele in the population was 15%. The odds ratio for myopathy was 4.5 (95% confidence interval [CI], 2.6 to 7.7) per copy of the C allele, and 16.9 (95% CI, 4.7 to 61.1) in CC as compared with TT homozygotes. More than 60% of these myopathy cases could be attributed to the C variant. The association of rs4149056 with myopathy was replicated in the trial of 40 mg of simvastatin daily, which also showed an association between rs4149056 and the cholesterol-lowering effects of simvastatin. No SNPs in any other region were clearly associated with myopathy. We have identified common variants in SLCO1B1 that are strongly associated with an increased risk of statin-induced myopathy. Genotyping these variants may help to achieve the benefits of statin therapy more safely and effectively. (Current Controlled Trials number, ISRCTN74348595.)", - "journal_title": "The New England journal of medicine", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/18650507/" - } - ], - "8a865bb9-a5fc-4023-9f54-2cc2863b73a6": [ - { - "pub_id": "18772396", - "title": "An integrated genomic analysis of human glioblastoma multiforme.", - "authors": "D Williams Parsons,Si\u00e2n Jones,Xiaosong Zhang,Jimmy Cheng-Ho Lin,Rebecca J Leary,Philipp Angenendt,Parminder Mankoo,Hannah Carter,I-Mei Siu,Gary L Gallia,Alessandro Olivi,Roger McLendon,B Ahmed Rasheed,Stephen Keir,Tatiana Nikolskaya,Yuri Nikolsky,Dana A Busam,Hanna Tekleab,Luis A Diaz,James Hartigan,Doug R Smith,Robert L Strausberg,Suely Kazue Nagahashi Marie,Sueli Mieko Oba Shinjo,Hai Yan,Gregory J Riggins,Darell D Bigner,Rachel Karchin,Nick Papadopoulos,Giovanni Parmigiani,Bert Vogelstein,Victor E Velculescu,Kenneth W Kinzler", - "abstract": "Glioblastoma multiforme (GBM) is the most common and lethal type of brain cancer. To identify the genetic alterations in GBMs, we sequenced 20,661 protein coding genes, determined the presence of amplifications and deletions using high-density oligonucleotide arrays, and performed gene expression analyses using next-generation sequencing technologies in 22 human tumor samples. This comprehensive analysis led to the discovery of a variety of genes that were not known to be altered in GBMs. Most notably, we found recurrent mutations in the active site of isocitrate dehydrogenase 1 (IDH1) in 12% of GBM patients. Mutations in IDH1 occurred in a large fraction of young patients and in most patients with secondary GBMs and were associated with an increase in overall survival. These studies demonstrate the value of unbiased genomic analyses in the characterization of human brain cancer and identify a potentially useful genetic alteration for the classification and targeted therapy of GBMs.", - "journal_title": "Science (New York, N.Y.)", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/18772396/" - } - ], - "b954224b-333b-4d82-bb9a-6e5b3837849e": [ - { - "pub_id": "15787657", - "title": "Animal models of diabetes mellitus.", - "authors": "D A Rees,J C Alcolado", - "abstract": "Animal models have been used extensively in diabetes research. Early studies used pancreatectomised dogs to confirm the central role of the pancreas in glucose homeostasis, culminating in the discovery and purification of insulin. Today, animal experimentation is contentious and subject to legal and ethical restrictions that vary throughout the world. Most experiments are carried out on rodents, although some studies are still performed on larger animals. Several toxins, including streptozotocin and alloxan, induce hyperglycaemia in rats and mice. Selective inbreeding has produced several strains of animal that are considered reasonable models of Type 1 diabetes, Type 2 diabetes and related phenotypes such as obesity and insulin resistance. Apart from their use in studying the pathogenesis of the disease and its complications, all new treatments for diabetes, including islet cell transplantation and preventative strategies, are initially investigated in animals. In recent years, molecular biological techniques have produced a large number of new animal models for the study of diabetes, including knock-in, generalized knock-out and tissue-specific knockout mice.", - "journal_title": "Diabetic medicine : a journal of the British Diabetic Association", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/15787657/" - } - ], - "25622783-ac42-479d-8698-905a7523c38a": [ - { - "pub_id": "18765388", - "title": "Genetic and genomic discovery using family studies.", - "authors": "Ingrid B Borecki,Michael A Province", - "abstract": "", - "journal_title": "Circulation", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/18765388/" - } - ], - "7e259094-bd70-4d68-b8a1-0a3d051cb31e": [ - { - "pub_id": "17460697", - "title": "A variant in CDKAL1 influences insulin response and risk of type 2 diabetes.", - "authors": "Valgerdur Steinthorsdottir,Gudmar Thorleifsson,Inga Reynisdottir,Rafn Benediktsson,Thorbjorg Jonsdottir,G Bragi Walters,Unnur Styrkarsdottir,Solveig Gretarsdottir,Valur Emilsson,Shyamali Ghosh,Adam Baker,Steinunn Snorradottir,Hjordis Bjarnason,Maggie C Y Ng,Torben Hansen,Yu Bagger,Robert L Wilensky,Muredach P Reilly,Adebowale Adeyemo,Yuanxiu Chen,Jie Zhou,Vilmundur Gudnason,Guanjie Chen,Hanxia Huang,Kerrie Lashley,Ayo Doumatey,Wing-Yee So,Ronald C Y Ma,Gitte Andersen,Knut Borch-Johnsen,Torben Jorgensen,Jana V van Vliet-Ostaptchouk,Marten H Hofker,Cisca Wijmenga,Claus Christiansen,Daniel J Rader,Charles Rotimi,Mark Gurney,Juliana C N Chan,Oluf Pedersen,Gunnar Sigurdsson,Jeffrey R Gulcher,Unnur Thorsteinsdottir,Augustine Kong,Kari Stefansson", - "abstract": "We conducted a genome-wide association study for type 2 diabetes (T2D) in Icelandic cases and controls, and we found that a previously described variant in the transcription factor 7-like 2 gene (TCF7L2) gene conferred the most significant risk. In addition to confirming two recently identified risk variants, we identified a variant in the CDKAL1 gene that was associated with T2D in individuals of European ancestry (allele-specific odds ratio (OR) = 1.20 (95% confidence interval, 1.13-1.27), P = 7.7 x 10(-9)) and individuals from Hong Kong of Han Chinese ancestry (OR = 1.25 (1.11-1.40), P = 0.00018). The genotype OR of this variant suggested that the effect was substantially stronger in homozygous carriers than in heterozygous carriers. The ORs for homozygotes were 1.50 (1.31-1.72) and 1.55 (1.23-1.95) in the European and Hong Kong groups, respectively. The insulin response for homozygotes was approximately 20% lower than for heterozygotes or noncarriers, suggesting that this variant confers risk of T2D through reduced insulin secretion.", - "journal_title": "Nature genetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/17460697/" - } - ], - "bdbd69ca-05b3-4262-8978-e55f07ab4797": [ - { - "pub_id": "9020271", - "title": "Dietary fiber, glycemic load, and risk of non-insulin-dependent diabetes mellitus in women.", - "authors": "J Salmer\u00f3n,J E Manson,M J Stampfer,G A Colditz,A L Wing,W C Willett", - "abstract": "To examine prospectively the relationship between glycemic diets, low fiber intake, and risk of non-insulin-dependent diabetes mellitus. Cohort study. In 1986, a total of 65173 US women 40 to 65 years of age and free from diagnosed cardiovascular disease, cancer, and diabetes completed a detailed dietary questionnaire from which we calculated usual intake of total and specific sources of dietary fiber, dietary glycemic index, and glycemic load. Non-insulin-dependent diabetes mellitus. During 6 years of follow-up, 915 incident cases of diabetes were documented. The dietary glycemic index was positively associated with risk of diabetes after adjustment for age, body mass index, smoking, physical activity, family history of diabetes, alcohol and cereal fiber intake, and total energy intake. Comparing the highest with the lowest quintile, the relative risk (RR) of diabetes was 1.37 (95% confidence interval [CI], 1.09-1.71, P trend=.005). The glycemic load (an indicator of a global dietary insulin demand) was also positively associated with diabetes (RR= 1.47; 95% CI, 1.16-1.86, P trend=.003). Cereal fiber intake was inversely associated with risk of diabetes when comparing the extreme quintiles (RR=0.72, 95% CI, 0.58-0.90, P trend=.001). The combination of a high glycemic load and a low cereal fiber intake further increased the risk of diabetes (RR=2.50, 95% CI, 1.14-5.51) when compared with a low glycemic load and high cereal fiber intake. Our results support the hypothesis that diets with a high glycemic load and a low cereal fiber content increase risk of diabetes in women. Further, they suggest that grains should be consumed in a minimally refined form to reduce the incidence of diabetes.", - "journal_title": "JAMA", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/9020271/" - } - ], - "fc48c27f-fef0-4234-9593-40075be9f458": [ - { - "pub_id": "11484071", - "title": "Uncoupling proteins: functional characteristics and role in the pathogenesis of obesity and Type II diabetes.", - "authors": "L T Dalgaard,O Pedersen", - "abstract": "Uncoupling proteins are mitochondrial carrier proteins which are able to dissipate the proton gradient of the inner mitochondrial membrane. This uncoupling process reduces the amount of ATP generated through an oxidation of fuels. The hypothesis that uncoupling proteins (UCPs) are candidate genes for human obesity or Type II (non-insulin-dependent) diabetes mellitus is based on the finding that a chemical uncoupling of the mitochondrial membrane reduces body adiposity, and that lower metabolic rates predict weight gain. It is straightforward to hypothesize that common polymorphisms of UCP1, UCP2 and UCP3 genes lower metabolic rate by a more efficient energy coupling in the mitochondria. Furthermore, genetically engineered mice over expressing different UCP homologues are lean and resistant to diet-induced obesity. The three uncoupling protein homologue genes UCP1, UCP2, and UCP3 have been investigated for polymorphisms and mutations and their impact on Type II diabetes mellitus, obesity, and body weight gain or BMI. The main conclusion is that variation in the UCP1, UCP2 or UCP3 genes is not associated with major alterations of body weight gain. The contribution of UCP genes towards polygenic obesity and Type II diabetes is evaluated and discussed.", - "journal_title": "Diabetologia", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/11484071/" - } - ], - "74f148ef-696c-4e25-80e5-1d44ae70540e": [ - { - "pub_id": "12970372", - "title": "Mouse Phenome Project: understanding human biology through mouse genetics and genomics.", - "authors": "Molly Bogue", - "abstract": "", - "journal_title": "Journal of applied physiology (Bethesda, Md. : 1985)", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/12970372/" - } - ], - "ade69bf7-115a-4c1c-b75b-4761351a9c5c": [ - { - "pub_id": "16046320", - "title": "Association between common polymorphisms of the proopiomelanocortin gene and body fat distribution: a family study.", - "authors": "Michelle Baker,Nicole Gaukrodger,Bongani M Mayosi,Helen Imrie,Martin Farrall,Hugh Watkins,John M C Connell,Peter J Avery,Bernard Keavney", - "abstract": "Rare mutations in the proopiomelanocortin (POMC) gene cause severe early-onset childhood obesity. However, it is unknown whether common variants in POMC are responsible for variation in body weight or fat distribution within the commonly observed range in the population. We tested for association between three polymorphisms spanning the POMC gene and obesity phenotypes in 1,428 members of 248 families. There was significant association between genotypes at the C8246T (P < 0.0001) and C1032G (P = 0.003) polymorphisms and waist-to-hip ratio (WHR) corrected for age, sex, smoking, exercise, and alcohol consumption. Each T allele at C8246T (or G allele at C1032G) was associated with a 0.2-SD-higher WHR in a codominant fashion. When WHR was additionally corrected for BMI, thus providing a measure of body fat distribution throughout the range of BMI, there remained significant evidence for association with both markers that was of similar magnitude and statistical significance. There was no association between genotype at any polymorphism and BMI or plasma leptin level. These data show that genetic variants at the POMC locus influence body fat distribution within the normal range, suggesting a novel role for POMC in metabolic regulation.", - "journal_title": "Diabetes", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/16046320/" - } - ], - "b978a189-6fbd-4791-8072-7db79f43746a": [ - { - "pub_id": "18469204", - "title": "Implication of genetic variants near TCF7L2, SLC30A8, HHEX, CDKAL1, CDKN2A/B, IGF2BP2, and FTO in type 2 diabetes and obesity in 6,719 Asians.", - "authors": "Maggie C Y Ng,Kyong Soo Park,Bermseok Oh,Claudia H T Tam,Young Min Cho,Hyoung Doo Shin,Vincent K L Lam,Ronald C W Ma,Wing Yee So,Yoon Shin Cho,Hyung-Lae Kim,Hong Kyu Lee,Juliana C N Chan,Nam H Cho", - "abstract": "Recent genome-wide association studies have identified six novel genes for type 2 diabetes and obesity and confirmed TCF7L2 as the major type 2 diabetes gene to date in Europeans. However, the implications of these genes in Asians are unclear. We studied 13 associated single nucleotide polymorphisms from these genes in 3,041 patients with type 2 diabetes and 3,678 control subjects of Asian ancestry from Hong Kong and Korea. We confirmed the associations of TCF7L2, SLC30A8, HHEX, CDKAL1, CDKN2A/CDKN2B, IGF2BP2, and FTO with risk for type 2 diabetes, with odds ratios ranging from 1.13 to 1.35 (1.3 x 10(-12) < P(unadjusted) < 0.016). In addition, the A allele of rs8050136 at FTO was associated with increased BMI in the control subjects (P(unadjusted) = 0.008). However, we did not observe significant association of any genetic variants with surrogate measures of insulin secretion or insulin sensitivity indexes in a subset of 2,662 control subjects. Compared with subjects carrying zero, one, or two risk alleles, each additional risk allele was associated with 17% increased risk, and there was an up to 3.3-fold increased risk for type 2 diabetes in those carrying eight or more risk alleles. Despite most of the effect sizes being similar between Asians and Europeans in the meta-analyses, the ethnic differences in risk allele frequencies in most of these genes lead to variable attributable risks in these two populations. Our findings support the important but differential contribution of these genetic variants to type 2 diabetes and obesity in Asians compared with Europeans.", - "journal_title": "Diabetes", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/18469204/" - } - ], - "58e02e44-b79f-498f-8199-ac2cd511b7fd": [ - { - "pub_id": "16123354", - "title": "Genome-wide linkage analyses of type 2 diabetes in Mexican Americans: the San Antonio Family Diabetes/Gallbladder Study.", - "authors": "Kelly J Hunt,Donna M Lehman,Rector Arya,Sharon Fowler,Robin J Leach,Harald H H G\u00f6ring,Laura Almasy,John Blangero,Tom D Dyer,Ravindranath Duggirala,Michael P Stern", - "abstract": "The San Antonio Family Diabetes/Gallbladder Study was initiated to identify susceptibility genes for type 2 diabetes. Evidence was previously reported of linkage to diabetes on 10q with suggestive evidence on 3p and 9p in a genome-wide scan of 440 individuals from 27 pedigrees ascertained through a single diabetic proband. Subsequently, the study was expanded to include 906 individuals from 39 extended Mexican-American pedigrees, two additional examination cycles approximately 5.3 and 7.6 years after baseline, and genotypes for a new set of genome-wide markers. Therefore, we completed a second genome-wide linkage scan. Using information from a participant's most recent exam, the prevalence of diabetes in nonprobands was 21.8%. We performed genome-wide variance components-based genetic analysis on the discrete trait diabetes using a liability model and on the quantitative Martingale residual obtained from modeling age of diabetes diagnosis using Cox proportional hazard models. Controlling for age and age(2), our strongest evidence for linkage to the trait diabetes and the quantitative Martingale residual was on chromosome 3p at marker D3S2406 with multipoint empirical logarithm of odds scores of 1.87 and 3.76, respectively. In summary, we report evidence for linkage to diabetes on chromosome 3p in a region previously identified in at least three independent populations.", - "journal_title": "Diabetes", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/16123354/" - } - ], - "0e80507d-f408-4836-b7e1-d8b12b6a3182": [ - { - "pub_id": "19079260", - "title": "Genome-wide association yields new sequence variants at seven loci that associate with measures of obesity.", - "authors": "Gudmar Thorleifsson,G Bragi Walters,Daniel F Gudbjartsson,Valgerdur Steinthorsdottir,Patrick Sulem,Anna Helgadottir,Unnur Styrkarsdottir,Solveig Gretarsdottir,Steinunn Thorlacius,Ingileif Jonsdottir,Thorbjorg Jonsdottir,Elinborg J Olafsdottir,Gudridur H Olafsdottir,Thorvaldur Jonsson,Frosti Jonsson,Knut Borch-Johnsen,Torben Hansen,Gitte Andersen,Torben Jorgensen,Torsten Lauritzen,Katja K Aben,Andr\u00e9 L M Verbeek,Nel Roeleveld,Ellen Kampman,Lisa R Yanek,Lewis C Becker,Laufey Tryggvadottir,Thorunn Rafnar,Diane M Becker,Jeffrey Gulcher,Lambertus A Kiemeney,Oluf Pedersen,Augustine Kong,Unnur Thorsteinsdottir,Kari Stefansson", - "abstract": "Obesity results from the interaction of genetic and environmental factors. To search for sequence variants that affect variation in two common measures of obesity, weight and body mass index (BMI), both of which are highly heritable, we performed a genome-wide association (GWA) study with 305,846 SNPs typed in 25,344 Icelandic, 2,998 Dutch, 1,890 European Americans and 1,160 African American subjects and combined the results with previously published results from the Diabetes Genetics Initiative (DGI) on 3,024 Scandinavians. We selected 43 variants in 19 regions for follow-up in 5,586 Danish individuals and compared the results to a genome-wide study on obesity-related traits from the GIANT consortium. In total, 29 variants, some correlated, in 11 chromosomal regions reached a genome-wide significance threshold of P < 1.6 x 10(-7). This includes previously identified variants close to or in the FTO, MC4R, BDNF and SH2B1 genes, in addition to variants at seven loci not previously connected with obesity.", - "journal_title": "Nature genetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/19079260/" - } - ], - "0391ea68-e68c-4e0a-95b2-4498f46bc5d9": [ - { - "pub_id": "9929969", - "title": "Genome-wide scanning for type 2 diabetes susceptibility in Canadian Oji-Cree, using 190 microsatellite markers.", - "authors": "R A Hegele,F Sun,S B Harris,C Anderson,A J Hanley,B Zinman", - "abstract": "We undertook a genome-wide scan using 190 markers with an average separation of 20 cM in 49 Canadian Oji-Cree sib pairs affected with type 2 diabetes. Four of these markers, one each on chromosomes 6, 8, 16, and 22, showed both suggestive linkage and suggestive association with type 2 diabetes in the Oji-Cree. None of these markers corresponded to any chromosomal region or marker that has so far been linked with type 2 diabetes in other populations. Thus, there might be several genetic loci that confer susceptibility to type 2 diabetes in this study sample. We are following up on these preliminary leads by increasing the density of the markers within these linked and associated regions, and also by increasing the number of study subjects. Also, we found instances in which there were wide disparities between the Oji-Cree and reference Caucasians with respect to marker heterozygosity. This suggests that a particular set of markers for genome-wide scanning will have different informativeness in different ethnic groups. Thus, different marker sets will likely be required for different ethnic groups in order to maximize their information content for linkage calculations.", - "journal_title": "Journal of human genetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/9929969/" - } - ], - "82fcaf77-adf7-47f4-8ebd-6b7a9df8d73e": [ - { - "pub_id": "17554260", - "title": "Robust associations of four new chromosome regions from genome-wide analyses of type 1 diabetes.", - "authors": "John A Todd,Neil M Walker,Jason D Cooper,Deborah J Smyth,Kate Downes,Vincent Plagnol,Rebecca Bailey,Sergey Nejentsev,Sarah F Field,Felicity Payne,Christopher E Lowe,Jeffrey S Szeszko,Jason P Hafler,Lauren Zeitels,Jennie H M Yang,Adrian Vella,Sarah Nutland,Helen E Stevens,Helen Schuilenburg,Gillian Coleman,Meeta Maisuria,William Meadows,Luc J Smink,Barry Healy,Oliver S Burren,Alex A C Lam,Nigel R Ovington,James Allen,Ellen Adlem,Hin-Tak Leung,Chris Wallace,Joanna M M Howson,Cristian Guja,Constantin Ionescu-T\u00eergovi\u015fte, ,Matthew J Simmonds,Joanne M Heward,Stephen C L Gough, ,David B Dunger,Linda S Wicker,David G Clayton", - "abstract": "The Wellcome Trust Case Control Consortium (WTCCC) primary genome-wide association (GWA) scan on seven diseases, including the multifactorial autoimmune disease type 1 diabetes (T1D), shows associations at P < 5 x 10(-7) between T1D and six chromosome regions: 12q24, 12q13, 16p13, 18p11, 12p13 and 4q27. Here, we attempted to validate these and six other top findings in 4,000 individuals with T1D, 5,000 controls and 2,997 family trios independent of the WTCCC study. We confirmed unequivocally the associations of 12q24, 12q13, 16p13 and 18p11 (P(follow-up) <or= 1.35 x 10(-9); P(overall) <or= 1.15 x 10(-14)), leaving eight regions with small effects or false-positive associations. We also obtained evidence for chromosome 18q22 (P(overall) = 1.38 x 10(-8)) from a GWA study of nonsynonymous SNPs. Several regions, including 18q22 and 18p11, showed association with autoimmune thyroid disease. This study increases the number of T1D loci with compelling evidence from six to at least ten.", - "journal_title": "Nature genetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/17554260/" - } - ], - "a336cce3-cd6a-4a9d-99da-4e4eda9a5363": [ - { - "pub_id": "7560085", - "title": "Identification of a new susceptibility locus for insulin-dependent diabetes mellitus by ancestral haplotype congenic mapping.", - "authors": "H Ikegami,S Makino,E Yamato,Y Kawaguchi,H Ueda,T Sakamoto,K Takekawa,T Ogihara", - "abstract": "The number and exact locations of the major histocompatibility complex (MHC)-linked diabetogenic genes (Idd-1) are unknown because of strong linkage disequilibrium within the MHC. By using a congenic NOD mouse strain that possesses a recombinant MHC from a diabetes-resistant sister strain, we have now shown that Idd-1 consists of at least two components, one in and one outside the class II A and E regions. A new susceptibility gene (Idd-16) was mapped to the < 11-centiMorgan segment of chromosome 17 adjacent to, but distinct from, previously known Idd-1 candidates, class II A, E, and Tap genes. The coding sequences and splicing donor and acceptor sequences of the Tnfa gene, a candidate gene for Idd-16, were identical in the NOD, CTS, and BALB/c alleles, ruling out amino acid changes in the TNF molecule as a determinant of insulin-dependent diabetes mellitus susceptibility. Our results not only map a new MHC-linked diabetogenic gene(s) but also suggest a new way to fine map disease susceptibility genes within a region where strong linkage disequilibrium exists.", - "journal_title": "The Journal of clinical investigation", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/7560085/" - } - ], - "ab37ae93-c6dd-41a2-a9d0-35666249c057": [ - { - "pub_id": "15316769", - "title": "A reverse genetic approach for generating gene replacement mutants in Ustilago maydis.", - "authors": "A Brachmann,J K\u00f6nig,C Julius,M Feldbr\u00fcgge", - "abstract": "We describe a versatile strategy for generating gene replacement mutants in the phytopathogenic fungus Ustilago maydis. The system includes the choice of 32 different insertion cassettes for genetic engineering purposes, such as gene disruption and more sophisticated insertions of reporter genes, heterologous promoters or combinations of the two. PCR-amplified flanking sequences needed for homologous recombination are ligated to the respective insertion cassettes via SfiI sites. As proof of principle we generated two replacement mutants in which the endogenous promoter of the pheromone gene mfa1 drives expression of the Green Fluorescent Protein gene (gfp). Simultaneously, expression of the mfa1 ORF is controlled either by the carbon source-regulated crg1 promoter or the nitrogen source-regulated nar1 promoter. In both cases gfp expression was pheromone-inducible and pheromone expression was only detected when the heterologous promoters were active.", - "journal_title": "Molecular genetics and genomics : MGG", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/15316769/" - } - ], - "8aee60c9-9bb4-4867-96c9-830c1e43c72e": [ - { - "pub_id": "11424233", - "title": "Genomic variation in pancreatic ion channel genes in Japanese type 2 diabetic patients.", - "authors": "Y Yamada,A Kuroe,Q Li,Y Someya,A Kubota,Y Ihara,Y Tsuura,Y Seino", - "abstract": "Many genetic diseases are caused by mutations in ion channel genes. Because type 2 diabetes is characterized by pancreatic beta-cell insensitivity to glucose, the genes responsible for glucose metabolism and calcium signaling in pancreatic beta-cells are candidate type 2 diabetes susceptibility genes. We have examined genomic variations in two ion channel genes relevant to the molecular pathology of diabetes mellitus, the Kir6.2 subunit of the ATP-sensitive potassium channel gene and alpha(1D) subunit of the voltage-dependent calcium channel (VDCC) gene among Japanese type 2 diabetic patients. There are two alleles in the Kir6.2 gene: EI, glutamic acid at codon 23 and isoleucine at codon 337 and KV, lysine at codon 23 and valine at codon 337. The allelic frequencies of these polymorphisms are similar in type 2 diabetic patients and normal subjects. We also detected trinucleotide repeat polymorphisms in the amino terminus and the carboxyl terminal region of the alpha(1D) gene. Expansion of the ATG trinucleotide repeat from seven to eight was detected only in type 2 diabetic patients, but the frequency was low and was similar in type 2 diabetic patients and normal subjects. Although variations of the Kir6.2 and alpha(1D) genes are not associated with the development of common type 2 diabetes, further studies may determine the role of these genomic variations, especially those in the alpha(1D) VDCC gene, in the pathogenesis of certain subsets of type 2 diabetes, or as a co-factor in the polygenic disorder generally.", - "journal_title": "Diabetes/metabolism research and reviews", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/11424233/" - } - ], - "d74380fc-c045-4d3e-bd50-390d3cee15a4": [ - { - "pub_id": "19651812", - "title": "Common genetic variation near melatonin receptor MTNR1B contributes to raised plasma glucose and increased risk of type 2 diabetes among Indian Asians and European Caucasians.", - "authors": "John C Chambers,Weihua Zhang,Delilah Zabaneh,Joban Sehmi,Piyush Jain,Mark I McCarthy,Philippe Froguel,Aimo Ruokonen,David Balding,Marjo-Riitta Jarvelin,James Scott,Paul Elliott,Jaspal S Kooner", - "abstract": "Fasting plasma glucose and risk of type 2 diabetes are higher among Indian Asians than among European and North American Caucasians. Few studies have investigated genetic factors influencing glucose metabolism among Indian Asians. We carried out genome-wide association studies for fasting glucose in 5,089 nondiabetic Indian Asians genotyped with the Illumina Hap610 BeadChip and 2,385 Indian Asians (698 with type 2 diabetes) genotyped with the Illumina 300 BeadChip. Results were compared with findings in 4,462 European Caucasians. We identified three single nucleotide polymorphisms (SNPs) associated with glucose among Indian Asians at P < 5 x 10(-8), all near melatonin receptor MTNR1B. The most closely associated was rs2166706 (combined P = 2.1 x 10(-9)), which is in moderate linkage disequilibrium with rs1387153 (r(2) = 0.60) and rs10830963 (r(2) = 0.45), both previously associated with glucose in European Caucasians. Risk allele frequency and effect sizes for rs2166706 were similar among Indian Asians and European Caucasians: frequency 46.2 versus 45.0%, respectively (P = 0.44); effect 0.05 (95% CI 0.01-0.08) versus 0.05 (0.03-0.07 mmol/l), respectively, higher glucose per allele copy (P = 0.84). SNP rs2166706 was associated with type 2 diabetes in Indian Asians (odds ratio 1.21 [95% CI 1.06-1.38] per copy of risk allele; P = 0.006). SNPs at the GCK, GCKR, and G6PC2 loci were also associated with glucose among Indian Asians. Risk allele frequencies of rs1260326 (GCKR) and rs560887 (G6PC2) were higher among Indian Asians compared with European Caucasians. Common genetic variation near MTNR1B influences blood glucose and risk of type 2 diabetes in Indian Asians. Genetic variation at the MTNR1B, GCK, GCKR, and G6PC2 loci may contribute to abnormal glucose metabolism and related metabolic disturbances among Indian Asians.", - "journal_title": "Diabetes", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/19651812/" - } - ], - "15524ac0-da3c-4c01-8ae2-1b8c901105ad": [ - { - "pub_id": "15823385", - "title": "Type 2 diabetes: principles of pathogenesis and therapy.", - "authors": "Michael Stumvoll,Barry J Goldstein,Timon W van Haeften", - "abstract": "Type 2 diabetes mellitus has become an epidemic, and virtually no physician is without patients who have the disease. Whereas insulin insensitivity is an early phenomenon partly related to obesity, pancreas beta-cell function declines gradually over time already before the onset of clinical hyperglycaemia. Several mechanisms have been proposed, including increased non-esterified fatty acids, inflammatory cytokines, adipokines, and mitochondrial dysfunction for insulin resistance, and glucotoxicity, lipotoxicity, and amyloid formation for beta-cell dysfunction. Moreover, the disease has a strong genetic component, but only a handful of genes have been identified so far: genes for calpain 10, potassium inward-rectifier 6.2, peroxisome proliferator-activated receptor gamma, insulin receptor substrate-1, and others. Management includes not only diet and exercise, but also combinations of anti-hyperglycaemic drug treatment with lipid-lowering, antihypertensive, and anti platelet therapy.", - "journal_title": "Lancet (London, England)", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/15823385/" - } - ], - "3bd9d1c6-6b4b-42dc-915a-b3323f1fb98a": [ - { - "pub_id": "35115689", - "title": "Combined effects of host genetics and diet on human gut microbiota and incident disease in a single population cohort.", - "authors": "Youwen Qin,Aki S Havulinna,Yang Liu,Pekka Jousilahti,Scott C Ritchie,Alex Tokolyi,Jon G Sanders,Liisa Valsta,Marta Bro\u017cy\u0144ska,Qiyun Zhu,Anupriya Tripathi,Yoshiki V\u00e1zquez-Baeza,Rohit Loomba,Susan Cheng,Mohit Jain,Teemu Niiranen,Leo Lahti,Rob Knight,Veikko Salomaa,Michael Inouye,Guillaume M\u00e9ric", - "abstract": "Human genetic variation affects the gut microbiota through a complex combination of environmental and host factors. Here we characterize genetic variations associated with microbial abundances in a single large-scale population-based cohort of 5,959 genotyped individuals with matched gut microbial metagenomes, and dietary and health records (prevalent and follow-up). We identified 567 independent SNP-taxon associations. Variants at the LCT locus associated with Bifidobacterium and other taxa, but they differed according to dairy intake. Furthermore, levels of Faecalicatena lactaris associated with ABO, and suggested preferential utilization of secreted blood antigens as energy source in the gut. Enterococcus faecalis levels associated with variants in the MED13L locus, which has been linked to colorectal cancer. Mendelian randomization analysis indicated a potential causal effect of Morganella on major depressive disorder, consistent with observational incident disease analysis. Overall, we identify and characterize the intricate nature of host-microbiota interactions and their association with disease.", - "journal_title": "Nature genetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/35115689/" - } - ], - "16b435dd-720c-4f59-ab34-b1b8b28b74e3": [ - { - "pub_id": "17909877", - "title": "Genetic studies of diabetes following the advent of the genome-wide association study: where do we go from here?", - "authors": "T M Frayling,M I McCarthy", - "abstract": "", - "journal_title": "Diabetologia", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/17909877/" - } - ], - "afb0bd31-df62-4a8d-8c20-9841e2d2dc4a": [ - { - "pub_id": "11102973", - "title": "Mutations in the LMNA gene encoding lamin A/C.", - "authors": "J Genschel,H H Schmidt", - "abstract": "Very recently, mutations within the LMNA gene on chromosome 1q21.2 were shown to result in forms of muscular dystrophy, conduction-system disease, cardiomyopathy, and partial lipodystrophy. The LMNA gene encodes for the nucleophilic A-type lamins, lamin A and lamin C. These isoforms are generated by different splicing within exon 10 of LMNA. Thus lamin A/C is, besides emerin, the first known nucleophilic protein which plays a role in human disease. To date, 41 different mutations, predominantly missense, in the LMNA gene are known causing variable phenotypes. Twenty-three different mutations of LMNA have so far been shown to cause autosomal-dominant Emery-Dreifuss muscular dystrophy (EDMD2), three mutations were reported to cause limb-girdle muscular dystrophy (LGMD1B), eight mutations are known to result in dilated cardiomyopathy (CMD1A), and seven mutations were reported to cause familial partial lipodystrophy (FPL). The reports of lamin mutations including the corresponding phenotype are of great interest in order to gain insights into the function of lamin A/C. Here we summarize the mutations published to date in LMNA encoding lamin A/C.", - "journal_title": "Human mutation", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/11102973/" - } - ], - "e9b48e14-aa0c-4331-a17d-82a7f424233c": [ - { - "pub_id": "18971439", - "title": "Public health genomics approach to type 2 diabetes.", - "authors": "Muin J Khoury,Rodolfo Valdez,Ann Albright", - "abstract": "", - "journal_title": "Diabetes", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/18971439/" - } - ], - "32e8633c-a660-4bbf-8a54-2dfc4d826283": [ - { - "pub_id": "20559924", - "title": "Cardiovascular genetic medicine: genomic assessment of prognosis and diagnosis in patients with cardiomyopathy and heart failure.", - "authors": "Bettina Heidecker,Joshua M Hare", - "abstract": "In the last half century, epidemiologic studies and basic science investigations revealed that hypertension (Kannel et al., Ann Intern Med 55:33-50, 1961), hyperlipidemia (Dawber et al., Am J Public Health Nations Health 49:1349-1356, 1959), diabetes (Kannel et al., Am J Cardiol 34(1):29-34, 1974), smoking (Dawber et al., Am J Public Health Nations Health 49:1349-1356, 1959), and inflammation (Rossmann et al., Exp Gerontol 43(3):229-237, 2008) posed increased risk for cardiovascular disease. These associations served both as risk factors and offered insight into disease pathophysiology. Currently, it is increasingly appreciated that polygenic factors may also play a role as etiologic or risk factors (Chakravarti and Little, Nature 421(6921):412-414, 2003; Dorn and Molkentin, Circulation 109(2):150-158, 2004). Recent technologic advances in genomic screening make the search for these factors possible, and robust technologies are now available for both entire genome screening for expression or single nucleotide polymorphisms. In this paper, we review the basic principles of gene expression and molecular signature analysis in the context of potential clinical applications of transcriptomics.", - "journal_title": "Journal of cardiovascular translational research", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/20559924/" - } - ], - "32aeff1a-b64b-47cf-a5a1-2d5ca91c1190": [ - { - "pub_id": "17395743", - "title": "Identification of PVT1 as a candidate gene for end-stage renal disease in type 2 diabetes using a pooling-based genome-wide single nucleotide polymorphism association study.", - "authors": "Robert L Hanson,David W Craig,Meredith P Millis,Kimberly A Yeatts,Sayuko Kobes,John V Pearson,Anne M Lee,William C Knowler,Robert G Nelson,Johanna K Wolford", - "abstract": "To identify genetic variants contributing to end-stage renal disease (ESRD) in type 2 diabetes, we performed a genome-wide analysis of 115,352 single nucleotide polymorphisms (SNPs) in pools of 105 unrelated case subjects with ESRD and 102 unrelated control subjects who have had type 2 diabetes for > or =10 years without macroalbuminuria. Using a sliding window statistic of ranked SNPs, we identified a 200-kb region on 8q24 harboring three SNPs showing substantial differences in allelic frequency between case and control pools. These SNPs were genotyped in individuals comprising each pool, and strong evidence for association was found with rs2720709 (P = 0.000021; odds ratio 2.57 [95% CI 1.66-3.96]), which is located in the plasmacytoma variant translocation gene PVT1. We sequenced all exons, exon-intron boundaries, and the promoter of PVT1 and identified 47 variants, 11 of which represented nonredundant markers with minor allele frequency > or =0.05. We subsequently genotyped these 11 variants and an additional 87 SNPs identified through public databases in 319-kb flanking rs2720709 ( approximately 1 SNP/3.5 kb); 23 markers were associated with ESRD at P < 0.01. The strongest evidence for association was found for rs2648875 (P = 0.0000018; 2.97 [1.90-4.65]), which maps to intron 8 of PVT1. Together, these results suggest that PVT1 may contribute to ESRD susceptibility in diabetes.", - "journal_title": "Diabetes", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/17395743/" - } - ], - "977994e6-80dc-4b82-9bb1-4a89455cd4da": [ - { - "pub_id": "11845220", - "title": "Genetic linkage and association studies of Type I diabetes: challenges and rewards.", - "authors": "L L Field", - "abstract": "Family and twin studies have shown clearly that Type I (insulin-dependent) diabetes mellitus has a genetic basis. However, only within the past decade has it been possible to systematically attempt to identify the genes that increase susceptibility to this disorder using linkage and association analysis of genetic markers distributed across the genome. More than 20 putative diabetes-predisposing genes have been localised in addition to HLA region susceptibility genes detected more than 25 years ago. Unfortunately, the effects of most diabetes-predisposing genes are weak, with the exception of HLA region susceptibility genes (which contribute about half of the genetic risk). The overall effects of diabetes-predisposing genes could be weak because the susceptibility gene occurs in only a small proportion of diabetic patients or the susceptibility gene (although it might be common) produces only a modest increase in risk, probably by acting in concert with other such genes to cause disease. The weak effects of these genes have made them difficult to locate, difficult to confirm in independent studies and difficult to isolate by genetic procedures. This paper summarizes the major challenges that have faced geneticists in mapping Type I diabetes genes, and reviews the progress achieved to date. The rewards of the genetic studies will be twofold: increased understanding of the causes of Type I diabetes, facilitating creation of preventative therapies, and enabling clinicians in the future to use genetic information to predict which children are predisposed to diabetes in order to target them for preventative therapies.", - "journal_title": "Diabetologia", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/11845220/" - } - ], - "d2856682-f650-4613-9637-d9716fa77550": [ - { - "pub_id": "8945470", - "title": "Mutations in the hepatocyte nuclear factor-1alpha gene in maturity-onset diabetes of the young (MODY3).", - "authors": "K Yamagata,N Oda,P J Kaisaki,S Menzel,H Furuta,M Vaxillaire,L Southam,R D Cox,G M Lathrop,V V Boriraj,X Chen,N J Cox,Y Oda,H Yano,M M Le Beau,S Yamada,H Nishigori,J Takeda,S S Fajans,A T Hattersley,N Iwasaki,T Hansen,O Pedersen,K S Polonsky,G I Bell", - "abstract": "The disease non-insulin-dependent (type 2) diabetes mellitus (NIDDM) is characterized by abnormally high blood glucose resulting from a relative deficiency of insulin. It affects about 2% of the world's population and treatment of diabetes and its complications are an increasing health-care burden. Genetic factors are important in the aetiology of NIDDM, and linkage studies are starting to localize some of the genes that influence the development of this disorder. Maturity-onset diabetes of the young (MODY), a single-gene disorder responsible for 2-5% of NIDDM, is characterized by autosomal dominant inheritance and an age of onset of 25 years or younger. MODY genes have been localized to chromosomes 7, 12 and 20 (refs 5, 7, 8) and clinical studies indicate that mutations in these genes are associated with abnormal patterns of glucose-stimulated insulin secretion. The gene on chromosome 7 (MODY2) encodes the glycolytic enzyme glucokinases which plays a key role in generating the metabolic signal for insulin secretion and in integrating hepatic glucose uptake. Here we show that subjects with the MODY3-form of NIDDM have mutations in the gene encoding hepatocyte nuclear factor-1alpha (HNF-1alpha, which is encoded by the gene TCF1). HNF-1alpha is a transcription factor that helps in the tissue-specific regulation of the expression of several liver genes and also functions as a weak transactivator of the rat insulin-I gene.", - "journal_title": "Nature", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/8945470/" - } - ], - "05698181-fa43-4a80-9018-7ef494577c35": [ - { - "pub_id": "18628523", - "title": "Zinc transporter-8 gene (SLC30A8) is associated with type 2 diabetes in Chinese.", - "authors": "Jie Xiang,Xiao-Ying Li,Min Xu,Jie Hong,Yun Huang,Jiao-Rong Tan,Xi Lu,Meng Dai,Bing Yu,Guang Ning", - "abstract": "Several genome-wide association studies identified a strong association of SLC30A8 with type 2 diabetes in individuals of European ancestry. The effect of the association of rs13266634 with type 2 diabetes or related glycemic traits has not been fully extended to non-European populations, and a comprehensive examination of common variants in the gene has not yet been carried out in Han Chinese. The objective of the study was to investigate the association of SLC30A8 with type 2 diabetes in Chinese. A comprehensive gene-based association study was performed using 14 tagging single-nucleotide polymorphism (SNPs) of SLC30A8 in Han Chinese subjects with normal glucose tolerance (NGT; n = 721), impaired glucose regulation (IGR; n = 375), and type 2 diabetes (n = 521). A significant association for SNP rs13266634 was observed between patients with type 2 diabetes and NGT controls (P = 0.016). The association was also observed between combined type 2 diabetes/IGR and NGT subjects (P = 0.002). The adjusted odds ratios for homozygote CC vs. TT at this locus were 1.71 for type 2 diabetes (95% confidence interval 1.19-2.45, P = 0.002) and 1.77 for type 2 diabetes and IGR (95% confidence interval 1.29-2.42, P = 0.0001). We further studied the genotype-phenotype correlation in 70 Han Chinese using iv glucose tolerance test and found an association between SNP rs13266634 and acute insulin response to glucose and disposition index (adjusted P = 0.012 and 0.004, respectively). Our results provide evidence that SLC30A8 is a susceptible locus for type 2 diabetes in Chinese population, and its variant can influence insulin secretion.", - "journal_title": "The Journal of clinical endocrinology and metabolism", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/18628523/" - } - ], - "8bc85643-2c03-464e-9c5a-d3017dabb5b3": [ - { - "pub_id": "15485350", - "title": "Proteomics.", - "authors": "Carmen L de Hoog,Matthias Mann", - "abstract": "The genome sequences of important model systems are available and the focus is now shifting to large-scale experiments enabled by this data. Following in the footsteps of genomics, we have functional genomics, proteomics, and even metabolomics, roughly paralleling the biological hierarchy of the transcription, translation, and production of small molecules. Proteomics is initially concerned with determining the structure, expression, localization, biochemical activity, interactions, and cellular roles of as many proteins as possible. There has been great progress owing to novel instrumentation, experimental strategies, and bioinformatics methods. The area of protein-protein interactions has been especially fruitful. First pass interaction maps of some model organisms exist, and the proteins in many important organelles are about to be determined. Researchers are also beginning to integrate large-scale data sets from various \"omics\" disciplines in targeted investigations of specific biomedical areas and in pursuit of a general framework for systems biology.", - "journal_title": "Annual review of genomics and human genetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/15485350/" - } - ], - "0999dbed-9588-479c-b620-6baae84312dd": [ - { - "pub_id": "17728769", - "title": "New models of collaboration in genome-wide association studies: the Genetic Association Information Network.", - "authors": " ,Teri A Manolio,Laura Lyman Rodriguez,Lisa Brooks,Gon\u00e7alo Abecasis, ,Dennis Ballinger,Mark Daly,Peter Donnelly,Stephen V Faraone, ,Kelly Frazer,Stacey Gabriel,Pablo Gejman, ,Alan Guttmacher,Emily L Harris,Thomas Insel,John R Kelsoe, ,Eric Lander,Norma McCowin,Matthew D Mailman,Elizabeth Nabel,James Ostell,Elizabeth Pugh,Stephen Sherry,Patrick F Sullivan, ,John F Thompson,James Warram, ,David Wholley,Patrice M Milos,Francis S Collins", - "abstract": "The Genetic Association Information Network (GAIN) is a public-private partnership established to investigate the genetic basis of common diseases through a series of collaborative genome-wide association studies. GAIN has used new approaches for project selection, data deposition and distribution, collaborative analysis, publication and protection from premature intellectual property claims. These demonstrate a new commitment to shared scientific knowledge that should facilitate rapid advances in understanding the genetics of complex diseases.", - "journal_title": "Nature genetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/17728769/" - } - ], - "803a6865-d2af-408c-8ae7-d31e820639b2": [ - { - "pub_id": "16954159", - "title": "Polymorphisms in the ghrelin gene are associated with serum high-density lipoprotein cholesterol level and not with type 2 diabetes mellitus in Koreans.", - "authors": "Hyung Jin Choi,Young Min Cho,Min Kyong Moon,Hye Hun Choi,Hyoung Doo Shin,Hak Chul Jang,Seong Yeon Kim,Hong Kyu Lee,Kyong Soo Park", - "abstract": "Ghrelin is known to play a role in glucose metabolism and in beta-cell function. There are controversies regarding the role of ghrelin polymorphisms in diabetes and diabetes-related phenotypes. The objective of this study was to examine polymorphisms of the ghrelin gene in a Korean cohort and investigate associations between them and susceptibility to type 2 diabetes and its related phenotypes. The ghrelin gene was sequenced to identify polymorphisms in 24 DNA samples. Common variants were then genotyped in 760 type 2 diabetic patients and 641 nondiabetic subjects. Genetic associations with diabetes-related phenotypes were also analyzed. Nine polymorphisms were identified, and four common polymorphisms [g.-1500C>G, g.-1062G > C, g.-994C > T, g.+408C > A (Leu72Met)] were genotyped in a larger study. The genotype distributions of these four common polymorphisms in type 2 diabetes patients were similar to those of normal nondiabetic controls. However, these four common polymorphisms were variably associated with several diabetes-related phenotypes, such as high-density lipoprotein (HDL) cholesterol, fasting plasma glucose, and homeostasis model assessment of insulin resistance. In particular, subjects harboring g.-1062C were associated with a lower serum HDL cholesterol level after adjusting for other variables (P = 0.0004 or 0.01 after Bonferroni correction for 24 tests). The aforementioned four common polymorphisms in the ghrelin gene were not found to be significantly associated with susceptibility to type 2 diabetes mellitus in the Korean population. However, the common polymorphism g.-1062G > C in the promoter region of the ghrelin gene was found to be significantly associated with serum HDL cholesterol levels.", - "journal_title": "The Journal of clinical endocrinology and metabolism", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/16954159/" - } - ], - "1f309305-e804-40c0-91ed-9203e4b798c5": [ - { - "pub_id": "23089364", - "title": "Effect of genome-wide genotyping and reference panels on rare variants imputation.", - "authors": "Hou-Feng Zheng,Martin Ladouceur,Celia M T Greenwood,J Brent Richards", - "abstract": "Common variants explain little of the variance of most common disease, prompting large-scale sequencing studies to understand the contribution of rare variants to these diseases. Imputation of rare variants from genome-wide genotypic arrays offers a cost-efficient strategy to achieve necessary sample sizes required for adequate statistical power. To estimate the performance of imputation of rare variants, we imputed 153 individuals, each of whom was genotyped on 3 different genotype arrays including 317k, 610k and 1 million single nucleotide polymorphisms (SNPs), to two different reference panels: HapMap2 and 1000 Genomes pilot March 2010 release (1KGpilot) by using IMPUTE version 2. We found that more than 94% and 84% of all SNPs yield acceptable accuracy (info > 0.4) in HapMap2 and 1KGpilot-based imputation, respectively. For rare variants (minor allele frequency (MAF) \u22645%), the proportion of well-imputed SNPs increased as the MAF increased from 0.3% to 5% across all 3 genome-wide association study (GWAS) datasets. The proportion of well-imputed SNPs was 69%, 60% and 49% for SNPs with a MAF from 0.3% to 5% for 1M, 610k and 317k, respectively. None of the very rare variants (MAF \u2264 0.3%) were well imputed. We conclude that the imputation accuracy of rare variants increases with higher density of genome-wide genotyping arrays when the size of the reference panel is small. Variants with lower MAF are more difficult to impute. These findings have important implications in the design and replication of large-scale sequencing studies.", - "journal_title": "Journal of genetics and genomics = Yi chuan xue bao", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/23089364/" - } - ], - "0d3d0b67-148d-4df2-8bd9-e89c3a726ec0": [ - { - "pub_id": "7704030", - "title": "Linkage disequilibrium mapping of a type 1 diabetes susceptibility gene (IDDM7) to chromosome 2q31-q33.", - "authors": "J B Copeman,F Cucca,C M Hearne,R J Cornall,P W Reed,K S R\u00f8nningen,D E Undlien,L Nistic\u00f2,R Buzzetti,R Tosi", - "abstract": "The role of human chromosome 2 in type 1 diabetes was evaluated by analysing linkage and linkage disequilibrium at 21 microsatellite marker loci, using 348 affected sibpair families and 107 simplex families. The microsatellite D2S152 was linked to, and associated with, disease in families from three different populations. Our evidence localizes a new diabetes susceptibility gene, IDDM7, to within two centiMorgans of D2S152. This places it in a region of chromosome 2q that shows conserved synteny with the region of mouse chromosome 1 containing the murine type 1 diabetes gene, Idd5. These results demonstrate the utility of polymorphic microsatellites for linkage disequilibrium mapping of genes for complex diseases.", - "journal_title": "Nature genetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/7704030/" - } - ], - "e51e88b2-bea3-4ab7-858f-824f7d5ccbdd": [ - { - "pub_id": "24582139", - "title": "Potential epigenetic dysregulation of genes associated with MODY and type 2 diabetes in humans exposed to a diabetic intrauterine environment: an analysis of genome-wide DNA methylation.", - "authors": "Melissa C del Rosario,Vicky Ossowski,William C Knowler,Clifton Bogardus,Leslie J Baier,Robert L Hanson", - "abstract": "The aim of this study is to investigate the potential role of DNA methylation in mediating the increased risk of developing type 2 diabetes in offspring of mothers who had diabetes during pregnancy. Peripheral blood leukocytes were collected from non-diabetic Pima Indians who were either offspring of diabetic mothers (ODM; n=14) or offspring of nondiabetic mothers (ONDM; n=14). The two groups were matched for age, sex, age of mother, and fraction of Pima ethnicity. Differentially methylated regions were determined using a MeDIP-chip assay on an Affymetrix Human Tiling 2.0R Array. Data were analyzed using the model based analysis of tiling arrays (MAT) algorithm, and 4883 regions overlapping with putative promoters, were identified as differentially methylated, having met an empirically derived threshold (nominal p<0.0077). The list of genes with differentially methylated promoters was subjected to KEGG pathway analysis to determine canonical metabolic pathways enriched by these genes. Pathway analysis of genes with differentially methylated promoters identified the top 3 enriched pathways as maturity onset diabetes of the young (MODY), type 2 diabetes, and Notch signaling. Several genes in these pathways are known to affect pancreatic development and insulin secretion. These findings support the hypothesis that epigenetic changes may increase the risk of type 2 diabetes via an effect on \u03b2-cell function in the offspring of mothers with diabetes during pregnancy.", - "journal_title": "Metabolism: clinical and experimental", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/24582139/" - } - ], - "be3e9fcb-5469-48eb-bc1b-118e58f82cc5": [ - { - "pub_id": "18349101", - "title": "Genetics and genomics for clinicians.", - "authors": "Phil B Fontanarosa,Boris Pasche,Catherine D DeAngelis", - "abstract": "", - "journal_title": "JAMA", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/18349101/" - } - ], - "5ab4c77b-f156-4c78-aada-3e67abed8f64": [ - { - "pub_id": "11445000", - "title": "Vitamin D receptor initiation codon polymorphism influences genetic susceptibility to type 1 diabetes mellitus in the Japanese population.", - "authors": "Y Ban,M Taniyama,T Yanagawa,S Yamada,T Maruyama,A Kasuga,Y Ban", - "abstract": "Vitamin D has been shown to exert manifold immunomodulatory effects. Type 1 diabetes mellitus (T1DM) is regarded to be immune-mediated and vitamin D prevents the development of diabetes in the NOD mouse. We studied the association between T1DM and the initiation codon polymorphism in exon 2 of the vitamin D receptor gene in a Japanese population. We also investigated associations between the vitamin D receptor polymorphism and GAD65-antibody (Ab) positivity. We carried out polymerase chain reaction-restriction fragment length polymorphism analysis in 110 Japanese T1DM patients and 250 control subjects. GAD65 antibodies were assessed in 78 patients with T1DM. We found a significantly higher prevalence of the F allele / the FF genotype in the patients compared to the controls (P = 0.0069 and P = 0.014, respectively). Genotype and allele frequencies differed significantly between GAD65-Ab-positive patients and controls (P = 0.017 and P = 0.012, respectively), but neither between GAD65-Ab-negative patients and controls (P = 0.68 and P = 0.66, respectively) nor between GAD65-Ab-positive and -negative patients (P = 0.19 and P = 0.16, respectively). Our findings suggest that the vitamin D receptor initiation codon polymorphism influences genetic susceptibility to T1DM among the Japanese. This polymorphism is also associated with GAD65-Ab-positive T1DM, although the absence of a significant difference between GAD65-Ab-negative patients and controls might be simply due to the small sample size of patients tested for GAD65 antibodies.", - "journal_title": "BMC medical genetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/11445000/" - } - ], - "e17ef791-e77a-486b-a3c1-c7f037fa530c": [ - { - "pub_id": "19768584", - "title": "SNPs: impact on gene function and phenotype.", - "authors": "Barkur S Shastry", - "abstract": "Single nucleotide polymorphism (SNP) is the simplest form of DNA variation among individuals. These simple changes can be of transition or transversion type and they occur throughout the genome at a frequency of about one in 1,000 bp. They may be responsible for the diversity among individuals, genome evolution, the most common familial traits such as curly hair, interindividual differences in drug response, and complex and common diseases such as diabetes, obesity, hypertension, and psychiatric disorders. SNPs may change the encoded amino acids (nonsynonymous) or can be silent (synonymous) or simply occur in the noncoding regions. They may influence promoter activity (gene expression), messenger RNA (mRNA) conformation (stability), and subcellular localization of mRNAs and/or proteins and hence may produce disease. Therefore, identification of numerous variations in genes and analysis of their effects may lead to a better understanding of their impact on gene function and health of an individual. This improved knowledge may provide a starting point for the development of new, useful SNP markers for medical testing and a safer individualized medication to treat the most common devastating disorders. This will revolutionize the medical field in the future. To illustrate the effect of SNPs on gene function and phenotype, this minireview focuses on evidences revealing the impact of SNPs on the development and progression of three human eye disorders (Norrie disease, familial exudative vitreoretinopathy, and retinopathy of prematurity) that have overlapping clinical manifestations.", - "journal_title": "Methods in molecular biology (Clifton, N.J.)", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/19768584/" - } - ], - "994ec7c3-b729-4868-a015-36f1fc4fc19e": [ - { - "pub_id": "10090898", - "title": "Linkage of type 2 diabetes mellitus and of age at onset to a genetic location on chromosome 10q in Mexican Americans.", - "authors": "R Duggirala,J Blangero,L Almasy,T D Dyer,K L Williams,R J Leach,P O'Connell,M P Stern", - "abstract": "Since little is known about chromosomal locations harboring type 2 diabetes-susceptibility genes, we conducted a genomewide scan for such genes in a Mexican American population. We used data from 27 low-income extended Mexican American pedigrees consisting of 440 individuals for whom genotypic data are available for 379 markers. We used a variance-components technique to conduct multipoint linkage analyses for two phenotypes: type 2 diabetes (a discrete trait) and age at onset of diabetes (a truncated quantitative trait). For the multipoint analyses, a subset of 295 markers was selected on the basis of optimal spacing and informativeness. We found significant evidence that a susceptibility locus near the marker D10S587 on chromosome 10q influences age at onset of diabetes (LOD score 3.75) and is also linked with type 2 diabetes itself (LOD score 2.88). This susceptibility locus explains 63.8%+/-9.9% (P=. 000016) of the total phenotypic variation in age at onset of diabetes and 65.7%+/-10.9% (P=.000135) of the total variation in liability to type 2 diabetes. Weaker evidence was found for linkage of diabetes and of age at onset to regions on chromosomes 3p, 4q, and 9p. In conclusion, our strongest evidence for linkage to both age at onset of diabetes and type 2 diabetes itself in the Mexican American population was for a region on chromosome 10q.", - "journal_title": "American journal of human genetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/10090898/" - } - ], - "fdc9783f-ddfd-49eb-bd93-970ee7479472": [ - { - "pub_id": "17823772", - "title": "SNPs in the KCNJ11-ABCC8 gene locus are associated with type 2 diabetes and blood pressure levels in the Japanese population.", - "authors": "Yukiko Sakamoto,Hiroshi Inoue,Parvaneh Keshavarz,Katsuyuki Miyawaki,Yuka Yamaguchi,Maki Moritani,Kiyoshi Kunika,Naoto Nakamura,Toshikazu Yoshikawa,Natsuo Yasui,Hiroshi Shiota,Toshihito Tanahashi,Mitsuo Itakura", - "abstract": "Many genetic association studies support a contribution of genetic variants in the KCNJ11-ABCC8 gene locus to type 2 diabetes (T2D) susceptibility in Caucasians. In non-Caucasian populations, however, there have been only a few association studies, and discordant results were obtained. Herein, we selected a total of 31 SNPs covering a 211.3-kb region of the KCNJ11-ABCC8 locus, characterized the patterns of linkage disequilibrium (LD) and haplotype structure, and performed a case-control association study in a Japanese population consisting of 909 T2D patients and 893 control subjects. We found significant associations between eight SNPs, including the KCNJ11 E23K and ABCC8 S1369A variants, and T2D. These disease-associated SNPs were genetically indistinguishable because of the presence of strong LD, as found previously in Caucasians. For the KCNJ11 E23K variant, the most significant association was obtained under a dominant genetic model (OR 1.32, 95% CI 1.09-1.60, P = 0.004). A meta-analysis of East Asian studies, comprising a total of 3,357 T2D patients (77.4% Japanese) and 2,836 control subjects (77.8% Japanese), confirmed the significant role of the KCNJ11 E23K variant in T2D susceptibility. Furthermore, we found evidence suggesting that the KCNJ11 E23K genotype is independently associated with higher blood-pressure levels.", - "journal_title": "Journal of human genetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/17823772/" - } - ], - "4d461731-b45b-468c-9bf6-b5f0503b0b78": [ - { - "pub_id": "16443794", - "title": "Quantitative trait loci on chromosome 8q24 for pancreatic beta-cell function and 7q11 for insulin sensitivity in obese nondiabetic white and black families: evidence from genome-wide linkage scans in the NHLBI Hypertension Genetic Epidemiology Network (HyperGEN) study.", - "authors": "Ping An,Barry I Freedman,Stephen S Rich,Stephen A Mandel,Donna K Arnett,Richard H Myers,Yii-Der I Chen,Steven C Hunt,D C Rao", - "abstract": "Genome-wide linkage scans were carried out using a multipoint variance components method in white and black families of the NHLBI Hypertension Genetic Epidemiology Network (HyperGEN) study to identify quantitative trait loci (QTLs) for pancreatic beta-cell function and insulin sensitivity estimated through the newly released nonlinear computer version of homeostasis model assessment 2. Participants fasting <8 h, with diagnosed type 2 diabetes, or taking blood glucose or blood lipid-lowering medications were excluded. Both phenotypes were adjusted separately by race and sex for the effects of age, BMI, and field center before linkage scans using 370 microsatellite markers were performed. A total of 685 white families (1,180 sibpairs) and 773 black families (775 sibpairs) were evaluated as well as subsets including 267 obese white families (757 sibpairs) and 427 obese black families (599 sibpairs) identified through tree-linkage analyses using interacting covariates of age, sex, and BMI. For beta-cell function in the obese white families, significant (logarithm of odds [LOD] score >3.6) evidence supporting linkages was detected on chromosome 8q24 at D8S1179 (135 cM, LOD score 4.2, empirical P = 0.002) and at D8S1128 (140 cM, LOD score 3.7, empirical P = 0.003). In addition, two regions supported linkage for insulin sensitivity index in the obese black families on chromosome 7q11 at D7S3046 (79 cM, LOD score 3.0, empirical P = 0.018) and on chromosome 6q26 at D6S1277 (173 cM, LOD score 3.0, empirical P = 0.018). Reducing clinical heterogeneity using obesity data and improved estimates of beta-cell function and insulin sensitivity may have permitted identification of a QTL on chromosome 8q24 for beta-cell function in the presence of estimated insulin resistance and a QTL on chromosome 7q11 for insulin sensitivity. These regions replicate previous reports for type 2 diabetes-associated traits.", - "journal_title": "Diabetes", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/16443794/" - } - ], - "7a8d7859-d7f3-4f05-8966-ecb7ab6e64d5": [ - { - "pub_id": "11176766", - "title": "Glucose tolerance and cardiovascular mortality: comparison of fasting and 2-hour diagnostic criteria.", - "authors": " ", - "abstract": "New diagnostic criteria for diabetes based on fasting blood glucose (FBG) level were approved by the American Diabetes Association. The impact of using FBG only has not been evaluated thoroughly. The fasting and the 2-hour glucose (2h-BG) criteria were compared with regard to the prediction of mortality. Existing baseline data on glucose level at fasting and 2 hours after a 75-g oral glucose tolerance test from 10 prospective European cohort studies including 15 388 men and 7126 women aged 30 to 89 years, with a median follow-up of 8.8 years, were analyzed. Hazards ratios for death from all causes, cardiovascular disease, coronary heart disease, and stroke were estimated. Multivariate Cox regression analyses showed that the inclusion of FBG did not add significant information on the prediction of 2h-BG alone (P>.10 for various causes), whereas the addition of 2h-BG to FBG criteria significantly improved the prediction (P<.001 for all causes and P<.005 for cardiovascular disease). In a model including FBG and 2h-BG simultaneously, hazards ratios (95% confidence intervals) in subjects with diabetes on 2h-BG were 1.73 (1.45-2.06) for all causes, 1.40 (1.02-1.92) for cardiovascular disease, 1.56 (1.03-2.36) for coronary heart disease, and 1.29 (0.66-2.54) for stroke mortality, compared with the normal 2h-BG group. Compared with the normal FBG group, the corresponding hazards ratios in subjects with diabetes on FBG were 1.21 (1.01-1.44), 1.20 (0.88-1.64), 1.09 (0.71-1.67), and 1.64 (0.88-3.07), respectively. The largest number of excess deaths was observed in subjects who had impaired glucose tolerance but normal FBG levels. The 2h-BG is a better predictor of deaths from all causes and cardiovascular disease than is FBG.", - "journal_title": "Archives of internal medicine", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/11176766/" - } - ], - "f5adaa9e-24e6-4633-8d92-ad98e19d318f": [ - { - "pub_id": "17692034", - "title": "Genetics and genomics of hepatic acute phase reactants: a mini-review.", - "authors": "Andras K Fulop", - "abstract": "Systemic acute phase response is a component of innate immunity and a consequence of local or systemic inflammation. A prominent feature of acute phase reaction is the alteration of gene expression in hepatocytes. The classical acute phase reactants are released into the blood and may be exuded into other body fluids. Generally, they exert anti-inflammatory action and are important players of the homeostasis maintenance. The genetic background influences a person's response to disturbances of homeostasis, including infections, stress and tissue injury. The most frequent and physiologically relevant genetic polymorphisms of the representatives of classical acute phase proteins are discussed herein. The genetic variations of acute phase proteins or their regulators are associated with several pathological conditions. The high-throughput genomic and proteomic technologies combined with bioinformatics give the most recent approaches to the study and analysis of acute phase proteins, thereby widening the scope of the term 'acute phase reactants' or discovering novel ones. Simultaneous testing of numerous analytes, including acute phase proteins from the same, small volume sample may give diagnostic tools for diseases. Accumulating knowledge about acute phase reaction may lead to the development of novel therapies and other prevention alternatives.", - "journal_title": "Inflammation & allergy drug targets", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/17692034/" - } - ], - "647571cd-ff36-4be4-97c4-cd006d9bfbaf": [ - { - "pub_id": "19336477", - "title": "SLC29A3 gene is mutated in pigmented hypertrichosis with insulin-dependent diabetes mellitus syndrome and interacts with the insulin signaling pathway.", - "authors": "Simon T Cliffe,Jamie M Kramer,Khalid Hussain,Joris H Robben,Eiko K de Jong,Arjan P de Brouwer,Esther Nibbeling,Erik-Jan Kamsteeg,Melanie Wong,Julie Prendiville,Chela James,Raja Padidela,Charlie Becknell,Hans van Bokhoven,Peter M T Deen,Raoul C M Hennekam,Robert Lindeman,Annette Schenck,Tony Roscioli,Michael F Buckley", - "abstract": "Pigmented hypertrichotic dermatosis with insulin-dependent diabetes (PHID) syndrome is a recently described autosomal recessive disorder associated with predominantly antibody negative, insulin-dependent diabetes mellitus. In order to identify the genetic basis of PHID and study its relationship with glucose metabolism, we performed homozygosity mapping in five unrelated families followed by candidate gene sequencing. Five loss-of-function mutations were identified in the SLC29A3 gene which encodes a member of a highly conserved protein family that transports nucleosides, nucleobases and nucleoside analogue drugs, hENT3. We show that PHID is allelic with a related syndrome without diabetes mellitus, H syndrome. The interaction of SLC29A3 with insulin signaling pathways was then studied using an established model in Drosophila melanogaster. Ubiquitous knockdown of the Drosophila ortholog of hENT3, dENT1 is lethal under stringent conditions; whereas milder knockdown induced scutellar bristle phenotypes similar to those previously reported in the knockdown of the Drosophila ortholog of the Islet gene. A cellular growth assay showed a reduction of cell size/number which could be rescued or enhanced by manipulation of the Drosophila insulin receptor and its downstream signaling effectors, dPI3K and dAkt. In summary, inactivating mutations in SLC29A3 cause a syndromic form of insulin-dependent diabetes in humans and in Drosophila profoundly affect cell size/number through interactions with the insulin signaling pathway. These data suggest that further investigation of the role of SLC29A3 in glucose metabolism is a priority for diabetes research.", - "journal_title": "Human molecular genetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/19336477/" - } - ], - "0c15fb57-68e0-4242-964f-6165eb23dbce": [ - { - "pub_id": "11916952", - "title": "Genome-wide search for type 2 diabetes in Japanese affected sib-pairs confirms susceptibility genes on 3q, 15q, and 20q and identifies two new candidate Loci on 7p and 11p.", - "authors": "Yasumichi Mori,Shuichi Otabe,Christian Dina,Kazuki Yasuda,C\u00e9line Populaire,C\u00e9cile Lecoeur,Vincent Vatin,Emmanuelle Durand,Kazuo Hara,Terumasa Okada,Kazuyuki Tobe,Philippe Boutin,Takashi Kadowaki,Philippe Froguel", - "abstract": "The genetic background that predisposes the Japanese population to type 2 diabetes is largely unknown. Therefore, we conducted a 10-cM genome-wide scan for type 2 diabetes traits in the 359 affected individuals from 159 families, yielding 224 affected sib-pairs of Japanese origin. Nonparametric multipoint linkage analyses performed in the whole population showed one suggestive linked region on 11p13-p12 (maximum logarithm of odds score [MLS] 3.08, near Pax6) and seven potentially linked regions (MLS >1.17) at 1p36-p32, 2q34, 3q26-q28, 6p23, 7p22-p21, 15q13-q21, and 20q12-q13 (near the gene for hepatocyte nuclear factor-4alpha [HNF-4alpha]). Subset analyses according to maximal BMI and early age at diagnosis added suggestive evidence of linkage with type 2 diabetes at 7p22-p21 (MLS 3.51), 15q13-q21 (MLS 3.91), and 20q12-q13 (MLS 2.32). These results support previous indication for linkage found on chromosome 3q, 15q, and 20q in other populations and identifies two new potential loci on 7p and 11p that may confer genetic risk for type 2 diabetes in the Japanese population.", - "journal_title": "Diabetes", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/11916952/" - } - ], - "9aaab43e-8e34-47b8-9175-7a321d9b79b1": [ - { - "pub_id": "9119224", - "title": "Hypothalamic expression of ART, a novel gene related to agouti, is up-regulated in obese and diabetic mutant mice.", - "authors": "J R Shutter,M Graham,A C Kinsey,S Scully,R L\u00fcthy,K L Stark", - "abstract": "We have isolated cDNA clones that encode a novel human gene related to agouti. Sequence analysis of this gene, named ART, for agouti-related transcript, predicts a 132-amino-acid protein that is 25% identical to human agouti. The highest degree of identity is within the carboxyl terminus of both proteins. Like agouti, ART contains a putative signal sequence and a cysteine rich carboxyl terminus, but lacks the region of basic residues and polyproline residues found in the middle of the agouti protein. Both agouti and ART contain 11 cysteines, and 9 of these are conserved spatially. ART is expressed primarily in the adrenal gland, subthalamic nucleus, and hypothalamus, with a lower level of expression occurring in testis, lung, and kidney. The murine homolog of ART was also isolated and is predicted to encode a 131-amino-acid protein that shares 81% amino acid identity to humans. The mouse was found to have the same expression pattern as human when assessed by RT-PCR. Examination by in situ hybridization using mouse tissues showed localized expression in the arcuate nucleus of the hypothalamus, the median eminence, and the adrenal medulla. In addition, the hypothalamic expression of ART was elevated approximately 10-fold in ob/ob and db/db mice. ART was mapped to human chromosome 16q22 and to mouse chromosome 8D1-D2. The expression pattern and transcriptional regulation of ART, coupled with the known actions of agouti, suggests a role for ART in the regulation of melanocortin receptors within the hypothalamus and adrenal gland, and implicates this novel gene in the central control of feeding.", - "journal_title": "Genes & development", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/9119224/" - } - ], - "1da4ca81-cc55-4507-8b55-08263e25901c": [ - { - "pub_id": "22030212", - "title": "Association between neighborhood walkability, cardiorespiratory fitness and body-mass index.", - "authors": "Christine M Hoehner,Susan L Handy,Yan Yan,Steven N Blair,David Berrigan", - "abstract": "Many studies have found cross-sectional associations between characteristics of the neighborhood built environment and physical activity (PA) behavior. However, most are based on self-reported PA, which is known to result in overestimation of PA and differential misclassification by demographic and biological characteristics. Cardiorespiratory fitness (CRF) is an objective marker of PA because it is primarily determined by PA. Furthermore, it is causally related to long-term health outcomes. Therefore, analyses of the association between CRF and built environment could strengthen arguments for the importance of built environment influences on health. We examined the association between neighborhood walkability and CRF and body-mass index (BMI). This cross-sectional analysis included 16,543 adults (5017 women, 11,526 men) aged 18-90 years with home addresses in Texas who had a comprehensive clinical examination between 1987 and 2005. Outcomes included CRF from total duration on a maximal exercise treadmill test and measured BMI. Three neighborhood walkability factors emerged from principal components analyses of block-group measures derived from the U.S. Census. In multilevel adjusted analyses, the neighborhood walkability factors were significantly associated with CRF and BMI among men and women in the expected direction. An interaction between one of the neighborhood factors and age was also observed. The interaction suggested that living in neighborhoods with older homes and with residents traveling shorter distances to work was more strongly positively associated with CRF among younger adults and more strongly negatively associated with BMI among older adults. In conclusion, neighborhood characteristics hypothesized to support more PA and less driving were associated with higher levels of CRF and lower BMI. Demonstration of an association between built environment characteristics and CRF is a significant advance over past studies based on self-reported PA. Nevertheless, stronger causal evidence depends on more robust study designs and sophisticated measures of the environment, behavior, and their physiological consequences.", - "journal_title": "Social science & medicine (1982)", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/22030212/" - } - ], - "833f89fa-ec58-4670-8f3b-8f5eb486a5bf": [ - { - "pub_id": "18550651", - "title": "Angiotensin converting enzyme insertion/deletion polymorphism and renoprotection in diabetic and nondiabetic nephropathies.", - "authors": "Piero Ruggenenti,Paola Bettinaglio,Franck Pinares,Giuseppe Remuzzi", - "abstract": "Despite the huge amount of studies looking for candidate genes, the ACE gene remains the unique, well-characterized locus clearly associated with pathogenesis and progression of chronic kidney disease, and with response to treatment with drugs that directly interfere with the renin angiotensin system (RAS), such as angiotensin converting enzyme (ACE) inhibitors and angiotensin II receptor antagonists (ARA). The II genotype is protective against development and progression of type I and type II nephropathy and is associated with a slower progression of nondiabetic proteinuric kidney disease. ACE inhibitors are particularly effective at the stage of normoalbuminuria or microalbuminuria in both type I and type II diabetics with the II genotype, whereas the DD genotype is associated with a better response to ARA therapy in overt nephropathy of type II diabetes and to ACE inhibitors in male patients with nondiabetic proteinuric nephropathies. The role of other RAS or non-RAS polymorphisms and their possible interactions with different ACE I/D genotypes are less clearly defined. Thus, evaluating the ACE I/D polymorphism is a reliable tool to identify patients at risk and those who may benefit the most of renoprotective therapy with ACE inhibitors or ARA. This may guide pharmacologic therapy in individual patients and help design clinical trials in progressive nephropathies. Moreover, it might help optimize prevention and intervention strategies at population levels, in particular, in countries where resources are extremely limited and 1 million patients continue to die every year of cardiovascular or renal disease.", - "journal_title": "Clinical journal of the American Society of Nephrology : CJASN", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/18550651/" - } - ], - "d7ae1883-9ba5-4933-bdcb-98c63bebd517": [ - { - "pub_id": "28267855", - "title": "Association Between Dietary Factors and Mortality From Heart Disease, Stroke, and Type 2 Diabetes in the United States.", - "authors": "Renata Micha,Jose L Pe\u00f1alvo,Frederick Cudhea,Fumiaki Imamura,Colin D Rehm,Dariush Mozaffarian", - "abstract": "In the United States, national associations of individual dietary factors with specific cardiometabolic diseases are not well established. To estimate associations of intake of 10 specific dietary factors with mortality due to heart disease, stroke, and type 2 diabetes (cardiometabolic mortality) among US adults. A comparative risk assessment model incorporated data and corresponding uncertainty on population demographics and dietary habits from National Health and Nutrition Examination Surveys (1999-2002: n\u2009=\u20098104; 2009-2012: n\u2009=\u20098516); estimated associations of diet and disease from meta-analyses of prospective studies and clinical trials with validity analyses to assess potential bias; and estimated disease-specific national mortality from the National Center for Health Statistics. Consumption of 10 foods/nutrients associated with cardiometabolic diseases: fruits, vegetables, nuts/seeds, whole grains, unprocessed red meats, processed meats, sugar-sweetened beverages (SSBs), polyunsaturated fats, seafood omega-3 fats, and sodium. Estimated absolute and percentage mortality due to heart disease, stroke, and type 2 diabetes in 2012. Disease-specific and demographic-specific (age, sex, race, and education) mortality and trends between 2002 and 2012 were also evaluated. In 2012, 702\u202f308 cardiometabolic deaths occurred in US adults, including 506\u202f100 from heart disease (371\u202f266 coronary heart disease, 35\u202f019 hypertensive heart disease, and 99\u202f815 other cardiovascular disease), 128\u202f294 from stroke (16\u202f125 ischemic, 32\u202f591 hemorrhagic, and 79\u202f578 other), and 67\u202f914 from type 2 diabetes. Of these, an estimated 318\u202f656 (95% uncertainty interval [UI], 306\u202f064-329\u202f755; 45.4%) cardiometabolic deaths per year were associated with suboptimal intakes-48.6% (95% UI, 46.2%-50.9%) of cardiometabolic deaths in men and 41.8% (95% UI, 39.3%-44.2%) in women; 64.2% (95% UI, 60.6%-67.9%) at younger ages (25-34 years) and 35.7% (95% UI, 33.1%-38.1%) at older ages (\u226575 years); 53.1% (95% UI, 51.6%-54.8%) among blacks, 50.0% (95% UI, 48.2%-51.8%) among Hispanics, and 42.8% (95% UI, 40.9%-44.5%) among whites; and 46.8% (95% UI, 44.9%-48.7%) among lower-, 45.7% (95% UI, 44.2%-47.4%) among medium-, and 39.1% (95% UI, 37.2%-41.2%) among higher-educated individuals. The largest numbers of estimated diet-related cardiometabolic deaths were related to high sodium (66\u202f508 deaths in 2012; 9.5% of all cardiometabolic deaths), low nuts/seeds (59\u202f374; 8.5%), high processed meats (57\u202f766; 8.2%), low seafood omega-3 fats (54\u202f626; 7.8%), low vegetables (53\u202f410; 7.6%), low fruits (52\u202f547; 7.5%), and high SSBs (51\u202f694; 7.4%). Between 2002 and 2012, population-adjusted US cardiometabolic deaths per year decreased by 26.5%. The greatest decline was associated with insufficient polyunsaturated fats (-20.8% relative change [95% UI, -18.5% to -22.8%]), nuts/seeds (-18.0% [95% UI, -14.6% to -21.0%]), and excess SSBs (-14.5% [95% UI, -12.0% to -16.9%]). The greatest increase was associated with unprocessed red meats (+14.4% [95% UI, 9.1%-19.5%]). Dietary factors were estimated to be associated with a substantial proportion of deaths from heart disease, stroke, and type 2 diabetes. These results should help identify priorities, guide public health planning, and inform strategies to alter dietary habits and improve health.", - "journal_title": "JAMA", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/28267855/" - } - ], - "9c6097d3-f47f-419e-810f-99775e92a644": [ - { - "pub_id": "18349099", - "title": "Centralized biorepositories for genetic and genomic research.", - "authors": "Geoffrey S Ginsburg,Thomas W Burke,Phillip Febbo", - "abstract": "", - "journal_title": "JAMA", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/18349099/" - } - ], - "0a960401-f382-47c7-8dc5-c38a85b9d7e1": [ - { - "pub_id": "15331559", - "title": "Functional variants in the glutathione peroxidase-1 (GPx-1) gene are associated with increased intima-media thickness of carotid arteries and risk of macrovascular diseases in japanese type 2 diabetic patients.", - "authors": "Tohru Hamanishi,Hiroto Furuta,Hisako Kato,Asako Doi,Masanori Tamai,Hiroko Shimomura,Setsuya Sakagashira,Masahiro Nishi,Hideyuki Sasaki,Tokio Sanke,Kishio Nanjo", - "abstract": "Atherosclerosis in type 2 diabetic patients has been linked to increased oxidative stress. Glutathione peroxidase-1 (GPx-1) plays an important role in the antioxidant defense of the vascular wall. To assess the association between variants in the GPx-1 gene and atherosclerosis, we screened the gene in 184 Japanese type 2 diabetic patients and identified four polymorphisms (-602A/G, +2C/T, Ala(5)/Ala(6), and Pro198Leu). Among these polymorphisms, -602G, +2T, Ala(6), and 198Leu were in strong linkage disequilibrium with each other. The patients were divided into two groups on the basis of the codon 198 polymorphism, Pro/Pro (n = 151) and Pro/Leu (n = 33), to analyze clinical characteristics. The mean intima-media thickness (IMT) of common carotid arteries (P = 0.0028) and the prevalence of cardiovascular disease (P = 0.035) and peripheral vascular disease (P = 0.027) were significantly higher in the Pro/Leu group than in the Pro/Pro group. In vitro functional analyses indicated that the combination of polymorphisms (Ala(6)/198Leu) of the GPx-1 gene had a 40% decrease in enzyme activity, and the combination of polymorphisms (-602G/+2T) had a 25% decrease in transcriptional activity. These results suggest that functional variants in the GPx-1 gene are associated with increased IMT of carotid arteries and risk of cardiovascular and peripheral vascular diseases in type 2 diabetic patients.", - "journal_title": "Diabetes", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/15331559/" - } - ], - "5c8c5649-dbaa-43cb-a8ce-7d3bc6458a38": [ - { - "pub_id": "17848624", - "title": "Adipocyte death, adipose tissue remodeling, and obesity complications.", - "authors": "Katherine J Strissel,Zlatina Stancheva,Hideaki Miyoshi,James W Perfield,Jason DeFuria,Zoe Jick,Andrew S Greenberg,Martin S Obin", - "abstract": "We sought to determine the role of adipocyte death in obesity-induced adipose tissue (AT) inflammation and obesity complications. Male C57BL/6 mice were fed a high-fat diet for 20 weeks to induce obesity. Every 4 weeks, insulin resistance was assessed by intraperitoneal insulin tolerance tests, and epididymal (eAT) and inguinal subcutaneous AT (iAT) and livers were harvested for histological, immunohistochemical, and gene expression analyses. Frequency of adipocyte death in eAT increased from <0.1% at baseline to 16% at week 12, coincident with increases in 1) depot weight; 2) AT macrophages (ATM Phi s) expressing F4/80 and CD11c; 3) mRNA for tumor necrosis factor (TNF)-alpha, monocyte chemotactic protein (MCP)-1, and interleukin (IL)-10; and 4) insulin resistance. ATM Phi s in crown-like structures surrounding dead adipocytes expressed TNF-alpha and IL-6 proteins. Adipocyte number began to decline at week 12. At week 16, adipocyte death reached approximately 80%, coincident with maximal expression of CD11c and inflammatory genes, loss (40%) of eAT mass, widespread collagen deposition, and accelerated hepatic macrosteatosis. By week 20, adipocyte number was restored with small adipocytes, coincident with reduced adipocyte death (fourfold), CD11c and MCP-1 gene expression (twofold), and insulin resistance (35%). eAT weight did not increase at week 20 and was inversely correlated with liver weight after week 12 (r = -0. 85, P < 0.001). In iAT, adipocyte death was first detected at week 12 and remained <or=3%. These results implicate depot-selective adipocyte death and M Phi-mediated AT remodeling in inflammatory and metabolic complications of murine obesity.", - "journal_title": "Diabetes", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/17848624/" - } - ], - "063a0254-1d1b-4caa-b782-6a1fe4ebca0d": [ - { - "pub_id": "17476355", - "title": "Pharmacogenetics of metformin response: a step in the path toward personalized medicine.", - "authors": "Marc L Reitman,Eric E Schadt", - "abstract": "Type 2 diabetes mellitus affects 9.6% of the adults in the United States and more than 200 million people worldwide. Diabetes can be a devastating disease, but it can now be treated with nine classes of approved drugs (insulins, sulfonylureas, glinides, biguanides, alpha-glucosidase inhibitors, thiazolidinediones, glucagon-like peptide 1 mimetics, amylin mimetics, and dipeptidyl peptidase 4 inhibitors), in addition to diet and exercise regimens. Choosing which drug to give a patient is based on efficacy and also availability, cost, safety, tolerability, and convenience. Personalized medicine promises a path for individually optimized treatment choices, but realizing this promise will require a more comprehensive characterization of disease and drug response. In this issue of the JCI, Shu et al. make significant progress by integrating diverse data supporting the hypothesis that genetic variation in organic cation transporter 1 (OCT1) affects the response to the widely used biguanide metformin (see the related article beginning on page 1422). We discuss metformin, OCT1, pharmacogenetics, and how the integrative genomics revolution is likely to change our understanding and treatment of diabetes.", - "journal_title": "The Journal of clinical investigation", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/17476355/" - } - ], - "bbfe03a8-70a8-43b5-b47d-24e1dc227e6d": [ - { - "pub_id": "15868134", - "title": "Genome-wide linkage scans for prediabetes phenotypes in response to 20 weeks of endurance exercise training in non-diabetic whites and blacks: the HERITAGE Family Study.", - "authors": "P An,M Teran-Garcia,T Rice,T Rankinen,S J Weisnagel,R N Bergman,R C Boston,S Mandel,D Stefanovski,A S Leon,J S Skinner,D C Rao,C Bouchard, ", - "abstract": "Impaired insulin secretion, insulin action, insulin-independent glucose effectiveness, glucose tolerance and the associated abnormalities in insulin and glucose metabolism phenotypes are precursors of type 2 diabetes. Genome-wide multipoint variance component linkage scans were carried out using 654 markers to identify quantitative trait loci for insulin sensitivity, acute insulin response to glucose, disposition index and glucose effectiveness training responses in whites and blacks in the HERITAGE Family Study. These phenotypes were obtained from an IVGTT with the minimal model. The distributions of insulin sensitivity, acute insulin response to glucose and disposition index training responses (post-training minus baseline) were approximately normalised using a square-root transformation. All phenotypes were adjusted for the effects of age, BMI and their respective baseline values within sex and generation by race prior to linkage scans. In blacks, a promising linkage with a maximum lod score of 3.1 on 19q (54-62 Mb) for glucose effectiveness training response was found. Six interesting linkages with lod scores of at least 1.0 were found for disposition index training response in whites. They included 1p (30 Mb), 3q (152 Mb), 6p (23-42 Mb), 7q (95-96 Mb), 10p (15 Mb) and 12q (119-126 Mb). Quantitative trait loci for 20 weeks of endurance exercise training responses in insulin action and glucose metabolism phenotypes were found on chromosome 19q as well as 6p and 7q, with nominal (6p, 7q) but consistent (6p) linkages across the races.", - "journal_title": "Diabetologia", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/15868134/" - } - ], - "14543634-0dd8-4086-a5d4-ef577c37a7e3": [ - { - "pub_id": "8584938", - "title": "Phenotypes of mouse diabetes and rat fatty due to mutations in the OB (leptin) receptor.", - "authors": "S C Chua,W K Chung,X S Wu-Peng,Y Zhang,S M Liu,L Tartaglia,R L Leibel", - "abstract": "Mice harboring mutations in the obese (ob) and diabetes (db) genes display similar phenotypes, and it has been proposed that these genes encode the ligand and receptor, respectively, for a physiologic pathway that regulates body weight. The cloning of ob, and the demonstration that it encodes a secreted protein (leptin) that binds specifically to a receptor (OB-R) in the brain, have validated critical aspects of this hypothesis. Here it is shown by genetic mapping and genomic analysis that mouse db, rat fatty (a homolog of db), and the gene encoding the OB-R are the same gene.", - "journal_title": "Science (New York, N.Y.)", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/8584938/" - } - ], - "cab903b3-3e07-48e1-be92-7f3093c979d5": [ - { - "pub_id": "12610047", - "title": "Association of the CTLA-4 gene 49 A/G polymorphism with type 1 diabetes and autoimmune thyroid disease in Japanese children.", - "authors": "Mie Mochizuki,Shin Amemiya,Kisho Kobayashi,Koji Kobayashi,Yoshie Shimura,Toshihide Ishihara,Yoshiko Nakagomi,Kazumichi Onigata,Shinya Tamai,Akira Kasuga,Shinpei Nanazawa", - "abstract": "To clarify the role of the T-lymphocyte-associated-4 (CTLA-4) polymorphism in the susceptibility to child-onset type 1 diabetes with regard to its clinical characteristics and complications with autoimmune thyroid disease (AITD) in the Japanese population. The CTLA-4 49 A/G polymorphism was detected by the PCR-restriction fragment-length polymorphism (RFLP) method in 97 type 1 diabetic subjects and 20 patients with Graves' disease, a cohort which included 4 patients who also had type 1 diabetes. The genotypes and allele frequencies of this polymorphism did not differ between the type 1 diabetic subjects and the control subjects. The G allele frequency was 63.9% in the type 1 diabetic subjects. The G allele frequency in the subgroup of patients with a high titer of autoantibodies to the GAD antibody (Ab) was 72.9% (P = 0.0499 vs. control subjects); in the subgroup of patients without HLA DRB1*0405, it was 72.6% (P = 0.0271 vs. control subjects); and in the subgroup of patients with a residual beta-cell function, it was 78.6% (P = 0.0391 vs. control subjects). The G allele frequency in the patients with Graves' disease was also significantly higher at 78.1% (P = 0.0405 vs. control subjects). Furthermore, the frequency in our diabetic subjects complicated with Graves' disease was even higher (87.5%). We have demonstrated that a distinct association exists between the G allele of CTLA-4 and high values of GAD Ab, residual beta-cell function, and the absence of HLA-DRB1*0405.", - "journal_title": "Diabetes care", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/12610047/" - } - ], - "d6f6642c-77f3-4e8a-9aea-ca0c8d9b91ea": [ - { - "pub_id": "19875619", - "title": "Metabolomics applied to diabetes research: moving from information to knowledge.", - "authors": "James R Bain,Robert D Stevens,Brett R Wenner,Olga Ilkayeva,Deborah M Muoio,Christopher B Newgard", - "abstract": "", - "journal_title": "Diabetes", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/19875619/" - } - ], - "8cb13eb6-a9b9-4f9f-8680-9b8add1c453d": [ - { - "pub_id": "17496368", - "title": "Animal models in type 2 diabetes research: an overview.", - "authors": "K Srinivasan,P Ramarao", - "abstract": "Type 2 diabetes is a complex and heterogeneous disorder presently affecting more than 100 million people worldwide and causing serious socio-economic problems. Appropriate experimental models are essential tools for understanding the pathogenesis, complications, and genetic or environmental influences that increase the risks of type 2 diabetes and testing of various therapeutic agents. The animal models of type 2 diabetes can be obtained either spontaneously or induced by chemicals or dietary or surgical manipulations and/or by combination thereof. In recent years, large number of new genetically modified animal models including transgenic, generalized knock-out and tissue-specific knockout mice have been engineered for the study of diabetes. This review gives an overview on the animal models of type 2 diabetes with reference to their origin/source, characteristic features, underlying causes/mechanism(s), advantages and disadvantages to the investigators in diabetes research. In addition, it especially describes the appropriate selection and usefulness of different animal models in preclinical testing of various new chemical entities (NCEs) for the treatment of type 2 diabetes.", - "journal_title": "The Indian journal of medical research", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/17496368/" - } - ], - "9d80d3cf-802e-4a58-966f-9e3fcea78701": [ - { - "pub_id": "11841615", - "title": "Approaches to understanding susceptibility to nephropathy: from genetics to genomics.", - "authors": "Sudha K Iyengar,Jeffrey R Schelling,John R Sedor", - "abstract": "The incidence of end-stage renal disease (ESRD) is increasing worldwide despite efforts to slow the progression of chronic renal failure (CRF) by controlling blood pressure and hyperglycemia. Two available therapies for ESRD, dialysis and transplantation, are expensive and are at best palliative. Recently, data from several laboratories have demonstrated that ESRD is under substantial genetic control, and efforts to identify these genetic determinants are underway. Identifying genes for ESRD pathogenesis has several goals. First, understanding the genetic basis of ESRD offers a means to clarify the mechanisms that result in kidney pathobiology. Second, better and new treatments for prevention of progression of CRF to ESRD may be developed. Third, individuals at risk could be identified early in their course and targeted for intensive therapy. Finally, the products of genes causing disease become target molecules for gene therapy. In this article, we discuss data from our laboratories, which employ two different molecular genetic strategies for identifying ESRD pathogenesis genes. In contrast to traditional experimental design, both approaches are hypothesis generating, identifying candidate molecules for further study, rather than hypothesis driven and may provide novel insights into mechanisms of renal disease progression.", - "journal_title": "Kidney international", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/11841615/" - } - ], - "4ba4d5e0-cb28-433d-8e9f-b09779e9d429": [ - { - "pub_id": "12421895", - "title": "Genomic medicine--a primer.", - "authors": "Alan E Guttmacher,Francis S Collins", - "abstract": "", - "journal_title": "The New England journal of medicine", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/12421895/" - } - ], - "80500e0d-0e39-4e46-bb60-8721f4f512c0": [ - { - "pub_id": "19020324", - "title": "Clinical risk factors, DNA variants, and the development of type 2 diabetes.", - "authors": "Valeriya Lyssenko,Anna Jonsson,Peter Almgren,Nicol\u00f3 Pulizzi,Bo Isomaa,Tiinamaija Tuomi,G\u00f6ran Berglund,David Altshuler,Peter Nilsson,Leif Groop", - "abstract": "Type 2 diabetes mellitus is thought to develop from an interaction between environmental and genetic factors. We examined whether clinical or genetic factors or both could predict progression to diabetes in two prospective cohorts. We genotyped 16 single-nucleotide polymorphisms (SNPs) and examined clinical factors in 16,061 Swedish and 2770 Finnish subjects. Type 2 diabetes developed in 2201 (11.7%) of these subjects during a median follow-up period of 23.5 years. We also studied the effect of genetic variants on changes in insulin secretion and action over time. Strong predictors of diabetes were a family history of the disease, an increased body-mass index, elevated liver-enzyme levels, current smoking status, and reduced measures of insulin secretion and action. Variants in 11 genes (TCF7L2, PPARG, FTO, KCNJ11, NOTCH2, WFS1, CDKAL1, IGF2BP2, SLC30A8, JAZF1, and HHEX) were significantly associated with the risk of type 2 diabetes independently of clinical risk factors; variants in 8 of these genes were associated with impaired beta-cell function. The addition of specific genetic information to clinical factors slightly improved the prediction of future diabetes, with a slight increase in the area under the receiver-operating-characteristic curve from 0.74 to 0.75; however, the magnitude of the increase was significant (P=1.0x10(-4)). The discriminative power of genetic risk factors improved with an increasing duration of follow-up, whereas that of clinical risk factors decreased. As compared with clinical risk factors alone, common genetic variants associated with the risk of diabetes had a small effect on the ability to predict the future development of type 2 diabetes. The value of genetic factors increased with an increasing duration of follow-up.", - "journal_title": "The New England journal of medicine", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/19020324/" - } - ], - "ff257789-521e-4ae9-aafd-a97552367e94": [ - { - "pub_id": "8622246", - "title": "The progression from hypertension to congestive heart failure.", - "authors": "D Levy,M G Larson,R S Vasan,W B Kannel,K K Ho", - "abstract": "- To study the relative and population-attributable risks of hypertension for the development of congestive heart failure (CHF), to assess the time course of progression from hypertension to CHF, and to identify risk factors that contribute to the development of overt heart failure in hypertensive subjects. - Inception cohort study. - General community. - Original Framingham Heart Study and Framingham Offspring Study participants aged 40 to 89 years and free of CHF. To reflect more contemporary experience, the starting point of this study was January 1, 1970. - Hypertension (blood pressure of at least 140 mm Hg systolic or 90 mm Hg diastolic or current use of medications for treatment of high blood pressure) and other potential CHF risk factors were assessed at periodic clinic examinations. - The development of CHF. - A total of 5143 eligible subjects contributed 72422 person-years of observation. During up to 20.1 years of follow-up (mean, 14.1 years), there were 392 new cases of heart failure; in 91% (357/392), hypertension antedated the development of heart failure. Adjusting for age and heart failure risk factors in proportional hazards regression models, the hazard for developing heart failure in hypertensive compared with normotensive subjects was about 2-fold in men and 3-fold in women. Multivariable analyses revealed that hypertension had a high population-attributable risk for CHF, accounting for 39% of cases in men and 59% in women. Among hypertensive subjects, myocardial infarction, diabetes, left ventricular hypertrophy, and valvular heart disease were predictive of increased risk for CHF in both sexes. Survival following the onset of hypertensive CHF was bleak; only 24% of men and 31% of women survived 5 years. - Hypertension was the most common risk factor for CHF, and it contributed a large proportion of heart failure cases in this population-based sample. Preventive strategies directed toward earlier and more aggressive blood pressure control are likely to offer the greatest promise for reducing the incidence of CHF and its associated mortality.", - "journal_title": "JAMA", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/8622246/" - } - ], - "e9daf364-3630-4006-bc05-e7e9f462d520": [ - { - "pub_id": "7490992", - "title": "Neurodegeneration and diabetes: UK nationwide study of Wolfram (DIDMOAD) syndrome.", - "authors": "T G Barrett,S E Bundey,A F Macleod", - "abstract": "Wolfram syndrome is the association of diabetes mellitus and optic atrophy, and is sometimes called DIDMOAD (diabetes insipidus, diabetes mellitus, optic atrophy, and deafness). Incomplete characterisation of this autosomal recessive syndrome has relied on case-reports, and there is confusion with mitochondrial genome disorders. We therefore undertook a UK nationwide cross-sectional case-finding study to describe the natural history, complications, prevalence, and inheritance of the syndrome. We identified 45 patients with Wolfram syndrome--a prevalence of one per 770,000. Non-autoimmune, insulin-deficient diabetes mellitus presented at a median age of 6 years, followed by optic atrophy (11 years). Cranial diabetes insipidus occurred in 33 patients (73%) with sensorineural deafness (28, 62%) in the second decade; renal-tract abnormalities (26, 58%) presented in the third decade followed by neurological complications (cerebellar ataxia, myoclonus [28, 62%]) in the fourth decade. Other abnormalities included gastrointestinal dysmotility in 11 (24%), and primary gonadal atrophy in seven of ten males investigated. Median age at death (commonly central respiratory failure with brain-stem atrophy) was 30 years (range 25-49). The natural history of Wolfram syndrome suggests that most patients will eventually develop most complications of this progressive, neurodegenerative disorder. Family studies indicate autosomal recessive inheritance with a carrier frequency of one in 354, an absence of a maternal history of diabetes or deafness, and an absence of the mitochondrial tRNA Leu (3243) mutation. Juvenile-onset diabetes mellitus and optic atrophy are the best available diagnostic criteria for Wolfram syndrome, the differential diagnosis of which includes other causes of neurodegeneration.", - "journal_title": "Lancet (London, England)", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/7490992/" - } - ], - "ee6e646f-d094-4f0a-ba05-b3718e3eed23": [ - { - "pub_id": "10545951", - "title": "Mutations in NEUROD1 are associated with the development of type 2 diabetes mellitus.", - "authors": "M T Malecki,U S Jhala,A Antonellis,L Fields,A Doria,T Orban,M Saad,J H Warram,M Montminy,A S Krolewski", - "abstract": "The helix-loop-helix (HLH) protein NEUROD1 (also known as BETA2) functions as a regulatory switch for endocrine pancreatic development. In mice homozygous for a targeted disruption of Neurod, pancreatic islet morphogenesis is abnormal and overt diabetes develops due in part to inadequate expression of the insulin gene (Ins2). NEUROD1, following its heterodimerization with the ubiquitous HLH protein E47, regulates insulin gene (INS) expression by binding to a critical E-box motif on the INS promoter. Here we describe two mutations in NEUROD1, which are associated with the development of type 2 diabetes in the heterozygous state. The first, a missense mutation at Arg 111 in the DNA-binding domain, abolishes E-box binding activity of NEUROD1. The second mutation gives rise to a truncated polypeptide lacking the carboxy-terminal trans-activation domain, a region that associates with the co-activators CBP and p300 (refs 3,4). The clinical profile of patients with the truncated NEUROD1 polypeptide is more severe than that of patients with the Arg 111 mutation. Our findings suggest that deficient binding of NEUROD1 or binding of a transcriptionally inactive NEUROD1 polypeptide to target promoters in pancreatic islets leads to the development of type 2 diabetes in humans.", - "journal_title": "Nature genetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/10545951/" - } - ], - "00da4d7c-879c-47f8-8648-89b2fdb19eda": [ - { - "pub_id": "12808457", - "title": "PGC-1alpha-responsive genes involved in oxidative phosphorylation are coordinately downregulated in human diabetes.", - "authors": "Vamsi K Mootha,Cecilia M Lindgren,Karl-Fredrik Eriksson,Aravind Subramanian,Smita Sihag,Joseph Lehar,Pere Puigserver,Emma Carlsson,Martin Ridderstr\u00e5le,Esa Laurila,Nicholas Houstis,Mark J Daly,Nick Patterson,Jill P Mesirov,Todd R Golub,Pablo Tamayo,Bruce Spiegelman,Eric S Lander,Joel N Hirschhorn,David Altshuler,Leif C Groop", - "abstract": "DNA microarrays can be used to identify gene expression changes characteristic of human disease. This is challenging, however, when relevant differences are subtle at the level of individual genes. We introduce an analytical strategy, Gene Set Enrichment Analysis, designed to detect modest but coordinate changes in the expression of groups of functionally related genes. Using this approach, we identify a set of genes involved in oxidative phosphorylation whose expression is coordinately decreased in human diabetic muscle. Expression of these genes is high at sites of insulin-mediated glucose disposal, activated by PGC-1alpha and correlated with total-body aerobic capacity. Our results associate this gene set with clinically important variation in human metabolism and illustrate the value of pathway relationships in the analysis of genomic profiling experiments.", - "journal_title": "Nature genetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/12808457/" - } - ], - "29963974-dd15-46c5-9f83-9b21c962f64b": [ - { - "pub_id": "19073967", - "title": "Shared and distinct genetic variants in type 1 diabetes and celiac disease.", - "authors": "Deborah J Smyth,Vincent Plagnol,Neil M Walker,Jason D Cooper,Kate Downes,Jennie H M Yang,Joanna M M Howson,Helen Stevens,Ross McManus,Cisca Wijmenga,Graham A Heap,Patrick C Dubois,David G Clayton,Karen A Hunt,David A van Heel,John A Todd", - "abstract": "Two inflammatory disorders, type 1 diabetes and celiac disease, cosegregate in populations, suggesting a common genetic origin. Since both diseases are associated with the HLA class II genes on chromosome 6p21, we tested whether non-HLA loci are shared. We evaluated the association between type 1 diabetes and eight loci related to the risk of celiac disease by genotyping and statistical analyses of DNA samples from 8064 patients with type 1 diabetes, 9339 control subjects, and 2828 families providing 3064 parent-child trios (consisting of an affected child and both biologic parents). We also investigated 18 loci associated with type 1 diabetes in 2560 patients with celiac disease and 9339 control subjects. Three celiac disease loci--RGS1 on chromosome 1q31, IL18RAP on chromosome 2q12, and TAGAP on chromosome 6q25--were associated with type 1 diabetes (P<1.00x10(-4)). The 32-bp insertion-deletion variant on chromosome 3p21 was newly identified as a type 1 diabetes locus (P=1.81x10(-8)) and was also associated with celiac disease, along with PTPN2 on chromosome 18p11 and CTLA4 on chromosome 2q33, bringing the total number of loci with evidence of a shared association to seven, including SH2B3 on chromosome 12q24. The effects of the IL18RAP and TAGAP alleles confer protection in type 1 diabetes and susceptibility in celiac disease. Loci with distinct effects in the two diseases included INS on chromosome 11p15, IL2RA on chromosome 10p15, and PTPN22 on chromosome 1p13 in type 1 diabetes and IL12A on 3q25 and LPP on 3q28 in celiac disease. A genetic susceptibility to both type 1 diabetes and celiac disease shares common alleles. These data suggest that common biologic mechanisms, such as autoimmunity-related tissue damage and intolerance to dietary antigens, may be etiologic features of both diseases.", - "journal_title": "The New England journal of medicine", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/19073967/" - } - ], - "4087c38a-430e-4d37-ae26-7f033fd959da": [ - { - "pub_id": "20477190", - "title": "Genetics and genomics in human lung transplantation.", - "authors": "Stavros Garantziotis,Scott M Palmer", - "abstract": "Lung transplantation is the only effective treatment for many advanced lung diseases. However, long-term survival after transplantation remains relatively poor, thus limiting the application of lung transplantation to patients with end-stage disease only. Acute and chronic rejection is the main reason for allograft failure. Attempts to treat or prevent rejection have been stymied by our incomplete understanding of the mechanisms leading to this devastating complication and the lack of representative animal models. A systems-biology approach to lung transplantation with the use of genomics and gene expression profiling has led to new insights into the pathogenesis of rejection, by elucidating the mechanisms of T-cell activation and uncovering the role of B cells and innate immunity. Systems-biology approaches, such as genetics and genomics, may allow minimally invasive diagnosis of rejection and permit individually tailored immunosuppressive regimens. Herein we review the emerging application of genomics and genetics to human lung transplantation and highlight the tremendous potential for these approaches to enhance clinical practice and augment our understanding of basic transplant biology.", - "journal_title": "Expert review of respiratory medicine", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/20477190/" - } - ], - "782103fd-2cb6-44c8-9b39-d82430d335c9": [ - { - "pub_id": "18647793", - "title": "From genetics to genomics: ethics, policy, and parental decision-making.", - "authors": "Benjamin Wilfond,Lainie Friedman Ross", - "abstract": "Ethical evaluation of genetic testing in children is traditionally based on balancing clinical benefits and risks. However, this focus can be inconsistent with the general practice of respecting parental decision-making about their children's health care. We argue that respect for parental decision-making should play a larger role in shaping pediatric genetic testing practices, and play a similar role regarding decisions to use emerging genomic technologies. Genomic testing involves the examination of thousands of DNA markers spanning genes throughout the genome and their interrelationships, yielding virtually limitless interpretations. We presume that parents and providers should proceed cautiously in applying genomic testing in children, as we explore how genomic testing will stress the fault lines of the traditional ethical analysis. Empirical data about the psychosocial risks and benefits of genetic testing of children do not reveal serious harms, yet virtually no such data exist yet about genomic testing. Unless empirical social and behavioral data indicate that genomic testing is highly likely to cause serious harms to the children, parental decisions to obtain comprehensive genomic testing in their children should be respected. Once comprehensive genomic testing of children becomes routine, resultant information may be more easily integrated by families than anticipated. Research on the social and behavioral impact of comprehensive genomic testing on children and their families is needed to further inform parents, clinicians, and policy makers.", - "journal_title": "Journal of pediatric psychology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/18647793/" - } - ], - "9a093914-e3b6-408a-b50f-f2482b7c91af": [ - { - "pub_id": "16552936", - "title": "Genomics research in the UK--the social science agenda.", - "authors": "Ian Diamond,Dawn Woodgate", - "abstract": "We sketch the development of UK genetics and genomics research, and emphasize the UK's key role in the international genetics and genomics research community. We highlight in particular the part played by the UK's Research Councils and other funders. With the move from genomics to post-genomics research, the field is diversifying, and interdisciplinarity becomes increasingly important, as traditional disciplinary boundaries become blurred, or break down, in the face of newly emerging sciences. We consider the changing nature of health and ill health in the developed and developing world, and questions about the complex nature of the relationships between genes and the environment, and their future implications for human health and human populations. We describe the ESRC's activities, stressing the importance of both the social, ethical and legal issues raised by these emerging disciplines, and of public engagement. Finally, we link the data handling and analysis issues raised by these emerging sciences, with other new research areas, in particular the UK's e-Science programme.", - "journal_title": "New genetics and society", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/16552936/" - } - ], - "e8dd8ca2-6fab-4acd-9b29-4e8583365d6d": [ - { - "pub_id": "19357773", - "title": "Common variants of inflammatory cytokine genes are associated with risk of nephropathy in type 2 diabetes among Asian Indians.", - "authors": "Tarunveer Singh Ahluwalia,Madhu Khullar,Monica Ahuja,Harbir Singh Kohli,Anil Bhansali,Viswanathan Mohan,Radha Venkatesan,Taranjit Singh Rai,Kamal Sud,Pawan K Singal", - "abstract": "Inflammatory cytokine genes have been proposed as good candidate genes for conferring susceptibility to diabetic nephropathy. In the present study, we examined the combined effect of multiple alleles of pro inflammatory cytokine genes for determining the risk of nephropathy in type 2 diabetic patients. Eight single nucleotide polymorphisms (SNPs) of pro-inflammatory cytokine genes (CCL2, TGFB1, IL8, CCR5, and MMP9) were genotyped in two independently ascertained type 2 diabetic cohorts with (DN) and without nephropathy (DM); consisting of patients from North India (n = 495) and South India (n = 188). Genotyping was carried out using PCR, allele specific oligonucleotide-PCR (ASO-PCR), PCR-RFLP and TaqMan allelic discrimination assays and the gene-gene interaction among genetic variants were determined by multi dimensional reduction (MDR) software. Serum high sensitive CRP (hs-CRP) levels were measured by ELISA. The hs-CRP levels were significantly higher in DN as compared to the DM group (p<0.05). The CCL2, IL8, CCR5 and MMP9 polymorphisms were found to be associated with the risk of diabetic nephropathy. Frequency of CCL2 II, IL8 -251AA, CCR5 59029AA and MMP9 279Gln/Gln genotypes were significantly higher in DN than in DM group (p<0.05) and associated with an increased risk of nephropathy in both North and South Indian cohorts. CCR5 DD and IL8 -251AA genotypes were more prevalent in North Indian DN group only. The co-occurrence of risk associated genotypes (II, -2518GG (CCL2), DD (CCR5) and 279Gln/Gln (MMP9) conferred a tenfold increased risk of nephropathy among type 2 diabetics (p<0.0002). The present study highlights that common variants of inflammatory cytokine genes exert a modest effect on risk of DN and a combination of risk alleles confer a substantial increased risk of nephropathy in type 2 diabetes among Asian Indians.", - "journal_title": "PloS one", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/19357773/" - } - ], - "51ded444-c5f9-4e0c-a443-3b0be9d908cf": [ - { - "pub_id": "9425261", - "title": "Molecular scanning of the human peroxisome proliferator activated receptor gamma (hPPAR gamma) gene in diabetic Caucasians: identification of a Pro12Ala PPAR gamma 2 missense mutation.", - "authors": "C J Yen,B A Beamer,C Negri,K Silver,K A Brown,D P Yarnall,D K Burns,J Roth,A R Shuldiner", - "abstract": "Peroxisome proliferator activated receptor-gamma (PPAR gamma) is a nuclear receptor that regulates adipocyte differentiation, and possibly lipid metabolism and insulin sensitivity. As such, PPAR gamma is a promising candidate gene for several human disorders including obesity and type 2 diabetes mellitus. Screening for mutations in the entire coding region of the PPAR gamma gene (both gamma 1 and gamma 2 isoforms) was performed with DNA of 26 diabetic Caucasians with or without obesity. Two base substitutions were identified: a silent mutation at nucleotide 1431 (CACHis-->CATHis) and a missense mutation (CCGPro-->GCGAla) at codon 12 of PPAR gamma 2. The allele frequency of the Pro12Ala PPAR gamma 2 variant was 0.12 in Caucasian Americans, 0.10 in Mexican Americans, 0.08 in Samoans, 0.03 in African Americans, 0.02 in Nauruans, and 0.01 in Chinese. We conclude that the Pro12Ala PPAR gamma 2 gene variant is present in diverse populations. Further studies of the Pro12Ala variant will determine its relevance to obesity, insulin resistance, and type 2 diabetes.", - "journal_title": "Biochemical and biophysical research communications", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/9425261/" - } - ], - "5a5fd793-4518-4cac-9ae3-8372f824c51f": [ - { - "pub_id": "17597095", - "title": "Successful design and conduct of genome-wide association studies.", - "authors": "Christopher I Amos", - "abstract": "Genome-wide association studies are becoming an increasingly effective tool for identifying genetic factors contributing to complex diseases. In this review, I discuss two sets of genome-wide association studies that identified novel genetic factors for age-related macular degeneration and genetic factors for type II diabetes. In reviewing these sets of studies, my goal is to identify factors that contributed to the success of these studies. Design-related factors include the selection of traits that show strong familiarity, the selection of clinically homogeneous populations and the selection of cases that have a family history. Ethnic stratification within the study sample can lead to biases, and methods to control for stratification are briefly reviewed. Finally, the impact of single nucleotide polymorphism selection on the power of a study and procedures for improving power by inferring genotypes, by combining data across studies and by performing multistage analyses are discussed. The continuing success of genome-wide association studies depends on careful selection of populations for study and on collaborative analytical approaches.", - "journal_title": "Human molecular genetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/17597095/" - } - ], - "68a3fa63-c9f3-4ca1-a3fa-0b588dd5496e": [ - { - "pub_id": "18045462", - "title": "Integrative analysis for finding genes and networks involved in diabetes and other complex diseases.", - "authors": "Regine Bergholdt,Zenia M St\u00f8rling,Kasper Lage,E Olof Karlberg,P\u00e1ll I Olason,Mogens Aalund,J\u00f8rn Nerup,S\u00f8ren Brunak,Christopher T Workman,Flemming Pociot", - "abstract": "We have developed an integrative analysis method combining genetic interactions, identified using type 1 diabetes genome scan data, and a high-confidence human protein interaction network. Resulting networks were ranked by the significance of the enrichment of proteins from interacting regions. We identified a number of new protein network modules and novel candidate genes/proteins for type 1 diabetes. We propose this type of integrative analysis as a general method for the elucidation of genes and networks involved in diabetes and other complex diseases.", - "journal_title": "Genome biology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/18045462/" - } - ], - "d9122700-a177-4c13-b14e-c7f3e9899511": [ - { - "pub_id": "16015371", - "title": "Conditioning the genome identifies additional diabetes resistance loci in Type I diabetes resistant NOR/Lt mice.", - "authors": "P C Reifsnyder,R Li,P A Silveira,G Churchill,D V Serreze,E H Leiter", - "abstract": "While sharing the H2g7 MHC and many other important Type I diabetes susceptibility (Idd) genes with NOD mice, the NOR strain remains disease free due to resistance alleles within the approximately 12% portion of their genome that is of C57BLKS/J origin. Previous F2 segregation analyses indicated multiple genes within the 'Idd13' locus on Chromosome 2 provide the primary component of NOR diabetes resistance. However, it was clear other genes also contribute to NOR diabetes resistance, but were difficult to detect in the original segregation analyses because they were relatively weak compared to the strong Idd13 protection component. To identify these further genetic components of diabetes resistance, we performed a new F2 segregation analyses in which NOD mice were outcrossed to a 'genome-conditioned' NOR stock in which a large component of Idd13-mediated resistance was replaced with NOD alleles. These F2 segregation studies combined with subsequent congenic analyses confirmed the presence of additional NOR resistance genes on Chr. 1 and Chr. 4, and also potentially on Chr. 11. These findings emphasize the value for diabetes gene discovery of stratifying not only MHC loci conferring the highest relative risk but also as many as possible of the non-MHC loci presumed to contribute significantly.", - "journal_title": "Genes and immunity", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/16015371/" - } - ], - "5e8e975c-0d05-4ae4-8787-0edad28bc965": [ - { - "pub_id": "18401346", - "title": "Adipocyte dysfunctions linking obesity to insulin resistance and type 2 diabetes.", - "authors": "Adilson Guilherme,Joseph V Virbasius,Vishwajeet Puri,Michael P Czech", - "abstract": "Acquired resistance to the action of insulin to stimulate glucose transport in skeletal muscle is associated with obesity and promotes the development of type 2 diabetes. In skeletal muscle, insulin resistance can result from high levels of circulating fatty acids that disrupt insulin signalling pathways. However, the severity of insulin resistance varies greatly among obese people. Here we postulate that this variability might reflect differences in levels of lipid-droplet proteins that promote the sequestration of fatty acids within adipocytes in the form of triglycerides, thereby lowering exposure of skeletal muscle to the inhibitory effects of fatty acids.", - "journal_title": "Nature reviews. Molecular cell biology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/18401346/" - } - ], - "7355ea4d-8c2b-454d-96d0-527645046e1e": [ - { - "pub_id": "17636114", - "title": "Physical activity modifies the effect of SNPs in the SLC2A2 (GLUT2) and ABCC8 (SUR1) genes on the risk of developing type 2 diabetes.", - "authors": "T O Kilpel\u00e4inen,T A Lakka,D E Laaksonen,O Laukkanen,J Lindstr\u00f6m,J G Eriksson,T T Valle,H H\u00e4m\u00e4l\u00e4inen,S Aunola,P Ilanne-Parikka,S Kein\u00e4nen-Kiukaanniemi,J Tuomilehto,M Uusitupa,M Laakso, ", - "abstract": "Single nucleotide polymorphisms (SNPs) in two genes regulating insulin secretion, SLC2A2 (encoding GLUT2) and ABCC8 (encoding SUR1), were associated with the conversion from impaired glucose tolerance (IGT) to type 2 diabetes (T2D) in the Finnish Diabetes Prevention Study (DPS). We determined whether physical activity (PA), assessed annually with a questionnaire, modified the association of SNPs in SLC2A2 and ABCC8 with the conversion to T2D in the combined intervention and control groups of the DPS. Finnish overweight subjects with IGT (N = 479) were followed for an average of 4.1 yr. The interaction of the SNPs with the change in PA on the conversion to T2D was assessed using Cox regression with adjustments for the other components of the intervention (dietary changes, weight reduction). The carriers of the common homozygous genotype of rs5393, rs5394, or rs5404 of SLC2A2 and rs3758947 of ABCC8 who were in the lower third of the change in moderate-to-vigorous PA during the follow-up had a 2.6- to 3.7-fold increased risk of developing T2D compared with the upper third, whereas the rare allele carriers seemed to be unresponsive to changes in moderate-to-vigorous PA (for the interaction of genotype with change in PA, P = 0.022-0.027 for the SNPs in SLC2A2, and P = 0.007 for rs3758947). We conclude that moderate-to-vigorous PA may modify the risk of developing T2D associated with genes regulating insulin secretion (SLC2A2, ABCC8) in persons with IGT.", - "journal_title": "Physiological genomics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/17636114/" - } - ], - "3cd881a9-3e3d-4e50-85fc-599efbc14efd": [ - { - "pub_id": "19060909", - "title": "A variant near MTNR1B is associated with increased fasting plasma glucose levels and type 2 diabetes risk.", - "authors": "Nabila Bouatia-Naji,Am\u00e9lie Bonnefond,Christine Cavalcanti-Proen\u00e7a,Thomas Spars\u00f8,Johan Holmkvist,Marion Marchand,J\u00e9r\u00f4me Delplanque,St\u00e9phane Lobbens,Ghislain Rocheleau,Emmanuelle Durand,Franck De Graeve,Jean-Claude Ch\u00e8vre,Knut Borch-Johnsen,Anna-Liisa Hartikainen,Aimo Ruokonen,Jean Tichet,Michel Marre,Jacques Weill,Barbara Heude,Maith\u00e9 Tauber,Katleen Lemaire,Frans Schuit,Paul Elliott,Torben J\u00f8rgensen,Guillaume Charpentier,Samy Hadjadj,St\u00e9phane Cauchi,Martine Vaxillaire,Robert Sladek,Sophie Visvikis-Siest,Beverley Balkau,Claire L\u00e9vy-Marchal,Fran\u00e7ois Pattou,David Meyre,Alexandra I F Blakemore,Marjo-Riita Jarvelin,Andrew J Walley,Torben Hansen,Christian Dina,Oluf Pedersen,Philippe Froguel", - "abstract": "In genome-wide association (GWA) data from 2,151 nondiabetic French subjects, we identified rs1387153, near MTNR1B (which encodes the melatonin receptor 2 (MT2)), as a modulator of fasting plasma glucose (FPG; P = 1.3 x 10(-7)). In European populations, the rs1387153 T allele is associated with increased FPG (beta = 0.06 mmol/l, P = 7.6 x 10(-29), N = 16,094), type 2 diabetes (T2D) risk (odds ratio (OR) = 1.15, 95% CI = 1.08-1.22, P = 6.3 x 10(-5), cases N = 6,332) and risk of developing hyperglycemia or diabetes over a 9-year period (hazard ratio (HR) = 1.20, 95% CI = 1.06-1.36, P = 0.005, incident cases N = 515). RT-PCR analyses confirm the presence of MT2 transcripts in neural tissues and show MT2 expression in human pancreatic islets and beta cells. Our data suggest a possible link between circadian rhythm regulation and glucose homeostasis through the melatonin signaling pathway.", - "journal_title": "Nature genetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/19060909/" - } - ], - "bd1ca72f-cd18-4926-b270-97c7c81b0094": [ - { - "pub_id": "18456185", - "title": "Genetics and genomics of primary biliary cirrhosis.", - "authors": "Brian D Juran,Konstantinos N Lazaridis", - "abstract": "The etiologic and pathogenic factors contributing to primary biliary cirrhosis (PBC) development, progression, response to treatment, and outcome remain a mystery. Recognition of the genomic regions harboring risk factors is hindered by the rarity and late onset of PBC. Recent advancements in genomics hold promise for understanding, prevention, and therapy of PBC. Large registries and biospecimen repositories of patients who have PBC, their family members, and controls are needed. Haplotype mapping-based association studies are necessary for defining genetic predisposition. Experimental data will provide the means for fine mapping studies, resequencing efforts, functional experimentation, and elucidation of gene-environment and gene-gene interaction.", - "journal_title": "Clinics in liver disease", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/18456185/" - } - ], - "5f35d266-6ac5-4531-9fcf-ef663d5b2991": [ - { - "pub_id": "11133066", - "title": "Pathophysiology and pharmacological treatment of insulin resistance.", - "authors": "S Matthaei,M Stumvoll,M Kellerer,H U H\u00e4ring", - "abstract": "Diabetes mellitus type 2 is a world-wide growing health problem affecting more than 150 million people at the beginning of the new millennium. It is believed that this number will double in the next 25 yr. The pathophysiological hallmarks of type 2 diabetes mellitus consist of insulin resistance, pancreatic beta-cell dysfunction, and increased endogenous glucose production. To reduce the marked increase of cardiovascular mortality of type 2 diabetic subjects, optimal treatment aims at normalization of body weight, glycemia, blood pressure, and lipidemia. This review focuses on the pathophysiology and molecular pathogenesis of insulin resistance and on the capability of antihyperglycemic pharmacological agents to treat insulin resistance, i.e., a-glucosidase inhibitors, biguanides, thiazolidinediones, sulfonylureas, and insulin. Finally, a rational treatment approach is proposed based on the dynamic pathophysiological abnormalities of this highly heterogeneous and progressive disease.", - "journal_title": "Endocrine reviews", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/11133066/" - } - ], - "1031c02c-61fe-4b06-a64d-770507d9714b": [ - { - "pub_id": "11344187", - "title": "Hypoadiponectinemia in obesity and type 2 diabetes: close association with insulin resistance and hyperinsulinemia.", - "authors": "C Weyer,T Funahashi,S Tanaka,K Hotta,Y Matsuzawa,R E Pratley,P A Tataranni", - "abstract": "Plasma concentrations of adiponectin, a novel adipose-specific protein with putative antiatherogenic and antiinflammatory effects, were found to be decreased in Japanese individuals with obesity, type 2 diabetes, and cardiovascular disease, conditions commonly associated with insulin resistance and hyperinsulinemia. To further characterize the relationship between adiponectinemia and adiposity, insulin sensitivity, insulinemia, and glucose tolerance, we measured plasma adiponectin concentrations, body composition (dual-energy x-ray absorptiometry), insulin sensitivity (M, hyperinsulinemic clamp), and glucose tolerance (75-g oral glucose tolerance test) in 23 Caucasians and 121 Pima Indians, a population with a high propensity for obesity and type 2 diabetes. Plasma adiponectin concentration was negatively correlated with percent body fat (r = -0.43), waist-to-thigh ratio (r = -0.46), fasting plasma insulin concentration (r = -0.63), and 2-h glucose concentration (r = -0.38), and positively correlated with M (r = 0.59) (all P < 0.001); all relations were evident in both ethnic groups. In a multivariate analysis, fasting plasma insulin concentration, M, and waist-to-thigh ratio, but not percent body fat or 2-h glucose concentration, were significant independent determinates of adiponectinemia, explaining 47% of the variance (r(2) = 0.47). Differences in adiponectinemia between Pima Indians and Caucasians (7.2 +/- 2.6 vs. 10.2 +/- 4.3 microg/ml, P < 0.0001) and between Pima Indians with normal, impaired, and diabetic glucose tolerance (7.5 +/- 2.7, 6.1 +/- 2.0, 5.5 +/- 1.6 microg/ml, P < 0.0001) remained significant after adjustment for adiposity, but not after additional adjustment for M or fasting insulin concentration. These results confirm that obesity and type 2 diabetes are associated with low plasma adiponectin concentrations in different ethnic groups and indicate that the degree of hypoadiponectinemia is more closely related to the degree of insulin resistance and hyperinsulinemia than to the degree of adiposity and glucose intolerance.", - "journal_title": "The Journal of clinical endocrinology and metabolism", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/11344187/" - } - ], - "f3b925cc-2556-4f30-809b-6bfe63a805b8": [ - { - "pub_id": "35551307", - "title": "Multi-ancestry genetic study of type 2 diabetes highlights the power of diverse populations for discovery and translation.", - "authors": "Anubha Mahajan,Cassandra N Spracklen,Weihua Zhang,Maggie C Y Ng,Lauren E Petty,Hidetoshi Kitajima,Grace Z Yu,Sina R\u00fceger,Leo Speidel,Young Jin Kim,Momoko Horikoshi,Josep M Mercader,Daniel Taliun,Sanghoon Moon,Soo-Heon Kwak,Neil R Robertson,Nigel W Rayner,Marie Loh,Bong-Jo Kim,Joshua Chiou,Irene Miguel-Escalada,Pietro Della Briotta Parolo,Kuang Lin,Fiona Bragg,Michael H Preuss,Fumihiko Takeuchi,Jana Nano,Xiuqing Guo,Amel Lamri,Masahiro Nakatochi,Robert A Scott,Jung-Jin Lee,Alicia Huerta-Chagoya,Mariaelisa Graff,Jin-Fang Chai,Esteban J Parra,Jie Yao,Lawrence F Bielak,Yasuharu Tabara,Yang Hai,Valgerdur Steinthorsdottir,James P Cook,Mart Kals,Niels Grarup,Ellen M Schmidt,Ian Pan,Tamar Sofer,Matthias Wuttke,Chloe Sarnowski,Christian Gieger,Darryl Nousome,Stella Trompet,Jirong Long,Meng Sun,Lin Tong,Wei-Min Chen,Meraj Ahmad,Raymond Noordam,Victor J Y Lim,Claudia H T Tam,Yoonjung Yoonie Joo,Chien-Hsiun Chen,Laura M Raffield,C\u00e9cile Lecoeur,Bram Peter Prins,Aude Nicolas,Lisa R Yanek,Guanjie Chen,Richard A Jensen,Salman Tajuddin,Edmond K Kabagambe,Ping An,Anny H Xiang,Hyeok Sun Choi,Brian E Cade,Jingyi Tan,Jack Flanagan,Fernando Abaitua,Linda S Adair,Adebowale Adeyemo,Carlos A Aguilar-Salinas,Masato Akiyama,Sonia S Anand,Alain Bertoni,Zheng Bian,Jette Bork-Jensen,Ivan Brandslund,Jennifer A Brody,Chad M Brummett,Thomas A Buchanan,Micka\u00ebl Canouil,Juliana C N Chan,Li-Ching Chang,Miao-Li Chee,Ji Chen,Shyh-Huei Chen,Yuan-Tsong Chen,Zhengming Chen,Lee-Ming Chuang,Mary Cushman,Swapan K Das,H Janaka de Silva,George Dedoussis,Latchezar Dimitrov,Ayo P Doumatey,Shufa Du,Qing Duan,Kai-Uwe Eckardt,Leslie S Emery,Daniel S Evans,Michele K Evans,Krista Fischer,James S Floyd,Ian Ford,Myriam Fornage,Oscar H Franco,Timothy M Frayling,Barry I Freedman,Christian Fuchsberger,Pauline Genter,Hertzel C Gerstein,Vilmantas Giedraitis,Clicerio Gonz\u00e1lez-Villalpando,Maria Elena Gonz\u00e1lez-Villalpando,Mark O Goodarzi,Penny Gordon-Larsen,David Gorkin,Myron Gross,Yu Guo,Sophie Hackinger,Sohee Han,Andrew T Hattersley,Christian Herder,Annie-Green Howard,Willa Hsueh,Mengna Huang,Wei Huang,Yi-Jen Hung,Mi Yeong Hwang,Chii-Min Hwu,Sahoko Ichihara,Mohammad Arfan Ikram,Martin Ingelsson,Md Tariqul Islam,Masato Isono,Hye-Mi Jang,Farzana Jasmine,Guozhi Jiang,Jost B Jonas,Marit E J\u00f8rgensen,Torben J\u00f8rgensen,Yoichiro Kamatani,Fouad R Kandeel,Anuradhani Kasturiratne,Tomohiro Katsuya,Varinderpal Kaur,Takahisa Kawaguchi,Jacob M Keaton,Abel N Kho,Chiea-Chuen Khor,Muhammad G Kibriya,Duk-Hwan Kim,Katsuhiko Kohara,Jennifer Kriebel,Florian Kronenberg,Johanna Kuusisto,Kristi L\u00e4ll,Leslie A Lange,Myung-Shik Lee,Nanette R Lee,Aaron Leong,Liming Li,Yun Li,Ruifang Li-Gao,Symen Ligthart,Cecilia M Lindgren,Allan Linneberg,Ching-Ti Liu,Jianjun Liu,Adam E Locke,Tin Louie,Jian'an Luan,Andrea O Luk,Xi Luo,Jun Lv,Valeriya Lyssenko,Vasiliki Mamakou,K Radha Mani,Thomas Meitinger,Andres Metspalu,Andrew D Morris,Girish N Nadkarni,Jerry L Nadler,Michael A Nalls,Uma Nayak,Suraj S Nongmaithem,Ioanna Ntalla,Yukinori Okada,Lorena Orozco,Sanjay R Patel,Mark A Pereira,Annette Peters,Fraser J Pirie,Bianca Porneala,Gauri Prasad,Sebastian Preissl,Laura J Rasmussen-Torvik,Alexander P Reiner,Michael Roden,Rebecca Rohde,Kathryn Roll,Charumathi Sabanayagam,Maike Sander,Kevin Sandow,Naveed Sattar,Sebastian Sch\u00f6nherr,Claudia Schurmann,Mohammad Shahriar,Jinxiu Shi,Dong Mun Shin,Daniel Shriner,Jennifer A Smith,Wing Yee So,Alena Stan\u010d\u00e1kov\u00e1,Adrienne M Stilp,Konstantin Strauch,Ken Suzuki,Atsushi Takahashi,Kent D Taylor,Barbara Thorand,Gudmar Thorleifsson,Unnur Thorsteinsdottir,Brian Tomlinson,Jason M Torres,Fuu-Jen Tsai,Jaakko Tuomilehto,Teresa Tusie-Luna,Miriam S Udler,Adan Valladares-Salgado,Rob M van Dam,Jan B van Klinken,Rohit Varma,Marijana Vujkovic,Niels Wacher-Rodarte,Eleanor Wheeler,Eric A Whitsel,Ananda R Wickremasinghe,Ko Willems van Dijk,Daniel R Witte,Chittaranjan S Yajnik,Ken Yamamoto,Toshimasa Yamauchi,Lo\u00efc Yengo,Kyungheon Yoon,Canqing Yu,Jian-Min Yuan,Salim Yusuf,Liang Zhang,Wei Zheng, , ,Leslie J Raffel,Michiya Igase,Eli Ipp,Susan Redline,Yoon Shin Cho,Lars Lind,Michael A Province,Craig L Hanis,Patricia A Peyser,Erik Ingelsson,Alan B Zonderman,Bruce M Psaty,Ya-Xing Wang,Charles N Rotimi,Diane M Becker,Fumihiko Matsuda,Yongmei Liu,Eleftheria Zeggini,Mitsuhiro Yokota,Stephen S Rich,Charles Kooperberg,James S Pankow,James C Engert,Yii-Der Ida Chen,Philippe Froguel,James G Wilson,Wayne H H Sheu,Sharon L R Kardia,Jer-Yuarn Wu,M Geoffrey Hayes,Ronald C W Ma,Tien-Yin Wong,Leif Groop,Dennis O Mook-Kanamori,Giriraj R Chandak,Francis S Collins,Dwaipayan Bharadwaj,Guillaume Par\u00e9,Mich\u00e8le M Sale,Habibul Ahsan,Ayesha A Motala,Xiao-Ou Shu,Kyong-Soo Park,J Wouter Jukema,Miguel Cruz,Roberta McKean-Cowdin,Harald Grallert,Ching-Yu Cheng,Erwin P Bottinger,Abbas Dehghan,E-Shyong Tai,Jos\u00e9e Dupuis,Norihiro Kato,Markku Laakso,Anna K\u00f6ttgen,Woon-Puay Koh,Colin N A Palmer,Simin Liu,Goncalo Abecasis,Jaspal S Kooner,Ruth J F Loos,Kari E North,Christopher A Haiman,Jose C Florez,Danish Saleheen,Torben Hansen,Oluf Pedersen,Reedik M\u00e4gi,Claudia Langenberg,Nicholas J Wareham,Shiro Maeda,Takashi Kadowaki,Juyoung Lee,Iona Y Millwood,Robin G Walters,Kari Stefansson,Simon R Myers,Jorge Ferrer,Kyle J Gaulton,James B Meigs,Karen L Mohlke,Anna L Gloyn,Donald W Bowden,Jennifer E Below,John C Chambers,Xueling Sim,Michael Boehnke,Jerome I Rotter,Mark I McCarthy,Andrew P Morris", - "abstract": "We assembled an ancestrally diverse collection of genome-wide association studies (GWAS) of type 2 diabetes (T2D) in 180,834 affected individuals and 1,159,055 controls (48.9% non-European descent) through the Diabetes Meta-Analysis of Trans-Ethnic association studies (DIAMANTE) Consortium. Multi-ancestry GWAS meta-analysis identified 237 loci attaining stringent genome-wide significance (P\u2009<\u20095\u2009\u00d7\u200910<sup>-9</sup>), which were delineated to 338 distinct association signals. Fine-mapping of these signals was enhanced by the increased sample size and expanded population diversity of the multi-ancestry meta-analysis, which localized 54.4% of T2D associations to a single variant with >50% posterior probability. This improved fine-mapping enabled systematic assessment of candidate causal genes and molecular mechanisms through which T2D associations are mediated, laying the foundations for functional investigations. Multi-ancestry genetic risk scores enhanced transferability of T2D prediction across diverse populations. Our study provides a step toward more effective clinical translation of T2D GWAS to improve global health for all, irrespective of genetic background.", - "journal_title": "Nature genetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/35551307/" - } - ], - "ee5128ff-94e6-4aa5-9369-58ec05692de0": [ - { - "pub_id": "10973253", - "title": "The common PPARgamma Pro12Ala polymorphism is associated with decreased risk of type 2 diabetes.", - "authors": "D Altshuler,J N Hirschhorn,M Klannemark,C M Lindgren,M C Vohl,J Nemesh,C R Lane,S F Schaffner,S Bolk,C Brewer,T Tuomi,D Gaudet,T J Hudson,M Daly,L Groop,E S Lander", - "abstract": "Genetic association studies are viewed as problematic and plagued by irreproducibility. Many associations have been reported for type 2 diabetes, but none have been confirmed in multiple samples and with comprehensive controls. We evaluated 16 published genetic associations to type 2 diabetes and related sub-phenotypes using a family-based design to control for population stratification, and replication samples to increase power. We were able to confirm only one association, that of the common Pro12Ala polymorphism in peroxisome proliferator-activated receptor-gamma(PPARgamma) with type 2 diabetes. By analysing over 3,000 individuals, we found a modest (1.25-fold) but significant (P=0.002) increase in diabetes risk associated with the more common proline allele (85% frequency). Moreover, our results resolve a controversy about common variation in PPARgamma. An initial study found a threefold effect, but four of five subsequent publications failed to confirm the association. All six studies are consistent with the odds ratio we describe. The data implicate inherited variation in PPARgamma in the pathogenesis of type 2 diabetes. Because the risk allele occurs at such high frequency, its modest effect translates into a large population attributable risk-influencing as much as 25% of type 2 diabetes in the general population.", - "journal_title": "Nature genetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/10973253/" - } - ], - "867d7697-f9ef-42c5-bf35-c841b5a67cce": [ - { - "pub_id": "12716802", - "title": "Fibrinogen is a marker for nephropathy and peripheral vascular disease in type 1 diabetes: studies of plasma fibrinogen and fibrinogen gene polymorphism in the DCCT/EDIC cohort.", - "authors": "Richard L Klein,Steven J Hunter,Alicia J Jenkins,Deyi Zheng,Andrea J Semler,Jennifer Clore,W Timothy Garvey, ", - "abstract": "We examined whether plasma fibrinogen levels and the beta-fibrinogen gene G(-455)-->A polymorphism were related to microvascular or macrovascular disease in patients (n = 909) with type 1 diabetes enrolled in the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/ EDIC). Univariate regression showed that fibrinogen levels were correlated with BMI (r = 0.15; P < 0.0001), HbA(1c) (r = 0.11; P = 0.0014), total cholesterol (r = 0.17; P < 0.0001), and LDL cholesterol (r = 0.16; P < 0.0001) in all patients. In men, but not women, waist-to-hip ratio (r = 0.20; P < 0.0001) and triglycerides (r = 0.13; P = 0.0047) also became powerful predictors of fibrinogen level; in women, but not men, fibrinogen was correlated with both diastolic (r = 0.16; P = 0.0011) and systolic (r = 0.11; P = 0.0241) blood pressure. Fibrinogen was correlated with urinary albumin excretion rates in men (r = 0.13; P = 0.0033), but not in women. In both sexes, however, the development of proteinuria (albumin excretion >300 mg/24 h) was accompanied by 1.5-fold increment in plasma fibrinogen compared with patients with normal excretion or microalbuminuria. In addition, high fibrinogen levels were associated with a lower average ankle-brachial index in women (r = -0.13; P = 0.0075), but not men. Multiple regression analyses demonstrated that plasma fibrinogen was independently correlated with high albumin excretion rate in men, and with low average ankle-brachial index in women. Fibrinogen was not correlated with the severity of retinopathy. Carotid artery intima-medial thickness was not correlated with fibrinogen, and the G(-455)-->A polymorphism in the 5' promoter region of the beta-fibrinogen gene did not influence circulating fibrinogen levels. However, the presence of the more common G(-455) allele was associated with greater intima-medial thickness in the internal carotid artery (ANCOVA P = 0.045). Last, hyperfibrinogenemia in type 1 diabetes is associated with components of the insulin resistance syndrome trait cluster, and the association is influenced by sex.", - "journal_title": "Diabetes care", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/12716802/" - } - ], - "25470a2a-c435-4618-b109-c1b7f007025a": [ - { - "pub_id": "9758619", - "title": "An autosomal genomic scan for loci linked to type II diabetes mellitus and body-mass index in Pima Indians.", - "authors": "R L Hanson,M G Ehm,D J Pettitt,M Prochazka,D B Thompson,D Timberlake,T Foroud,S Kobes,L Baier,D K Burns,L Almasy,J Blangero,W T Garvey,P H Bennett,W C Knowler", - "abstract": "Genetic factors influence the development of type II diabetes mellitus, but genetic loci for the most common forms of diabetes have not been identified. A genomic scan was conducted to identify loci linked to diabetes and body-mass index (BMI) in Pima Indians, a Native American population with a high prevalence of type II diabetes. Among 264 nuclear families containing 966 siblings, 516 autosomal markers with a median distance between adjacent markers of 6.4 cM were genotyped. Variance-components methods were used to test for linkage with an age-adjusted diabetes score and with BMI. In multipoint analyses, the strongest evidence for linkage with age-adjusted diabetes (LOD = 1.7) was on chromosome 11q, in the region that was also linked most strongly with BMI (LOD = 3.6). Bivariate linkage analyses strongly rejected both the null hypothesis of no linkage with either trait and the null hypothesis of no contribution of the locus to the covariation among the two traits. Sib-pair analyses suggest additional potential diabetes-susceptibility loci on chromosomes 1q and 7q.", - "journal_title": "American journal of human genetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/9758619/" - } - ], - "6ba4ba64-d0f2-4a8e-bb08-7d062091aa11": [ - { - "pub_id": "15504984", - "title": "Association of protein tyrosine phosphatase 1B gene polymorphisms with type 2 diabetes.", - "authors": "Jennifer L Bento,Nicholette D Palmer,Josyf C Mychaleckyj,Leslie A Lange,Carl D Langefeld,Stephen S Rich,Barry I Freedman,Donald W Bowden", - "abstract": "The PTPN1 gene codes for protein tyrosine phosphatase 1B (PTP1B) (EC 3.1.3.48), which negatively regulates insulin signaling by dephosphorylating the phosphotyrosine residues of the insulin receptor kinase activation segment. PTPN1 is located in 20q13, a genomic region linked to type 2 diabetes in multiple genetic studies. Surveys of the gene have previously identified only a few uncommon coding single nucleotide polymorphisms (SNPs). We have carried out a detailed association analysis of 23 noncoding SNPs spanning the 161-kb genomic region, which includes the PTPN1 gene. These SNPs have been assessed for association with type 2 diabetes in two independently ascertained collections of Caucasian subjects with type 2 diabetes and two control groups. Association is observed between multiple SNPs and type 2 diabetes. The most consistent evidence for association occurred with SNPs spanning the 3' end of intron 1 of PTPN1 through intron 8 (P values ranging from 0.043 to 0.004 in one case-control set and 0.038-0.002 in a second case-control set). Analysis of the combined case-control data increased the evidence of SNP association with type 2 diabetes (P = 0.005-0.0016). All of the associated SNPs lie in a single 100-kb haplotype block that encompasses the PTPN1 gene. Analysis of haplotypes indicates a significant difference between haplotype frequencies in type 2 diabetes case and control subjects (P = 0.0035-0.0056), with one common haplotype (36%) contributing strongly to the evidence for association with type 2 diabetes. Odds ratios calculated from single SNP or haplotype data are in the proximity of 1.3. Haplotype-based calculation of population-attributable risk (PAR) results in an estimated PAR of 17-20% based on different models and assumptions. These results suggest that PTPN1 is a significant contributor to type 2 diabetes susceptibility in the Caucasian population. This risk is likely due to noncoding polymorphisms.", - "journal_title": "Diabetes", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/15504984/" - } - ], - "81e0134b-95c9-4b5e-961f-7ecde79a3038": [ - { - "pub_id": "17245407", - "title": "TCF7L2 polymorphisms are associated with type 2 diabetes in northern Sweden.", - "authors": "Sofia Mayans,Kurt Lackovic,Petter Lindgren,Karin Ruikka,Asa Agren,Mats Eliasson,Dan Holmberg", - "abstract": "A recent study found association of one microsatellite and five single nucleotide polymorphisms (SNPs) in intron 3 of the TCF7L2 gene with type 2 diabetes (T2D) in the Icelandic, Danish and American populations. The aim of the present study was to investigate if those SNPs were associated to T2D in two (family- and population-based) cohorts from northern Sweden. We genotyped four of the associated SNPs in a case-control cohort consisting of 872 T2D cases and 857 controls matched with respect to age, sex and geographical origin and in a sample of 59 extended families (148 affected and 83 unaffected individuals). Here, we report replication of association between T2D and three SNPs in the case-control (rs7901695, P=0.003; rs7901346, P=0.00002; and rs12255372, P=0.000004) and two SNPs in the family-based (rs7901695, P=0.01 and rs7901346, P=0.04) samples from northern Sweden. This replication strengthens the evidence for involvement of TCF7L2 in T2D.", - "journal_title": "European journal of human genetics : EJHG", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/17245407/" - } - ], - "73e26273-682e-4454-b095-84c3cf5bc13e": [ - { - "pub_id": "16306329", - "title": "Interleukin-6 and diabetes: the good, the bad, or the indifferent?", - "authors": "Ole P Kristiansen,Thomas Mandrup-Poulsen", - "abstract": "Inflammatory mechanisms play a key role in the pathogenesis of type 1 diabetes. Individuals who progress to type 2 diabetes display features of low-grade inflammation years in advance of disease onset. This low-grade inflammation has been proposed to be involved in the pathogenetic processes causing type 2 diabetes. Mediators of inflammation such as tumor necrosis factor-alpha, interleukin (IL)-1beta, the IL-6 family of cytokines, IL-18, and certain chemokines have been proposed to be involved in the events causing both forms of diabetes. IL-6 has in addition to its immunoregulatory actions been proposed to affect glucose homeostasis and metabolism directly and indirectly by action on skeletal muscle cells, adipocytes, hepatocytes, pancreatic beta-cells, and neuroendocrine cells. Here we argue that IL-6 action-in part regulated by variance in the IL-6 and IL-6alpha receptor genes-contributes to, but is probably neither necessary nor sufficient for, the development of both type 1 and type 2 diabetes. Thus, the two types of diabetes are also in this respect less apart than apparent. However, the mechanisms are not clear, and we therefore propose future directions for studies in this field.", - "journal_title": "Diabetes", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/16306329/" - } - ], - "ace3a3d7-d2f6-4b8f-89b9-2c181f000e90": [ - { - "pub_id": "18785807", - "title": "Genetics and genome-wide association studies: surgery-guided algorithm and promise for future breast cancer personalized surgery.", - "authors": "Dimitrios H Roukos", - "abstract": "Although personalized medicine and oncology in clinical practice is still a dream, some isolated first steps have been taken. Effective preventive and therapeutic interventions are now tailored in some individual breast cancer patients on the basis of BRCA, estrogen receptor and HER2 status. Personal genome-wide tests hold rational promise toward a true personalized management. The recent dramatic increase of more aggressive surgery by 150% in the USA is effective for preventing local recurrence and contralateral breast cancer but represents a surgical overtreatment that may harm patients and health systems. This article is based on three subpopulations: familial BRCA-positive patients and BRCA-negative patients, and sporadic breast cancer patients. Combining established classic and new risk factors, including familial BRCA susceptibility to breast cancer, an integrated surgery-guided algorithm for clinical validity is proposed. Future genome-wide association studies larger than those currently available using newer genotyping platforms with more than 1 million single-nucleotide polymorphisms and copy number variants will complete the genetic map. Due to the small effects of all these risk variants, further functional studies to explore the intracellular interactions of these variants and signaling pathways networks will be required. Ultimately, large, prospective, population-based studies recording family and medical history and genetic and environmental risk factors will lead to true personalized breast cancer local control.", - "journal_title": "Expert review of molecular diagnostics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/18785807/" - } - ], - "b72de324-d40f-41a7-8ad5-a2daf8b3eeae": [ - { - "pub_id": "19888896", - "title": "Future of osteoporosis genetics: enhancing genome-wide association studies.", - "authors": "Charles R Farber,Aldons J Lusis", - "abstract": "", - "journal_title": "Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/19888896/" - } - ], - "c4c5c626-51f7-4b87-84a3-8323a9233ca1": [ - { - "pub_id": "19667185", - "title": "Mutations at the BLK locus linked to maturity onset diabetes of the young and beta-cell dysfunction.", - "authors": "Maciej Borowiec,Chong W Liew,Ryan Thompson,Watip Boonyasrisawat,Jiang Hu,Wojciech M Mlynarski,Ilham El Khattabi,Sung-Hoon Kim,Lorella Marselli,Stephen S Rich,Andrzej S Krolewski,Susan Bonner-Weir,Arun Sharma,Michele Sale,Josyf C Mychaleckyj,Rohit N Kulkarni,Alessandro Doria", - "abstract": "Maturity-onset diabetes of the young (MODY) is a subtype of diabetes defined by an autosomal pattern of inheritance and a young age at onset, often before age 25. MODY is genetically heterogeneous, with 8 distinct MODY genes identified to date and more believed to exist. We resequenced 732 kb of genomic sequence at 8p23 in 6 MODY families unlinked to known MODY genes that showed evidence of linkage at that location. Of the 410 sequence differences that we identified, 5 had a frequency <1% in the general population and segregated with diabetes in 3 of the families, including the 2 showing the strongest support for linkage at this location. The 5 mutations were all placed within 100 kb corresponding to the BLK gene. One resulted in an Ala71Thr substitution; the other 4 were noncoding and determined decreased in vitro promoter activity in reporter gene experiments. We found that BLK--a nonreceptor tyrosine-kinase of the src family of proto-oncogenes--is expressed in beta-cells where it enhances insulin synthesis and secretion in response to glucose by up-regulating transcription factors Pdx1 and Nkx6.1. These actions are greatly attenuated by the Ala71Thr mutation. These findings point to BLK as a previously unrecognized modulator of beta-cell function, the deficit of which may lead to the development of diabetes.", - "journal_title": "Proceedings of the National Academy of Sciences of the United States of America", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/19667185/" - } - ], - "45686425-1cfe-407d-bc1f-ee87489f2c05": [ - { - "pub_id": "11791443", - "title": "Localising quantitative trait loci in the NOD mouse model of type 1 diabetes.", - "authors": "P A Lyons,L S Wicker", - "abstract": "", - "journal_title": "Current directions in autoimmunity", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/11791443/" - } - ], - "75699e3f-2905-42e0-b4d9-2918250a81df": [ - { - "pub_id": "18556336", - "title": "The common P446L polymorphism in GCKR inversely modulates fasting glucose and triglyceride levels and reduces type 2 diabetes risk in the DESIR prospective general French population.", - "authors": "Martine Vaxillaire,Christine Cavalcanti-Proen\u00e7a,Aur\u00e9lie Dechaume,Jean Tichet,Michel Marre,Beverley Balkau,Philippe Froguel, ", - "abstract": "Hepatic glucokinase (GCK) is a key regulator of glucose storage and disposal in the liver, where its activity is competitively modulated, with respect to glucose, by binding to glucokinase regulatory protein (GCKR) in the presence of fructose 6-phosphate. Genome-wide association studies for type 2 diabetes identified GCKR as a potential locus for modulating triglyceride levels. We evaluated, in a general French population, the contribution of the GCKR rs1260326-P446L polymorphism to quantitative metabolic parameters and to dyslipidemia and hyperglycemia risk. Genotype effects of rs1260326 were studied in 4,833 participants from the prospective DESIR (Data from an Epidemiological Study on the Insulin Resistance syndrome) cohort both at inclusion and using the measurements at follow-up. The minor T-allele of rs1260326 was strongly associated with lower fasting glucose (-1.43% per T-allele; P = 8 x 10(-13)) and fasting insulin levels (-4.23%; P = 3 x 10(-7)), lower homeostasis model assessment of insulin resistance index (-5.69%; P = 1 x 10(-8)), and, conversely, higher triglyceride levels (3.41%; P = 1 x 10(-4)) during the 9-year study. These effects relate to a lower risk of hyperglycemia (odds ratio [OR] 0.79 [95% CI 0.70-0.88]; P = 4 x 10(-5)) and of incident cases during the study (hazard ratio [HR] 0.83 [0.74-0.95]; P = 0.005). Moreover, an additive effect of GCKR rs1260326(T) and GCK (-30G) alleles conferred lower fasting glycemia (P = 1 x 10(-13)), insulinemia (P = 5 x 10(-6)), and hyperglycemia risk (P = 1 x 10(-6)). GCKR-L446 carriers are protected against type 2 diabetes despite higher triglyceride levels and risk of dyslipidemia, which suggests a potential molecular mechanism by which these two components of the metabolic syndrome can be dissociated.", - "journal_title": "Diabetes", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/18556336/" - } - ], - "1a17d68f-1d1e-456b-91ed-eb37ada1806d": [ - { - "pub_id": "19643913", - "title": "The P446L variant in GCKR associated with fasting plasma glucose and triglyceride levels exerts its effect through increased glucokinase activity in liver.", - "authors": "Nicola L Beer,Nicholas D Tribble,Laura J McCulloch,Charlotta Roos,Paul R V Johnson,Marju Orho-Melander,Anna L Gloyn", - "abstract": "Genome-wide association studies have identified a number of signals for both Type 2 Diabetes and related quantitative traits. For the majority of loci, the transition from association signal to mutational mechanism has been difficult to establish. Glucokinase (GCK) regulates glucose storage and disposal in the liver where its activity is regulated by glucokinase regulatory protein (GKRP; gene name GCKR). Fructose-6 and fructose-1 phosphate (F6P and F1P) enhance or reduce GKRP-mediated inhibition, respectively. A common GCKR variant (P446L) is reproducibly associated with triglyceride and fasting plasma glucose levels in the general population. The aim of this study was to determine the mutational mechanism responsible for this genetic association. Recombinant human GCK and both human wild-type (WT) and P446L-GKRP proteins were generated. GCK kinetic activity was observed spectrophotometrically using an NADP(+)-coupled assay. WT and P446L-GKRP-mediated inhibition of GCK activity and subsequent regulation by phosphate esters were determined. Assays matched for GKRP activity demonstrated no difference in dose-dependent inhibition of GCK activity or F1P-mediated regulation. However, the response to physiologically relevant F6P levels was significantly attenuated with P446L-GKRP (n = 18; P <or= 0.03). Experiments using equimolar concentrations of both regulatory proteins confirmed these findings (n = 9; P < 0.001). In conclusion, P446L-GKRP has reduced regulation by physiological concentrations of F6P, resulting indirectly in increased GCK activity. Altered GCK regulation in liver is predicted to enhance glycolytic flux, promoting hepatic glucose metabolism and elevating concentrations of malonyl-CoA, a substrate for de novo lipogenesis, providing a mutational mechanism for the reported association of this variant with raised triglycerides and lower glucose levels.", - "journal_title": "Human molecular genetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/19643913/" - } - ], - "e04e12ba-9cff-4cc0-8084-66266d6a603e": [ - { - "pub_id": "19296077", - "title": "Agreement among type 2 diabetes linkage studies but a poor correlation with results from genome-wide association studies.", - "authors": "S Lillioja,A Wilton", - "abstract": "Little of the genetic basis for type 2 diabetes has been explained, despite numerous genetic linkage studies and the discovery of multiple genes in genome-wide association (GWA) studies. To begin to resolve the genetic component of this disease, we searched for sites at which genetic results had been corroborated in different studies, in the expectation that replication among studies should direct us to the genomic locations of causative genes with more confidence than the results of individual studies. We have mapped the physical location of results from 83 linkage reports (for type 2 diabetes and diabetes precursor quantitative traits [QTs, e.g. plasma insulin levels]) and recent large GWA reports (for type 2 diabetes) onto the same human genome sequence to identify replicated results in diabetes genetic 'hot spots'. Genetic linkage has been found at least ten times at 18 different locations, and at least five times in 56 locations. All replication clusters contained study populations from more than one ethnic background and most contained results for both diabetes and QTs. There is no close relationship between the GWA results and linkage clusters, and the nine best replication clusters have no nearby GWA result. Many of the genes for type 2 diabetes remain unidentified. This analysis identifies the broad location of yet to be identified genes on 6q, 1q, 18p, 2q, 20q, 17pq, 8p, 19q and 9q. The discrepancy between the linkage and GWA studies may be explained by the presence of multiple, uncommon, mildly deleterious polymorphisms scattered throughout the regulatory and coding regions of genes for type 2 diabetes.", - "journal_title": "Diabetologia", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/19296077/" - } - ], - "a9b5b1eb-9421-47e5-99eb-2adc1540ee14": [ - { - "pub_id": "18263617", - "title": "Commonality of functional annotation: a method for prioritization of candidate genes from genome-wide linkage studies.", - "authors": "Daniel Shriner,Tesfaye M Baye,Miguel A Padilla,Shiju Zhang,Laura K Vaughan,Ann E Loraine", - "abstract": "Linkage studies of complex traits frequently yield multiple linkage regions covering hundreds of genes. Testing each candidate gene from every region is prohibitively expensive and computational methods that simplify this process would benefit genetic research. We present a new method based on commonality of functional annotation (CFA) that aids dissection of complex traits for which multiple causal genes act in a single pathway or process. CFA works by testing individual Gene Ontology (GO) terms for enrichment among candidate gene pools, performs multiple hypothesis testing adjustment using an estimate of independent tests based on correlation of GO terms, and then scores and ranks genes annotated with significantly-enriched terms based on the number of quantitative trait loci regions in which genes bearing those annotations appear. We evaluate CFA using simulated linkage data and show that CFA has good power despite being conservative. We apply CFA to published linkage studies investigating age-of-onset of Alzheimer's disease and body mass index and obtain previously known and new candidate genes. CFA provides a new tool for studies in which causal genes are expected to participate in a common pathway or process and can easily be extended to utilize annotation schemes in addition to the GO.", - "journal_title": "Nucleic acids research", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/18263617/" - } - ], - "0da4d3d4-10d5-4a58-9e50-c1fa0b414427": [ - { - "pub_id": "18394465", - "title": "Molecular memory traces.", - "authors": "Wayne S Sossin", - "abstract": "To understand the essence of memory, one must examine the working of the brain on many levels. It is important to find the appropriate level to study the particular aspect of memory under investigation. In this review, I will focus on insights gained from examining memory at the molecular level. I will illustrate these insights with specific examples from examining the molecular and cellular mechanisms underlying long-term facilitation in the marine mollusk Aplysia and long-term potentiation, studied mainly in rodents. In particular, I will discuss how molecular memory traces are formed and focus in detail on what role increasing the level of proteins through protein synthesis and gene expression plays in memory formation. I will point out three important constraints from molecular work that should impact on cognitive modeling of the nervous system: (i) the induction of plasticity depends on the 'state' of the synapse; (ii) there are multiple independent molecular traces formed after experience with different half-lives; and (iii) the requirement for the conjunction of synaptic activation and new protein synthesis implies that new conjunctions are required to induce long-term memory formation.", - "journal_title": "Progress in brain research", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/18394465/" - } - ], - "e9a398f1-eee9-45e1-b563-0f399d383b19": [ - { - "pub_id": "11679445", - "title": "Mapping by genetic interaction: high-resolution congenic mapping of the type 1 diabetes loci Idd10 and Idd18 in the NOD mouse.", - "authors": "P A Lyons,N Armitage,C J Lord,M S Phillips,J A Todd,L B Peterson,L S Wicker", - "abstract": "As many of the linked chromosome regions that predispose to type 1 diabetes in the NOD mouse have been dissected, it has become apparent that the initially observed effect is in fact attributable to several loci. One such cluster of loci on distal chromosome 3, originally described as Idd10, is now known to comprise three separate loci, Idd10, Idd17, and Idd18. Although these loci have a significant combined effect on diabetes development, their individual effects are barely detectable when diabetes is used as a read-out, which makes fine-mapping them by use of a conventional congenic approach impractical. In this study, we demonstrate that it is possible to map loci, with modest effects, to regions small enough for systematic gene identification by capitalizing on the fact that the combined loci provide more profound, measurable protection. We have mapped the Idd10 and Idd18 loci to 1.3- and 2.0-cM intervals, respectively, by holding the Idd3 allele constant. In addition, we have excluded Csf1 and Nras as candidates for both loci.", - "journal_title": "Diabetes", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/11679445/" - } - ], - "ed2d6ad9-40cb-4618-9d1c-a1d81d146a2d": [ - { - "pub_id": "15286800", - "title": "Impaired glucose homeostasis in transgenic mice expressing the human transient neonatal diabetes mellitus locus, TNDM.", - "authors": "Dan Ma,Julian P H Shield,Wendy Dean,Isabelle Leclerc,Claude Knauf,R \u00e9My Burcelin R,Guy A Rutter,Gavin Kelsey", - "abstract": "Transient neonatal diabetes mellitus (TNDM) is a rare inherited diabetic syndrome apparent in the first weeks of life and again during early adulthood. The relative contributions of reduced islet beta cell number and impaired beta cell function to the observed hypoinsulinemia are unclear. The inheritance pattern of this imprinted disorder implicates overexpression of one or both genes within the TNDM locus: ZAC, which encodes a proapoptotic zinc finger protein, and HYMAI, which encodes an untranslated mRNA. To investigate the consequences for pancreatic function, we have developed a high-copy transgenic mouse line, TNDM29, carrying the human TNDM locus. TNDM29 neonates display hyperglycemia, and older adults, impaired glucose tolerance. Neonatal hyperglycemia occurs only on paternal transmission, analogous to paternal dependence of TNDM in humans. Embryonic pancreata of TNDM29 mice showed reductions in expression of endocrine differentiation factors and numbers of insulin-staining structures. By contrast, beta cell mass was normal or elevated at all postnatal stages, whereas pancreatic insulin content in neonates and peak serum insulin levels after glucose infusion in adults were reduced. Expression of human ZAC and HYMAI in these transgenic mice thus recapitulates key features of TNDM and implicates impaired development of the endocrine pancreas and beta cell function in disease pathogenesis.", - "journal_title": "The Journal of clinical investigation", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/15286800/" - } - ], - "cecabb27-9681-491c-a901-5ad3a5a709b7": [ - { - "pub_id": "19060908", - "title": "Common variant in MTNR1B associated with increased risk of type 2 diabetes and impaired early insulin secretion.", - "authors": "Valeriya Lyssenko,Cecilia L F Nagorny,Michael R Erdos,Nils Wierup,Anna Jonsson,Peter Sp\u00e9gel,Marco Bugliani,Richa Saxena,Malin Fex,Nicolo Pulizzi,Bo Isomaa,Tiinamaija Tuomi,Peter Nilsson,Johanna Kuusisto,Jaakko Tuomilehto,Michael Boehnke,David Altshuler,Frank Sundler,Johan G Eriksson,Anne U Jackson,Markku Laakso,Piero Marchetti,Richard M Watanabe,Hindrik Mulder,Leif Groop", - "abstract": "Genome-wide association studies have shown that variation in MTNR1B (melatonin receptor 1B) is associated with insulin and glucose concentrations. Here we show that the risk genotype of this SNP predicts future type 2 diabetes (T2D) in two large prospective studies. Specifically, the risk genotype was associated with impairment of early insulin response to both oral and intravenous glucose and with faster deterioration of insulin secretion over time. We also show that the MTNR1B mRNA is expressed in human islets, and immunocytochemistry confirms that it is primarily localized in beta cells in islets. Nondiabetic individuals carrying the risk allele and individuals with T2D showed increased expression of the receptor in islets. Insulin release from clonal beta cells in response to glucose was inhibited in the presence of melatonin. These data suggest that the circulating hormone melatonin, which is predominantly released from the pineal gland in the brain, is involved in the pathogenesis of T2D. Given the increased expression of MTNR1B in individuals at risk of T2D, the pathogenic effects are likely exerted via a direct inhibitory effect on beta cells. In view of these results, blocking the melatonin ligand-receptor system could be a therapeutic avenue in T2D.", - "journal_title": "Nature genetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/19060908/" - } - ], - "f903e70d-7935-4caa-a6c0-63ef7e2095b5": [ - { - "pub_id": "35357919", - "title": "The complete sequence of a human genome.", - "authors": "Sergey Nurk,Sergey Koren,Arang Rhie,Mikko Rautiainen,Andrey V Bzikadze,Alla Mikheenko,Mitchell R Vollger,Nicolas Altemose,Lev Uralsky,Ariel Gershman,Sergey Aganezov,Savannah J Hoyt,Mark Diekhans,Glennis A Logsdon,Michael Alonge,Stylianos E Antonarakis,Matthew Borchers,Gerard G Bouffard,Shelise Y Brooks,Gina V Caldas,Nae-Chyun Chen,Haoyu Cheng,Chen-Shan Chin,William Chow,Leonardo G de Lima,Philip C Dishuck,Richard Durbin,Tatiana Dvorkina,Ian T Fiddes,Giulio Formenti,Robert S Fulton,Arkarachai Fungtammasan,Erik Garrison,Patrick G S Grady,Tina A Graves-Lindsay,Ira M Hall,Nancy F Hansen,Gabrielle A Hartley,Marina Haukness,Kerstin Howe,Michael W Hunkapiller,Chirag Jain,Miten Jain,Erich D Jarvis,Peter Kerpedjiev,Melanie Kirsche,Mikhail Kolmogorov,Jonas Korlach,Milinn Kremitzki,Heng Li,Valerie V Maduro,Tobias Marschall,Ann M McCartney,Jennifer McDaniel,Danny E Miller,James C Mullikin,Eugene W Myers,Nathan D Olson,Benedict Paten,Paul Peluso,Pavel A Pevzner,David Porubsky,Tamara Potapova,Evgeny I Rogaev,Jeffrey A Rosenfeld,Steven L Salzberg,Valerie A Schneider,Fritz J Sedlazeck,Kishwar Shafin,Colin J Shew,Alaina Shumate,Ying Sims,Arian F A Smit,Daniela C Soto,Ivan Sovi\u0107,Jessica M Storer,Aaron Streets,Beth A Sullivan,Fran\u00e7oise Thibaud-Nissen,James Torrance,Justin Wagner,Brian P Walenz,Aaron Wenger,Jonathan M D Wood,Chunlin Xiao,Stephanie M Yan,Alice C Young,Samantha Zarate,Urvashi Surti,Rajiv C McCoy,Megan Y Dennis,Ivan A Alexandrov,Jennifer L Gerton,Rachel J O'Neill,Winston Timp,Justin M Zook,Michael C Schatz,Evan E Eichler,Karen H Miga,Adam M Phillippy", - "abstract": "Since its initial release in 2000, the human reference genome has covered only the euchromatic fraction of the genome, leaving important heterochromatic regions unfinished. Addressing the remaining 8% of the genome, the Telomere-to-Telomere (T2T) Consortium presents a complete 3.055 billion-base pair sequence of a human genome, T2T-CHM13, that includes gapless assemblies for all chromosomes except Y, corrects errors in the prior references, and introduces nearly 200 million base pairs of sequence containing 1956 gene predictions, 99 of which are predicted to be protein coding. The completed regions include all centromeric satellite arrays, recent segmental duplications, and the short arms of all five acrocentric chromosomes, unlocking these complex regions of the genome to variational and functional studies.", - "journal_title": "Science (New York, N.Y.)", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/35357919/" - } - ], - "be32a861-a32f-4026-8c5c-fc53624af332": [ - { - "pub_id": "17416853", - "title": "Meta-analysis of BRCA1 and BRCA2 penetrance.", - "authors": "Sining Chen,Giovanni Parmigiani", - "abstract": "Genetic counseling is now routinely offered to individuals at high risk of carrying a BRCA1 or BRCA2 mutation. Risk prediction provided by the counselor requires reliable estimates of the mutation penetrance. Such penetrance has been investigated by studies worldwide. The reported estimates vary. To facilitate clinical management and counseling of the at-risk population, we address this issue through a meta-analysis. We conducted a literature search on PubMed and selected studies that had nonoverlapping patient data, contained genotyping information, used statistical methods that account for the ascertainment, and reported risks in a useable format. We subsequently combined the published estimates using the DerSimonian and Laird random effects modeling approach. Ten studies were eligible under the selection criteria. Between-study heterogeneity was observed. Study population, mutation type, design, and estimation methods did not seem to be systematic sources of heterogeneity. Meta-analytic mean cumulative cancer risks for mutation carriers at age 70 years were as follows: breast cancer risk of 57% (95% CI, 47% to 66%) for BRCA1 and 49% (95% CI, 40% to 57%) for BRCA2 mutation carriers; and ovarian cancer risk of 40% (95% CI, 35% to 46%) for BRCA1 and 18% (95% CI, 13% to 23%) for BRCA2 mutation carriers. We also report the prospective risks of developing cancer for currently asymptomatic carriers. This article provides a set of risk estimates for BRCA1 and BRCA2 mutation carriers that can be used by counselors and clinicians who are interested in advising patients based on a comprehensive set of studies rather than one specific study.", - "journal_title": "Journal of clinical oncology : official journal of the American Society of Clinical Oncology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/17416853/" - } - ], - "b48c5252-605e-4144-b1df-4569c21c0e7c": [ - { - "pub_id": "16816970", - "title": "A maternal hypomethylation syndrome presenting as transient neonatal diabetes mellitus.", - "authors": "D J G Mackay,S E Boonen,J Clayton-Smith,J Goodship,J M D Hahnemann,S G Kant,P R Nj\u00f8lstad,N H Robin,D O Robinson,R Siebert,J P H Shield,H E White,I K Temple", - "abstract": "The expression of imprinted genes is mediated by allele-specific epigenetic modification of genomic DNA and chromatin, including parent of origin-specific DNA methylation. Dysregulation of these genes causes a range of disorders affecting pre- and post-natal growth and neurological function. We investigated a cohort of 12 patients with transient neonatal diabetes whose disease was caused by loss of maternal methylation at the TNDM locus. We found that six of these patients showed a spectrum of methylation loss, mosaic with respect to the extent of the methylation loss, the tissues affected and the genetic loci involved. Five maternally methylated loci were affected, while one maternally methylated and two paternally methylated loci were spared. These patients had higher birth weight and were more phenotypically diverse than other TNDM patients with different aetiologies, presumably reflecting the influence of dysregulation of multiple imprinted genes. We propose the existence of a maternal hypomethylation syndrome, and therefore suggest that any patient with methylation loss at one maternally-methylated locus may also manifest methylation loss at other loci, potentially complicating or even confounding the clinical presentation.", - "journal_title": "Human genetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/16816970/" - } - ], - "c2a479f1-3fbd-4a06-a310-2f2d7b1d99ad": [ - { - "pub_id": "11812768", - "title": "Asian-specific HLA haplotypes reveal heterogeneity of the contribution of HLA-DR and -DQ haplotypes to susceptibility to type 1 diabetes.", - "authors": "Yumiko Kawabata,Hiroshi Ikegami,Yoshihiko Kawaguchi,Tomomi Fujisawa,Maki Shintani,Masaya Ono,Masanori Nishino,Yasuko Uchigata,Inkyu Lee,Toshio Ogihara", - "abstract": "To assess the effect of Asian-specific HLA haplotypes on susceptibility to type 1 diabetes, we investigated the association of genotypic combinations of DRB1-DQB1 haplotypes with susceptibility to type 1 diabetes. We studied 132 Japanese patients with type 1 diabetes and 157 control subjects, along with 67 Korean patients and 109 control subjects. DRB1*0405-DQB1*0401 and DRB1*0901-DQB1*0303 were confirmed to be two major susceptible HLA haplotypes in the Japanese population. The frequencies of heterozygotes and homozygotes with DRB1*0405-DQB1*0401 were similarly higher in patients than in control subjects (homozygotes, 5.3% vs. 3.8%; heterozygotes, 48.5% vs. 26.1%). In contrast, homozygotes, but not heterozygotes, with DRB1*0901-DQB1*0303 were more frequent in patients with type 1 diabetes than in control subjects (homozygotes, 12.9% vs. 0.6%; heterozygotes, 22.0% vs. 24.8%). A similar tendency was also observed in the Korean population. In multiple logistic regression analysis, DRB1*0405-DQB1*0401 fitted a dominant model and DRB1*0901-DQB1*0303 fitted a recessive model. These data, which indicate that the contribution of HLA haplotypes to the genetic susceptibility to type 1 diabetes differs depending on the genotypic combination of HLA haplotypes, suggest the importance of extensive analysis of genotypes in studies on HLA and disease association in general.", - "journal_title": "Diabetes", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/11812768/" - } - ], - "94e8620c-2fb8-4143-b397-a561e61535e2": [ - { - "pub_id": "17554300", - "title": "Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls.", - "authors": " ", - "abstract": "There is increasing evidence that genome-wide association (GWA) studies represent a powerful approach to the identification of genes involved in common human diseases. We describe a joint GWA study (using the Affymetrix GeneChip 500K Mapping Array Set) undertaken in the British population, which has examined approximately 2,000 individuals for each of 7 major diseases and a shared set of approximately 3,000 controls. Case-control comparisons identified 24 independent association signals at P < 5 x 10(-7): 1 in bipolar disorder, 1 in coronary artery disease, 9 in Crohn's disease, 3 in rheumatoid arthritis, 7 in type 1 diabetes and 3 in type 2 diabetes. On the basis of prior findings and replication studies thus-far completed, almost all of these signals reflect genuine susceptibility effects. We observed association at many previously identified loci, and found compelling evidence that some loci confer risk for more than one of the diseases studied. Across all diseases, we identified a large number of further signals (including 58 loci with single-point P values between 10(-5) and 5 x 10(-7)) likely to yield additional susceptibility loci. The importance of appropriately large samples was confirmed by the modest effect sizes observed at most loci identified. This study thus represents a thorough validation of the GWA approach. It has also demonstrated that careful use of a shared control group represents a safe and effective approach to GWA analyses of multiple disease phenotypes; has generated a genome-wide genotype database for future studies of common diseases in the British population; and shown that, provided individuals with non-European ancestry are excluded, the extent of population stratification in the British population is generally modest. Our findings offer new avenues for exploring the pathophysiology of these important disorders. We anticipate that our data, results and software, which will be widely available to other investigators, will provide a powerful resource for human genetics research.", - "journal_title": "Nature", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/17554300/" - } - ], - "1e929a97-af99-4fde-bb24-8cdc18b0b72f": [ - { - "pub_id": "19836853", - "title": "Next generation disparities in human genomics: concerns and remedies.", - "authors": "Anna C Need,David B Goldstein", - "abstract": "Studies of human genetics, particularly genome-wide association studies (GWAS), have concentrated heavily on European populations, with individuals of African ancestry rarely represented. Reasons for this include the distribution of biomedical funding and the increased population structure and reduced linkage disequilibrium in African populations. Currently, few GWAS findings have clinical utility and, therefore, the field has not yet contributed to health-care disparities. As human genomics research progresses towards the whole-genome sequencing era, however, more clinically relevant results are likely to be discovered. As we discuss here, to avoid the genetics community contributing to healthcare disparities, it is important to adopt measures to ensure that populations of diverse ancestry are included in genomic studies, and that no major population groups are excluded.", - "journal_title": "Trends in genetics : TIG", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/19836853/" - } - ], - "aef1a825-89fa-4566-9a9e-297802a9ba8e": [ - { - "pub_id": "17096114", - "title": "TCF7L2: the biggest story in diabetes genetics since HLA?", - "authors": "E Zeggini,M I McCarthy", - "abstract": "", - "journal_title": "Diabetologia", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/17096114/" - } - ], - "ae333983-6054-4788-90fd-f82d93c8a515": [ - { - "pub_id": "19481926", - "title": "Common vs. rare allele hypotheses for complex diseases.", - "authors": "Nicholas J Schork,Sarah S Murray,Kelly A Frazer,Eric J Topol", - "abstract": "There has been growing debate over the nature of the genetic contribution to individual susceptibility to common complex diseases such as diabetes, osteoporosis, and cancer. The 'Common Disease, Common Variant (CDCV)' hypothesis argues that genetic variations with appreciable frequency in the population at large, but relatively low 'penetrance' (or the probability that a carrier of the relevant variants will express the disease), are the major contributors to genetic susceptibility to common diseases. The 'Common Disease, Rare Variant (CDRV)' hypothesis, on the contrary, argues that multiple rare DNA sequence variations, each with relatively high penetrance, are the major contributors to genetic susceptibility to common diseases. Both hypotheses have their place in current research efforts.", - "journal_title": "Current opinion in genetics & development", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/19481926/" - } - ], - "f6231931-6b32-417f-8f68-2222a4a3f723": [ - { - "pub_id": "15592662", - "title": "Common polymorphisms of the PPAR-gamma2 (Pro12Ala) and PGC-1alpha (Gly482Ser) genes are associated with the conversion from impaired glucose tolerance to type 2 diabetes in the STOP-NIDDM trial.", - "authors": "L Andrulionyt\u00e8,J Zacharova,J-L Chiasson,M Laakso, ", - "abstract": "We investigated the effects of the common polymorphisms in the peroxisome proliferator-activated receptor gamma2 (PPAR-gamma2; Pro12Ala) and in PPAR-gamma coactivator 1alpha (PGC-1alpha; Gly482Ser) genes on the conversion from impaired glucose tolerance to type 2 diabetes in participants in the STOP-NIDDM trial. This trial aimed to study the effect of acarbose in the prevention of type 2 diabetes. Genotyping was performed in 770 study subjects whose DNA was available. The Gly482Ser variant in the PGC-1alpha gene was determined with the polymerase chain reaction amplification, Hpa II enzyme digestion, and gel electrophoresis. The Pro12Ala polymorphism of the PPAR-gamma2 gene was determined by the polymerase chain reaction-single-strand conformation polymorphism analysis. The Pro12Pro genotype of the PPAR-gamma2 gene predicted the conversion to diabetes in women in the acarbose group (odds ratio 2.89, 95% CI 1.20 to 6.96; p=0.018). The 482Ser allele of the PGC-1alpha gene had a significant interaction with the mode of treatment (p=0.012), and in the placebo group the 482Ser allele was associated with a 1.6-fold higher risk for type 2 diabetes compared to the Gly482Gly genotype (95% CI 1.06 to 2.33; p=0.023). Acarbose prevented the development of diabetes independently of the genotype of the PPAR-gamma2 gene, but only the carriers of the 482Ser allele of the PGC-1alpha gene were responsive to acarbose treatment. We conclude that the Pro12Pro genotype of the PPAR-gamma2 gene and the 482Ser allele of the PGC-1alpha gene are associated with the conversion from impaired glucose tolerance to type 2 diabetes in the STOP-NIDDM trial.", - "journal_title": "Diabetologia", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/15592662/" - } - ], - "6cf37df4-2abe-4289-a3fd-bd8892e91331": [ - { - "pub_id": "18356407", - "title": "The diabetic phenotype in HNF4A mutation carriers is moderated by the expression of HNF4A isoforms from the P1 promoter during fetal development.", - "authors": "Lorna W Harries,Jonathan M Locke,Beverley Shields,Neil A Hanley,Karen Piper Hanley,Anna Steele,P\u00e5l R Nj\u00f8lstad,Sian Ellard,Andrew T Hattersley", - "abstract": "Mutations in the alternatively spliced HNF4A gene cause maturity-onset diabetes of the young (MODY). We characterized the spatial and developmental expression patterns of HNF4A transcripts in human tissues and investigated their role as potential moderators of the MODY phenotype. We measured the expression of HNF4A isoforms in human adult tissues and gestationally staged fetal pancreas by isoform-specific real-time PCR. The correlation between mutation position and age of diagnosis or age-related penetrance was assessed in a cohort of 190 patients with HNF4A mutations. HNF4A was expressed exclusively from the P2 promoter in adult pancreas, but from 9 weeks until at least 26 weeks after conception, up to 23% of expression in fetal pancreas was of P1 origin. HNF4A4-6 transcripts were not detected in any tissue. In whole pancreas, HNF4A9 expression was greater than in islets isolated from the endocrine pancreas (relative level 22 vs. 7%). Patients with mutations in exons 9 and 10 (absent from HNF4A3, HNF4A6, and HNF4A9 isoforms) developed diabetes later than those with mutations in exons 2-8, where all isoforms were affected (40 vs. 24 years; P = 0.029). Exon 9/10 mutations were also associated with a reduced age-related penetrance (53 vs. 10% without diabetes at age 55 years; P < 0.00001). We conclude that isoforms derived from the HNF4A P1 promoter are expressed in human fetal, but not adult, pancreas, and that their presence during pancreatic development may moderate the diabetic phenotype in individuals with mutations in the HNF4A gene.", - "journal_title": "Diabetes", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/18356407/" - } - ], - "35a32979-81b5-497c-98e6-cef8d5bdf8e4": [ - { - "pub_id": "16823476", - "title": "Adiponectin and adiponectin receptors in insulin resistance, diabetes, and the metabolic syndrome.", - "authors": "Takashi Kadowaki,Toshimasa Yamauchi,Naoto Kubota,Kazuo Hara,Kohjiro Ueki,Kazuyuki Tobe", - "abstract": "Adiponectin is an adipokine that is specifically and abundantly expressed in adipose tissue and directly sensitizes the body to insulin. Hypoadiponectinemia, caused by interactions of genetic factors such as SNPs in the Adiponectin gene and environmental factors causing obesity, appears to play an important causal role in insulin resistance, type 2 diabetes, and the metabolic syndrome, which are linked to obesity. The adiponectin receptors, AdipoR1 and AdipoR2, which mediate the antidiabetic metabolic actions of adiponectin, have been cloned and are downregulated in obesity-linked insulin resistance. Upregulation of adiponectin is a partial cause of the insulin-sensitizing and antidiabetic actions of thiazolidinediones. Therefore, adiponectin and adiponectin receptors represent potential versatile therapeutic targets to combat obesity-linked diseases characterized by insulin resistance. This Review describes the pathophysiology of adiponectin and adiponectin receptors in insulin resistance, diabetes, and the metabolic syndrome.", - "journal_title": "The Journal of clinical investigation", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/16823476/" - } - ], - "37d53e91-459c-4b9f-b753-9a5b1c8e705b": [ - { - "pub_id": "18413782", - "title": "Current challenges in metabolomics for diabetes research: a vital functional genomic tool or just a ploy for gaining funding?", - "authors": "Julian L Griffin,Antonio Vidal-Puig", - "abstract": "Metabolomics aims to profile all the small molecule metabolites found within a cell, tissue, organ, or organism and use this information to understand a biological manipulation such as a drug intervention or a gene knockout. While neither mass spectrometry or NMR spectroscopy, the two most commonly used analytical tools in metabolomics, can provide a complete coverage of the metabolome, compared with other functional genomic tools for profiling biological moieties the approach is cheap and high throughput. In diabetes and obesity research this has provided the opportunity to assess large human populations or investigate a range of different tissues in animal studies both rapidly and cheaply. However, the approach has a number of major challenges, particularly with the interpretation of the data obtained. For example, some key pathways are better represented by high concentration metabolites inside the cell, and thus, the coverage of the metabolome may become biased towards these pathways (e.g., the TCA cycle, amino acid metabolism). There is also the challenge of statistically modeling datasets with large numbers of variables but relatively small sample sizes. This perspective discusses our own experience of some of the benefits and pitfalls with using metabolomics to understand diseases associated with type 2 diabetes.", - "journal_title": "Physiological genomics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/18413782/" - } - ], - "f54c42a7-cba6-4d2c-b5a1-484d3ab107db": [ - { - "pub_id": "9585427", - "title": "Genetic dissection of \"OLETF\", a rat model for non-insulin-dependent diabetes mellitus.", - "authors": "N Kanemoto,H Hishigaki,A Miyakita,K Oga,S Okuno,A Tsuji,T Takagi,E Takahashi,Y Nakamura,T K Watanabe", - "abstract": "To elucidate the genetic factors underlying non-insulin-dependent diabetes mellitus (NIDDM), we performed genome-wide quantitative trait locus (QTL) analysis, using the Otsuka Long-Evans Tokushima Fatty (OLETF) rat. The OLETF rat is an excellent animal model of NIDDM because the features of the disease closely resemble human NIDDM. Genetic dissection with two kinds of F2 intercross progeny, from matings between the OLETF rat and non-diabetic control rats F344 or BN, allowed us to identify on Chromosome (Chr) 1 a major QTL associated with features of NIDDM that was common to both crosses. We also mapped two additional significant loci, on Chrs 7 and 14, in the (OLETF x F344)F2 cross alone, and designated these three loci as Diabetes mellitus, OLETF type Dmo 1, Dmo2 and Dmo3 respectively. With regard to suggestive QTLs, we found loci on Chrs 10, 11, and 16 that were common to both crosses, as well as loci on Chrs 5 and 12 in the (OLETF x F344)F2 cross and on Chrs 4 and 13 in the (OLETF x BN)F2 cross. Our results showed that NIDDM in the OLETF rat is polygenic and demonstrated that different genetic backgrounds could affect \"fitness\" for QTLs and produce different phenotypic effects from the same locus.", - "journal_title": "Mammalian genome : official journal of the International Mammalian Genome Society", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/9585427/" - } - ], - "266b7aef-0eae-40e9-a386-de8821af59db": [ - { - "pub_id": "36009236", - "title": "Potential Molecular Targets of Oleanolic Acid in Insulin Resistance and Underlying Oxidative Stress: A Systematic Review.", - "authors": "\u00c1ngel Fern\u00e1ndez-Aparicio,Mar\u00eda Correa-Rodr\u00edguez,Jose M Castellano,Jacqueline Schmidt-RioValle,Javier S Perona,Emilio Gonz\u00e1lez-Jim\u00e9nez", - "abstract": "Oleanolic acid (OA) is a natural triterpene widely found in olive leaves that possesses antioxidant, anti-inflammatory, and insulin-sensitizing properties, among others. These OA characteristics could be of special interest in the treatment and prevention of insulin resistance (IR), but greater in-depth knowledge on the pathways involved in these properties is still needed. We aimed to systematically review the effects of OA on the molecular mechanisms and signaling pathways involved in the development of IR and underlying oxidative stress in insulin-resistant animal models or cell lines. The bibliographic search was carried out on PubMed, Web of Science, Scopus, Cochrane, and CINHAL databases between January 2001 and May 2022. The electronic search produced 5034 articles but, after applying the inclusion criteria, 13 animal studies and 3 cell experiments were identified, using SYRCLE's Risk of Bias for assessing the risk of bias of the animal studies. OA was found to enhance insulin sensitivity and glucose uptake, and was found to suppress the hepatic glucose production, probably by modulating the IRS/PI3K/Akt/FoxO1 signaling pathway and by mitigating oxidative stress through regulating MAPK pathways. Future randomized controlled clinical trials to assess the potential benefit of OA as new therapeutic and preventive strategies for IR are warranted.", - "journal_title": "Antioxidants (Basel, Switzerland)", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/36009236/" - } - ], - "a3b42164-cf44-4ef4-837b-fbdd5060136d": [ - { - "pub_id": "10868975", - "title": "Vitamin D receptor allele combinations influence genetic susceptibility to type 1 diabetes in Germans.", - "authors": "M A Pani,M Knapp,H Donner,J Braun,M P Baur,K H Usadel,K Badenhoop", - "abstract": "Vitamin D has been shown to exert manifold immunomodulatory effects. Because type 1 diabetes is regarded to be immune-mediated and vitamin D prevents the development of diabetes in the NOD mouse, we investigated the role of the vitamin D receptor (VDR) gene as a candidate for type 1 diabetes susceptibility. A total of 152 Caucasian families with at least one affected offspring were genotyped for four VDR restriction-site polymorphisms (FokI, BsmI, ApaI, and TaqI). Whereas the BsmI, ApaI, and TaqI polymorphisms are in strong linkage disequilibrium with each other, no significant linkage disequilibrium with the FokI site was observed. Extended transmission disequilibrium testing (ETDT) was used to detect preferential transmission of allelic combinations to affected offspring. We found significant haplotype-wise ETDT results for the BsmI/ApaI/TaqI (chi2 = 18.886, df = 7, P = 0.0086), the BsmI/TaqI (chi2 = 8.373, df = 3, P = 0.0389), and theApaI/TaqI (chi2 = 17.182, df = 3, P = 0.0006) haplotypes. The \"At\" and \"Bt\" alleles confer an increased risk, whereas \"AT\" and \"at\" are protective. The combination with the strongest susceptibility was the \"BAt\" haplotype (64% transmitted, P = 0.0106). Analysis of the FokI site does not provide more information on susceptibility (FokI/BsmI/ApaI/TaqI [chi2 = 24.702, df = 15, P = 0.0541]). These findings suggest a linkage of VDR itself or a nearby gene with type 1 diabetes susceptibility in Germans, confirming respective observations previously made in Indian Asians.", - "journal_title": "Diabetes", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/10868975/" - } - ], - "dffb1ab7-ca1e-487d-9c3d-0ebed58d215e": [ - { - "pub_id": "18645605", - "title": "Megsin gene: its genomic analysis, pathobiological functions, and therapeutic perspectives.", - "authors": "Toshio Miyata,Ming Li,Xueqing Yu,Noriaki Hirayama", - "abstract": "It is critical to uncover genes specifically expressed in individual cell types for further understanding of cell biology and pathology. In order to elucidate pathogenesis of renal disease, we performed functional quantitative analysis of the genome in human kidney cells and compared the expression levels of a variety of kidney transcripts with those in other non-kidney cells. As a result, we identified a novel human gene, megsin, which is a new serine protease inhibitor (serpin) predominantly expressed in the kidney. Megsin is up-regulated in kidney disease. Genomic analysis revealed an association of the polymorphisms of megsin gene with susceptibility and/or progression of kidney disease. Its overexpression in rodents has led to the recognition of two different kidney abnormalities. The first disorder is linked to megsin biological effect itself and the other to its conformational abnormality recently called the serpinopathy. In the latter model, the cellular and tissue damage is induced by the endoplasmic reticulum (ER) stress due to conformational disorder resulting from megsin tertiary structure. In both types, the inhibition of megsin's activity or abnormal conformational change should open new therapeutic perspectives. The desire to prevent these abnormalities with the hope to offer new therapeutic strategies has stimulated the development of megsin inhibitors by a structure based drug design approach relying on a precisely known three dimensional megsin structure.", - "journal_title": "Current genomics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/18645605/" - } - ], - "91f87f68-691b-451e-9e4d-3aac3c3b1160": [ - { - "pub_id": "9315766", - "title": "A prospective study of pregravid determinants of gestational diabetes mellitus.", - "authors": "C G Solomon,W C Willett,V J Carey,J Rich-Edwards,D J Hunter,G A Colditz,M J Stampfer,F E Speizer,D Spiegelman,J E Manson", - "abstract": "Gestational diabetes mellitus (GDM) affects 3% to 5% of pregnancies. Knowledge of risk factors for GDM is needed to identify possible preventive strategies. To assess whether recognized determinants of noninsulin-dependent diabetes mellitus also may be markers for increased risk of GDM. Prospective cohort study. The Nurses' Health Study II, which involves female US nurses aged 25 to 42 years at entry. The analyses included 14613 women without previous GDM or other known diabetes who reported a singleton pregnancy between 1990 and 1994. Of these women, 722 (4.9%) reported a new diagnosis of GDM. Self-report of GDM, validated by medical record review in a subset. In multivariate analyses including age, pregravid body mass index (BMI), and other GDM risk factors, the risk for GDM increased significantly with increasing maternal age (P for trend, <.01) and family history of diabetes mellitus (relative risk, 1.68; 95% confidence interval [CI], 1.39-2.04). Relative risks for GDM were 2.13 (95% CI, 1.65-2.74) for pregravid BMI of 25 to 29.9 kg/m2 and 2.90 (95% CI, 2.15-3.91) for BMI of 30 kg/m2 or more (vs BMI of <20 kg/m2). Risk for GDM increased with greater weight gain in early adulthood, and it also increased among nonwhite women. Pregravid current smokers had a relative risk for GDM of 1.43 (95% CI, 1.14-1.80), and pregravid vigorous exercise was associated with a nonsignificant reduction in GDM risk. Advanced maternal age, family history of diabetes mellitus, nonwhite ethnicity, higher BMI, weight gain in early adulthood, and cigarette smoking predict increased GDM risk. These observations may facilitate the identification of women at particular risk for GDM and suggest potential strategies for reducing this risk even before a woman becomes pregnant, such as avoiding substantial weight gain and smoking.", - "journal_title": "JAMA", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/9315766/" - } - ], - "fe39161b-60b7-42b9-9c87-a23f4c199fa0": [ - { - "pub_id": "10051618", - "title": "Type 2 diabetes: evidence for linkage on chromosome 20 in 716 Finnish affected sib pairs.", - "authors": "S Ghosh,R M Watanabe,E R Hauser,T Valle,V L Magnuson,M R Erdos,C D Langefeld,J Balow,D S Ally,K Kohtamaki,P Chines,G Birznieks,H S Kaleta,A Musick,C Te,J Tannenbaum,W Eldridge,S Shapiro,C Martin,A Witt,A So,J Chang,B Shurtleff,R Porter,K Kudelko,A Unni,L Segal,R Sharaf,J Blaschak-Harvan,J Eriksson,T Tenkula,G Vidgren,C Ehnholm,E Tuomilehto-Wolf,W Hagopian,T A Buchanan,J Tuomilehto,R N Bergman,F S Collins,M Boehnke", - "abstract": "We are conducting a genome scan at an average resolution of 10 centimorgans (cM) for type 2 diabetes susceptibility genes in 716 affected sib pairs from 477 Finnish families. To date, our best evidence for linkage is on chromosome 20 with potentially separable peaks located on both the long and short arms. The unweighted multipoint maximum logarithm of odds score (MLS) was 3.08 on 20p (location, chi = 19.5 cM) under an additive model, whereas the weighted MLS was 2.06 on 20q (chi = 57 cM, recurrence risk,lambda(s) = 1. 25, P = 0.009). Weighted logarithm of odds scores of 2.00 (chi = 69.5 cM, P = 0.010) and 1.92 (chi = 18.5 cM, P = 0.013) were also observed. Ordered subset analyses based on sibships with extreme mean values of diabetes-related quantitative traits yielded sets of families who contributed disproportionately to the peaks. Two-hour glucose levels in offspring of diabetic individuals gave a MLS of 2. 12 (P = 0.0018) at 9.5 cM. Evidence from this and other studies suggests at least two diabetes-susceptibility genes on chromosome 20. We have also screened the gene for maturity-onset diabetes of the young 1, hepatic nuclear factor 4-a (HNF-4alpha) in 64 affected sibships with evidence for high chromosomal sharing at its location on chromosome 20q. We found no evidence that sequence changes in this gene accounted for the linkage results we observed.", - "journal_title": "Proceedings of the National Academy of Sciences of the United States of America", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/10051618/" - } - ], - "6c45bd96-d6c2-407a-a228-c43eef17290a": [ - { - "pub_id": "11941369", - "title": "Mutations in ALMS1 cause obesity, type 2 diabetes and neurosensory degeneration in Alstr\u00f6m syndrome.", - "authors": "Gayle B Collin,Jan D Marshall,Akihiro Ikeda,W Venus So,Isabelle Russell-Eggitt,Pietro Maffei,Sebastian Beck,Cornelius F Boerkoel,Nicola Sicolo,Mitchell Martin,Patsy M Nishina,J\u00fcrgen K Naggert", - "abstract": "Alstr\u00f6m syndrome is a homogeneous autosomal recessive disorder that is characterized by childhood obesity associated with hyperinsulinemia, chronic hyperglycemia and neurosensory deficits. The gene involved in Alstr\u00f6m syndrome probably interacts with genetic modifiers, as subsets of affected individuals present with additional features such as dilated cardiomyopathy, hepatic dysfunction, hypothyroidism, male hypogonadism, short stature and mild to moderate developmental delay, and with secondary complications normally associated with type 2 diabetes, such as hyperlipidemia and atherosclerosis. Our detection of an uncharacterized transcript, KIAA0328, led us to identify the gene ALMS1, which contains sequence variations, including four frameshift mutations and two nonsense mutations, that segregate with Alstr\u00f6m syndrome in six unrelated families. ALMS1 is ubiquitously expressed at low levels and does not share significant sequence homology with other genes reported so far. The identification of ALMS1 provides an entry point into a new pathway leading toward the understanding of both Alstr\u00f6m syndrome and the common diseases that characterize it.", - "journal_title": "Nature genetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/11941369/" - } - ], - "63752d7d-dfdd-48a2-9f39-e1672255a519": [ - { - "pub_id": "14527304", - "title": "The inherited basis of diabetes mellitus: implications for the genetic analysis of complex traits.", - "authors": "Jose C Florez,Joel Hirschhorn,David Altshuler", - "abstract": "Diabetes encompasses a heterogeneous group of diseases, each with a substantial genetic component. We review the division of diabetes into different subtypes based on clinical phenotype, the fruitful pursuit of genes underlying monogenic forms of the disease, the successes and drawbacks of whole-genome linkage scans in type 1 and type 2 diabetes, and the recent identification of several diabetes genes by large association studies. We use the lessons learned from this extensive body of evidence to illustrate general implications for the genetic analysis of complex traits.", - "journal_title": "Annual review of genomics and human genetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/14527304/" - } - ], - "e891454d-f893-4f19-9adc-faaa270ece2f": [ - { - "pub_id": "18391952", - "title": "Genome-wide association analysis identifies 20 loci that influence adult height.", - "authors": "Michael N Weedon,Hana Lango,Cecilia M Lindgren,Chris Wallace,David M Evans,Massimo Mangino,Rachel M Freathy,John R B Perry,Suzanne Stevens,Alistair S Hall,Nilesh J Samani,Beverly Shields,Inga Prokopenko,Martin Farrall,Anna Dominiczak, , ,Toby Johnson,Sven Bergmann,Jacques S Beckmann,Peter Vollenweider,Dawn M Waterworth,Vincent Mooser,Colin N A Palmer,Andrew D Morris,Willem H Ouwehand, ,Jing Hua Zhao,Shengxu Li,Ruth J F Loos,In\u00eas Barroso,Panagiotis Deloukas,Manjinder S Sandhu,Eleanor Wheeler,Nicole Soranzo,Michael Inouye,Nicholas J Wareham,Mark Caulfield,Patricia B Munroe,Andrew T Hattersley,Mark I McCarthy,Timothy M Frayling", - "abstract": "Adult height is a model polygenic trait, but there has been limited success in identifying the genes underlying its normal variation. To identify genetic variants influencing adult human height, we used genome-wide association data from 13,665 individuals and genotyped 39 variants in an additional 16,482 samples. We identified 20 variants associated with adult height (P < 5 x 10(-7), with 10 reaching P < 1 x 10(-10)). Combined, the 20 SNPs explain approximately 3% of height variation, with a approximately 5 cm difference between the 6.2% of people with 17 or fewer 'tall' alleles compared to the 5.5% with 27 or more 'tall' alleles. The loci we identified implicate genes in Hedgehog signaling (IHH, HHIP, PTCH1), extracellular matrix (EFEMP1, ADAMTSL3, ACAN) and cancer (CDK6, HMGA2, DLEU7) pathways, and provide new insights into human growth and developmental processes. Finally, our results provide insights into the genetic architecture of a classic quantitative trait.", - "journal_title": "Nature genetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/18391952/" - } - ], - "7eaf38ba-809b-4594-ae98-b4a3445dc6b3": [ - { - "pub_id": "18439548", - "title": "Loci related to metabolic-syndrome pathways including LEPR,HNF1A, IL6R, and GCKR associate with plasma C-reactive protein: the Women's Genome Health Study.", - "authors": "Paul M Ridker,Guillaume Pare,Alex Parker,Robert Y L Zee,Jacqueline S Danik,Julie E Buring,David Kwiatkowski,Nancy R Cook,Joseph P Miletich,Daniel I Chasman", - "abstract": "Although elevated levels of C-reactive protein (CRP) independently predict increased risk of development of metabolic syndrome, diabetes, myocardial infarction, and stroke, comprehensive analysis of the influence of genetic variation on CRP is not available. To address this issue, we performed a genome-wide association study among 6345 apparently healthy women in which we evaluated 336,108 SNPs as potential determinants of plasma CRP concentration. Overall, seven loci that associate with plasma CRP at levels achieving genome-wide statistical significance were found (range of p values for lead SNPs within the seven loci: 1.9 x 10(-)(8) to 6.2 x 10(-)(28)). Two of these loci (GCKR and HNF1A) are suspected or known to be associated with maturity-onset diabetes of the young, one is a gene-desert region on 12q23.2, and the remaining four loci are in or near the leptin receptor protein gene, the apolipoprotein E gene, the interleukin-6 receptor protein gene, or the CRP gene itself. The protein products of six of these seven loci are directly involved in metabolic syndrome, insulin resistance, beta cell function, weight homeostasis, and/or premature atherothrombosis. Thus, common variation in several genes involved in metabolic and inflammatory regulation have significant effects on CRP levels, consistent with CRP's identification as a useful biomarker of risk for incident vascular disease and diabetes.", - "journal_title": "American journal of human genetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/18439548/" - } - ], - "ac6533a1-fd89-4ffd-b2cb-cc0918cff22f": [ - { - "pub_id": "7773291", - "title": "Susceptibility to human type 1 diabetes at IDDM2 is determined by tandem repeat variation at the insulin gene minisatellite locus.", - "authors": "S T Bennett,A M Lucassen,S C Gough,E E Powell,D E Undlien,L E Pritchard,M E Merriman,Y Kawaguchi,M J Dronsfield,F Pociot", - "abstract": "The IDDM2 locus encoding susceptibility to type 1 diabetes was mapped previously to a 4.1-kb region spanning the insulin gene and a minisatellite or variable number of tandem repeats (VNTR) locus on human chromosome 11p15.5. By 'cross-match' haplotype analysis and linkage disequilibrium mapping, we have mapped the mutation IDDM2 to within the VNTR itself. Other polymorphisms were systematically excluded as primary disease determinants. Transmission of IDDM2 may be influenced by parent-of-origin phenomena. Although we show that the insulin gene is expressed biallelically in the adult pancreas, we present preliminary evidence that the level of transcription in vivo is correlated with allelic variation within the VNTR. Allelic variation at VNTRs may play an important general role in human disease.", - "journal_title": "Nature genetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/7773291/" - } - ], - "b7b24dc8-2b03-4f78-b7e0-0a16c7aa44d6": [ - { - "pub_id": "12726923", - "title": "Genes, environment and Oji-Cree type 2 diabetes.", - "authors": "Robert A Hegele,Bernard Zinman,Anthony J G Hanley,Stewart B Harris,P Hugh Barrett,Henian Cao", - "abstract": "The prevalence of type 2 diabetes in Canadian Oji-Cree is among the highest in the world. Our research has uncovered genetic determinants of Oji-Cree type 2 diabetes and related metabolic traits. The most important genetic discovery by far was the private G319S mutation in transcription factor HNF-1alpha, encoded by the HNF1A gene. HNF1A G319S was discovered by candidate gene sequencing and would have been missed using the currently favored strategy of genome-wide scanning. G319S was associated with increased odds of having type 2 diabetes across the whole study sample and in all subgroups, including adolescent Oji-Cree. Furthermore, G319S had specificity and positive predictive value of 97% and 95%, respectively, for developing type 2 diabetes by age 50. The protein bearing the G319S mutation had impaired function in vitro. Sigmoidal modeling showed that each dose of the G319S allele accelerated the median age of diabetes onset by about 7 yr. This approach also showed that environment more strongly accelerated the median age-of-onset of Oji-Cree diabetes onset than did G319S, which could have implications for intervention strategies to reduce the burden of this epidemic. There is also evidence for genetic determination of related metabolic traits in the Oji-Cree.", - "journal_title": "Clinical biochemistry", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/12726923/" - } - ], - "3804b8c5-d764-49d1-afcc-841b670ea737": [ - { - "pub_id": "11976443", - "title": "Balancing life-style and genomics research for disease prevention.", - "authors": "Walter C Willett", - "abstract": "Genetic and environmental factors, including diet and life-style, both contribute to cardiovascular disease, cancers, and other major causes of mortality, but various lines of evidence indicate that environmental factors are most important. Overly enthusiastic expectations regarding the benefits of genetic research for disease prevention have the potential to distort research priorities and spending for health. However, integration of new genetic information into epidemiologic studies can help clarify causal relations between both life-style and genetic factors and risks of disease. Thus, a balanced approach should provide the best data to make informed choices about the most effective means to prevent disease.", - "journal_title": "Science (New York, N.Y.)", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/11976443/" - } - ], - "b973bd17-aac9-4d68-8ac4-1c683165b68f": [ - { - "pub_id": "19346957", - "title": "Gene prioritization based on biological plausibility over genome wide association studies renders new loci associated with type 2 diabetes.", - "authors": "Silvia Sookoian,Tomas Fern\u00e1ndez Gianotti,Mariano Schuman,Carlos Jose Pirola", - "abstract": "We present an approach to prioritize single nucleotide polymorphisms for further follow-up in genome-wide association studies of type 2 diabetes. The proposed method combines both the use of open data access from two type 2 diabetes-genome-wide association studies (granted by the Diabetes Genetics Initiative and the Welcome Trust Case Control Consortium) and the comprehensive analysis of candidate regions generated by the freely accessible ENDEAVOUR software. The algorithm prioritized all genes of the whole genome in relation to type 2 diabetes. There were six of 1096 single nucleotide polymorphisms in five genes potentially associated with type 2 diabetes: tachykinin receptor 3 (rs1384401), anaplastic lymphoma receptor tyrosine kinase (rs4319896), calcium channel, voltage-dependent, L type, alpha 1D subunit (rs12487452), FOXO1A (rs10507486 and rs7323267), and v-akt murine thymoma viral oncogene homolog 3 (rs897959). We estimated the fixed effect and P values of each single nucleotide polymorphism in the combined dataset by Mantel-Haenszel meta-analysis and we observed significant P values for all single nucleotide polymorphisms except for rs897959 at v-akt murine thymoma viral oncogene homolog 3. The proposed strategy may be used as an alternative tool for optimizing the information of the nearly 500,000 gene variants in which markers with modest significant P value for disease association are currently disregarded. Additionally, the said single nucleotide polymorphisms may be incorporated into the replication of the multistage design involved in the genome-wide association studies.", - "journal_title": "Genetics in medicine : official journal of the American College of Medical Genetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/19346957/" - } - ], - "976e2b74-91b0-4616-aaf0-d1ecf8dc770d": [ - { - "pub_id": "17463248", - "title": "A genome-wide association study of type 2 diabetes in Finns detects multiple susceptibility variants.", - "authors": "Laura J Scott,Karen L Mohlke,Lori L Bonnycastle,Cristen J Willer,Yun Li,William L Duren,Michael R Erdos,Heather M Stringham,Peter S Chines,Anne U Jackson,Ludmila Prokunina-Olsson,Chia-Jen Ding,Amy J Swift,Narisu Narisu,Tianle Hu,Randall Pruim,Rui Xiao,Xiao-Yi Li,Karen N Conneely,Nancy L Riebow,Andrew G Sprau,Maurine Tong,Peggy P White,Kurt N Hetrick,Michael W Barnhart,Craig W Bark,Janet L Goldstein,Lee Watkins,Fang Xiang,Jouko Saramies,Thomas A Buchanan,Richard M Watanabe,Timo T Valle,Leena Kinnunen,Gon\u00e7alo R Abecasis,Elizabeth W Pugh,Kimberly F Doheny,Richard N Bergman,Jaakko Tuomilehto,Francis S Collins,Michael Boehnke", - "abstract": "Identifying the genetic variants that increase the risk of type 2 diabetes (T2D) in humans has been a formidable challenge. Adopting a genome-wide association strategy, we genotyped 1161 Finnish T2D cases and 1174 Finnish normal glucose-tolerant (NGT) controls with >315,000 single-nucleotide polymorphisms (SNPs) and imputed genotypes for an additional >2 million autosomal SNPs. We carried out association analysis with these SNPs to identify genetic variants that predispose to T2D, compared our T2D association results with the results of two similar studies, and genotyped 80 SNPs in an additional 1215 Finnish T2D cases and 1258 Finnish NGT controls. We identify T2D-associated variants in an intergenic region of chromosome 11p12, contribute to the identification of T2D-associated variants near the genes IGF2BP2 and CDKAL1 and the region of CDKN2A and CDKN2B, and confirm that variants near TCF7L2, SLC30A8, HHEX, FTO, PPARG, and KCNJ11 are associated with T2D risk. This brings the number of T2D loci now confidently identified to at least 10.", - "journal_title": "Science (New York, N.Y.)", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/17463248/" - } - ], - "7e75c52c-59ac-43fc-8fc8-28d2131c5531": [ - { - "pub_id": "24892707", - "title": "Molecular mechanisms of diabetic kidney disease.", - "authors": "Kimberly Reidy,Hyun Mi Kang,Thomas Hostetter,Katalin Susztak", - "abstract": "Diabetic kidney disease (DKD) is the leading cause of kidney failure worldwide and the single strongest predictor of mortality in patients with diabetes. DKD is a prototypical disease of gene and environmental interactions. Tight glucose control significantly decreases DKD incidence, indicating that hyperglycemia-induced metabolic alterations, including changes in energy utilization and mitochondrial dysfunction, play critical roles in disease initiation. Blood pressure control, especially with medications that inhibit the angiotensin system, is the only effective way to slow disease progression. While DKD is considered a microvascular complication of diabetes, growing evidence indicates that podocyte loss and epithelial dysfunction play important roles. Inflammation, cell hypertrophy, and dedifferentiation by the activation of classic pathways of regeneration further contribute to disease progression. Concerted clinical and basic research efforts will be needed to understand DKD pathogenesis and to identify novel drug targets.", - "journal_title": "The Journal of clinical investigation", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/24892707/" - } - ], - "9864689f-2c1e-4fb2-a621-f39d4c57f140": [ - { - "pub_id": "20181961", - "title": "Genome-wide analysis of histone modifications in human pancreatic islets.", - "authors": "Reena Bhandare,Jonathan Schug,John Le Lay,Alan Fox,Olga Smirnova,Chengyang Liu,Ali Naji,Klaus H Kaestner", - "abstract": "The global diabetes epidemic poses a major challenge. Epigenetic events contribute to the etiology of diabetes; however, the lack of epigenomic analysis has limited the elucidation of the mechanistic basis for this link. To determine the epigenetic architecture of human pancreatic islets we mapped the genome-wide locations of four histone marks: three associated with gene activation-H3K4me1, H3K4me2, and H3K4me3-and one associated with gene repression, H3K27me3. Interestingly, the promoters of the highly transcribed insulin and glucagon genes are occupied only sparsely by H3K4me2 and H3K4me3. Globally, we identified important relationships between promoter structure, histone modification, and gene expression. We demonstrated co-occurrences of histone modifications including bivalent marks in mature islets. Furthermore, we found a set of promoters that is differentially modified between islets and other cell types. We also use our histone marks to determine which of the known diabetes-associated single-nucleotide polymorphisms are likely to be part of regulatory elements. Our global map of histone marks will serve as an important resource for understanding the epigenetic basis of type 2 diabetes.", - "journal_title": "Genome research", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/20181961/" - } - ], - "18d5231c-050f-4dc1-bc71-188ca39130ad": [ - { - "pub_id": "22377712", - "title": "Association between type 2 diabetes genetic susceptibility loci and visceral and subcutaneous fat area as determined by computed tomography.", - "authors": "Kikuko Hotta,Aya Kitamoto,Takuya Kitamoto,Seiho Mizusawa,Hajime Teranishi,Rina So,Tomoaki Matsuo,Yoshio Nakata,Hideyuki Hyogo,Hidenori Ochi,Takahiro Nakamura,Seika Kamohara,Nobuyuki Miyatake,Kazuaki Kotani,Ryoya Komatsu,Naoto Itoh,Ikuo Mineo,Jun Wada,Masato Yoneda,Atsushi Nakajima,Tohru Funahashi,Shigeru Miyazaki,Katsuto Tokunaga,Hiroaki Masuzaki,Takato Ueno,Kazuaki Chayama,Kazuyuki Hamaguchi,Kentaro Yamada,Toshiaki Hanafusa,Shinichi Oikawa,Hironobu Yoshimatsu,Toshiie Sakata,Kiyoji Tanaka,Yuji Matsuzawa,Kazuwa Nakao,Akihiro Sekine", - "abstract": "Visceral fat accumulation has an important role in the development of several metabolic disorders, such as type 2 diabetes, dyslipidemia and hypertension. New genetic loci that contribute to the development of type 2 diabetes have been identified by genome-wide association studies. To examine the association of type 2 diabetes susceptibility loci and visceral fat accumulation, we genotyped 1279 Japanese subjects (556 men and 723 women), who underwent computed tomography for measurements of visceral fat area (VFA) and subcutaneous fat area (SFA) for the following single-nucleotide polymorphisms (SNPs): NOTCH2 rs10923931, THADA rs7578597, PPARG rs1801282, ADAMTS9 rs4607103, IGF2BP2 rs1470579, VEGFA rs9472138, JAZF1 rs864745, CDKN2A/CDKN2B rs564398 and rs10811661, HHEX rs1111875 and rs5015480, TCF7L2 rs7901695, KCNQ1 rs2237892, KCNJ11 rs5215 and rs5219, EXT2 rs1113132, rs11037909, and rs3740878, MTNR1B rs10830963, DCD rs1153188, TSPAN8/LGR5 rs7961581, and FTO rs8050136 and rs9939609. None of the above SNPs were significantly associated with VFA. The FTO rs8050136 and rs9939609 risk alleles exhibited significant associations with body mass index (BMI; P=0.00088 and P=0.0010, respectively) and SFA (P=0.00013 and P=0.00017, respectively). No other SNPs were significantly associated with BMI or SFA. Our results suggest that two SNPs in the FTO gene are associated with subcutaneous fat accumulation. The contributions of other SNPs are inconclusive because of a limitation of the sample power.", - "journal_title": "Journal of human genetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/22377712/" - } - ], - "1039378d-078c-4e90-a055-c7337aa7abf5": [ - { - "pub_id": "21124985", - "title": "Integrated genetic and epigenetic analysis identifies haplotype-specific methylation in the FTO type 2 diabetes and obesity susceptibility locus.", - "authors": "Christopher G Bell,Sarah Finer,Cecilia M Lindgren,Gareth A Wilson,Vardhman K Rakyan,Andrew E Teschendorff,Pelin Akan,Elia Stupka,Thomas A Down,Inga Prokopenko,Ian M Morison,Jonathan Mill,Ruth Pidsley, ,Panos Deloukas,Timothy M Frayling,Andrew T Hattersley,Mark I McCarthy,Stephan Beck,Graham A Hitman", - "abstract": "Recent multi-dimensional approaches to the study of complex disease have revealed powerful insights into how genetic and epigenetic factors may underlie their aetiopathogenesis. We examined genotype-epigenotype interactions in the context of Type 2 Diabetes (T2D), focussing on known regions of genomic susceptibility. We assayed DNA methylation in 60 females, stratified according to disease susceptibility haplotype using previously identified association loci. CpG methylation was assessed using methylated DNA immunoprecipitation on a targeted array (MeDIP-chip) and absolute methylation values were estimated using a Bayesian algorithm (BATMAN). Absolute methylation levels were quantified across LD blocks, and we identified increased DNA methylation on the FTO obesity susceptibility haplotype, tagged by the rs8050136 risk allele A (p\u200a=\u200a9.40\u00d710(-4), permutation p\u200a=\u200a1.0\u00d710(-3)). Further analysis across the 46 kb LD block using sliding windows localised the most significant difference to be within a 7.7 kb region (p\u200a=\u200a1.13\u00d710(-7)). Sequence level analysis, followed by pyrosequencing validation, revealed that the methylation difference was driven by the co-ordinated phase of CpG-creating SNPs across the risk haplotype. This 7.7 kb region of haplotype-specific methylation (HSM), encapsulates a Highly Conserved Non-Coding Element (HCNE) that has previously been validated as a long-range enhancer, supported by the histone H3K4me1 enhancer signature. This study demonstrates that integration of Genome-Wide Association (GWA) SNP and epigenomic DNA methylation data can identify potential novel genotype-epigenotype interactions within disease-associated loci, thus providing a novel route to aid unravelling common complex diseases.", - "journal_title": "PloS one", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/21124985/" - } - ], - "7f4d5a4d-f9f4-48d4-bfc3-d57c393eed07": [ - { - "pub_id": "30634657", - "title": "The Effect of a Multidisciplinary Lifestyle Intervention on Obesity Status, Body Composition, Physical Fitness, and Cardiometabolic Risk Markers in Children and Adolescents with Obesity.", - "authors": "Young-Gyun Seo,Hyunjung Lim,YoonMyung Kim,Young-Su Ju,Hye-Ja Lee,Han Byul Jang,Sang Ick Park,Kyung Hee Park", - "abstract": "This study aimed to develop a multidisciplinary lifestyle intervention program targeted at children and adolescents with moderate to severe obesity, and assess the additional effects of exercise intervention when compared to usual care. Overall, the 103 enrolled participants were \u226585th percentile of age and sex-specific body mass index (BMI). Participants were divided into groups that received 16 weeks of either usual care or exercise intervention. The BMI <i>z</i>-score of the overall completers decreased by about 0.05 after the 16-week intervention (<i>p</i> = 0.02). After the intervention, only the exercise group had a significantly lower BMI <i>z</i>-score than the baseline score by about 0.1 (<i>p</i> = 0.03), but no significant group by time interaction effects were observed. At the 16-week follow-up, significant group by time interaction effects were observed in percentage body fat (%BF) (\u03b2 = -1.52, 95%CI = -2.58\u207b-0.45), lean body mass (LM) (\u03b2 = 1.20, 95%CI = 0.12\u207b2.29), diastolic blood pressure (\u03b2 = -5.24, 95%CI = -9.66\u207b-0.83), high-sensitivity C-reactive protein (\u03b2 = -1.67, 95%CI = -2.77\u207b-1.01), and wall sit test score (\u03b2 = 50.74, 95%CI = 32.30\u207b69.18). We developed a moderate-intensity intervention program that can be sustained in the real-world setting and is practically applicable to both moderate and severe obesity. After interventions, the exercise group had lower %BF and cardiometabolic risk markers, and higher LM and leg muscle strength compared to the usual care group.", - "journal_title": "Nutrients", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/30634657/" - } - ], - "abfb9f3b-8f36-4696-aa42-f43ded30869c": [ - { - "pub_id": "24098138", - "title": "Integrated enrichment analysis of variants and pathways in genome-wide association studies indicates central role for IL-2 signaling genes in type 1 diabetes, and cytokine signaling genes in Crohn's disease.", - "authors": "Peter Carbonetto,Matthew Stephens", - "abstract": "Pathway analyses of genome-wide association studies aggregate information over sets of related genes, such as genes in common pathways, to identify gene sets that are enriched for variants associated with disease. We develop a model-based approach to pathway analysis, and apply this approach to data from the Wellcome Trust Case Control Consortium (WTCCC) studies. Our method offers several benefits over existing approaches. First, our method not only interrogates pathways for enrichment of disease associations, but also estimates the level of enrichment, which yields a coherent way to promote variants in enriched pathways, enhancing discovery of genes underlying disease. Second, our approach allows for multiple enriched pathways, a feature that leads to novel findings in two diseases where the major histocompatibility complex (MHC) is a major determinant of disease susceptibility. Third, by modeling disease as the combined effect of multiple markers, our method automatically accounts for linkage disequilibrium among variants. Interrogation of pathways from eight pathway databases yields strong support for enriched pathways, indicating links between Crohn's disease (CD) and cytokine-driven networks that modulate immune responses; between rheumatoid arthritis (RA) and \"Measles\" pathway genes involved in immune responses triggered by measles infection; and between type 1 diabetes (T1D) and IL2-mediated signaling genes. Prioritizing variants in these enriched pathways yields many additional putative disease associations compared to analyses without enrichment. For CD and RA, 7 of 8 additional non-MHC associations are corroborated by other studies, providing validation for our approach. For T1D, prioritization of IL-2 signaling genes yields strong evidence for 7 additional non-MHC candidate disease loci, as well as suggestive evidence for several more. Of the 7 strongest associations, 4 are validated by other studies, and 3 (near IL-2 signaling genes RAF1, MAPK14, and FYN) constitute novel putative T1D loci for further study.", - "journal_title": "PLoS genetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/24098138/" - } - ], - "0f429b12-5d8d-45e3-9011-4794123cfb19": [ - { - "pub_id": "25538312", - "title": "Insights into the role of the microbiome in obesity and type 2 diabetes.", - "authors": "Annick V Hartstra,Kristien E C Bouter,Fredrik B\u00e4ckhed,Max Nieuwdorp", - "abstract": "The worldwide prevalence of obesity and type 2 diabetes mellitus (T2DM) continues to rise at an alarming pace. Recently the potential role of the gut microbiome in these metabolic disorders has been identified. Obesity is associated with changes in the composition of the intestinal microbiota, and the obese microbiome seems to be more efficient in harvesting energy from the diet. Lean male donor fecal microbiota transplantation (FMT) in males with metabolic syndrome resulted in a significant improvement in insulin sensitivity in conjunction with an increased intestinal microbial diversity, including a distinct increase in butyrate-producing bacterial strains. Such differences in gut microbiota composition might function as early diagnostic markers for the development of T2DM in high-risk patients. Products of intestinal microbes such as butyrate may induce beneficial metabolic effects through enhancement of mitochondrial activity, prevention of metabolic endotoxemia, and activation of intestinal gluconeogenesis via different routes of gene expression and hormone regulation. Future research should focus on whether bacterial products (like butyrate) have the same effects as the intestinal bacteria that produce it, in order to ultimately pave the way for more successful interventions for obesity and T2DM. The rapid development of the currently available techniques, including use of fecal transplantations, has already shown promising results, so there is hope for novel therapies based on the microbiota in the future.", - "journal_title": "Diabetes care", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/25538312/" - } - ], - "6ec45055-8c2a-4c49-a499-023cd79c11ec": [ - { - "pub_id": "24577154", - "title": "Impact of delivery models on understanding genomic risk for type 2 diabetes.", - "authors": "S B Haga,W T Barry,R Mills,L Svetkey,S Suchindran,H F Willard,G S Ginsburg", - "abstract": "Genetic information, typically communicated in-person by genetic counselors, can be challenging to comprehend; delivery of this information online--as is becoming more common--has the potential of increasing these challenges. To address the impact of the mode of delivery of genomic risk information, 300 individuals were recruited from the general public and randomized to receive genomic risk information for type 2 diabetes mellitus in-person from a board-certified genetic counselor or online through the testing company's website. Participants were asked to indicate their genomic risk and overall lifetime risk as reported on their test report as well as to interpret their genomic risk (increased, decreased, or same as population). For each question, 59% of participants correctly indicated their risk. Participants who received their results in-person were more likely than those who reviewed their results on-line to correctly interpret their genomic risk (72 vs. 47%, p = 0.0002) and report their actual genomic risk (69 vs. 49%, p = 0.002). The delivery of personal genomic risk through a trained health professional resulted in significantly higher comprehension. Therefore, if the online delivery of genomic test results is to become more widespread, further evaluation of this method of communication may be needed to ensure the effective presentation of results to promote comprehension.", - "journal_title": "Public health genomics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/24577154/" - } - ], - "8ff3f07d-4894-49bb-a92d-38647f46814b": [ - { - "pub_id": "21045787", - "title": "Epigenetic phenomena linked to diabetic complications.", - "authors": "Luciano Pirola,Aneta Balcerczyk,Jun Okabe,Assam El-Osta", - "abstract": "Diabetes mellitus (type 1 and type 2) and the complications associated with this condition are an urgent public health problem, as the incidence of diabetes mellitus is steadily increasing. Environmental factors, such as diet and exposure to hyperglycemia, contribute to the etiology of diabetes mellitus and its associated microvascular and macrovascular complications. These vascular complications are the main cause of the morbidity and mortality burden of diabetes mellitus. The DCCT-EDIC and UKPDS epidemiological studies correlated poor glycemic control with the development of vascular complications in patients with type 1 or type 2 diabetes mellitus. The findings of these studies suggest that early exposure to hyperglycemia predisposes individuals to the development of diabetic complications, a phenomenon referred to as metabolic memory or the legacy effect. The first experimental evidence for metabolic memory was reported >20 years ago and the underlying molecular mechanisms are currently being characterized. Interestingly, transient exposure to hyperglycemia results in long-lasting epigenetic modifications that lead to changes in chromatin structure and gene expression, which mediate these persistent metabolic characteristics.", - "journal_title": "Nature reviews. Endocrinology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/21045787/" - } - ], - "dc2f6b02-5c9a-4764-b70e-d2321135e148": [ - { - "pub_id": "19398610", - "title": "When family means more (or less) than genetics: the intersection of culture, family and genomics.", - "authors": "Barbara Burns McGrath,Karen L Edwards", - "abstract": "There is renewed interest in the use of family history to predict individual disease susceptibility, and as a result, standardized online family history tools are being developed and marketed as a \"new genetic test.\" It is not known how cultural variations in definitions of family influence collection of these data or what is the best format to use. This is significant given that the populations who carry the greatest burden of the target diseases have not been considered in efforts to test these tools. A qualitative study with a convenience sample of 19 Japanese Americans and Samoan Americans, two groups at high risk for type 2 diabetes, was conducted to explore the process of collecting family history. A particularly strong finding was the high degree of acceptance experienced by the participants with the process and their pride in visualizing their family graphically displayed in pedigrees. It was also found that Samoans included those linked by nonbiological ties in their families, which reflects their cultural practices. Further research is needed to assess the most effective and efficient way to gather family history given the complexities surrounding the deceptively simple concept of family.", - "journal_title": "Journal of transcultural nursing : official journal of the Transcultural Nursing Society", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/19398610/" - } - ], - "559a3a15-da15-4132-a8b5-5401bfe770ef": [ - { - "pub_id": "23243555", - "title": "Type 2 Diabetes Genetics: Beyond GWAS.", - "authors": "Dharambir K Sanghera,Piers R Blackett", - "abstract": "The global epidemic of type 2 diabetes mellitus (T2D) is one of the most challenging problems of the 21(st) century leading cause of and the fifth death worldwide. Substantial evidence suggests that T2D is a multifactorial disease with a strong genetic component. Recent genome-wide association studies (GWAS) have successfully identified and replicated nearly 75 susceptibility loci associated with T2D and related metabolic traits, mostly in Europeans, and some in African, and South Asian populations. The GWAS serve as a starting point for future genetic and functional studies since the mechanisms of action by which these associated loci influence disease is still unclear and it is difficult to predict potential implication of these findings in clinical settings. Despite extensive replication, no study has unequivocally demonstrated their clinical role in the disease management beyond progression to T2D from impaired glucose tolerance. However, these studies are revealing new molecular pathways underlying diabetes etiology, gene-environment interactions, epigenetic modifications, and gene function. This review highlights evolving progress made in the rapidly moving field of T2D genetics that is starting to unravel the pathophysiology of a complex phenotype and has potential to show clinical relevance in the near future.", - "journal_title": "Journal of diabetes & metabolism", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/23243555/" - } - ], - "cea13566-9d52-4423-9280-d46da486dd7f": [ - { - "pub_id": "24297835", - "title": "Genetics and genomics for the prevention and treatment of cardiovascular disease: update: a scientific statement from the American Heart Association.", - "authors": "Santhi K Ganesh,Donna K Arnett,Themistocles L Assimes,Craig T Basson,Aravinda Chakravarti,Patrick T Ellinor,Mary B Engler,Elizabeth Goldmuntz,David M Herrington,Ray E Hershberger,Yuling Hong,Julie A Johnson,Steven J Kittner,Deborah A McDermott,James F Meschia,Luisa Mestroni,Christopher J O'Donnell,Bruce M Psaty,Ramachandran S Vasan,Marc Ruel,Win-Kuang Shen,Andre Terzic,Scott A Waldman, , , , , , ", - "abstract": "", - "journal_title": "Circulation", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/24297835/" - } - ], - "38be907c-70ea-45f2-a8c1-7aed203a5256": [ - { - "pub_id": "25845659", - "title": "Dietary Polyphenols Promote Growth of the Gut Bacterium Akkermansia muciniphila and Attenuate High-Fat Diet-Induced Metabolic Syndrome.", - "authors": "Diana E Roopchand,Rachel N Carmody,Peter Kuhn,Kristin Moskal,Patricio Rojas-Silva,Peter J Turnbaugh,Ilya Raskin", - "abstract": "Dietary polyphenols protect against metabolic syndrome, despite limited absorption and digestion, raising questions about their mechanism of action. We hypothesized that one mechanism may involve the gut microbiota. To test this hypothesis, C57BL/6J mice were fed a high-fat diet (HFD) containing 1% Concord grape polyphenols (GP). Relative to vehicle controls, GP attenuated several effects of HFD feeding, including weight gain, adiposity, serum inflammatory markers (tumor necrosis factor [TNF]\u03b1, interleukin [IL]-6, and lipopolysaccharide), and glucose intolerance. GP lowered intestinal expression of inflammatory markers (TNF\u03b1, IL-6, inducible nitric oxide synthase) and a gene for glucose absorption (Glut2). GP increased intestinal expression of genes involved in barrier function (occludin) and limiting triglyceride storage (fasting-induced adipocyte factor). GP also increased intestinal gene expression of proglucagon, a precursor of proteins that promote insulin production and gut barrier integrity. 16S rRNA gene sequencing and quantitative PCR of cecal and fecal samples demonstrated that GP dramatically increased the growth of Akkermansia muciniphila and decreased the proportion of Firmicutes to Bacteroidetes, consistent with prior reports that similar changes in microbial community structure can protect from diet-induced obesity and metabolic disease. These data suggest that GP act in the intestine to modify gut microbial community structure, resulting in lower intestinal and systemic inflammation and improved metabolic outcomes. The gut microbiota may thus provide the missing link in the mechanism of action of poorly absorbed dietary polyphenols.", - "journal_title": "Diabetes", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/25845659/" - } - ], - "2c6a650e-0c14-409d-aa2b-3d5516f319bf": [ - { - "pub_id": "21130952", - "title": "Cardiovascular disease risk factors, type 2 diabetes mellitus, and the Framingham Heart Study.", - "authors": "Caroline S Fox", - "abstract": "Type 2 diabetes is a common disorder and an important risk factor for cardiovascular disease. The Framingham Heart Study is a population-based epidemiologic study that has contributed to our knowledge of cardiovascular disease and its risk factors. This review will focus on the contemporary contributions of the Framingham Heart Study to the field of diabetes epidemiology, including data on diabetes trends, genetics, and future advances in population-based studies.", - "journal_title": "Trends in cardiovascular medicine", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/21130952/" - } - ], - "a5a0cd4f-8acf-4e89-9033-04f448dc0b15": [ - { - "pub_id": "26194074", - "title": "Genetic Studies on Diabetic Microvascular Complications: Focusing on Genome-Wide Association Studies.", - "authors": "Soo Heon Kwak,Kyong Soo Park", - "abstract": "Diabetes is a common metabolic disorder with a worldwide prevalence of 8.3% and is the leading cause of visual loss, end-stage renal disease and amputation. Recently, genome-wide association studies (GWASs) have identified genetic risk factors for diabetic microvascular complications of retinopathy, nephropathy, and neuropathy. We summarized the recent findings of GWASs on diabetic microvascular complications and highlighted the challenges and our opinion on future directives. Five GWASs were conducted on diabetic retinopathy, nine on nephropathy, and one on neuropathic pain. The majority of recent GWASs were underpowered and heterogeneous in terms of study design, inclusion criteria and phenotype definition. Therefore, few reached the genome-wide significance threshold and the findings were inconsistent across the studies. Recent GWASs provided novel information on genetic risk factors and the possible pathophysiology of diabetic microvascular complications. However, further collaborative efforts to standardize phenotype definition and increase sample size are necessary for successful genetic studies on diabetic microvascular complications.", - "journal_title": "Endocrinology and metabolism (Seoul, Korea)", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/26194074/" - } - ], - "4fe0a01d-3be8-4cd5-ac59-8b0ef085b20c": [ - { - "pub_id": "20972439", - "title": "Genome-wide association studies of 14 agronomic traits in rice landraces.", - "authors": "Xuehui Huang,Xinghua Wei,Tao Sang,Qiang Zhao,Qi Feng,Yan Zhao,Canyang Li,Chuanrang Zhu,Tingting Lu,Zhiwu Zhang,Meng Li,Danlin Fan,Yunli Guo,Ahong Wang,Lu Wang,Liuwei Deng,Wenjun Li,Yiqi Lu,Qijun Weng,Kunyan Liu,Tao Huang,Taoying Zhou,Yufeng Jing,Wei Li,Zhang Lin,Edward S Buckler,Qian Qian,Qi-Fa Zhang,Jiayang Li,Bin Han", - "abstract": "Uncovering the genetic basis of agronomic traits in crop landraces that have adapted to various agro-climatic conditions is important to world food security. Here we have identified \u223c 3.6 million SNPs by sequencing 517 rice landraces and constructed a high-density haplotype map of the rice genome using a novel data-imputation method. We performed genome-wide association studies (GWAS) for 14 agronomic traits in the population of Oryza sativa indica subspecies. The loci identified through GWAS explained \u223c 36% of the phenotypic variance, on average. The peak signals at six loci were tied closely to previously identified genes. This study provides a fundamental resource for rice genetics research and breeding, and demonstrates that an approach integrating second-generation genome sequencing and GWAS can be used as a powerful complementary strategy to classical biparental cross-mapping for dissecting complex traits in rice.", - "journal_title": "Nature genetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/20972439/" - } - ], - "00591f6a-0d6f-4993-ae6c-e9a8109a95ec": [ - { - "pub_id": "21248163", - "title": "Type 1 diabetes: etiology, immunology, and therapeutic strategies.", - "authors": "Tom L van Belle,Ken T Coppieters,Matthias G von Herrath", - "abstract": "Type 1 diabetes (T1D) is a chronic autoimmune disease in which destruction or damaging of the beta-cells in the islets of Langerhans results in insulin deficiency and hyperglycemia. We only know for sure that autoimmunity is the predominant effector mechanism of T1D, but may not be its primary cause. T1D precipitates in genetically susceptible individuals, very likely as a result of an environmental trigger. Current genetic data point towards the following genes as susceptibility genes: HLA, insulin, PTPN22, IL2Ra, and CTLA4. Epidemiological and other studies suggest a triggering role for enteroviruses, while other microorganisms might provide protection. Efficacious prevention of T1D will require detection of the earliest events in the process. So far, autoantibodies are most widely used as serum biomarker, but T-cell readouts and metabolome studies might strengthen and bring forward diagnosis. Current preventive clinical trials mostly focus on environmental triggers. Therapeutic trials test the efficacy of antigen-specific and antigen-nonspecific immune interventions, but also include restoration of the affected beta-cell mass by islet transplantation, neogenesis and regeneration, and combinations thereof. In this comprehensive review, we explain the genetic, environmental, and immunological data underlying the prevention and intervention strategies to constrain T1D.", - "journal_title": "Physiological reviews", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/21248163/" - } - ], - "98e30ad9-231c-4eb0-97a7-af3206777abd": [ - { - "pub_id": "20638243", - "title": "Update on the genetics and genomics of PBC.", - "authors": "Brian D Juran,Konstantinos N Lazaridis", - "abstract": "Despite recent progress, the pathogenic mechanisms governing PBC development, treatment response and outcome remain unknown. This deficiency is in large part due to the complex nature of PBC, wherein various environmental factors may be capable of prompting disease, but only in the context of underlying genetic susceptibility. Identification of genomic loci containing these heritable risk factors has been slowed by the rarity and late onset of PBC, which has made difficult the collection of sufficient numbers of patients and family members for meaningful genetic analyses. Advancements in our ability to catalog the genetic variation in large numbers of individuals at a genome-wide scale, coupled with unprecedented efforts to recruit PBC patients for genetic study, positions us to generate data that could fundamentally change our understanding of PBC and lead to clinical innovation. Indeed, the first genome-wide association study for PBC has been published, in which multiple genes involved with IL12 signaling, a pathway that is being targeted in treatment of other inflammatory conditions, were implicated in disease. However, this study was relatively small in the genome-wide milieu and a significantly expanded effort will be necessary to truly elucidate the genetic architecture of PBC. Moving ahead, cooperation between the groups collecting biospecimens and generating genome-wide data from large numbers of patients with PBC will be essential, not only to increase power for fine mapping and future studies of rare variants and epistasis; but to streamline efforts to perform functional validation of novel discoveries. Here we provide a brief update of the current state of genetics in PBC to form a basis for understanding the considerable progress that is likely to be made in the coming years.", - "journal_title": "Journal of autoimmunity", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/20638243/" - } - ], - "b0b3377e-b9f2-4810-8fc2-722dfb9899a8": [ - { - "pub_id": "22187472", - "title": "Diagnosis and classification of diabetes mellitus.", - "authors": " ", - "abstract": "", - "journal_title": "Diabetes care", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/22187472/" - } - ], - "3d8e4c25-e01b-40e0-9993-68d4e9d54822": [ - { - "pub_id": "23308243", - "title": "Systems biology approach reveals genome to phenome correlation in type 2 diabetes.", - "authors": "Priyanka Jain,Saurabh Vig,Malabika Datta,Dinesh Jindel,Ashok Kumar Mathur,Sandeep Kumar Mathur,Abhay Sharma", - "abstract": "Genome-wide association studies (GWASs) have discovered association of several loci with Type 2 diabetes (T2D), a common complex disease characterized by impaired insulin secretion by pancreatic \u03b2 cells and insulin signaling in target tissues. However, effect of genetic risk variants on continuous glycemic measures in nondiabetic subjects mainly elucidates perturbation of insulin secretion. Also, the disease associated genes do not clearly converge on functional categories consistent with the known aspects of T2D pathophysiology. We used a systems biology approach to unravel genome to phenome correlation in T2D. We first examined enrichment of pathways in genes identified in T2D GWASs at genome-wide or lower levels of significance. Genes at lower significance threshold showed enrichment of insulin secretion related pathway. Notably, physical and genetic interaction network of these genes showed robust enrichment of insulin signaling and other T2D pathophysiology related pathways including insulin secretion. The network also overrepresented genes reported to interact with insulin secretion and insulin action targeting antidiabetic drugs. The drug interacting genes themselves showed overrepresentation of insulin signaling and other T2D relevant pathways. Next, we generated genome-wide expression profiles of multiple insulin responsive tissues from nondiabetic and diabetic patients. Remarkably, the differentially expressed genes showed significant overlap with the network genes, with the intersection showing enrichment of insulin signaling and other pathways consistent with T2D pathophysiology. Literature search led our genomic, interactomic, transcriptomic and toxicogenomic evidence to converge on TGF-beta signaling, a pathway known to play a crucial role in pancreatic islets development and function, and insulin signaling. Cumulatively, we find that GWAS genes relate directly to insulin secretion and indirectly, through collaborating with other genes, to insulin resistance. This seems to support the epidemiological evidence that environmentally triggered insulin resistance interacts with genetically programmed \u03b2 cell dysfunction to precipitate diabetes.", - "journal_title": "PloS one", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/23308243/" - } - ], - "2ee3f340-13a6-4ad6-8193-042eece0853b": [ - { - "pub_id": "24595857", - "title": "Genome-wide association study of urinary albumin excretion rate in patients with type 1 diabetes.", - "authors": "Niina Sandholm,Carol Forsblom,Ville-Petteri M\u00e4kinen,Amy Jayne McKnight,Anne-May Osterholm,Bing He,Valma Harjutsalo,Raija Lithovius,Daniel Gordin,Maija Parkkonen,Markku Saraheimo,Lena M Thorn,Nina Tolonen,Johan Wad\u00e9n,Jaakko Tuomilehto,Maria Lajer,Emma Ahlqvist,Anna M\u00f6llsten,M Loredana Marcovecchio,Jason Cooper,David Dunger,Andrew D Paterson,Gianpaolo Zerbini,Leif Groop, ,Lise Tarnow,Alexander P Maxwell,Karl Tryggvason,Per-Henrik Groop, ", - "abstract": "An abnormal urinary albumin excretion rate (AER) is often the first clinically detectable manifestation of diabetic nephropathy. Our aim was to estimate the heritability and to detect genetic variation associated with elevated AER in patients with type 1 diabetes. The discovery phase genome-wide association study (GWAS) included 1,925 patients with type 1 diabetes and with data on 24 h AER. AER was analysed as a continuous trait and the analysis was stratified by the use of antihypertensive medication. Signals with a p value <10(-4) were followed up in 3,750 additional patients with type 1 diabetes from seven studies. The narrow-sense heritability, captured with our genotyping platform, was estimated to explain 27.3% of the total AER variability, and 37.6% after adjustment for covariates. In the discovery stage, five single nucleotide polymorphisms in the GLRA3 gene were strongly associated with albuminuria (p\u2009<\u20095\u2009\u00d7\u200910(-8)). In the replication group, a nominally significant association (p\u2009=\u20090.035) was observed between albuminuria and rs1564939 in GLRA3, but this was in the opposite direction. Sequencing of the surrounding genetic region in 48 Finnish and 48 UK individuals supported the possibility that population-specific rare variants contribute to the synthetic association observed at the common variants in GLRA3. The strongest replication (p\u2009=\u20090.026) was obtained for rs2410601 between the PSD3 and SH2D4A genes. Pathway analysis highlighted natural killer cell mediated immunity processes. This study suggests novel pathways and molecular mechanisms for the pathogenesis of albuminuria in type 1 diabetes.", - "journal_title": "Diabetologia", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/24595857/" - } - ], - "e740b5de-8bea-4dfd-bd19-fc21dbb0df90": [ - { - "pub_id": "21188420", - "title": "Natural selection at genomic regions associated with obesity and type-2 diabetes: East Asians and sub-Saharan Africans exhibit high levels of differentiation at type-2 diabetes regions.", - "authors": "Yann C Klimentidis,Marshall Abrams,Jelai Wang,Jose R Fernandez,David B Allison", - "abstract": "Different populations suffer from different rates of obesity and type-2 diabetes (T2D). Little is known about the genetic or adaptive component, if any, that underlies these differences. Given the cultural, geographic, and dietary variation that accumulated among humans over the last 60,000\u00a0years, we examined whether loci identified by genome-wide association studies for these traits have been subject to recent selection pressures. Using genome-wide SNP data on 938 individuals in 53 populations from the Human Genome Diversity Panel, we compare population differentiation and haplotype patterns at these loci to the rest of the genome. Using an \"expanding window\" approach (100-1,600\u00a0kb) for the individual loci as well as the loci as ensembles, we find a high degree of differentiation for the ensemble of T2D loci. This differentiation is most pronounced for East Asians and sub-Saharan Africans, suggesting that these groups experienced natural selection at loci associated with T2D. Haplotype analysis suggests an excess of obesity loci with evidence of recent positive selection among South Asians and Europeans, compared to sub-Saharan Africans and Native Americans. We also identify individual loci that may have been subjected to natural selection, such as the T2D locus, HHEX, which displays both elevated differentiation and extended haplotype homozygosity in comparisons of East Asians with other groups. Our findings suggest that there is an evolutionary genetic basis for population differences in these traits, and we have identified potential group-specific genetic risk factors.", - "journal_title": "Human genetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/21188420/" - } - ], - "f304d864-108a-417c-b162-e960fa3e9076": [ - { - "pub_id": "25333069", - "title": "Disease variants in genomes of 44 centenarians.", - "authors": "Yun Freudenberg-Hua,Jan Freudenberg,Vladimir Vacic,Avinash Abhyankar,Anne-Katrin Emde,Danny Ben-Avraham,Nir Barzilai,Dayna Oschwald,Erika Christen,Jeremy Koppel,Blaine Greenwald,Robert B Darnell,Soren Germer,Gil Atzmon,Peter Davies", - "abstract": "To identify previously reported disease mutations that are compatible with extraordinary longevity, we screened the coding regions of the genomes of 44 Ashkenazi Jewish centenarians. Individual genome sequences were generated with 30\u00d7 coverage on the Illumina HiSeq 2000 and single-nucleotide variants were called with the genome analysis toolkit (GATK). We identified 130 coding variants that were annotated as \"pathogenic\" or \"likely pathogenic\" based on the ClinVar database and that are infrequent in the general population. These variants were previously reported to cause a wide range of degenerative, neoplastic, and cardiac diseases with autosomal dominant, autosomal recessive, and X-linked inheritance. Several of these variants are located in genes that harbor actionable incidental findings, according to the recommendations of the American College of Medical Genetics. In addition, we found risk variants for late-onset neurodegenerative diseases, such as the APOE \u03b54 allele that was even present in a homozygous state in one centenarian who did not develop Alzheimer's disease. Our data demonstrate that the incidental finding of certain reported disease variants in an individual genome may not preclude an extraordinarily long life. When the observed variants are encountered in the context of clinical sequencing, it is thus important to exercise caution in justifying clinical decisions.", - "journal_title": "Molecular genetics & genomic medicine", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/25333069/" - } - ], - "3e809889-2704-4cd2-90fb-f17f895d14be": [ - { - "pub_id": "34079329", - "title": "Prognostic and Predictive Value of Circulating Inflammation Signature in Non-Metastatic Nasopharyngeal Carcinoma: Potential Role for Individualized Induction Chemotherapy.", - "authors": "Shu-Hui Lv,Wang-Zhong Li,Hu Liang,Guo-Ying Liu,Wei-Xiong Xia,Yan-Qun Xiang", - "abstract": "We sought to assess the prognostic and predictive value of a circulating inflammation signature (CISIG) and develop CISIG-based tools for predicting prognosis and guiding individualized induction chemotherapy (ICT) in non-metastatic nasopharyngeal carcinoma (NPC). We retrospectively collected a candidate inflammatory biomarker panel from patients with NPC treated with definitive radiotherapy between 2012 and 2017. We developed the CISIG using candidate biomarkers identified by a least absolute shrinkage and selection operator (LASSO) Cox regression model. The Cox regression analyses were used to evaluate the CISIG prognostic value. A CISIG-based prediction model was constructed, validated, and assessed. Potential stratified ICT treatment effects were examined. A total of 1149 patients were analyzed. Nine biomarkers selected by LASSO regression in the training cohort were used to construct the CISIG, including hyaluronidase, laminin, procollagen III, neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio, lymphocyte-to-monocyte ratio, high-density lipoprotein, lactate dehydrogenase, and C-reactive protein-to-albumin ratio. CISIG was an independent prognostic factor for disease-free survival (DFS; hazard ratio: 2.65, 95% confidence interval: 1.93-3.64; <i>P</i> < 0.001). High CISIG group (>-0.2) was associated with worse 3-year DFS than low CISIG group in both the training (67.5% vs 88.3%, <i>P</i> < 0.001) and validation cohorts (72.3% vs 85.1%, <i>P</i> < 0.001). We constructed and validated a CISIG-based nomogram, which showed better performance than the clinical stage and Epstein-Barr virus DNA classification methods. A significant interaction between CISIG and the ICT treatment effect was observed (<i>P</i> for interaction = 0.036). Patients with high CISIG values did not benefit from ICT, whereas patients with low CISIG values significantly benefited from ICT. The developed CISIG, based on a circulating inflammatory biomarker panel, adds prognostic information for patients with NPC. The proposed CISIG-based tools offer individualized risk estimation to facilitate suitable ICT candidate identification.", - "journal_title": "Journal of inflammation research", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/34079329/" - } - ], - "ad88aed6-75ba-469d-b96b-7be4a65be8fc": [ - { - "pub_id": "26160912", - "title": "Recent advances in understanding the genetic architecture of type 2 diabetes.", - "authors": "Karen L Mohlke,Michael Boehnke", - "abstract": "Genome-wide association (GWAS) and sequencing studies are providing new insights into the genetic basis of type 2 diabetes (T2D) and the inter-individual variation in glycemic traits, including levels of glucose, insulin, proinsulin and hemoglobin A1c (HbA1c). At the end of 2011, established loci (P < 5 \u00d7 10(-8)) totaled 55 for T2D and 32 for glycemic traits. Since then, most new loci have been detected by analyzing common [minor allele frequency (MAF)>0.05] variants in increasingly large sample sizes from populations around the world, and in trans-ancestry studies that successfully combine data from diverse populations. Most recently, advances in sequencing have led to the discovery of four loci for T2D or glycemic traits based on low-frequency (0.005 < MAF \u2264 0.05) variants, and additional low-frequency, potentially functional variants have been identified at GWAS loci. Established published loci now total \u223c88 for T2D and 83 for one or more glycemic traits, and many additional loci likely remain to be discovered. Future studies will build on these successes by identifying additional loci and by determining the pathogenic effects of the underlying variants and genes.", - "journal_title": "Human molecular genetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/26160912/" - } - ], - "a5bf198e-e2eb-4b76-9421-731ffbf3400d": [ - { - "pub_id": "20463486", - "title": "Recent advances in the genetics and genomics of asthma and related traits.", - "authors": "Patrick M A Sleiman,Hakon Hakonarson", - "abstract": "Asthma is a complex phenotype caused by a combination of genetic and environmental factors that remain poorly understood. The common variants involved in the pathogenesis of asthma have proved difficult to identify by candidate gene association studies. Recently genome-wide association (GWA) studies have been applied to asthma with considerable success. The past 12 months have seen some notable advances in the genetics of asthma including five GWA studies using asthma status as an endpoint, as well as one chronic obstructive pulmonary disease study and five GWA studies of intermediate phenotypes, one each on serum immunoglobulin E (IgE) levels, blood eosinophil counts and three on lung function as measured by spirometry. There have also been several publications on the previously reported asthma locus on 17q21 replicating the association in multiple populations and showing specific association in patients with early tobacco smoke exposure and with early-onset asthma as well as with nonatopic asthma. A wealth of genetic data has been generated on asthma since the publication of the first GWA study in 2007 resulting in the identification of a novel asthma locus as well as novel loci for lung function, eosinophil count and IgE levels. In this review we summarize the most pertinent of these advances.", - "journal_title": "Current opinion in pediatrics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/20463486/" - } - ], - "0018c797-5a74-441f-8167-e7ab4cfd66ec": [ - { - "pub_id": "26740948", - "title": "Genetic analysis of nonalcoholic fatty liver disease within a Caribbean-Hispanic population.", - "authors": "Deborah Edelman,Harmit Kalia,Maria Delio,Mustafa Alani,Karthik Krishnamurthy,Mortadha Abd,Adam Auton,Tao Wang,Allan W Wolkoff,Bernice E Morrow", - "abstract": "We explored potential genetic risk factors implicated in nonalcoholic fatty liver disease (NAFLD) within a Caribbean-Hispanic population in New York City. A total of 316 individuals including 40 subjects with biopsy-proven NAFLD, 24 ethnically matched non-NAFLD controls, and a 252 ethnically mixed random sampling of Bronx County, New York were analyzed. Genotype analysis was performed to determine allelic frequencies of 74 known single-nucleotide polymorphisms (SNPs) associated with NAFLD risk based on previous genome-wide association study (GWAS) and candidate gene studies. Additionally, the entire coding region of PNPLA3, a gene showing the strongest association to NAFLD was subjected to Sanger sequencing. Results suggest that both rare and common DNA variations in PNPLA3 and SAMM50 may be correlated with NAFLD in this small population study, while common DNA variations in CHUK and ERLIN1, may have a protective interaction. Common SNPs in ENPP1 and ABCC2 have suggestive association with fatty liver, but with less compelling significance. In conclusion, Hispanic patients of Caribbean ancestry may have different interactions with NAFLD genetic modifiers; therefore, further investigation with a larger sample size, into this Caribbean-Hispanic population is warranted.", - "journal_title": "Molecular genetics & genomic medicine", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/26740948/" - } - ], - "5f2e8622-aedf-46dc-98d9-7b0b30937d63": [ - { - "pub_id": "22567146", - "title": "Association of the CpG methylation pattern of the proximal insulin gene promoter with type 1 diabetes.", - "authors": "Delphine Fradin,Sophie Le Fur,Cl\u00e9mence Mille,Nadia Naoui,Chris Groves,Diana Zelenika,Mark I McCarthy,Mark Lathrop,Pierre Bougn\u00e8res", - "abstract": "The insulin (INS) region is the second most important locus associated with Type 1 Diabetes (T1D). The study of the DNA methylation pattern of the 7 CpGs proximal to the TSS in the INS gene promoter revealed that T1D patients have a lower level of methylation of CpG -19, -135 and -234 (p\u200a=\u200a2.10(-16)) and a higher methylation of CpG -180 than controls, while methylation was comparable for CpG -69, -102, -206. The magnitude of the hypomethylation relative to a control population was 8-15% of the corresponding levels in controls and was correlated in CpGs -19 and -135 (r\u200a=\u200a0.77) and CpG -135 and -234 (r\u200a=\u200a0.65). 70/485 (14%) of T1D patients had a simultaneous decrease in methylation of CpG -19, -135, -234 versus none in 317 controls. CpG methylation did not correlate with glycated hemoglobin or with T1D duration. The methylation of CpG -69, -102, -180, -206, but not CpG -19, -135, -234 was strongly influenced by the cis-genotype at rs689, a SNP known to show a strong association with T1D. We hypothesize that part of this genetic association could in fact be mediated at the statistical and functional level by the underlying changes in neighboring CpG methylation. Our observation of a CpG-specific, locus-specific methylation pattern, although it can provide an epigenetic biomarker of a multifactorial disease, does not indicate whether the reported epigenetic pattern preexists or follows the establishment of T1D. To explore the effect of chronic hyperglycemia on CpG methylation, we studied non obese patients with type 2 diabetes (T2D) who were found to have decreased CpG-19 methylation versus age-matched controls, similar to T1D (p\u200a=\u200a2.10(-6)) but increased CpG-234 methylation (p\u200a=\u200a5.10(-8)), the opposite of T1D. The causality and natural history of the different epigenetic changes associated with T1D or T2D remain to be determined.", - "journal_title": "PloS one", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/22567146/" - } - ], - "675e8df5-d8e4-4f5d-bdae-300f87520977": [ - { - "pub_id": "26363598", - "title": "Insights into the Genetic Susceptibility to Type 2 Diabetes from Genome-Wide Association Studies of Obesity-Related Traits.", - "authors": "Tugce Karaderi,Alexander W Drong,Cecilia M Lindgren", - "abstract": "Obesity and type 2 diabetes (T2D) are common and complex metabolic diseases, which are caused by an interchange between environmental and genetic factors. Recently, a number of large-scale genome-wide association studies (GWAS) have improved our knowledge of the genetic architecture and biological mechanisms of these diseases. Currently, more than ~250 genetic loci have been found for monogenic, syndromic, or common forms of T2D and/or obesity-related traits. In this review, we discuss the implications of these GWAS for obesity and T2D, and investigate the overlap of loci for obesity-related traits and T2D, highlighting potential mechanisms that affect T2D susceptibility.", - "journal_title": "Current diabetes reports", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/26363598/" - } - ], - "1643f445-62fc-4415-a5c8-774ccb131d03": [ - { - "pub_id": "24758549", - "title": "Multi-ethnic minority nurses' knowledge and practice of genetics and genomics.", - "authors": "Bernice Coleman,Kathleen A Calzone,Jean Jenkins,Carmen Paniagua,Reynaldo Rivera,Oi Saeng Hong,Ida Spruill,Vence Bonham", - "abstract": "Exploratory studies establishing how well nurses have integrated genomics into practice have demonstrated there remains opportunity for education. However, little is known about educational gaps in multi-ethnic minority nurse populations. The purpose of this study was to determine minority nurses' beliefs, practices, and competency in integrating genetics-genomics information into practice using an online survey tool. A cross-sectional survey with registered nurses (RNs) from the participating National Coalition of Ethnic Minority Organizations (NCEMNA). Two phases were used: Phase one had a sample of 27 nurses who determined the feasibility of an online approach to survey completion and need for tool revision. Phase two was a main survey with 389 participants who completed the revised survey. The survey ascertained the genomic knowledge, beliefs, and practice of a sample of multi-ethnic minority nurses who were members of associations comprising the NCEMNA. The survey was administered online. Descriptive survey responses were analyzed using frequencies and percentages. Categorical responses in which comparisons were analyzed used chi square tests. About 40% of the respondents held a master's degree (39%) and 42% worked in direct patient care. The majority of respondents (79%) reported that education in genomics was important. Ninety-five percent agreed or strongly agreed that family health history could identify at-risk families, 85% reported knowing how to complete a second- and third-generation family history, and 63% felt family history was important to nursing. Conversely, 50% of the respondents felt that their understanding of the genetics of common disease was fair or poor, supported by 54% incorrectly reporting they thought heart disease and diabetes are caused by a single gene variant. Only 30% reported taking a genetics course since licensure, and 94% reported interest in learning more about genomics. Eighty-four percent believed that their ethnic minority nurses' organizations should have a visible role in genetics and genomics in their communities. Most respondents felt genomics is important to integrate into practice but demonstrated knowledge deficits. There was strong interest in the need for continuing education and the role of the ethnic minority organizations in facilitating the continuing education efforts. This study provides evidence of the need for targeted genomic education to prepare ethnic minority nurses to better translate genetics and genomics into practice. Genomics is critical to the practice of all nurses, most especially family health history assessment and the genomics of common complex diseases. There is a great opportunity and interest to address the genetic-genomic knowledge deficits in the nursing workforce as a strategy to impact patient outcomes.", - "journal_title": "Journal of nursing scholarship : an official publication of Sigma Theta Tau International Honor Society of Nursing", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/24758549/" - } - ], - "7d4a197e-3774-40a4-9897-ed7c71f213b6": [ - { - "pub_id": "21630414", - "title": "Genome-wide association studies (GWAS): impact on elucidating the aetiology of diabetes.", - "authors": "Hakon Hakonarson,Struan F A Grant", - "abstract": "It has proven to be challenging to isolate the genes underlying the genetic components conferring susceptibility to type 1 and type 2 diabetes. Unlike previous approaches, 'genome-wide association studies' have extensively delivered on the promise of uncovering genetic determinants of complex diseases, with a number of novel disease-associated variants being largely replicated by independent groups. This review provides an overview of these recent breakthroughs in the context of type 1 and type 2 diabetes, and outlines strategies on how these findings will be applied to impact clinical care for these two highly prevalent disorders.", - "journal_title": "Diabetes/metabolism research and reviews", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/21630414/" - } - ], - "3a066437-9d88-46c7-bc55-9992728847a7": [ - { - "pub_id": "22843023", - "title": "TCF7L2 gene polymorphisms and type 2 diabetes: association with diabetic retinopathy and cardiovascular autonomic neuropathy.", - "authors": "Cinzia Ciccacci,Davide Di Fusco,Laura Cacciotti,Roberto Morganti,Cinzia D'Amato,Giuseppe Novelli,Federica Sangiuolo,Vincenza Spallone,Paola Borgiani", - "abstract": "Type 2 diabetes (T2DM) is a complex disease resulting from the contribution of both environmental and genetic factors. Recently, the list of genes implicated in the susceptibility to T2DM has substantially grown, also as a consequence of the great development of the genome-wide association studies in the last decade. Common polymorphisms in TCF7L2 gene have shown to have a strong effect with respect to many other involved genes. The aims of our study were to confirm the role of TCF7L2 in the susceptibility to T2DM in the Italian population and to investigate whether TCF7L2 genotypes also contribute to the clinical phenotypes variability and to diabetic complications development. Three TCF7L2 polymorphisms (rs7903146, rs7901695 and rs12255372) have been analyzed by allelic discrimination assays in a cohort of 154 Italian patients with T2DM and 171 healthy controls. A case-control association study and a genotype-phenotype correlation study have been carried out. Consistent with previous studies, all three SNPs showed a strong association with susceptibility to T2DM, both at genotypic (P\u00a0=\u00a00.003, P\u00a0=\u00a00.004 and P\u00a0=\u00a00.012) and at allelic level (P\u00a0=\u00a00.0004, P\u00a0=\u00a00.0004 and P\u00a0=\u00a00.003). Moreover, we observed associations between TCF7L2 variants and the following diabetic complications: diabetic retinopathy, cardiovascular disease and coronary artery disease. We also found a strong correlation between the rs7903146 and the presence of cardiovascular autonomic neuropathy (P\u00a0=\u00a00.02 with a high OR\u00a0=\u00a08.28). In conclusion, our study, in addition to confirming the involvement of TCF7L2 gene in the T2DM susceptibility, has shown that TCF7L2 genetic variability also contributes to the development of diabetic complications such as retinopathy and cardiovascular autonomic neuropathy.", - "journal_title": "Acta diabetologica", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/22843023/" - } - ], - "2e6881b6-52f2-4506-b89e-e4cb466e85ef": [ - { - "pub_id": "25231526", - "title": "The role of iron in brain ageing and neurodegenerative disorders.", - "authors": "Roberta J Ward,Fabio A Zucca,Jeff H Duyn,Robert R Crichton,Luigi Zecca", - "abstract": "In the CNS, iron in several proteins is involved in many important processes such as oxygen transportation, oxidative phosphorylation, myelin production, and the synthesis and metabolism of neurotransmitters. Abnormal iron homoeostasis can induce cellular damage through hydroxyl radical production, which can cause the oxidation and modification of lipids, proteins, carbohydrates, and DNA. During ageing, different iron complexes accumulate in brain regions associated with motor and cognitive impairment. In various neurodegenerative diseases, such as Alzheimer's disease and Parkinson's disease, changes in iron homoeostasis result in altered cellular iron distribution and accumulation. MRI can often identify these changes, thus providing a potential diagnostic biomarker of neurodegenerative diseases. An important avenue to reduce iron accumulation is the use of iron chelators that are able to cross the blood-brain barrier, penetrate cells, and reduce excessive iron accumulation, thereby affording neuroprotection.", - "journal_title": "The Lancet. Neurology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/25231526/" - } - ], - "13af95a1-38be-4c46-9ad5-a85e501d262e": [ - { - "pub_id": "20368234", - "title": "Co-existence of risk and protective haplotypes of Calpain 10 gene to type 2 diabetes in the eastern Indian population.", - "authors": "Sangeeta Adak,Sanghamitra Sengupta,Subhankar Chowdhury,Maitree Bhattacharyya", - "abstract": "Linkage and association studies have detected a role for Calpain-10 (CAPN10) polymorphisms in susceptibility to T2DM in many populations. This study aimed to evaluate possible associations between three SNPs in the CAPN10 (UCSNPs -43, -19 and -63) gene and T2DM in the east Indian population. The distribution of genotype frequency of UCSNP-63 varied significantly between T2DM patients and controls under a dominant model. The uncommon (T) allele (OR = 3.74, 95% CI: 1.44-9.7) of the UCSNP-63 and haplotype 112 (OR = 3.4, 95% CI: 1.17-9.9) were associated with increased risk of T2DM. On the contrary, the most common haplotype 121 (OR = 0.70 95% CI: 0.50-0.99) was associated with a reduced risk for T2DM. In our population a novel 111/112-haplotype combination created by the CAPN10 UCSNP-43, -19 and -63 was associated with risk of T2DM. Haplotypes 112 and 121 with opposite genetic influences also co-exist in our population.", - "journal_title": "Diabetes & vascular disease research", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/20368234/" - } - ], - "99b1e2cc-c500-449e-8bdd-acfbd65af79a": [ - { - "pub_id": "21148447", - "title": "Epigenetics: mechanisms and implications for diabetic complications.", - "authors": "Mark E Cooper,Assam El-Osta", - "abstract": "Epigenetic modifications regulate critical functions that underlie chromosome metabolism. Understanding the molecular changes to chromatin structure and the functional relationship with altered signaling pathways is now considered to represent an important conceptual challenge to explain diabetes and the phenomenon of metabolic or hyperglycemic memory. Although it remains unknown as to the specific molecular mechanisms whereby hyperglycemic memory leads to the development of diabetic vascular complications, emerging evidence now indicates that critical gene-activating epigenetic changes may confer future cell memories. Chemical modification of the H3 histone tail of lysine 4 and 9 has recently been identified with gene expression conferred by hyperglycemia. The persistence of these key epigenetic determinants in models of glycemic variability and the development of diabetic complications has been associated with these primary findings. Transient hyperglycemia promotes gene-activating epigenetic changes and signaling events critical in the development and progression of vascular complications. As for the role of specific epigenomic changes, it is postulated that further understanding enzymes involved in writing and erasing chemical changes could transform our understanding of the pathways implicated in diabetic vascular injury providing new therapeutic strategies.", - "journal_title": "Circulation research", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/21148447/" - } - ], - "08858a32-d736-4d8d-a135-f86568152a81": [ - { - "pub_id": "21705072", - "title": "Type 2 diabetes across generations: from pathophysiology to prevention and management.", - "authors": "Christopher J Nolan,Peter Damm,Marc Prentki", - "abstract": "Type 2 diabetes is now a pandemic and shows no signs of abatement. In this Seminar we review the pathophysiology of this disorder, with particular attention to epidemiology, genetics, epigenetics, and molecular cell biology. Evidence is emerging that a substantial part of diabetes susceptibility is acquired early in life, probably owing to fetal or neonatal programming via epigenetic phenomena. Maternal and early childhood health might, therefore, be crucial to the development of effective prevention strategies. Diabetes develops because of inadequate islet \u03b2-cell and adipose-tissue responses to chronic fuel excess, which results in so-called nutrient spillover, insulin resistance, and metabolic stress. The latter damages multiple organs. Insulin resistance, while forcing \u03b2 cells to work harder, might also have an important defensive role against nutrient-related toxic effects in tissues such as the heart. Reversal of overnutrition, healing of the \u03b2 cells, and lessening of adipose tissue defects should be treatment priorities.", - "journal_title": "Lancet (London, England)", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/21705072/" - } - ], - "78aa075a-710a-4fc2-aa50-8ba27e5e607b": [ - { - "pub_id": "22154244", - "title": "From candidate gene to genome-wide association studies in cardiovascular disease.", - "authors": "Francesco Gianfagna,Daniela Cugino,Iolanda Santimone,Licia Iacoviello", - "abstract": "Continuous updating of the genotyping technology has led to improvement of genetic study design. The recent advances in technology coupled with the advances in our understanding of the molecular mechanisms have allowed a more comprehensive examination of the role of genetics, environment and their interaction in determining the individual risk of cardiovascular disease (CVD). Initial candidate gene studies identified a limited number of polymorphisms associated with disease, explaining only a minor part of trait variance. Furthermore, results were not often concordant, with meta-analyses not reaching the statistical power to confirm an association in many cases. The advent of the genome-wide design furnished an enormous quantity of information and decreased time of genotyping, while increased complexity of analyses and costs. Their results were more concordant, even when they suggested associations between CVD and polymorphisms distant from codifying regions or in genes involved in previously unsuspected pathways. Future results from genome-wide studies coupled with results from functional studies and investigation on gene-environment interactions will allow improvement of cardiovascular risk assessment and discovery of new targets for therapy and prevention. In this review, a brief history of cardiovascular genetics is reported, from candidate gene to genome wide association studies, that led to the identification of association between CVD and SNPs in the 9p21 region, firstly thought a gene desert without importance.", - "journal_title": "Thrombosis research", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/22154244/" - } - ], - "e35e41a0-2d5b-4d3b-a99c-3dda93efbd4a": [ - { - "pub_id": "21779625", - "title": "The role of uncoupling protein 2 (UCP2) on the development of type 2 diabetes mellitus and its chronic complications.", - "authors": "Bianca Marmontel de Souza,Ta\u00eds Silveira Assmann,L\u00facia Maria Kliemann,Jorge Luiz Gross,Lu\u00eds Henrique Canani,Daisy Crispim", - "abstract": "It is well established that genetic factors play an important role in the development of type 2 diabetes mellitus (DM2) and its chronic complications, and that genetically susceptible subjects can develop the disease after being exposed to environmental risk factors. Therefore, great efforts have been made to identify genes associated with DM2. Uncoupling protein 2 (UCP2) is expressed in several tissues, and acts in the protection against oxidative stress; in the negative regulation of insulin secretion by beta cells, and in fatty acid metabolism. All these mechanisms are associated with DM2 pathogenesis and its chronic complications. Therefore, UCP2 is a candidate gene for the development of these disorders. Indeed, several studies have reported that three common polymorphisms in UCP2 gene are possibly associated with DM2 and/or obesity. Only a few studies investigated these polymorphisms in relation to chronic complications of diabetes, with inconclusive results.", - "journal_title": "Arquivos brasileiros de endocrinologia e metabologia", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/21779625/" - } - ], - "bac22f02-a313-45e5-99cc-c2e6615876fd": [ - { - "pub_id": "25006567", - "title": "Genome-wide Association Studies for Osteoporosis: A 2013 Update.", - "authors": "Yong-Jun Liu,Lei Zhang,Christopher J Papasian,Hong-Wen Deng", - "abstract": "In the past few years, the bone field has witnessed great advances in genome-wide association studies (GWASs) of osteoporosis, with a number of promising genes identified. In particular, meta-analysis of GWASs, aimed at increasing the power of studies by combining the results from different study populations, have led to the identification of novel associations that would not otherwise have been identified in individual GWASs. Recently, the first whole genome sequencing study for osteoporosis and fractures was published, reporting a novel rare nonsense mutation. This review summarizes the important and representative findings published by December 2013. Comments are made on the notable findings and representative studies for their potential influence and implications on our present understanding of the genetics of osteoporosis. Potential limitations of GWASs and their meta-analyses are evaluated, with an emphasis on understanding the reasons for inconsistent results between different studies and clarification of misinterpretation of GWAS meta-analysis results. Implications and challenges of GWAS are also discussed, including the need for multi- and inter-disciplinary studies.", - "journal_title": "Journal of bone metabolism", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/25006567/" - } - ], - "102b534a-86e3-4a30-a135-b3e800f0d848": [ - { - "pub_id": "22101970", - "title": "Use of diverse electronic medical record systems to identify genetic risk for type 2 diabetes within a genome-wide association study.", - "authors": "Abel N Kho,M Geoffrey Hayes,Laura Rasmussen-Torvik,Jennifer A Pacheco,William K Thompson,Loren L Armstrong,Joshua C Denny,Peggy L Peissig,Aaron W Miller,Wei-Qi Wei,Suzette J Bielinski,Christopher G Chute,Cynthia L Leibson,Gail P Jarvik,David R Crosslin,Christopher S Carlson,Katherine M Newton,Wendy A Wolf,Rex L Chisholm,William L Lowe", - "abstract": "Genome-wide association studies (GWAS) require high specificity and large numbers of subjects to identify genotype-phenotype correlations accurately. The aim of this study was to identify type 2 diabetes (T2D) cases and controls for a GWAS, using data captured through routine clinical care across five institutions using different electronic medical record (EMR) systems. An algorithm was developed to identify T2D cases and controls based on a combination of diagnoses, medications, and laboratory results. The performance of the algorithm was validated at three of the five participating institutions compared against clinician review. A GWAS was subsequently performed using cases and controls identified by the algorithm, with samples pooled across all five institutions. The algorithm achieved 98% and 100% positive predictive values for the identification of diabetic cases and controls, respectively, as compared against clinician review. By standardizing and applying the algorithm across institutions, 3353 cases and 3352 controls were identified. Subsequent GWAS using data from five institutions replicated the TCF7L2 gene variant (rs7903146) previously associated with T2D. By applying stringent criteria to EMR data collected through routine clinical care, cases and controls for a GWAS were identified that subsequently replicated a known genetic variant. The use of standard terminologies to define data elements enabled pooling of subjects and data across five different institutions to achieve the robust numbers required for GWAS. An algorithm using commonly available data from five different EMR can accurately identify T2D cases and controls for genetic study across multiple institutions.", - "journal_title": "Journal of the American Medical Informatics Association : JAMIA", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/22101970/" - } - ], - "8264bcad-c83c-468c-a848-119797db534f": [ - { - "pub_id": "36268928", - "title": "Antibiotic use in endodontic treatment during pregnancy: A narrative review.", - "authors": "Tahere Aliabadi,Eshagh Ali Saberi,Amin Motameni Tabatabaei,Ebadolah Tahmasebi", - "abstract": "More than half of pregnant women are usually affected by odontogenic pain affects. Pain often accompanies periapical or pulp infections and increases the risks to pregnant patients and their fetuses. The American Dental Association, in partnership with the American College of Obstetricians and Gynecologists, has offered a strong declaration reaffirming the significance of suitable and timely oral health care as an indispensable constituent of a healthy pregnancy. However, there is lack of knowledge about the use of antibiotics in endodontic treatment. Therefore, the present study would review the researches done in this area and tries to provide comprehensive and complete information about the use of antibiotics in endodontic treatment during pregnancy. Based on the results, it can be said that using antibiotics during pregnancy are allowed, and they can be used normally and safely by pregnant women.", - "journal_title": "European journal of translational myology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/36268928/" - } - ], - "7d0f2b5c-0e6b-400a-ae22-8dd4feec9608": [ - { - "pub_id": "26909576", - "title": "Genomic analyses identify molecular subtypes of pancreatic cancer.", - "authors": "Peter Bailey,David K Chang,Katia Nones,Amber L Johns,Ann-Marie Patch,Marie-Claude Gingras,David K Miller,Angelika N Christ,Tim J C Bruxner,Michael C Quinn,Craig Nourse,L Charles Murtaugh,Ivon Harliwong,Senel Idrisoglu,Suzanne Manning,Ehsan Nourbakhsh,Shivangi Wani,Lynn Fink,Oliver Holmes,Venessa Chin,Matthew J Anderson,Stephen Kazakoff,Conrad Leonard,Felicity Newell,Nick Waddell,Scott Wood,Qinying Xu,Peter J Wilson,Nicole Cloonan,Karin S Kassahn,Darrin Taylor,Kelly Quek,Alan Robertson,Lorena Pantano,Laura Mincarelli,Luis N Sanchez,Lisa Evers,Jianmin Wu,Mark Pinese,Mark J Cowley,Marc D Jones,Emily K Colvin,Adnan M Nagrial,Emily S Humphrey,Lorraine A Chantrill,Amanda Mawson,Jeremy Humphris,Angela Chou,Marina Pajic,Christopher J Scarlett,Andreia V Pinho,Marc Giry-Laterriere,Ilse Rooman,Jaswinder S Samra,James G Kench,Jessica A Lovell,Neil D Merrett,Christopher W Toon,Krishna Epari,Nam Q Nguyen,Andrew Barbour,Nikolajs Zeps,Kim Moran-Jones,Nigel B Jamieson,Janet S Graham,Fraser Duthie,Karin Oien,Jane Hair,Robert Gr\u00fctzmann,Anirban Maitra,Christine A Iacobuzio-Donahue,Christopher L Wolfgang,Richard A Morgan,Rita T Lawlor,Vincenzo Corbo,Claudio Bassi,Borislav Rusev,Paola Capelli,Roberto Salvia,Giampaolo Tortora,Debabrata Mukhopadhyay,Gloria M Petersen, ,Donna M Munzy,William E Fisher,Saadia A Karim,James R Eshleman,Ralph H Hruban,Christian Pilarsky,Jennifer P Morton,Owen J Sansom,Aldo Scarpa,Elizabeth A Musgrove,Ulla-Maja Hagbo Bailey,Oliver Hofmann,Robert L Sutherland,David A Wheeler,Anthony J Gill,Richard A Gibbs,John V Pearson,Nicola Waddell,Andrew V Biankin,Sean M Grimmond", - "abstract": "Integrated genomic analysis of 456 pancreatic ductal adenocarcinomas identified 32 recurrently mutated genes that aggregate into 10 pathways: KRAS, TGF-\u03b2, WNT, NOTCH, ROBO/SLIT signalling, G1/S transition, SWI-SNF, chromatin modification, DNA repair and RNA processing. Expression analysis defined 4 subtypes: (1) squamous; (2) pancreatic progenitor; (3) immunogenic; and (4) aberrantly differentiated endocrine exocrine (ADEX) that correlate with histopathological characteristics. Squamous tumours are enriched for TP53 and KDM6A mutations, upregulation of the TP63\u2206N transcriptional network, hypermethylation of pancreatic endodermal cell-fate determining genes and have a poor prognosis. Pancreatic progenitor tumours preferentially express genes involved in early pancreatic development (FOXA2/3, PDX1 and MNX1). ADEX tumours displayed upregulation of genes that regulate networks involved in KRAS activation, exocrine (NR5A2 and RBPJL), and endocrine differentiation (NEUROD1 and NKX2-2). Immunogenic tumours contained upregulated immune networks including pathways involved in acquired immune suppression. These data infer differences in the molecular evolution of pancreatic cancer subtypes and identify opportunities for therapeutic development.", - "journal_title": "Nature", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/26909576/" - } - ], - "82ad689c-e6f4-43df-93ca-202e4cebcf3e": [ - { - "pub_id": "26153245", - "title": "Alterations of a Cellular Cholesterol Metabolism Network Are a Molecular Feature of Obesity-Related Type 2 Diabetes and Cardiovascular Disease.", - "authors": "Jingzhong Ding,Lindsay M Reynolds,Tanja Zeller,Christian M\u00fcller,Kurt Lohman,Barbara J Nicklas,Stephen B Kritchevsky,Zhiqing Huang,Alberto de la Fuente,Nicola Soranzo,Robert E Settlage,Chia-Chi Chuang,Timothy Howard,Ning Xu,Mark O Goodarzi,Y-D Ida Chen,Jerome I Rotter,David S Siscovick,John S Parks,Susan Murphy,David R Jacobs,Wendy Post,Russell P Tracy,Philipp S Wild,Stefan Blankenberg,Ina Hoeschele,David Herrington,Charles E McCall,Yongmei Liu", - "abstract": "Obesity is linked to type 2 diabetes (T2D) and cardiovascular diseases; however, the underlying molecular mechanisms remain unclear. We aimed to identify obesity-associated molecular features that may contribute to obesity-related diseases. Using circulating monocytes from 1,264 Multi-Ethnic Study of Atherosclerosis (MESA) participants, we quantified the transcriptome and epigenome. We discovered that alterations in a network of coexpressed cholesterol metabolism genes are a signature feature of obesity and inflammatory stress. This network included 11 BMI-associated genes related to sterol uptake (\u2191LDLR, \u2193MYLIP), synthesis (\u2191SCD, FADS1, HMGCS1, FDFT1, SQLE, CYP51A1, SC4MOL), and efflux (\u2193ABCA1, ABCG1), producing a molecular profile expected to increase intracellular cholesterol. Importantly, these alterations were associated with T2D and coronary artery calcium (CAC), independent from cardiometabolic factors, including serum lipid profiles. This network mediated the associations between obesity and T2D/CAC. Several genes in the network harbored C-phosphorus-G dinucleotides (e.g., ABCG1/cg06500161), which overlapped Encyclopedia of DNA Elements (ENCODE)-annotated regulatory regions and had methylation profiles that mediated the associations between BMI/inflammation and expression of their cognate genes. Taken together with several lines of previous experimental evidence, these data suggest that alterations of the cholesterol metabolism gene network represent a molecular link between obesity/inflammation and T2D/CAC.", - "journal_title": "Diabetes", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/26153245/" - } - ], - "57ea517d-447a-48ae-8670-788938f6843d": [ - { - "pub_id": "24731673", - "title": "Heritability of variation in glycaemic response to metformin: a genome-wide complex trait analysis.", - "authors": "Kaixin Zhou,Louise Donnelly,Jian Yang,Miaoxin Li,Harshal Deshmukh,Natalie Van Zuydam,Emma Ahlqvist, ,Chris C Spencer,Leif Groop,Andrew D Morris,Helen M Colhoun,Pak C Sham,Mark I McCarthy,Colin N A Palmer,Ewan R Pearson", - "abstract": "Metformin is a first-line oral agent used in the treatment of type 2 diabetes, but glycaemic response to this drug is highly variable. Understanding the genetic contribution to metformin response might increase the possibility of personalising metformin treatment. We aimed to establish the heritability of glycaemic response to metformin using the genome-wide complex trait analysis (GCTA) method. In this GCTA study, we obtained data about HbA1c concentrations before and during metformin treatment from patients in the Genetics of Diabetes Audit and Research in Tayside Scotland (GoDARTS) study, which includes a cohort of patients with type 2 diabetes and is linked to comprehensive clinical databases and genome-wide association study data. We applied the GCTA method to estimate heritability for four definitions of glycaemic response to metformin: absolute reduction in HbA1c; proportional reduction in HbA1c; adjusted reduction in HbA1c; and whether or not the target on-treatment HbA1c of less than 7% (53 mmol/mol) was achieved, with adjustment for baseline HbA1c and known clinical covariates. Chromosome-wise heritability estimation was used to obtain further information about the genetic architecture. 5386 individuals were included in the final dataset, of whom 2085 had enough clinical data to define glycaemic response to metformin. The heritability of glycaemic response to metformin varied by response phenotype, with a heritability of 34% (95% CI 1-68; p=0\u00b7022) for the absolute reduction in HbA1c, adjusted for pretreatment HbA1c. Chromosome-wise heritability estimates suggest that the genetic contribution is probably from individual variants scattered across the genome, which each have a small to moderate effect, rather than from a few loci that each have a large effect. Glycaemic response to metformin is heritable, thus glycaemic response to metformin is, in part, intrinsic to individual biological variation. Further genetic analysis might enable us to make better predictions for stratified medicine and to unravel new mechanisms of metformin action. Wellcome Trust.", - "journal_title": "The lancet. Diabetes & endocrinology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/24731673/" - } - ], - "a2e62868-c700-4d3f-a7a4-15491a150fc8": [ - { - "pub_id": "23257691", - "title": "Association of rs734312 and rs10010131 polymorphisms in WFS1 gene with type 2 diabetes mellitus: a meta-analysis.", - "authors": "Shuo Cheng,Yili Wu,Wenlong Wu,Dongfeng Zhang", - "abstract": "Recently, many studies have investigated the association of allelic variants of Wolfram syndrome gene (WFS1) with insulin secretion, insulin sensitivity and the risk of hyperglycemia and type 2 diabetes (T2D). Although it is clear that WFS1 mutations cause diabetes, the genetic basis of the association of common WFS1 variants with T2D is still unclear. To date, many case-control studies have been carried out to investigate the role of the WFS1 gene polymorphism in the development of T2D. However, these studies are controversial and individual studies may have insufficient power to reach a comprehensive and reliable conclusion. The aim of this study was to investigate association of WFS1 genes polymorphisms (rs734312 and rs10010131) with T2D by conducting a meta-analysis. Seven studies with 6705 T2D cases and 11144 controls were enrolled in the meta-analysis of the association between rs734312 polymorphism and T2D, and 12 studies with 16304 T2D cases and 22004 controls were enrolled in the meta-analysis of rs10010131 polymorphism. Summary odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using fixed and random-effects models. Heterogeneity among studies was evaluated using the I\u00b2 and Begg's test was used to evaluate publication bias. Sensitivity analysis was also performed. Our results suggested that the G allele of rs734312 polymorphism [dominant: FEM OR 0.873, 95%CI (0.810 - 0.940), recessive: FEM OR 0.876, 95% CI (0.800 - 0.959)] and A allele of rs10010131 polymorphism [dominant:FEM OR 0.853, 95% CI (0.817 - 0.892), recessive:REM OR 0.833, 95% CI (0.756 - 0.917)] in WFS1 gene had significant protective effects on risk of T2D.", - "journal_title": "Endocrine journal", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/23257691/" - } - ], - "4a1a2496-1172-4262-8158-a3a96b80bcf4": [ - { - "pub_id": "24039891", - "title": "Beta cell 5'-shifted isomiRs are candidate regulatory hubs in type 2 diabetes.", - "authors": "Jeanette Baran-Gale,Emily E Fannin,C Lisa Kurtz,Praveen Sethupathy", - "abstract": "Next-generation deep sequencing of small RNAs has unveiled the complexity of the microRNA (miRNA) transcriptome, which is in large part due to the diversity of miRNA sequence variants (\"isomiRs\"). Changes to a miRNA's seed sequence (nucleotides 2-8), including shifted start positions, can redirect targeting to a dramatically different set of RNAs and alter biological function. We performed deep sequencing of small RNA from mouse insulinoma (MIN6) cells (widely used as a surrogate for the study of pancreatic beta cells) and developed a bioinformatic analysis pipeline to profile isomiR diversity. Additionally, we applied the pipeline to recently published small RNA-seq data from primary human beta cells and whole islets and compared the miRNA profiles with that of MIN6. We found that: (1) the miRNA expression profile in MIN6 cells is highly correlated with those of primary human beta cells and whole islets; (2) miRNA loci can generate multiple highly expressed isomiRs with different 5'-start positions (5'-isomiRs); (3) isomiRs with shifted start positions (5'-shifted isomiRs) are highly expressed, and can be as abundant as their unshifted counterparts (5'-reference miRNAs). Finally, we identified 10 beta cell miRNA families as candidate regulatory hubs in a type 2 diabetes (T2D) gene network. The most significant candidate hub was miR-29, which we demonstrated regulates the mRNA levels of several genes critical to beta cell function and implicated in T2D. Three of the candidate miRNA hubs were novel 5'-shifted isomiRs: miR-375+1, miR-375-1 and miR-183-5p+1. We showed by in silico target prediction and in vitro transfection studies that both miR-375+1 and miR-375-1 are likely to target an overlapping, but distinct suite of beta cell genes compared to canonical miR-375. In summary, this study characterizes the isomiR profile in beta cells for the first time, and also highlights the potential functional relevance of 5'-shifted isomiRs to T2D.", - "journal_title": "PloS one", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/24039891/" - } - ], - "ffff627b-c955-4a06-b3b3-1d1ab20391bf": [ - { - "pub_id": "26633628", - "title": "Disentangling type 2 diabetes and metformin treatment signatures in the human gut microbiota.", - "authors": "Kristoffer Forslund,Falk Hildebrand,Trine Nielsen,Gwen Falony,Emmanuelle Le Chatelier,Shinichi Sunagawa,Edi Prifti,Sara Vieira-Silva,Valborg Gudmundsdottir,Helle K Pedersen,Manimozhiyan Arumugam,Karsten Kristiansen,Anita Yvonne Voigt,Henrik Vestergaard,Rajna Hercog,Paul Igor Costea,Jens Roat Kultima,Junhua Li,Torben J\u00f8rgensen,Florence Levenez,Jo\u00ebl Dore, ,H Bj\u00f8rn Nielsen,S\u00f8ren Brunak,Jeroen Raes,Torben Hansen,Jun Wang,S Dusko Ehrlich,Peer Bork,Oluf Pedersen", - "abstract": "In recent years, several associations between common chronic human disorders and altered gut microbiome composition and function have been reported. In most of these reports, treatment regimens were not controlled for and conclusions could thus be confounded by the effects of various drugs on the microbiota, which may obscure microbial causes, protective factors or diagnostically relevant signals. Our study addresses disease and drug signatures in the human gut microbiome of type 2 diabetes mellitus (T2D). Two previous quantitative gut metagenomics studies of T2D patients that were unstratified for treatment yielded divergent conclusions regarding its associated gut microbial dysbiosis. Here we show, using 784 available human gut metagenomes, how antidiabetic medication confounds these results, and analyse in detail the effects of the most widely used antidiabetic drug metformin. We provide support for microbial mediation of the therapeutic effects of metformin through short-chain fatty acid production, as well as for potential microbiota-mediated mechanisms behind known intestinal adverse effects in the form of a relative increase in abundance of Escherichia species. Controlling for metformin treatment, we report a unified signature of gut microbiome shifts in T2D with a depletion of butyrate-producing taxa. These in turn cause functional microbiome shifts, in part alleviated by metformin-induced changes. Overall, the present study emphasizes the need to disentangle gut microbiota signatures of specific human diseases from those of medication.", - "journal_title": "Nature", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/26633628/" - } - ], - "38f0171c-7952-4ab8-8e52-983a72888903": [ - { - "pub_id": "24084141", - "title": "Investigation of osteopontin levels and genomic variation of osteopontin and its receptors in Type 1 diabetes mellitus.", - "authors": "Z Karamizadeh,E Kamali Sarvestani,F Saki,H Karamifar,G H Amirhakimi,M H Namavar Shooshtarian,S Ashkani-Esfahani", - "abstract": "Failure in self-tolerance towards \u03b2-cells in diabetes mellitus (DM) pathogenesis involves a series of complex events that are governed by environmental and genetic factors. Considering the importance of osteopontin (OPN) in T-helper-1 (Th1) cells development, the aim of this study was to evaluate the serum level and gene polymorphism of OPN in Iranian Type 1 diabetic (T1DM) children. In this case-control study, 87 T1DM children and 86 healthy ones were enrolled. Blood samples of both groups were checked for OPN level. The single nucleotide polymorphisms (SNP) were genotyped by RFLP analysis for OPN rs1126772, its receptor integrin \u03b14 (ITGA4) rs 1449263, and CD44 rs8193. Serum levels of OPN in diabetic children were significantly higher in cases compared to the control group (p=0.023), but there was no significant relationship between OPN rs1126772 (p=0.79), its receptor integrin \u03b14 (p=0.31), and CD44 rs8193 (p=0.45), and T1DM. Higher amounts of OPN were seen in T1DM children. It is assumed that OPN might have inducing effects on T1DM development, particularly when genetically susceptible individuals are predisposed by an environmental insult. However, the 3 SNPs of OPN and its receptors did not show noticeable association with T1DM. The power of our study (~19%) was insufficient to observe any significant statistical difference between the groups; moreover, this study does not exclude the possibility of association of other SNPs of OPN and its receptors with this disease, and more studies are needed to clarify the issue.", - "journal_title": "Journal of endocrinological investigation", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/24084141/" - } - ], - "195cace4-f298-4910-8b7c-c4e6f208cd35": [ - { - "pub_id": "21602457", - "title": "Obesity and type 2 diabetes: what can be unified and what needs to be individualized?", - "authors": "Robert H Eckel,Steven E Kahn,Ele Ferrannini,Allison B Goldfine,David M Nathan,Michael W Schwartz,Robert J Smith,Steven R Smith", - "abstract": "This report examines what is known about the relationship between obesity and type 2 diabetes and how future research in these areas might be directed to benefit prevention, interventions, and overall patient care. An international working group of 32 experts in the pathophysiology, genetics, clinical trials, and clinical care of obesity and/or type 2 diabetes participated in a conference held on 6-7 January 2011 and cosponsored by The Endocrine Society, the American Diabetes Association, and the European Association for the Study of Diabetes. A writing group comprising eight participants subsequently prepared this summary and recommendations. Participants reviewed and discussed published literature and their own unpublished data. The writing group unanimously supported the summary and recommendations as representing the working group's majority or unanimous opinions. The major questions linking obesity to type 2 diabetes that need to be addressed by combined basic, clinical, and population-based scientific approaches include the following: 1) Why do not all patients with obesity develop type 2 diabetes? 2) Through what mechanisms do obesity and insulin resistance contribute to \u03b2-cell decompensation, and if/when obesity prevention ensues, how much reduction in type 2 diabetes incidence will follow? 3) How does the duration of type 2 diabetes relate to the benefits of weight reduction by lifestyle, weight-loss drugs, and/or bariatric surgery on \u03b2-cell function and glycemia? 4) What is necessary for regulatory approval of medications and possibly surgical approaches for preventing type 2 diabetes in patients with obesity? Improved understanding of how obesity relates to type 2 diabetes may help advance effective and cost-effective interventions for both conditions, including more tailored therapy. To expedite this process, we recommend further investigation into the pathogenesis of these coexistent conditions and innovative approaches to their pharmacological and surgical management.", - "journal_title": "The Journal of clinical endocrinology and metabolism", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/21602457/" - } - ], - "6e80ed3b-2be6-4775-a3c5-89cb4ddc88ae": [ - { - "pub_id": "25849081", - "title": "Reduced Tyk2 gene expression in \u03b2-cells due to natural mutation determines susceptibility to virus-induced diabetes.", - "authors": "Kenichi Izumi,Keiichiro Mine,Yoshitaka Inoue,Miho Teshima,Shuichiro Ogawa,Yuji Kai,Toshinobu Kurafuji,Kanako Hirakawa,Daiki Miyakawa,Haruka Ikeda,Akari Inada,Manami Hara,Hisakata Yamada,Koichi Akashi,Yoshiyuki Niho,Keisuke Ina,Takashi Kobayashi,Yasunobu Yoshikai,Keizo Anzai,Teruo Yamashita,Hiroko Minagawa,Shuji Fujimoto,Hironori Kurisaki,Kazuya Shimoda,Hitoshi Katsuta,Seiho Nagafuchi", - "abstract": "Accumulating evidence suggests that viruses play an important role in the development of diabetes. Although the diabetogenic encephalomyocarditis strain D virus induces diabetes in restricted lines of inbred mice, the susceptibility genes to virus-induced diabetes have not been identified. We report here that novel Tyrosine kinase 2 (Tyk2) gene mutations are present in virus-induced diabetes-sensitive SJL and SWR mice. Mice carrying the mutant Tyk2 gene on the virus-resistant C57BL/6 background are highly sensitive to virus-induced diabetes. Tyk2 gene expression is strongly reduced in Tyk2-mutant mice, associated with low Tyk2 promoter activity, and leads to decreased expression of interferon-inducible genes, resulting in significantly compromised antiviral response. Tyk2-mutant pancreatic \u03b2-cells are unresponsive even to high dose of Type I interferon. Reversal of virus-induced diabetes could be achieved by \u03b2-cell-specific Tyk2 gene expression. Thus, reduced Tyk2 gene expression in pancreatic \u03b2-cells due to natural mutation is responsible for susceptibility to virus-induced diabetes.", - "journal_title": "Nature communications", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/25849081/" - } - ], - "76f1e8d2-15bf-4ce6-9cd0-2ab889c23664": [ - { - "pub_id": "19567529", - "title": "X-chromosome gene dosage and the risk of diabetes in Turner syndrome.", - "authors": "Vladimir K Bakalov,Clara Cheng,Jian Zhou,Carolyn A Bondy", - "abstract": "Turner syndrome (TS) is caused by the absence or fragmentation of the second sex chromosome. An increased risk of diabetes mellitus (DM) has consistently been noted, but the specific phenotype and genetic etiology of this trait are unknown. In a prospective study, we examined the prevalence of DM in adult participants in an intramural National Institutes of Health (NIH) TS study. Results were analyzed with respect to karyotype, age, body mass index (BMI), and autoimmune indices. Insulin sensitivity and secretion were compared in age- and BMI-matched euglycemic women with TS and healthy female controls. We compared gene expression profiles in lymphocytes from differentially affected TS groups. Type 2 DM was present in 56 of 224 (25%) of the women with TS; type 1 DM was found in only one woman (<0.5%). DM was more prevalent among women with an isoXq chromosome compared to X monosomy (40.0 vs. 17.3%; P = 0.004). Euglycemic women with TS (n = 72; age, 33 +/- 12 yr; BMI, 23 +/- 3 kg/m(2)) had significantly higher glycemic and lower insulin responses to OGTT, with insulin sensitivity similar to controls. Gene expression profiles comparing 46,X,i(X)q vs. 45,X groups showed a significant increase in Xq transcripts and in potentially diabetogenic autosomal transcripts in the isoXq group. Type 2 DM associated with deficient insulin release is significantly increased among women with monosomy for the X-chromosome but is increased even more among women with monosomy for Xp coupled with trisomy for Xq. These data suggest that haploinsufficiency for unknown Xp genes increases risk for DM and that excess dosage of Xq genes compounds the risk.", - "journal_title": "The Journal of clinical endocrinology and metabolism", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/19567529/" - } - ], - "4ab80ffa-0ff3-4d42-b226-fa685555420c": [ - { - "pub_id": "23056442", - "title": "Transcriptome sequencing and de novo analysis for Ma bamboo (Dendrocalamus latiflorus Munro) using the Illumina platform.", - "authors": "Mingying Liu,Guirong Qiao,Jing Jiang,Huiqin Yang,Lihua Xie,Jinzhong Xie,Renying Zhuo", - "abstract": "Bamboo occupies an important phylogenetic node in the grass family with remarkable sizes, woodiness and a striking life history. However, limited genetic research has focused on bamboo partially because of the lack of genomic resources. The advent of high-throughput sequencing technologies enables generation of genomic resources in a short time and at a minimal cost, and therefore provides a turning point for bamboo research. In the present study, we performed de novo transcriptome sequencing for the first time to produce a comprehensive dataset for the Ma bamboo (Dendrocalamus latiflorus Munro). The Ma bamboo transcriptome was sequenced using the Illumina paired-end sequencing technology. We produced 15,138,726 reads and assembled them into 103,354 scaffolds. A total of 68,229 unigenes were identified, among which 46,087 were annotated in the NCBI non-redundant protein database and 28,165 were annotated in the Swiss-Prot database. Of these annotated unigenes, 11,921 and 10,147 unigenes were assigned to gene ontology categories and clusters of orthologous groups, respectively. We could map 45,649 unigenes onto 292 pathways using the Kyoto Encyclopedia of Genes and Genomes Pathway database. The annotated unigenes were compared against Moso bamboo, rice and millet. Unigenes that did not match any of those three sequence datasets are considered to be Ma bamboo unique. We predicted 105 unigenes encoding eight key enzymes involved in lignin biosynthesis. In addition, 621 simple sequence repeats (SSRs) were detected. Our data provide the most comprehensive transcriptomic resource currently available for D. latiflorus Munro. Candidate genes potentially involved in growth and development were identified, and those predicted to be unique to Ma bamboo are expected to give a better insight on Ma bamboo gene diversity. Numerous SSRs characterized contributed to marker development. These data constitute a new valuable resource for genomic studies on D. latiflorus Munro and, more generally, bamboo.", - "journal_title": "PloS one", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/23056442/" - } - ], - "1e3a2816-2a1f-41c3-88d6-03330f04652b": [ - { - "pub_id": "24204828", - "title": "Genome-wide contribution of genotype by environment interaction to variation of diabetes-related traits.", - "authors": "Ju-Sheng Zheng,Donna K Arnett,Yu-Chi Lee,Jian Shen,Laurence D Parnell,Caren E Smith,Kris Richardson,Duo Li,Ingrid B Borecki,Jos\u00e9 M Ordov\u00e1s,Chao-Qiang Lai", - "abstract": "While genome-wide association studies (GWAS) and candidate gene approaches have identified many genetic variants that contribute to disease risk as main effects, the impact of genotype by environment (GxE) interactions remains rather under-surveyed. To explore the importance of GxE interactions for diabetes-related traits, a tool for Genome-wide Complex Trait Analysis (GCTA) was used to examine GxE variance contribution of 15 macronutrients and lifestyle to the total phenotypic variance of diabetes-related traits at the genome-wide level in a European American population. GCTA identified two key environmental factors making significant contributions to the GxE variance for diabetes-related traits: carbohydrate for fasting insulin (25.1% of total variance, P-nominal = 0.032) and homeostasis model assessment of insulin resistance (HOMA-IR) (24.2% of total variance, P-nominal = 0.035), n-6 polyunsaturated fatty acid (PUFA) for HOMA-\u03b2-cell-function (39.0% of total variance, P-nominal = 0.005). To demonstrate and support the results from GCTA, a GxE GWAS was conducted with each of the significant dietary factors and a control E factor (dietary protein), which contributed a non-significant GxE variance. We observed that GxE GWAS for the environmental factor contributing a significant GxE variance yielded more significant SNPs than the control factor. For each trait, we selected all significant SNPs produced from GxE GWAS, and conducted anew the GCTA to estimate the variance they contributed. We noted the variance contributed by these SNPs is higher than that of the control. In conclusion, we utilized a novel method that demonstrates the importance of genome-wide GxE interactions in explaining the variance of diabetes-related traits.", - "journal_title": "PloS one", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/24204828/" - } - ], - "8ab10856-5df7-4f76-897a-84e6f25cd3f5": [ - { - "pub_id": "22540253", - "title": "Gene-environment interactions in the development of type 2 diabetes: recent progress and continuing challenges.", - "authors": "Marilyn C Cornelis,Frank B Hu", - "abstract": "Type 2 diabetes (T2D) is thought to arise from the complex interplay of both genetic and environmental factors. Since the advent of genome-wide association studies (GWAS), we have seen considerable progress in our understanding of the role that genetics and gene-environment interactions play in the development of T2D. Recent work suggests that the adverse effect of several T2D loci may be abolished or at least attenuated by higher physical activity levels or healthy lifestyle, whereas low physical activity and dietary factors characterizing a Western dietary pattern may augment it. However, there still remain inconsistencies warranting further investigation. Lack of statistical power and measurement errors for the environmental factors continue to challenge our efforts for characterizing interactions. Although our recent focus on established T2D loci is reasonable, we may be overlooking many other potential loci not captured by recent T2D GWAS. Agnostic approaches to the discovery of gene and environment interactions may address this possibility, but their application to the field is currently limited and still faces conceptual challenges. Nonetheless, continued investment in gene-environment interaction studies through large collaborative efforts holds promise in furthering our understanding of the interplay between genetic and environmental factors.", - "journal_title": "Annual review of nutrition", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/22540253/" - } - ], - "d23e9456-8ee8-46e0-9870-18ff69965c28": [ - { - "pub_id": "24089659", - "title": "MicroRNAs in kidney fibrosis and diabetic nephropathy: roles on EMT and EndMT.", - "authors": "Swayam Prakash Srivastava,Daisuke Koya,Keizo Kanasaki", - "abstract": "MicroRNAs (miRNAs) are a family of small, noncoding RNAs that regulate gene expression in diverse biological and pathological processes, including cell proliferation, differentiation, apoptosis, and carcinogenesis. As a result, miRNAs emerged as major area of biomedical research with relevance to kidney fibrosis. Fibrosis is characterized by the excess deposition of extracellular matrix (ECM) components, which is the end result of an imbalance of metabolism of the ECM molecule. Recent evidence suggests that miRNAs participate in the fibrotic process in a number of organs including the heart, kidney, liver, and lung. Epithelial mesenchymal transition (EMT) and endothelial mesenchymal transition (EndMT) programs play vital roles in the development of fibrosis in the kidney. A growing number of the extracellular and intracellular molecules that control EMT and EndMT have been identified and could be exploited in developing therapeutics for fibrosis. This review highlights recent advances on the role of miRNAs in the kidney diseases; diabetic nephropathy especially focused on EMT and EndMT program responsible for the development of kidney fibrosis. These miRNAs can be utilized as a potential novel drug target for the studying of underlying mechanism and treatment of kidney fibrosis.", - "journal_title": "BioMed research international", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/24089659/" - } - ], - "a579db95-2a40-43ff-b237-d47f90aaf64f": [ - { - "pub_id": "21536720", - "title": "Prioritizing candidate disease genes by network-based boosting of genome-wide association data.", - "authors": "Insuk Lee,U Martin Blom,Peggy I Wang,Jung Eun Shim,Edward M Marcotte", - "abstract": "Network \"guilt by association\" (GBA) is a proven approach for identifying novel disease genes based on the observation that similar mutational phenotypes arise from functionally related genes. In principle, this approach could account even for nonadditive genetic interactions, which underlie the synergistic combinations of mutations often linked to complex diseases. Here, we analyze a large-scale, human gene functional interaction network (dubbed HumanNet). We show that candidate disease genes can be effectively identified by GBA in cross-validated tests using label propagation algorithms related to Google's PageRank. However, GBA has been shown to work poorly in genome-wide association studies (GWAS), where many genes are somewhat implicated, but few are known with very high certainty. Here, we resolve this by explicitly modeling the uncertainty of the associations and incorporating the uncertainty for the seed set into the GBA framework. We observe a significant boost in the power to detect validated candidate genes for Crohn's disease and type 2 diabetes by comparing our predictions to results from follow-up meta-analyses, with incorporation of the network serving to highlight the JAK-STAT pathway and associated adaptors GRB2/SHC1 in Crohn's disease and BACH2 in type 2 diabetes. Consideration of the network during GWAS thus conveys some of the benefits of enrolling more participants in the GWAS study. More generally, we demonstrate that a functional network of human genes provides a valuable statistical framework for prioritizing candidate disease genes, both for candidate gene-based and GWAS-based studies.", - "journal_title": "Genome research", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/21536720/" - } - ], - "9e3a4f4a-24d6-4a12-a798-ca654e225e7e": [ - { - "pub_id": "20981092", - "title": "A map of human genome variation from population-scale sequencing.", - "authors": " ,Gon\u00e7alo R Abecasis,David Altshuler,Adam Auton,Lisa D Brooks,Richard M Durbin,Richard A Gibbs,Matt E Hurles,Gil A McVean", - "abstract": "The 1000 Genomes Project aims to provide a deep characterization of human genome sequence variation as a foundation for investigating the relationship between genotype and phenotype. Here we present results of the pilot phase of the project, designed to develop and compare different strategies for genome-wide sequencing with high-throughput platforms. We undertook three projects: low-coverage whole-genome sequencing of 179 individuals from four populations; high-coverage sequencing of two mother-father-child trios; and exon-targeted sequencing of 697 individuals from seven populations. We describe the location, allele frequency and local haplotype structure of approximately 15 million single nucleotide polymorphisms, 1 million short insertions and deletions, and 20,000 structural variants, most of which were previously undescribed. We show that, because we have catalogued the vast majority of common variation, over 95% of the currently accessible variants found in any individual are present in this data set. On average, each person is found to carry approximately 250 to 300 loss-of-function variants in annotated genes and 50 to 100 variants previously implicated in inherited disorders. We demonstrate how these results can be used to inform association and functional studies. From the two trios, we directly estimate the rate of de novo germline base substitution mutations to be approximately 10(-8) per base pair per generation. We explore the data with regard to signatures of natural selection, and identify a marked reduction of genetic variation in the neighbourhood of genes, due to selection at linked sites. These methods and public data will support the next phase of human genetic research.", - "journal_title": "Nature", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/20981092/" - } - ], - "b42bfab2-62f0-49c4-98f0-5e64fd5039a2": [ - { - "pub_id": "21059061", - "title": "Reviewe: Genetics and genomics in equine exercise physiology: an overview of the new applications of molecular biology as positive and negative markers of performance and health.", - "authors": "E Barrey", - "abstract": "Equine breeding selection has been developed by applying quantitative genetic methods for calculating the heritability of the complex traits such as performance in racing or sport competitions. With the great development of biotechnologies, equine molecular genetics has come of age. The recent sequencing of the equine genome by an international consortium was a major advance that will impact equine genomics in the near future. With the rapid progress in equine genetics, new applications in early performance evaluation and the detection of disease markers become available. Many new biomolecular tools will change management of horse selection, disease diagnosis and treatment. The purpose of this review is to present new developments in equine genetics and genomics for performance evaluation and health markers after a short summary of the previous knowledge about the genetic components of the exercise performance traits.", - "journal_title": "Equine veterinary journal. Supplement", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/21059061/" - } - ], - "3548bb7f-727c-4ccb-acc7-a97553b89992": [ - { - "pub_id": "21617109", - "title": "Globalization of diabetes: the role of diet, lifestyle, and genes.", - "authors": "Frank B Hu", - "abstract": "Type 2 diabetes is a global public health crisis that threatens the economies of all nations, particularly developing countries. Fueled by rapid urbanization, nutrition transition, and increasingly sedentary lifestyles, the epidemic has grown in parallel with the worldwide rise in obesity. Asia's large population and rapid economic development have made it an epicenter of the epidemic. Asian populations tend to develop diabetes at younger ages and lower BMI levels than Caucasians. Several factors contribute to accelerated diabetes epidemic in Asians, including the \"normal-weight metabolically obese\" phenotype; high prevalence of smoking and heavy alcohol use; high intake of refined carbohydrates (e.g., white rice); and dramatically decreased physical activity levels. Poor nutrition in utero and in early life combined with overnutrition in later life may also play a role in Asia's diabetes epidemic. Recent advances in genome-wide association studies have contributed substantially to our understanding of diabetes pathophysiology, but currently identified genetic loci are insufficient to explain ethnic differences in diabetes risk. Nonetheless, interactions between Westernized diet and lifestyle and genetic background may accelerate the growth of diabetes in the context of rapid nutrition transition. Epidemiologic studies and randomized clinical trials show that type 2 diabetes is largely preventable through diet and lifestyle modifications. Translating these findings into practice, however, requires fundamental changes in public policies, the food and built environments, and health systems. To curb the escalating diabetes epidemic, primary prevention through promotion of a healthy diet and lifestyle should be a global public policy priority.", - "journal_title": "Diabetes care", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/21617109/" - } - ], - "5341ea0f-13b5-4f9c-9466-7739514eab95": [ - { - "pub_id": "26079957", - "title": "Genetic and genomic markers of anti-TNF treatment response in rheumatoid arthritis.", - "authors": "James Oliver,Darren Plant,Amy P Webster,Anne Barton", - "abstract": "Despite the success of anti-TNF drugs in the treatment of rheumatoid arthritis, a significant rate of nonresponse remains. Current clinical factors confer little power for predicting response and, in current practice, an unsatisfactory 'trial and error' approach governs therapeutic decisions. Candidate gene and unbiased genome-wide investigations have sought to identify genetic biomarkers that predict who will respond to anti-TNF drugs before the drug is administered. To date, few studies have yielded robust associations; herein, we discuss currently identified associations and the issues that need to be addressed in future investigations including insufficient power and an inadequate measure of disease activity. The potential for alternative predictors of anti-TNF therapy response from transcriptomic and epigenetic data will also be explored.", - "journal_title": "Biomarkers in medicine", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/26079957/" - } - ], - "cd9f4acc-1e47-4898-98f8-e27b8b290a3d": [ - { - "pub_id": "22446960", - "title": "Bayesian inference analyses of the polygenic architecture of rheumatoid arthritis.", - "authors": "Eli A Stahl,Daniel Wegmann,Gosia Trynka,Javier Gutierrez-Achury,Ron Do,Benjamin F Voight,Peter Kraft,Robert Chen,Henrik J Kallberg,Fina A S Kurreeman, , ,Sekar Kathiresan,Cisca Wijmenga,Peter K Gregersen,Lars Alfredsson,Katherine A Siminovitch,Jane Worthington,Paul I W de Bakker,Soumya Raychaudhuri,Robert M Plenge", - "abstract": "The genetic architectures of common, complex diseases are largely uncharacterized. We modeled the genetic architecture underlying genome-wide association study (GWAS) data for rheumatoid arthritis and developed a new method using polygenic risk-score analyses to infer the total liability-scale variance explained by associated GWAS SNPs. Using this method, we estimated that, together, thousands of SNPs from rheumatoid arthritis GWAS explain an additional 20% of disease risk (excluding known associated loci). We further tested this method on datasets for three additional diseases and obtained comparable estimates for celiac disease (43% excluding the major histocompatibility complex), myocardial infarction and coronary artery disease (48%) and type 2 diabetes (49%). Our results are consistent with simulated genetic models in which hundreds of associated loci harbor common causal variants and a smaller number of loci harbor multiple rare causal variants. These analyses suggest that GWAS will continue to be highly productive for the discovery of additional susceptibility loci for common diseases.", - "journal_title": "Nature genetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/22446960/" - } - ], - "41bc85bc-314f-4d92-9007-5d1571506ef3": [ - { - "pub_id": "23442068", - "title": "Diabetes genes identified by genome-wide association studies are regulated in mice by nutritional factors in metabolically relevant tissues and by glucose concentrations in islets.", - "authors": "Maggie M Ho,Piriya Yoganathan,Kwan Yi Chu,Subashini Karunakaran,James D Johnson,Susanne M Clee", - "abstract": "Genome-wide association studies (GWAS) have recently identified many new genetic variants associated with the development of type 2 diabetes. Many of these variants are in introns of known genes or between known genes, suggesting they affect the expression of these genes. The regulation of gene expression is often tissue and context dependent, for example occurring in response to dietary changes, hormone levels, or many other factors. Thus, to understand how these new genetic variants associated with diabetes risk may act, it is necessary to understand the regulation of their cognate genes. We identified fourteen type 2 diabetes-associated genes discovered by the first waves of GWAS for which there was little prior evidence of their potential role in diabetes (Adam30, Adamts9, Camk1d, Cdc123, Cdkal1, Cdkn2a, Cdkn2b, Ext2, Hhex, Ide, Jazf1, Lgr5, Thada and Tspan8). We examined their expression in metabolically relevant tissues including liver, adipose tissue, brain, and hypothalamus obtained from mice under fasted, non-fasted and high fat diet-fed conditions. In addition, we examined their expression in pancreatic islets from these mice cultured in low and high glucose. We found that the expression of Jazf1 was reduced by high fat feeding in liver, with similar tendencies in adipose tissue and the hypothalamus. Adamts9 expression was decreased in the hypothalamus of high fat fed mice. In contrast, the expression of Camk1d, Ext2, Jazf1 and Lgr5 were increased in the brain of non-fasted animals compared to fasted mice. Most notably, the expression levels of most of the genes were decreased in islets cultured in high glucose. These data provide insight into the metabolic regulation of these new type 2 diabetes genes that will be important for determining how the GWAS variants affect gene expression and ultimately the development of type 2 diabetes.", - "journal_title": "BMC genetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/23442068/" - } - ], - "0ae5d2bb-b09d-4646-922a-277188b53cbb": [ - { - "pub_id": "25792090", - "title": "Maternal diabetes, gestational diabetes and the role of epigenetics in their long term effects on offspring.", - "authors": "Ronald C W Ma,Greg E Tutino,Karen A Lillycrop,Mark A Hanson,Wing Hung Tam", - "abstract": "There is a global epidemic of obesity and diabetes, and current efforts to curb the diabetes epidemic have had limited success. Epidemiological studies have highlighted increased risk of obesity, diabetes and cardiovascular complications in offspring exposed to maternal diabetes, and gestational diabetes increases the risk of diabetes in subsequent generations, thereby setting up a vicious cycle of \"diabetes begetting diabetes\". This relationship between maternal hyperglycaemia and long-term health in the offspring is likely to become even more important with an increasing proportion of young woman being affected by diabetes, and the number of pregnancies complicated by hyperglycaemia continuing to rise. Animal models of gestational diabetes or maternal hyperglycaemia have highlighted long-term changes in the offspring with some instances of sex bias, including increased adiposity, insulin resistance, \u03b2-cell dysfunction, hypertension, as well as other structural and functional changes. Furthermore, several of these changes appear to be transmissible to later generations through the maternal line. Epigenetic changes play an important role in regulating gene expression, especially during early development. Recent studies have identified a number of epigenetic modifications in the offspring associated with maternal hyperglycaemia. In this review, we provide an overview of the epidemiological evidence linking maternal hyperglycaemia with adverse long-term outcome in the offspring, as well as of some of the studies that explore the underlying epigenetic mechanisms. A better understanding of the pathways involved may provide novel approaches for combating this global epidemic.", - "journal_title": "Progress in biophysics and molecular biology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/25792090/" - } - ], - "b07d827c-136a-4938-b3f5-b1cde90a2332": [ - { - "pub_id": "21198561", - "title": "Genetics of type 2 diabetes: pathophysiologic and clinical relevance.", - "authors": "Christian Herder,Michael Roden", - "abstract": "Recent genome-wide association studies enlarged our knowledge about the genetic background of type 2 diabetes. This review provides an overview of the role of these novel genetic findings for the pathophysiology, prediction and treatment of type 2 diabetes. The genetic susceptibility to type 2 diabetes appears to be determined by many common variants in multiple gene loci with low effect sizes. Although at least 36 diabetes-associated genes were identified, only about 10% of the heritability of type 2 diabetes can be explained. Most of the discovered gene variants have been linked to beta-cell dysfunction rather than insulin resistance, which might challenge established thinking of type 2 diabetes as a predominant disorder of insulin action. Genetic data can lead to statistically significant, but not to clinically relevant contributions to risk prediction for type 2 diabetes. Nevertheless, preliminary evidence suggests interactions between genotypes and response to lifestyle changes or drug treatment. Future studies need to target the issue of hidden heritability and to detect the causal gene variants within the identified gene loci. Improved understanding of the genetic contribution to type 2 diabetes may then help addressing the questions whether genotyping is useful to predict individual diabetes risk, identifies individual responsiveness to preventive and therapeutic interventions or at least allows for breaking down type 2 diabetes into smaller, clinically meaningful subtypes.", - "journal_title": "European journal of clinical investigation", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/21198561/" - } - ], - "a56721cb-b86f-4ef8-b81c-d8189d4ffac1": [ - { - "pub_id": "23674605", - "title": "The CTRB1/2 locus affects diabetes susceptibility and treatment via the incretin pathway.", - "authors": "Leen M 't Hart,Andreas Fritsche,Giel Nijpels,Nienke van Leeuwen,Louise A Donnelly,Jacqueline M Dekker,Marjan Alssema,Joao Fadista,Fran\u00e7oise Carlotti,Anette P Gjesing,Colin N A Palmer,Timon W van Haeften,Silke A Herzberg-Sch\u00e4fer,Annemarie M C Simonis-Bik,Jeanine J Houwing-Duistermaat,Quinta Helmer,Joris Deelen,Bruno Guigas,Torben Hansen,Fausto Machicao,Gonneke Willemsen,Robert J Heine,Mark H H Kramer,Jens J Holst,Eelco J P de Koning,Hans-Ulrich H\u00e4ring,Oluf Pedersen,Leif Groop,Eco J C de Geus,P Eline Slagboom,Dorret I Boomsma,Elisabeth M W Eekhoff,Ewan R Pearson,Michaela Diamant", - "abstract": "The incretin hormone glucagon-like peptide 1 (GLP-1) promotes glucose homeostasis and enhances \u03b2-cell function. GLP-1 receptor agonists (GLP-1 RAs) and dipeptidyl peptidase-4 (DPP-4) inhibitors, which inhibit the physiological inactivation of endogenous GLP-1, are used for the treatment of type 2 diabetes. Using the Metabochip, we identified three novel genetic loci with large effects (30-40%) on GLP-1-stimulated insulin secretion during hyperglycemic clamps in nondiabetic Caucasian individuals (TMEM114; CHST3 and CTRB1/2; n = 232; all P \u2264 8.8 \u00d7 10(-7)). rs7202877 near CTRB1/2, a known diabetes risk locus, also associated with an absolute 0.51 \u00b1 0.16% (5.6 \u00b1 1.7 mmol/mol) lower A1C response to DPP-4 inhibitor treatment in G-allele carriers, but there was no effect on GLP-1 RA treatment in type 2 diabetic patients (n = 527). Furthermore, in pancreatic tissue, we show that rs7202877 acts as expression quantitative trait locus for CTRB1 and CTRB2, encoding chymotrypsinogen, and increases fecal chymotrypsin activity in healthy carriers. Chymotrypsin is one of the most abundant digestive enzymes in the gut where it cleaves food proteins into smaller peptide fragments. Our data identify chymotrypsin in the regulation of the incretin pathway, development of diabetes, and response to DPP-4 inhibitor treatment.", - "journal_title": "Diabetes", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/23674605/" - } - ], - "d404784f-962d-41be-bea9-e4e1e5555165": [ - { - "pub_id": "24345642", - "title": "Neuronatin gene: Imprinted and misfolded: Studies in Lafora disease, diabetes and cancer may implicate NNAT-aggregates as a common downstream participant in neuronal loss.", - "authors": "Rajiv Madathiparambil Joseph", - "abstract": "Neuronatin (NNAT) is a ubiquitous and highly conserved mammalian gene involved in brain development. Its mRNA isoforms, chromosomal location, genomic DNA structure and regulation have been characterized. More recently there has been rapid progress in the understanding of its function in physiology and human disease. In particular there is fairly direct evidence implicating neuronatin in the causation of Lafora disease and diabetes. Neuronatin protein has a strong predisposition to misfold and form cellular aggregates that cause cell death by apoptosis. Aggregation of Neuronatin within cortical neurons and resulting cell death is the hallmark of Lafora disease, a progressive and fatal neurodegenerative disease. Under high glucose conditions simulating diabetes, neuronatin protein also accumulates and destroys pancreatic beta cells. The neuronatin gene is imprinted and only the paternal allele is normally expressed in the adult. However, changes in DNA methylation may cause the maternal allele to lose imprinting and trigger cell proliferation and metastasis. Neuronatin has also been shown to be translated peripherally within the dendrites of neurons, a finding of relevance in synaptic plasticity. The current understanding of the function of neuronatin raises the possibility that this gene may participate in the common downstream mechanisms associated with aberrant neuronal growth and death. A better understanding of these mechanisms may open new therapeutic targets to help modify the progression of devastating neurodegenerative conditions such as Alzheimer's and anterior horn cell disease.", - "journal_title": "Genomics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/24345642/" - } - ], - "7774c5a5-c9c8-42fd-ab00-0deb2a32028d": [ - { - "pub_id": "26251408", - "title": "Effects of metformin on metabolite profiles and LDL cholesterol in patients with type 2 diabetes.", - "authors": "Tao Xu,Stefan Brandmaier,Ana C Messias,Christian Herder,Harmen H M Draisma,Ayse Demirkan,Zhonghao Yu,Janina S Ried,Toomas Haller,Margit Heier,Monica Campillos,Gisela Fobo,Renee Stark,Christina Holzapfel,Jonathan Adam,Shen Chi,Markus Rotter,Tommaso Panni,Anne S Quante,Ying He,Cornelia Prehn,Werner Roemisch-Margl,Gabi Kastenm\u00fcller,Gonneke Willemsen,Ren\u00e9 Pool,Katarina Kasa,Ko Willems van Dijk,Thomas Hankemeier,Christa Meisinger,Barbara Thorand,Andreas Ruepp,Martin Hrab\u00e9 de Angelis,Yixue Li,H-Erich Wichmann,Bernd Stratmann,Konstantin Strauch,Andres Metspalu,Christian Gieger,Karsten Suhre,Jerzy Adamski,Thomas Illig,Wolfgang Rathmann,Michael Roden,Annette Peters,Cornelia M van Duijn,Dorret I Boomsma,Thomas Meitinger,Rui Wang-Sattler", - "abstract": "Metformin is used as a first-line oral treatment for type 2 diabetes (T2D). However, the underlying mechanism is not fully understood. Here, we aimed to comprehensively investigate the pleiotropic effects of metformin. We analyzed both metabolomic and genomic data of the population-based KORA cohort. To evaluate the effect of metformin treatment on metabolite concentrations, we quantified 131 metabolites in fasting serum samples and used multivariable linear regression models in three independent cross-sectional studies (n = 151 patients with T2D treated with metformin [mt-T2D]). Additionally, we used linear mixed-effect models to study the longitudinal KORA samples (n = 912) and performed mediation analyses to investigate the effects of metformin intake on blood lipid profiles. We combined genotyping data with the identified metformin-associated metabolites in KORA individuals (n = 1,809) and explored the underlying pathways. We found significantly lower (P < 5.0E-06) concentrations of three metabolites (acyl-alkyl phosphatidylcholines [PCs]) when comparing mt-T2D with four control groups who were not using glucose-lowering oral medication. These findings were controlled for conventional risk factors of T2D and replicated in two independent studies. Furthermore, we observed that the levels of these metabolites decreased significantly in patients after they started metformin treatment during 7 years' follow-up. The reduction of these metabolites was also associated with a lowered blood level of LDL cholesterol (LDL-C). Variations of these three metabolites were significantly associated with 17 genes (including FADS1 and FADS2) and controlled by AMPK, a metformin target. Our results indicate that metformin intake activates AMPK and consequently suppresses FADS, which leads to reduced levels of the three acyl-alkyl PCs and LDL-C. Our findings suggest potential beneficial effects of metformin in the prevention of cardiovascular disease.", - "journal_title": "Diabetes care", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/26251408/" - } - ], - "538c6234-b5bf-43b7-97ce-091531a139b7": [ - { - "pub_id": "24277301", - "title": "Ecological epigenetics.", - "authors": "Holly J Kilvitis,Mariano Alvarez,Christy M Foust,Aaron W Schrey,Marta Robertson,Christina L Richards", - "abstract": "Biologists have assumed that heritable variation due to DNA sequence differences (i.e., genetic variation) allows populations of organisms to be both robust and adaptable to extreme environmental conditions. Natural selection acts on the variation among different genotypes and ultimately changes the genetic composition of the population. While there is compelling evidence about the importance of genetic polymorphisms, evidence is accumulating that epigenetic mechanisms (e.g., chromatin modifications, DNA methylation) can affect ecologically important traits, even in the absence of genetic variation. In this chapter, we review this evidence and discuss the consequences of epigenetic variation in natural populations. We begin by defining the term epigenetics, providing a brief overview of various epigenetic mechanisms, and noting the potential importance of epigenetics in the study of ecology. We continue with a review of the ecological epigenetics literature to demonstrate what is currently known about the amount and distribution of epigenetic variation in natural populations. Then, we consider the various ecological contexts in which epigenetics has proven particularly insightful and discuss the potential evolutionary consequences of epigenetic variation. Finally, we conclude with suggestions for future directions of ecological epigenetics research.", - "journal_title": "Advances in experimental medicine and biology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/24277301/" - } - ], - "e88b610f-8afa-46f7-a03c-d7bd579a7496": [ - { - "pub_id": "25211022", - "title": "Identification of a regulatory variant that binds FOXA1 and FOXA2 at the CDC123/CAMK1D type 2 diabetes GWAS locus.", - "authors": "Marie P Fogarty,Maren E Cannon,Swarooparani Vadlamudi,Kyle J Gaulton,Karen L Mohlke", - "abstract": "Many of the type 2 diabetes loci identified through genome-wide association studies localize to non-protein-coding intronic and intergenic regions and likely contain variants that regulate gene transcription. The CDC123/CAMK1D type 2 diabetes association signal on chromosome 10 spans an intergenic region between CDC123 and CAMK1D and also overlaps the CDC123 3'UTR. To gain insight into the molecular mechanisms underlying the association signal, we used open chromatin, histone modifications and transcription factor ChIP-seq data sets from type 2 diabetes-relevant cell types to identify SNPs overlapping predicted regulatory regions. Two regions containing type 2 diabetes-associated variants were tested for enhancer activity using luciferase reporter assays. One SNP, rs11257655, displayed allelic differences in transcriptional enhancer activity in 832/13 and MIN6 insulinoma cells as well as in human HepG2 hepatocellular carcinoma cells. The rs11257655 risk allele T showed greater transcriptional activity than the non-risk allele C in all cell types tested. Using electromobility shift and supershift assays we demonstrated that the rs11257655 risk allele showed allele-specific binding to FOXA1 and FOXA2. We validated FOXA1 and FOXA2 enrichment at the rs11257655 risk allele using allele-specific ChIP in human islets. These results suggest that rs11257655 affects transcriptional activity through altered binding of a protein complex that includes FOXA1 and FOXA2, providing a potential molecular mechanism at this GWAS locus.", - "journal_title": "PLoS genetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/25211022/" - } - ], - "9cce7fe9-cb40-4e75-85bc-d8655c3343d6": [ - { - "pub_id": "19442898", - "title": "Zinc and diabetes--clinical links and molecular mechanisms.", - "authors": "Judith Jansen,Wolfram Karges,Lothar Rink", - "abstract": "Zinc is an essential trace element crucial for the function of more than 300 enzymes and it is important for cellular processes like cell division and apoptosis. Hence, the concentration of zinc in the human body is tightly regulated and disturbances of zinc homeostasis have been associated with several diseases including diabetes mellitus, a disease characterized by high blood glucose concentrations as a consequence of decreased secretion or action of insulin. Zinc supplementation of animals and humans has been shown to ameliorate glycemic control in type 1 and 2 diabetes, the two major forms of diabetes mellitus, but the underlying molecular mechanisms have only slowly been elucidated. Zinc seems to exert insulin-like effects by supporting the signal transduction of insulin and by reducing the production of cytokines, which lead to beta-cell death during the inflammatory process in the pancreas in the course of the disease. Furthermore, zinc might play a role in the development of diabetes, since genetic polymorphisms in the gene of zinc transporter 8 and in metallothionein (MT)-encoding genes could be demonstrated to be associated with type 2 diabetes mellitus. The fact that antibodies against this zinc transporter have been detected in type 1 diabetic patients offers new diagnostic possibilities. This article reviews the influence of zinc on the diabetic state including the molecular mechanisms, the role of the zinc transporter 8 and MT for diabetes development and the resulting diagnostic and therapeutic options.", - "journal_title": "The Journal of nutritional biochemistry", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/19442898/" - } - ], - "8f74252a-5ce1-4109-86b6-5b0228b23bba": [ - { - "pub_id": "21647602", - "title": "Type 2 diabetes and obesity: genomics and the clinic.", - "authors": "Mary E Travers,Mark I McCarthy", - "abstract": "Type 2 diabetes (T2D) and obesity represent major challenges for global public health. They are at the forefront of international efforts to identify the genetic variation contributing to complex disease susceptibility, and recent years have seen considerable success in identifying common risk-variants. Given the clinical impact of molecular diagnostics in rarer monogenic forms of these diseases, expectations have been high that genetic discoveries will transform the prospects for risk stratification, development of novel therapeutics and personalised medicine. However, so far, clinical translation has been limited. Difficulties in defining the alleles and transcripts mediating association effects have frustrated efforts to gain early biological insights, whilst the fact that variants identified account for only a modest proportion of observed familiarity has limited their value in guiding treatment of individual patients. Ongoing efforts to track causal variants through fine-mapping and to illuminate the biological mechanisms through which they act, as well as sequence-based discovery of lower-frequency alleles (of potentially larger effect), should provide welcome acceleration in the capacity for clinical translation. This review will summarise recent advances in identifying risk alleles for T2D and obesity, and existing contributions to understanding disease pathology. It will consider the progress made in translating genetic knowledge into clinical utility, the challenges remaining, and the realistic potential for further progress.", - "journal_title": "Human genetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/21647602/" - } - ], - "a83987ea-607c-4952-a1cc-69c6f193ba2a": [ - { - "pub_id": "22243964", - "title": "Five years of GWAS discovery.", - "authors": "Peter M Visscher,Matthew A Brown,Mark I McCarthy,Jian Yang", - "abstract": "The past five years have seen many scientific and biological discoveries made through the experimental design of genome-wide association studies (GWASs). These studies were aimed at detecting variants at genomic loci that are associated with complex traits in the population and, in particular, at detecting associations between common single-nucleotide polymorphisms (SNPs) and common diseases such as heart disease, diabetes, auto-immune diseases, and psychiatric disorders. We start by giving a number of quotes from scientists and journalists about perceived problems with GWASs. We will then briefly give the history of GWASs and focus on the discoveries made through this experimental design, what those discoveries tell us and do not tell us about the genetics and biology of complex traits, and what immediate utility has come out of these studies. Rather than giving an exhaustive review of all reported findings for all diseases and other complex traits, we focus on the results for auto-immune diseases and metabolic diseases. We return to the perceived failure or disappointment about GWASs in the concluding section.", - "journal_title": "American journal of human genetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/22243964/" - } - ], - "5d7a863d-1811-4eea-9fb0-fbc3067aa664": [ - { - "pub_id": "25532137", - "title": "Selecting causal genes from genome-wide association studies via functionally coherent subnetworks.", - "authors": "Murat Ta\u015fan,Gabriel Musso,Tong Hao,Marc Vidal,Calum A MacRae,Frederick P Roth", - "abstract": "Genome-wide association (GWA) studies have linked thousands of loci to human diseases, but the causal genes and variants at these loci generally remain unknown. Although investigators typically focus on genes closest to the associated polymorphisms, the causal gene is often more distal. Reliance on published work to prioritize candidates is biased toward well-characterized genes. We describe a 'prix fixe' strategy and software that uses genome-scale shared-function networks to identify sets of mutually functionally related genes spanning multiple GWA loci. Using associations from \u223c100 GWA studies covering ten cancer types, our approach outperformed the common alternative strategy in ranking known cancer genes. As more GWA loci are discovered, the strategy will have increased power to elucidate the causes of human disease.", - "journal_title": "Nature methods", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/25532137/" - } - ], - "455a2e62-ffcd-4e70-8c9a-95928904d697": [ - { - "pub_id": "25102153", - "title": "A population genetic signal of polygenic adaptation.", - "authors": "Jeremy J Berg,Graham Coop", - "abstract": "Adaptation in response to selection on polygenic phenotypes may occur via subtle allele frequencies shifts at many loci. Current population genomic techniques are not well posed to identify such signals. In the past decade, detailed knowledge about the specific loci underlying polygenic traits has begun to emerge from genome-wide association studies (GWAS). Here we combine this knowledge from GWAS with robust population genetic modeling to identify traits that may have been influenced by local adaptation. We exploit the fact that GWAS provide an estimate of the additive effect size of many loci to estimate the mean additive genetic value for a given phenotype across many populations as simple weighted sums of allele frequencies. We use a general model of neutral genetic value drift for an arbitrary number of populations with an arbitrary relatedness structure. Based on this model, we develop methods for detecting unusually strong correlations between genetic values and specific environmental variables, as well as a generalization of [Q(ST)/F(ST)] comparisons to test for over-dispersion of genetic values among populations. Finally we lay out a framework to identify the individual populations or groups of populations that contribute to the signal of overdispersion. These tests have considerably greater power than their single locus equivalents due to the fact that they look for positive covariance between like effect alleles, and also significantly outperform methods that do not account for population structure. We apply our tests to the Human Genome Diversity Panel (HGDP) dataset using GWAS data for height, skin pigmentation, type 2 diabetes, body mass index, and two inflammatory bowel disease datasets. This analysis uncovers a number of putative signals of local adaptation, and we discuss the biological interpretation and caveats of these results.", - "journal_title": "PLoS genetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/25102153/" - } - ], - "84b037c5-8e75-434f-aad1-d270257963f6": [ - { - "pub_id": "24752583", - "title": "The genetic basis of obesity-associated type 2 diabetes (diabesity) in polygenic mouse models.", - "authors": "Hans-Georg Joost,Annette Sch\u00fcrmann", - "abstract": "Obesity-associated diabetes (\"diabesity\") in mouse strains is characterized by severe insulin resistance, hyperglycaemia and progressive failure, and loss of beta cells. This condition is observed in inbred obese mouse strains such as the New Zealand Obese (NZO/HlLt and NZO/HlBomDife) or the TALLYHO/JngJ mouse. In lean strains such as C57BLKS/J, BTBR T+tf/J or DBA/2 J carrying diabetes susceptibility genes (\"diabetes susceptible\" background), it can be induced by introgression of the obesity-causing mutations Lep <ob> (ob) or Lepr <db> (db). Outcross populations of these models have been employed in the genome-wide search for mouse diabetes genes, and have led to positional cloning of the strong candidates Pctp, Tbc1d1, Zfp69, and Ifi202b (NZO-derived obesity) and Sorcs1, Lisch-like, Tomosyn-2, App, Tsc2, and Ube2l6 (obesity caused by the ob or db mutation). Some of these genes have been shown to play a role in the regulation of the human glucose or lipid metabolism. Thus, dissection of the genetic basis of obesity and diabetes in mouse models can identify regulatory mechanisms that are relevant for the human disease.", - "journal_title": "Mammalian genome : official journal of the International Mammalian Genome Society", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/24752583/" - } - ], - "845adde7-823a-4bfc-9f5e-7082d2e26102": [ - { - "pub_id": "22492527", - "title": "Reduced insulin exocytosis in human pancreatic \u03b2-cells with gene variants linked to type 2 diabetes.", - "authors": "Anders H Rosengren,Matthias Braun,Taman Mahdi,Sofia A Andersson,Mary E Travers,Makoto Shigeto,Enming Zhang,Peter Almgren,Claes Ladenvall,Annika S Axelsson,Anna Edlund,Morten Gram Pedersen,Anna Jonsson,Reshma Ramracheya,Yunzhao Tang,Jonathan N Walker,Amy Barrett,Paul R V Johnson,Valeriya Lyssenko,Mark I McCarthy,Leif Groop,Albert Salehi,Anna L Gloyn,Erik Renstr\u00f6m,Patrik Rorsman,Lena Eliasson", - "abstract": "The majority of genetic risk variants for type 2 diabetes (T2D) affect insulin secretion, but the mechanisms through which they influence pancreatic islet function remain largely unknown. We functionally characterized human islets to determine secretory, biophysical, and ultrastructural features in relation to genetic risk profiles in diabetic and nondiabetic donors. Islets from donors with T2D exhibited impaired insulin secretion, which was more pronounced in lean than obese diabetic donors. We assessed the impact of 14 disease susceptibility variants on measures of glucose sensing, exocytosis, and structure. Variants near TCF7L2 and ADRA2A were associated with reduced glucose-induced insulin secretion, whereas susceptibility variants near ADRA2A, KCNJ11, KCNQ1, and TCF7L2 were associated with reduced depolarization-evoked insulin exocytosis. KCNQ1, ADRA2A, KCNJ11, HHEX/IDE, and SLC2A2 variants affected granule docking. We combined our results to create a novel genetic risk score for \u03b2-cell dysfunction that includes aberrant granule docking, decreased Ca(2+) sensitivity of exocytosis, and reduced insulin release. Individuals with a high risk score displayed an impaired response to intravenous glucose and deteriorating insulin secretion over time. Our results underscore the importance of defects in \u03b2-cell exocytosis in T2D and demonstrate the potential of cellular phenotypic characterization in the elucidation of complex genetic disorders.", - "journal_title": "Diabetes", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/22492527/" - } - ], - "09f7d532-8f7d-4b23-9049-7548fd697137": [ - { - "pub_id": "20013250", - "title": "Genomic research in rat models of kidney disease.", - "authors": "Yoram Yagil,Chana Yagil", - "abstract": "Current understanding of the mechanisms underlying renal disease in humans is incomplete. Consequently, our ability to prevent the occurrence of renal disease or treat kidney disease once it develops is limited. There are objective difficulties in investigating kidney disease directly in humans, leading investigators to resort to experimental animal models that simulate renal disease in humans. Animal models have thus been a tool of major importance in the study of normal renal physiology and have been crucial in shedding light on the complex mechanisms involved in normal kidney function and in our current understanding of and ability to treat renal disease. Among the animal models, rat has been the preferred and most commonly used species for the investigation of renal disease. This chapter reviews what has been achieved over the years, using rat as a tool for the investigation of renal disease in humans, focusing on the contribution of rat genetics and genomics to the elucidation of the mechanisms underlying the pathophysiology of the major types of renal disease, including primary and secondary renal diseases.", - "journal_title": "Methods in molecular biology (Clifton, N.J.)", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/20013250/" - } - ], - "602b3b63-ede6-44ca-a790-9e39b08bc29a": [ - { - "pub_id": "21175269", - "title": "Genetic variations in the FTO gene are associated with type 2 diabetes and obesity in south Indians (CURES-79).", - "authors": "Kandaswamy Ramya,Venkatesan Radha,Saurabh Ghosh,Partha P Majumder,Viswanathan Mohan", - "abstract": "the present study investigated the association of six variants-rs9940128, rs7193144, and rs8050136 (in intron 1), rs918031 and rs1588413 (in intron 8), and rs11076023 (3' untranslated region)-across three regulatory regions of the fat mass and obesity-associated (FTO) gene with obesity and type 2 diabetes mellitus (T2DM) in a South Indian population. unrelated study subjects (n\u2009=\u20091,852; 1,001 normal glucose-tolerant [NGT] controls and 851 cases [T2DM]) were randomly selected from the Chennai Urban Rural Epidemiological Study (CURES). Genotyping was done by the polymerase chain reaction-restriction fragment length polymorphism method, and 20% of samples were sequenced to validate the genotypes obtained. Haplotype analysis was also carried out. the three polymorphisms rs9940128 A/G, rs1588413 C/T, and rs11076023 A/T of the FTO gene were associated with T2DM in our study population. The rs8050136 C/A variant was associated with obesity, and its association with T2DM was also mediated through obesity. The rs1588413 C/T variant showed an association with obesity in the total study subjects, but when the NGT subjects alone were analyzed, the association with obesity was lost. The haplotype ACCTCT confers a lower risk of T2DM in this South Indian population. among South Indians, the rs9940128 A/G, rs11076023 A/T, and rs1588413 C/T variants of the FTO gene were associated with T2DM, whereas the rs8050136 C/A variant was associated with obesity.", - "journal_title": "Diabetes technology & therapeutics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/21175269/" - } - ], - "cdc51e45-5165-414e-969f-bc8bcec1d26c": [ - { - "pub_id": "22891504", - "title": "Development of the essential genetic and genomic competencies for nurses with graduate degrees.", - "authors": "Karen E Greco,Susan Tinley,Diane Seibert", - "abstract": "Scientific advances in genetics and genomics are rapidly redefining our understanding of health and illness and creating a significant shift in practice for all health care disciplines. Nurses educated at the graduate level are well-prepared to assume clinical and leadership roles in health care systems and must also be prepared to assume similar roles related to genetic/genomic health care. This chapter describes the processes used to create a consensus document identifying the genetic/genomic competencies essential for nurses prepared at the graduate level. Three groups were involved in the competency development; a steering committee provided leadership and used qualitative methods to review and analyze pertinent source documents and create an initial competency draft; an advisory board evaluated and revised the draft, and a consensus panel refined and validated the final set of competencies. The concensus process resulted in 38 competencies organized under the following categories: risk assessment and interpretation; genetic education, counseling, testing and results interpretation; clinical management; ethical, legal, and social implications; professional role; leadership, and research. These competencies apply to all individuals functioning at the graduate level in nursing, including but not limited to advanced practice registered nurses, clinical nurse leaders, nurse educators, nurse administrators, and nurse scientists and are intended to inform and guide their practice.", - "journal_title": "Annual review of nursing research", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/22891504/" - } - ], - "552070a0-c161-4b52-b0a3-d3ad547824b4": [ - { - "pub_id": "21112374", - "title": "AluYb8 insertion in the MUTYH gene is related to increased 8-OHdG in genomic DNA and could be a risk factor for type 2 diabetes in a Chinese population.", - "authors": "Huimei Chen,Caixia Sun,Wenwen Guo,Ran Meng,Hong Du,Qiufeng Qi,Xin Gu,Lirong Li,Kui Zhang,Dalong Zhu,Yaping Wang", - "abstract": "The Mutyh DNA glycosylase is involved in the repair of oxidized DNA bases. Because oxidative stress may contribute to increased diabetes risk, the common variant of the MUTYH gene (AluYb8MUTYH) was investigated for its possible role in type 2 diabetes mellitus (T2DM). A total of 565 T2DM patients and 565 healthy subjects from China were enrolled in a case-control study. The distribution of AluYb8MUTYH differed in diabetic patients from controls, with a moderately increased percentage of the mutant allele (P) (44.7% versus 40.3%, P = 0.033, OR = 1.199). However, this distribution was similar between the diabetic early-onset and late-onset subgroups. Another 66 T2DM patients were further evaluated for 8-hydroxy-2'deoxyguanosine (8-OHdG) levels in leukocytic DNA. The average value of 8-OHdG/10(6) dG was 10.4 in patients with the wild-type genotype, 15.9 in heterozygotes, and 22.3 in homozygotes with the variation (P < 0.001, compared with the wild-type). Therefore, the AluYb8MUTYH polymorphism could be a novel genetic risk factor for T2DM, and accumulated 8-OHdG could contribute to this disease.", - "journal_title": "Molecular and cellular endocrinology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/21112374/" - } - ], - "2c97b26f-3298-4ab9-8a00-6184f4c68290": [ - { - "pub_id": "24604425", - "title": "Evidence for the presence of somatic mitochondrial DNA mutations in right atrial appendage tissues of coronary artery disease patients.", - "authors": "Kavitha Matam,Noor Ahmad Shaik,Sunil Aggarwal,Sameer Diwale,Babajan Banaganapalli,Jumana Yousuf Al-Aama,Ramu Elango,Pragna Rao,Qurratulain Hasan", - "abstract": "Coronary artery disease (CAD) is a multifactorial disease with the underlying involvement of environment, life style and nuclear genetics. However, the role of extranuclear genetic material in terms of somatically acquired mutations in mitochondrial tRNA and protein coding genes in the initiation or progression of CAD is not well defined. Hence, in the present study, right atrial appendage tissues and matched blood samples of 150 CAD patients were screened for mutations in nucleotide regions encompassing the Cytochrome c oxidase subunit II (MT-CO2), tRNA lysine (MT-TK), ATP synthase F0 subunit 8 (MT-ATP8) and Cytochrome b (MT-CYB) genes of mitochondrial DNA. We have found 9 different somatic mutations in 6 % of the CAD patients. Out of these mutations, 4 each were localized in MT-TK gene (T8324A, A8326G, A8331G and A8344G) and MT-CYB genes (T15062C, C15238A, T15378G and C15491G) in addition to one mutation in non-coding region 7 (A8270T) of mitochondrial genome. In addition, we noticed that majority (85.3 %) of CAD patients showed double repeats of germ-line \"CCCCCTCTA\" intergenic sequence between MT-CO2 and MT-TK genes. Our in-silico investigations of missense mutations revealed that they may alter the free energy and stability of polypeptide chains of MT-CYB protein of complex III of mitochondrial respiratory chain. Based on our study findings, we hypothesize that the somatically acquired variations in MT-TK and MT-CYB genes may negatively impact the energy metabolism of cardiomyocytes in right atrial appendage tissues and contribute in the cardiac dysfunction among CAD patients. In conclusion, our findings may be likely to have potential implications in understanding the disease pathophysiology, diagnosis as well as for the better therapeutic management of CAD patients.", - "journal_title": "Molecular genetics and genomics : MGG", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/24604425/" - } - ], - "9c9cc0b3-5dde-4077-ae41-1410db9aeb24": [ - { - "pub_id": "27980006", - "title": "Differentiation of Diabetes by Pathophysiology, Natural History, and Prognosis.", - "authors": "Jay S Skyler,George L Bakris,Ezio Bonifacio,Tamara Darsow,Robert H Eckel,Leif Groop,Per-Henrik Groop,Yehuda Handelsman,Richard A Insel,Chantal Mathieu,Allison T McElvaine,Jerry P Palmer,Alberto Pugliese,Desmond A Schatz,Jay M Sosenko,John P H Wilding,Robert E Ratner", - "abstract": "The American Diabetes Association, JDRF, the European Association for the Study of Diabetes, and the American Association of Clinical Endocrinologists convened a research symposium, \"The Differentiation of Diabetes by Pathophysiology, Natural History and Prognosis\" on 10-12 October 2015. International experts in genetics, immunology, metabolism, endocrinology, and systems biology discussed genetic and environmental determinants of type 1 and type 2 diabetes risk and progression, as well as complications. The participants debated how to determine appropriate therapeutic approaches based on disease pathophysiology and stage and defined remaining research gaps hindering a personalized medical approach for diabetes to drive the field to address these gaps. The authors recommend a structure for data stratification to define the phenotypes and genotypes of subtypes of diabetes that will facilitate individualized treatment.", - "journal_title": "Diabetes", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/27980006/" - } - ], - "f650f2c3-aa1b-4b1e-98c6-b15331eee667": [ - { - "pub_id": "22806142", - "title": "Systems analysis of eleven rodent disease models reveals an inflammatome signature and key drivers.", - "authors": "I-Ming Wang,Bin Zhang,Xia Yang,Jun Zhu,Serguei Stepaniants,Chunsheng Zhang,Qingying Meng,Mette Peters,Yudong He,Chester Ni,Deborah Slipetz,Michael A Crackower,Hani Houshyar,Christopher M Tan,Ernest Asante-Appiah,Gary O'Neill,Mingjuan Jane Luo,Rolf Thieringer,Jeffrey Yuan,Chi-Sung Chiu,Pek Yee Lum,John Lamb,Yves Boie,Hilary A Wilkinson,Eric E Schadt,Hongyue Dai,Christopher Roberts", - "abstract": "Common inflammatome gene signatures as well as disease-specific signatures were identified by analyzing 12 expression profiling data sets derived from 9 different tissues isolated from 11 rodent inflammatory disease models. The inflammatome signature significantly overlaps with known drug targets and co-expressed gene modules linked to metabolic disorders and cancer. A large proportion of genes in this signature are tightly connected in tissue-specific Bayesian networks (BNs) built from multiple independent mouse and human cohorts. Both the inflammatome signature and the corresponding consensus BNs are highly enriched for immune response-related genes supported as causal for adiposity, adipokine, diabetes, aortic lesion, bone, muscle, and cholesterol traits, suggesting the causal nature of the inflammatome for a variety of diseases. Integration of this inflammatome signature with the BNs uncovered 151 key drivers that appeared to be more biologically important than the non-drivers in terms of their impact on disease phenotypes. The identification of this inflammatome signature, its network architecture, and key drivers not only highlights the shared etiology but also pinpoints potential targets for intervention of various common diseases.", - "journal_title": "Molecular systems biology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/22806142/" - } - ], - "d0f94be6-ea2f-41ca-841a-3805822e8a28": [ - { - "pub_id": "23729657", - "title": "The non-obese diabetic mouse sequence, annotation and variation resource: an aid for investigating type 1 diabetes.", - "authors": "Charles A Steward,Jose M Gonzalez,Steve Trevanion,Dan Sheppard,Giselle Kerry,James G R Gilbert,Linda S Wicker,Jane Rogers,Jennifer L Harrow", - "abstract": "Model organisms are becoming increasingly important for the study of complex diseases such as type 1 diabetes (T1D). The non-obese diabetic (NOD) mouse is an experimental model for T1D having been bred to develop the disease spontaneously in a process that is similar to humans. Genetic analysis of the NOD mouse has identified around 50 disease loci, which have the nomenclature Idd for insulin-dependent diabetes, distributed across at least 11 different chromosomes. In total, 21 Idd regions across 6 chromosomes, that are major contributors to T1D susceptibility or resistance, were selected for finished sequencing and annotation at the Wellcome Trust Sanger Institute. Here we describe the generation of 40.4 mega base-pairs of finished sequence from 289 bacterial artificial chromosomes for the NOD mouse. Manual annotation has identified 738 genes in the diabetes sensitive NOD mouse and 765 genes in homologous regions of the diabetes resistant C57BL/6J reference mouse across 19 candidate Idd regions. This has allowed us to call variation consequences between homologous exonic sequences for all annotated regions in the two mouse strains. We demonstrate the importance of this resource further by illustrating the technical difficulties that regions of inter-strain structural variation between the NOD mouse and the C57BL/6J reference mouse can cause for current next generation sequencing and assembly techniques. Furthermore, we have established that the variation rate in the Idd regions is 2.3 times higher than the mean found for the whole genome assembly for the NOD/ShiLtJ genome, which we suggest reflects the fact that positive selection for functional variation in immune genes is beneficial in regard to host defence. In summary, we provide an important resource, which aids the analysis of potential causative genes involved in T1D susceptibility. Database URLs: http://www.sanger.ac.uk/resources/mouse/nod/; http://vega-previous.sanger.ac.uk/info/data/mouse_regions.html#Idd", - "journal_title": "Database : the journal of biological databases and curation", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/23729657/" - } - ], - "31281794-5c04-4274-8ae7-e3f9ac0bfef5": [ - { - "pub_id": "25751624", - "title": "Fine mapping of type 1 diabetes susceptibility loci and evidence for colocalization of causal variants with lymphoid gene enhancers.", - "authors": "Suna Onengut-Gumuscu,Wei-Min Chen,Oliver Burren,Nick J Cooper,Aaron R Quinlan,Josyf C Mychaleckyj,Emily Farber,Jessica K Bonnie,Michal Szpak,Ellen Schofield,Premanand Achuthan,Hui Guo,Mary D Fortune,Helen Stevens,Neil M Walker,Lucas D Ward,Anshul Kundaje,Manolis Kellis,Mark J Daly,Jeffrey C Barrett,Jason D Cooper,Panos Deloukas, ,John A Todd,Chris Wallace,Patrick Concannon,Stephen S Rich", - "abstract": "Genetic studies of type 1 diabetes (T1D) have identified 50 susceptibility regions, finding major pathways contributing to risk, with some loci shared across immune disorders. To make genetic comparisons across autoimmune disorders as informative as possible, a dense genotyping array, the Immunochip, was developed, from which we identified four new T1D-associated regions (P < 5 \u00d7 10(-8)). A comparative analysis with 15 immune diseases showed that T1D is more similar genetically to other autoantibody-positive diseases, significantly most similar to juvenile idiopathic arthritis and significantly least similar to ulcerative colitis, and provided support for three additional new T1D risk loci. Using a Bayesian approach, we defined credible sets for the T1D-associated SNPs. The associated SNPs localized to enhancer sequences active in thymus, T and B cells, and CD34(+) stem cells. Enhancer-promoter interactions can now be analyzed in these cell types to identify which particular genes and regulatory sequences are causal.", - "journal_title": "Nature genetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/25751624/" - } - ], - "82148af9-b60e-40a0-8450-47970498e13d": [ - { - "pub_id": "21085649", - "title": "Metabolic footprint of diabetes: a multiplatform metabolomics study in an epidemiological setting.", - "authors": "Karsten Suhre,Christa Meisinger,Angela D\u00f6ring,Elisabeth Altmaier,Petra Belcredi,Christian Gieger,David Chang,Michael V Milburn,Walter E Gall,Klaus M Weinberger,Hans-Werner Mewes,Martin Hrab\u00e9 de Angelis,H-Erich Wichmann,Florian Kronenberg,Jerzy Adamski,Thomas Illig", - "abstract": "Metabolomics is the rapidly evolving field of the comprehensive measurement of ideally all endogenous metabolites in a biological fluid. However, no single analytic technique covers the entire spectrum of the human metabolome. Here we present results from a multiplatform study, in which we investigate what kind of results can presently be obtained in the field of diabetes research when combining metabolomics data collected on a complementary set of analytical platforms in the framework of an epidemiological study. 40 individuals with self-reported diabetes and 60 controls (male, over 54 years) were randomly selected from the participants of the population-based KORA (Cooperative Health Research in the Region of Augsburg) study, representing an extensively phenotyped sample of the general German population. Concentrations of over 420 unique small molecules were determined in overnight-fasting blood using three different techniques, covering nuclear magnetic resonance and tandem mass spectrometry. Known biomarkers of diabetes could be replicated by this multiple metabolomic platform approach, including sugar metabolites (1,5-anhydroglucoitol), ketone bodies (3-hydroxybutyrate), and branched chain amino acids. In some cases, diabetes-related medication can be detected (pioglitazone, salicylic acid). Our study depicts the promising potential of metabolomics in diabetes research by identification of a series of known and also novel, deregulated metabolites that associate with diabetes. Key observations include perturbations of metabolic pathways linked to kidney dysfunction (3-indoxyl sulfate), lipid metabolism (glycerophospholipids, free fatty acids), and interaction with the gut microflora (bile acids). Our study suggests that metabolic markers hold the potential to detect diabetes-related complications already under sub-clinical conditions in the general population.", - "journal_title": "PloS one", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/21085649/" - } - ], - "d3ea9177-082e-4ab0-a226-7244192c2c25": [ - { - "pub_id": "25691689", - "title": "Quantitative serum nuclear magnetic resonance metabolomics in cardiovascular epidemiology and genetics.", - "authors": "Pasi Soininen,Antti J Kangas,Peter W\u00fcrtz,Teemu Suna,Mika Ala-Korpela", - "abstract": "Metabolomics is becoming common in epidemiology due to recent developments in quantitative profiling technologies and appealing results from their applications for understanding health and disease. Our team has developed an automated high-throughput serum NMR metabolomics platform that provides quantitative molecular data on 14 lipoprotein subclasses, their lipid concentrations and composition, apolipoprotein A-I and B, multiple cholesterol and triglyceride measures, albumin, various fatty acids as well as on numerous low-molecular-weight metabolites, including amino acids, glycolysis related measures and ketone bodies. The molar concentrations of these measures are obtained from a single serum sample with costs comparable to standard lipid measurements. We have analyzed almost 250 000 samples from around 100 epidemiological cohorts and biobanks and the new international set-up of multiple platforms will allow an annual throughput of more than 250 000 samples. The molecular data have been used to study type 1 and type 2 diabetes etiology as well as to characterize the molecular reflections of the metabolic syndrome, long-term physical activity, diet and lipoprotein metabolism. The results have revealed new biomarkers for early atherosclerosis, type 2 diabetes, diabetic nephropathy, cardiovascular disease and all-cause mortality. We have also combined genomics and metabolomics in diverse studies. We envision that quantitative high-throughput NMR metabolomics will be incorporated as a routine in large biobanks; this would make perfect sense both from the biological research and cost point of view - the standard output of over 200 molecular measures would vastly extend the relevance of the sample collections and make many separate clinical chemistry assays redundant.", - "journal_title": "Circulation. Cardiovascular genetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/25691689/" - } - ], - "0dba86a4-d6dc-40ab-b4a5-49d02047a388": [ - { - "pub_id": "20144966", - "title": "African ancestry allelic variation at the MYH9 gene contributes to increased susceptibility to non-diabetic end-stage kidney disease in Hispanic Americans.", - "authors": "Doron M Behar,Saharon Rosset,Shay Tzur,Sara Selig,Guennady Yudkovsky,Sivan Bercovici,Jeffrey B Kopp,Cheryl A Winkler,George W Nelson,Walter G Wasser,Karl Skorecki", - "abstract": "Recent studies identified MYH9 as a major susceptibility gene for common forms of non-diabetic end-stage kidney disease (ESKD). A set of African ancestry DNA sequence variants comprising the E-1 haplotype, was significantly associated with ESKD. In order to determine whether African ancestry variants are also associated with disease susceptibility in admixed populations with differing genomic backgrounds, we genotyped a total of 1425 African and Hispanic American subjects comprising dialysis patients with diabetic and non-diabetic ESKD and controls, using 42 single nucleotide polymorphisms (SNPs) within the MYH9 gene and 40 genome-wide and 38 chromosome 22 ancestry informative markers. Following ancestry correction, logistic regression demonstrated that three of the E-1 SNPs are also associated with non-diabetic ESKD in the new sample sets of both African and Hispanic Americans, with a stronger association in Hispanic Americans. We also identified MYH9 SNPs that are even more powerfully associated with the disease phenotype than the E-1 SNPs. These newly associated SNPs, could be divided into those comprising a haplotype termed S-1 whose association was significant under a recessive or additive inheritance mode (rs5750248, OR 4.21, P < 0.01, Hispanic Americans, recessive), and those comprising a haplotype termed F-1 whose association was significant under a dominant or additive inheritance mode (rs11912763, OR 4.59, P < 0.01, Hispanic Americans, dominant). These findings strengthen the contention that a sequence variant of MYH9, common in populations with varying degrees of African ancestry admixture, and in strong linkage disequilibrium with the associated SNPs and haplotypes reported herein, strongly predisposes to non-diabetic ESKD.", - "journal_title": "Human molecular genetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/20144966/" - } - ], - "18d88787-096b-4fc1-ad4e-3d1b1f3a90d9": [ - { - "pub_id": "28655017", - "title": "Prevalence and Ethnic Pattern of Diabetes and Prediabetes in China in 2013.", - "authors": "Limin Wang,Pei Gao,Mei Zhang,Zhengjing Huang,Dudan Zhang,Qian Deng,Yichong Li,Zhenping Zhao,Xueying Qin,Danyao Jin,Maigeng Zhou,Xun Tang,Yonghua Hu,Linhong Wang", - "abstract": "Previous studies have shown increasing prevalence of diabetes in China, which now has the world's largest diabetes epidemic. To estimate the recent prevalence and to investigate the ethnic variation of diabetes and prediabetes in the Chinese adult population. A nationally representative cross-sectional survey in 2013 in mainland China, which consisted of 170\u202f287 participants. Fasting plasma glucose and hemoglobin A1c levels were measured for all participants. A 2-hour oral glucose tolerance test was conducted for all participants without diagnosed diabetes. Primary outcomes were total diabetes and prediabetes defined according to the 2010 American Diabetes Association criteria. Awareness and treatment were also evaluated. Hemoglobin A1c concentration of less than 7.0% among treated diabetes patients was considered adequate glycemic control. Minority ethnic groups in China with at least 1000 participants (Tibetan, Zhuang, Manchu, Uyghur, and Muslim) were compared with Han participants. Among the Chinese adult population, the estimated standardized prevalence of total diagnosed and undiagnosed diabetes was 10.9% (95% CI, 10.4%-11.5%); that of diagnosed diabetes, 4.0% (95% CI, 3.6%-4.3%); and that of prediabetes, 35.7% (95% CI, 34.1%-37.4%). Among persons with diabetes, 36.5% (95% CI, 34.3%-38.6%) were aware of their diagnosis and 32.2% (95% CI, 30.1%-34.2%) were treated; 49.2% (95% CI, 46.9%-51.5%) of patients treated had adequate glycemic control. Tibetan and Muslim Chinese had significantly lower crude prevalence of diabetes than Han participants (14.7% [95% CI, 14.6%-14.9%] for Han, 4.3% [95% CI, 3.5%-5.0%] for Tibetan, and 10.6% [95% CI, 9.3%-11.9%] for Muslim; P\u2009<\u2009.001 for Tibetan and Muslim compared with Han). In the multivariable logistic models, the adjusted odds ratios compared with Han participants were 0.42 (95% CI, 0.35-0.50) for diabetes and 0.77 (95% CI, 0.71-0.84) for prediabetes for Tibetan Chinese and 0.73 (95% CI, 0.63-0.85) for diabetes and 0.78 (95% CI, 0.71-0.86) for prediabetes in Muslim Chinese. Among adults in China, the estimated overall prevalence of diabetes was 10.9%, and that for prediabetes was 35.7%. Differences from previous estimates for 2010 may be due to an alternate method of measuring hemoglobin A1c.", - "journal_title": "JAMA", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/28655017/" - } - ], - "be313a5a-60f9-4fe7-a1e7-e89cc194a6dc": [ - { - "pub_id": "23010998", - "title": "Novel biomarkers for pre-diabetes identified by metabolomics.", - "authors": "Rui Wang-Sattler,Zhonghao Yu,Christian Herder,Ana C Messias,Anna Floegel,Ying He,Katharina Heim,Monica Campillos,Christina Holzapfel,Barbara Thorand,Harald Grallert,Tao Xu,Erik Bader,Cornelia Huth,Kirstin Mittelstrass,Angela D\u00f6ring,Christa Meisinger,Christian Gieger,Cornelia Prehn,Werner Roemisch-Margl,Maren Carstensen,Lu Xie,Hisami Yamanaka-Okumura,Guihong Xing,Uta Ceglarek,Joachim Thiery,Guido Giani,Heiko Lickert,Xu Lin,Yixue Li,Heiner Boeing,Hans-Georg Joost,Martin Hrab\u00e9 de Angelis,Wolfgang Rathmann,Karsten Suhre,Holger Prokisch,Annette Peters,Thomas Meitinger,Michael Roden,H-Erich Wichmann,Tobias Pischon,Jerzy Adamski,Thomas Illig", - "abstract": "Type 2 diabetes (T2D) can be prevented in pre-diabetic individuals with impaired glucose tolerance (IGT). Here, we have used a metabolomics approach to identify candidate biomarkers of pre-diabetes. We quantified 140 metabolites for 4297 fasting serum samples in the population-based Cooperative Health Research in the Region of Augsburg (KORA) cohort. Our study revealed significant metabolic variation in pre-diabetic individuals that are distinct from known diabetes risk indicators, such as glycosylated hemoglobin levels, fasting glucose and insulin. We identified three metabolites (glycine, lysophosphatidylcholine (LPC) (18:2) and acetylcarnitine) that had significantly altered levels in IGT individuals as compared to those with normal glucose tolerance, with P-values ranging from 2.4\u00d710(-4) to 2.1\u00d710(-13). Lower levels of glycine and LPC were found to be predictors not only for IGT but also for T2D, and were independently confirmed in the European Prospective Investigation into Cancer and Nutrition (EPIC)-Potsdam cohort. Using metabolite-protein network analysis, we identified seven T2D-related genes that are associated with these three IGT-specific metabolites by multiple interactions with four enzymes. The expression levels of these enzymes correlate with changes in the metabolite concentrations linked to diabetes. Our results may help developing novel strategies to prevent T2D.", - "journal_title": "Molecular systems biology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/23010998/" - } - ], - "7b7ce30c-f398-4b0e-bcb6-52f2644201fd": [ - { - "pub_id": "20587799", - "title": "Genetics of type 1 diabetes: what's next?", - "authors": "Flemming Pociot,Beena Akolkar,Patrick Concannon,Henry A Erlich,C\u00e9cile Julier,Grant Morahan,Concepcion R Nierras,John A Todd,Stephen S Rich,J\u00f8rn Nerup", - "abstract": "", - "journal_title": "Diabetes", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/20587799/" - } - ], - "ab97c3f0-f7a4-439b-8706-842826aa529f": [ - { - "pub_id": "28216801", - "title": "Genomic Justice for Native Americans: Impact of the Havasupai Case on Genetic Research.", - "authors": "Nanibaa' A Garrison", - "abstract": "In 2004, the Havasupai Tribe filed a lawsuit against the Arizona Board of Regents and Arizona State University (ASU) researchers upon discovering their DNA samples, initially collected for genetic studies on type 2 diabetes, had been used in several other genetic studies. The lawsuit reached a settlement in April 2010 that included monetary compensation and return of DNA samples to the Havasupai but left no legal precedent for researchers. Through semistructured interviews, institutional review board (IRB) chairs and human genetics researchers at US research institutions revealed their perspectives on the Havasupai lawsuit. For interviewees, the suit drew attention to indigenous concerns over genetic studies and increased their awareness of indigenous views. However, interviewees perceived no direct impact from the Havasupai case on their work; if they did, it was the perceived need to safeguard themselves by obtaining broad consent or shying away from research with indigenous communities altogether, raising important questions of justice for indigenous and minority participants. If researchers and IRBs do not change their practices in light of this case, these populations will likely continue to be excluded from a majority of research studies and left with less access to resources and potential benefit from genetic research participation.", - "journal_title": "Science, technology & human values", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/28216801/" - } - ], - "96942da5-2223-4afc-b2a6-09ebf64b3c69": [ - { - "pub_id": "25819087", - "title": "Genome-wide linkage and positional association analyses identify associations of novel AFF3 and NTM genes with triglycerides: the GenSalt study.", - "authors": "Changwei Li,Lydia A L Bazzano,Dabeeru C Rao,James E Hixson,Jiang He,Dongfeng Gu,Charles C Gu,Lawrence C Shimmin,Cashell E Jaquish,Karen Schwander,De-Pei Liu,Jianfeng Huang,Fanghong Lu,Jie Cao,Shen Chong,Xiangfeng Lu,Tanika N Kelly", - "abstract": "We conducted a genome-wide linkage scan and positional association study to identify genes and variants influencing blood lipid levels among participants of the Genetic Epidemiology Network of Salt-Sensitivity (GenSalt) study. The GenSalt study was conducted among 1906 participants from 633 Han Chinese families. Lipids were measured from overnight fasting blood samples using standard methods. Multipoint quantitative trait genome-wide linkage scans were performed on the high-density lipoprotein, low-density lipoprotein, and log-transformed triglyceride phenotypes. Using dense panels of single nucleotide polymorphisms (SNPs), single-marker and gene-based association analyses were conducted to follow-up on promising linkage signals. Additive associations between each SNP and lipid phenotypes were tested using mixed linear regression models. Gene-based analyses were performed by combining P-values from single-marker analyses within each gene using the truncated product method (TPM). Significant associations were assessed for replication among 777 Asian participants of the Multi-ethnic Study of Atherosclerosis (MESA). Bonferroni correction was used to adjust for multiple testing. In the GenSalt study, suggestive linkage signals were identified at 2p11.2\u20122q12.1 [maximum multipoint LOD score (MML) = 2.18 at 2q11.2] and 11q24.3\u201211q25 (MML = 2.29 at 11q25) for the log-transformed triglyceride phenotype. Follow-up analyses of these two regions revealed gene-based associations of charged multivesicular body protein 3 (CHMP3), ring finger protein 103 (RNF103), AF4/FMR2 family, member 3 (AFF3), and neurotrimin (NTM) with triglycerides (P = 4 \u00d7 10(-4), 1.00 \u00d7 10(-5), 2.00 \u00d7 10(-5), and 1.00 \u00d7 10(-7), respectively). Both the AFF3 and NTM triglyceride associations were replicated among MESA study participants (P = 1.00 \u00d7 10(-7) and 8.00 \u00d7 10(-5), respectively). Furthermore, NTM explained the linkage signal on chromosome 11. In conclusion, we identified novel genes associated with lipid phenotypes in linkage regions on chromosomes 2 and 11.", - "journal_title": "Journal of genetics and genomics = Yi chuan xue bao", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/25819087/" - } - ], - "553ae95d-0a2b-4f2a-8123-da9a9e9e7a77": [ - { - "pub_id": "29203323", - "title": "[Association between type 2 diabetes and physical activity in individuals with family history of diabetes].", - "authors": "Fanny Petermann,Ximena D\u00edaz-Mart\u00ednez,\u00c1lex Garrido-M\u00e9ndez,Ana Mar\u00eda Leiva,Mar\u00eda Adela Mart\u00ednez,Carlos Salas,Felipe Poblete-Valderrama,Carlos Celis-Morales", - "abstract": "To investigate whether the association between type 2 diabetes (T2D) and family history of diabetes is modified by the levels of physical activity in the Chilean population. In this study were included 5129 participants from the cross-sectional 2009-2010 National Health Survey. Physical activity level was assessed using the Global Physical Activity Questionnaire and family history of T2D, through self-reporting. The association between diabetes, family history of diabetes and physical activity was determined using logistic regression. The odds of developing T2D in people with family history of this pathology is high, independent of their levels of physical activity and adiposity. Both men and women with family history of T2D have a higher probability of developing T2D. The odds ratio for having T2D was 5,49 (95%CI: 3,85-7,84; p <0,0001) in women, and 8,16 (95%CI: 4,96-13,4; p <0,0001) in men with family history of T2D and low levels of physical activity in comparison to those with high levels of physical activity and without a family history. Given the elevated risk of developing T2D presented by individuals with a family history of this pathology, and the effect of physical activity in reducing such risk, people with family history of diabetes may need higher levels of physical activity to attenuate their susceptibility to T2D.", - "journal_title": "Gaceta sanitaria", - "languages": [ - "spa" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/29203323/" - } - ], - "2e01129f-ddee-4be7-9e89-fda821e449b0": [ - { - "pub_id": "23539138", - "title": "Gene expression drives local adaptation in humans.", - "authors": "Hunter B Fraser", - "abstract": "The molecular basis of adaptation--and, in particular, the relative roles of protein-coding versus gene expression changes--has long been the subject of speculation and debate. Recently, the genotyping of diverse human populations has led to the identification of many putative \"local adaptations\" that differ between populations. Here I show that these local adaptations are over 10-fold more likely to affect gene expression than amino acid sequence. In addition, a novel framework for identifying polygenic local adaptations detects recent positive selection on the expression levels of genes involved in UV radiation response, immune cell proliferation, and diabetes-related pathways. These results provide the first examples of polygenic gene expression adaptation in humans, as well as the first genome-scale support for the hypothesis that changes in gene expression have driven human adaptation.", - "journal_title": "Genome research", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/23539138/" - } - ], - "c5ae22bf-0abc-41ae-a35e-cfdad0156d15": [ - { - "pub_id": "24736664", - "title": "Validation of type 2 diabetes risk variants identified by genome-wide association studies in Han Chinese population: a replication study and meta-analysis.", - "authors": "Yi-Cheng Chang,Pi-Hua Liu,Yu-Hsiang Yu,Shan-Shan Kuo,Tien-Jyun Chang,Yi-Der Jiang,Jiun-Yi Nong,Juey-Jen Hwang,Lee-Ming Chuang", - "abstract": "Several genome-wide association studies (GWAS) involving European populations have successfully identified risk genetic variants associated with type 2 diabetes mellitus (T2DM). However, the effects conferred by these variants in Han Chinese population have not yet been fully elucidated. We analyzed the effects of 24 risk genetic variants with reported associations from European GWAS in 3,040 Han Chinese subjects in Taiwan (including 1,520 T2DM cases and 1,520 controls). The discriminative power of the prediction models with and without genotype scores was compared. We further meta-analyzed the association of these variants with T2DM by pooling all candidate-gene association studies conducted in Han Chinese. Five risk variants in IGF2BP2 (rs4402960, rs1470579), CDKAL1 (rs10946398), SLC30A8 (rs13266634), and HHEX (rs1111875) genes were nominally associated with T2DM in our samples. The odds ratio was 2.22 (95% confidence interval, 1.81-2.73, P<0.0001) for subjects with the highest genetic score quartile (score>34) as compared with subjects with the lowest quartile (score<29). The incoporation of genotype score into the predictive model increased the C-statistics from 0.627 to 0.657 (P<0.0001). These estimates are very close to those observed in European populations. Gene-environment interaction analysis showed a significant interaction between rs13266634 in SLC30A8 gene and age on T2DM risk (P<0.0001). Further meta-analysis pooling 20 studies in Han Chinese confirmed the association of 10 genetic variants in IGF2BP2, CDKAL1, JAZF1, SCL30A8, HHEX, TCF7L2, EXT2, and FTO genes with T2DM. The effect sizes conferred by these risk variants in Han Chinese were similar to those observed in Europeans but the allele frequencies differ substantially between two populations. We confirmed the association of 10 variants identified by European GWAS with T2DM in Han Chinese population. The incorporation of genotype scores into the prediction model led to a small but significant improvement in T2DM prediction.", - "journal_title": "PloS one", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/24736664/" - } - ], - "971d0afa-a50c-409d-942a-ab747a9f4663": [ - { - "pub_id": "21121051", - "title": "The reference human genome demonstrates high risk of type 1 diabetes and other disorders.", - "authors": "Rong Chen,Atul J Butte", - "abstract": "Personal genome resequencing has provided promising lead to personalized medicine. However, due to the limited samples and the lack of case/control design, current interpretation of personal genome sequences has been mainly focused on the identification and functional annotation of the DNA variants that are different from the reference genome. The reference genome was deduced from a collection of DNAs from anonymous individuals, some of whom might be carriers of disease risk alleles. We queried the reference genome against a large high-quality disease-SNP association database and found 3,556 disease-susceptible variants, including 15 rare variants. We assessed the likelihood ratio for risk for the reference genome on 104 diseases and found high risk for type 1 diabetes (T1D) and hypertension. We further demonstrated that the risk of T1D was significantly higher in the reference genome than those in a healthy patient with a whole human genome sequence. We found that the high T1D risk was mainly driven by a R260W mutation in PTPN22 in the reference genome. Therefore, we recommend that the disease-susceptible variants in the reference genome should be taken into consideration and future genome sequences should be interpreted with curated and predicted disease-susceptible loci to assess personal disease risk.", - "journal_title": "Pacific Symposium on Biocomputing. Pacific Symposium on Biocomputing", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/21121051/" - } - ], - "f68b645e-05e0-4640-a3a1-42c66fb4b822": [ - { - "pub_id": "21292721", - "title": "Enterovirus infection and type 1 diabetes mellitus: systematic review and meta-analysis of observational molecular studies.", - "authors": "Wing-Chi G Yeung,William D Rawlinson,Maria E Craig", - "abstract": "To review the association between current enterovirus infection diagnosed with molecular testing and development of autoimmunity or type 1 diabetes. Systematic review and meta-analysis of observational studies, analysed with random effects models. PubMed (until May 2010) and Embase (until May 2010), no language restrictions, studies in humans only; reference lists of identified articles; and contact with authors. Study eligibility criteria Cohort or case-control studies measuring enterovirus RNA or viral protein in blood, stool, or tissue of patients with pre-diabetes and diabetes, with adequate data to calculate an odds ratio and 95% confidence intervals. The 24 papers and two abstracts (all case-control studies) that met the eligibility criteria included 4448 participants. Study design varied greatly, with a high level of statistical heterogeneity. The two separate outcomes were diabetes related autoimmunity or type 1 diabetes. Meta-analysis showed a significant association between enterovirus infection and type 1 diabetes related autoimmunity (odds ratio 3.7, 95% confidence interval 2.1 to 6.8; heterogeneity \u03c7(2)/df = 1.3) and clinical type 1 diabetes (9.8, 5.5 to 17.4; \u03c7(2)/df = 3.2). There is a clinically significant association between enterovirus infection, detected with molecular methods, and autoimmunity/type 1 diabetes. Larger prospective studies would be needed to establish a clear temporal relation between enterovirus infection and the development of autoimmunity and type 1 diabetes.", - "journal_title": "BMJ (Clinical research ed.)", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/21292721/" - } - ], - "f8567357-ce71-4d2a-9e32-036893bb964c": [ - { - "pub_id": "30817261", - "title": "The Mediterranean Diet and Cardiovascular Health.", - "authors": "Miguel A Mart\u00ednez-Gonz\u00e1lez,Alfredo Gea,Miguel Ruiz-Canela", - "abstract": "The Mediterranean diet (MedDiet), abundant in minimally processed plant-based foods, rich in monounsaturated fat from olive oil, but lower in saturated fat, meats, and dairy products, seems an ideal nutritional model for cardiovascular health. Methodological aspects of Mediterranean intervention trials, limitations in the quality of some meta-analyses, and other issues may have raised recent controversies. It remains unclear whether such limitations are important enough as to attenuate the postulated cardiovascular benefits of the MedDiet. We aimed to critically review current evidence on the role of the MedDiet in cardiovascular health. We systematically searched observational prospective cohorts and randomized controlled trials which explicitly reported to assess the effect of the MedDiet on hard cardiovascular end points. We critically assessed all the original cohorts and randomized controlled trials included in the 5 most comprehensive meta-analyses published between 2014 and 2018 and additional prospective studies not included in these meta-analyses, totaling 45 reports of prospective studies (including 4 randomized controlled trials and 32 independent observational cohorts). We addressed the existing controversies on methodology and other issues. Some departures from individual randomization in a subsample of the landmark Spanish trial (PREDIMED [Prevenci\u00f3n con Dieta Mediterr\u00e1nea]) did not represent any clinically meaningful attenuation in the strength of its findings and the results of PREDIMED were robust in a wide range of sensitivity analyses. The criteria for causality were met and potential sources of controversies did not represent any reason to compromise the main findings of the available observational studies and randomized controlled trials. The available evidence is large, strong, and consistent. Better conformity with the traditional MedDiet is associated with better cardiovascular health outcomes, including clinically meaningful reductions in rates of coronary heart disease, ischemic stroke, and total cardiovascular disease.", - "journal_title": "Circulation research", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/30817261/" - } - ], - "3ccc39c5-e0c4-4686-9d08-c3214c57ad41": [ - { - "pub_id": "23907645", - "title": "Recommendations for returning genomic incidental findings? We need to talk!", - "authors": "Wylie Burke,Armand H Matheny Antommaria,Robin Bennett,Jeffrey Botkin,Ellen Wright Clayton,Gail E Henderson,Ingrid A Holm,Gail P Jarvik,Muin J Khoury,Bartha Maria Knoppers,Nancy A Press,Lainie Friedman Ross,Mark A Rothstein,Howard Saal,Wendy R Uhlmann,Benjamin Wilfond,Susan M Wolf,Ron Zimmern", - "abstract": "The American College of Medical Genetics and Genomics recently issued recommendations for reporting incidental findings from clinical whole-genome sequencing and whole-exome sequencing. The recommendations call for evaluating a specific set of genes as part of all whole-genome sequencing/whole-exome sequencing and reporting all pathogenic variants irrespective of patient age. The genes are associated with highly penetrant disorders for which treatment or prevention is available. The effort to generate a list of genes with actionable findings is commendable, but the recommendations raise several concerns. They constitute a call for opportunistic screening, through intentional effort to identify pathogenic variants in specified genes unrelated to the clinical concern that prompted testing. Yet for most of the genes, we lack evidence about the predictive value of testing, genotype penetrance, spectrum of phenotypes, and efficacy of interventions in unselected populations. Furthermore, the recommendations do not allow patients to decline the additional findings, a position inconsistent with established norms. Finally, the recommendation to return adult-onset disease findings when children are tested is inconsistent with current professional consensus, including other policy statements of the American College of Medical Genetics and Genomics. Instead of premature practice recommendations, we call for robust dialogue among stakeholders to define a pathway to normatively sound, evidence-based guidelines.", - "journal_title": "Genetics in medicine : official journal of the American College of Medical Genetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/23907645/" - } - ], - "c9a56d3b-f8bd-44d5-bf2c-a1e2b8d166f3": [ - { - "pub_id": "24567124", - "title": "Comparative genomics analysis of Lactobacillus species associated with weight gain or weight protection.", - "authors": "F Drissi,V Merhej,E Angelakis,A El Kaoutari,F Carri\u00e8re,B Henrissat,D Raoult", - "abstract": "Some Lactobacillus species are associated with obesity and weight gain while others are associated with weight loss. Lactobacillus spp. and bifidobacteria represent a major bacterial population of the small intestine where lipids and simple carbohydrates are absorbed, particularly in the duodenum and jejunum. The objective of this study was to identify Lactobacillus spp. proteins involved in carbohydrate and lipid metabolism associated with weight modifications. We examined a total of 13 complete genomes belonging to seven different Lactobacillus spp. previously associated with weight gain or weight protection. We combined the data obtained from the Rapid Annotation using Subsystem Technology, Batch CD-Search and Gene Ontology to classify gene function in each genome. We observed major differences between the two groups of genomes. Weight gain-associated Lactobacillus spp. appear to lack enzymes involved in the catabolism of fructose, defense against oxidative stress and the synthesis of dextrin, L-rhamnose and acetate. Weight protection-associated Lactobacillus spp. encoded a significant gene amount of glucose permease. Regarding lipid metabolism, thiolases were only encoded in the genome of weight gain-associated Lactobacillus spp. In addition, we identified 18 different types of bacteriocins in the studied genomes, and weight gain-associated Lactobacillus spp. encoded more bacteriocins than weight protection-associated Lactobacillus spp. The results of this study revealed that weight protection-associated Lactobacillus spp. have developed defense mechanisms for enhanced glycolysis and defense against oxidative stress. Weight gain-associated Lactobacillus spp. possess a limited ability to breakdown fructose or glucose and might reduce ileal brake effects.", - "journal_title": "Nutrition & diabetes", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/24567124/" - } - ], - "999c655b-b078-4129-b141-178867aca79f": [ - { - "pub_id": "21457499", - "title": "Inherited destiny? Genetics and gestational diabetes mellitus.", - "authors": "Richard M Watanabe", - "abstract": "Despite years of investigation, very little is known about the genetic predisposition for gestational diabetes mellitus (GDM). However, the advent of genome-wide association and identification of loci contributing to susceptibility to type 2 diabetes mellitus has opened a small window into the genetics of GDM. More importantly, the study of the genetics of GDM has not only illuminated potential new biology underlying diabetes in pregnancy, but has also provided insights into fetal outcomes. Here, I review some of the insights into GDM and fetal outcomes gained through the study of both rare and common genetic variation. I also discuss whether recent testing of type 2 diabetes mellitus susceptibility loci in GDM case-control samples changes views of whether GDM is a distinct form of diabetes. Finally, I examine how the study of susceptibility loci can be used to influence clinical care, one of the great promises of the new era of human genome analysis.", - "journal_title": "Genome medicine", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/21457499/" - } - ], - "8f081899-5f01-415c-a5e6-5a25592804a0": [ - { - "pub_id": "22387117", - "title": "Early-life gut microbiota under physiological and pathological conditions: the central role of combined meta-omics-based approaches.", - "authors": "Federica Del Chierico,Pamela Vernocchi,Luigi Bonizzi,Rita Carsetti,Anna Maria Castellazzi,Bruno Dallapiccola,Willem de Vos,Maria Elisabetta Guerzoni,Melania Manco,Gian Luigi Marseglia,Maurizio Muraca,Paola Roncada,Guglielmo Salvatori,Fabrizio Signore,Andrea Urbani,Lorenza Putignani", - "abstract": "The establishment of gut microbiota immediately after birth is modulated by different mechanisms that can be considered specific determinants of temporal and spatial variability. Over the last few years, molecular methods have been offering a complementary support to the classical microbiology, often underpowered by its inability to provide unbiased representation of gut microbiota. The advent of high-throughput-omics-based methods has opened new avenues in the knowledge of the gut ecosystem by shedding light on its shape and modulation. Such methods may unveil taxa distribution, role and density of microbial habitants, hence highlighting individual phenotyping (physiological traits) and their relationship with gut dysbiosis, inflammation processes, metabolic disorders (pathological conditions). Synergic meta-omics or \"systems biology\"-based approaches may concur in providing advanced information on microbiota establishment and pathogen control. During early-life stages this massive amount of data may provide gut microbiota descriptive and functional charts which can be exploited to perform a good practice in childcare and pediatrics, thus providing nutraceutical benefits and endorsing healthy development and aging. This article is part of a Special Issue entitled: Translational Proteomics.", - "journal_title": "Journal of proteomics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/22387117/" - } - ], - "b942c082-a734-47d7-8494-8457ce995ce2": [ - { - "pub_id": "22187377", - "title": "Targeted loss of GHR signaling in mouse skeletal muscle protects against high-fat diet-induced metabolic deterioration.", - "authors": "Archana Vijayakumar,YingJie Wu,Hui Sun,Xiaosong Li,Zuha Jeddy,Chengyu Liu,Gary J Schwartz,Shoshana Yakar,Derek LeRoith", - "abstract": "Growth hormone (GH) exerts diverse tissue-specific metabolic effects that are not revealed by global alteration of GH action. To study the direct metabolic effects of GH in the muscle, we specifically inactivated the growth hormone receptor (ghr) gene in postnatal mouse skeletal muscle using the Cre/loxP system (mGHRKO model). The metabolic state of the mGHRKO mice was characterized under lean and obese states. High-fat diet feeding in the mGHRKO mice was associated with reduced adiposity, improved insulin sensitivity, lower systemic inflammation, decreased muscle and hepatic triglyceride content, and greater energy expenditure compared with control mice. The obese mGHRKO mice also had an increased respiratory exchange ratio, suggesting increased carbohydrate utilization. GH-regulated suppressor of cytokine signaling-2 (socs2) expression was decreased in obese mGHRKO mice. Interestingly, muscles of both lean and obese mGHRKO mice demonstrated a higher interleukin-15 and lower myostatin expression relative to controls, indicating a possible mechanism whereby GHR signaling in muscle could affect liver and adipose tissue function. Thus, our study implicates skeletal muscle GHR signaling in mediating insulin resistance in obesity and, more importantly, reveals a novel role of muscle GHR signaling in facilitating cross-talk between muscle and other metabolic tissues.", - "journal_title": "Diabetes", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/22187377/" - } - ], - "3829213f-5834-46f4-8499-70448505296d": [ - { - "pub_id": "26209735", - "title": "Genome-wide studies to identify risk factors for kidney disease with a focus on patients with diabetes.", - "authors": "Florina Regele,Kira Jelencsics,Dov Shiffman,Guillaume Par\u00e9,Matthew J McQueen,Johannes F E Mann,Rainer Oberbauer", - "abstract": "Chronic kidney disease (CKD) affects 10-13% of the general population and diabetic nephropathy (DN) is the leading cause of end-stage renal disease (ESRD). In addition to known demographic, biochemical and lifestyle risk factors, genetics is also contributing to CKD risk. In recent years, genome-wide association studies (GWAS) have provided a hypothesis-free approach to identify common genetic variants that could account for the genetic risk component of common diseases such as CKD. The identification of these variants might reveal the biological processes underlying renal impairment and could aid in improving risk estimates for CKD. This review aims to describe the methods as well as strengths and limitations of GWAS in CKD and to summarize the findings of recent GWAS in DN. Several loci and SNPs have been found to be associated with distinct CKD traits such as eGFR and albuminuria. For diabetic kidney disease, several loci were identified in different populations. Subsequent functional studies provided insights into the mechanism of action of some of these variants, such as UMOD or CERS2. However, overall, the results were ambiguous, and a few of the variants were not consistently replicated. In addition, the slow progression from albuminuria to ESRD could limit the power of longitudinal studies. The typically small effect size associated with genetic variants as well as the small portion of the variability of the phenotype explained by these variants limits the utility of genetic variants in improving risk prediction. Nevertheless, identifying these variants could give a deeper understanding of the molecular pathways underlying CKD, which in turn, could potentially lead to the development of new diagnostic and therapeutic tools.", - "journal_title": "Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/26209735/" - } - ], - "93389995-ec48-4d65-8435-96c4a57f36fc": [ - { - "pub_id": "25064373", - "title": "Mendelian randomization: genetic anchors for causal inference in epidemiological studies.", - "authors": "George Davey Smith,Gibran Hemani", - "abstract": "Observational epidemiological studies are prone to confounding, reverse causation and various biases and have generated findings that have proved to be unreliable indicators of the causal effects of modifiable exposures on disease outcomes. Mendelian randomization (MR) is a method that utilizes genetic variants that are robustly associated with such modifiable exposures to generate more reliable evidence regarding which interventions should produce health benefits. The approach is being widely applied, and various ways to strengthen inference given the known potential limitations of MR are now available. Developments of MR, including two-sample MR, bidirectional MR, network MR, two-step MR, factorial MR and multiphenotype MR, are outlined in this review. The integration of genetic information into population-based epidemiological studies presents translational opportunities, which capitalize on the investment in genomic discovery research.", - "journal_title": "Human molecular genetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/25064373/" - } - ], - "c5df256a-792c-4768-95bc-33e1a913d802": [ - { - "pub_id": "23780460", - "title": "Seroconversion to multiple islet autoantibodies and risk of progression to diabetes in children.", - "authors": "Anette G Ziegler,Marian Rewers,Olli Simell,Tuula Simell,Johanna Lempainen,Andrea Steck,Christiane Winkler,Jorma Ilonen,Riitta Veijola,Mikael Knip,Ezio Bonifacio,George S Eisenbarth", - "abstract": "Type 1 diabetes usually has a preclinical phase identified by circulating islet autoantibodies, but the rate of progression to diabetes after seroconversion to islet autoantibodies is uncertain. To determine the rate of progression to diabetes after islet autoantibody seroconversion. Data were pooled from prospective cohort studies performed in Colorado (recruitment, 1993-2006), Finland (recruitment, 1994-2009), and Germany (recruitment, 1989-2006) examining children genetically at risk for type 1 diabetes for the development of insulin autoantibodies, glutamic acid decarboxylase 65 (GAD65) autoantibodies, insulinoma antigen 2 (IA2) autoantibodies, and diabetes. Participants were all children recruited and followed up in the 3 studies (Colorado, 1962; Finland, 8597; Germany, 2818). Follow-up assessment in each study was concluded by July 2012. The primary analysis was the diagnosis of type 1 diabetes in children with 2 or more autoantibodies. The secondary analysis was the diagnosis of type 1 diabetes in children with 1 autoantibody or no autoantibodies. Progression to type 1 diabetes at 10-year follow-up after islet autoantibody seroconversion in 585 children with multiple islet autoantibodies was 69.7% (95% CI, 65.1%-74.3%), and in 474 children with a single islet autoantibody was 14.5% (95% CI, 10.3%-18.7%). Risk of diabetes in children who had no islet autoantibodies was 0.4% (95% CI, 0.2%-0.6%) by the age of 15 years. Progression to type 1 diabetes in the children with multiple islet autoantibodies was faster for children who had islet autoantibody seroconversion younger than age 3 years (hazard ratio [HR], 1.65 [95% CI, 1.30-2.09; P < .001]; 10-year risk, 74.9% [95% CI, 69.7%-80.1%]) vs children 3 years or older (60.9% [95% CI, 51.5%-70.3%]); for children with the human leukocyte antigen (HLA) genotype DR3/DR4-DQ8 (HR, 1.35 [95% CI, 1.09-1.68; P = .007]; 10-year risk, 76.6% [95% CI, 69.2%-84%]) vs other HLA genotypes (66.2% [95% CI, 60.2%-72.2%]); and for girls (HR, 1.28 [95% CI, 1.04-1.58; P = .02];10-year risk, 74.8% [95% CI, 68.0%-81.6%]) vs boys (65.7% [95% CI, 59.3%-72.1%]). The majority of children at risk of type 1 diabetes who had multiple islet autoantibody seroconversion progressed to diabetes over the next 15 years. Future prevention studies should focus on this high-risk population.", - "journal_title": "JAMA", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/23780460/" - } - ], - "cb451da9-faae-4cb7-9b49-b1b38f8f1dd9": [ - { - "pub_id": "23762820", - "title": "Variants of insulin-signaling inhibitor genes in type 2 diabetes and related metabolic abnormalities.", - "authors": "Carlo de Lorenzo,Annalisa Greco,Teresa Vanessa Fiorentino,Gaia Chiara Mannino,Marta Letizia Hribal", - "abstract": "Insulin resistance has a central role in the pathogenesis of several metabolic diseases, including type 2 diabetes, obesity, glucose intolerance, metabolic syndrome, atherosclerosis, and cardiovascular diseases. Insulin resistance and related traits are likely to be caused by abnormalities in the genes encoding for proteins involved in the composite network of insulin-signaling; in this review we have focused our attention on genetic variants of insulin-signaling inhibitor molecules. These proteins interfere with different steps in insulin-signaling: ENPP1/PC-1 and the phosphatases PTP1B and PTPRF/LAR inhibit the insulin receptor activation; INPPL1/SHIP-2 hydrolyzes PI3-kinase products, hampering the phosphoinositide-mediated downstream signaling; and TRIB3 binds the serine-threonine kinase Akt, reducing its phosphorylation levels. While several variants have been described over the years for all these genes, solid evidence of an association with type 2 diabetes and related diseases seems to exist only for rs1044498 of the ENPP1 gene and for rs2295490 of the TRIB3 gene. However, overall the data recapitulated in this Review article may supply useful elements to interpret the results of novel, more technically advanced genetic studies; indeed it is becoming increasingly evident that genetic information on metabolic diseases should be interpreted taking into account the complex biological pathways underlying their pathogenesis.", - "journal_title": "International journal of genomics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/23762820/" - } - ], - "67f74829-7056-439a-a993-43311353d7de": [ - { - "pub_id": "23144785", - "title": "PICARA, an analytical pipeline providing probabilistic inference about a priori candidates genes underlying genome-wide association QTL in plants.", - "authors": "Charles Chen,Genevieve DeClerck,Feng Tian,William Spooner,Susan McCouch,Edward Buckler", - "abstract": "PICARA is an analytical pipeline designed to systematically summarize observed SNP/trait associations identified by genome wide association studies (GWAS) and to identify candidate genes involved in the regulation of complex trait variation. The pipeline provides probabilistic inference about a priori candidate genes using integrated information derived from genome-wide association signals, gene homology, and curated gene sets embedded in pathway descriptions. In this paper, we demonstrate the performance of PICARA using data for flowering time variation in maize - a key trait for geographical and seasonal adaption of plants. Among 406 curated flowering time-related genes from Arabidopsis, we identify 61 orthologs in maize that are significantly enriched for GWAS SNP signals, including key regulators such as FT (Flowering Locus T) and GI (GIGANTEA), and genes centered in the Arabidopsis circadian pathway, including TOC1 (Timing of CAB Expression 1) and LHY (Late Elongated Hypocotyl). In addition, we discover a regulatory feature that is characteristic of these a priori flowering time candidates in maize. This new probabilistic analytical pipeline helps researchers infer the functional significance of candidate genes associated with complex traits and helps guide future experiments by providing statistical support for gene candidates based on the integration of heterogeneous biological information.", - "journal_title": "PloS one", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/23144785/" - } - ], - "f44149e0-d183-48c1-a937-729e7abd87f5": [ - { - "pub_id": "19716569", - "title": "Association of Gly972Arg polymorphism of IRS1 gene with type 2 diabetes mellitus in lean participants of a national health survey in Mexico: a candidate gene study.", - "authors": "Ana I Burguete-Garcia,Miguel Cruz-Lopez,Vicente Madrid-Marina,Ruy Lopez-Ridaura,Mauricio Hern\u00e1ndez-Avila,Bernardo Cortina,Rosa E G\u00f3mez,Eduardo Velasco-Mondrag\u00f3n", - "abstract": "Type 2 diabetes mellitus (T2D) is a main public health problem in the Mexican population. It is characterized by insulin resistance in peripheral tissues and a relative deficiency in the pancreatic beta-cell functions. Diverse single nucleotide polymorphisms (SNPs) of the IRS1 gene have been associated with insulin resistance and T2D risk. The aim of this study was to identify the association between known IRS1 polymorphisms (Pro512Ala, Asn1137Asp, Gly972Arg, and Arg158Pro) in a sample of diabetic patients compared with healthy controls selected from Mexico's 2000 National Health Survey, both with normal body mass index (BMI). We identified 444 diabetes cases that were age matched with the same number of controls. Genotypic and allelic frequencies were evaluated, and conditional logistic regression was used to evaluate the association between the SNPs and diabetes risk. Of the 4 SNPs studied, only Gly972Arg showed significant differences between cases and controls, with allele frequency of 2.6% in controls as compared with 7.9% in cases. Subjects with at least 1 copy of the Gly972Arg polymorphism of the IRS1 gene showed a greater risk for diabetes, with a crude odds ratio of 3.26 (95% confidence interval, 2.00-5.33); after adjusting for BMI, age, family history of T2D, and sex, the odds ratio was 2.91 (95% confidence interval, 1.73-4.90). Our results suggest the participation of Gly972Arg polymorphism of IRS1 in the genetic susceptibility to TD2 in Mexican population. The restriction of including only participants with normal BMI might increase the power to detect genetic determinants of T2D.", - "journal_title": "Metabolism: clinical and experimental", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/19716569/" - } - ], - "0c6f74c6-7cc6-477b-bfe8-69a8951d0297": [ - { - "pub_id": "20462972", - "title": "The role of epigenetics in the pathology of diabetic complications.", - "authors": "Louisa M Villeneuve,Rama Natarajan", - "abstract": "Diabetes is associated with significantly accelerated rates of several debilitating microvascular complications such as nephropathy, retinopathy, and neuropathy, and macrovascular complications such as atherosclerosis and stroke. While several studies have been devoted to the evaluation of genetic factors related to type 1 and type 2 diabetes and associated complications, much less is known about epigenetic changes that occur without alterations in the DNA sequence. Environmental factors and nutrition have been implicated in diabetes and can also affect epigenetic states. Exciting research has shown that epigenetic changes in chromatin can affect gene transcription in response to environmental stimuli, and changes in key chromatin histone methylation patterns have been noted under diabetic conditions. Reports also suggest that epigenetics may be involved in the phenomenon of metabolic memory observed in clinic trials and animal studies. Further exploration into epigenetic mechanisms can yield new insights into the pathogenesis of diabetes and its complications and uncover potential therapeutic targets and treatment options to prevent the continued development of diabetic complications even after glucose control has been achieved.", - "journal_title": "American journal of physiology. Renal physiology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/20462972/" - } - ], - "374c7dcd-919a-4562-aa70-00fc33f918ed": [ - { - "pub_id": "25473429", - "title": "Developing patient-friendly genetic and genomic test reports: formats to promote patient engagement and understanding.", - "authors": "Susanne B Haga,Rachel Mills,Kathryn I Pollak,Catherine Rehder,Adam H Buchanan,Isaac M Lipkus,Jennifer H Crow,Michael Datto", - "abstract": "With the emergence of electronic medical records and patient portals, patients are increasingly able to access their health records, including laboratory reports. However, laboratory reports are usually written for clinicians rather than patients, who may not understand much of the information in the report. While several professional guidelines define the content of test reports, there are no guidelines to inform the development of a patient-friendly laboratory report. In this Opinion, we consider patient barriers to comprehension of lab results and suggest several options to reformat the lab report to promote understanding of test results and their significance to patient care, and to reduce patient anxiety and confusion. In particular, patients' health literacy, genetic literacy, e-health literacy and risk perception may influence their overall understanding of lab results and affect patient care. We propose four options to reformat lab reports: 1) inclusion of an interpretive summary section, 2) a summary letter to accompany the lab report, 3) development of a patient user guide to be provided with the report, and 4) a completely revised patient-friendly report. The complexity of genetic and genomic test reports poses a major challenge to patient understanding that warrants the development of a report more appropriate for patients.", - "journal_title": "Genome medicine", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/25473429/" - } - ], - "be3acd18-3613-4a3a-a8ce-cff8ba55d450": [ - { - "pub_id": "26430284", - "title": "Filipino-American Nurses' Knowledge, Perceptions, Beliefs and Practice of Genetics and Genomics.", - "authors": "Leorey N Saligan,Reynaldo R Rivera", - "abstract": "There is limited information on the knowledge, perceptions, beliefs, and practice, about genetics and genomics among Filipino-American nurses. The National Coalition of Ethnic Minority Organizations (NCEMNA), in which the Philippine Nurses Association of America (PNAA) is a member organization, conducted an online survey to describe the genomic knowledge, perceptions, beliefs, and practice of minority nurses. This study reports on responses from Filipino-American survey participants, which is a subset analysis of the larger NCEMNA survey. The purpose of this study was to explore the knowledge, perceptions, beliefs, practice and genomic education of Filipino-American nurses. An online survey of 112 Filipino-American nurses was conducted to describe the knowledge, perceptions, beliefs, and practice of genetics/genomics. Survey responses were analyzed using descriptive statistics. Most (94%) Filipino-American nurses wanted to learn more about genetics. Although 41% of the respondents indicated good understanding of genetics of common diseases, 60% had not attended any related continuing education courses since RN licensure, and 73% reported unavailability of genetic courses to take. The majority (83%) of PNAA respondents indicated that they would attend genetics/genomics awareness training if it was offered by their national organization during their annual conference, and 86% reported that the national organization should have a visible role in genetics/genomics initiatives in their community. Filipino-American nurses wanted to learn more about genetics and were willing to attend genetics/genomics trainings if offered by PNAA. The study findings can assist PNAA in planning future educational programs that incorporates genetics and genomics information.", - "journal_title": "The Philippine journal of nursing", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/26430284/" - } - ], - "85f3a390-15cf-40d9-91dc-e6238b58f171": [ - { - "pub_id": "20564432", - "title": "Neural tube defect genes and maternal diabetes during pregnancy.", - "authors": "J Michael Salbaum,Claudia Kappen", - "abstract": "Maternal diabetes during pregnancy is a well-known teratogen that increases the risk for birth defects, such as neural tube defects (NTDs). We have previously shown that maternal diabetes profoundly affects gene expression in the developing embryo, in particular a suite of known NTD genes. In rodent experimental systems, NTDs present as phenotypes of incomplete penetrance in diabetic pregnancies. This property is difficult to reconcile with observations of consistently altered gene expression in exposed embryos. We here show that maternal diabetes increases the overall variability of gene expression levels in embryos. Altered gene expression and increased variability of gene expression together may constitute the molecular correlates for incomplete phenotype penetrance. Based on this model, we suggest that maternal diabetes reduces the precision of gene regulation in exposed individuals. Loss of precision in embryonic gene regulation may include changes to the epigenome via deregulated expression of chromatin-modifying factors. Unraveling the mechanisms underlying such epigenetic modifications in diabetic pregnancies will help to understand how teratogenic insults compromise embryonic development and possibly provide avenues for therapeutic intervention.", - "journal_title": "Birth defects research. Part A, Clinical and molecular teratology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/20564432/" - } - ], - "2f6521cf-fc78-45b3-a32d-8738ded6efa9": [ - { - "pub_id": "25341961", - "title": "Current and best practices of genetic testing for maturity onset diabetes of the young: views of professional experts.", - "authors": "Angeli M van der Zwaag,Stephanie S Weinreich,Astrid R Bosma,Tessel Rigter,Monique Losekoot,Lidewij Henneman,Martina C Cornel", - "abstract": "Currently, many patients with maturity onset diabetes of the young (MODY) are undiagnosed or misdiagnosed with type 1 or 2 diabetes. This study aims to assess professional experts' views on factors which may influence the current practice of genetic testing for MODY and to explore next steps toward best practice. Twelve semistructured interviews were conducted with professional experts. These experts included physicians with potential or actual experience with genetic testing for MODY, representatives of (para)medical professional associations and a staff member of a diabetes patients' organization. Participants differed in their valuation of genetic testing for MODY. While most considered the test useful, not all were convinced of its clinical utility. Other factors mentioned to influence current practice were: (perceived lack of) possibilities for treatment and prevention, patients' perspectives and perceived barriers, such as costs and a lack of knowledge and awareness. Participants agreed that guidelines would be helpful to facilitate expedient testing. This study identified next steps that should be taken to improve genetic diagnosis and care for patients with MODY. Besides the development of a consensus guideline, other suggestions included more education of healthcare professionals, a clearer allocation of responsibilities with regard to genetic testing for MODY and further research.", - "journal_title": "Public health genomics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/25341961/" - } - ], - "a2e1b50b-9396-4d7d-b6db-bdd0f34529ae": [ - { - "pub_id": "24974787", - "title": "A genome-wide association study suggests an association of Chr8p21.3 (GFRA2) with diabetic neuropathic pain.", - "authors": "W Meng,H A Deshmukh,N R van Zuydam,Y Liu,L A Donnelly,K Zhou, , ,A D Morris,H M Colhoun,C N A Palmer,B H Smith", - "abstract": "Neuropathic pain, caused by a lesion or a disease affecting the somatosensory system, is one of the most common complications in diabetic patients. The purpose of this study is to identify genetic factors contributing to this type of pain in a general diabetic population. We accessed the Genetics of Diabetes Audit and Research Tayside (GoDARTS) datasets that contain prescription information and monofilament test results for 9439 diabetic patients, among which 6927 diabetic individuals were genotyped by Affymetrix SNP6.0 or Illumina OmniExpress chips. Cases of neuropathic pain were defined as diabetic patients with a prescription history of at least one of five drugs specifically indicated for the treatment of neuropathic pain and in whom monofilament test result was positive for sensory neuropathy in at least one foot. Controls were individuals who did not have a record of receiving any opioid analgesics. Imputation of non-genotyped SNPs was performed by IMPUTE2, with reference files from 1000 Genomes Phase I datasets. After data cleaning and relevant exclusions, imputed genotypes of 572 diabetic neuropathic pain cases and 2491 diabetic controls were used in the Fisher's exact test. We identified a cluster in the Chr8p21.3, next to GFRA2 with a lowest p-value of 1.77\u2009\u00d7\u200910(-7) at rs17428041. The narrow-sense heritability of this phenotype was 11.00%. This genome-wide association study on diabetic neuropathic pain suggests new evidence for the involvement of variants near GFRA2 with the disorder, which needs to be verified in an independent cohort and at the molecular level.", - "journal_title": "European journal of pain (London, England)", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/24974787/" - } - ], - "95a5a00b-9cf4-4988-bc6c-9df0e8e1b155": [ - { - "pub_id": "23613601", - "title": "Gene-environment and gene-treatment interactions in type 2 diabetes: progress, pitfalls, and prospects.", - "authors": "Paul W Franks,Ewan Pearson,Jose C Florez", - "abstract": "", - "journal_title": "Diabetes care", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/23613601/" - } - ], - "6e570a0b-a876-4263-b32f-cee85088756d": [ - { - "pub_id": "21531985", - "title": "The aging hippocampus: interactions between exercise, depression, and BDNF.", - "authors": "Kirk I Erickson,Destiny L Miller,Kathryn A Roecklein", - "abstract": "Late adulthood is associated with increased hippocampal atrophy and dysfunction. Although there are multiple paths by which hippocampal deterioration occurs in late life, the authors discuss the evidence that a single nucleotide polymorphism in the brain-derived neurotrophic factor (BDNF) gene and age-related changes in BDNF protein or receptor expression contribute to hippocampal atrophy. The authors conclude that few studies have tested whether BDNF mediates age-related hippocampal atrophy and memory impairment. However, there is strong evidence that decreased BDNF is associated with age-related hippocampal dysfunction, memory impairment, and increased risk for depression, whereas increasing BDNF by aerobic exercise appears to ameliorate hippocampal atrophy, improve memory function, and reduce depression. Importantly, the most consistent associations between BDNF and hippocampal dysfunction have emerged from research on BDNF protein expression in rodents and serum and plasma concentrations of BDNF in humans. Current research suggests that the BDNF val66met polymorphism may be only weakly associated with hippocampal atrophy in late adulthood. These conclusions are interpreted in relation to age-related memory impairment and preventions for hippocampal atrophy.", - "journal_title": "The Neuroscientist : a review journal bringing neurobiology, neurology and psychiatry", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/21531985/" - } - ], - "29e232a4-a580-411d-83a3-7ff6a4e8f0ad": [ - { - "pub_id": "23236292", - "title": "Integrative analysis of a cross-loci regulation network identifies App as a gene regulating insulin secretion from pancreatic islets.", - "authors": "Zhidong Tu,Mark P Keller,Chunsheng Zhang,Mary E Rabaglia,Danielle M Greenawalt,Xia Yang,I-Ming Wang,Hongyue Dai,Matthew D Bruss,Pek Y Lum,Yun-Ping Zhou,Daniel M Kemp,Christina Kendziorski,Brian S Yandell,Alan D Attie,Eric E Schadt,Jun Zhu", - "abstract": "Complex diseases result from molecular changes induced by multiple genetic factors and the environment. To derive a systems view of how genetic loci interact in the context of tissue-specific molecular networks, we constructed an F2 intercross comprised of >500 mice from diabetes-resistant (B6) and diabetes-susceptible (BTBR) mouse strains made genetically obese by the Leptin(ob/ob) mutation (Lep(ob)). High-density genotypes, diabetes-related clinical traits, and whole-transcriptome expression profiling in five tissues (white adipose, liver, pancreatic islets, hypothalamus, and gastrocnemius muscle) were determined for all mice. We performed an integrative analysis to investigate the inter-relationship among genetic factors, expression traits, and plasma insulin, a hallmark diabetes trait. Among five tissues under study, there are extensive protein-protein interactions between genes responding to different loci in adipose and pancreatic islets that potentially jointly participated in the regulation of plasma insulin. We developed a novel ranking scheme based on cross-loci protein-protein network topology and gene expression to assess each gene's potential to regulate plasma insulin. Unique candidate genes were identified in adipose tissue and islets. In islets, the Alzheimer's gene App was identified as a top candidate regulator. Islets from 17-week-old, but not 10-week-old, App knockout mice showed increased insulin secretion in response to glucose or a membrane-permeant cAMP analog, in agreement with the predictions of the network model. Our result provides a novel hypothesis on the mechanism for the connection between two aging-related diseases: Alzheimer's disease and type 2 diabetes.", - "journal_title": "PLoS genetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/23236292/" - } - ], - "fd03b865-0589-4d11-9c2a-f9409a52cf82": [ - { - "pub_id": "23975224", - "title": "Gestational diabetes mellitus epigenetically affects genes predominantly involved in metabolic diseases.", - "authors": "Stephanie-May Ruchat,Andr\u00e9e-Anne Houde,Gr\u00e9gory Voisin,Julie St-Pierre,Patrice Perron,Jean-Patrice Baillargeon,Daniel Gaudet,Marie-France Hivert,Diane Brisson,Luigi Bouchard", - "abstract": "Offspring exposed to gestational diabetes mellitus (GDM) have an increased risk for chronic diseases, and one promising mechanism for fetal metabolic programming is epigenetics. Therefore, we postulated that GDM exposure impacts the offspring's methylome and used an epigenomic approach to explore this hypothesis. Placenta and cord blood samples were obtained from 44 newborns, including 30 exposed to GDM. Women were recruited at first trimester of pregnancy and followed until delivery. GDM was assessed after a 75-g oral glucose tolerance test at 24-28 weeks of pregnancy. DNA methylation was measured at>485,000 CpG sites (Infinium HumanMethylation450 BeadChips). Ingenuity Pathway Analysis was conducted to identify metabolic pathways epigenetically affected by GDM. Our results showed that 3,271 and 3,758 genes in placenta and cord blood, respectively, were potentially differentially methylated between samples exposed or not to GDM (p-values down to 1 \u00d7 10(-06); none reached the genome-wide significance levels), with more than 25% (n = 1,029) being common to both tissues. Mean DNA methylation differences between groups were 5.7 \u00b1 3.2% and 3.4 \u00b1 1.9% for placenta and cord blood, respectively. These genes were likely involved in the metabolic diseases pathway (up to 115 genes (11%), p-values for pathways = 1.9 \u00d7 10(-13)<p<4.0 \u00d7 10(-03); including diabetes mellitus p = 4.3 \u00d7 10(-11)). Among the differentially methylated genes, 326 in placenta and 117 in cord blood were also associated with newborn weight. Our results therefore suggest that GDM has epigenetic effects on genes preferentially involved in the metabolic diseases pathway, with consequences on fetal growth and development, and provide supportive evidence that DNA methylation is involved in fetal metabolic programming.", - "journal_title": "Epigenetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/23975224/" - } - ], - "1f5f2923-ca25-496c-b70e-5d15825c5575": [ - { - "pub_id": "21132113", - "title": "Direct-to-Consumer Genetic and Genomic Testing: Preparing Nurse Practitioners for Genomic Healthcare.", - "authors": "Jennifer T Loud", - "abstract": "Rapidly emerging technologies make it possible for consumers to acquire information that is intended to explain their inherited susceptibility to disease and facilitate tailored healthcare services through direct-to-consumer (DTC) marketing of personal genetic (PG) and personal genomic (PGM) testing. However, the health benefits and risks associated with these technologies are largely unknown. Consumers will turn to their healthcare providers, including nurse practitioners, to interpret test results and seek guidance on how to use these test results for medical decision-making. Nurse practitioners will need to constantly update their practice skills in response to advances in genomic technology that create new expectations among patients and lead to substantial changes in healthcare delivery.", - "journal_title": "The journal for nurse practitioners : JNP", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/21132113/" - } - ], - "4c7bbf98-aed3-4899-8080-9ee81f62c67e": [ - { - "pub_id": "21654741", - "title": "Biomarkers for the prediction of type 2 diabetes and cardiovascular disease.", - "authors": "C Herder,M Karakas,W Koenig", - "abstract": "Risk prediction for type 2 diabetes (T2D) and cardiovascular disease (CVD) remains suboptimal even after the introduction of global risk assessment by various scores. This has prompted the search for additional biomarkers. A variety of blood biomarkers representing various pathophysiological pathways of insulin resistance and atherosclerosis, as well as markers of subclinical disease and genetic markers, have been investigated. This review provides an overview of studies assessing the clinical utility of various biomarkers on the basis of hypothesis-driven selection as well as hypothesis-free approaches from novel \"-omics\" technologies. So far, the assessment of genotypes and of several candidate biomarkers from blood has resulted in only small improvements in the accuracy of prediction of CVD and T2D over and above that predicted on the basis of established risk factors. Integrated approaches, combining biomarkers from genomics, transcriptomics, proteomics, and metabolomics, as well as serial measurements of biomarkers, are required to make a complete assessment of the potential clinical usefulness of biomarkers for risk prediction of cardiometabolic disease.", - "journal_title": "Clinical pharmacology and therapeutics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/21654741/" - } - ], - "1680144d-1283-431e-aaf9-75a84f5599dd": [ - { - "pub_id": "23023125", - "title": "A metagenome-wide association study of gut microbiota in type 2 diabetes.", - "authors": "Junjie Qin,Yingrui Li,Zhiming Cai,Shenghui Li,Jianfeng Zhu,Fan Zhang,Suisha Liang,Wenwei Zhang,Yuanlin Guan,Dongqian Shen,Yangqing Peng,Dongya Zhang,Zhuye Jie,Wenxian Wu,Youwen Qin,Wenbin Xue,Junhua Li,Lingchuan Han,Donghui Lu,Peixian Wu,Yali Dai,Xiaojuan Sun,Zesong Li,Aifa Tang,Shilong Zhong,Xiaoping Li,Weineng Chen,Ran Xu,Mingbang Wang,Qiang Feng,Meihua Gong,Jing Yu,Yanyan Zhang,Ming Zhang,Torben Hansen,Gaston Sanchez,Jeroen Raes,Gwen Falony,Shujiro Okuda,Mathieu Almeida,Emmanuelle LeChatelier,Pierre Renault,Nicolas Pons,Jean-Michel Batto,Zhaoxi Zhang,Hua Chen,Ruifu Yang,Weimou Zheng,Songgang Li,Huanming Yang,Jian Wang,S Dusko Ehrlich,Rasmus Nielsen,Oluf Pedersen,Karsten Kristiansen,Jun Wang", - "abstract": "Assessment and characterization of gut microbiota has become a major research area in human disease, including type 2 diabetes, the most prevalent endocrine disease worldwide. To carry out analysis on gut microbial content in patients with type 2 diabetes, we developed a protocol for a metagenome-wide association study (MGWAS) and undertook a two-stage MGWAS based on deep shotgun sequencing of the gut microbial DNA from 345 Chinese individuals. We identified and validated approximately 60,000 type-2-diabetes-associated markers and established the concept of a metagenomic linkage group, enabling taxonomic species-level analyses. MGWAS analysis showed that patients with type 2 diabetes were characterized by a moderate degree of gut microbial dysbiosis, a decrease in the abundance of some universal butyrate-producing bacteria and an increase in various opportunistic pathogens, as well as an enrichment of other microbial functions conferring sulphate reduction and oxidative stress resistance. An analysis of 23 additional individuals demonstrated that these gut microbial markers might be useful for classifying type 2 diabetes.", - "journal_title": "Nature", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/23023125/" - } - ], - "eaca0f25-4a6b-4c0e-a6df-12e25060b169": [ - { - "pub_id": "25640731", - "title": "Rare and common genetic events in type 2 diabetes: what should biologists know?", - "authors": "Am\u00e9lie Bonnefond,Philippe Froguel", - "abstract": "Type 2 diabetes (T2D) had long been referred to as the \"geneticist's nightmare.\" Genome-wide association studies have fully confirmed the polygenic nature of T2D, demonstrating the role of many genes in T2D risk. The increasingly busier picture of T2D genetics is quite difficult to understand for the diabetes research community, which can create misunderstandings with geneticists, and can eventually limit both basic research and translational outcomes of these genetic discoveries. The present review wishes to lift the fog around genetics of T2D with the hope that it will foster integrated diabetes modeling approaches from genetic defects to personalized medicine.", - "journal_title": "Cell metabolism", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/25640731/" - } - ], - "752b2413-8c90-4af7-b65b-db429145b3bb": [ - { - "pub_id": "26018601", - "title": "Whole transcriptome analysis with sequencing: methods, challenges and potential solutions.", - "authors": "Zhihua Jiang,Xiang Zhou,Rui Li,Jennifer J Michal,Shuwen Zhang,Michael V Dodson,Zhiwu Zhang,Richard M Harland", - "abstract": "Whole transcriptome analysis plays an essential role in deciphering genome structure and function, identifying genetic networks underlying cellular, physiological, biochemical and biological systems and establishing molecular biomarkers that respond to diseases, pathogens and environmental challenges. Here, we review transcriptome analysis methods and technologies that have been used to conduct whole transcriptome shotgun sequencing or whole transcriptome tag/target sequencing analyses. We focus on how adaptors/linkers are added to both 5' and 3' ends of mRNA molecules for cloning or PCR amplification before sequencing. Challenges and potential solutions are also discussed. In brief, next generation sequencing platforms have accelerated releases of the large amounts of gene expression data. It is now time for the genome research community to assemble whole transcriptomes of all species and collect signature targets for each gene/transcript, and thus use known genes/transcripts to determine known transcriptomes directly in the near future.", - "journal_title": "Cellular and molecular life sciences : CMLS", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/26018601/" - } - ], - "b54c30da-8275-464c-8729-9269585850a1": [ - { - "pub_id": "20432533", - "title": "Genetics, pathogenesis and clinical interventions in type 1 diabetes.", - "authors": "Jeffrey A Bluestone,Kevan Herold,George Eisenbarth", - "abstract": "Type 1 diabetes is an autoimmune disorder afflicting millions of people worldwide. Once diagnosed, patients require lifelong insulin treatment and can experience numerous disease-associated complications. The last decade has seen tremendous advances in elucidating the causes and treatment of the disease based on extensive research both in rodent models of spontaneous diabetes and in humans. Integrating these advances has led to the recognition that the balance between regulatory and effector T cells determines disease risk, timing of disease activation, and disease tempo. Here we describe current progress, the challenges ahead and the new interventions that are being tested to address the unmet need for preventative or curative therapies.", - "journal_title": "Nature", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/20432533/" - } - ], - "2d0d119b-3242-4358-9661-f5c2b362d8dc": [ - { - "pub_id": "21269473", - "title": "The eMERGE Network: a consortium of biorepositories linked to electronic medical records data for conducting genomic studies.", - "authors": "Catherine A McCarty,Rex L Chisholm,Christopher G Chute,Iftikhar J Kullo,Gail P Jarvik,Eric B Larson,Rongling Li,Daniel R Masys,Marylyn D Ritchie,Dan M Roden,Jeffery P Struewing,Wendy A Wolf, ", - "abstract": "The eMERGE (electronic MEdical Records and GEnomics) Network is an NHGRI-supported consortium of five institutions to explore the utility of DNA repositories coupled to Electronic Medical Record (EMR) systems for advancing discovery in genome science. eMERGE also includes a special emphasis on the ethical, legal and social issues related to these endeavors. The five sites are supported by an Administrative Coordinating Center. Setting of network goals is initiated by working groups: (1) Genomics, (2) Informatics, and (3) Consent & Community Consultation, which also includes active participation by investigators outside the eMERGE funded sites, and (4) Return of Results Oversight Committee. The Steering Committee, comprised of site PIs and representatives and NHGRI staff, meet three times per year, once per year with the External Scientific Panel. The primary site-specific phenotypes for which samples have undergone genome-wide association study (GWAS) genotyping are cataract and HDL, dementia, electrocardiographic QRS duration, peripheral arterial disease, and type 2 diabetes. A GWAS is also being undertaken for resistant hypertension in \u2248 2,000 additional samples identified across the network sites, to be added to data available for samples already genotyped. Funded by ARRA supplements, secondary phenotypes have been added at all sites to leverage the genotyping data, and hypothyroidism is being analyzed as a cross-network phenotype. Results are being posted in dbGaP. Other key eMERGE activities include evaluation of the issues associated with cross-site deployment of common algorithms to identify cases and controls in EMRs, data privacy of genomic and clinically-derived data, developing approaches for large-scale meta-analysis of GWAS data across five sites, and a community consultation and consent initiative at each site. Plans are underway to expand the network in diversity of populations and incorporation of GWAS findings into clinical care. By combining advanced clinical informatics, genome science, and community consultation, eMERGE represents a first step in the development of data-driven approaches to incorporate genomic information into routine healthcare delivery.", - "journal_title": "BMC medical genomics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/21269473/" - } - ], - "bbb4af44-2659-4207-b9a1-0ff85d379a9f": [ - { - "pub_id": "20424228", - "title": "Impact of common variants of PPARG, KCNJ11, TCF7L2, SLC30A8, HHEX, CDKN2A, IGF2BP2, and CDKAL1 on the risk of type 2 diabetes in 5,164 Indians.", - "authors": "Ganesh Chauhan,Charles J Spurgeon,Rubina Tabassum,Seema Bhaskar,Smita R Kulkarni,Anubha Mahajan,Sreenivas Chavali,M V Kranthi Kumar,Swami Prakash,Om Prakash Dwivedi,Saurabh Ghosh,Chittaranjan S Yajnik,Nikhil Tandon,Dwaipayan Bharadwaj,Giriraj R Chandak", - "abstract": "Common variants in PPARG, KCNJ11, TCF7L2, SLC30A8, HHEX, CDKN2A, IGF2BP2, and CDKAL1 genes have been shown to be associated with type 2 diabetes in European populations by genome-wide association studies. We have studied the association of common variants in these eight genes with type 2 diabetes and related traits in Indians by combining the data from two independent case-control studies. We genotyped eight single nucleotide polymorphisms (PPARG-rs1801282, KCNJ11-rs5219, TCF7L2-rs7903146, SLC30A8-rs13266634, HHEX-rs1111875, CDKN2A-rs10811661, IGF2BP2-rs4402960, and CDKAL1-rs10946398) in 5,164 unrelated Indians of Indo-European ethnicity, including 2,486 type 2 diabetic patients and 2,678 ethnically matched control subjects. We confirmed the association of all eight loci with type 2 diabetes with odds ratio (OR) ranging from 1.18 to 1.89 (P = 1.6 x 10(-3) to 4.6 x 10(-34)). The strongest association with the highest effect size was observed for TCF7L2 (OR 1.89 [95% CI 1.71-2.09], P = 4.6 x 10(-34)). We also found significant association of PPARG and TCF7L2 with homeostasis model assessment of beta-cell function (P = 6.9 x 10(-8) and 3 x 10(-4), respectively), which looked consistent with recessive and under-dominant models, respectively. Our study replicates the association of well-established common variants with type 2 diabetes in Indians and shows larger effect size for most of them than those reported in Europeans.", - "journal_title": "Diabetes", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/20424228/" - } - ], - "17a737cd-80b8-45ef-a0d5-159d4bcf3593": [ - { - "pub_id": "30478444", - "title": "Discovery of the first genome-wide significant risk loci for attention deficit/hyperactivity disorder.", - "authors": "Ditte Demontis,Raymond K Walters,Joanna Martin,Manuel Mattheisen,Thomas D Als,Esben Agerbo,G\u00edsli Baldursson,Rich Belliveau,Jonas Bybjerg-Grauholm,Marie B\u00e6kvad-Hansen,Felecia Cerrato,Kimberly Chambert,Claire Churchhouse,Ashley Dumont,Nicholas Eriksson,Michael Gandal,Jacqueline I Goldstein,Katrina L Grasby,Jakob Grove,Olafur O Gudmundsson,Christine S Hansen,Mads Engel Hauberg,Mads V Hollegaard,Daniel P Howrigan,Hailiang Huang,Julian B Maller,Alicia R Martin,Nicholas G Martin,Jennifer Moran,Jonatan Pallesen,Duncan S Palmer,Carsten B\u00f8cker Pedersen,Marianne Gi\u00f8rtz Pedersen,Timothy Poterba,Jesper Buchhave Poulsen,Stephan Ripke,Elise B Robinson,F Kyle Satterstrom,Hreinn Stefansson,Christine Stevens,Patrick Turley,G Bragi Walters,Hyejung Won,Margaret J Wright, , , ,Ole A Andreassen,Philip Asherson,Christie L Burton,Dorret I Boomsma,Bru Cormand,S\u00f8ren Dalsgaard,Barbara Franke,Joel Gelernter,Daniel Geschwind,Hakon Hakonarson,Jan Haavik,Henry R Kranzler,Jonna Kuntsi,Kate Langley,Klaus-Peter Lesch,Christel Middeldorp,Andreas Reif,Luis Augusto Rohde,Panos Roussos,Russell Schachar,Pamela Sklar,Edmund J S Sonuga-Barke,Patrick F Sullivan,Anita Thapar,Joyce Y Tung,Irwin D Waldman,Sarah E Medland,Kari Stefansson,Merete Nordentoft,David M Hougaard,Thomas Werge,Ole Mors,Preben Bo Mortensen,Mark J Daly,Stephen V Faraone,Anders D B\u00f8rglum,Benjamin M Neale", - "abstract": "Attention deficit/hyperactivity disorder (ADHD) is a highly heritable childhood behavioral disorder affecting 5% of children and 2.5% of adults. Common genetic variants contribute substantially to ADHD susceptibility, but no variants have been robustly associated with ADHD. We report a genome-wide association meta-analysis of 20,183 individuals diagnosed with ADHD and 35,191 controls that identifies variants surpassing genome-wide significance in 12 independent loci, finding important new information about the underlying biology of ADHD. Associations are enriched in evolutionarily constrained genomic regions and loss-of-function intolerant genes and around brain-expressed regulatory marks. Analyses of three replication studies: a cohort of individuals diagnosed with ADHD, a self-reported ADHD sample and a meta-analysis of quantitative measures of ADHD symptoms in the population, support these findings while highlighting study-specific differences on genetic overlap with educational attainment. Strong concordance with GWAS of quantitative population measures of ADHD symptoms supports that clinical diagnosis of ADHD is an extreme expression of continuous heritable traits.", - "journal_title": "Nature genetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/30478444/" - } - ], - "3ab6368e-8b4a-422e-b019-2d80ce121908": [ - { - "pub_id": "25303482", - "title": "Decreased N(6)-methyladenosine in peripheral blood RNA from diabetic patients is associated with FTO expression rather than ALKBH5.", - "authors": "Fan Shen,Wei Huang,Jing-Tao Huang,Jun Xiong,Ying Yang,Ke Wu,Gui-Fang Jia,Jinyun Chen,Yu-Qi Feng,Bi-Feng Yuan,Song-Mei Liu", - "abstract": "N(6)-methyladenosine (m(6)A) modification plays a fundamental role in the epigenetic regulation of the mammalian transcriptome. m(6)A can be demethylated by fat mass- and obesity-associated (FTO) protein and \u03b1-ketoglutarate-dependent dioxygenase alkB homolog 5 (ALKBH5) protein. However, the importance of m(6)A alteration in type 2 diabetes mellitus (T2DM) has not been explored. The objective of the study was to investigate whether m(6)A content was reduced in T2DM patients and whether m(6)A content was correlated with the mRNA expression levels of the FTO and ALKBH5 genes. In this case-control study, peripheral blood samples were obtained from 88 T2DM patients and 92 healthy controls. For the diabetic animal model experiment, blood samples were obtained from seven diabetic and eight nondiabetic rats. A sensitive liquid chromatography-electrospray ionization-tandem mass spectrometry method was developed for the determination of the m(6)A content in RNA, quantitative real-time PCR was used to examine the mRNA expression levels of the FTO and ALKBH5 genes, and high-resolution melting and DNA sequencing were used to detect FTO single-nucleotide polymorphisms. Our results showed that the m(6)A contents in the RNA from T2DM patients and diabetic rats were significantly lower compared with the control groups (P = 2.6 \u00d7 10(-24) for T2DM patients; P = .001 for diabetic rats, respectively), and T2DM can be characterized by the content of m(6)A. The mRNA expression level of FTO was significantly higher in T2DM patients than that of the controls (P = .0007) and was associated with the risk of T2DM (odds ratio 2.797, 95% confidence interval 1.452-5.389, P = .002). Moreover, the m(6)A contents were correlated with FTO mRNA expression. These data suggest that the increased mRNA expression of FTO could be responsible for the reduction of m(6)A in T2DM, which may further increase the risk of complications of T2DM. Low m(6)A should be investigated further as a novel potential biomarker of T2DM.", - "journal_title": "The Journal of clinical endocrinology and metabolism", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/25303482/" - } - ], - "e3ecfea9-c849-453d-9ac1-b1db6b0052e7": [ - { - "pub_id": "22209866", - "title": "Pharmacogenomic analysis of ATP-sensitive potassium channels coexpressing the common type 2 diabetes risk variants E23K and S1369A.", - "authors": "Veronica Y Lang,Mohammad Fatehi,Peter E Light", - "abstract": "The common ATP-sensitive potassium (KATP) channel variants E23K and S1369A, found in the KCNJ11 and ABCC8 genes, respectively, form a haplotype that is associated with an increased risk for type 2 diabetes. Our previous studies showed that KATP channel inhibition by the A-site sulfonylurea gliclazide was increased in the K23/A1369 haplotype. Therefore, we studied the pharmacogenomics of seven clinically used sulfonylureas and glinides to determine their structure-activity relationships in KATP channels containing either the E23/S1369 nonrisk or K23/A1369 risk haplotypes. The patch-clamp technique was used to determine sulfonylurea and glinide inhibition of recombinant human KATP channels containing either the E23/S1369 or the K23/A1369 haplotype. KATP channels containing the K23/A1369 risk haplotype were significantly less sensitive to inhibition by tolbutamide, chlorpropamide, and glimepiride (IC50 values for K23/A1369 vs. E23/S1369=1.15 vs. 0.71 \u03bcmol/l; 4.19 vs. 3.04 \u03bcmol/l; 4.38 vs. 2.41 nmol/l, respectively). In contrast, KATP channels containing the K23/A1369 haplotype were significantly more sensitive to inhibition by mitiglinide (IC50=9.73 vs. 28.19 nmol/l for K23/A1369 vs. E23/S1369) and gliclazide. Nateglinide, glipizide, and glibenclamide showed similar inhibitory profiles in KATP channels containing either haplotype. Our results demonstrate that the ring-fused pyrrole moiety in several A-site drugs likely underlies the observed inhibitory potency of these drugs on KATP channels containing the K23/A1369 risk haplotype. It may therefore be possible to tailor existing therapy or design novel drugs that display an increased efficacy in type 2 diabetes patients homozygous for these common KATP channel haplotypes.", - "journal_title": "Pharmacogenetics and genomics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/22209866/" - } - ], - "d1f8656e-e58a-4461-b75b-89815b2c7369": [ - { - "pub_id": "23047653", - "title": "The genetic and epigenetic basis of type 2 diabetes and obesity.", - "authors": "A W Drong,C M Lindgren,M I McCarthy", - "abstract": "Type 2 diabetes (T2D) and obesity are complex disorders that constitute major public health problems. The evidence for familial aggregation of both T2D and obesity is substantial. To date, more than 150 genetic loci are associated with the development of monogenic, syndromic, or multifactorial forms of T2D or obesity. However, the proportion of overall trait variance explained by these associated loci is modest (~5-10% for T2D, ~2% for body mass index (BMI)). Some of the familial aggregation not attributable to known genetic variation, as well as many of the effects of environmental exposures, may reflect epigenetic processes. In this review, we discuss the evidence concerning the genetic contribution to individual risk of T2D and obesity, and explore the potential role of epigenetic mechanisms. We also explain how genetics, epigenetics, and environment are likely to interact to define the individual risk of disease.", - "journal_title": "Clinical pharmacology and therapeutics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/23047653/" - } - ], - "66d69e35-7d29-436d-b4fe-c25f922bb3ba": [ - { - "pub_id": "20057316", - "title": "Impact of limited population diversity of genome-wide association studies.", - "authors": "Susanne B Haga", - "abstract": "The article describes the limited population diversity of genome-wide association studies and its resulting impact on the development of commercial genetic tests with restricted applicability and usefulness to certain groups, potentially increasing existing disparities. To enable development of new clinical tools applicable to all groups, much more focus is needed to engage minority communities to enroll in genetics or genomic research studies and on investigators to reach out to underrepresented communities.", - "journal_title": "Genetics in medicine : official journal of the American College of Medical Genetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/20057316/" - } - ], - "5564cfa4-6a5c-4328-a0b6-5cd1cc0b2338": [ - { - "pub_id": "20081858", - "title": "New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk.", - "authors": "Jos\u00e9e Dupuis,Claudia Langenberg,Inga Prokopenko,Richa Saxena,Nicole Soranzo,Anne U Jackson,Eleanor Wheeler,Nicole L Glazer,Nabila Bouatia-Naji,Anna L Gloyn,Cecilia M Lindgren,Reedik M\u00e4gi,Andrew P Morris,Joshua Randall,Toby Johnson,Paul Elliott,Denis Rybin,Gudmar Thorleifsson,Valgerdur Steinthorsdottir,Peter Henneman,Harald Grallert,Abbas Dehghan,Jouke Jan Hottenga,Christopher S Franklin,Pau Navarro,Kijoung Song,Anuj Goel,John R B Perry,Josephine M Egan,Taina Lajunen,Niels Grarup,Thomas Spars\u00f8,Alex Doney,Benjamin F Voight,Heather M Stringham,Man Li,Stavroula Kanoni,Peter Shrader,Christine Cavalcanti-Proen\u00e7a,Meena Kumari,Lu Qi,Nicholas J Timpson,Christian Gieger,Carina Zabena,Ghislain Rocheleau,Erik Ingelsson,Ping An,Jeffrey O'Connell,Jian'an Luan,Amanda Elliott,Steven A McCarroll,Felicity Payne,Rosa Maria Roccasecca,Fran\u00e7ois Pattou,Praveen Sethupathy,Kristin Ardlie,Yavuz Ariyurek,Beverley Balkau,Philip Barter,John P Beilby,Yoav Ben-Shlomo,Rafn Benediktsson,Amanda J Bennett,Sven Bergmann,Murielle Bochud,Eric Boerwinkle,Am\u00e9lie Bonnefond,Lori L Bonnycastle,Knut Borch-Johnsen,Yvonne B\u00f6ttcher,Eric Brunner,Suzannah J Bumpstead,Guillaume Charpentier,Yii-Der Ida Chen,Peter Chines,Robert Clarke,Lachlan J M Coin,Matthew N Cooper,Marilyn Cornelis,Gabe Crawford,Laura Crisponi,Ian N M Day,Eco J C de Geus,Jerome Delplanque,Christian Dina,Michael R Erdos,Annette C Fedson,Antje Fischer-Rosinsky,Nita G Forouhi,Caroline S Fox,Rune Frants,Maria Grazia Franzosi,Pilar Galan,Mark O Goodarzi,J\u00fcrgen Graessler,Christopher J Groves,Scott Grundy,Rhian Gwilliam,Ulf Gyllensten,Samy Hadjadj,G\u00f6ran Hallmans,Naomi Hammond,Xijing Han,Anna-Liisa Hartikainen,Neelam Hassanali,Caroline Hayward,Simon C Heath,Serge Hercberg,Christian Herder,Andrew A Hicks,David R Hillman,Aroon D Hingorani,Albert Hofman,Jennie Hui,Joe Hung,Bo Isomaa,Paul R V Johnson,Torben J\u00f8rgensen,Antti Jula,Marika Kaakinen,Jaakko Kaprio,Y Antero Kesaniemi,Mika Kivimaki,Beatrice Knight,Seppo Koskinen,Peter Kovacs,Kirsten Ohm Kyvik,G Mark Lathrop,Debbie A Lawlor,Olivier Le Bacquer,C\u00e9cile Lecoeur,Yun Li,Valeriya Lyssenko,Robert Mahley,Massimo Mangino,Alisa K Manning,Mar\u00eda Teresa Mart\u00ednez-Larrad,Jarred B McAteer,Laura J McCulloch,Ruth McPherson,Christa Meisinger,David Melzer,David Meyre,Braxton D Mitchell,Mario A Morken,Sutapa Mukherjee,Silvia Naitza,Narisu Narisu,Matthew J Neville,Ben A Oostra,Marco Orr\u00f9,Ruth Pakyz,Colin N A Palmer,Giuseppe Paolisso,Cristian Pattaro,Daniel Pearson,John F Peden,Nancy L Pedersen,Markus Perola,Andreas F H Pfeiffer,Irene Pichler,Ozren Polasek,Danielle Posthuma,Simon C Potter,Anneli Pouta,Michael A Province,Bruce M Psaty,Wolfgang Rathmann,Nigel W Rayner,Kenneth Rice,Samuli Ripatti,Fernando Rivadeneira,Michael Roden,Olov Rolandsson,Annelli Sandbaek,Manjinder Sandhu,Serena Sanna,Avan Aihie Sayer,Paul Scheet,Laura J Scott,Udo Seedorf,Stephen J Sharp,Beverley Shields,Gunnar Sigurethsson,Eric J G Sijbrands,Angela Silveira,Laila Simpson,Andrew Singleton,Nicholas L Smith,Ulla Sovio,Amy Swift,Holly Syddall,Ann-Christine Syv\u00e4nen,Toshiko Tanaka,Barbara Thorand,Jean Tichet,Anke T\u00f6njes,Tiinamaija Tuomi,Andr\u00e9 G Uitterlinden,Ko Willems van Dijk,Mandy van Hoek,Dhiraj Varma,Sophie Visvikis-Siest,Veronique Vitart,Nicole Vogelzangs,G\u00e9rard Waeber,Peter J Wagner,Andrew Walley,G Bragi Walters,Kim L Ward,Hugh Watkins,Michael N Weedon,Sarah H Wild,Gonneke Willemsen,Jaqueline C M Witteman,John W G Yarnell,Eleftheria Zeggini,Diana Zelenika,Bj\u00f6rn Zethelius,Guangju Zhai,Jing Hua Zhao,M Carola Zillikens, , , ,Ingrid B Borecki,Ruth J F Loos,Pierre Meneton,Patrik K E Magnusson,David M Nathan,Gordon H Williams,Andrew T Hattersley,Kaisa Silander,Veikko Salomaa,George Davey Smith,Stefan R Bornstein,Peter Schwarz,Joachim Spranger,Fredrik Karpe,Alan R Shuldiner,Cyrus Cooper,George V Dedoussis,Manuel Serrano-R\u00edos,Andrew D Morris,Lars Lind,Lyle J Palmer,Frank B Hu,Paul W Franks,Shah Ebrahim,Michael Marmot,W H Linda Kao,James S Pankow,Michael J Sampson,Johanna Kuusisto,Markku Laakso,Torben Hansen,Oluf Pedersen,Peter Paul Pramstaller,H Erich Wichmann,Thomas Illig,Igor Rudan,Alan F Wright,Michael Stumvoll,Harry Campbell,James F Wilson, , ,Richard N Bergman,Thomas A Buchanan,Francis S Collins,Karen L Mohlke,Jaakko Tuomilehto,Timo T Valle,David Altshuler,Jerome I Rotter,David S Siscovick,Brenda W J H Penninx,Dorret I Boomsma,Panos Deloukas,Timothy D Spector,Timothy M Frayling,Luigi Ferrucci,Augustine Kong,Unnur Thorsteinsdottir,Kari Stefansson,Cornelia M van Duijn,Yurii S Aulchenko,Antonio Cao,Angelo Scuteri,David Schlessinger,Manuela Uda,Aimo Ruokonen,Marjo-Riitta Jarvelin,Dawn M Waterworth,Peter Vollenweider,Leena Peltonen,Vincent Mooser,Goncalo R Abecasis,Nicholas J Wareham,Robert Sladek,Philippe Froguel,Richard M Watanabe,James B Meigs,Leif Groop,Michael Boehnke,Mark I McCarthy,Jose C Florez,In\u00eas Barroso", - "abstract": "Levels of circulating glucose are tightly regulated. To identify new loci influencing glycemic traits, we performed meta-analyses of 21 genome-wide association studies informative for fasting glucose, fasting insulin and indices of beta-cell function (HOMA-B) and insulin resistance (HOMA-IR) in up to 46,186 nondiabetic participants. Follow-up of 25 loci in up to 76,558 additional subjects identified 16 loci associated with fasting glucose and HOMA-B and two loci associated with fasting insulin and HOMA-IR. These include nine loci newly associated with fasting glucose (in or near ADCY5, MADD, ADRA2A, CRY2, FADS1, GLIS3, SLC2A2, PROX1 and C2CD4B) and one influencing fasting insulin and HOMA-IR (near IGF1). We also demonstrated association of ADCY5, PROX1, GCK, GCKR and DGKB-TMEM195 with type 2 diabetes. Within these loci, likely biological candidate genes influence signal transduction, cell proliferation, development, glucose-sensing and circadian regulation. Our results demonstrate that genetic studies of glycemic traits can identify type 2 diabetes risk loci, as well as loci containing gene variants that are associated with a modest elevation in glucose levels but are not associated with overt diabetes.", - "journal_title": "Nature genetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/20081858/" - } - ], - "144c9105-3ce9-46cc-b9c6-cc14cf40e945": [ - { - "pub_id": "21085585", - "title": "Genome-wide analysis of copy number variation in type 1 diabetes.", - "authors": "Britney L Grayson,Mary Ellen Smith,James W Thomas,Lily Wang,Phil Dexheimer,Joy Jeffrey,Pamela R Fain,Priyaanka Nanduri,George S Eisenbarth,Thomas M Aune", - "abstract": "Type 1 diabetes (T1D) tends to cluster in families, suggesting there may be a genetic component predisposing to disease. However, a recent large-scale genome-wide association study concluded that identified genetic factors, single nucleotide polymorphisms, do not account for overall familiality. Another class of genetic variation is the amplification or deletion of >1 kilobase segments of the genome, also termed copy number variations (CNVs). We performed genome-wide CNV analysis on a cohort of 20 unrelated adults with T1D and a control (Ctrl) cohort of 20 subjects using the Affymetrix SNP Array 6.0 in combination with the Birdsuite copy number calling software. We identified 39 CNVs as enriched or depleted in T1D versus Ctrl. Additionally, we performed CNV analysis in a group of 10 monozygotic twin pairs discordant for T1D. Eleven of these 39 CNVs were also respectively enriched or depleted in the Twin cohort, suggesting that these variants may be involved in the development of islet autoimmunity, as the presently unaffected twin is at high risk for developing islet autoimmunity and T1D in his or her lifetime. These CNVs include a deletion on chromosome 6p21, near an HLA-DQ allele. CNVs were found that were both enriched or depleted in patients with or at high risk for developing T1D. These regions may represent genetic variants contributing to development of islet autoimmunity in T1D.", - "journal_title": "PloS one", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/21085585/" - } - ], - "fd143578-73cd-4046-aecf-e546026c35ee": [ - { - "pub_id": "25262148", - "title": "The association between lipid metabolism gene polymorphisms and nephropathy in type 2 diabetes: a meta-analysis.", - "authors": "Tingting Li,Yun Shi,Jieyun Yin,Qin Qin,Sheng Wei,Shaofa Nie,Li Liu", - "abstract": "Hyperlipidaemia has been identified as a risk factor for diabetic nephropathy via exacerbation of glomerular injury through the activation of multiple signaling pathways. This study's aim is to assess the associations between polymorphisms of genes involved in lipid metabolism, such as apolipoprotein E (ApoE), peroxisome proliferator-activated receptor \u03b3 (PPAR\u03b3), acetyl-CoA carboxylase \u03b2 (ACACB), and type 2 diabetic nephropathy (T2DN). A search of the MEDLINE and Web of Science databases was used to identify relevant studies, and allele or genotype frequencies were pooled using fixed- or random-effects models. Forty-five studies were included in this meta-analysis, consisting of 10,920 type 2 diabetic patients with nephropathy and 16,203 type 2 diabetic patients without nephropathy. The OR for ApoE \u03b52 versus \u03b53 was 1.49 (95% CI 1.13-1.95) in T2DN. The progression of T2DN was related to the presence of the \u03b52 allele and \u03b52 carrier with ORs of 1.72 (95% CI 1.10-2.69) and 1.78 (95% CI 1.18-2.69), respectively. The rs1801282 C>G variant in PPAR\u03b3 presented a significant association with decreased T2DN risk, both in the G allele and GC/GG genotype with ORs of 0.77 (95% CI 0.68-0.87) and 0.79 (95% CI 0.69-0.92), respectively. The T allele in rs2268388 within ACACB showed an increased risk for T2DN, exhibiting an OR of 1.35 (95% CI 1.12-1.63). Our meta-analysis supports that the ApoE \u03b52 allele and ACACB rs2268388 C>T might act as promotion factors of nephropathy in type 2 diabetes, whereas PPAR\u03b3 rs1801282 C>G is a promising candidate genetic variation for reducing susceptibility to T2DN.", - "journal_title": "International urology and nephrology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/25262148/" - } - ], - "3b403824-5be6-4799-84c4-70bf6155a28e": [ - { - "pub_id": "23328391", - "title": "Sex differences in the gut microbiome drive hormone-dependent regulation of autoimmunity.", - "authors": "Janet G M Markle,Daniel N Frank,Steven Mortin-Toth,Charles E Robertson,Leah M Feazel,Ulrike Rolle-Kampczyk,Martin von Bergen,Kathy D McCoy,Andrew J Macpherson,Jayne S Danska", - "abstract": "Microbial exposures and sex hormones exert potent effects on autoimmune diseases, many of which are more prevalent in women. We demonstrate that early-life microbial exposures determine sex hormone levels and modify progression to autoimmunity in the nonobese diabetic (NOD) mouse model of type 1 diabetes (T1D). Colonization by commensal microbes elevated serum testosterone and protected NOD males from T1D. Transfer of gut microbiota from adult males to immature females altered the recipient's microbiota, resulting in elevated testosterone and metabolomic changes, reduced islet inflammation and autoantibody production, and robust T1D protection. These effects were dependent on androgen receptor activity. Thus, the commensal microbial community alters sex hormone levels and regulates autoimmune disease fate in individuals with high genetic risk.", - "journal_title": "Science (New York, N.Y.)", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/23328391/" - } - ], - "df1cc001-06bb-4070-84ed-dc48d12395fc": [ - { - "pub_id": "29768754", - "title": "Are health professionals ready for direct-to-consumer genetic and genomic testing?", - "authors": "Heather Skirton,Leigh Jackson,Lesley Goldsmith,Anita O'Connor", - "abstract": "Direct-to-consumer genetic and genomic tests have been offered for over a decade. With the reduction in the cost of sequencing, the options for consumers will increase, with subsequent pressure on health services to interpret data and integrate the results into healthcare management. However, indications are that health professionals are grossly unprepared to deal with requests for support from those who have undertaken direct-to-consumer genetic or genomic tests. While benefits may be derived from patient-driven investigations, distinction needs to be made between the mostly uncertain clinical utility of susceptibility testing and the potential benefits of a reliably interpreted sequencing result. It is essential that we develop strategies, including enhanced professional education, to cope with the potential impact on the health services, rather than ignoring these developments. There may also be implications for the future of genetic counseling, with potential changes in the current paradigm.", - "journal_title": "Personalized medicine", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/29768754/" - } - ], - "fdbabc3c-ec60-45ce-9f5c-683f745c4d00": [ - { - "pub_id": "20581827", - "title": "Twelve type 2 diabetes susceptibility loci identified through large-scale association analysis.", - "authors": "Benjamin F Voight,Laura J Scott,Valgerdur Steinthorsdottir,Andrew P Morris,Christian Dina,Ryan P Welch,Eleftheria Zeggini,Cornelia Huth,Yurii S Aulchenko,Gudmar Thorleifsson,Laura J McCulloch,Teresa Ferreira,Harald Grallert,Najaf Amin,Guanming Wu,Cristen J Willer,Soumya Raychaudhuri,Steve A McCarroll,Claudia Langenberg,Oliver M Hofmann,Jos\u00e9e Dupuis,Lu Qi,Ayellet V Segr\u00e8,Mandy van Hoek,Pau Navarro,Kristin Ardlie,Beverley Balkau,Rafn Benediktsson,Amanda J Bennett,Roza Blagieva,Eric Boerwinkle,Lori L Bonnycastle,Kristina Bengtsson Bostr\u00f6m,Bert Bravenboer,Suzannah Bumpstead,Nois\u00ebl P Burtt,Guillaume Charpentier,Peter S Chines,Marilyn Cornelis,David J Couper,Gabe Crawford,Alex S F Doney,Katherine S Elliott,Amanda L Elliott,Michael R Erdos,Caroline S Fox,Christopher S Franklin,Martha Ganser,Christian Gieger,Niels Grarup,Todd Green,Simon Griffin,Christopher J Groves,Candace Guiducci,Samy Hadjadj,Neelam Hassanali,Christian Herder,Bo Isomaa,Anne U Jackson,Paul R V Johnson,Torben J\u00f8rgensen,Wen H L Kao,Norman Klopp,Augustine Kong,Peter Kraft,Johanna Kuusisto,Torsten Lauritzen,Man Li,Aloysius Lieverse,Cecilia M Lindgren,Valeriya Lyssenko,Michel Marre,Thomas Meitinger,Kristian Midthjell,Mario A Morken,Narisu Narisu,Peter Nilsson,Katharine R Owen,Felicity Payne,John R B Perry,Ann-Kristin Petersen,Carl Platou,Christine Proen\u00e7a,Inga Prokopenko,Wolfgang Rathmann,N William Rayner,Neil R Robertson,Ghislain Rocheleau,Michael Roden,Michael J Sampson,Richa Saxena,Beverley M Shields,Peter Shrader,Gunnar Sigurdsson,Thomas Spars\u00f8,Klaus Strassburger,Heather M Stringham,Qi Sun,Amy J Swift,Barbara Thorand,Jean Tichet,Tiinamaija Tuomi,Rob M van Dam,Timon W van Haeften,Thijs van Herpt,Jana V van Vliet-Ostaptchouk,G Bragi Walters,Michael N Weedon,Cisca Wijmenga,Jacqueline Witteman,Richard N Bergman,Stephane Cauchi,Francis S Collins,Anna L Gloyn,Ulf Gyllensten,Torben Hansen,Winston A Hide,Graham A Hitman,Albert Hofman,David J Hunter,Kristian Hveem,Markku Laakso,Karen L Mohlke,Andrew D Morris,Colin N A Palmer,Peter P Pramstaller,Igor Rudan,Eric Sijbrands,Lincoln D Stein,Jaakko Tuomilehto,Andre Uitterlinden,Mark Walker,Nicholas J Wareham,Richard M Watanabe,Gon\u00e7alo R Abecasis,Bernhard O Boehm,Harry Campbell,Mark J Daly,Andrew T Hattersley,Frank B Hu,James B Meigs,James S Pankow,Oluf Pedersen,H-Erich Wichmann,In\u00eas Barroso,Jose C Florez,Timothy M Frayling,Leif Groop,Rob Sladek,Unnur Thorsteinsdottir,James F Wilson,Thomas Illig,Philippe Froguel,Cornelia M van Duijn,Kari Stefansson,David Altshuler,Michael Boehnke,Mark I McCarthy, , ", - "abstract": "By combining genome-wide association data from 8,130 individuals with type 2 diabetes (T2D) and 38,987 controls of European descent and following up previously unidentified meta-analysis signals in a further 34,412 cases and 59,925 controls, we identified 12 new T2D association signals with combined P<5x10(-8). These include a second independent signal at the KCNQ1 locus; the first report, to our knowledge, of an X-chromosomal association (near DUSP9); and a further instance of overlap between loci implicated in monogenic and multifactorial forms of diabetes (at HNF1A). The identified loci affect both beta-cell function and insulin action, and, overall, T2D association signals show evidence of enrichment for genes involved in cell cycle regulation. We also show that a high proportion of T2D susceptibility loci harbor independent association signals influencing apparently unrelated complex traits.", - "journal_title": "Nature genetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/20581827/" - } - ], - "05c26b4c-cc56-49bc-914e-066ba0f05e97": [ - { - "pub_id": "25514087", - "title": "Gestational Diabetes Alters Offspring DNA Methylation Profiles in Human and Rat: Identification of Key Pathways Involved in Endocrine System Disorders, Insulin Signaling, Diabetes Signaling, and ILK Signaling.", - "authors": "Sophie Petropoulos,Claire Guillemin,Zivanit Ergaz,Sergiy Dimov,Matthew Suderman,Liza Weinstein-Fudim,Asher Ornoy,Moshe Szyf", - "abstract": "Gestational diabetes is associated with risk for metabolic disease later in life. Using a cross-species approach in rat and humans, we examined the hypothesis that gestational diabetes during pregnancy triggers changes in the methylome of the offspring that might be mediating these risks. We show in a gestation diabetes rat model, the Cohen diabetic rat, that gestational diabetes triggers wide alterations in DNA methylation in the placenta in both candidate diabetes genes and genome-wide promoters, thus providing evidence for a causal relationship between diabetes during pregnancy and DNA methylation alterations. There is a significant overlap between differentially methylated genes in the placenta and the liver of the rat offspring. Several genes differentially methylated in rat placenta exposed to maternal diabetes are also differentially methylated in the human placenta of offspring exposed to gestational diabetes in utero. DNA methylation changes inversely correlate with changes in expression. The changes in DNA methylation affect known functional gene pathways involved in endocrine function, metabolism, and insulin responses. These data provide support to the hypothesis that early-life exposures and their effects on metabolic disease are mediated by DNA methylation changes. This has important diagnostic and therapeutic implications.", - "journal_title": "Endocrinology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/25514087/" - } - ], - "52fbc21d-e3c9-4f79-bdb9-deb5152e207c": [ - { - "pub_id": "22210626", - "title": "Genome-wide association study in multiple human prion diseases suggests genetic risk factors additional to PRNP.", - "authors": "Simon Mead,James Uphill,John Beck,Mark Poulter,Tracy Campbell,Jessica Lowe,Gary Adamson,Holger Hummerich,Norman Klopp,Ina-Maria R\u00fcckert,H-Erich Wichmann,Dhoyazan Azazi,Vincent Plagnol,Wandagi H Pako,Jerome Whitfield,Michael P Alpers,John Whittaker,David J Balding,Inga Zerr,Hans Kretzschmar,John Collinge", - "abstract": "Prion diseases are fatal neurodegenerative diseases of humans and animals caused by the misfolding and aggregation of prion protein (PrP). Mammalian prion diseases are under strong genetic control but few risk factors are known aside from the PrP gene locus (PRNP). No genome-wide association study (GWAS) has been done aside from a small sample of variant Creutzfeldt-Jakob disease (CJD). We conducted GWAS of sporadic CJD (sCJD), variant CJD (vCJD), iatrogenic CJD, inherited prion disease, kuru and resistance to kuru despite attendance at mortuary feasts. After quality control, we analysed 2000 samples and 6015 control individuals (provided by the Wellcome Trust Case Control Consortium and KORA-gen) for 491032-511862 SNPs in the European study. Association studies were done in each geographical and aetiological group followed by several combined analyses. The PRNP locus was highly associated with risk in all geographical and aetiological groups. This association was driven by the known coding variation at rs1799990 (PRNP codon 129). No non-PRNP loci achieved genome-wide significance in the meta-analysis of all human prion disease. SNPs at the ZBTB38-RASA2 locus were associated with CJD in the UK (rs295301, P = 3.13 \u00d7 10(-8); OR, 0.70) but these SNPs showed no replication evidence of association in German sCJD or in Papua New Guinea-based tests. A SNP in the CHN2 gene was associated with vCJD [P = 1.5 \u00d7 10(-7); odds ratio (OR), 2.36], but not in UK sCJD (P = 0.049; OR, 1.24), in German sCJD or in PNG groups. In the overall meta-analysis of CJD, 14 SNPs were associated (P < 10(-5); two at PRNP, three at ZBTB38-RASA2, nine at nine other independent non-PRNP loci), more than would be expected by chance. None of the loci recently identified as genome-wide significant in studies of other neurodegenerative diseases showed any clear evidence of association in prion diseases. Concerning common genetic variation, it is likely that the PRNP locus contains the only strong risk factors that act universally across human prion diseases. Our data are most consistent with several other risk loci of modest overall effects which will require further genetic association studies to provide definitive evidence.", - "journal_title": "Human molecular genetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/22210626/" - } - ], - "8e42498d-ca77-4580-9c4c-2c7b0885431a": [ - { - "pub_id": "25193495", - "title": "Reference genes for expression studies in hypoxia and hyperglycemia models in human umbilical vein endothelial cells.", - "authors": "Sherin Bakhashab,Sahira Lary,Farid Ahmed,Hans-Juergen Schulten,Ayat Bashir,Fahad W Ahmed,Abdulrahman L Al-Malki,Hasan S Jamal,Mamdooh A Gari,Jolanta U Weaver", - "abstract": "Human umbilical vein endothelial cell (HUVEC)-based gene expression studies performed under hypoxia and/or hyperglycemia show huge potential for modeling endothelial cell response in cardiovascular disease and diabetes. However, such studies require reference genes that are stable across the whole range of experimental conditions. These reference genes have not been comprehensively defined to date. We applied human genome-wide microarrays and quantitative real-time PCR (qRT-PCR) on RNA obtained from primary HUVEC cultures that were incubated for 24 hr either in euglycemic or in hyperglycemic conditions and then subjected to short-term CoCl2-induced hypoxia for 1, 3, or 12 hr. Using whole-transcript arrays, we selected 10 commonly used reference genes with no significant expression variation across eight different conditions. These genes were ranked using NormFinder software according to their stability values. Consequently, five genes were selected for validation by qRT-PCR. These were ribosomal protein large P0 (RPLP0), transferrin receptor (TFRC), glyceraldehyde-3-phosphate dehydrogenase (GAPDH), \u03b2-glucuronidase (GUSB), and \u03b2-actin (ACTB). All five genes displayed stable expression under hyperglycemia. However, only RPLP0 and TFRC genes were stable under hypoxia up to 12 hr. Under hyperglycemia combined with hypoxia up to 12 hr, the expression of RPLP0, TFRC, GUSB, and ACTB genes remained unchanged. Our findings strongly confirm that RPLP0 and TFRC are the most suitable reference genes for HUVEC gene expression experiments subjected to hypoxia and/or hyperglycemia for the given experimental conditions. We provide further evidence that even commonly known references genes require experimental validation for all conditions involved.", - "journal_title": "G3 (Bethesda, Md.)", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/25193495/" - } - ], - "1871276b-11a6-4cff-9c2c-25eb442db144": [ - { - "pub_id": "30291106", - "title": "Management of Hyperglycemia in Type 2 Diabetes, 2018. A Consensus Report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD).", - "authors": "Melanie J Davies,David A D'Alessio,Judith Fradkin,Walter N Kernan,Chantal Mathieu,Geltrude Mingrone,Peter Rossing,Apostolos Tsapas,Deborah J Wexler,John B Buse", - "abstract": "The American Diabetes Association and the European Association for the Study of Diabetes convened a panel to update the prior position statements, published in 2012 and 2015, on the management of type 2 diabetes in adults. A systematic evaluation of the literature since 2014 informed new recommendations. These include additional focus on lifestyle management and diabetes self-management education and support. For those with obesity, efforts targeting weight loss, including lifestyle, medication, and surgical interventions, are recommended. With regards to medication management, for patients with clinical cardiovascular disease, a sodium-glucose cotransporter 2 (SGLT2) inhibitor or a glucagon-like peptide 1 (GLP-1) receptor agonist with proven cardiovascular benefit is recommended. For patients with chronic kidney disease or clinical heart failure and atherosclerotic cardiovascular disease, an SGLT2 inhibitor with proven benefit is recommended. GLP-1 receptor agonists are generally recommended as the first injectable medication.", - "journal_title": "Diabetes care", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/30291106/" - } - ], - "82fdf358-5073-4f7b-97a0-01328a639ccc": [ - { - "pub_id": "22953038", - "title": "Investigation of the biological properties of Cinnulin PF in the context of diabetes: mechanistic insights by genome-wide mRNA-Seq analysis.", - "authors": "Haloom Rafehi,Katherine Ververis,Aneta Balcerczyk,Mark Ziemann,Jenny Ooi,Sean Hu,Faith A A Kwa,Shanon J Loveridge,George T Georgiadis,Assam El-Osta,Tom C Karagiannis", - "abstract": "The accumulating evidence of the beneficial effects of cinnamon (Cinnamomum burmanni) in type-2 diabetes, a chronic age-associated disease, has prompted the commercialisation of various supplemental forms of the spice. One such supplement, Cinnulin PF(\u00ae), represents the water soluble fraction containing relatively high levels of the double-linked procyanidin type-A polymers of flavanoids. The overall aim of this study was to utilize genome-wide mRNA-Seq analysis to characterise the changes in gene expression caused by Cinnulin PF in immortalised human keratinocytes and microvascular endothelial cells, which are relevant with respect to diabetic complications. In summary, our findings provide insights into the mechanisms of action of Cinnulin PF in diabetes and diabetic complications. More generally, we identify relevant candidate genes which could provide the basis for further investigation.", - "journal_title": "Pathobiology of aging & age related diseases", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/22953038/" - } - ], - "62af87d7-7290-4ad1-9914-fb1488841ad8": [ - { - "pub_id": "21915815", - "title": "Lifestyle and genetics in obesity and type 2 diabetes.", - "authors": "T Temelkova-Kurktschiev,T Stefanov", - "abstract": "Obesity and type 2 diabetes mellitus are multifactorial health threats caused by a complex interplay between genetic predisposition and the environment with dramatically increasing worldwide prevalence. The role of heritability in their etiology is well recognized, however, the numerous attempts made in order certain genetic variants determining individual susceptibility to be identified have had limited success, until recently. At present the advancements in human genetics and the utilization of the genome-wide association approach have led to the identification of over 20 genetic loci associated with, respectively obesity and type 2 diabetes. Most of the genes identified to date, however, have modest effect on disease risk suggesting that both diseases are unlikely to develop without the individual being exposed to obesity- and/or type 2 diabetes-promoting environment. Indeed, unhealthy lifestyle, characterized by physical inactivity and food overconsumption is an unequivocally established risk factor for obesity and type 2 diabetes. Numerous epidemiological studies and randomized controlled trials, on the other hand, have demonstrated that lifestyle modification is effective in obesity and type 2 diabetes prevention. Furthermore, gene-lifestyle interaction studies suggest that genetic susceptibility to obesity and type 2 diabetes may be partially or totally kept under control by healthy lifestyle or lifestyle modification and that lifestyle determines whether an individual is likely to develop the disease. Inherited factors, however, seem to influence individual response to a lifestyle intervention program and even the motivation for lifestyle change. Personalized interventions according to genotype may be, therefore, considered in the future. By then lifestyle modification targeting dietary change and increased physical activity may be recommended for successful obesity and type 2 diabetes prevention irrespectively of genetic susceptibility.", - "journal_title": "Experimental and clinical endocrinology & diabetes : official journal, German Society of Endocrinology [and] German Diabetes Association", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/21915815/" - } - ], - "8b494a5b-c9c0-46b9-8ce7-388a5ba8e5b2": [ - { - "pub_id": "25073516", - "title": "Meta-analysis of genome-wide association study of homeostasis model assessment \u03b2 cell function and insulin resistance in an East Asian population and the European results.", - "authors": "Kyung-Won Hong,Myunggen Chung,Seong Beom Cho", - "abstract": "Compared with Western populations, Asians develop diabetes at younger ages, at lower degrees of obesity. Because diabetes and the related traits are influenced by the interplay between genetic and environmental factors, it is important to understand the genetic differences between Asian and Western populations. Recently, a large-scale meta-analysis of genome-wide association studies for beta cell function and insulin resistance in the European ancestry was reported by the Meta-Analyses of Glucose and Insulin-related traits Consortium (MAGIC). The MAGIC study reported 17 SNPs for homeostasis model assessments (HOMA-%B: beta cell function and HOMA-IR: insulin resistance). In this study, we tried to replicate the effects of reported SNPs by MAGIC study, which were influencing HOMAs in two Korean populations. HOMA-IR and HOMA-B were computed using two HOMA models (HOMA1 and HOMA2). The HOMA2 model has recently been updated with physiological adjustments into a computer version, providing a more accurate index. Dupuis et al. (Nat Genet 42: 105-116, 2010). In this study, we examined the reported SNPs in two Korean community-based cohorts (Ansung and Ansan). The Korean genotypes and glucose and insulin traits for 5,974 non-diabetic subjects were obtained from a previous genome-wide association study. Although we expected the HOMA2 to be suitable to replicate the results of different ethnics, our results revealed that the HOMA1 was more significantly replicated. As a result, 5 SNPs (rs10830963 in MTNR1B, rs4607517 in GCK, rs2191349 in DGKB/TMEM195, rs174550 in FADS1, rs7034200 in GLIS3) were significantly replicated with HOMA-%B, but no SNP was replicated with HOMA-IR. Two SNPs (rs560887 in G6PC, rs13266634 in SLC30A8) and one SNP (rs35767 in IGF1) showed the weak association p values (unadjusted p values lower than 0.05) for HOMA-%B and HOMA-IR, respectively. The replicated SNPs and the weakly associated SNPs were also significantly associated with the fasting glucose levels. They revealed the same direction of the effect sizes in both studies, but the effect sizes were stronger in Koreans than in MAGIC. Conclusively, our results indicated that SNPs from MTNR1B, GCK, DGKB, FADS1, and GLIS3 were consistently associated with HOMA-%B in both Korean and MAGIC populations.", - "journal_title": "Molecular genetics and genomics : MGG", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/25073516/" - } - ], - "8d53b2e9-f00f-45c5-9403-43c2ae8ee330": [ - { - "pub_id": "20074523", - "title": "Drosophila genome-wide obesity screen reveals hedgehog as a determinant of brown versus white adipose cell fate.", - "authors": "J Andrew Pospisilik,Daniel Schramek,Harald Schnidar,Shane J F Cronin,Nadine T Nehme,Xiaoyun Zhang,Claude Knauf,Patrice D Cani,Karin Aumayr,Jelena Todoric,Martina Bayer,Arvand Haschemi,Vijitha Puviindran,Krisztina Tar,Michael Orthofer,G Gregory Neely,Georg Dietzl,Armen Manoukian,Martin Funovics,Gerhard Prager,Oswald Wagner,Dominique Ferrandon,Fritz Aberger,Chi-chung Hui,Harald Esterbauer,Josef M Penninger", - "abstract": "Over 1 billion people are estimated to be overweight, placing them at risk for diabetes, cardiovascular disease, and cancer. We performed a systems-level genetic dissection of adiposity regulation using genome-wide RNAi screening in adult Drosophila. As a follow-up, the resulting approximately 500 candidate obesity genes were functionally classified using muscle-, oenocyte-, fat-body-, and neuronal-specific knockdown in vivo and revealed hedgehog signaling as the top-scoring fat-body-specific pathway. To extrapolate these findings into mammals, we generated fat-specific hedgehog-activation mutant mice. Intriguingly, these mice displayed near total loss of white, but not brown, fat compartments. Mechanistically, activation of hedgehog signaling irreversibly blocked differentiation of white adipocytes through direct, coordinate modulation of early adipogenic factors. These findings identify a role for hedgehog signaling in white/brown adipocyte determination and link in vivo RNAi-based scanning of the Drosophila genome to regulation of adipocyte cell fate in mammals.", - "journal_title": "Cell", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/20074523/" - } - ], - "f1a4645e-0e52-4699-8b9b-19f7ca526e2b": [ - { - "pub_id": "27524441", - "title": "An Isogenic Human ESC Platform for Functional Evaluation of Genome-wide-Association-Study-Identified Diabetes Genes and Drug Discovery.", - "authors": "Hui Zeng,Min Guo,Ting Zhou,Lei Tan,Chi Nok Chong,Tuo Zhang,Xue Dong,Jenny Zhaoying Xiang,Albert S Yu,Lixia Yue,Qibin Qi,Todd Evans,Johannes Graumann,Shuibing Chen", - "abstract": "Genome-wide association studies (GWASs) have increased our knowledge of loci associated with a\u00a0range of human diseases. However, applying such findings to elucidate pathophysiology and promote drug discovery remains challenging. Here, we created isogenic human ESCs (hESCs) with mutations in GWAS-identified susceptibility genes for type 2 diabetes. In pancreatic beta-like cells differentiated from these lines, we found that mutations\u00a0in\u00a0CDKAL1, KCNQ1, and KCNJ11 led to impaired glucose secretion in\u00a0vitro and in\u00a0vivo, coinciding with defective glucose homeostasis. CDKAL1 mutant insulin+ cells were also hypersensitive to glucolipotoxicity. A high-content chemical screen identified a candidate drug that rescued CDKAL1-specific defects in\u00a0vitro and in\u00a0vivo by inhibiting the\u00a0FOS/JUN pathway. Our approach of a proof-of-principle platform, which uses isogenic hESCs for functional evaluation of GWAS-identified loci and identification of a drug candidate that rescues gene-specific defects, paves the way for precision therapy of metabolic diseases.", - "journal_title": "Cell stem cell", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/27524441/" - } - ], - "783dfac9-29b7-4755-9b36-9124de398c78": [ - { - "pub_id": "36729053", - "title": "Updated clinical practice recommendations for managing children with 22q11.2 deletion syndrome.", - "authors": "S\u00f3lveig \u00d3skarsd\u00f3ttir,Erik Boot,Terrence Blaine Crowley,Joanne C Y Loo,Jill M Arganbright,Marco Armando,Adriane L Baylis,Elemi J Breetvelt,Ren\u00e9 M Castelein,Madeline Chadehumbe,Christopher M Cielo,Steven de Reuver,Stephan Eliez,Ania M Fiksinski,Brian J Forbes,Emily Gallagher,Sarah E Hopkins,Oksana A Jackson,Lorraine Levitz-Katz,Gunilla Klingberg,Michele P Lambert,Bruno Marino,Maria R Mascarenhas,Julie Moldenhauer,Edward M Moss,Beata Anna Nowakowska,Ani Orchanian-Cheff,Carolina Putotto,Gabriela M Repetto,Erica Schindewolf,Maude Schneider,Cynthia B Solot,Kathleen E Sullivan,Ann Swillen,Marta Unolt,Jason P Van Batavia,Claudia Vingerhoets,Jacob Vorstman,Anne S Bassett,Donna M McDonald-McGinn", - "abstract": "This review aimed to update the clinical practice guidelines for managing children and adolescents with 22q11.2 deletion syndrome (22q11.2DS). The 22q11.2 Society, the international scientific organization studying chromosome 22q11.2 differences and related conditions, recruited expert clinicians worldwide to revise the original 2011 pediatric clinical practice guidelines in a stepwise process: (1) a systematic literature search (1992-2021), (2) study selection and data extraction by clinical experts from 9 different countries, covering 24 subspecialties, and (3) creation of a draft consensus document based on the literature and expert opinion, which was further shaped by survey results from family support organizations regarding perceived needs. Of 2441 22q11.2DS-relevant publications initially identified, 2344 received full-text reviews, including 1545 meeting criteria for potential relevance to clinical care of children and adolescents. Informed by the available literature, recommendations were formulated. Given evidence base limitations, multidisciplinary recommendations represent consensus statements of good practice for this evolving field. These recommendations provide contemporary guidance for evaluation, surveillance, and management of the many 22q11.2DS-associated physical, cognitive, behavioral, and psychiatric morbidities while addressing important genetic counseling and psychosocial issues.", - "journal_title": "Genetics in medicine : official journal of the American College of Medical Genetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/36729053/" - } - ], - "ef2c8463-5169-46aa-938b-7d04ea8da6b7": [ - { - "pub_id": "20643313", - "title": "Autism spectrum disorders and epigenetics.", - "authors": "Daria Grafodatskaya,Brian Chung,Peter Szatmari,Rosanna Weksberg", - "abstract": "Current research suggests that the causes of autism spectrum disorders (ASD) are multifactorial and include both genetic and environmental factors. Several lines of evidence suggest that epigenetics also plays an important role in ASD etiology and that it might, in fact, integrate genetic and environmental influences to dysregulate neurodevelopmental processes. The objective of this review is to illustrate how epigenetic modifications that are known to alter gene expression without changing primary DNA sequence may play a role in the etiology of ASD. In this review, we summarize current knowledge about epigenetic modifications to genes and genomic regions possibly involved in the etiology of ASD. Several genetic syndromes comorbid with ASD, which include Rett, Fragile X, Prader-Willi, Angelman, and CHARGE (Coloboma of the eye, Heart defects, Atresia of the nasal choanae, Retardation of growth and/or development, Genital and/or urinary abnormalities, and Ear abnormalities and deafness), all demonstrate dysregulation of epigenetic marks or epigenetic mechanisms. We report also on genes or genomic regions exhibiting abnormal epigenetic regulation in association with either syndromic (15q11-13 maternal duplication) or nonsyndromic forms of ASD. Finally, we discuss the state of current knowledge regarding the etiologic role of environmental factors linked to both the development of ASD and epigenetic dysregulation. Data reviewed in this article highlight a variety of situations in which epigenetic dysregulation is associated with the development of ASD, thereby supporting a role for epigenetics in the multifactorial etiologies of ASD.", - "journal_title": "Journal of the American Academy of Child and Adolescent Psychiatry", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/20643313/" - } - ], - "fd65cdbd-68b6-4ca3-b7de-4353662ea33d": [ - { - "pub_id": "29166840", - "title": "Ethics in nursing: A systematic review of the framework of evidence perspective.", - "authors": "Erman Y\u0131ld\u0131z", - "abstract": "To determine the current state of knowledge on nursing and ethics and to assess the knowledge and experience based on the evidence in this regard. Although ethics is at the center of the nursing profession and the ethical issues affecting nurses are given much importance, few studies have focused on professional ethics in nursing. In this respect, ethics has become a concept that contains controversial and ambiguous situations. The Preferred Reporting Items for Systematic Reviews and Meta-analyses guide, a basic search algorithm, was taken. Cochrane, PubMed, CINAHL Complete, PsycINFO, and ULAKBIM from 2012 to 2016. Following a systematic search strategy, all papers were assessed in relation to inclusion criteria and type of study. When sufficient information was not available in the title and summary of the works, the necessary data were evaluated in full texts. This review was completed with 27 articles meeting the research criteria. The evaluation identified six themes: (1) ethics and nursing, (2) ethical difficulties/ethical dilemmas and nursing, (3) ethical competence and nursing, (4) professional ethics and nursing, (5) ethics, education, and nursing, and (6) ethics in health research. As a result of the review, a synthesis of high evidence-level research relating to nursing ethics was obtained. The emphasis was on the importance of further research and education so that the ethical aspects of nursing can be better understood throughout the studies. Nursing researchers' level of evidence on ethics and their orientation to high research design will shed light on uncertain and controversial aspects of the subject. Since this was a systematic review, no ethical approval was required. There is no conflict of interest in this literature review.", - "journal_title": "Nursing ethics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/29166840/" - } - ], - "72aa5d47-336b-4e4f-8593-ee215b8891d2": [ - { - "pub_id": "22389870", - "title": "Molecular characterization of neuroendocrine prostate cancer and identification of new drug targets.", - "authors": "Himisha Beltran,David S Rickman,Kyung Park,Sung Suk Chae,Andrea Sboner,Theresa Y MacDonald,Yuwei Wang,Karen L Sheikh,St\u00e9phane Terry,Scott T Tagawa,Rajiv Dhir,Joel B Nelson,Alexandre de la Taille,Yves Allory,Mark B Gerstein,Sven Perner,Kenneth J Pienta,Arul M Chinnaiyan,Yuzhuo Wang,Colin C Collins,Martin E Gleave,Francesca Demichelis,David M Nanus,Mark A Rubin", - "abstract": "Neuroendocrine prostate cancer (NEPC) is an aggressive subtype of prostate cancer that most commonly evolves from preexisting prostate adenocarcinoma (PCA). Using Next Generation RNA-sequencing and oligonucleotide arrays, we profiled 7 NEPC, 30 PCA, and 5 benign prostate tissue (BEN), and validated findings on tumors from a large cohort of patients (37 NEPC, 169 PCA, 22 BEN) using IHC and FISH. We discovered significant overexpression and gene amplification of AURKA and MYCN in 40% of NEPC and 5% of PCA, respectively, and evidence that that they cooperate to induce a neuroendocrine phenotype in prostate cells. There was dramatic and enhanced sensitivity of NEPC (and MYCN overexpressing PCA) to Aurora kinase inhibitor therapy both in vitro and in vivo, with complete suppression of neuroendocrine marker expression following treatment. We propose that alterations in Aurora kinase A and N-myc are involved in the development of NEPC, and future clinical trials will help determine from the efficacy of Aurora kinase inhibitor therapy. We report on the largest in-depth molecular analysis of NEPC and provide new insight into molecular events involved in the progression of prostate cancer.", - "journal_title": "Cancer discovery", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/22389870/" - } - ], - "9f21007a-1487-46d8-8e9e-cde8df4af6d5": [ - { - "pub_id": "21596359", - "title": "Establishing the outcome indicators for the essential nursing competencies and curricula guidelines for genetics and genomics.", - "authors": "Kathleen A Calzone,Jean Jenkins,Cynthia A Prows,Agnes Masny", - "abstract": "The translation of genetics/genomics to clinical care has implications for nurses. The Essential Nursing Competencies and Curricula Guidelines for Genetics and Genomics, established by consensus, apply to all registered nurses. Learning outcomes and clinical practice indicators have been developed to provide additional guidance. The Essentials Advisory Group (EAG) established a team to establish the Outcome Indicators. A draft was developed based on published peer-reviewed documents and syllabi. The draft underwent three layers of review: (a) critique by the EAG; (b) review by representatives at a Genetics/Genomics Toolkit for Faculty meeting; and (c) review by workshop attendees of the American Association of Colleges of Nursing's baccalaureate and master's education conferences, followed by EAG's final approval. Outcome Indicators clarify specific knowledge areas and suggest clinical performance indicators for each competency. They provide the foundation to establish a competency-based education repository with outcome indicator mapping matrixes for genetic/genomic education resources. A gap analysis of education resources identified resource deficits, and online unfolding case studies were developed. Outcome Indicators assist the academic and continuing education nurse community to prepare the nursing workforce in genetics/genomics and provide a platform from which to build tools needed to achieve this goal.", - "journal_title": "Journal of professional nursing : official journal of the American Association of Colleges of Nursing", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/21596359/" - } - ], - "15db26fd-b49f-42ca-9fee-622649e9a4f8": [ - { - "pub_id": "24983941", - "title": "Large-scale genome-wide association studies and meta-analyses of longitudinal change in adult lung function.", - "authors": "Wenbo Tang,Matthew Kowgier,Daan W Loth,Mar\u00eda Soler Artigas,Bonnie R Joubert,Emily Hodge,Sina A Gharib,Albert V Smith,Ingo Ruczinski,Vilmundur Gudnason,Rasika A Mathias,Tamara B Harris,Nadia N Hansel,Lenore J Launer,Kathleen C Barnes,Joyanna G Hansen,Eva Albrecht,Melinda C Aldrich,Michael Allerhand,R Graham Barr,Guy G Brusselle,David J Couper,Ivan Curjuric,Gail Davies,Ian J Deary,Jos\u00e9e Dupuis,Tove Fall,Millennia Foy,Nora Franceschini,Wei Gao,Sven Gl\u00e4ser,Xiangjun Gu,Dana B Hancock,Joachim Heinrich,Albert Hofman,Medea Imboden,Erik Ingelsson,Alan James,Stefan Karrasch,Beate Koch,Stephen B Kritchevsky,Ashish Kumar,Lies Lahousse,Guo Li,Lars Lind,Cecilia Lindgren,Yongmei Liu,Kurt Lohman,Thomas Lumley,Wendy L McArdle,Bernd Meibohm,Andrew P Morris,Alanna C Morrison,Bill Musk,Kari E North,Lyle J Palmer,Nicole M Probst-Hensch,Bruce M Psaty,Fernando Rivadeneira,Jerome I Rotter,Holger Schulz,Lewis J Smith,Akshay Sood,John M Starr,David P Strachan,Alexander Teumer,Andr\u00e9 G Uitterlinden,Henry V\u00f6lzke,Arend Voorman,Louise V Wain,Martin T Wells,Jemma B Wilk,O Dale Williams,Susan R Heckbert,Bruno H Stricker,Stephanie J London,Myriam Fornage,Martin D Tobin,George T O'Connor,Ian P Hall,Patricia A Cassano", - "abstract": "Genome-wide association studies (GWAS) have identified numerous loci influencing cross-sectional lung function, but less is known about genes influencing longitudinal change in lung function. We performed GWAS of the rate of change in forced expiratory volume in the first second (FEV1) in 14 longitudinal, population-based cohort studies comprising 27,249 adults of European ancestry using linear mixed effects model and combined cohort-specific results using fixed effect meta-analysis to identify novel genetic loci associated with longitudinal change in lung function. Gene expression analyses were subsequently performed for identified genetic loci. As a secondary aim, we estimated the mean rate of decline in FEV1 by smoking pattern, irrespective of genotypes, across these 14 studies using meta-analysis. The overall meta-analysis produced suggestive evidence for association at the novel IL16/STARD5/TMC3 locus on chromosome 15 (P \u200a=\u200a 5.71 \u00d7 10(-7)). In addition, meta-analysis using the five cohorts with \u22653 FEV1 measurements per participant identified the novel ME3 locus on chromosome 11 (P \u200a=\u200a 2.18 \u00d7 10(-8)) at genome-wide significance. Neither locus was associated with FEV1 decline in two additional cohort studies. We confirmed gene expression of IL16, STARD5, and ME3 in multiple lung tissues. Publicly available microarray data confirmed differential expression of all three genes in lung samples from COPD patients compared with controls. Irrespective of genotypes, the combined estimate for FEV1 decline was 26.9, 29.2 and 35.7 mL/year in never, former, and persistent smokers, respectively. In this large-scale GWAS, we identified two novel genetic loci in association with the rate of change in FEV1 that harbor candidate genes with biologically plausible functional links to lung function.", - "journal_title": "PloS one", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/24983941/" - } - ], - "294842fb-9af9-404f-baa3-d2f3e1a4789d": [ - { - "pub_id": "21129364", - "title": "Etiological heterogeneity in autism spectrum disorders: more than 100 genetic and genomic disorders and still counting.", - "authors": "Catalina Betancur", - "abstract": "There is increasing evidence that autism spectrum disorders (ASDs) can arise from rare highly penetrant mutations and genomic imbalances. The rare nature of these variants, and the often differing orbits of clinical and research geneticists, can make it difficult to fully appreciate the extent to which we have made progress in understanding the genetic etiology of autism. In fact, there is a persistent view in the autism research community that there are only a modest number of autism loci known. We carried out an exhaustive review of the clinical genetics and research genetics literature in an attempt to collate all genes and recurrent genomic imbalances that have been implicated in the etiology of ASD. We provide data on 103 disease genes and 44 genomic loci reported in subjects with ASD or autistic behavior. These genes and loci have all been causally implicated in intellectual disability, indicating that these two neurodevelopmental disorders share common genetic bases. A genetic overlap between ASD and epilepsy is also apparent in many cases. Taken together, these findings clearly show that autism is not a single clinical entity but a behavioral manifestation of tens or perhaps hundreds of genetic and genomic disorders. Increased recognition of the etiological heterogeneity of ASD will greatly expand the number of target genes for neurobiological investigations and thereby provide additional avenues for the development of pathway-based pharmacotherapy. Finally, the data provide strong support for high-resolution DNA microarrays as well as whole-exome and whole-genome sequencing as critical approaches for identifying the genetic causes of ASDs.", - "journal_title": "Brain research", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/21129364/" - } - ], - "b00b9753-c198-4f8a-a8b9-dd5e94dc5896": [ - { - "pub_id": "20936101", - "title": "Pharmacogenetics of Anti-Diabetes Drugs.", - "authors": "Johanna K Distefano,Richard M Watanabe", - "abstract": "A variety of treatment modalities exist for individuals with type 2 diabetes mellitus (T2D). In addition to dietary and physical activity interventions, T2D is also treated pharmacologically with nine major classes of approved drugs. These medications include insulin and its analogues, sulfonylureas, biguanides, thiazolidinediones (TZDs), meglitinides, \u03b1-glucosidase inhibitors, amylin analogues, incretin hormone mimetics, and dipeptidyl peptidase 4 (DPP4) inhibitors. Pharmacological treatment strategies for T2D are typically based on efficacy, yet favorable responses to such therapeutics are oftentimes variable and difficult to predict. Characterization of drug response is expected to substantially enhance our ability to provide patients with the most effective treatment strategy given their individual backgrounds, yet pharmacogenetic study of diabetes medications is still in its infancy. To date, major pharmacogenetic studies have focused on response to sulfonylureas, biguanides, and TZDs. Here, we provide a comprehensive review of pharmacogenetics investigations of these specific anti-diabetes medications. We focus not only on the results of these studies, but also on how experimental design, study sample issues, and definition of 'response' can significantly impact our interpretation of findings. Understanding the pharmacogenetics of anti-diabetes medications will provide critical baseline information for the development and implementation of genetic screening into therapeutic decision making, and lay the foundation for \"individualized medicine\" for patients with T2D.", - "journal_title": "Pharmaceuticals (Basel, Switzerland)", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/20936101/" - } - ], - "41ba5319-e77d-4838-8f50-e59fe86b94f8": [ - { - "pub_id": "22275439", - "title": "Predicting diabetes: our relentless quest for genomic nuggets.", - "authors": "Samuel Dagogo-Jack", - "abstract": "", - "journal_title": "Diabetes care", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/22275439/" - } - ], - "d15b3490-241d-4766-8e3e-feb683503d1b": [ - { - "pub_id": "23144361", - "title": "Evaluation of genome-wide association study-identified type 2 diabetes loci in African Americans.", - "authors": "Jirong Long,Todd Edwards,Lisa B Signorello,Qiuyin Cai,Wei Zheng,Xiao-Ou Shu,William J Blot", - "abstract": "Type 2 diabetes (T2D) is up to twice as prevalent among African Americans as Caucasians. Recent genome-wide association studies (GWAS) have identified multiple common genetic risk variants for T2D; however, none of these studies were conducted exclusively among subjects of African ancestry. Investigating these known loci in other populations would be an expedient way to evaluate the generalizability of the current findings. The authors evaluated 29 known T2D loci in a large southeastern US cohort study including 4,288 African Americans (1,554 cases and 2,734 controls) enrolled during 2002-2009. Seven of the 29 single nucleotide polymorphisms (SNPs) examined were found to be associated with T2D risk at P \u2264 0.05, including rs6769511 (IGF2BP2), 2 SNPs in the WFS1 gene (rs4689388 and rs1801214), rs7903146 (TCF7L2), and 3 SNPs in the KCNQ1 gene (rs231362, rs2237892, and rs2237897). Notably, the association for rs7903146 reached the GWAS significance level (P = 3.6 \u00d7 10(-8)), with an odds ratio per T allele of 1.32 (95% confidence interval: 1.20, 1.46). Regional analyses using GWAS data from Vanderbilt University's BioVU DNA biobank showed significant associations (P < 0.05) with 9 loci, though no association was observed for the index SNPs reported in European- or Asian-ancestry populations. These results extend some of the recent GWAS findings to African Americans and may guide future efforts to identify causal variants for T2D.", - "journal_title": "American journal of epidemiology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/23144361/" - } - ], - "a50a70cb-4c16-4b7e-b532-fe7db9ab435e": [ - { - "pub_id": "27088241", - "title": "Diabetes Medications as Monotherapy or Metformin-Based Combination Therapy for Type 2 Diabetes: A Systematic Review and Meta-analysis.", - "authors": "Nisa M Maruthur,Eva Tseng,Susan Hutfless,Lisa M Wilson,Catalina Suarez-Cuervo,Zackary Berger,Yue Chu,Emmanuel Iyoha,Jodi B Segal,Shari Bolen", - "abstract": "Clinicians and patients need updated evidence on the comparative effectiveness and safety of diabetes medications to make informed treatment choices. To evaluate the comparative effectiveness and safety of monotherapy (thiazolidinediones, metformin, sulfonylureas, dipeptidyl peptidase-4 [DPP-4] inhibitors, sodium-glucose cotransporter 2 [SGLT-2] inhibitors, and glucagon-like peptide-1 [GLP-1] receptor agonists) and selected metformin-based combinations in adults with type 2 diabetes. English-language studies from MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials, indexed from inception through March 2015 (MEDLINE search updated through December 2015). Paired reviewers independently identified 179 trials and 25 observational studies of head-to-head monotherapy or metformin-based combinations. Two reviewers independently assessed study quality and serially extracted data and graded the strength of evidence. Cardiovascular mortality was lower for metformin versus sulfonylureas; the evidence on all-cause mortality, cardiovascular morbidity, and microvascular complications was insufficient or of low strength. Reductions in hemoglobin A1c values were similar across monotherapies and metformin-based combinations, except that DPP-4 inhibitors had smaller effects. Body weight was reduced or maintained with metformin, DPP-4 inhibitors, GLP-1 receptor agonists, and SGLT-2 inhibitors and increased with sulfonylureas, thiazolidinediones, and insulin (between-group differences up to 5 kg). Hypoglycemia was more frequent with sulfonylureas. Gastrointestinal adverse events were highest with metformin and GLP-1 receptor agonists. Genital mycotic infections were increased with SGLT-2 inhibitors. Most studies were short, with limited ability to assess rare safety and long-term clinical outcomes. The evidence supports metformin as first-line therapy for type 2 diabetes, given its relative safety and beneficial effects on hemoglobin A1c, weight, and cardiovascular mortality (compared with sulfonylureas). On the basis of less evidence, results for add-on therapies to metformin were similar to those for monotherapies. Agency for Healthcare Research and Quality.", - "journal_title": "Annals of internal medicine", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/27088241/" - } - ], - "b8797cf2-24c2-49c4-b050-b7a191aa7157": [ - { - "pub_id": "26029709", - "title": "Functional consequences of transferrin receptor-2 mutations causing hereditary hemochromatosis type 3.", - "authors": "Ricky Joshi,Maya Shvartsman,Erica Mor\u00e1n,Sergi Lois,Jessica Aranda,Anna Barqu\u00e9,Xavier de la Cruz,Miquel Bruguera,Jos\u00e9 Manuel Vagace,Guillermo Gervasini,Cristina Sanz,Mayka S\u00e1nchez", - "abstract": "Hereditary hemochromatosis (HH) type 3 is an autosomal recessive disorder of iron metabolism characterized by excessive iron deposition in the liver and caused by mutations in the transferrin receptor 2 (TFR2) gene. Here, we describe three new HH type 3 Spanish families with four TFR2 mutations (p.Gly792Arg, c.1606-8A>G, Gln306*, and Gln672*). The missense variation p.Gly792Arg was found in homozygosity in two adult patients of the same family, and in compound heterozygosity in an adult proband that also carries a novel intronic change (c.1606-8A>G). Two new nonsense TFR2 mutations (Gln306* and Gln672*) were detected in a pediatric case. We examine the functional consequences of two TFR2 variants (p.Gly792Arg and c.1606-8A>G) using molecular and computational methods. Cellular protein localization studies using immunofluorescence demonstrated that the plasma membrane localization of p.Gly792Arg TFR2 is impaired. Splicing studies in vitro and in vivo reveal that the c.1606-8A>G mutation leads to the creation of a new acceptor splice site and an aberrant TFR2 mRNA. The reported mutations caused HH type 3 by protein truncation, altering TFR2 membrane localization or by mRNA splicing defect, producing a nonfunctional TFR2 protein and a defective signaling transduction for hepcidin regulation. TFR2 genotyping should be considered in adult but also in pediatric cases with early-onset of iron overload.", - "journal_title": "Molecular genetics & genomic medicine", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/26029709/" - } - ], - "ec62a4d9-2fe2-49b0-84d8-13b1597e2067": [ - { - "pub_id": "25003613", - "title": "Diabetic nephropathy--emerging epigenetic mechanisms.", - "authors": "Mitsuo Kato,Rama Natarajan", - "abstract": "Diabetic nephropathy (DN), a severe microvascular complication frequently associated with both type 1 and type 2 diabetes mellitus, is a leading cause of renal failure. The condition can also lead to accelerated cardiovascular disease and macrovascular complications. Currently available therapies have not been fully efficacious in the treatment of DN, suggesting that further understanding of the molecular mechanisms underlying the pathogenesis of DN is necessary for the improved management of this disease. Although key signal transduction and gene regulation mechanisms have been identified, especially those related to the effects of hyperglycaemia, transforming growth factor \u03b21 and angiotensin II, progress in functional genomics, high-throughput sequencing technology, epigenetics and systems biology approaches have greatly expanded our knowledge and uncovered new molecular mechanisms and factors involved in DN. These mechanisms include DNA methylation, chromatin histone modifications, novel transcripts and functional noncoding RNAs, such as microRNAs and long noncoding RNAs. In this Review, we discuss the significance of these emerging mechanisms, how they mediate the actions of growth factors to augment the expression of extracellular matrix and inflammatory genes associated with DN and their potential usefulness as diagnostic biomarkers or novel therapeutic targets for DN.", - "journal_title": "Nature reviews. Nephrology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/25003613/" - } - ], - "7fd7dbde-cd35-47c4-945a-1b1e22c41c5d": [ - { - "pub_id": "24927802", - "title": "Information-seeking and sharing behavior following genomic testing for diabetes risk.", - "authors": "Rachel Mills,Jill Powell,William Barry,Susanne B Haga", - "abstract": "As the practice of medicine has become more patient-driven, patients are increasingly seeking health information within and outside of their doctor's office. Patients looking for information and support are often turning to the Internet as well as family and friends. As part of a study to understand the impact of delivery method of genomic testing for type 2 diabetes risk on comprehension and health-related behaviors, we assessed participants' information-seeking and sharing behaviors after receiving their results in-person with a genetic counselor or online through the testing company's website. We found that 32.6\u00a0% of participants sought information after receiving the genomic test results for T2DM; 80.8\u00a0% of those that did seek information turned to the Internet. Eighty-eight percent of participants reported that they shared their T2DM risk results, primarily with their spouse/partner (65\u00a0%) and other family members (57\u00a0%) and children (19\u00a0%); 14\u00a0% reported sharing results with their health provider. Sharing was significantly increased in those who received results in-person from the genetic counselor (p\u2009=\u20090.0001). Understanding patients' interests and needs for additional information after genomic testing and with whom they share details of their health is important as more information and clinical services are available and accessed outside the clinician's office. Genetic counselors' expertise and experience in creating educational materials and promoting sharing of genetic information can facilitate patient engagement and education.", - "journal_title": "Journal of genetic counseling", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/24927802/" - } - ], - "174869dd-e433-4b27-8f9b-f77599358c3f": [ - { - "pub_id": "22891496", - "title": "Molecular genomic research designs.", - "authors": "Kelley Baumgartel,Jamie Zelazny,Theresa Timcheck,Chantel Snyder,Mandy Bell,Yvette P Conley", - "abstract": "Genetic and genomic research approaches have the capability to expand our understanding of the complex pathophysiology of disease susceptibility, susceptibility to complications related to disease, trajectory of recovery from acquired injuries and infections, patient response to interventions and therapeutics, as well as informing diagnoses and prognoses. Nurse scientists are actively involved in all of these fields of inquiry, and the goal of this chapter is to assist with incorporation of genetic and genomic trajectories into their research and facilitate the design and execution of these studies. New studies that are going to embark on recruitment, phenotyping, and sample collection will benefit from forethought about research design to ensure that it addresses the research questions or hypotheses being tested. Studies that will use existing data or samples will also benefit from forethought about research design for the same reason but will also address the fact that some designs may not be feasible with the available data or samples. This chapter discusses candidate gene association, genome-wide association, candidate gene expression, global gene expression, and epigenetic/epigenomic study designs. Information provided includes rationale for selecting an appropriate study design, important methodology considerations for each design, key technologies available to accomplish each type of study, and online resources available to assist in executing each type of study design.", - "journal_title": "Annual review of nursing research", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/22891496/" - } - ], - "fffba592-600d-49d1-8e6c-321786d0ad8f": [ - { - "pub_id": "20687937", - "title": "Genome-wide DNA methylation analysis for diabetic nephropathy in type 1 diabetes mellitus.", - "authors": "Christopher G Bell,Andrew E Teschendorff,Vardhman K Rakyan,Alexander P Maxwell,Stephan Beck,David A Savage", - "abstract": "Diabetic nephropathy is a serious complication of diabetes mellitus and is associated with considerable morbidity and high mortality. There is increasing evidence to suggest that dysregulation of the epigenome is involved in diabetic nephropathy. We assessed whether epigenetic modification of DNA methylation is associated with diabetic nephropathy in a case-control study of 192 Irish patients with type 1 diabetes mellitus (T1D). Cases had T1D and nephropathy whereas controls had T1D but no evidence of renal disease. We performed DNA methylation profiling in bisulphite converted DNA from cases and controls using the recently developed Illumina Infinium HumanMethylation27 BeadChip, that enables the direct investigation of 27,578 individual cytosines at CpG loci throughout the genome, which are focused on the promoter regions of 14,495 genes. Singular Value Decomposition (SVD) analysis indicated that significant components of DNA methylation variation correlated with patient age, time to onset of diabetic nephropathy, and sex. Adjusting for confounding factors using multivariate Cox-regression analyses, and with a false discovery rate (FDR) of 0.05, we observed 19 CpG sites that demonstrated correlations with time to development of diabetic nephropathy. Of note, this included one CpG site located 18 bp upstream of the transcription start site of UNC13B, a gene in which the first intronic SNP rs13293564 has recently been reported to be associated with diabetic nephropathy. This high throughput platform was able to successfully interrogate the methylation state of individual cytosines and identified 19 prospective CpG sites associated with risk of diabetic nephropathy. These differences in DNA methylation are worthy of further follow-up in replication studies using larger cohorts of diabetic patients with and without nephropathy.", - "journal_title": "BMC medical genomics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/20687937/" - } - ], - "b260f1bd-5522-484f-bcdf-94074e6a6e7c": [ - { - "pub_id": "25239219", - "title": "Advances in Setaria genomics for genetic improvement of cereals and bioenergy grasses.", - "authors": "Mehanathan Muthamilarasan,Manoj Prasad", - "abstract": "Recent advances in Setaria genomics appear promising for genetic improvement of cereals and biofuel crops towards providing multiple securities to the steadily increasing global population. The prominent attributes of foxtail millet (Setaria italica, cultivated) and green foxtail (S. viridis, wild) including small genome size, short life-cycle, in-breeding nature, genetic close-relatedness to several cereals, millets and bioenergy grasses, and potential abiotic stress tolerance have accentuated these two Setaria species as novel model system for studying C4 photosynthesis, stress biology and biofuel traits. Considering this, studies have been performed on structural and functional genomics of these plants to develop genetic and genomic resources, and to delineate the physiology and molecular biology of stress tolerance, for the improvement of millets, cereals and bioenergy grasses. The release of foxtail millet genome sequence has provided a new dimension to Setaria genomics, resulting in large-scale development of genetic and genomic tools, construction of informative databases, and genome-wide association and functional genomic studies. In this context, this review discusses the advancements made in Setaria genomics, which have generated a considerable knowledge that could be used for the improvement of millets, cereals and biofuel crops. Further, this review also shows the nutritional potential of foxtail millet in providing health benefits to global population and provides a preliminary information on introgressing the nutritional properties in graminaceous species through molecular breeding and transgene-based approaches.", - "journal_title": "TAG. Theoretical and applied genetics. Theoretische und angewandte Genetik", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/25239219/" - } - ], - "1a51265b-1ec8-4c31-9d46-a192906f539e": [ - { - "pub_id": "24055485", - "title": "Genetic association of ADIPOQ gene variants with type 2 diabetes, obesity and serum adiponectin levels in south Indian population.", - "authors": "Kandaswamy Ramya,Kuppuswamy Ashok Ayyappa,Saurabh Ghosh,Viswanathan Mohan,Venkatesan Radha", - "abstract": "To investigate the genetic association of eight variants of the adiponectin gene with type 2 diabetes mellitus (T2DM), obesity and serum adiponectin level in the south Indian population. The study comprised of 1100 normal glucose tolerant (NGT) and 1100 type 2 diabetic, unrelated subjects randomly selected from the Chennai Urban Rural Epidemiology Study (CURES), in southern India. Fasting serum adiponectin levels were measured by radioimmunoassay. The variants were screened by polymerase chain reaction-restriction fragment length polymorphism. Linkage disequilibrium was estimated from the estimates of haplotype frequencies. Of the 8 variants, four SNPs namely, +276 G/T (rs1501299), -4522 C/T (rs822393), -11365 C/G (rs266729), and +712 G/A (rs3774261) were significantly associated with T2DM in our study population. The -3971 A/G (rs822396) and -11391 G/A (rs17300539) SNPs' association with T2DM diabetes was mediated through obesity (where the association with type 2 diabetes was lost after adjusting for BMI). There was an independent association of +276 G/T (rs1501299) and -3971 A/G (rs822396) SNPs with generalized obesity and +349 A/G (rs2241767) with central obesity. Four SNPs, -3971 A/G (rs822396), +276 G/T (rs1501299), -4522 C/T (rs822393) and Y111H T/C (rs17366743) were significantly associated with hypoadiponectinemia. The haplotypes GCCATGAAT and AGCGTGGGT conferred lower risk of T2DM in this south Indian population. The adiponectin gene variants and haplotype contribute to the genetic risk towards the development of type 2 diabetes, obesity and hypoadiponectinemia in the south Indian population.", - "journal_title": "Gene", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/24055485/" - } - ], - "f54c692a-eae6-4516-ba43-7d8b0ac88477": [ - { - "pub_id": "21133856", - "title": "Genome-wide association scan allowing for epistasis in type 2 diabetes.", - "authors": "Jordana T Bell,Nicholas J Timpson,N William Rayner,Eleftheria Zeggini,Timothy M Frayling,Andrew T Hattersley,Andrew P Morris,Mark I McCarthy", - "abstract": "In the presence of epistasis multilocus association tests of human complex traits can provide powerful methods to detect susceptibility variants. We undertook multilocus analyses in 1924 type 2 diabetes cases and 2938 controls from the Wellcome Trust Case Control Consortium (WTCCC). We performed a two-dimensional genome-wide association (GWA) scan using joint two-locus tests of association including main and epistatic effects in 70,236 markers tagging common variants. We found two-locus association at 79 SNP-pairs at a Bonferroni-corrected P-value = 0.05 (uncorrected P-value = 2.14 \u00d7 10\u207b\u00b9\u00b9). The 79 pair-wise results always contained rs11196205 in TCF7L2 paired with 79 variants including confirmed variants in FTO, TSPAN8, and CDKAL1, which are associated in the absence of epistasis. However, the majority (82%) of the 79 variants did not have compelling single-locus association signals (P-value = 5 \u00d7 10\u207b\u2074). Analyses conditional on the single-locus effects at TCF7L2 established that the joint two-locus results could be attributed to single-locus association at TCF7L2 alone. Interaction analyses among the peak 80 regions and among 23 previously established diabetes candidate genes identified five SNP-pairs with case-control and case-only epistatic signals. Our results demonstrate the feasibility of systematic scans in GWA data, but confirm that single-locus association can underlie and obscure multilocus findings.", - "journal_title": "Annals of human genetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/21133856/" - } - ], - "6f277be5-2f33-47dd-9983-8ca75a28ad29": [ - { - "pub_id": "20215397", - "title": "Implication of genetic variants near NEGR1, SEC16B, TMEM18, ETV5/DGKG, GNPDA2, LIN7C/BDNF, MTCH2, BCDIN3D/FAIM2, SH2B1, FTO, MC4R, and KCTD15 with obesity and type 2 diabetes in 7705 Chinese.", - "authors": "Maggie C Y Ng,Claudia H T Tam,Wing Yee So,Janice S K Ho,Alfred W Chan,Heung Man Lee,Ying Wang,Vincent K L Lam,Juliana C N Chan,Ronald C W Ma", - "abstract": "Recent genome-wide association studies have identified multiple novel loci associated with obesity in Europeans. We hypothesized that these genetic variants may be associated with obesity and type 2 diabetes (T2D) in Chinese. We examined 14 associated single-nucleotide polymorphisms at 12 loci (NEGR1, SEC16B, TMEM18, ETV5/DGKG, GNPDA2, LIN7C/BDNF, MTCH2, BCDIN3D/FAIM2, SH2B1, FTO, MC4R, and KCTD15) in 605 healthy adults, 1087 healthy adolescents and 6013 T2D patients from Hong Kong. The European at-risk alleles at five loci including GNPDA2, BCDIN3D/FAIM2, SH2B1, FTO, and KCTD15 were significantly associated with increased body mass index (BMI), waist circumference (4.5 x 10(-8) < P < 0.024), and/or obesity risk (odds ratio 1.14-1.22, 2.0 x 10(-5) < P < 0.002) in our Chinese populations. The former four loci as well as LIN7C/BDNF were also modestly associated with T2D risk (odds ratio 1.09-1.22, 0.008 < P < 0.041), but the associations were lost after adjustment for BMI, suggesting their roles in T2D risk are mediated through modulation of adiposity. Joint effect analyses of the five adiposity loci revealed an increase of about 0.29 kg/m(2) in BMI with each additional copy of at-risk allele (P(trend) = 4.2 x 10(-12)). Our findings support the important contribution of GNPDA2, BCDIN3D/FAIM2, SH2B1, FTO, and KCTD15 in the regulation of adiposity, which in turn affects T2D risk in Chinese.", - "journal_title": "The Journal of clinical endocrinology and metabolism", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/20215397/" - } - ], - "b666545f-6a53-45de-8562-55d88fc6f7ee": [ - { - "pub_id": "25186316", - "title": "Dorothy Hodgkin Lecture 2014. Understanding genes identified by genome-wide association studies for type 2 diabetes.", - "authors": "G A Rutter", - "abstract": "Whilst the heritable nature of Type 2 diabetes has been recognized for many years, only in the past two decades have linkage analyses in families and genome-wide association studies in large populations begun to reveal the genetic landscape of the disease in detail. Whilst the former have provided a powerful means of identifying the genes responsible for monogenic forms of the disease, the latter highlight relatively large genomic regions. These often harbour multiple genes, whose relative contribution to exaggerated disease risk is uncertain. In the present study, the approaches that have been used to dissect the role of just a few (TCF7L2, SLC30A8, ADCY5, MTNR1B and CDKAL1) of the ~\u00a0500 genes identified at dozens of implicated loci are described. These are usually selected based on the strength of their effect on disease risk, and predictions as to their likely biological role. Direct determination of the effects of identified polymorphisms on gene expression in disease-relevant tissues, notably the pancreatic islet, are then performed to identify genes whose expression is affected by a particular polymorphism. Subsequent functional analyses then involve perturbing gene expression in vitro in \u03b2-cell lines or isolated islets and in vivo in animal models. Although the majority of polymorphisms affect insulin production rather than action, and mainly affect the \u03b2 cell, effects via other tissues may also contribute, requiring careful consideration in the design and interpretation of experiments in model systems. These considerations illustrate the scale of the task needed to exploit genome-wide association study data for the development of new therapeutic strategies.", - "journal_title": "Diabetic medicine : a journal of the British Diabetic Association", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/25186316/" - } - ], - "76cbb6b8-d9b0-482d-b724-08892633bb62": [ - { - "pub_id": "24097068", - "title": "Discovery and refinement of loci associated with lipid levels.", - "authors": "Cristen J Willer,Ellen M Schmidt,Sebanti Sengupta,Gina M Peloso,Stefan Gustafsson,Stavroula Kanoni,Andrea Ganna,Jin Chen,Martin L Buchkovich,Samia Mora,Jacques S Beckmann,Jennifer L Bragg-Gresham,Hsing-Yi Chang,Ay\u015fe Demirkan,Heleen M Den Hertog,Ron Do,Louise A Donnelly,Georg B Ehret,T\u00f5nu Esko,Mary F Feitosa,Teresa Ferreira,Krista Fischer,Pierre Fontanillas,Ross M Fraser,Daniel F Freitag,Deepti Gurdasani,Kauko Heikkil\u00e4,Elina Hypp\u00f6nen,Aaron Isaacs,Anne U Jackson,\u00c5sa Johansson,Toby Johnson,Marika Kaakinen,Johannes Kettunen,Marcus E Kleber,Xiaohui Li,Jian'an Luan,Leo-Pekka Lyytik\u00e4inen,Patrik K E Magnusson,Massimo Mangino,Evelin Mihailov,May E Montasser,Martina M\u00fcller-Nurasyid,Ilja M Nolte,Jeffrey R O'Connell,Cameron D Palmer,Markus Perola,Ann-Kristin Petersen,Serena Sanna,Richa Saxena,Susan K Service,Sonia Shah,Dmitry Shungin,Carlo Sidore,Ci Song,Rona J Strawbridge,Ida Surakka,Toshiko Tanaka,Tanya M Teslovich,Gudmar Thorleifsson,Evita G Van den Herik,Benjamin F Voight,Kelly A Volcik,Lindsay L Waite,Andrew Wong,Ying Wu,Weihua Zhang,Devin Absher,Gershim Asiki,In\u00eas Barroso,Latonya F Been,Jennifer L Bolton,Lori L Bonnycastle,Paolo Brambilla,Mary S Burnett,Giancarlo Cesana,Maria Dimitriou,Alex S F Doney,Angela D\u00f6ring,Paul Elliott,Stephen E Epstein,Gudmundur Ingi Eyjolfsson,Bruna Gigante,Mark O Goodarzi,Harald Grallert,Martha L Gravito,Christopher J Groves,G\u00f6ran Hallmans,Anna-Liisa Hartikainen,Caroline Hayward,Dena Hernandez,Andrew A Hicks,Hilma Holm,Yi-Jen Hung,Thomas Illig,Michelle R Jones,Pontiano Kaleebu,John J P Kastelein,Kay-Tee Khaw,Eric Kim,Norman Klopp,Pirjo Komulainen,Meena Kumari,Claudia Langenberg,Terho Lehtim\u00e4ki,Shih-Yi Lin,Jaana Lindstr\u00f6m,Ruth J F Loos,Fran\u00e7ois Mach,Wendy L McArdle,Christa Meisinger,Braxton D Mitchell,Gabrielle M\u00fcller,Ramaiah Nagaraja,Narisu Narisu,Tuomo V M Nieminen,Rebecca N Nsubuga,Isleifur Olafsson,Ken K Ong,Aarno Palotie,Theodore Papamarkou,Cristina Pomilla,Anneli Pouta,Daniel J Rader,Muredach P Reilly,Paul M Ridker,Fernando Rivadeneira,Igor Rudan,Aimo Ruokonen,Nilesh Samani,Hubert Scharnagl,Janet Seeley,Kaisa Silander,Alena Stan\u010d\u00e1kov\u00e1,Kathleen Stirrups,Amy J Swift,Laurence Tiret,Andre G Uitterlinden,L Joost van Pelt,Sailaja Vedantam,Nicholas Wainwright,Cisca Wijmenga,Sarah H Wild,Gonneke Willemsen,Tom Wilsgaard,James F Wilson,Elizabeth H Young,Jing Hua Zhao,Linda S Adair,Dominique Arveiler,Themistocles L Assimes,Stefania Bandinelli,Franklyn Bennett,Murielle Bochud,Bernhard O Boehm,Dorret I Boomsma,Ingrid B Borecki,Stefan R Bornstein,Pascal Bovet,Michel Burnier,Harry Campbell,Aravinda Chakravarti,John C Chambers,Yii-Der Ida Chen,Francis S Collins,Richard S Cooper,John Danesh,George Dedoussis,Ulf de Faire,Alan B Feranil,Jean Ferri\u00e8res,Luigi Ferrucci,Nelson B Freimer,Christian Gieger,Leif C Groop,Vilmundur Gudnason,Ulf Gyllensten,Anders Hamsten,Tamara B Harris,Aroon Hingorani,Joel N Hirschhorn,Albert Hofman,G Kees Hovingh,Chao Agnes Hsiung,Steve E Humphries,Steven C Hunt,Kristian Hveem,Carlos Iribarren,Marjo-Riitta J\u00e4rvelin,Antti Jula,Mika K\u00e4h\u00f6nen,Jaakko Kaprio,Antero Kes\u00e4niemi,Mika Kivimaki,Jaspal S Kooner,Peter J Koudstaal,Ronald M Krauss,Diana Kuh,Johanna Kuusisto,Kirsten O Kyvik,Markku Laakso,Timo A Lakka,Lars Lind,Cecilia M Lindgren,Nicholas G Martin,Winfried M\u00e4rz,Mark I McCarthy,Colin A McKenzie,Pierre Meneton,Andres Metspalu,Leena Moilanen,Andrew D Morris,Patricia B Munroe,Inger Nj\u00f8lstad,Nancy L Pedersen,Chris Power,Peter P Pramstaller,Jackie F Price,Bruce M Psaty,Thomas Quertermous,Rainer Rauramaa,Danish Saleheen,Veikko Salomaa,Dharambir K Sanghera,Jouko Saramies,Peter E H Schwarz,Wayne H-H Sheu,Alan R Shuldiner,Agneta Siegbahn,Tim D Spector,Kari Stefansson,David P Strachan,Bamidele O Tayo,Elena Tremoli,Jaakko Tuomilehto,Matti Uusitupa,Cornelia M van Duijn,Peter Vollenweider,Lars Wallentin,Nicholas J Wareham,John B Whitfield,Bruce H R Wolffenbuttel,Jose M Ordovas,Eric Boerwinkle,Colin N A Palmer,Unnur Thorsteinsdottir,Daniel I Chasman,Jerome I Rotter,Paul W Franks,Samuli Ripatti,L Adrienne Cupples,Manjinder S Sandhu,Stephen S Rich,Michael Boehnke,Panos Deloukas,Sekar Kathiresan,Karen L Mohlke,Erik Ingelsson,Gon\u00e7alo R Abecasis, ", - "abstract": "Levels of low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, triglycerides and total cholesterol are heritable, modifiable risk factors for coronary artery disease. To identify new loci and refine known loci influencing these lipids, we examined 188,577 individuals using genome-wide and custom genotyping arrays. We identify and annotate 157 loci associated with lipid levels at P < 5 \u00d7 10(-8), including 62 loci not previously associated with lipid levels in humans. Using dense genotyping in individuals of European, East Asian, South Asian and African ancestry, we narrow association signals in 12 loci. We find that loci associated with blood lipid levels are often associated with cardiovascular and metabolic traits, including coronary artery disease, type 2 diabetes, blood pressure, waist-hip ratio and body mass index. Our results demonstrate the value of using genetic data from individuals of diverse ancestry and provide insights into the biological mechanisms regulating blood lipids to guide future genetic, biological and therapeutic research.", - "journal_title": "Nature genetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/24097068/" - } - ], - "6a2d9ea5-7018-42fe-bed9-2c9c508531cb": [ - { - "pub_id": "21490949", - "title": "Transferability of type 2 diabetes implicated loci in multi-ethnic cohorts from Southeast Asia.", - "authors": "Xueling Sim,Rick Twee-Hee Ong,Chen Suo,Wan-Ting Tay,Jianjun Liu,Daniel Peng-Keat Ng,Michael Boehnke,Kee-Seng Chia,Tien-Yin Wong,Mark Seielstad,Yik-Ying Teo,E-Shyong Tai", - "abstract": "Recent large genome-wide association studies (GWAS) have identified multiple loci which harbor genetic variants associated with type 2 diabetes mellitus (T2D), many of which encode proteins not previously suspected to be involved in the pathogenesis of T2D. Most GWAS for T2D have focused on populations of European descent, and GWAS conducted in other populations with different ancestry offer a unique opportunity to study the genetic architecture of T2D. We performed genome-wide association scans for T2D in 3,955 Chinese (2,010 cases, 1,945 controls), 2,034 Malays (794 cases, 1,240 controls), and 2,146 Asian Indians (977 cases, 1,169 controls). In addition to the search for novel variants implicated in T2D, these multi-ethnic cohorts serve to assess the transferability and relevance of the previous findings from European descent populations in the three major ethnic populations of Asia, comprising half of the world's population. Of the SNPs associated with T2D in previous GWAS, only variants at CDKAL1 and HHEX/IDE/KIF11 showed the strongest association with T2D in the meta-analysis including all three ethnic groups. However, consistent direction of effect was observed for many of the other SNPs in our study and in those carried out in European populations. Close examination of the associations at both the CDKAL1 and HHEX/IDE/KIF11 loci provided some evidence of locus and allelic heterogeneity in relation to the associations with T2D. We also detected variation in linkage disequilibrium between populations for most of these loci that have been previously identified. These factors, combined with limited statistical power, may contribute to the failure to detect associations across populations of diverse ethnicity. These findings highlight the value of surveying across diverse racial/ethnic groups towards the fine-mapping efforts for the casual variants and also of the search for variants, which may be population-specific.", - "journal_title": "PLoS genetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/21490949/" - } - ], - "956048af-a512-4b39-8555-a8fe97f5b7ba": [ - { - "pub_id": "24412096", - "title": "Revisiting the thrifty gene hypothesis via 65 loci associated with susceptibility to type 2 diabetes.", - "authors": "Qasim Ayub,Loukas Moutsianas,Yuan Chen,Kalliope Panoutsopoulou,Vincenza Colonna,Luca Pagani,Inga Prokopenko,Graham R S Ritchie,Chris Tyler-Smith,Mark I McCarthy,Eleftheria Zeggini,Yali Xue", - "abstract": "We have investigated the evidence for positive selection in samples of African, European, and East Asian ancestry at 65 loci associated with susceptibility to type 2 diabetes (T2D) previously identified through genome-wide association studies. Selection early in human evolutionary history is predicted to lead to ancestral risk alleles shared between populations, whereas late selection would result in population-specific signals at derived risk alleles. By using a wide variety of tests based on the site frequency spectrum, haplotype structure, and population differentiation, we found no global signal of enrichment for positive selection when we considered all T2D risk loci collectively. However, in a locus-by-locus analysis, we found nominal evidence for positive selection at 14 of the loci. Selection favored the protective and risk alleles in similar proportions, rather than the risk alleles specifically as predicted by the thrifty gene hypothesis, and may not be related to influence on diabetes. Overall, we conclude that past positive selection has not been a powerful influence driving the prevalence of T2D risk alleles.", - "journal_title": "American journal of human genetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/24412096/" - } - ], - "b1d09a6d-334a-48f4-b4ed-4754f398d046": [ - { - "pub_id": "22885924", - "title": "Large-scale association analyses identify new loci influencing glycemic traits and provide insight into the underlying biological pathways.", - "authors": "Robert A Scott,Vasiliki Lagou,Ryan P Welch,Eleanor Wheeler,May E Montasser,Jian'an Luan,Reedik M\u00e4gi,Rona J Strawbridge,Emil Rehnberg,Stefan Gustafsson,Stavroula Kanoni,Laura J Rasmussen-Torvik,Lo\u00efc Yengo,Cecile Lecoeur,Dmitry Shungin,Serena Sanna,Carlo Sidore,Paul C D Johnson,J Wouter Jukema,Toby Johnson,Anubha Mahajan,Niek Verweij,Gudmar Thorleifsson,Jouke-Jan Hottenga,Sonia Shah,Albert V Smith,Bengt Sennblad,Christian Gieger,Perttu Salo,Markus Perola,Nicholas J Timpson,David M Evans,Beate St Pourcain,Ying Wu,Jeanette S Andrews,Jennie Hui,Lawrence F Bielak,Wei Zhao,Momoko Horikoshi,Pau Navarro,Aaron Isaacs,Jeffrey R O'Connell,Kathleen Stirrups,Veronique Vitart,Caroline Hayward,T\u00f5nu Esko,Evelin Mihailov,Ross M Fraser,Tove Fall,Benjamin F Voight,Soumya Raychaudhuri,Han Chen,Cecilia M Lindgren,Andrew P Morris,Nigel W Rayner,Neil Robertson,Denis Rybin,Ching-Ti Liu,Jacques S Beckmann,Sara M Willems,Peter S Chines,Anne U Jackson,Hyun Min Kang,Heather M Stringham,Kijoung Song,Toshiko Tanaka,John F Peden,Anuj Goel,Andrew A Hicks,Ping An,Martina M\u00fcller-Nurasyid,Anders Franco-Cereceda,Lasse Folkersen,Letizia Marullo,Hanneke Jansen,Albertine J Oldehinkel,Marcel Bruinenberg,James S Pankow,Kari E North,Nita G Forouhi,Ruth J F Loos,Sarah Edkins,Tibor V Varga,G\u00f6ran Hallmans,Heikki Oksa,Mulas Antonella,Ramaiah Nagaraja,Stella Trompet,Ian Ford,Stephan J L Bakker,Augustine Kong,Meena Kumari,Bruna Gigante,Christian Herder,Patricia B Munroe,Mark Caulfield,Jula Antti,Massimo Mangino,Kerrin Small,Iva Miljkovic,Yongmei Liu,Mustafa Atalay,Wieland Kiess,Alan L James,Fernando Rivadeneira,Andre G Uitterlinden,Colin N A Palmer,Alex S F Doney,Gonneke Willemsen,Johannes H Smit,Susan Campbell,Ozren Polasek,Lori L Bonnycastle,Serge Hercberg,Maria Dimitriou,Jennifer L Bolton,Gerard R Fowkes,Peter Kovacs,Jaana Lindstr\u00f6m,Tatijana Zemunik,Stefania Bandinelli,Sarah H Wild,Hanneke V Basart,Wolfgang Rathmann,Harald Grallert, ,Winfried Maerz,Marcus E Kleber,Bernhard O Boehm,Annette Peters,Peter P Pramstaller,Michael A Province,Ingrid B Borecki,Nicholas D Hastie,Igor Rudan,Harry Campbell,Hugh Watkins,Martin Farrall,Michael Stumvoll,Luigi Ferrucci,Dawn M Waterworth,Richard N Bergman,Francis S Collins,Jaakko Tuomilehto,Richard M Watanabe,Eco J C de Geus,Brenda W Penninx,Albert Hofman,Ben A Oostra,Bruce M Psaty,Peter Vollenweider,James F Wilson,Alan F Wright,G Kees Hovingh,Andres Metspalu,Matti Uusitupa,Patrik K E Magnusson,Kirsten O Kyvik,Jaakko Kaprio,Jackie F Price,George V Dedoussis,Panos Deloukas,Pierre Meneton,Lars Lind,Michael Boehnke,Alan R Shuldiner,Cornelia M van Duijn,Andrew D Morris,Anke Toenjes,Patricia A Peyser,John P Beilby,Antje K\u00f6rner,Johanna Kuusisto,Markku Laakso,Stefan R Bornstein,Peter E H Schwarz,Timo A Lakka,Rainer Rauramaa,Linda S Adair,George Davey Smith,Tim D Spector,Thomas Illig,Ulf de Faire,Anders Hamsten,Vilmundur Gudnason,Mika Kivimaki,Aroon Hingorani,Sirkka M Keinanen-Kiukaanniemi,Timo E Saaristo,Dorret I Boomsma,Kari Stefansson,Pim van der Harst,Jos\u00e9e Dupuis,Nancy L Pedersen,Naveed Sattar,Tamara B Harris,Francesco Cucca,Samuli Ripatti,Veikko Salomaa,Karen L Mohlke,Beverley Balkau,Philippe Froguel,Anneli Pouta,Marjo-Riitta Jarvelin,Nicholas J Wareham,Nabila Bouatia-Naji,Mark I McCarthy,Paul W Franks,James B Meigs,Tanya M Teslovich,Jose C Florez,Claudia Langenberg,Erik Ingelsson,Inga Prokopenko,In\u00eas Barroso", - "abstract": "Through genome-wide association meta-analyses of up to 133,010 individuals of European ancestry without diabetes, including individuals newly genotyped using the Metabochip, we have increased the number of confirmed loci influencing glycemic traits to 53, of which 33 also increase type 2 diabetes risk (q < 0.05). Loci influencing fasting insulin concentration showed association with lipid levels and fat distribution, suggesting impact on insulin resistance. Gene-based analyses identified further biologically plausible loci, suggesting that additional loci beyond those reaching genome-wide significance are likely to represent real associations. This conclusion is supported by an excess of directionally consistent and nominally significant signals between discovery and follow-up studies. Functional analysis of these newly discovered loci will further improve our understanding of glycemic control.", - "journal_title": "Nature genetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/22885924/" - } - ], - "b3bdc337-4b5b-41fd-bd6e-612ac558422e": [ - { - "pub_id": "23125199", - "title": "The pathogenesis and natural history of type 1 diabetes.", - "authors": "Mark A Atkinson", - "abstract": "The purpose of this article is to provide an overview that summarizes much in the way of our current state of knowledge regarding the pathogenesis and natural history of type 1 diabetes in humans. This information is presented to the reader as a series of seminal historical discoveries that, when advanced through research, transformed our understanding of the roles for the immune system, genes, and environment in the formation of this disease. In addition, where longitudinal investigations of these three facets occurred, their roles within the development of type 1 diabetes, from birth to symptomatic onset and beyond, are discussed, including their most controversial elements. Having an understanding of this disorder's pathogenesis and natural history is key for attempts seeking to understand the issues of what causes type 1 diabetes, as well as to develop a means to prevent and cure the disorder.", - "journal_title": "Cold Spring Harbor perspectives in medicine", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/23125199/" - } - ], - "f06773a6-5f81-4d74-883d-c0819b81b68e": [ - { - "pub_id": "21721943", - "title": "Comparative genetics and genomics of nematodes: genome structure, development, and lifestyle.", - "authors": "Ralf J Sommer,Adrian Streit", - "abstract": "Nematodes are found in virtually all habitats on earth. Many of them are parasites of plants and animals, including humans. The free-living nematode, Caenorhabditis elegans, is one of the genetically best-studied model organisms and was the first metazoan whose genome was fully sequenced. In recent years, the draft genome sequences of another six nematodes representing four of the five major clades of nematodes were published. Compared to mammalian genomes, all these genomes are very small. Nevertheless, they contain almost the same number of genes as the human genome. Nematodes are therefore a very attractive system for comparative genetic and genomic studies, with C. elegans as an excellent baseline. Here, we review the efforts that were made to extend genetic analysis to nematodes other than C. elegans, and we compare the seven available nematode genomes. One of the most striking findings is the unexpectedly high incidence of gene acquisition through horizontal gene transfer (HGT).", - "journal_title": "Annual review of genetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/21721943/" - } - ], - "183f165e-4d5c-4580-9aff-4e6b2e5a6463": [ - { - "pub_id": "24864266", - "title": "Genetics of type 2 diabetes: insights into the pathogenesis and its clinical application.", - "authors": "Xue Sun,Weihui Yu,Cheng Hu", - "abstract": "With rapidly increasing prevalence, diabetes has become one of the major causes of mortality worldwide. According to the latest studies, genetic information makes substantial contributions towards the prediction of diabetes risk and individualized antidiabetic treatment. To date, approximately 70 susceptibility genes have been identified as being associated with type 2 diabetes (T2D) at a genome-wide significant level (P < 5 \u00d7 10(-8)). However, all the genetic loci identified so far account for only about 10% of the overall heritability of T2D. In addition, how these novel susceptibility loci correlate with the pathophysiology of the disease remains largely unknown. This review covers the major genetic studies on the risk of T2D based on ethnicity and briefly discusses the potential mechanisms and clinical utility of the genetic information underlying T2D.", - "journal_title": "BioMed research international", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/24864266/" - } - ], - "e2dffbbd-ae00-4cc9-947c-0e28b49c880d": [ - { - "pub_id": "23557707", - "title": "Association of ketone body levels with hyperglycemia and type 2 diabetes in 9,398 Finnish men.", - "authors": "Yuvaraj Mahendran,Jagadish Vangipurapu,Henna Cederberg,Alena Stanc\u00e1kov\u00e1,Jussi Pihlajam\u00e4ki,Pasi Soininen,Antti J Kangas,Jussi Paananen,Mete Civelek,Niyas K Saleem,P\u00e4ivi Pajukanta,Aldons J Lusis,Lori L Bonnycastle,Mario A Morken,Francis S Collins,Karen L Mohlke,Michael Boehnke,Mika Ala-Korpela,Johanna Kuusisto,Markku Laakso", - "abstract": "We investigated the association of the levels of ketone bodies (KBs) with hyperglycemia and with 62 genetic risk variants regulating glucose levels or type 2 diabetes in the population-based Metabolic Syndrome in Men (METSIM) study, including 9,398 Finnish men without diabetes or newly diagnosed type 2 diabetes. Increasing fasting and 2-h plasma glucose levels were associated with elevated levels of acetoacetate (AcAc) and \u03b2-hydroxybutyrate (BHB). AcAc and BHB predicted an increase in the glucose area under the curve in an oral glucose tolerance test, and AcAc predicted the conversion to type 2 diabetes in a 5-year follow-up of the METSIM cohort. Impaired insulin secretion, but not insulin resistance, explained these findings. Of the 62 single nucleotide polymorphisms associated with the risk of type 2 diabetes or hyperglycemia, the glucose-increasing C allele of GCKR significantly associated with elevated levels of fasting BHB levels. Adipose tissue mRNA expression levels of genes involved in ketolysis were significantly associated with insulin sensitivity (Matsuda index). In conclusion, high levels of KBs predicted subsequent worsening of hyperglycemia, and a common variant of GCKR was significantly associated with BHB levels.", - "journal_title": "Diabetes", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/23557707/" - } - ], - "a7bad429-5f6a-464f-a666-f9cb1be60338": [ - { - "pub_id": "28437734", - "title": "IDF Diabetes Atlas: Global estimates for the prevalence of diabetes for 2015 and 2040.", - "authors": "K Ogurtsova,J D da Rocha Fernandes,Y Huang,U Linnenkamp,L Guariguata,N H Cho,D Cavan,J E Shaw,L E Makaroff", - "abstract": "To produce current estimates of the national, regional and global impact of diabetes for 2015 and 2040. A systematic literature review was conducted to identify data sources on the prevalence of diabetes from studies conducted in the period from 1990 to 2015. An analytic hierarchy process was used to select the most appropriate studies for each country, and estimates for countries without data were modelled using extrapolation from similar countries that had available data. A logistic regression model was used to generate smoothed age-specific estimates, which were applied to UN population estimates. 540 data sources were reviewed, of which 196 sources from 111 countries were selected. In 2015 it was estimated that there were 415 million (uncertainty interval: 340-536 million) people with diabetes aged 20-79years, 5.0 million deaths attributable to diabetes, and the total global health expenditure due to diabetes was estimated at 673 billion US dollars. Three quarters (75%) of those with diabetes were living in low- and middle-income countries. The number of people with diabetes aged 20-79years was predicted to rise to 642 million (uncertainty interval: 521-829 million) by 2040. Diabetes prevalence, deaths attributable to diabetes, and health expenditure due to diabetes continue to rise across the globe with important social, financial and health system implications.", - "journal_title": "Diabetes research and clinical practice", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/28437734/" - } - ], - "d2b7db1d-2821-4ca0-a6ea-b99108eb3f94": [ - { - "pub_id": "24270849", - "title": "Systematic comparison of phenome-wide association study of electronic medical record data and genome-wide association study data.", - "authors": "Joshua C Denny,Lisa Bastarache,Marylyn D Ritchie,Robert J Carroll,Raquel Zink,Jonathan D Mosley,Julie R Field,Jill M Pulley,Andrea H Ramirez,Erica Bowton,Melissa A Basford,David S Carrell,Peggy L Peissig,Abel N Kho,Jennifer A Pacheco,Luke V Rasmussen,David R Crosslin,Paul K Crane,Jyotishman Pathak,Suzette J Bielinski,Sarah A Pendergrass,Hua Xu,Lucia A Hindorff,Rongling Li,Teri A Manolio,Christopher G Chute,Rex L Chisholm,Eric B Larson,Gail P Jarvik,Murray H Brilliant,Catherine A McCarty,Iftikhar J Kullo,Jonathan L Haines,Dana C Crawford,Daniel R Masys,Dan M Roden", - "abstract": "Candidate gene and genome-wide association studies (GWAS) have identified genetic variants that modulate risk for human disease; many of these associations require further study to replicate the results. Here we report the first large-scale application of the phenome-wide association study (PheWAS) paradigm within electronic medical records (EMRs), an unbiased approach to replication and discovery that interrogates relationships between targeted genotypes and multiple phenotypes. We scanned for associations between 3,144 single-nucleotide polymorphisms (previously implicated by GWAS as mediators of human traits) and 1,358 EMR-derived phenotypes in 13,835 individuals of European ancestry. This PheWAS replicated 66% (51/77) of sufficiently powered prior GWAS associations and revealed 63 potentially pleiotropic associations with P < 4.6 \u00d7 10\u207b\u2076 (false discovery rate < 0.1); the strongest of these novel associations were replicated in an independent cohort (n = 7,406). These findings validate PheWAS as a tool to allow unbiased interrogation across multiple phenotypes in EMR-based cohorts and to enhance analysis of the genomic basis of human disease.", - "journal_title": "Nature biotechnology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/24270849/" - } - ], - "3036f895-8263-405c-8273-365b39275ea5": [ - { - "pub_id": "24833634", - "title": "Microbiota and diabetes: an evolving relationship.", - "authors": "Herbert Tilg,Alexander R Moschen", - "abstract": "The gut microbiota affects numerous biological functions throughout the body and its characterisation has become a major research area in biomedicine. Recent studies have suggested that gut bacteria play a fundamental role in diseases such as obesity, diabetes and cardiovascular disease. Data are accumulating in animal models and humans suggesting that obesity and type 2 diabetes (T2D) are associated with a profound dysbiosis. First human metagenome-wide association studies demonstrated highly significant correlations of specific intestinal bacteria, certain bacterial genes and respective metabolic pathways with T2D. Importantly, especially butyrate-producing bacteria such as Roseburia intestinalis and Faecalibacterium prausnitzii concentrations were lower in T2D subjects. This supports the increasing evidence, that butyrate and other short-chain fatty acids are able to exert profound immunometabolic effects. Endotoxaemia, most likely gut-derived has also been observed in patients with metabolic syndrome and T2D and might play a key role in metabolic inflammation. A further hint towards an association between microbiota and T2D has been derived from studies in pregnancy showing that major gut microbial shifts occurring during pregnancy affect host metabolism. Interestingly, certain antidiabetic drugs such as metformin also interfere with the intestinal microbiota. Specific members of the microbiota such as Akkermansia muciniphila might be decreased in diabetes and when administered to murines exerted antidiabetic effects. Therefore, as a 'gut signature' becomes more evident in T2D, a better understanding of the role of the microbiota in diabetes might provide new aspects regarding its pathophysiological relevance and pave the way for new therapeutic principles.", - "journal_title": "Gut", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/24833634/" - } - ], - "f413d09d-cc53-4f6c-b990-dec57ab9a253": [ - { - "pub_id": "21437087", - "title": "Type 2 diabetes mellitus and inflammation: Prospects for biomarkers of risk and nutritional intervention.", - "authors": "Alaa Badawi,Amira Klip,Pierre Haddad,David Ec Cole,Bibiana Garcia Bailo,Ahmed El-Sohemy,Mohamed Karmali", - "abstract": "Obesity is a major risk factor for type 2 diabetes mellitus (T2DM), which is a significant health problem worldwide. Active disease is associated with low-grade chronic inflammation resulting in part from the activation of the innate immune system. In obesity, this activation leads to the release of pro-inflammatory cytokines such as tumor necrosis factor-\u03b1, interleukin-1\u03b2 and interleukin-6 that block major anabolic cascades downstream of insulin signaling and thus disrupt insulin homeostasis and action. Cytokines also trigger the production of acute-phase reactants such as C-reactive protein, plasminogen activator inhibitor-1, serum amyloid-A, and haptoglobin. The elevated synthesis of pro-inflammatory cytokines and acute-phase proteins (inflammatory network) characterizes the early (or pre-clinical) stages of T2DM and exhibits a graded increase with the disease progression. Current evidence suggests that understanding inflammatory networks can point to new biomarkers that may permit capturing the interaction between genetic and environmental risk factors in the pathogenesis of T2DM. Such biomarkers have a significant public health potential in the prediction of disease occurrence beyond risk factors presently monitored, such as family history, lifestyle assessment and standard clinical chemistry profiles. Furthermore, inflammatory markers may assist in the evaluation of novel strategies for prevention, particularly in relation to micronutrients. This review discusses the current knowledge linking T2DM risk to inflammatory signaling pathways interacting with the innate immunity system and the prospect of inflammatory markers serving as molecular targets for prevention and/or biomarkers for early risk prediction of T2DM. The potential of micronutrients replenishment to improve insulin action by attenuating inflammation is also evaluated in the context of the public health relevance of this approach.", - "journal_title": "Diabetes, metabolic syndrome and obesity : targets and therapy", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/21437087/" - } - ], - "57d91713-225c-4c04-a9e7-e275588e2a68": [ - { - "pub_id": "22643932", - "title": "SNP in the genome-wide association study hotspot on chromosome 9p21 confers susceptibility to diabetic nephropathy in type 1 diabetes.", - "authors": "E Fagerholm,E Ahlqvist,C Forsblom,N Sandholm,A Syreeni,M Parkkonen,A J McKnight,L Tarnow,A P Maxwell,H-H Parving,L Groop,P-H Groop, ", - "abstract": "Parental type 2 diabetes mellitus increases the risk of diabetic nephropathy in offspring with type 1 diabetes mellitus. Several single nucleotide polymorphisms (SNPs) that predispose to type 2 diabetes mellitus have recently been identified. It is, however, not known whether such SNPs also confer susceptibility to diabetic nephropathy in patients with type 1 diabetes mellitus. We genotyped nine SNPs associated with type 2 diabetes mellitus in genome-wide association studies in the Finnish population, and tested for their association with diabetic nephropathy as well as with severe retinopathy and cardiovascular disease in 2,963 patients with type 1 diabetes mellitus. Replication of significant SNPs was sought in 2,980 patients from three other cohorts. In the discovery cohort, rs10811661 near gene CDKN2A/B was associated with diabetic nephropathy. The association remained after robust Bonferroni correction for the total number of tests performed in this study (OR 1.33 [95% CI 1.14, 1.56], p = 0.00045, p (36tests) = 0.016). In the meta-analysis, the combined result for diabetic nephropathy was significant, with a fixed effects p value of 0.011 (OR 1.15 [95% CI 1.02, 1.29]). The association was particularly strong when patients with end-stage renal disease were compared with controls (OR 1.35 [95% CI 1.13, 1.60], p = 0.00038). The same SNP was also associated with severe retinopathy (OR 1.37 [95% CI 1.10, 1.69] p = 0.0040), but the association did not remain after Bonferroni correction (p (36tests) = 0.14). None of the other selected SNPs was associated with nephropathy, severe retinopathy or cardiovascular disease. A SNP predisposing to type 2 diabetes mellitus, rs10811661 near CDKN2A/B, is associated with diabetic nephropathy in patients with type 1 diabetes mellitus.", - "journal_title": "Diabetologia", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/22643932/" - } - ], - "dad48e98-2dcc-41ae-866a-139f5540a24c": [ - { - "pub_id": "26101197", - "title": "Novel epigenetic determinants of type 2 diabetes in Mexican-American families.", - "authors": "Hemant Kulkarni,Mark Z Kos,Jennifer Neary,Thomas D Dyer,Jack W Kent,Harald H H G\u00f6ring,Shelley A Cole,Anthony G Comuzzie,Laura Almasy,Michael C Mahaney,Joanne E Curran,John Blangero,Melanie A Carless", - "abstract": "Although DNA methylation is now recognized as an important mediator of complex diseases, the extent to which the genetic basis of such diseases is accounted for by DNA methylation is unknown. In the setting of large, extended families representing a minority, high-risk population of the USA, we aimed to characterize the role of epigenome-wide DNA methylation in type 2 diabetes (T2D). Using Illumina HumanMethylation450 BeadChip arrays, we tested for association of DNA methylation at 446 356 sites with age, sex and phenotypic traits related to T2D in 850 pedigreed Mexican-American individuals. Robust statistical analyses showed that (i) 15% of the methylome is significantly heritable, with a median heritability of 0.14; (ii) DNA methylation at 14% of CpG sites is associated with nearby sequence variants; (iii) 22% and 3% of the autosomal CpG sites are associated with age and sex, respectively; (iv) 53 CpG sites were significantly associated with liability to T2D, fasting blood glucose and insulin resistance; (v) DNA methylation levels at five CpG sites, mapping to three well-characterized genes (TXNIP, ABCG1 and SAMD12) independently explained 7.8% of the heritability of T2D (vi) methylation at these five sites was unlikely to be influenced by neighboring DNA sequence variation. Our study has identified novel epigenetic indicators of T2D risk in Mexican Americans who have increased risk for this disease. These results provide new insights into potential treatment targets of T2D.", - "journal_title": "Human molecular genetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/26101197/" - } - ], - "f8659e89-3f2f-4c83-8069-f015862b7377": [ - { - "pub_id": "20352309", - "title": "Considerations for the impact of personal genome information: a study of genomic profiling among genetics and genomics professionals.", - "authors": "Julianne M O'Daniel,Susanne B Haga,Huntington F Willard", - "abstract": "With the expansion of genomic-based clinical applications, it is important to consider the potential impact of this information particularly in terms of how it may be interpreted and applied to personal perceptions of health. As an initial step to exploring this question, we conducted a study to gain insight into potential psychosocial and health motivations for, as well as impact associated with, undergoing testing and disclosure of individual \"variomes\" (catalogue of genetic variations). To enable the collection of fully informed opinions, 14 participants with advanced training in genetics underwent whole-genome profiling and received individual reports of estimated genomic ancestry, genotype data and reported disease associations. Emotional, cognitive and health behavioral impact was assessed through one-on-one interviews and questionnaires administered pre-testing and 1-week and 3-months post-testing. Notwithstanding the educational and professional bias of our study population, the results identify several areas of research for consideration within additional populations. With the development of new and less costly approaches to genome risk profiling, now available for purchase direct-to-consumers, it is essential that genome science research be conducted in parallel with studies assessing the societal and policy implications of genome information for personal use.", - "journal_title": "Journal of genetic counseling", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/20352309/" - } - ], - "893e83e6-05f4-4917-9dee-6ec2cb847def": [ - { - "pub_id": "24802877", - "title": "Association of dioxin and other persistent organic pollutants (POPs) with diabetes: epidemiological evidence and new mechanisms of beta cell dysfunction.", - "authors": "Vincenzo De Tata", - "abstract": "The worldwide explosion of the rates of diabetes and other metabolic diseases in the last few decades cannot be fully explained only by changes in the prevalence of classical lifestyle-related risk factors, such as physical inactivity and poor diet. For this reason, it has been recently proposed that other \"nontraditional\" risk factors could contribute to the diabetes epidemics. In particular, an increasing number of reports indicate that chronic exposure to and accumulation of a low concentration of environmental pollutants (especially the so-called persistent organic pollutants (POPs)) within the body might be associated with diabetogenesis. In this review, the epidemiological evidence suggesting a relationship between dioxin and other POPs exposure and diabetes incidence will be summarized, and some recent developments on the possible underlying mechanisms, with particular reference to dioxin, will be presented and discussed.", - "journal_title": "International journal of molecular sciences", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/24802877/" - } - ], - "370a3b80-64ed-42df-a480-2fc62b563131": [ - { - "pub_id": "24174433", - "title": "Progress in genetics and genomics of nonhuman primates. Introduction.", - "authors": "John D Harding", - "abstract": "", - "journal_title": "ILAR journal", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/24174433/" - } - ], - "df262ebc-bd7f-4866-a165-afae227974db": [ - { - "pub_id": "23386860", - "title": "Exploring genome-wide - dietary heme iron intake interactions and the risk of type 2 diabetes.", - "authors": "Louis R Pasquale,Stephanie J Loomis,Hugues Aschard,Jae H Kang,Marilyn C Cornelis,Lu Qi,Peter Kraft,Frank B Hu", - "abstract": "Genome-wide association studies have identified over 50 new genetic loci for type 2 diabetes (T2D). Several studies conclude that higher dietary heme iron intake increases the risk of T2D. Therefore we assessed whether the relation between genetic loci and T2D is modified by dietary heme iron intake. We used Affymetrix Genome-Wide Human 6.0 array data [681,770 single nucleotide polymorphisms (SNPs)] and dietary information collected in the Health Professionals Follow-up Study (n = 725 cases; n = 1,273 controls) and the Nurses' Health Study (n = 1,081 cases; n = 1,692 controls). We assessed whether genome-wide SNPs or iron metabolism SNPs interacted with dietary heme iron intake in relation to T2D, testing for associations in each cohort separately and then meta-analyzing to pool the results. Finally, we created 1,000 synthetic pathways matched to an iron metabolism pathway on number of genes, and number of SNPs in each gene. We compared the iron metabolic pathway SNPs with these synthetic SNP assemblies in their relation to T2D to assess if the pathway as a whole interacts with dietary heme iron intake. Using a genomic approach, we found no significant gene-environment interactions with dietary heme iron intake in relation to T2D at a Bonferroni corrected genome-wide significance level of 7.33 \u00d710(-) (8) (top SNP in pooled analysis: intergenic rs10980508; p = 1.03 \u00d7 10(-) (6)). Furthermore, no SNP in the iron metabolic pathway significantly interacted with dietary heme iron intake at a Bonferroni corrected significance level of 2.10 \u00d7 10(-) (4) (top SNP in pooled analysis: rs1805313; p = 1.14 \u00d7 10(-) (3)). Finally, neither the main genetic effects (pooled empirical p by SNP = 0.41), nor gene - dietary heme-iron interactions (pooled empirical p-value for the interactions = 0.72) were significant for the iron metabolic pathway as a whole. We found no significant interactions between dietary heme iron intake and common SNPs in relation to T2D.", - "journal_title": "Frontiers in genetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/23386860/" - } - ], - "6011e960-6a6e-47fe-94f2-2c21c224fd25": [ - { - "pub_id": "21252517", - "title": "Discovery of genes related to diabetic nephropathy in various animal models by current techniques.", - "authors": "Jun Wada,Lin Sun,Yashpal S Kanwar", - "abstract": "One of the major problems facing clinical nephrology currently throughout the world is an exponential increase in patients with end-stage renal disease (ESRD), which is largely related to a high incidence of diabetic nephropathy. The latter is characterized by a multitude of metabolic and signaling events following excessive channeling of glucose, which leads to an increased synthesis of extracellular matrix (ECM) glycoproteins resulting in glomerulosclerosis, interstitial fibrosis and ultimately ESRD. With the incidence of nephropathy at pandemic levels and a high rate of ESRD, physicians around the world must treat a disproportionately large number of diabetic patients with upto-date innovative measures. In this regard, identification of genes that are crucially involved in the progression of diabetic nephropathy would enhance the discovery of new biomarkers and could also promote the development of novel therapeutic strategies. Over the last decade, we focused on the recent methodologies of high-throughput and genome-wide screening for identification of relevant genes in various animal models, which included the following: (1) single nucleotide polymorphism-based genome- wide screening; (2) the transcriptome approach, such as differential display reverse transcription polymerase chain reaction (DDRT-PCR), representational difference analysis of cDNA (cDNA-RDA)/suppressive subtractive hybridization, SAGE (serial analysis of gene expression) and DNA Microarray; and (3) the proteomic approach and 2- dimensional polyacrylamide gel electrophoresis (2D- PAGE) coupled with mass spectroscopic analysis. Several genes, such as Tim44 (translocase of inner mitochondrial membrane- 44), RSOR/MIOX (renal specific oxidoreductase/myo-inositol oxygenase), UbA52, Rap1b (Ras-related GTPase), gremlin, osteopontin, hydroxysteroid dehydrogenase- 3\u03b2 isotype 4 and those of the Wnt signaling pathway, were identified as differentially expressed genes in kidneys of diabetic rodents. Functional analysis of these genes and the subsequent translational research in the clinical settings would be very valuable in the prevention and treatment of diabetic nephropathy. Future trends for identification of the biomarkers and therapeutic target genes should also include genome scale DNA/histonemethylation profiling, metabolomic approaches (e.g. metabolic phenotyping by 1H spectroscopy) and lectin microarray for glycan profiling along with the development of robust data-mining strategies.", - "journal_title": "Contributions to nephrology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/21252517/" - } - ], - "8cd81e24-a326-4443-bc37-0e6e421e70b2": [ - { - "pub_id": "25421534", - "title": "Nutrigenetics and nutrigenomics insights into diabetes etiopathogenesis.", - "authors": "Genoveva Bern\u00e1,Mar\u00eda Jes\u00fas Oliveras-L\u00f3pez,Enrique Jurado-Ru\u00edz,Juan Tejedo,Francisco Bedoya,Bernat Soria,Franz Mart\u00edn", - "abstract": "Diabetes mellitus (DM) is considered a global pandemic, and the incidence of DM continues to grow worldwide. Nutrients and dietary patterns are central issues in the prevention, development and treatment of this disease. The pathogenesis of DM is not completely understood, but nutrient-gene interactions at different levels, genetic predisposition and dietary factors appear to be involved. Nutritional genomics studies generally focus on dietary patterns according to genetic variations, the role of gene-nutrient interactions, gene-diet-phenotype interactions and epigenetic modifications caused by nutrients; these studies will facilitate an understanding of the early molecular events that occur in DM and will contribute to the identification of better biomarkers and diagnostics tools. In particular, this approach will help to develop tailored diets that maximize the use of nutrients and other functional ingredients present in food, which will aid in the prevention and delay of DM and its complications. This review discusses the current state of nutrigenetics, nutrigenomics and epigenomics research on DM. Here, we provide an overview of the role of gene variants and nutrient interactions, the importance of nutrients and dietary patterns on gene expression, how epigenetic changes and micro RNAs (miRNAs) can alter cellular signaling in response to nutrients and the dietary interventions that may help to prevent the onset of DM.", - "journal_title": "Nutrients", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/25421534/" - } - ], - "8a9fe1bc-7fa3-40ee-ade0-9a498bcf9def": [ - { - "pub_id": "23673148", - "title": "The genomics of preterm birth: from animal models to human studies.", - "authors": "Katherine Y Bezold,Minna K Karjalainen,Mikko Hallman,Kari Teramo,Louis J Muglia", - "abstract": "Preterm birth (delivery at less than 37 weeks of gestation) is the leading cause of infant mortality worldwide. So far, the application of animal models to understand human birth timing has not substantially revealed mechanisms that could be used to prevent prematurity. However, with amassing data implicating an important role for genetics in the timing of the onset of human labor, the use of modern genomic approaches, such as genome-wide association studies, rare variant analyses using whole-exome or genome sequencing, and family-based designs, holds enormous potential. Although some progress has been made in the search for causative genes and variants associated with preterm birth, the major genetic determinants remain to be identified. Here, we review insights from and limitations of animal models for understanding the physiology of parturition, recent human genetic and genomic studies to identify genes involved in preterm birth, and emerging areas that are likely to be informative in future investigations. Further advances in understanding fundamental mechanisms, and the development of preventative measures, will depend upon the acquisition of greater numbers of carefully phenotyped pregnancies, large-scale informatics approaches combining genomic information with information on environmental exposures, and new conceptual models for studying the interaction between the maternal and fetal genomes to personalize therapies for mothers and infants. Information emerging from these advances will help us to identify new biomarkers for earlier detection of preterm labor, develop more effective therapeutic agents, and/or promote prophylactic measures even before conception.", - "journal_title": "Genome medicine", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/23673148/" - } - ], - "17cd95a4-6e8e-4696-8881-ea43fa80ccce": [ - { - "pub_id": "22100807", - "title": "Next steps in cardiovascular disease genomic research--sequencing, epigenetics, and transcriptomics.", - "authors": "Renate B Schnabel,Andrea Baccarelli,Honghuang Lin,Patrick T Ellinor,Emelia J Benjamin", - "abstract": "Genomic research in cardiovascular disease (CVD) has progressed rapidly over the last 5 years. In most cases, however, these groundbreaking observations have not yet been accompanied by clinically applicable tools for risk prediction, diagnosis, or therapeutic interventions. We reviewed the scientific literature published in English for novel methods and promising genomic targets that would permit large-scale screening and follow-up of recent genomic findings for CVD. We anticipate that advances in 3 key areas will be critical for the success of these projects. First, exome-centered and whole-genome next-generation sequencing will identify rare and novel genetic variants associated with CVD and its risk factors. Improvements in methods will also greatly advance the field of epigenetics and gene expression in humans. Second, research is increasingly acknowledging that static DNA sequence variation explains only a fraction of the inherited phenotype. Therefore, we expect that multiple epigenetic and gene expression signatures will be related to CVD in experimental and clinical settings. Leveraging existing large-scale consortia and clinical biobanks in combination with electronic health records holds promise for integrating epidemiological and clinical genomics data. Finally, a systems biology approach will be needed to integrate the accumulated multidimensional data. Novel methods in sequencing, epigenetics, and transcriptomics, plus unprecedented large-scale cooperative efforts, promise to generate insights into the complexity of CVD. The rapid accumulation and integration of knowledge will shed light on a considerable proportion of the missing heritability for CVD.", - "journal_title": "Clinical chemistry", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/22100807/" - } - ], - "99d5e3d6-c802-468a-a13c-723bcc7000cb": [ - { - "pub_id": "21342419", - "title": "Implications for educating the next generation of nurses on genetics and genomics in the 21st century.", - "authors": "Dale Halsey Lea,Heather Skirton,Catherine Y Read,Janet K Williams", - "abstract": "To provide nurse educators with an updated overview of advances in genetics and genomics in the context of the holistic perspective of nursing. Recent advances in genetic and genomic research, testing, therapies, and resources are presented, and the continuing importance of the family history is discussed. Genomic nurse experts reviewed recent literature and consumer resources to elucidate updates in technology through the lens of the genetically vulnerable patient and family. Genetic and genomic technologies are becoming routinely used in health care, and nurse educators will be challenged to incorporate these technologies and implications for patients and families into educational programs. New technology and its applications are perennial challenges to nurse educators, but the common focus for nursing, historically and geographically, is health promotion, symptom management, and disease prevention. Education for the next generation of nurses can lay a foundation in genetics and genomics that will enable interpretation and responsible integration of new technologies in a context of individual and family value systems, personal experiences, risk perception, decision consequences, and available resources. Nurses are ideally situated to inform patients about new options in healthcare, and nurse educators are challenged to prepare their students to interpret and responsibly integrate new genetic-genomic information into practice.", - "journal_title": "Journal of nursing scholarship : an official publication of Sigma Theta Tau International Honor Society of Nursing", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/21342419/" - } - ], - "6303851b-5bac-4c62-bafc-78f9276c0285": [ - { - "pub_id": "24078135", - "title": "The potential of novel biomarkers to improve risk prediction of type 2 diabetes.", - "authors": "Christian Herder,Bernd Kowall,Adam G Tabak,Wolfgang Rathmann", - "abstract": "The incidence of type 2 diabetes can be reduced substantially by implementing preventive measures in high-risk individuals, but this requires prior knowledge of disease risk in the individual. Various diabetes risk models have been designed, and these have all included a similar combination of factors, such as age, sex, obesity, hypertension, lifestyle factors, family history of diabetes and metabolic traits. The accuracy of prediction models is often assessed by the area under the receiver operating characteristic curve (AROC) as a measure of discrimination, but AROCs should be complemented by measures of calibration and reclassification to estimate the incremental value of novel biomarkers. This review discusses the potential of novel biomarkers to improve model accuracy. The range of molecules that serve as potential predictors of type 2 diabetes includes genetic variants, RNA transcripts, peptides and proteins, lipids and small metabolites. Some of these biomarkers lead to a statistically significant increase of model accuracy, but their incremental value currently seems too small for routine clinical use. However, only a fraction of potentially relevant biomarkers have been assessed with regard to their predictive value. Moreover, serial measurements of biomarkers may help determine individual risk. In conclusion, current risk models provide valuable tools of risk estimation, but perform suboptimally in the prediction of individual diabetes risk. Novel biomarkers still fail to have a clinically applicable impact. However, more efficient use of biomarker data and technological advances in their measurement in clinical settings may allow the development of more accurate predictive models in the future.", - "journal_title": "Diabetologia", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/24078135/" - } - ], - "6f3e85af-5c85-4fa2-bd76-9b735aec379e": [ - { - "pub_id": "21627411", - "title": "Genetic determinants of on-clopidogrel high platelet reactivity.", - "authors": "Gianluca Campo,Matteo Miccoli,Matteo Tebaldi,Jlenia Marchesini,Luca Fileti,Monia Monti,Marco Valgimigli,Roberto Ferrari", - "abstract": "Clopidogrel has been used (alone or in association with aspirin) to prevent vascular complications in atherothrombotic patients, to prevent stent thrombosis (ST) in patients undergoing percutaneous coronary intervention (PCI) and as a long-term prevention of cardiovascular and cerebrovascular events. Unfortunately, it is important to note that there are a number of patients who, during clopidogrel therapy, show and maintain a high platelet reactivity (PR), similar to that observed before the start of antiplatelet therapy. Clopidogrel pro-drug is absorbed in the intestine and this process is influenced by P-glycoprotein-1 (P-GP). Its conversion into 2-oxo clopidogrel is regulated by cytochromes (CYP) called CYP2C19, CYP2B6 and CYP1A2. Whereas, the final transformation into the active metabolite is regulated by CYP called CYP2C19, CYP2C9, CYP2B6, CYP3A4, CYP3A5 and, as recently emerged, by the glycoprotein paraoxonase-1 (PON1). The genes encoding these enzymes are characterized by several polymorphisms. Some of these are able to modify the activity of proteins, reducing the concentration of active metabolite and the values of on-clopidogrel PR. Only one gene polymorphism (CYP2C19*17) increases the clopidogrel metabolization and so the clopidogrel-induced platelet inhibition. Several studies have clearly associated these gene polymorphisms to both ischemic and bleeding complications in patients receiving dual antiplatelet therapy. The aim of this review is to describe the principal gene polymorphisms influencing on-clopidogrel PR and their relationship with long-term clinical outcome.", - "journal_title": "Platelets", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/21627411/" - } - ], - "6c0eb981-977a-42f5-a3b1-136e1ccfc5aa": [ - { - "pub_id": "25561044", - "title": "Basic concepts and potential applications of genetics and genomics for cardiovascular and stroke clinicians: a scientific statement from the American Heart Association.", - "authors": "Kiran Musunuru,Kathleen T Hickey,Sana M Al-Khatib,Christian Delles,Myriam Fornage,Caroline S Fox,Lorraine Frazier,Bruce D Gelb,David M Herrington,David E Lanfear,Jonathan Rosand, ", - "abstract": "", - "journal_title": "Circulation. Cardiovascular genetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/25561044/" - } - ], - "3035a342-be3f-41ad-b0e3-36a67c5f2491": [ - { - "pub_id": "21826100", - "title": "Targeting gut microbiota in obesity: effects of prebiotics and probiotics.", - "authors": "Nathalie M Delzenne,Audrey M Neyrinck,Fredrik B\u00e4ckhed,Patrice D Cani", - "abstract": "At birth, the human colon is rapidly colonized by gut microbes. Owing to their vast number and their capacity to ferment nutrients and secrete bioactive compounds, these gastrointestinal microbes act as an environmental factor that affects the host's physiology and metabolism, particularly in the context of obesity and its related metabolic disorders. Experiments that compared germ-free and colonized mice or analyzed the influence of nutrients that qualitatively change the composition of the gut microbiota (namely prebiotics) showed that gut microbes induce a wide variety of host responses within the intestinal mucosa and thereby control the gut's barrier and endocrine functions. Gut microbes also influence the metabolism of cells in tissues outside of the intestines (in the liver and adipose tissue) and thereby modulate lipid and glucose homeostasis, as well as systemic inflammation, in the host. A number of studies describe characteristic differences between the composition and/or activity of the gut microbiota of lean individuals and those with obesity. Although these data are controversial, they suggest that specific phyla, classes or species of bacteria, or bacterial metabolic activities could be beneficial or detrimental to patients with obesity. The gut microbiota is, therefore, a potential nutritional and pharmacological target in the management of obesity and obesity-related disorders.", - "journal_title": "Nature reviews. Endocrinology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/21826100/" - } - ], - "af5bb4ab-62ee-4e30-9112-0eefef3685ed": [ - { - "pub_id": "34932836", - "title": "Transfusion thresholds for guiding red blood cell transfusion.", - "authors": "Jeffrey L Carson,Simon J Stanworth,Jane A Dennis,Marialena Trivella,Nareg Roubinian,Dean A Fergusson,Darrell Triulzi,Carolyn Dor\u00e9e,Paul C H\u00e9bert", - "abstract": "The optimal haemoglobin threshold for use of red blood cell (RBC) transfusions in anaemic patients remains\u00a0an active field of research.\u00a0Blood is a scarce resource, and in some countries, transfusions are less safe than in others because of inadequate testing for viral pathogens. If a liberal transfusion policy does not improve clinical outcomes, or if it is equivalent, then adopting a more restrictive approach could be recognised as the standard of care.\u00a0 OBJECTIVES: The aim of this review update was to compare 30-day mortality and other clinical outcomes for participants randomised to restrictive versus liberal red blood cell (RBC) transfusion thresholds (triggers) for all clinical conditions. The restrictive transfusion threshold uses a lower haemoglobin concentration\u00a0as a threshold for\u00a0transfusion (most commonly, 7.0 g/dL to 8.0 g/dL), and the liberal transfusion threshold uses a higher haemoglobin concentration as a threshold for transfusion (most commonly, 9.0 g/dL to 10.0 g/dL). We identified trials\u00a0through updated searches: CENTRAL (2020, Issue 11), MEDLINE (1946 to November 2020), Embase (1974 to November 2020), Transfusion Evidence Library (1950 to November 2020), Web of Science Conference Proceedings Citation Index (1990 to\u00a0November 2020), and trial registries (November\u00a02020). We\u00a0 checked the reference lists of other published reviews and relevant papers to identify additional trials. We were aware of one trial identified in earlier searching that was in the process of being published (in February 2021), and we were able to include it before this review was finalised. We included randomised trials of surgical or medical participants that recruited adults or children, or both. We excluded studies that focused on neonates. Eligible trials assigned intervention groups on the basis of different transfusion schedules or thresholds or 'triggers'. These thresholds would be defined by a haemoglobin (Hb) or haematocrit (Hct) concentration\u00a0below which an\u00a0RBC\u00a0transfusion would be administered; the\u00a0haemoglobin concentration remains the most commonly applied marker\u00a0of the need for RBC transfusion in clinical practice.\u00a0We included trials in which investigators had allocated participants to higher thresholds or more liberal transfusion strategies compared to more restrictive ones, which might include no transfusion. As in previous versions of this review, we did not exclude unregistered trials published after 2010 (as per the policy of the Cochrane Injuries Group, 2015), however, we did conduct analyses to consider the differential impact of results of trials for which prospective registration could not be confirmed. \u00a0 DATA COLLECTION AND ANALYSIS: We identified trials for inclusion and extracted data using Cochrane methods. We pooled risk ratios of clinical outcomes across trials using a random-effects model. Two review authors\u00a0independently extracted data and assessed risk of bias. We conducted predefined analyses by clinical subgroups. We defined participants randomly allocated to the lower transfusion threshold as being in the 'restrictive transfusion' group and those randomly allocated to the higher transfusion threshold as being in the 'liberal transfusion' group. A total of\u00a048\u00a0trials, involving data from 21,433 participants (at baseline), across a range of clinical contexts (e.g. orthopaedic, cardiac, or vascular surgery; critical care; acute blood loss (including gastrointestinal bleeding); acute coronary syndrome; cancer; leukaemia; haematological malignancies), met the eligibility criteria. The haemoglobin concentration used to define the restrictive transfusion group in most trials (36) was between 7.0 g/dL and 8.0 g/dL. \u00a0Most trials included only adults; three trials focused on children. The included studies were generally at low risk of bias for key domains including allocation concealment and incomplete outcome data. Restrictive transfusion strategies reduced the risk of receiving at least one RBC transfusion by 41% across a broad range of clinical contexts (risk ratio (RR) 0.59, 95% confidence interval (CI) 0.53 to 0.66; 42 studies, 20,057\u00a0participants; high-quality evidence), with a large amount of heterogeneity between trials (I\u00b2 = 96%). Overall, restrictive transfusion strategies did not increase or decrease the risk of 30-day mortality compared with liberal transfusion strategies (RR 0.99, 95% CI 0.86 to 1.15; 31 studies, 16,729 participants; I\u00b2 = 30%; moderate-quality evidence) or any of the other outcomes assessed (i.e. cardiac events (low-quality evidence), myocardial infarction, stroke, thromboembolism (all high-quality evidence)). High-quality evidence shows that the liberal transfusion threshold did not affect the risk of infection (pneumonia, wound infection, or bacteraemia). Transfusion-specific reactions are uncommon and were inconsistently reported within trials. We noted less certainty in the strength of evidence to support the safety of restrictive transfusion thresholds for the following predefined clinical subgroups: myocardial infarction, vascular surgery, haematological malignancies, and chronic bone-marrow disorders. Transfusion\u00a0at a restrictive haemoglobin concentration decreased the proportion of people exposed to RBC transfusion by 41% across a broad range of clinical contexts. Across all trials, no evidence suggests that a restrictive transfusion strategy impacted\u00a030-day mortality, mortality at other time points, or morbidity (i.e. cardiac events, myocardial infarction, stroke, pneumonia, thromboembolism, infection) compared with a liberal transfusion strategy. Despite including 17 more randomised trials (and 8846 participants), data remain insufficient to inform the safety of transfusion policies in important and selected clinical contexts, such as myocardial infarction, chronic cardiovascular disease, neurological injury or traumatic brain injury, stroke, thrombocytopenia, and cancer or haematological malignancies, including chronic\u00a0bone marrow failure.\u00a0 Further work is needed to improve our understanding of outcomes other than mortality.\u00a0Most trials compared only two\u00a0separate thresholds for haemoglobin concentration, which may not identify the\u00a0actual optimal threshold for transfusion in a particular patient. Haemoglobin concentration may not be the most informative marker of the need for transfusion in individual patients with different degrees of physiological adaptation to anaemia. Notwithstanding these issues, overall findings provide good evidence that transfusions with allogeneic RBCs can be avoided in most patients with haemoglobin thresholds between the range of 7.0 g/dL and 8.0 g/dL.\u00a0Some patient subgroups\u00a0might benefit from RBCs\u00a0to maintain higher haemoglobin concentrations; research efforts should focus on these clinical contexts.", - "journal_title": "The Cochrane database of systematic reviews", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/34932836/" - } - ], - "3d681d63-2ed3-4675-acd8-04bd00f152a6": [ - { - "pub_id": "23049381", - "title": "Genomic instability in patients with type 2 diabetes mellitus on hemodialysis.", - "authors": "Roberta Passos Palazzo,Pamela Brambilla Bagatini,Patr\u00edcia Brandt Schefer,Fabiana Michelsen de Andrade,Sharbel Weidner Maluf", - "abstract": "A previous study by our research group evaluated the levels of DNA damage using the comet assay in hemodialysis patients with type 2 diabetes mellitus. The same blood samples were also evaluated using the cytochalasin B micronucleus assay. A comparison of the results of the two assays is presented here. Whole blood samples were collected from 22 type 2 diabetes mellitus patients on hemodialysis and from 22 control subjects. Samples were collected from patients early in the morning on Mondays, before the first weekly hemodialysis session. The cytokinesis-block micronucleus assay (CBMN) was used to evaluate genomic instability. The frequencies of micronuclei and nuclear buds were higher in patients than in controls (p-value = 0.001 and p-value < 0.001, respectively). There was a correlation between the frequency of micronuclei and DNA damage with the results of the comet assay (p-value < 0.001). The difference in the frequency of micronuclei and nuclear buds between patients and controls was more pronounced in the group with higher median comet values than in the group with lower comet values. Our results suggest that the increased rates of DNA damage as measured by the comet assay and influenced by the weekly routine therapy of these patients has a mutagenic effect, thereby increasing the risk of cancer in this group.", - "journal_title": "Revista brasileira de hematologia e hemoterapia", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/23049381/" - } - ], - "f06a22ff-cf91-46e8-8a2f-6690d7ba90d9": [ - { - "pub_id": "31915891", - "title": "Impact of circadian disruption on glucose metabolism: implications for type 2 diabetes.", - "authors": "Ivy C Mason,Jingyi Qian,Gail K Adler,Frank A J L Scheer", - "abstract": "The circadian system generates endogenous rhythms of approximately 24\u00a0h, the synchronisation of which are vital for healthy bodily function. The timing of many physiological processes, including glucose metabolism, are coordinated by the circadian system, and circadian disruptions that desynchronise or misalign these rhythms can result in adverse health outcomes. In this review, we cover the role of the circadian system and its disruption in glucose metabolism in healthy individuals and individuals with type 2 diabetes mellitus. We begin by defining circadian rhythms and circadian disruption and then we provide an overview of circadian regulation of glucose metabolism. We next discuss the impact of circadian disruptions on glucose control and type 2 diabetes. Given the concurrent high prevalence of type 2 diabetes and circadian disruption, understanding the mechanisms underlying the impact of circadian disruption on glucose metabolism may aid in improving glycaemic control.", - "journal_title": "Diabetologia", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/31915891/" - } - ], - "8d723c99-bd3c-43eb-9b31-14ee233c2ed4": [ - { - "pub_id": "24458354", - "title": "Evaluating the role of epigenetic histone modifications in the metabolic memory of type 1 diabetes.", - "authors": "Feng Miao,Zhuo Chen,Saul Genuth,Andrew Paterson,Lingxiao Zhang,Xiwei Wu,Sierra Min Li,Patricia Cleary,Arthur Riggs,David M Harlan,Gayle Lorenzi,Orville Kolterman,Wanjie Sun,John M Lachin,Rama Natarajan, ", - "abstract": "We assessed whether epigenetic histone posttranslational modifications are associated with the prolonged beneficial effects (metabolic memory) of intensive versus conventional therapy during the Diabetes Control and Complications Trial (DCCT) on the progression of microvascular outcomes in the long-term Epidemiology of Diabetes Interventions and Complications (EDIC) study. We performed chromatin immunoprecipitation linked to promoter tiling arrays to profile H3 lysine-9 acetylation (H3K9Ac), H3 lysine-4 trimethylation (H3K4Me3), and H3K9Me2 in blood monocytes and lymphocytes obtained from 30 DCCT conventional treatment group subjects (case subjects: mean DCCT HbA1c level >9.1% [76 mmol/mol] and progression of retinopathy or nephropathy by EDIC year 10 of follow-up) versus 30 DCCT intensive treatment subjects (control subjects: mean DCCT HbA1c level <7.3% [56 mmol/mol] and without progression of retinopathy or nephropathy). Monocytes from case subjects had statistically greater numbers of promoter regions with enrichment in H3K9Ac (active chromatin mark) compared with control subjects (P = 0.0096). Among the patients in the two groups combined, monocyte H3K9Ac was significantly associated with the mean HbA1c level during the DCCT and EDIC (each P < 2.2E-16). Of note, the top 38 case hyperacetylated promoters (P < 0.05) included >15 genes related to the nuclear factor-\u03baB inflammatory pathway and were enriched in genes related to diabetes complications. These results suggest an association between HbA1c level and H3K9Ac, and a possible epigenetic explanation for metabolic memory in humans.", - "journal_title": "Diabetes", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/24458354/" - } - ], - "f5691980-91d6-40c9-adf3-9b3daab14841": [ - { - "pub_id": "22426310", - "title": "Conditional and joint multiple-SNP analysis of GWAS summary statistics identifies additional variants influencing complex traits.", - "authors": "Jian Yang,Teresa Ferreira,Andrew P Morris,Sarah E Medland, , ,Pamela A F Madden,Andrew C Heath,Nicholas G Martin,Grant W Montgomery,Michael N Weedon,Ruth J Loos,Timothy M Frayling,Mark I McCarthy,Joel N Hirschhorn,Michael E Goddard,Peter M Visscher", - "abstract": "We present an approximate conditional and joint association analysis that can use summary-level statistics from a meta-analysis of genome-wide association studies (GWAS) and estimated linkage disequilibrium (LD) from a reference sample with individual-level genotype data. Using this method, we analyzed meta-analysis summary data from the GIANT Consortium for height and body mass index (BMI), with the LD structure estimated from genotype data in two independent cohorts. We identified 36 loci with multiple associated variants for height (38 leading and 49 additional SNPs, 87 in total) via a genome-wide SNP selection procedure. The 49 new SNPs explain approximately 1.3% of variance, nearly doubling the heritability explained at the 36 loci. We did not find any locus showing multiple associated SNPs for BMI. The method we present is computationally fast and is also applicable to case-control data, which we demonstrate in an example from meta-analysis of type 2 diabetes by the DIAGRAM Consortium.", - "journal_title": "Nature genetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/22426310/" - } - ], - "4d681730-97a5-4efd-89ef-76da9f49f793": [ - { - "pub_id": "26429807", - "title": "Exercise genomics--a paradigm shift is needed: a commentary.", - "authors": "Claude Bouchard", - "abstract": "The overarching goal of exercise genomics is to illuminate exercise biology and behaviour in order to better understand the preventive and therapeutic values of exercise. An ancillary aim is to understand the role of genomic variation in human physical attributes and sports performance. The aim of this report is to briefly comment on the current status of exercise genetics and genomics and to suggest potential improvements to the research agenda and translational activities. First, the genomic features of interest to the biology of exercise are defined. Then, the limit of the current focus on common variants and their implications for exercise genomics is highlighted. The need for a major paradigm shift in exercise genomics research is discussed with an emphasis on study designs and appropriately powered studies as well as on more mechanistic and functional research. Finally, a summary of current practices in translational activities compared with what best practice demands is introduced. One suggestion is that the research portfolio of exercise genomics be composed of a larger fraction of experimental and mechanistic investigations and a smaller fraction of observational studies. It is also recommended that research should shift to unbiased exploration of the genome using all the power of genomics, epigenomics and transcriptomics in combination with large observational but preferably experimental study designs, including Mendelian randomisation. In all cases, emphasis on replications is of paramount importance. This represents an extraordinary challenge that can only be met with large-scale collaborative and multicentre research programmes.", - "journal_title": "British journal of sports medicine", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/26429807/" - } - ], - "251d15dc-e1ec-4fea-8c29-b000f51a62cd": [ - { - "pub_id": "21035756", - "title": "Global epigenomic analysis of primary human pancreatic islets provides insights into type 2 diabetes susceptibility loci.", - "authors": "Michael L Stitzel,Praveen Sethupathy,Daniel S Pearson,Peter S Chines,Lingyun Song,Michael R Erdos,Ryan Welch,Stephen C J Parker,Alan P Boyle,Laura J Scott, ,Elliott H Margulies,Michael Boehnke,Terrence S Furey,Gregory E Crawford,Francis S Collins", - "abstract": "Identifying cis-regulatory elements is important to understanding how human pancreatic islets modulate gene expression in physiologic or pathophysiologic (e.g., diabetic) conditions. We conducted genome-wide analysis of DNase I hypersensitive sites, histone H3 lysine methylation modifications (K4me1, K4me3, K79me2), and CCCTC factor (CTCF) binding in human islets. This identified \u223c18,000 putative promoters (several hundred unannotated and islet-active). Surprisingly, active promoter modifications were absent at genes encoding islet-specific hormones, suggesting a distinct regulatory mechanism. Of 34,039 distal (nonpromoter) regulatory elements, 47% are islet unique and 22% are CTCF bound. In the 18 type 2 diabetes (T2D)-associated loci, we identified 118 putative regulatory elements and confirmed enhancer activity for 12 of 33 tested. Among six regulatory elements harboring T2D-associated variants, two exhibit significant allele-specific differences in activity. These findings present a global snapshot of the human islet epigenome and should provide functional context for noncoding variants emerging from genetic studies of T2D and other islet disorders.", - "journal_title": "Cell metabolism", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/21035756/" - } - ], - "d7738041-0387-489b-b2ed-9b42a62dbba8": [ - { - "pub_id": "24269772", - "title": "Medicinal plants for women's healthcare in southeast Asia: a meta-analysis of their traditional use, chemical constituents, and pharmacology.", - "authors": "Hugo J de Boer,Crystle Cotingting", - "abstract": "This is an extensive review of plants used traditionally for women's healthcare in Southeast Asia and surrounding countries. Medicinal plants have a significant role in women's healthcare in many rural areas of the world. Plants with numerous efficacious observations have historically been used as a starting point in the development of new drugs, and a large percentage of modern pharmaceuticals have been derived from medicinal plants. A review was conducted for all plant use mentioned specifically for female healthcare, such as medicine to increase fertility, induce menstruation or abortion, ease pregnancy and parturition, reduce menstrual bleeding and postpartum hemorrhage, alleviate menstrual, parturition and postpartum pain, increase or inhibit lactation, and treat mastitis and uterine prolapse, in 200 studies focusing on medicinal plant use, either general studies or studies focusing specifically on women's healthcare. Nearly 2000 different plant species are reported to be used in over 5000 combinations. Most common are Achyranthes aspera, Artemisia vulgaris, Blumea balsamifera, Carica papaya, Curcuma longa, Hibiscus rosa-sinensis, Leonurus japonicus, Psidium guajava and Ricinus communis, and each of these species had been reported in more than 10 different scientific articles. This review provides a basis for traditional plant use in women's healthcare, and these species can be used as the starting point in the discovery of new drugs.", - "journal_title": "Journal of ethnopharmacology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/24269772/" - } - ], - "770beab7-59a4-4bbe-94a5-79a965ab696a": [ - { - "pub_id": "22352879", - "title": "The use of animal models in diabetes research.", - "authors": "Aileen J F King", - "abstract": "Diabetes is a disease characterized by a relative or absolute lack of insulin, leading to hyperglycaemia. There are two main types of diabetes: type 1 diabetes and type 2 diabetes. Type 1 diabetes is due to an autoimmune destruction of the insulin-producing pancreatic beta cells, and type 2 diabetes is caused by insulin resistance coupled by a failure of the beta cell to compensate. Animal models for type 1 diabetes range from animals with spontaneously developing autoimmune diabetes to chemical ablation of the pancreatic beta cells. Type 2 diabetes is modelled in both obese and non-obese animal models with varying degrees of insulin resistance and beta cell failure. This review outlines some of the models currently used in diabetes research. In addition, the use of transgenic and knock-out mouse models is discussed. Ideally, more than one animal model should be used to represent the diversity seen in human diabetic patients.", - "journal_title": "British journal of pharmacology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/22352879/" - } - ], - "e117552b-06d5-4ad4-9520-39e1c5c1f587": [ - { - "pub_id": "24336571", - "title": "Genome-scale CRISPR-Cas9 knockout screening in human cells.", - "authors": "Ophir Shalem,Neville E Sanjana,Ella Hartenian,Xi Shi,David A Scott,Tarjei Mikkelson,Dirk Heckl,Benjamin L Ebert,David E Root,John G Doench,Feng Zhang", - "abstract": "The simplicity of programming the CRISPR (clustered regularly interspaced short palindromic repeats)-associated nuclease Cas9 to modify specific genomic loci suggests a new way to interrogate gene function on a genome-wide scale. We show that lentiviral delivery of a genome-scale CRISPR-Cas9 knockout (GeCKO) library targeting 18,080 genes with 64,751 unique guide sequences enables both negative and positive selection screening in human cells. First, we used the GeCKO library to identify genes essential for cell viability in cancer and pluripotent stem cells. Next, in a melanoma model, we screened for genes whose loss is involved in resistance to vemurafenib, a therapeutic RAF inhibitor. Our highest-ranking candidates include previously validated genes NF1 and MED12, as well as novel hits NF2, CUL3, TADA2B, and TADA1. We observe a high level of consistency between independent guide RNAs targeting the same gene and a high rate of hit confirmation, demonstrating the promise of genome-scale screening with Cas9.", - "journal_title": "Science (New York, N.Y.)", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/24336571/" - } - ], - "f14a6713-c827-4d4d-9b64-256de84b926e": [ - { - "pub_id": "28002404", - "title": "Epigenome-wide association study of body mass index, and the adverse outcomes of adiposity.", - "authors": "Simone Wahl,Alexander Drong,Benjamin Lehne,Marie Loh,William R Scott,Sonja Kunze,Pei-Chien Tsai,Janina S Ried,Weihua Zhang,Youwen Yang,Sili Tan,Giovanni Fiorito,Lude Franke,Simonetta Guarrera,Silva Kasela,Jennifer Kriebel,Rebecca C Richmond,Marco Adamo,Uzma Afzal,Mika Ala-Korpela,Benedetta Albetti,Ole Ammerpohl,Jane F Apperley,Marian Beekman,Pier Alberto Bertazzi,S Lucas Black,Christine Blancher,Marc-Jan Bonder,Mario Brosch,Maren Carstensen-Kirberg,Anton J M de Craen,Simon de Lusignan,Abbas Dehghan,Mohamed Elkalaawy,Krista Fischer,Oscar H Franco,Tom R Gaunt,Jochen Hampe,Majid Hashemi,Aaron Isaacs,Andrew Jenkinson,Sujeet Jha,Norihiro Kato,Vittorio Krogh,Michael Laffan,Christa Meisinger,Thomas Meitinger,Zuan Yu Mok,Valeria Motta,Hong Kiat Ng,Zacharoula Nikolakopoulou,Georgios Nteliopoulos,Salvatore Panico,Natalia Pervjakova,Holger Prokisch,Wolfgang Rathmann,Michael Roden,Federica Rota,Michelle Ann Rozario,Johanna K Sandling,Clemens Schafmayer,Katharina Schramm,Reiner Siebert,P Eline Slagboom,Pasi Soininen,Lisette Stolk,Konstantin Strauch,E-Shyong Tai,Letizia Tarantini,Barbara Thorand,Ettje F Tigchelaar,Rosario Tumino,Andre G Uitterlinden,Cornelia van Duijn,Joyce B J van Meurs,Paolo Vineis,Ananda Rajitha Wickremasinghe,Cisca Wijmenga,Tsun-Po Yang,Wei Yuan,Alexandra Zhernakova,Rachel L Batterham,George Davey Smith,Panos Deloukas,Bastiaan T Heijmans,Christian Herder,Albert Hofman,Cecilia M Lindgren,Lili Milani,Pim van der Harst,Annette Peters,Thomas Illig,Caroline L Relton,Melanie Waldenberger,Marjo-Riitta J\u00e4rvelin,Valentina Bollati,Richie Soong,Tim D Spector,James Scott,Mark I McCarthy,Paul Elliott,Jordana T Bell,Giuseppe Matullo,Christian Gieger,Jaspal S Kooner,Harald Grallert,John C Chambers", - "abstract": "Approximately 1.5 billion people worldwide are overweight or affected by obesity, and are at risk of developing type 2 diabetes, cardiovascular disease and related metabolic and inflammatory disturbances. Although the mechanisms linking adiposity to associated clinical conditions are poorly understood, recent studies suggest that adiposity may influence DNA methylation, a key regulator of gene expression and molecular phenotype. Here we use epigenome-wide association to show that body mass index (BMI; a key measure of adiposity) is associated with widespread changes in DNA methylation (187 genetic loci with P\u2009<\u20091\u2009\u00d7\u200910<sup>-7</sup>, range P\u2009=\u20099.2\u2009\u00d7\u200910<sup>-8</sup> to 6.0\u2009\u00d7\u200910<sup>-46</sup>; n\u2009=\u200910,261 samples). Genetic association analyses demonstrate that the alterations in DNA methylation are predominantly the consequence of adiposity, rather than the cause. We find that methylation loci are enriched for functional genomic features in multiple tissues (P\u2009<\u20090.05), and show that sentinel methylation markers identify gene expression signatures at 38 loci (P\u2009<\u20099.0\u2009\u00d7\u200910<sup>-6</sup>, range P\u2009=\u20095.5\u2009\u00d7\u200910<sup>-6</sup> to 6.1\u2009\u00d7\u200910<sup>-35</sup>, n\u2009=\u20091,785 samples). The methylation loci identify genes involved in lipid and lipoprotein metabolism, substrate transport and inflammatory pathways. Finally, we show that the disturbances in DNA methylation predict future development of type 2 diabetes (relative risk per 1 standard deviation increase in methylation risk score: 2.3 (2.07-2.56); P\u2009=\u20091.1\u2009\u00d7\u200910<sup>-54</sup>). Our results provide new insights into the biologic pathways influenced by adiposity, and may enable development of new strategies for prediction and prevention of type 2 diabetes and other adverse clinical consequences of obesity.", - "journal_title": "Nature", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/28002404/" - } - ], - "07e4d0a6-79a9-421f-8431-2569b3c0c006": [ - { - "pub_id": "25950729", - "title": "Exploring human brain lateralization with molecular genetics and genomics.", - "authors": "Clyde Francks", - "abstract": "Lateralizations of brain structure and motor behavior have been observed in humans as early as the first trimester of gestation, and are likely to arise from asymmetrical genetic-developmental programs, as in other animals. Studies of gene expression levels in postmortem tissue samples, comparing the left and right sides of the human cerebral cortex, have generally not revealed striking transcriptional differences between the hemispheres. This is likely due to lateralization of gene expression being subtle and quantitative. However, a recent re-analysis and meta-analysis of gene expression data from the adult superior temporal and auditory cortex found lateralization of transcription of genes involved in synaptic transmission and neuronal electrophysiology. Meanwhile, human subcortical mid- and hindbrain structures have not been well studied in relation to lateralization of gene activity, despite being potentially important developmental origins of asymmetry. Genetic polymorphisms with small effects on adult brain and behavioral asymmetries are beginning to be identified through studies of large datasets, but the core genetic mechanisms of lateralized human brain development remain unknown. Identifying subtly lateralized genetic networks in the brain will lead to a new understanding of how neuronal circuits on the left and right are differently fine-tuned to preferentially support particular cognitive and behavioral functions.", - "journal_title": "Annals of the New York Academy of Sciences", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/25950729/" - } - ], - "481df52b-2ef8-4afa-b3b3-588a01476907": [ - { - "pub_id": "23372846", - "title": "The miRNA profile of human pancreatic islets and beta-cells and relationship to type 2 diabetes pathogenesis.", - "authors": "Martijn van de Bunt,Kyle J Gaulton,Leopold Parts,Ignasi Moran,Paul R Johnson,Cecilia M Lindgren,Jorge Ferrer,Anna L Gloyn,Mark I McCarthy", - "abstract": "Recent advances in the understanding of the genetics of type 2 diabetes (T2D) susceptibility have focused attention on the regulation of transcriptional activity within the pancreatic beta-cell. MicroRNAs (miRNAs) represent an important component of regulatory control, and have proven roles in the development of human disease and control of glucose homeostasis. We set out to establish the miRNA profile of human pancreatic islets and of enriched beta-cell populations, and to explore their potential involvement in T2D susceptibility. We used Illumina small RNA sequencing to profile the miRNA fraction in three preparations each of primary human islets and of enriched beta-cells generated by fluorescence-activated cell sorting. In total, 366 miRNAs were found to be expressed (i.e. >100 cumulative reads) in islets and 346 in beta-cells; of the total of 384 unique miRNAs, 328 were shared. A comparison of the islet-cell miRNA profile with those of 15 other human tissues identified 40 miRNAs predominantly expressed (i.e. >50% of all reads seen across the tissues) in islets. Several highly-expressed islet miRNAs, such as miR-375, have established roles in the regulation of islet function, but others (e.g. miR-27b-3p, miR-192-5p) have not previously been described in the context of islet biology. As a first step towards exploring the role of islet-expressed miRNAs and their predicted mRNA targets in T2D pathogenesis, we looked at published T2D association signals across these sites. We found evidence that predicted mRNA targets of islet-expressed miRNAs were globally enriched for signals of T2D association (p-values <0.01, q-values <0.1). At six loci with genome-wide evidence for T2D association (AP3S2, KCNK16, NOTCH2, SCL30A8, VPS26A, and WFS1) predicted mRNA target sites for islet-expressed miRNAs overlapped potentially causal variants. In conclusion, we have described the miRNA profile of human islets and beta-cells and provide evidence linking islet miRNAs to T2D pathogenesis.", - "journal_title": "PloS one", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/23372846/" - } - ], - "9f27addf-3ea2-4538-aa24-12cc14bbd690": [ - { - "pub_id": "22266139", - "title": "Next-generation sequencing identifies TGF-\u03b21-associated gene expression profiles in renal epithelial cells reiterated in human diabetic nephropathy.", - "authors": "Eoin P Brennan,Melissa J Morine,David W Walsh,Sarah A Roxburgh,Maja T Lindenmeyer,Derek P Brazil,Peadar \u00d3 Gaora,Helen M Roche,Denise M Sadlier,Clemens D Cohen, ,Catherine Godson,Finian Martin", - "abstract": "Transforming growth factor-beta (TGF-\u03b21) is implicated in the onset and progression of renal fibrosis and diabetic nephropathy (DN), leading to a loss of epithelial characteristics of tubular cells. The transcriptional profile of renal tubular epithelial cells stimulated with TGF-\u03b21 was assessed using RNA-Seq, with 2027 differentially expressed genes identified. Promoter analysis of transcription factor binding sites in the TGF-\u03b21 responsive gene set predicted activation of multiple transcriptional networks, including NF\u03baB. Comparison of RNA-Seq with microarray data from identical experimental conditions identified low abundance transcripts exclusive to RNA-Seq data. We compared these findings to human disease by analyzing transcriptomic data from renal biopsies of patients with DN versus control groups, identifying a shared subset of 179 regulated genes. ARK5, encoding an AMP-related kinase, and TGFBI - encoding transforming growth factor, beta-induced protein were induced by TGF-\u03b21 and also upregulated in human DN. Suppression of ARK5 attenuated fibrotic responses of renal epithelia to TGF-\u03b21 exposure; and silencing of TGFBI induced expression of the epithelial cell marker - E-cadherin. We identified low abundance transcripts in sequence data and validated expression levels of several transcripts (ANKRD56, ENTPD8) in tubular enriched kidney biopsies of DN patients versus living donors. In conclusion, we have defined a TGF-\u03b21-driven pro-fibrotic signal in renal epithelial cells that is also evident in the DN renal transcriptome.", - "journal_title": "Biochimica et biophysica acta", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/22266139/" - } - ], - "35c60b97-b5b0-40e4-99c5-66cbec9c96b2": [ - { - "pub_id": "24551085", - "title": "Evaluation of candidate nephropathy susceptibility genes in a genome-wide association study of African American diabetic kidney disease.", - "authors": "Nicholette D Palmer,Maggie C Y Ng,Pamela J Hicks,Poorva Mudgal,Carl D Langefeld,Barry I Freedman,Donald W Bowden", - "abstract": "Type 2 diabetes (T2D)-associated end-stage kidney disease (ESKD) is a complex disorder resulting from the combined influence of genetic and environmental factors. This study contains a comprehensive genetic analysis of putative nephropathy loci in 965 African American (AA) cases with T2D-ESKD and 1029 AA population-based controls extending prior findings. Analysis was based on 4,341 directly genotyped and imputed single nucleotide polymorphisms (SNPs) in 22 nephropathy candidate genes. After admixture adjustment and correction for multiple comparisons, 37 SNPs across eight loci were significantly associated (1.6E-05<P(emp)<0.049). Among these, variants in MYH9 were the most significant (1.6E-05<P(emp)<0.049), followed by additional chromosome 22 loci (APOL1, SFI1, and LIMK2). Nominal signals were observed in AGTR1, RPS12, CHN2 and CNDP1. Additional adjustment for APOL1 G1/G2 risk variants attenuated association at MYH9 (P(emp)\u200a=\u200a0.00026-0.043) while marginally improving significance of other APOL1 SNPs (rs136161, rs713753, and rs767855; P(emp)\u200a=\u200a0.0060-0.037); association at other loci was markedly reduced except for CHN2 (chimerin; rs17157914, P(emp)=\u200a0.029). In addition, SNPs in other candidate loci (FRMD3 and TRPC6) trended toward association with T2D-ESKD (P(emp)<0.05). These results suggest that risk contributed by putative nephropathy genes is shared across populations of African and European ancestry.", - "journal_title": "PloS one", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/24551085/" - } - ], - "16a19a42-1f27-43e4-a4df-46d5e9c81096": [ - { - "pub_id": "20346094", - "title": "Tailoring the process of informed consent in genetic and genomic research.", - "authors": "Charles N Rotimi,Patricia A Marshall", - "abstract": "Genomic science and associated technologies are facilitating an unprecedented rate of discovery of novel insights into the relationship between human genetic variation and health. The willingness of large numbers of individuals from different ethnic and cultural backgrounds to donate biological samples is one of the major factors behind the success of the ongoing genomic revolution. Although current informed consent documents and processes demonstrate a commitment to ensuring that study participants are well informed of the risks and benefits of participating in genomic studies, there continues to be a need to develop effective new approaches for adequately informing participants of the changing complexities of the scientific and ethical issues that arise in the conduct of genomics research. Examples of these complexities in genomic research include more widespread use of whole-genome sequencing technologies, broad sharing of individual-level data, evolving information technology, the growing demand for the return of genetic results to participants, and changing attitudes about privacy and the expansion of genomics studies to global populations representing diverse cultural, linguistic and socio-economic backgrounds. We highlight and briefly discuss the importance of ten core scientific, cultural and social factors that are particularly relevant to tailoring informed consent in genomic research, and we draw attention to the need for the informed consent document and process to be responsive to the evolving nature of genomic research.", - "journal_title": "Genome medicine", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/20346094/" - } - ], - "3a70f8f8-9aec-4f54-b80d-7c5c157c552a": [ - { - "pub_id": "25122641", - "title": "Translational pain research: Lessons from genetics and genomics.", - "authors": "Sulayman D Dib-Hajj,Stephen G Waxman", - "abstract": "Pharmacological, surgical, psychological, and alternative medicine approaches for the treatment of chronic pain, including neuropathic pain, provide only partial relief for most patients, with the efficacy of existing medications often blunted by dose-limiting side effects arising from drug actions on cells outside the pain-signaling axis. The development of more effective treatments for pain--particularly chronic pain states such as neuropathic pain--has been hampered by lack of predictive animal models and biomarkers, variation in pain characteristics between patients or on a day-to-day basis for single patients, patient stratification on the basis of symptoms rather than mechanism, and a high rate of placebo responses. We discuss genetic and genomic approaches to translational pain research. We review examples of the identification and validation of human pain targets through rodent genome-wide association studies (GWAS) and global mRNA expression studies, functional screening in flies and mice, human GWAS and whole-exome sequencing studies, and the targeted candidate gene approach. These and other emerging genetic and genomic strategies are likely to facilitate the development of new, more effective pain therapeutics.", - "journal_title": "Science translational medicine", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/25122641/" - } - ], - "c929b525-7ab9-422a-be19-df86f3167f4e": [ - { - "pub_id": "21665207", - "title": "Genetic variants of 11 telomere-pathway gene loci and the risk of incident type 2 diabetes mellitus: the Women's Genome Health Study.", - "authors": "Robert Y L Zee,Paul M Ridker,Daniel I Chasman", - "abstract": "Leukocyte telomere length shortening has recently been associated with type 2 diabetes mellitus (T2D). Whether this observation was modulated by genetic variation within the telomere-pathway genes remains elusive. To date, no prospective epidemiological data on the relationship of telomere-pathway gene variation with T2D are available. The association between 150 tagging-SNPs (tSNPs) of 11 telomere-pathway genes (TERC, UCP1, TERT, POT1, TNKS, TERF1, TNKS2, TEP1, ACD, TERF2 and TERF2IP) and incident T2D was investigated in 22,715 Caucasian female participants of the prospective Women's Genome Health Study. All were free of known cardiovascular disease, cancer and diabetes at baseline. During a 13-year follow-up period, 1445 participants developed an incident T2D. Multivariable Cox regression analysis was performed to investigate the relationship between genotypes and T2D risk assuming an additive genetic model. Haplotype block analysis was also performed. A total of eleven tSNPs within TERF1, TNKS, TEP1, ACD, and TERF2 were associated with T2D risk (all p-uncorrected <0.050). Further investigation using the haplotype-block analysis again revealed an association of several prespecified haplotypes of TERF1, and TEP1 with T2D risk (all p-uncorrected <0.040). If corroborated in other prospective studies, the present findings suggest that genetic variation within the telomere-pathway gene loci examined may be useful predictor for T2D risk assessment.", - "journal_title": "Atherosclerosis", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/21665207/" - } - ], - "5c14a921-3200-44d8-8210-fcf86bd7915c": [ - { - "pub_id": "20463879", - "title": "Liver and adipose expression associated SNPs are enriched for association to type 2 diabetes.", - "authors": "Hua Zhong,John Beaulaurier,Pek Yee Lum,Cliona Molony,Xia Yang,Douglas J Macneil,Drew T Weingarth,Bin Zhang,Danielle Greenawalt,Radu Dobrin,Ke Hao,Sangsoon Woo,Christine Fabre-Suver,Su Qian,Michael R Tota,Mark P Keller,Christina M Kendziorski,Brian S Yandell,Victor Castro,Alan D Attie,Lee M Kaplan,Eric E Schadt", - "abstract": "Genome-wide association studies (GWAS) have demonstrated the ability to identify the strongest causal common variants in complex human diseases. However, to date, the massive data generated from GWAS have not been maximally explored to identify true associations that fail to meet the stringent level of association required to achieve genome-wide significance. Genetics of gene expression (GGE) studies have shown promise towards identifying DNA variations associated with disease and providing a path to functionally characterize findings from GWAS. Here, we present the first empiric study to systematically characterize the set of single nucleotide polymorphisms associated with expression (eSNPs) in liver, subcutaneous fat, and omental fat tissues, demonstrating these eSNPs are significantly more enriched for SNPs that associate with type 2 diabetes (T2D) in three large-scale GWAS than a matched set of randomly selected SNPs. This enrichment for T2D association increases as we restrict to eSNPs that correspond to genes comprising gene networks constructed from adipose gene expression data isolated from a mouse population segregating a T2D phenotype. Finally, by restricting to eSNPs corresponding to genes comprising an adipose subnetwork strongly predicted as causal for T2D, we dramatically increased the enrichment for SNPs associated with T2D and were able to identify a functionally related set of diabetes susceptibility genes. We identified and validated malic enzyme 1 (Me1) as a key regulator of this T2D subnetwork in mouse and provided support for the association of this gene to T2D in humans. This integration of eSNPs and networks provides a novel approach to identify disease susceptibility networks rather than the single SNPs or genes traditionally identified through GWAS, thereby extracting additional value from the wealth of data currently being generated by GWAS.", - "journal_title": "PLoS genetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/20463879/" - } - ], - "4feda561-1914-404d-9092-3c629d5251bd": [ - { - "pub_id": "26181639", - "title": "Pharmacogenetics and individual responses to treatment of hyperglycemia in type 2 diabetes.", - "authors": "Line Engelbrechtsen,Ehm Andersson,Soeren Roepstorff,Torben Hansen,Henrik Vestergaard", - "abstract": "The aim of this study was to summarize current knowledge and provide perspectives on the relationships between human genetic variants, type 2 diabetes, antidiabetic treatment, and disease progression. Type 2 diabetes is a complex disease with clear-cut diagnostic criteria and treatment guidelines. Yet, the interindividual response to therapy and slope of disease progression varies markedly among patients with type 2 diabetes. Gene-gene, gene-environment, and gene-treatment interactions may explain some of the variation in disease progression. Several genetic variants have been suggested to be associated with response to antidiabetic drugs. Some are present in drug receptors or drug metabolizers (OCT genes, KCNJ11, ABCC8, and CYP2C9). Numerous type 2 diabetes risk variants have been identified, but genetic risk score models applying these variants have failed to identify 'disease progressors' among patients with diabetes. Although genetic risk scores are based on a few known loci and only explain a fraction of the heritability of type 2 diabetes, it seems that the genes responsible for the development of diabetes may not be the same driving disease progression after the diagnosis has been made. Pharmacogenetic interactions explain some of the interindividual variation in responses to antidiabetic treatment and may provide the foundation for future genotype-based treatment standards.", - "journal_title": "Pharmacogenetics and genomics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/26181639/" - } - ], - "d28444c1-b67e-4ea5-84c4-6bb18d048c92": [ - { - "pub_id": "21111713", - "title": "Implications of genome wide association studies for the understanding of type 2 diabetes pathophysiology.", - "authors": "John R Petrie,Ewan R Pearson,Calum Sutherland", - "abstract": "The rapid rise in prevalence of type 2 diabetes mellitus (T2DM) has been driven by changes in environmental factors - primarily increased caloric intake and reduced energy expenditure - resulting in reduced whole body insulin sensitivity (often termed insulin resistance). Insulin resistance has been proposed to be a major driver of progression to T2DM. However, of 38 individual susceptibility loci for T2DM recently identified by genome wide association studies, by far the majority code for proteins involved in \u03b2-cell function. In this review, we discuss the possible reasons for the paucity of insulin resistance genes and ask whether the new genetic susceptibility data should focus attention on \u03b2-cell targets in the development of therapies for T2DM.", - "journal_title": "Biochemical pharmacology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/21111713/" - } - ], - "4d3330eb-acd0-4f72-aadf-b056d3c8b389": [ - { - "pub_id": "25624707", - "title": "Liver enzymes, metabolomics and genome-wide association studies: from systems biology to the personalized medicine.", - "authors": "Silvia Sookoian,Carlos J Pirola", - "abstract": "For several decades, serum levels of alanine (ALT) and aspartate (AST) aminotransferases have been regarded as markers of liver injury, including a wide range of etiologies from viral hepatitis to fatty liver. The increasing worldwide prevalence of metabolic syndrome and cardiovascular disease revealed that transaminases are strong predictors of type 2 diabetes, coronary heart disease, atherothrombotic risk profile, and overall risk of metabolic disease. Therefore, it is plausible to suggest that aminotransferases are surrogate biomarkers of \"liver metabolic functioning\" beyond the classical concept of liver cellular damage, as their enzymatic activity might actually reflect key aspects of the physiology and pathophysiology of the liver function. In this study, we summarize the background information and recent findings on the biological role of ALT and AST, and review the knowledge gained from the application of genome-wide approaches and \"omics\" technologies that uncovered new concepts on the role of aminotransferases in human diseases and systemic regulation of metabolic functions. Prediction of biomolecular interactions between the candidate genes recently discovered to be associated with plasma concentrations of liver enzymes showed interesting interconnectivity nodes, which suggest that regulation of aminotransferase activity is a complex and highly regulated trait. Finally, links between aminotransferase genes and metabolites are explored to understand the genetic contributions to the metabolic diversity.", - "journal_title": "World journal of gastroenterology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/25624707/" - } - ], - "1fd1a511-e2f6-405a-921e-9c3b1fbd34cd": [ - { - "pub_id": "22475005", - "title": "Sex-specific mouse liver gene expression: genome-wide analysis of developmental changes from pre-pubertal period to young adulthood.", - "authors": "Tara L Conforto,David J Waxman", - "abstract": "Early liver development and the transcriptional transitions during hepatogenesis are well characterized. However, gene expression changes during the late postnatal/pre-pubertal to young adulthood period are less well understood, especially with regards to sex-specific gene expression. Microarray analysis of male and female mouse liver was carried out at 3, 4, and 8 wk of age to elucidate developmental changes in gene expression from the late postnatal/pre-pubertal period to young adulthood. A large number of sex-biased and sex-independent genes showed significant changes during this developmental period. Notably, sex-independent genes involved in cell cycle, chromosome condensation, and DNA replication were down regulated from 3 wk to 8 wk, while genes associated with metal ion binding, ion transport and kinase activity were up regulated. A majority of genes showing sex differential expression in adult liver did not display sex differences prior to puberty, at which time extensive changes in sex-specific gene expression were seen, primarily in males. Thus, in male liver, 76% of male-specific genes were up regulated and 47% of female-specific genes were down regulated from 3 to 8 wk of age, whereas in female liver 67% of sex-specific genes showed no significant change in expression. In both sexes, genes up regulated from 3 to 8 wk were significantly enriched (p < E-76) in the set of genes positively regulated by the liver transcription factor HNF4\u03b1, as determined in a liver-specific HNF4\u03b1 knockout mouse model, while genes down regulated during this developmental period showed significant enrichment (p < E-65) for negative regulation by HNF4\u03b1. Significant enrichment of the developmentally regulated genes in the set of genes subject to positive and negative regulation by pituitary hormone was also observed. Five sex-specific transcriptional regulators showed sex-specific expression at 4 wk (male-specific Ihh; female-specific Cdx4, Cux2, Tox, and Trim24) and may contribute to the developmental changes that lead to global acquisition of liver sex-specificity by 8 wk of age. Overall, the observed changes in gene expression during postnatal liver development reflect the deceleration of liver growth and the induction of specialized liver functions, with widespread changes in sex-specific gene expression primarily occurring in male liver.", - "journal_title": "Biology of sex differences", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/22475005/" - } - ], - "711e3d33-a196-4072-bc31-ffaa6bb3efa0": [ - { - "pub_id": "22238593", - "title": "A genome-wide association search for type 2 diabetes genes in African Americans.", - "authors": "Nicholette D Palmer,Caitrin W McDonough,Pamela J Hicks,Bong H Roh,Maria R Wing,S Sandy An,Jessica M Hester,Jessica N Cooke,Meredith A Bostrom,Megan E Rudock,Matthew E Talbert,Joshua P Lewis, , ,Assiamira Ferrara,Lingyi Lu,Julie T Ziegler,Michele M Sale,Jasmin Divers,Daniel Shriner,Adebowale Adeyemo,Charles N Rotimi,Maggie C Y Ng,Carl D Langefeld,Barry I Freedman,Donald W Bowden,Benjamin F Voight,Laura J Scott,Valgerdur Steinthorsdottir,Andrew P Morris,Christian Dina,Ryan P Welch,Eleftheria Zeggini,Cornelia Huth,Yurii S Aulchenko,Gudmar Thorleifsson,Laura J McCulloch,Teresa Ferreira,Harald Grallert,Najaf Amin,Guanming Wu,Cristen J Willer,Soumya Raychaudhuri,Steve A McCarroll,Claudia Langenberg,Oliver M Hofmann,Jos\u00e9e Dupuis,Lu Qi,Ayellet V Segr\u00e8,Mandy van Hoek,Pau Navarro,Kristin Ardlie,Beverley Balkau,Rafn Benediktsson,Amanda J Bennett,Roza Blagieva,Eric Boerwinkle,Lori L Bonnycastle,Kristina Bengtsson Bostr\u00f6m,Bert Bravenboer,Suzannah Bumpstead,No\u00ebl P Burtt,Guillaume Charpentier,Peter S Chines,Marilyn Cornelis,David J Couper,Gabe Crawford,Alex S F Doney,Katherine S Elliott,Amanda L Elliott,Michael R Erdos,Caroline S Fox,Christopher S Franklin,Martha Ganser,Christian Gieger,Niels Grarup,Todd Green,Simon Griffin,Christopher J Groves,Candace Guiducci,Samy Hadjadj,Neelam Hassanali,Christian Herder,Bo Isomaa,Anne U Jackson,Paul R V Johnson,Torben J\u00f8rgensen,Wen H L Kao,Norman Klopp,Augustine Kong,Peter Kraft,Johanna Kuusisto,Torsten Lauritzen,Man Li,Aloysius Lieverse,Cecilia M Lindgren,Valeriya Lyssenko,Michel Marre,Thomas Meitinger,Kristian Midthjell,Mario A Morken,Narisu Narisu,Peter Nilsson,Katharine R Owen,Felicity Payne,John R B Perry,Ann-Kristin Petersen,Carl Platou,Christine Proen\u00e7a,Inga Prokopenko,Wolfgang Rathmann,N William Rayner,Neil R Robertson,Ghislain Rocheleau,Michael Roden,Michael J Sampson,Richa Saxena,Beverley M Shields,Peter Shrader,Gunnar Sigurdsson,Thomas Spars\u00f8,Klaus Strassburger,Heather M Stringham,Qi Sun,Amy J Swift,Barbara Thorand,Jean Tichet,Tiinamaija Tuomi,Rob M van Dam,Timon W van Haeften,Thijs van Herpt,Jana V van Vliet-Ostaptchouk,G Bragi Walters,Michael N Weedon,Cisca Wijmenga,Jacqueline Witteman,Richard N Bergman,Stephane Cauchi,Francis S Collins,Anna L Gloyn,Ulf Gyllensten,Torben Hansen,Winston A Hide,Graham A Hitman,Albert Hofman,David J Hunter,Kristian Hveem,Markku Laakso,Karen L Mohlke,Andrew D Morris,Colin N A Palmer,Peter P Pramstaller,Igor Rudan,Eric Sijbrands,Lincoln D Stein,Jaakko Tuomilehto,Andre Uitterlinden,Mark Walker,Nicholas J Wareham,Richard M Watanabe,Goncalo R Abecasis,Bernhard O Boehm,Harry Campbell,Mark J Daly,Andrew T Hattersley,Frank B Hu,James B Meigs,James S Pankow,Oluf Pedersen,H-Erich Wichmann,In\u00eas Barroso,Jose C Florez,Timothy M Frayling,Leif Groop,Rob Sladek,Unnur Thorsteinsdottir,James F Wilson,Thomas Illig,Philippe Froguel,Cornelia M van Duijn,Kari Stefansson,David Altshuler,Michael Boehnke,Mark I McCarthy,Nicole Soranzo,Eleanor Wheeler,Nicole L Glazer,Nabila Bouatia-Naji,Reedik M\u00e4gi,Joshua Randall,Toby Johnson,Paul Elliott,Denis Rybin,Peter Henneman,Abbas Dehghan,Jouke Jan Hottenga,Kijoung Song,Anuj Goel,Josephine M Egan,Taina Lajunen,Alex Doney,Stavroula Kanoni,Christine Cavalcanti-Proen\u00e7a,Meena Kumari,Nicholas J Timpson,Carina Zabena,Erik Ingelsson,Ping An,Jeffrey O'Connell,Jian'an Luan,Amanda Elliott,Steven A McCarroll,Rosa Maria Roccasecca,Fran\u00e7ois Pattou,Praveen Sethupathy,Yavuz Ariyurek,Philip Barter,John P Beilby,Yoav Ben-Shlomo,Sven Bergmann,Murielle Bochud,Am\u00e9lie Bonnefond,Knut Borch-Johnsen,Yvonne B\u00f6ttcher,Eric Brunner,Suzannah J Bumpstead,Yii-Der Ida Chen,Peter Chines,Robert Clarke,Lachlan J M Coin,Matthew N Cooper,Laura Crisponi,Ian N M Day,Eco J C de Geus,Jerome Delplanque,Annette C Fedson,Antje Fischer-Rosinsky,Nita G Forouhi,Rune Frants,Maria Grazia Franzosi,Pilar Galan,Mark O Goodarzi,J\u00fcrgen Graessler,Scott Grundy,Rhian Gwilliam,G\u00f6ran Hallmans,Naomi Hammond,Xijing Han,Anna-Liisa Hartikainen,Caroline Hayward,Simon C Heath,Serge Hercberg,Andrew A Hicks,David R Hillman,Aroon D Hingorani,Jennie Hui,Joe Hung,Antti Jula,Marika Kaakinen,Jaakko Kaprio,Y Antero Kesaniemi,Mika Kivimaki,Beatrice Knight,Seppo Koskinen,Peter Kovacs,Kirsten Ohm Kyvik,G Mark Lathrop,Debbie A Lawlor,Olivier Le Bacquer,C\u00e9cile Lecoeur,Yun Li,Robert Mahley,Massimo Mangino,Alisa K Manning,Mar\u00eda Teresa Mart\u00ednez-Larrad,Jarred B McAteer,Ruth McPherson,Christa Meisinger,David Melzer,David Meyre,Braxton D Mitchell,Sutapa Mukherjee,Silvia Naitza,Matthew J Neville,Ben A Oostra,Marco Orr\u00f9,Ruth Pakyz,Giuseppe Paolisso,Cristian Pattaro,Daniel Pearson,John F Peden,Nancy L Pedersen,Markus Perola,Andreas F H Pfeiffer,Irene Pichler,Ozren Polasek,Danielle Posthuma,Simon C Potter,Anneli Pouta,Michael A Province,Bruce M Psaty,Nigel W Rayner,Kenneth Rice,Samuli Ripatti,Fernando Rivadeneira,Olov Rolandsson,Annelli Sandbaek,Manjinder Sandhu,Serena Sanna,Avan Aihie Sayer,Paul Scheet,Udo Seedorf,Stephen J Sharp,Beverley Shields,Eric J G Sijbrands,Angela Silveira,Laila Simpson,Andrew Singleton,Nicholas L Smith,Ulla Sovio,Amy Swift,Holly Syddall,Ann-Christine Syv\u00e4nen,Toshiko Tanaka,Anke T\u00f6njes,Andr\u00e9 G Uitterlinden,Ko Willems van Dijk,Dhiraj Varma,Sophie Visvikis-Siest,Veronique Vitart,Nicole Vogelzangs,G\u00e9rard Waeber,Peter J Wagner,Andrew Walley,Kim L Ward,Hugh Watkins,Sarah H Wild,Gonneke Willemsen,Jaqueline C M Witteman,John W G Yarnell,Diana Zelenika,Bj\u00f6rn Zethelius,Guangju Zhai,Jing Hua Zhao,M Carola Zillikens,Ingrid B Borecki,Ruth J F Loos,Pierre Meneton,Patrik K E Magnusson,David M Nathan,Gordon H Williams,Kaisa Silander,Veikko Salomaa,George Davey Smith,Stefan R Bornstein,Peter Schwarz,Joachim Spranger,Fredrik Karpe,Alan R Shuldiner,Cyrus Cooper,George V Dedoussis,Manuel Serrano-R\u00edos,Lars Lind,Lyle J Palmer,Paul W Franks,Shah Ebrahim,Michael Marmot,W H Linda Kao,Peter Paul Pramstaller,Alan F Wright,Michael Stumvoll,Anders Hamsten,Thomas A Buchanan,Timo T Valle,Jerome I Rotter,David S Siscovick,Brenda W J H Penninx,Dorret I Boomsma,Panos Deloukas,Timothy D Spector,Luigi Ferrucci,Antonio Cao,Angelo Scuteri,David Schlessinger,Manuela Uda,Aimo Ruokonen,Marjo-Riitta Jarvelin,Dawn M Waterworth,Peter Vollenweider,Leena Peltonen,Vincent Mooser,Robert Sladek", - "abstract": "African Americans are disproportionately affected by type 2 diabetes (T2DM) yet few studies have examined T2DM using genome-wide association approaches in this ethnicity. The aim of this study was to identify genes associated with T2DM in the African American population. We performed a Genome Wide Association Study (GWAS) using the Affymetrix 6.0 array in 965 African-American cases with T2DM and end-stage renal disease (T2DM-ESRD) and 1029 population-based controls. The most significant SNPs (n\u200a=\u200a550 independent loci) were genotyped in a replication cohort and 122 SNPs (n\u200a=\u200a98 independent loci) were further tested through genotyping three additional validation cohorts followed by meta-analysis in all five cohorts totaling 3,132 cases and 3,317 controls. Twelve SNPs had evidence of association in the GWAS (P<0.0071), were directionally consistent in the Replication cohort and were associated with T2DM in subjects without nephropathy (P<0.05). Meta-analysis in all cases and controls revealed a single SNP reaching genome-wide significance (P<2.5\u00d710(-8)). SNP rs7560163 (P\u200a=\u200a7.0\u00d710(-9), OR (95% CI)\u200a=\u200a0.75 (0.67-0.84)) is located intergenically between RND3 and RBM43. Four additional loci (rs7542900, rs4659485, rs2722769 and rs7107217) were associated with T2DM (P<0.05) and reached more nominal levels of significance (P<2.5\u00d710(-5)) in the overall analysis and may represent novel loci that contribute to T2DM. We have identified novel T2DM-susceptibility variants in the African-American population. Notably, T2DM risk was associated with the major allele and implies an interesting genetic architecture in this population. These results suggest that multiple loci underlie T2DM susceptibility in the African-American population and that these loci are distinct from those identified in other ethnic populations.", - "journal_title": "PloS one", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/22238593/" - } - ], - "48376df6-3da4-4974-8148-ecd7d2c555c4": [ - { - "pub_id": "23445342", - "title": "A Drosophila functional evaluation of candidates from human genome-wide association studies of type\u20092\u2009diabetes and related metabolic traits identifies tissue-specific roles for dHHEX.", - "authors": "Jay Pendse,Prasanna V Ramachandran,Jianbo Na,Narisu Narisu,Jill L Fink,Ross L Cagan,Francis S Collins,Thomas J Baranski", - "abstract": "Genome-wide association studies (GWAS) identify regions of the genome that are associated with particular traits, but do not typically identify specific causative genetic elements. For example, while a large number of single nucleotide polymorphisms associated with type\u20092\u2009diabetes (T2D) and related traits have been identified by human GWAS, only a few genes have functional evidence to support or to rule out a role in cellular metabolism or dietary interactions. Here, we use a recently developed Drosophila model in which high-sucrose feeding induces phenotypes similar to T2D to assess orthologs of human GWAS-identified candidate genes for risk of T2D and related traits. Disrupting orthologs of certain T2D candidate genes (HHEX, THADA, PPARG, KCNJ11) led to sucrose-dependent toxicity. Tissue-specific knockdown of the HHEX ortholog dHHEX (CG7056) directed metabolic defects and enhanced lethality; for example, fat-body-specific loss of dHHEX led to increased hemolymph glucose and reduced insulin sensitivity. Candidate genes identified in human genetic studies of metabolic traits can be prioritized and functionally characterized using a simple Drosophila approach. To our knowledge, this is the first large-scale effort to study the functional interaction between GWAS-identified candidate genes and an environmental risk factor such as diet in a model organism system.", - "journal_title": "BMC genomics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/23445342/" - } - ], - "81ca527f-c0f7-417f-8b27-8d6a03ec1c43": [ - { - "pub_id": "24646408", - "title": "Informed consent for human genetic and genomic studies: a systematic review.", - "authors": "A Khan,B J Capps,M Y Sum,C N Kuswanto,K Sim", - "abstract": "As genetic and genomic studies grow in scale, there are ethical concerns related to the collection and use of genetic information. The emergence of large public databases potentially redefine the terms of participation in genetic and genomic research, and suggests the changing application of traditional ethical principles such as privacy or consent. For this study, we wanted to see whether such developments are reflected in the informed consent processes in human genetic and genomic studies. Therefore, we performed a systematic review of the empirical studies that examined informed consent involving large genetic databases in human genetic and genomic studies, grouped the identified issues related to the different stakeholders (including subjects, researchers, and institutional review boards) and discussed the limitations and implications of these findings. Major themes related to the place of bioethical considerations, procured tissues, people involved, process of informed consent and study procedures. Frequently raised issues included confidentiality of participants, documentation of informed consent, public attitudes, future use of participant samples or data, and disclosure of results. Awareness and attention to these bioethical issues as well as assiduousness in managing these concerns in genetic/genomic research would further strengthen and safeguard the rights, safety and well-being of genetic research participants.", - "journal_title": "Clinical genetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/24646408/" - } - ], - "646689fd-501b-4b27-b8fa-dc098f613044": [ - { - "pub_id": "30409037", - "title": "Type-2 diabetes mellitus and cardiovascular disease.", - "authors": "Robert J Henning", - "abstract": "The global prevalence of diabetes has risen in adults from 4.7% in 1980 to 8.5% in 2014. 90-95% of adults with diabetes have Type 2 diabetes (T2D). This paper focuses on the diagnosis and treatment of T2D patients who have or are at risk for cardiovascular disease. Hyperglycemia, insulin resistance and excess fatty acids increase oxidative stress, disrupt protein kinase C signaling and increase advanced glycation end-products that result in vascular inflammation, vasoconstriction, thrombosis and atherogenesis. Intensive T2D treatment produces a \u226510% risk reduction in major macrovascular and microvascular events. Glucose-lowering therapies must be individualized. Metformin is an optimal drug for monotherapy. If hemoglobin A1c is not at goal, a sodium-glucose cotransporter-2 inhibitor or a dipeptidyl peptidase-4 inhibitor should be considered for therapy with metformin. Coronary angioplasty/stenting is recommended for diabetic patients with acute myocardial infarctions. Coronary artery bypass grafting is recommended for symptomatic diabetic patients with multivessel disease.", - "journal_title": "Future cardiology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/30409037/" - } - ], - "bdf22103-8331-4320-9bf4-c008da48ebdc": [ - { - "pub_id": "25597830", - "title": "Biological interpretation of genome-wide association studies using predicted gene functions.", - "authors": "Tune H Pers,Juha M Karjalainen,Yingleong Chan,Harm-Jan Westra,Andrew R Wood,Jian Yang,Julian C Lui,Sailaja Vedantam,Stefan Gustafsson,Tonu Esko,Tim Frayling,Elizabeth K Speliotes, ,Michael Boehnke,Soumya Raychaudhuri,Rudolf S N Fehrmann,Joel N Hirschhorn,Lude Franke", - "abstract": "The main challenge for gaining biological insights from genetic associations is identifying which genes and pathways explain the associations. Here we present DEPICT, an integrative tool that employs predicted gene functions to systematically prioritize the most likely causal genes at associated loci, highlight enriched pathways and identify tissues/cell types where genes from associated loci are highly expressed. DEPICT is not limited to genes with established functions and prioritizes relevant gene sets for many phenotypes.", - "journal_title": "Nature communications", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/25597830/" - } - ], - "45c14654-f263-4031-9941-206d7b6a97f3": [ - { - "pub_id": "22110171", - "title": "Emerging applications of metabolomic and genomic profiling in diabetic clinical medicine.", - "authors": "Aine M McKillop,Peter R Flatt", - "abstract": "Clinical and epidemiological metabolomics provides a unique opportunity to look at genotype-phenotype relationships as well as the body\\x{2019}s responses to environmental and lifestyle factors. Fundamentally, it provides information on the universal outcome of influencing factors on disease states and has great potential in the early diagnosis, therapy monitoring, and understanding of the pathogenesis of disease. Diseases, such as diabetes, with a complex set of interactions between genetic and environmental factors, produce changes in the body\\x{2019}s biochemical profile, thereby providing potential markers for diagnosis and initiation of therapies. There is clearly a need to discover new ways to aid diagnosis and assessment of glycemic status to help reduce diabetes complications and improve the quality of life. Many factors, including peptides, proteins, metabolites, nucleic acids, and polymorphisms, have been proposed as putative biomarkers for diabetes. Metabolomics is an approach used to identify and assess metabolic characteristics, changes, and phenotypes in response to influencing factors, such as environment, diet, lifestyle, and pathophysiological states. The specificity and sensitivity using metabolomics to identify biomarkers of disease have become increasingly feasible because of advances in analytical and information technologies. Likewise, the emergence of high-throughput genotyping technologies and genome-wide association studies has prompted the search for genetic markers of diabetes predisposition or susceptibility. In this review, we consider the application of key metabolomic and genomic methodologies in diabetes and summarize the established, new, and emerging metabolomic and genomic biomarkers for the disease. We conclude by summarizing future insights into the search for improved biomarkers for diabetes research and human diagnostics.", - "journal_title": "Diabetes care", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/22110171/" - } - ], - "bac1c937-ca95-4f16-a608-b2b4e9a6186a": [ - { - "pub_id": "35333364", - "title": "Association of Habitual Alcohol Intake With Risk of Cardiovascular Disease.", - "authors": "Kiran J Biddinger,Connor A Emdin,Mary E Haas,Minxian Wang,George Hindy,Patrick T Ellinor,Sekar Kathiresan,Amit V Khera,Krishna G Aragam", - "abstract": "Observational studies have consistently proposed cardiovascular benefits associated with light alcohol consumption, while recent genetic analyses (ie, mendelian randomization studies) have suggested a possible causal link between alcohol intake and increased risk of cardiovascular disease. However, traditional approaches to genetic epidemiology assume a linear association and thus have not fully evaluated dose-response estimates of risk across different levels of alcohol intake. To assess the association of habitual alcohol intake with cardiovascular disease risk and to evaluate the direction and relative magnitude of cardiovascular risk associated with different amounts of alcohol consumption. This cohort study used the UK Biobank (2006-2010, follow-up until 2016) to examine confounding in epidemiologic associations between alcohol intake and cardiovascular diseases. Using both traditional (ie, linear) and nonlinear mendelian randomization, potential associations between alcohol consumption and cardiovascular diseases (eg, hypertension and coronary artery disease) as well as corresponding association shapes were assessed. Data analysis was conducted from July 2019 to January 2022. Genetic predisposition to alcohol intake. The association between alcohol consumption and cardiovascular diseases, including hypertension, coronary artery disease, myocardial infarction, stroke, heart failure, and atrial fibrillation. This study included 371\u202f463 participants (mean [SD] age, 57.0 [7.9] years; 172\u202f400 [46%] men), who consumed a mean (SD) 9.2 (10.6) standard drinks per week. Overall, 121\u202f708 participants (33%) had hypertension. Light to moderate alcohol consumption was associated with healthier lifestyle factors, adjustment for which attenuated the cardioprotective epidemiologic associations with modest intake. In linear mendelian randomization analyses, a 1-SD increase in genetically predicted alcohol consumption was associated with 1.3-fold (95% CI, 1.2-1.4) higher risk of hypertension (P\u2009<\u2009.001) and 1.4-fold (95% CI, 1.1-1.8) higher risk of coronary artery disease (P\u2009=\u2009.006). Nonlinear mendelian randomization analyses suggested nonlinear associations between alcohol consumption and both hypertension and coronary artery disease: light alcohol intake was associated with minimal increases in cardiovascular risk, whereas heavier consumption was associated with exponential increases in risk of both clinical and subclinical cardiovascular disease. In this cohort study, coincident, favorable lifestyle factors attenuated the observational benefits of modest alcohol intake. Genetic epidemiology suggested that alcohol consumption of all amounts was associated with increased cardiovascular risk, but marked risk differences exist across levels of intake, including those accepted by current national guidelines.", - "journal_title": "JAMA network open", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/35333364/" - } - ], - "973fb168-c1d9-4d0d-83f7-6936aecb1047": [ - { - "pub_id": "22249968", - "title": "Impact of data fragmentation across healthcare centers on the accuracy of a high-throughput clinical phenotyping algorithm for specifying subjects with type 2 diabetes mellitus.", - "authors": "Wei-Qi Wei,Cynthia L Leibson,Jeanine E Ransom,Abel N Kho,Pedro J Caraballo,High Seng Chai,Barbara P Yawn,Jennifer A Pacheco,Christopher G Chute", - "abstract": "To evaluate data fragmentation across healthcare centers with regard to the accuracy of a high-throughput clinical phenotyping (HTCP) algorithm developed to differentiate (1) patients with type 2 diabetes mellitus (T2DM) and (2) patients with no diabetes. This population-based study identified all Olmsted County, Minnesota residents in 2007. We used provider-linked electronic medical record data from the two healthcare centers that provide >95% of all care to County residents (ie, Olmsted Medical Center and Mayo Clinic in Rochester, Minnesota, USA). Subjects were limited to residents with one or more encounter January 1, 2006 through December 31, 2007 at both healthcare centers. DM-relevant data on diagnoses, laboratory results, and medication from both centers were obtained during this period. The algorithm was first executed using data from both centers (ie, the gold standard) and then from Mayo Clinic alone. Positive predictive values and false-negative rates were calculated, and the McNemar test was used to compare categorization when data from the Mayo Clinic alone were used with the gold standard. Age and sex were compared between true-positive and false-negative subjects with T2DM. Statistical significance was accepted as p<0.05. With data from both medical centers, 765 subjects with T2DM (4256 non-DM subjects) were identified. When single-center data were used, 252 T2DM subjects (1573 non-DM subjects) were missed; an additional false-positive 27 T2DM subjects (215 non-DM subjects) were identified. The positive predictive values and false-negative rates were 95.0% (513/540) and 32.9% (252/765), respectively, for T2DM subjects and 92.6% (2683/2898) and 37.0% (1573/4256), respectively, for non-DM subjects. Age and sex distribution differed between true-positive (mean age 62.1; 45% female) and false-negative (mean age 65.0; 56.0% female) T2DM subjects. The findings show that application of an HTCP algorithm using data from a single medical center contributes to misclassification. These findings should be considered carefully by researchers when developing and executing HTCP algorithms.", - "journal_title": "Journal of the American Medical Informatics Association : JAMIA", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/22249968/" - } - ], - "4a23a74f-4853-43e1-b6da-af7a84e7021f": [ - { - "pub_id": "23396134", - "title": "Genome-wide meta-analyses of multiancestry cohorts identify multiple new susceptibility loci for refractive error and myopia.", - "authors": "Virginie J M Verhoeven,Pirro G Hysi,Robert Wojciechowski,Qiao Fan,Jeremy A Guggenheim,Ren\u00e9 H\u00f6hn,Stuart MacGregor,Alex W Hewitt,Abhishek Nag,Ching-Yu Cheng,Ekaterina Yonova-Doing,Xin Zhou,M Kamran Ikram,Gabri\u00eblle H S Buitendijk,George McMahon,John P Kemp,Beate St Pourcain,Claire L Simpson,Kari-Matti M\u00e4kel\u00e4,Terho Lehtim\u00e4ki,Mika K\u00e4h\u00f6nen,Andrew D Paterson,S Mohsen Hosseini,Hoi Suen Wong,Liang Xu,Jost B Jonas,Olavi P\u00e4rssinen,Juho Wedenoja,Shea Ping Yip,Daniel W H Ho,Chi Pui Pang,Li Jia Chen,Kathryn P Burdon,Jamie E Craig,Barbara E K Klein,Ronald Klein,Toomas Haller,Andres Metspalu,Chiea-Chuen Khor,E-Shyong Tai,Tin Aung,Eranga Vithana,Wan-Ting Tay,Veluchamy A Barathi, ,Peng Chen,Ruoying Li,Jiemin Liao,Yingfeng Zheng,Rick T Ong,Angela D\u00f6ring, ,David M Evans,Nicholas J Timpson,Annemieke J M H Verkerk,Thomas Meitinger,Olli Raitakari,Felicia Hawthorne,Tim D Spector,Lennart C Karssen,Mario Pirastu,Federico Murgia,Wei Ang, ,Aniket Mishra,Grant W Montgomery,Craig E Pennell,Phillippa M Cumberland,Ioana Cotlarciuc,Paul Mitchell,Jie Jin Wang,Maria Schache,Sarayut Janmahasatian,Robert P Igo,Jonathan H Lass,Emily Chew,Sudha K Iyengar, ,Theo G M F Gorgels,Igor Rudan,Caroline Hayward,Alan F Wright,Ozren Polasek,Zoran Vatavuk,James F Wilson,Brian Fleck,Tanja Zeller,Alireza Mirshahi,Christian M\u00fcller,Andr\u00e9 G Uitterlinden,Fernando Rivadeneira,Johannes R Vingerling,Albert Hofman,Ben A Oostra,Najaf Amin,Arthur A B Bergen,Yik-Ying Teo,Jugnoo S Rahi,Veronique Vitart,Cathy Williams,Paul N Baird,Tien-Yin Wong,Konrad Oexle,Norbert Pfeiffer,David A Mackey,Terri L Young,Cornelia M van Duijn,Seang-Mei Saw,Joan E Bailey-Wilson,Dwight Stambolian,Caroline C Klaver,Christopher J Hammond", - "abstract": "Refractive error is the most common eye disorder worldwide and is a prominent cause of blindness. Myopia affects over 30% of Western populations and up to 80% of Asians. The CREAM consortium conducted genome-wide meta-analyses, including 37,382 individuals from 27 studies of European ancestry and 8,376 from 5 Asian cohorts. We identified 16 new loci for refractive error in individuals of European ancestry, of which 8 were shared with Asians. Combined analysis identified 8 additional associated loci. The new loci include candidate genes with functions in neurotransmission (GRIA4), ion transport (KCNQ5), retinoic acid metabolism (RDH5), extracellular matrix remodeling (LAMA2 and BMP2) and eye development (SIX6 and PRSS56). We also confirmed previously reported associations with GJD2 and RASGRF1. Risk score analysis using associated SNPs showed a tenfold increased risk of myopia for individuals carrying the highest genetic load. Our results, based on a large meta-analysis across independent multiancestry studies, considerably advance understanding of the mechanisms involved in refractive error and myopia.", - "journal_title": "Nature genetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/23396134/" - } - ], - "a1db9e3f-939d-4fc9-8c6b-5a23d52e2177": [ - { - "pub_id": "24123702", - "title": "Common quantitative trait locus downstream of RETN gene identified by genome-wide association study is associated with risk of type 2 diabetes mellitus in Han Chinese: a Mendelian randomization effect.", - "authors": "Chia-Min Chung,Tsung-Hsien Lin,Jaw-Wen Chen,Hsin-Bang Leu,Wei-Hsian Yin,Hung-Yun Ho,Sheng-Hsiung Sheu,Wei-Chuan Tsai,Jyh-Hong Chen,Shing-Jong Lin,Wen-Harn Pan", - "abstract": "Plasma resistin level is a potential molecular link between obesity and diabetes. Causal role of resistin, type 2 diabetes mellitus (T2DM) and genetic variants have not been thoroughly investigated. Therefore, we conducted a genome-wide association study (GWAS) to identify quantitative trait loci associated with resistin levels and investigated whether these variants were prospectively associated with the development of metabolic syndrome (MetS) and T2DM in an independent community-based cohort, the CardioVascular Disease risk FACtors Two-township Study (CVDFACTS). We genotyped 382 young-onset hypertensive (YOH) subjects with Illumina HumanHap550 chips and searched for quantitative trait loci (QTLs) of resistin in the 1(st) stage GWAS and confirmed the finding in another 559 YOH subjects. Logistic regression was used to examine the Mendelian randomization effects between genotypes of confirmed QTLs and metabolic outcomes in 3400 subjects of CVDFACTS. Two single nucleotide polymorphisms (SNP) (rs3745367 and rs1423096) were significantly associated with resistin levels (p\u2009=\u20095.52\u2009\u00d7\u200910(-15) and p\u2009=\u20092.54\u2009\u00d7\u200910(-20) ) and replicated in another 559 YOH subjects (p\u2009=\u20091.29\u2009\u00d7\u200910(-3) and p\u2009=\u20091.13\u2009\u00d7\u200910(-7) ), respectively. The SNP rs1423096 was further associated with the levels of HDL-C (p\u2009=\u20090.006), the risk of MetS (OR\u2009=\u20092.21, p\u2009=\u20090.0034) and T2DM (OR\u2009=\u20091.62, p\u2009=\u20090.0063) in the CVDFACTS. People with the haplotypes A-G and G-G determined by rs3745367 and rs1423096 showed a significantly increased T2DM risk (p\u2009=\u20090.0068 and p\u2009=\u20090.0035, respectively) compared with those with A-A haplotype. We have found that rs3745367 and rs1423096 on the RETN gene were significantly associated with resistin levels. However, rs1423096, downstream of RETN, seems to be associated with MetS and T2DM risk more so than rs3745367. The established genotype-disease association points to a causal association of resistin and T2DM.", - "journal_title": "Diabetes/metabolism research and reviews", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/24123702/" - } - ], - "4322db2f-5f43-4fc0-8968-b24438a7d6b9": [ - { - "pub_id": "22293752", - "title": "DNA methylation profiling identifies epigenetic dysregulation in pancreatic islets from type 2 diabetic patients.", - "authors": "Michael Volkmar,Sarah Dedeurwaerder,Daniel A Cunha,Matladi N Ndlovu,Matthieu Defrance,Rachel Deplus,Emilie Calonne,Ute Volkmar,Mariana Igoillo-Esteve,Najib Naamane,Silvia Del Guerra,Matilde Masini,Marco Bugliani,Piero Marchetti,Miriam Cnop,Decio L Eizirik,Fran\u00e7ois Fuks", - "abstract": "In addition to genetic predisposition, environmental and lifestyle factors contribute to the pathogenesis of type 2 diabetes (T2D). Epigenetic changes may provide the link for translating environmental exposures into pathological mechanisms. In this study, we performed the first comprehensive DNA methylation profiling in pancreatic islets from T2D and non-diabetic donors. We uncovered 276 CpG loci affiliated to promoters of 254 genes displaying significant differential DNA methylation in diabetic islets. These methylation changes were not present in blood cells from T2D individuals nor were they experimentally induced in non-diabetic islets by exposure to high glucose. For a subgroup of the differentially methylated genes, concordant transcriptional changes were present. Functional annotation of the aberrantly methylated genes and RNAi experiments highlighted pathways implicated in \u03b2-cell survival and function; some are implicated in cellular dysfunction while others facilitate adaptation to stressors. Together, our findings offer new insights into the intricate mechanisms of T2D pathogenesis, underscore the important involvement of epigenetic dysregulation in diabetic islets and may advance our understanding of T2D aetiology.", - "journal_title": "The EMBO journal", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/22293752/" - } - ], - "3992d979-8089-49a5-b0f1-84d04eaf79ad": [ - { - "pub_id": "25896377", - "title": "Strategies for addressing vaccine hesitancy - A systematic review.", - "authors": "Caitlin Jarrett,Rose Wilson,Maureen O'Leary,Elisabeth Eckersberger,Heidi J Larson, ", - "abstract": "The purpose of this systematic review is to identify, describe and assess the potential effectiveness of strategies to respond to issues of vaccine hesitancy that have been implemented and evaluated across diverse global contexts. A systematic review of peer reviewed (January 2007-October 2013) and grey literature (up to October 2013) was conducted using a broad search strategy, built to capture multiple dimensions of public trust, confidence and hesitancy concerning vaccines. This search strategy was applied and adapted across several databases and organizational websites. Descriptive analyses were undertaken for 166 (peer reviewed) and 15 (grey literature) evaluation studies. In addition, the quality of evidence relating to a series of PICO (population, intervention, comparison/control, outcomes) questions defined by the SAGE Working Group on Vaccine Hesitancy (WG) was assessed using Grading of Recommendations Assessment, Development and Evaluation (GRADE) criteria; data were analyzed using Review Manager. Across the literature, few strategies to address vaccine hesitancy were found to have been evaluated for impact on either vaccination uptake and/or changes in knowledge, awareness or attitude (only 14% of peer reviewed and 25% of grey literature). The majority of evaluation studies were based in the Americas and primarily focused on influenza, human papillomavirus (HPV) and childhood vaccines. In low- and middle-income regions, the focus was on diphtheria, tetanus and pertussis, and polio. Across all regions, most interventions were multi-component and the majority of strategies focused on raising knowledge and awareness. Thirteen relevant studies were used for the GRADE assessment that indicated evidence of moderate quality for the use of social mobilization, mass media, communication tool-based training for health-care workers, non-financial incentives and reminder/recall-based interventions. Overall, our results showed that multicomponent and dialogue-based interventions were most effective. However, given the complexity of vaccine hesitancy and the limited evidence available on how it can be addressed, identified strategies should be carefully tailored according to the target population, their reasons for hesitancy, and the specific context.", - "journal_title": "Vaccine", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/25896377/" - } - ], - "3ddde56a-a480-41c4-a2ec-d14ca406964d": [ - { - "pub_id": "22891507", - "title": "Shared genomics of type 2 and gestational diabetes mellitus.", - "authors": "Shu-Fen Wung,Pei-Chao Lin", - "abstract": "Gestational diabetes mellitus (GDM) is one of the most common complications of pregnancy and the prevalence of GDM is increasing worldwide. Short- and long-term complications of GDM on mothers and fetuses are well-recognized. These include more than seven-fold higher risk for type 2 diabetes mellitus (T2DM) later in life in women with GDM than those without. Evidence supports that GDM shares several risk factors with T2DM, including genetic risks. This chapter reviewed studies on candidate genes shared by T2DM and GDM published from 1990 to 2011. At least 20 susceptible genes of T2DM have been studied in women with GDM in various races. Results from current association studies on T2DM susceptible genes in GDM have shown significant heterogeneity There may be primary evidence that polymorphisms of susceptible genes of T2DM such as transcription factor 7-like 2 (TCF7L2) gene, potassium channel voltage-gate KQT-like subfamily member 1 (KCNQ1) gene, and cyclin-dependent kinase 5 regulatory subunit-associated protein 1-like 1 (CDKAL1) gene, may increase risk of GDM. Associations between GDM and many genetic variants have led to different findings across populations. Many genetic polymorphisms related to GDM were investigated in a single study or a single population. Replication studies to verify contributions of both common and rare genetic variants for GDM and T2DM in specific racial/ethnic groups are needed.", - "journal_title": "Annual review of nursing research", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/22891507/" - } - ], - "0125981a-00a6-4143-bab4-f5d5180ee919": [ - { - "pub_id": "24628412", - "title": "The intestinal microbiome in type 1 diabetes.", - "authors": "J L Dunne,E W Triplett,D Gevers,R Xavier,R Insel,J Danska,M A Atkinson", - "abstract": "Few concepts in recent years have garnered more disease research attention than that of the intestinal (i.e. 'gut') microbiome. This emerging interest has included investigations of the microbiome's role in the pathogenesis of a variety of autoimmune disorders, including type 1 diabetes (T1D). Indeed, a growing number of recent studies of patients with T1D or at varying levels of risk for this disease, as well as in animal models of the disorder, lend increasing support to the notion that alterations in the microbiome precede T1D onset. Herein, we review these investigations, examining the mechanisms by which the microbiome may influence T1D development and explore how multi-disciplinary analysis of the microbiome and the host immune response may provide novel biomarkers and therapeutic options for prevention of T1D.", - "journal_title": "Clinical and experimental immunology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/24628412/" - } - ], - "4e447887-0f0f-48b3-b085-2b2fa59e687b": [ - { - "pub_id": "24174441", - "title": "The essential detail: the genetics and genomics of the primate immune response.", - "authors": "Shu Shen,Chul-Woo Pyo,Quyen Vu,Ruihan Wang,Daniel E Geraghty", - "abstract": "Next-generation sequencing technologies have led to rapid progress in the fields of human and nonhuman primate (NHP) genomics. The less expensive and more efficient technologies have enabled the sequencing of human genomes from multiple populations and the sequencing of many NHP species. NHP genomes have been sequenced for two main reasons: (1) their importance as animal models in biomedical research and (2) their phylogenetic relationship to humans and use in derivative evolutionary studies. NHPs are valuable animal models for a variety of diseases, most notably for human immunodeficiency virus/acquired immunodeficiency syndrome research, and for vaccine development. Knowledge about the variation in primate immune response loci can provide essential insights into relevant immune function. However, perhaps ironically considering their central role in infectious disease, the accumulation of sequence detail from genomic regions harboring immune response loci, such as the major histocompatibility complex and killer immunoglobulin-like receptors, has been slow. This deficiency is, at least in part, due to the highly repetitive and polymorphic nature of these regions and is being addressed by the application of special approaches to targeted sequencing of the immune response genomic regions. We discuss one such targeting approach that has successfully yielded complete phased genomic sequences from complex genomic regions and is now being used to resequence macaque and other primate major histocompatibility complex regions. The essential detail contained within the genomics of the NHP immune response is now being assembled, and the realization of precise comparisons between NHP and human immune genomics is close at hand, further enhancing the NHP animal model in the search for effective treatments for human disease.", - "journal_title": "ILAR journal", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/24174441/" - } - ], - "04e193a3-e55b-461e-b884-8bf251a5ada9": [ - { - "pub_id": "20539295", - "title": "Diet-dependent genetic and genomic imprinting effects on obesity in mice.", - "authors": "James M Cheverud,Heather A Lawson,Gloria L Fawcett,Bing Wang,L Susan Pletscher,Ashley R Fox,Taylor J Maxwell,Thomas H Ehrich,Jane P Kenney-Hunt,Jason B Wolf,Clay F Semenkovich", - "abstract": "Although the current obesity epidemic is of environmental origin, there is substantial genetic variation in individual response to an obesogenic environment. In this study, we perform a genome-wide scan for quantitative trait loci (QTLs) affecting obesity per se, or an obese response to a high-fat diet in mice from the LG/J by SM/J Advanced Intercross (AI) Line (Wustl:LG,SM-G16). A total of 1,002 animals from 78 F\u2081\u2086 full sibships were weaned at 3 weeks of age and half of each litter placed on high- and low-fat diets. Animals remained on the diet until 20 weeks of age when they were necropsied and the weights of the reproductive, kidney, mesenteric, and inguinal fat depots were recorded. Effects on these phenotypes, along with total fat depot weight and carcass weight at necropsy, were mapped across the genome using 1,402 autosomal single-nucleotide polymorphism (SNP) markers. Haplotypes were reconstructed and additive, dominance, and imprinting genotype scores were derived every 1 cM along the F\u2081\u2086 map. Analysis was performed using a mixed model with additive, dominance, and imprinting genotype scores, their interactions with sex, diet, and with sex-by-diet as fixed effects and with family and its interaction with sex, diet, and sex-by-diet as random effects. We discovered 95 trait-specific QTLs mapping to 40 locations. Most QTLs had additive effects with dominance and imprinting effects occurring at two-thirds of the loci. Nearly every locus interacted with sex and/or diet in important ways demonstrating that gene effects are primarily context dependent, changing depending on sex and/or diet.", - "journal_title": "Obesity (Silver Spring, Md.)", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/20539295/" - } - ], - "9ecacdf6-60be-4790-a431-ccb77aa09231": [ - { - "pub_id": "21574069", - "title": "Editorial: genetic and genomic research-changing patterns of accountability.", - "authors": "Jeantine E Lunshof,Ruth Chadwick", - "abstract": "Debates about genomic science have raised questions about the implications for ethics and accountability. Accountability has external and internal aspects. Whereas ethical review, including attention to appropriate consent procedures, has been central to 'giving an account' externally, there are also issues internal to the practice of science itself. The pursuit of truth is central to the scientific endeavour, but truths can sometimes be 'inconvenient', leading to complex questions of accountability that go beyond the issues of consent. This is illustrated by the case of the Havasupai.", - "journal_title": "Accountability in research", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/21574069/" - } - ], - "89a3d588-d85b-4655-ae25-86116d0893cc": [ - { - "pub_id": "37758268", - "title": "Association between changes in carbohydrate intake and long term weight changes: prospective cohort study.", - "authors": "Yi Wan,Deirdre K Tobias,Kristine K Dennis,Marta Guasch-Ferr\u00e9,Qi Sun,Eric B Rimm,Frank B Hu,David S Ludwig,Orrin Devinsky,Walter C Willett", - "abstract": "To comprehensively examine the associations between changes in carbohydrate intake and weight change at four year intervals. Prospective cohort study. Nurses' Health Study (1986-2010), Nurses' Health Study II (1991-2015), and Health Professionals Follow-Up Study (1986-2014). 136\u2009432 men and women aged 65 years or younger and free of diabetes, cancer, cardiovascular disease, respiratory disease, neurodegenerative disorders, gastric conditions, chronic kidney disease, and systemic lupus erythematosus before baseline. Weight change within a four year period. The final analyses included 46\u2009722 women in the Nurses' Health Study, 67\u2009186 women in the Nurses' Health Study II, and 22\u2009524 men in the Health Professionals Follow-up Study. On average, participants gained 1.5 kg (5th to 95th centile -6.8 to 10.0) every four years, amounting to 8.8 kg on average over 24 years. Among men and women, increases in glycemic index and glycemic load were positively associated with weight gain. For example, a 100 g/day increase in starch or added sugar was associated with 1.5 kg and 0.9 kg greater weight gain over four years, respectively, whereas a 10 g/day increase in fiber was associated with 0.8 kg less weight gain. Increased carbohydrate intake from whole grains (0.4 kg less weight gain per 100 g/day increase), fruit (1.6 kg less weight gain per 100 g/day increase), and non-starchy vegetables (3.0 kg less weight gain per 100 g/day increase) was inversely associated with weight gain, whereas increased intake from refined grains (0.8 kg more weight gain per 100 g/day increase) and starchy vegetables (peas, corn, and potatoes) (2.6 kg more weight gain per 100 g/day increase) was positively associated with weight gain. In substitution analyses, replacing refined grains, starchy vegetables, and sugar sweetened beverages with equal servings of whole grains, fruit, and non-starchy vegetables was associated with less weight gain. The magnitude of these associations was stronger among participants with overweight or obesity compared with those with normal weight (P<0.001 for interaction). Most of these associations were also stronger among women. The findings of this study highlight the potential importance of carbohydrate quality and source for long term weight management, especially for people with excessive body weight. Limiting added sugar, sugar sweetened beverages, refined grains, and starchy vegetables in favor of whole grains, fruit, and non-starchy vegetables may support efforts to control weight.", - "journal_title": "BMJ (Clinical research ed.)", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/37758268/" - } - ], - "1293a323-c0a2-4f10-ae75-1e2ee4380a54": [ - { - "pub_id": "20209122", - "title": "Sequence variation in DDAH1 and DDAH2 genes is strongly and additively associated with serum ADMA concentrations in individuals with type 2 diabetes.", - "authors": "Sotoodeh Abhary,Kathryn P Burdon,Abraham Kuot,Shahrbanou Javadiyan,Malcolm J Whiting,Nicholas Kasmeridis,Nikolai Petrovsky,Jamie E Craig", - "abstract": "Asymmetric dimethylarginine (ADMA), present in human serum, is an endogenous inhibitor of nitric oxide synthase and contributes to vascular disease. Dimethylarginine dimethylaminohydrolase (DDAH) is an ADMA degrading enzyme that has two isoforms: DDAHI and DDAHII. We sought to determine whether serum ADMA levels in type 2 diabetes are influenced by common polymorphisms in the DDAH1 and DDAH2 genes. Relevant clinical parameters were measured and peripheral whole blood obtained for serum and genetic analysis on 343 participants with type 2 diabetes. Serum ADMA concentrations were determined by mass spectroscopy. Twenty six tag SNPs in the DDAH1 and 10 in the DDAH2 gene were genotyped in all subjects and tested for association with serum ADMA levels. Several SNPs and haplotypes in the DDAH genes were strongly associated with ADMA levels. Most significantly in the DDAH1 gene, rs669173 (p = 2.96x10(-7)), rs7521189 (p = 6.40x10(-7)), rs2474123 (p = 0.00082) and rs13373844 (p = 0.00027), and in the DDAH2 gene, rs3131383 (p = 0.0029) and the TGCCCAGGAG haplotype (p = 0.0012) were significantly associated with ADMA levels. Sub-analysis by diabetic retinopathy (DR) status revealed these variants were associated with ADMA levels predominantly in participants without DR. Combined analysis of the most strongly associated SNPs in DDAH1 (rs669173) and DDAH2 (rs3131383) revealed an additive effect (p = 1.37x10(-8)) on ADMA levels. Genetic variation in the DDAH1 and 2 genes is significantly associated with serum ADMA levels. Further studies are required to determine the pathophysiological significance of elevated serum ADMA in type 2 diabetes and to better understand how DDAH gene variation influences ADMA levels.", - "journal_title": "PloS one", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/20209122/" - } - ], - "049e1d89-52e3-4d15-ade5-7f54db927fcb": [ - { - "pub_id": "25828275", - "title": "Gestational diabetes mellitus.", - "authors": "Eman M Alfadhli", - "abstract": "Gestational diabetes mellitus (GDM) is the most common medical complication of pregnancy. It is associated with maternal and neonatal adverse outcomes. Maintaining adequate blood glucose levels in GDM reduces morbidity for both mother and baby. There is a lack of uniform strategies for screening and diagnosing GDM globally. This review covers the latest update in the diagnosis and management of GDM. The initial treatment of GDM consists of diet and exercise. If these measures fail to achieve glycemic goals, insulin should be initiated. Insulin analogs are more physiological than human insulin, and are associated with less risk of hypoglycemia, and may provide better glycemic control. Insulin lispro, aspart, and detemir are approved to be used in pregnancy. Insulin glargine is not approved in pregnancy, but the existing studies did not show any contraindications. The use of oral hypoglycemic agents; glyburide and metformin seems to be safe and effective in pregnancy.", - "journal_title": "Saudi medical journal", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/25828275/" - } - ], - "3589de1c-19c6-4f76-a2be-b8e14ce63b8b": [ - { - "pub_id": "21555865", - "title": "Public perspectives on returning genetics and genomics research results.", - "authors": "J O'Daniel,S B Haga", - "abstract": "The debate about returning research results has revealed different perspectives among researchers, participants and advisory groups with participants generally interested in obtaining their results. Given this preference, policies regarding return of individual research results may affect whether a potential subject chooses to participate in a study. Public attitudes, particularly those of African-Americans, toward this issue have been understudied. In 2008-2009, we convened 10 focus groups in Durham, N.C. to explore attitudes about returning research results and how different policies might influence their likelihood to participate in genetic/genomic studies. Transcripts were complimented by a short anonymous survey. Of 100 participants, 73% were female and 76% African-American with a median age of 40-49 years. Although there was general interest in obtaining genetics research results, particularly individual results, discussants recognized many potential complexities. The option to obtain research results (individual or summary) was clearly valued and lack thereof was potentially a deterrent for genetic/genomic research enrollment. Providing the option to learn research results may help strengthen relationships between investigators and participants and thereby serve as a positive influencing factor for minority communities. Consideration of the broader implications of returning research results is warranted. Engaging diverse publics is essential to gain a balance between the interests and burdens of participants and investigators.", - "journal_title": "Public health genomics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/21555865/" - } - ], - "5d1d5baa-75f4-42d5-8e4c-fb038a71bbec": [ - { - "pub_id": "21142536", - "title": "Genomics, type 2 diabetes, and obesity.", - "authors": "Mark I McCarthy", - "abstract": "", - "journal_title": "The New England journal of medicine", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/21142536/" - } - ], - "20b47cd4-95ea-4503-9019-80e6648d432f": [ - { - "pub_id": "24449572", - "title": "Novel rheumatoid arthritis susceptibility locus at 22q12 identified in an extended UK genome-wide association study.", - "authors": "Gisela Orozco,Sebastien Viatte,John Bowes,Paul Martin,Anthony G Wilson,Ann W Morgan,Sophia Steer,Paul Wordsworth,Lynne J Hocking, , , ,Anne Barton,Jane Worthington,Stephen Eyre", - "abstract": "The number of confirmed rheumatoid arthritis (RA) loci currently stands at 32, but many lines of evidence indicate that expansion of existing genome-wide association studies (GWAS) enhances the power to detect additional loci. This study was undertaken to extend our previous RA GWAS in a UK cohort, adding more independent RA cases and healthy controls, with the aim of detecting novel association signals for susceptibility to RA in a homogeneous UK cohort. A total of 3,223 UK RA cases and 5,272 UK controls were available for association analyses, with the extension adding 1,361 cases and 2,334 controls to the original GWAS data set. The genotype data for all RA cases were imputed using the Impute program version 2. After stringent quality control thresholds were applied, 3,034 cases and 5,271 controls (1,831,729 single-nucleotide polymorphisms [SNPs]) were available for analysis. Association testing was performed using Plink software. The analyses indicated a suggestive association with susceptibility to RA (P < 0.0001) for 6 novel RA loci that have been previously found to be associated with other autoimmune diseases; these 6 SNPs were genotyped in independent samples. Two of the associated loci were validated, one of which was associated with RA at genome-wide levels of significance in the combined analysis, identifying a novel RA locus at 22q12 (P = 6.9 \u00d7 10(-9) ). In addition, most of the previously known RA susceptibility loci were confirmed to be associated with RA, and for 16 of the loci, the strength of the association was increased. This study identified a new RA locus mapping to 22q12. These results support the notion that increasing the power of GWAS enhances novel gene discovery.", - "journal_title": "Arthritis & rheumatology (Hoboken, N.J.)", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/24449572/" - } - ], - "9818093b-803d-41bc-9412-2e18a7bfb21b": [ - { - "pub_id": "26358829", - "title": "Circulating 25-hydroxyvitamin D and risk of lung cancer: a dose-response meta-analysis.", - "authors": "Guo-Chong Chen,Zeng-Li Zhang,Zhongxiao Wan,Ling Wang,Peter Weber,Manfred Eggersdorfer,Li-Qiang Qin,Weiguo Zhang", - "abstract": "Mounting experimental evidence supports a protective effect of high 25-hydroxyvitamin D (25[OH]D), a good indicator of vitamin D status, on risk of various cancers including lung cancer. However, prospective observational studies examining the 25(OH)D-lung cancer association reported inconsistent findings. A dose-response meta-analysis was carried out to elucidate the subject. Potentially eligible studies were identified by searching PubMed and EMBASE databases, and by carefully reviewing the bibliographies of retrieved publications. The summary relative risks (RRs) with 95% confidence intervals (CIs) were calculated using the random-effects model. Thirteen reports from ten prospective studies were included, totaling 2,227 lung cancer events. Results of the meta-analysis showed a significant 5% (RR 0.95, 95% CI 0.91-0.99) reduction in the risk of lung cancer for each 10 nmol/L increment in 25(OH)D concentrations. This inverse association was not significantly modified by area, study duration, sex, methods for 25(OH)D measurement, baseline 25(OH)D levels, or quality score of included studies. There was evidence of a nonlinear relationship between 25(OH)D and risk of lung cancer (p-nonlinearity = 0.02), with the greatest reductions in risk observed at 25(OH)D of nearly 53 nmol/L, and remained protective until approximately 90 nmol/L. Further increases showed no significant association with cancer risk, but scanty data were included in the analyses of high-level 25(OH)D. There was no evidence of publication bias. This dose-response meta-analysis of prospective studies suggests that 25(OH)D may be associated with reduced risk of lung cancer, in particular among subjects with vitamin D deficiencies.", - "journal_title": "Cancer causes & control : CCC", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/26358829/" - } - ], - "4dd608e1-c16d-40ff-b92f-c765da39af28": [ - { - "pub_id": "26908156", - "title": "Epigenetic Mechanisms in Diabetic Kidney Disease.", - "authors": "Merlin C Thomas", - "abstract": "Progressive kidney disease is a common companion to both type 1 and type 2 diabetes. However, the majority of people with diabetes do not develop diabetic kidney disease. This may in part be explained by good control of glucose, blood pressure, obesity and other risk factors for kidney disease. It may also be partly due to their genetic makeup or ethnicity. However, the vast majority of the variability in incident nephropathy remains unaccounted for by conventional risk factors or genetics. Epigenetics has recently emerged as an increasingly powerful paradigm to understand and potentially explain complex non-Mendelian conditions-including diabetic kidney disease. Persistent epigenetic changes can be acquired during development or as adaptations to environmental exposure, including metabolic fluctuations associated with diabetes. These epigenetic modifications-including DNA methylation, histone modifications, non-coding RNAs and other changes in chromatin structure and function-individually and co-operatively act to register, store, retain and recall past experiences in a way to shape the transcription of specific genes and, therefore, cellular functions. This review will explore the emerging evidence for the role of epigenetic modifications in programming the legacy of hyperglycaemia for kidney disease in diabetes.", - "journal_title": "Current diabetes reports", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/26908156/" - } - ], - "01013a04-f594-4520-8c73-e13226f203a6": [ - { - "pub_id": "25839939", - "title": "Genetic association of IL-6, TNF-\u03b1 and SDF-1 polymorphisms with serum cytokine levels in diabetic foot ulcer.", - "authors": "Umapathy Dhamodharan,Vijay Viswanathan,Ezhilarasi Krishnamoorthy,Rama Rajaram,Vivekanandhan Aravindhan", - "abstract": "The IL-6 -174G/C (rs1800795), TNF-\u03b1 -308G/A (rs1800629) and -238G/A (rs361525) and SDF-1 801G/A (rs1801157) are well characterized SNPs which have previously been linked to various diabetic complications. However, the involvement of these SNPs in DFU remains poorly studied. In the present study we looked at the association of these SNPs with DFU (disease phenotype) and correlated it with the serum levels of cytokines (intermediate phenotype) along with other clinical risk factors of DFU (adiponectin, leptin and hsCRP). Genotyping was carried out in Normal glucose tolerance ((NGT)/Control=106), T2DM without DFU (T2DM=139), T2DM with neuropathy (DFU-DN=191) and T2DM with PVD (DFU-PVD=79) subjects by PCR-RFLP and the serum cytokine levels were determined by ELISA. IL-6 -176 \"C\" allele conferred significant protection against T2DM but not against DFU. TNF-\u03b1 -308 \"A\" allele (but not -238 SNP) conferred significant susceptibility towards both T2DM and DFU-DN. The SDF-1 \"A\" allele conferred significant protection against both DM and DFU-DN but not against DFU-PVD. Further, these alleles were shown to influence the serum cytokine/chemokine levels under diabetic conditions. Thus SNPs in cytokine/chemokine genes serve as valuable biomarkers for DFU.", - "journal_title": "Gene", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/25839939/" - } - ], - "2e317f9d-c028-41b7-a99e-28da61db9970": [ - { - "pub_id": "21980299", - "title": "A genome-wide meta-analysis of six type 1 diabetes cohorts identifies multiple associated loci.", - "authors": "Jonathan P Bradfield,Hui-Qi Qu,Kai Wang,Haitao Zhang,Patrick M Sleiman,Cecilia E Kim,Frank D Mentch,Haijun Qiu,Joseph T Glessner,Kelly A Thomas,Edward C Frackelton,Rosetta M Chiavacci,Marcin Imielinski,Dimitri S Monos,Rahul Pandey,Marina Bakay,Struan F A Grant,Constantin Polychronakos,Hakon Hakonarson", - "abstract": "Diabetes impacts approximately 200 million people worldwide, of whom approximately 10% are affected by type 1 diabetes (T1D). The application of genome-wide association studies (GWAS) has robustly revealed dozens of genetic contributors to the pathogenesis of T1D, with the most recent meta-analysis identifying in excess of 40 loci. To identify additional genetic loci for T1D susceptibility, we examined associations in the largest meta-analysis to date between the disease and \u223c2.54 million SNPs in a combined cohort of 9,934 cases and 16,956 controls. Targeted follow-up of 53 SNPs in 1,120 affected trios uncovered three new loci associated with T1D that reached genome-wide significance. The most significantly associated SNP (rs539514, P\u200a=\u200a5.66\u00d710\u207b\u00b9\u00b9) resides in an intronic region of the LMO7 (LIM domain only 7) gene on 13q22. The second most significantly associated SNP (rs478222, P\u200a=\u200a3.50\u00d710\u207b\u2079 resides in an intronic region of the EFR3B (protein EFR3 homolog B) gene on 2p23; however, the region of linkage disequilibrium is approximately 800 kb and harbors additional multiple genes, including NCOA1, C2orf79, CENPO, ADCY3, DNAJC27, POMC, and DNMT3A. The third most significantly associated SNP (rs924043, P\u200a=\u200a8.06\u00d710\u207b\u2079 lies in an intergenic region on 6q27, where the region of association is approximately 900 kb and harbors multiple genes including WDR27, C6orf120, PHF10, TCTE3, C6orf208, LOC154449, DLL1, FAM120B, PSMB1, TBP, and PCD2. These latest associated regions add to the growing repertoire of gene networks predisposing to T1D.", - "journal_title": "PLoS genetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/21980299/" - } - ], - "7e816722-443f-463c-8a79-852752df28e6": [ - { - "pub_id": "25422764", - "title": "Identification of novel risk genes associated with type\u00a01 diabetes mellitus using a genome-wide gene-based association analysis.", - "authors": "Ying-Hua Qiu,Fei-Yan Deng,Min-Jing Li,Shu-Feng Lei", - "abstract": "Type 1 diabetes mellitus is a serious disorder characterized by destruction of pancreatic \u03b2-cells, culminating in absolute insulin deficiency. Genetic factors contribute to the susceptibility of type 1 diabetes mellitus. The aim of the present study was to identify more susceptibility genes of type 1 diabetes mellitus. We carried out an initial gene-based genome-wide association study in a total of 4,075 type 1 diabetes mellitus cases and 2,604 controls by using the Gene-based Association Test using Extended Simes procedure. Furthermore, we carried out replication studies, differential expression analysis and functional annotation clustering analysis to support the significance of the identified susceptibility genes. We identified 452 genes associated with type 1 diabetes mellitus, even after adapting the genome-wide threshold for significance (P\u00a0<\u00a09.05E-04). Among these genes, 171 were newly identified for type 1 diabetes mellitus, which were ignored in single-nucleotide polymorphism-based association analysis and were not previously reported. We found that 53 genes have supportive evidence from replication studies and/or differential expression studies. In particular, seven genes including four non-human leukocyte antigen (HLA) genes (RASIP1, STRN4, BCAR1 and MYL2) are replicated in at least one independent population and also differentially expressed in peripheral blood mononuclear cells or monocytes. Furthermore, the associated genes tend to enrich in immune-related pathways or Gene Ontology project terms. The present results suggest the high power of gene-based association analysis in detecting disease-susceptibility genes. Our findings provide more insights into the genetic basis of type\u00a01 diabetes mellitus.", - "journal_title": "Journal of diabetes investigation", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/25422764/" - } - ], - "0e3dbf93-305e-40a6-9843-23afd2a18d7d": [ - { - "pub_id": "24011576", - "title": "Epigenetic modifications in the pathogenesis of diabetic nephropathy.", - "authors": "Marpadga A Reddy,Jung Tak Park,Rama Natarajan", - "abstract": "Diabetic nephropathy (DN) is a leading cause of end-stage renal disease. Diabetic vascular complications such as DN can progress despite subsequent glycemic control, suggesting a metabolic memory of previous exposure to hyperglycemia. Diabetes profoundly impacts transcription programs in target cells through activation of multiple signaling pathways and key transcription factors leading to aberrant expression of pathologic genes. Emerging evidence suggests that these factors associated with the pathophysiology of diabetic complications and metabolic memory also might be influenced by epigenetic mechanisms in chromatin such as DNA methylation, histone lysine acetylation, and methylation. Key histone modifications and the related histone methyltransferases and acetyltransferases have been implicated in the regulation of inflammatory and profibrotic genes in renal and vascular cells under diabetic conditions. Advances in epigenome profiling approaches have provided novel insights into the chromatin states and functional outcomes in target cells affected by diabetes. Because epigenetic changes are potentially reversible, they can provide a window of opportunity for the development of much-needed new therapies for DN in the future. In this review, we discuss recent developments in the field of epigenetics and their relevance to diabetic vascular complications and DN pathogenesis.", - "journal_title": "Seminars in nephrology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/24011576/" - } - ], - "27ebf515-68b1-4365-a719-e252cd6639ea": [ - { - "pub_id": "28601585", - "title": "Prevalence of diabetes and prediabetes in 15 states of India: results from the ICMR-INDIAB population-based cross-sectional study.", - "authors": "Ranjit Mohan Anjana,Mohan Deepa,Rajendra Pradeepa,Jagadish Mahanta,Kanwar Narain,Hiranya Kumar Das,Prabha Adhikari,Paturi Vishnupriya Rao,Banshi Saboo,Ajay Kumar,Anil Bhansali,Mary John,Rosang Luaia,Taranga Reang,Somorjit Ningombam,Lobsang Jampa,Richard O Budnah,Nirmal Elangovan,Radhakrishnan Subashini,Ulagamathesan Venkatesan,Ranjit Unnikrishnan,Ashok Kumar Das,Sri Venkata Madhu,Mohammed K Ali,Arvind Pandey,Rupinder Singh Dhaliwal,Tanvir Kaur,Soumya Swaminathan,Viswanathan Mohan, ", - "abstract": "Previous studies have not adequately captured the heterogeneous nature of the diabetes epidemic in India. The aim of the ongoing national Indian Council of Medical Research-INdia DIABetes study is to estimate the national prevalence of diabetes and prediabetes in India by estimating the prevalence by state. We used a stratified multistage design to obtain a community-based sample of 57\u2008117 individuals aged 20 years or older. The sample population represented 14 of India's 28 states (eight from the mainland and six from the northeast of the country) and one union territory. States were sampled in a phased manner: phase I included Tamil Nadu, Chandigarh, Jharkhand, and Maharashtra, sampled between Nov 17, 2008, and April 16, 2010; phase II included Andhra Pradesh, Bihar, Gujarat, Karnataka, and Punjab, sampled between Sept 24, 2012, and July 26, 2013; and the northeastern phase included Assam, Mizoram, Arunachal Pradesh, Tripura, Manipur, and Meghalaya, with sampling done between Jan 5, 2012, and July 3, 2015. Capillary oral glucose tolerance tests were used to diagnose diabetes and prediabetes in accordance with WHO criteria. Our methods did not allow us to differentiate between type 1 and type 2 diabetes. The prevalence of diabetes in different states was assessed in relation to socioeconomic status (SES) of individuals and the per-capita gross domestic product (GDP) of each state. We used multiple logistic regression analysis to examine the association of various factors with the prevalence of diabetes and prediabetes. The overall prevalence of diabetes in all 15 states of India was 7\u00b73% (95% CI 7\u00b70-7\u00b75). The prevalence of diabetes varied from 4\u00b73% in Bihar (95% CI 3\u00b77-5\u00b70) to 10\u00b70% (8\u00b77-11\u00b72) in Punjab and was higher in urban areas (11\u00b72%, 10\u00b76-11\u00b78) than in rural areas (5\u00b72%, 4\u00b79-5\u00b74; p<0\u00b70001) and higher in mainland states (8\u00b73%, 7\u00b79-8\u00b77) than in the northeast (5\u00b79%, 5\u00b75-6\u00b72; p<0\u00b70001). Overall, 1862 (47\u00b73%) of 3938 individuals identified as having diabetes had not been diagnosed previously. States with higher per-capita GDP seemed to have a higher prevalence of diabetes (eg, Chandigarh, which had the highest GDP of US$ 3433, had the highest prevalence of 13\u00b76%, 12.8-15\u00b72). In rural areas of all states, diabetes was more prevalent in individuals of higher SES. However, in urban areas of some of the more affluent states (Chandigarh, Maharashtra, and Tamil Nadu), diabetes prevalence was higher in people with lower SES. The overall prevalence of prediabetes in all 15 states was 10\u00b73% (10\u00b70-10\u00b76). The prevalence of prediabetes varied from 6\u00b70% (5\u00b71-6\u00b78) in Mizoram to 14\u00b77% (13\u00b76-15\u00b79) in Tripura, and the prevalence of impaired fasting glucose was generally higher than the prevalence of impaired glucose tolerance. Age, male sex, obesity, hypertension, and family history of diabetes were independent risk factors for diabetes in both urban and rural areas. There are large differences in diabetes prevalence between states in India. Our results show evidence of an epidemiological transition, with a higher prevalence of diabetes in low SES groups in the urban areas of the more economically developed states. The spread of diabetes to economically disadvantaged sections of society is a matter of great concern, warranting urgent preventive measures. Indian Council of Medical Research and Department of Health Research, Ministry of Health and Family Welfare, Government of India.", - "journal_title": "The lancet. Diabetes & endocrinology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/28601585/" - } - ], - "2dc80127-89ba-47be-9e94-d90c2105be8d": [ - { - "pub_id": "25481708", - "title": "Epigenetic mechanisms in diabetic complications and metabolic memory.", - "authors": "Marpadga A Reddy,Erli Zhang,Rama Natarajan", - "abstract": "The incidence of diabetes and its associated micro- and macrovascular complications is greatly increasing worldwide. The most prevalent vascular complications of both type 1 and type 2 diabetes include nephropathy, retinopathy, neuropathy and cardiovascular diseases. Evidence suggests that both genetic and environmental factors are involved in these pathologies. Clinical trials have underscored the beneficial effects of intensive glycaemic control for preventing the progression of complications. Accumulating evidence suggests a key role for epigenetic mechanisms such as DNA methylation, histone post-translational modifications in chromatin, and non-coding RNAs in the complex interplay between genes and the environment. Factors associated with the pathology of diabetic complications, including hyperglycaemia, growth factors, oxidant stress and inflammatory factors can lead to dysregulation of these epigenetic mechanisms to alter the expression of pathological genes in target cells such as endothelial, vascular smooth muscle, retinal and cardiac cells, without changes in the underlying DNA sequence. Furthermore, long-term persistence of these alterations to the epigenome may be a key mechanism underlying the phenomenon of 'metabolic memory' and sustained vascular dysfunction despite attainment of glycaemic control. Current therapies for most diabetic complications have not been fully efficacious, and hence a study of epigenetic mechanisms that may be involved is clearly warranted as they can not only shed novel new insights into the pathology of diabetic complications, but also lead to the identification of much needed new drug targets. In this review, we highlight the emerging role of epigenetics and epigenomics in the vascular complications of diabetes and metabolic memory.", - "journal_title": "Diabetologia", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/25481708/" - } - ], - "3e53b34f-5bdf-43d5-9594-736cf83071db": [ - { - "pub_id": "22885922", - "title": "Large-scale association analysis provides insights into the genetic architecture and pathophysiology of type 2 diabetes.", - "authors": "Andrew P Morris,Benjamin F Voight,Tanya M Teslovich,Teresa Ferreira,Ayellet V Segr\u00e8,Valgerdur Steinthorsdottir,Rona J Strawbridge,Hassan Khan,Harald Grallert,Anubha Mahajan,Inga Prokopenko,Hyun Min Kang,Christian Dina,Tonu Esko,Ross M Fraser,Stavroula Kanoni,Ashish Kumar,Vasiliki Lagou,Claudia Langenberg,Jian'an Luan,Cecilia M Lindgren,Martina M\u00fcller-Nurasyid,Sonali Pechlivanis,N William Rayner,Laura J Scott,Steven Wiltshire,Loic Yengo,Leena Kinnunen,Elizabeth J Rossin,Soumya Raychaudhuri,Andrew D Johnson,Antigone S Dimas,Ruth J F Loos,Sailaja Vedantam,Han Chen,Jose C Florez,Caroline Fox,Ching-Ti Liu,Denis Rybin,David J Couper,Wen Hong L Kao,Man Li,Marilyn C Cornelis,Peter Kraft,Qi Sun,Rob M van Dam,Heather M Stringham,Peter S Chines,Krista Fischer,Pierre Fontanillas,Oddgeir L Holmen,Sarah E Hunt,Anne U Jackson,Augustine Kong,Robert Lawrence,Julia Meyer,John R B Perry,Carl G P Platou,Simon Potter,Emil Rehnberg,Neil Robertson,Suthesh Sivapalaratnam,Alena Stan\u010d\u00e1kov\u00e1,Kathleen Stirrups,Gudmar Thorleifsson,Emmi Tikkanen,Andrew R Wood,Peter Almgren,Mustafa Atalay,Rafn Benediktsson,Lori L Bonnycastle,No\u00ebl Burtt,Jason Carey,Guillaume Charpentier,Andrew T Crenshaw,Alex S F Doney,Mozhgan Dorkhan,Sarah Edkins,Valur Emilsson,Elodie Eury,Tom Forsen,Karl Gertow,Bruna Gigante,George B Grant,Christopher J Groves,Candace Guiducci,Christian Herder,Astradur B Hreidarsson,Jennie Hui,Alan James,Anna Jonsson,Wolfgang Rathmann,Norman Klopp,Jasmina Kravic,Kaarel Krjut\u0161kov,Cordelia Langford,Karin Leander,Eero Lindholm,St\u00e9phane Lobbens,Satu M\u00e4nnist\u00f6,Ghazala Mirza,Thomas W M\u00fchleisen,Bill Musk,Melissa Parkin,Loukianos Rallidis,Jouko Saramies,Bengt Sennblad,Sonia Shah,Gunnar Sigur\u00f0sson,Angela Silveira,Gerald Steinbach,Barbara Thorand,Joseph Trakalo,Fabrizio Veglia,Roman Wennauer,Wendy Winckler,Delilah Zabaneh,Harry Campbell,Cornelia van Duijn,Andre G Uitterlinden,Albert Hofman,Eric Sijbrands,Goncalo R Abecasis,Katharine R Owen,Eleftheria Zeggini,Mieke D Trip,Nita G Forouhi,Ann-Christine Syv\u00e4nen,Johan G Eriksson,Leena Peltonen,Markus M N\u00f6then,Beverley Balkau,Colin N A Palmer,Valeriya Lyssenko,Tiinamaija Tuomi,Bo Isomaa,David J Hunter,Lu Qi, , , , , ,Alan R Shuldiner,Michael Roden,Ines Barroso,Tom Wilsgaard,John Beilby,Kees Hovingh,Jackie F Price,James F Wilson,Rainer Rauramaa,Timo A Lakka,Lars Lind,George Dedoussis,Inger Nj\u00f8lstad,Nancy L Pedersen,Kay-Tee Khaw,Nicholas J Wareham,Sirkka M Keinanen-Kiukaanniemi,Timo E Saaristo,Eeva Korpi-Hy\u00f6v\u00e4lti,Juha Saltevo,Markku Laakso,Johanna Kuusisto,Andres Metspalu,Francis S Collins,Karen L Mohlke,Richard N Bergman,Jaakko Tuomilehto,Bernhard O Boehm,Christian Gieger,Kristian Hveem,Stephane Cauchi,Philippe Froguel,Damiano Baldassarre,Elena Tremoli,Steve E Humphries,Danish Saleheen,John Danesh,Erik Ingelsson,Samuli Ripatti,Veikko Salomaa,Raimund Erbel,Karl-Heinz J\u00f6ckel,Susanne Moebus,Annette Peters,Thomas Illig,Ulf de Faire,Anders Hamsten,Andrew D Morris,Peter J Donnelly,Timothy M Frayling,Andrew T Hattersley,Eric Boerwinkle,Olle Melander,Sekar Kathiresan,Peter M Nilsson,Panos Deloukas,Unnur Thorsteinsdottir,Leif C Groop,Kari Stefansson,Frank Hu,James S Pankow,Jos\u00e9e Dupuis,James B Meigs,David Altshuler,Michael Boehnke,Mark I McCarthy, ", - "abstract": "To extend understanding of the genetic architecture and molecular basis of type 2 diabetes (T2D), we conducted a meta-analysis of genetic variants on the Metabochip, including 34,840 cases and 114,981 controls, overwhelmingly of European descent. We identified ten previously unreported T2D susceptibility loci, including two showing sex-differentiated association. Genome-wide analyses of these data are consistent with a long tail of additional common variant loci explaining much of the variation in susceptibility to T2D. Exploration of the enlarged set of susceptibility loci implicates several processes, including CREBBP-related transcription, adipocytokine signaling and cell cycle regulation, in diabetes pathogenesis.", - "journal_title": "Nature genetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/22885922/" - } - ], - "08ef2d90-1578-4d3e-bb53-21f12b43a0ed": [ - { - "pub_id": "22232542", - "title": "Combination treatment with metronomic temozolomide, bevacizumab and long-acting octreotide for malignant neuroendocrine tumours.", - "authors": "Anna Koumarianou,Stavroula Antoniou,George Kanakis,Nikolaos Economopoulos,Dimitra Rontogianni,Anastasios Ntavatzikos,Nikolaos Tsavaris,Dimitrios Pectasides,George Dimitriadis,Gregory Kaltsas", - "abstract": "", - "journal_title": "Endocrine-related cancer", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/22232542/" - } - ], - "937fe28b-dbaf-422b-a2de-9ffeafd94172": [ - { - "pub_id": "22155605", - "title": "Human genetics and genomics a decade after the release of the draft sequence of the human genome.", - "authors": "Nasheen Naidoo,Yudi Pawitan,Richie Soong,David N Cooper,Chee-Seng Ku", - "abstract": "Substantial progress has been made in human genetics and genomics research over the past ten years since the publication of the draft sequence of the human genome in 2001. Findings emanating directly from the Human Genome Project, together with those from follow-on studies, have had an enormous impact on our understanding of the architecture and function of the human genome. Major developments have been made in cataloguing genetic variation, the International HapMap Project, and with respect to advances in genotyping technologies. These developments are vital for the emergence of genome-wide association studies in the investigation of complex diseases and traits. In parallel, the advent of high-throughput sequencing technologies has ushered in the 'personal genome sequencing' era for both normal and cancer genomes, and made possible large-scale genome sequencing studies such as the 1000 Genomes Project and the International Cancer Genome Consortium. The high-throughput sequencing and sequence-capture technologies are also providing new opportunities to study Mendelian disorders through exome sequencing and whole-genome sequencing. This paper reviews these major developments in human genetics and genomics over the past decade.", - "journal_title": "Human genomics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/22155605/" - } - ], - "9fd49699-612f-48c0-b1d9-e01158472be6": [ - { - "pub_id": "26470680", - "title": "Advances in therapeutic CRISPR/Cas9 genome editing.", - "authors": "Nata\u0161a Savi\u0107,Gerald Schwank", - "abstract": "Targeted nucleases are widely used as tools for genome editing. Two years ago the clustered regularly interspaced short palindromic repeat (CRISPR)-associated Cas9 nuclease was used for the first time, and since then has largely revolutionized the field. The tremendous success of the CRISPR/Cas9 genome editing tool is powered by the ease design principle of the guide RNA that targets Cas9 to the desired DNA locus, and by the high specificity and efficiency of CRISPR/Cas9-generated DNA breaks. Several studies recently used CRISPR/Cas9 to successfully modulate disease-causing alleles in\u00a0vivo in animal models and ex\u00a0vivo in somatic and induced pluripotent stem cells, raising hope for therapeutic genome editing in the clinics. In this review, we will summarize and discuss such preclinical CRISPR/Cas9 gene therapy reports.", - "journal_title": "Translational research : the journal of laboratory and clinical medicine", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/26470680/" - } - ], - "022c37a3-3ea8-4bb7-9997-98ed87635770": [ - { - "pub_id": "28566273", - "title": "An Expanded Genome-Wide Association Study of Type 2 Diabetes in Europeans.", - "authors": "Robert A Scott,Laura J Scott,Reedik M\u00e4gi,Letizia Marullo,Kyle J Gaulton,Marika Kaakinen,Natalia Pervjakova,Tune H Pers,Andrew D Johnson,John D Eicher,Anne U Jackson,Teresa Ferreira,Yeji Lee,Clement Ma,Valgerdur Steinthorsdottir,Gudmar Thorleifsson,Lu Qi,Natalie R Van Zuydam,Anubha Mahajan,Han Chen,Peter Almgren,Ben F Voight,Harald Grallert,Martina M\u00fcller-Nurasyid,Janina S Ried,Nigel W Rayner,Neil Robertson,Lennart C Karssen,Elisabeth M van Leeuwen,Sara M Willems,Christian Fuchsberger,Phoenix Kwan,Tanya M Teslovich,Pritam Chanda,Man Li,Yingchang Lu,Christian Dina,Dorothee Thuillier,Loic Yengo,Longda Jiang,Thomas Sparso,Hans A Kestler,Himanshu Chheda,Lewin Eisele,Stefan Gustafsson,Mattias Fr\u00e5nberg,Rona J Strawbridge,Rafn Benediktsson,Astradur B Hreidarsson,Augustine Kong,Gunnar Sigur\u00f0sson,Nicola D Kerrison,Jian'an Luan,Liming Liang,Thomas Meitinger,Michael Roden,Barbara Thorand,T\u00f5nu Esko,Evelin Mihailov,Caroline Fox,Ching-Ti Liu,Denis Rybin,Bo Isomaa,Valeriya Lyssenko,Tiinamaija Tuomi,David J Couper,James S Pankow,Niels Grarup,Christian T Have,Marit E J\u00f8rgensen,Torben J\u00f8rgensen,Allan Linneberg,Marilyn C Cornelis,Rob M van Dam,David J Hunter,Peter Kraft,Qi Sun,Sarah Edkins,Katharine R Owen,John R B Perry,Andrew R Wood,Eleftheria Zeggini,Juan Tajes-Fernandes,Goncalo R Abecasis,Lori L Bonnycastle,Peter S Chines,Heather M Stringham,Heikki A Koistinen,Leena Kinnunen,Bengt Sennblad,Thomas W M\u00fchleisen,Markus M N\u00f6then,Sonali Pechlivanis,Damiano Baldassarre,Karl Gertow,Steve E Humphries,Elena Tremoli,Norman Klopp,Julia Meyer,Gerald Steinbach,Roman Wennauer,Johan G Eriksson,Satu M\u04d3nnist\u00f6,Leena Peltonen,Emmi Tikkanen,Guillaume Charpentier,Elodie Eury,St\u00e9phane Lobbens,Bruna Gigante,Karin Leander,Olga McLeod,Erwin P Bottinger,Omri Gottesman,Douglas Ruderfer,Matthias Bl\u00fcher,Peter Kovacs,Anke Tonjes,Nisa M Maruthur,Chiara Scapoli,Raimund Erbel,Karl-Heinz J\u00f6ckel,Susanne Moebus,Ulf de Faire,Anders Hamsten,Michael Stumvoll,Panagiotis Deloukas,Peter J Donnelly,Timothy M Frayling,Andrew T Hattersley,Samuli Ripatti,Veikko Salomaa,Nancy L Pedersen,Bernhard O Boehm,Richard N Bergman,Francis S Collins,Karen L Mohlke,Jaakko Tuomilehto,Torben Hansen,Oluf Pedersen,In\u00eas Barroso,Lars Lannfelt,Erik Ingelsson,Lars Lind,Cecilia M Lindgren,Stephane Cauchi,Philippe Froguel,Ruth J F Loos,Beverley Balkau,Heiner Boeing,Paul W Franks,Aurelio Barricarte Gurrea,Domenico Palli,Yvonne T van der Schouw,David Altshuler,Leif C Groop,Claudia Langenberg,Nicholas J Wareham,Eric Sijbrands,Cornelia M van Duijn,Jose C Florez,James B Meigs,Eric Boerwinkle,Christian Gieger,Konstantin Strauch,Andres Metspalu,Andrew D Morris,Colin N A Palmer,Frank B Hu,Unnur Thorsteinsdottir,Kari Stefansson,Jos\u00e9e Dupuis,Andrew P Morris,Michael Boehnke,Mark I McCarthy,Inga Prokopenko, ", - "abstract": "To characterize type 2 diabetes (T2D)-associated variation across the allele frequency spectrum, we conducted a meta-analysis of genome-wide association data from 26,676 T2D case and 132,532 control subjects of European ancestry after imputation using the 1000 Genomes multiethnic reference panel. Promising association signals were followed up in additional data sets (of 14,545 or 7,397 T2D case and 38,994 or 71,604 control subjects). We identified 13 novel T2D-associated loci (<i>P</i> < 5 \u00d7 10<sup>-8</sup>), including variants near the <i>GLP2R</i>, <i>GIP</i>, and <i>HLA-DQA1</i> genes. Our analysis brought the total number of independent T2D associations to 128 distinct signals at 113 loci. Despite substantially increased sample size and more complete coverage of low-frequency variation, all novel associations were driven by common single nucleotide variants. Credible sets of potentially causal variants were generally larger than those based on imputation with earlier reference panels, consistent with resolution of causal signals to common risk haplotypes. Stratification of T2D-associated loci based on T2D-related quantitative trait associations revealed tissue-specific enrichment of regulatory annotations in pancreatic islet enhancers for loci influencing insulin secretion and in adipocytes, monocytes, and hepatocytes for insulin action-associated loci. These findings highlight the predominant role played by common variants of modest effect and the diversity of biological mechanisms influencing T2D pathophysiology.", - "journal_title": "Diabetes", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/28566273/" - } - ], - "ba6454a1-cc8e-48d4-9df9-c0314734535f": [ - { - "pub_id": "31537524", - "title": "Genome-Wide Association Study on the Early-Phase Insulin Response to a Liquid Mixed Meal: Results From the NEO Study.", - "authors": "Ruifang Li-Gao,Fran\u00e7oise Carlotti,Ren\u00e9e de Mutsert,Astrid van Hylckama Vlieg,Eelco J P de Koning,J Wouter Jukema,Frits R Rosendaal,Ko Willems van Dijk,Dennis O Mook-Kanamori", - "abstract": "Early-phase insulin secretion is a determinant of postprandial glucose homeostasis. In this study, we aimed to identify novel genetic variants associated with the early-phase insulin response to a liquid mixed meal by a genome-wide association study using a discovery and replication design embedded in the Netherlands Epidemiology of Obesity (NEO) study. The early-phase insulin response was defined as the difference between the natural logarithm-transformed insulin concentrations of the postprandial state at 30 min after a meal challenge and the fasting state (\u0394insulin). After Bonferroni correction, rs505922 (\u03b2: -6.5% [minor allele frequency (MAF) 0.32, <i>P</i> = 3.3 \u00d7 10<sup>-8</sup>]) located in the <i>ABO</i> gene reached genome-wide significant level (<i>P</i> < 5 \u00d7 10<sup>-8</sup>) and was also replicated successfully (\u03b2: -7.8% [MAF 0.32, <i>P</i> = 7.2 \u00d7 10<sup>-5</sup>]). The function of the <i>ABO</i> gene was assessed using in vitro shRNA-mediated knockdown of gene expression in the murine pancreatic \u03b2-cell line MIN6. Knocking down the <i>ABO</i> gene led to decreased insulin secretion in the murine pancreatic \u03b2-cell line. These data indicate that the previously identified elevated risk of type 2 diabetes for carriers of the <i>ABO</i> rs505922:C allele may be caused by decreased early-phase insulin secretion.", - "journal_title": "Diabetes", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/31537524/" - } - ], - "461123d9-7d30-4cf6-8fa0-179c0938177a": [ - { - "pub_id": "32396277", - "title": "Genetic analysis resolves differential diagnosis of a familial syndromic dilated cardiomyopathy: A new case of Alstr\u00f6m syndrome.", - "authors": "Barbara Lombardo,Valeria D'Argenio,Emanuele Monda,Andrea Vitale,Martina Caiazza,Lucia Sacchetti,Lucio Pastore,Giuseppe Limongelli,Giulia Frisso,Cristina Mazzaccara", - "abstract": "Syndromic dilated cardiomyopathy (DCM) includes a group of complex disorders with a very heterogeneous genetic etiology, leading to\u00a0delay\u00a0in\u00a0definitive diagnosis.\u00a0Conversely, an early genetic diagnosis is very important in determining the disease course, the prognosis, and may guide personalized treatments and family counseling. We analyzed two brothers with a multisystemic disorder, including dilated cardiomyopathy, diabetes, bilateral neurosensorial hearing loss, and optic atrophy, using different genetic approaches, namely mitochondrial DNA sequencing, comparative genomic hybridization-array (a-CGH) and whole exome sequencing (WES). Sequencing of the wide mitochondrial genome revealed, in both brothers, the known homoplasmic variant rs2853826 in the subunit 3 of the NADH dehydrogenase gene (MT-ND3), whose pathogenicity was conflicting. Comparative genomic hybridization-array analysis revealed in both patients and their father two heterozygous deletions in Phosphodiesterase 4d-Interacting Protein (PDE4DIP) and Protocadherin-related 15 (PCDH15) genes, respectively. The use of WES detected a pathogenetic mutation in ALMS1, enabling the definitive diagnosis of Alstr\u00f6m syndrome. We demonstrated how the diagnosis of a complex heterogeneous disease may be difficult, due to several overlapping manifestations and the possible interaction of more genetic variants that could lead to a more severe and complex phenotype. This paper strongly evidences how genomics is revolutionizing the diagnosis of rare complex disease, representing one of the most essential steps to enable a definitive diagnosis and to establish the etiology for diseases, such as syndromic DCM.", - "journal_title": "Molecular genetics & genomic medicine", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/32396277/" - } - ], - "39b9bd2d-c6fa-49c7-8071-646be8d9c574": [ - { - "pub_id": "31222982", - "title": "Association between IL1B gene and cervical cancer susceptibility in Chinese Uygur Population: A Case-Control study.", - "authors": "Li Wang,Wenhui Zhao,Jiajing Hong,Fanglin Niu,Jing Li,Shanshan Zhang,Tianbo Jin", - "abstract": "Interleukin-1\u03b2 (IL-1B) has been recognized as a pro-inflammatory cytokine and associated with tumorigenesis. We aimed to evaluate the contribution of IL-1B polymorphisms to the susceptibility of cervical cancer in Chinese Uygur population. Seven variants were genotyped by Agena MassARRAY platform in 267 cervical cancer patients and 302 healthy controls. Allelic, genotypic, and haplotypic association analyses adjusted for age were investigated using odds ratios (OR) and 95% confidence intervals (CI). GEPIA and UALCAN databases were used to evaluate expression and prognostic of IL-1B gene in cervical cancer. Our result revealed IL-1B rs1143627-AA (OR\u00a0=\u00a01.98, p\u00a0=\u00a00.029) and rs16944-GG (OR\u00a0=\u00a02.01, p\u00a0=\u00a00.025) was associated with an increased risk of cervical cancer. Besides, we also found two protective single nucleotide polymorphisms (SNPs) rs3136558 (OR\u00a0=\u00a00.63, p\u00a0=\u00a00.011) and rs1143630 (OR\u00a0=\u00a00.63, p\u00a0=\u00a00.019). Haplotype \u2033TGA\u2033 in the block (rs1143630, rs1143627, and rs16944) significantly decreased the susceptibility of cervical cancer (OR\u00a0=\u00a00.53, p\u00a0=\u00a00.0007). IL-1B mRNA level was up-regulated in the cervical cancer patients, which was related with poor prognosis in silico. For the first time, our results provide evidence on polymorphism of IL-1B gene associated with cervical cancer risk in Chinese Uygur population.", - "journal_title": "Molecular genetics & genomic medicine", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/31222982/" - } - ], - "d2eb3f52-43c5-4b3f-a501-0a6e1b00e19b": [ - { - "pub_id": "28898207", - "title": "Shotgun metagenomics, from sampling to analysis.", - "authors": "Christopher Quince,Alan W Walker,Jared T Simpson,Nicholas J Loman,Nicola Segata", - "abstract": "Diverse microbial communities of bacteria, archaea, viruses and single-celled eukaryotes have crucial roles in the environment and in human health. However, microbes are frequently difficult to culture in the laboratory, which can confound cataloging of members and understanding of how communities function. High-throughput sequencing technologies and a suite of computational pipelines have been combined into shotgun metagenomics methods that have transformed microbiology. Still, computational approaches to overcome the challenges that affect both assembly-based and mapping-based metagenomic profiling, particularly of high-complexity samples or environments containing organisms with limited similarity to sequenced genomes, are needed. Understanding the functions and characterizing specific strains of these communities offers biotechnological promise in therapeutic discovery and innovative ways to synthesize products using microbial factories and can pinpoint the contributions of microorganisms to planetary, animal and human health.", - "journal_title": "Nature biotechnology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/28898207/" - } - ], - "775c4a80-54c5-4cc1-ba8c-4975720126ba": [ - { - "pub_id": "33773637", - "title": "Genetic basis of lacunar stroke: a pooled analysis of individual patient data and genome-wide association studies.", - "authors": "Matthew Traylor,Elodie Persyn,Liisa Tomppo,Sofia Klasson,Vida Abedi,Mark K Bakker,Nuria Torres,Linxin Li,Steven Bell,Loes Rutten-Jacobs,Daniel J Tozer,Christoph J Griessenauer,Yanfei Zhang,Annie Pedersen,Pankaj Sharma,Jordi Jimenez-Conde,Tatjana Rundek,Raji P Grewal,Arne Lindgren,James F Meschia,Veikko Salomaa,Aki Havulinna,Christina Kourkoulis,Katherine Crawford,Sandro Marini,Braxton D Mitchell,Steven J Kittner,Jonathan Rosand,Martin Dichgans,Christina Jern,Daniel Strbian,Israel Fernandez-Cadenas,Ramin Zand,Ynte Ruigrok,Natalia Rost,Robin Lemmens,Peter M Rothwell,Christopher D Anderson,Joanna Wardlaw,Cathryn M Lewis,Hugh S Markus, , , , ", - "abstract": "The genetic basis of lacunar stroke is poorly understood, with a single locus on 16q24 identified to date. We sought to identify novel associations and provide mechanistic insights into the disease. We did a pooled analysis of data from newly recruited patients with an MRI-confirmed diagnosis of lacunar stroke and existing genome-wide association studies (GWAS). Patients were recruited from hospitals in the UK as part of the UK DNA Lacunar Stroke studies 1 and 2 and from collaborators within the International Stroke Genetics Consortium. Cases and controls were stratified by ancestry and two meta-analyses were done: a European ancestry analysis, and a transethnic analysis that included all ancestry groups. We also did a multi-trait analysis of GWAS, in a joint analysis with a study of cerebral white matter hyperintensities (an aetiologically related radiological trait), to find additional genetic associations. We did a transcriptome-wide association study (TWAS) to detect genes for which expression is associated with lacunar stroke; identified significantly enriched pathways using multi-marker analysis of genomic annotation; and evaluated cardiovascular risk factors causally associated with the disease using mendelian randomisation. Our meta-analysis comprised studies from Europe, the USA, and Australia, including 7338 cases and 254\u2009798 controls, of which 2987 cases (matched with 29\u2009540 controls) were confirmed using MRI. Five loci (ICA1L-WDR12-CARF-NBEAL1, ULK4, SPI1-SLC39A13-PSMC3-RAPSN, ZCCHC14, ZBTB14-EPB41L3) were found to be associated with lacunar stroke in the European or transethnic meta-analyses. A further seven loci (SLC25A44-PMF1-BGLAP, LOX-ZNF474-LOC100505841, FOXF2-FOXQ1, VTA1-GPR126, SH3PXD2A, HTRA1-ARMS2, COL4A2) were found to be associated in the multi-trait analysis with cerebral white matter hyperintensities (n=42\u2009310). Two of the identified loci contain genes (COL4A2 and HTRA1) that are involved in monogenic lacunar stroke. The TWAS identified associations between the expression of six genes (SCL25A44, ULK4, CARF, FAM117B, ICA1L, NBEAL1) and lacunar stroke. Pathway analyses implicated disruption of the extracellular matrix, phosphatidylinositol 5 phosphate binding, and roundabout binding (false discovery rate <0\u00b705). Mendelian randomisation analyses identified positive associations of elevated blood pressure, history of smoking, and type 2 diabetes with lacunar stroke. Lacunar stroke has a substantial heritable component, with 12 loci now identified that could represent future treatment targets. These loci provide insights into lacunar stroke pathogenesis, highlighting disruption of the vascular extracellular matrix (COL4A2, LOX, SH3PXD2A, GPR126, HTRA1), pericyte differentiation (FOXF2, GPR126), TGF-\u03b2 signalling (HTRA1), and myelination (ULK4, GPR126) in disease risk. British Heart Foundation.", - "journal_title": "The Lancet. Neurology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/33773637/" - } - ], - "d4d3cb27-76d2-4218-8506-25bcecdb975e": [ - { - "pub_id": "29632379", - "title": "Regulatory variants at KLF14 influence type 2 diabetes risk via a female-specific effect on adipocyte size and body composition.", - "authors": "Kerrin S Small,Marijana Todor\u010devi\u0107,Mete Civelek,Julia S El-Sayed Moustafa,Xiao Wang,Michelle M Simon,Juan Fernandez-Tajes,Anubha Mahajan,Momoko Horikoshi,Alison Hugill,Craig A Glastonbury,Lydia Quaye,Matt J Neville,Siddharth Sethi,Marianne Yon,Calvin Pan,Nam Che,Ana Vi\u00f1uela,Pei-Chien Tsai,Abhishek Nag,Alfonso Buil,Gudmar Thorleifsson,Avanthi Raghavan,Qiurong Ding,Andrew P Morris,Jordana T Bell,Unnur Thorsteinsdottir,Kari Stefansson,Markku Laakso,Ingrid Dahlman,Peter Arner,Anna L Gloyn,Kiran Musunuru,Aldons J Lusis,Roger D Cox,Fredrik Karpe,Mark I McCarthy", - "abstract": "Individual risk of type 2 diabetes (T2D) is modified by perturbations to the mass, distribution and function of adipose tissue. To investigate the mechanisms\u00a0underlying these associations, we explored the molecular, cellular and whole-body effects of T2D-associated alleles near KLF14. We show that KLF14 diabetes-risk alleles act in adipose tissue to reduce KLF14 expression and modulate, in trans, the expression of 385 genes. We demonstrate, in human cellular studies, that reduced KLF14 expression increases pre-adipocyte proliferation but disrupts lipogenesis, and in mice, that adipose tissue-specific deletion of Klf14 partially recapitulates the human phenotype of insulin resistance, dyslipidemia and T2D. We show that carriers of the KLF14 T2D risk allele shift body fat from gynoid stores to abdominal stores and display a marked increase in adipocyte cell size, and that these effects on fat distribution, and the T2D association, are female specific. The metabolic risk associated with variation at this imprinted locus depends on the sex both of the subject and of the parent from whom the risk allele derives.", - "journal_title": "Nature genetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/29632379/" - } - ], - "039589d5-c2a7-417f-b58d-7af5ee424a99": [ - { - "pub_id": "31385057", - "title": "How Recent Advances in Genomics Improve Precision Diagnosis and Personalized Care of Maturity-Onset Diabetes of the Young.", - "authors": "Martine Vaxillaire,Philippe Froguel,Am\u00e9lie Bonnefond", - "abstract": "Non-autoimmune monogenic diabetes (MD) in young people shows a broad spectrum of clinical presentations, which is largely explained by multiple genetic etiologies. This review discusses how the application of state-of-the-art genomics research to precision diagnosis of MD, particularly the various subtypes of maturity-onset diabetes of the young (MODY), has increasingly informed diabetes precision medicine and patient care throughout life. Due to extended genetic and clinical heterogeneity of MODY, diagnosis approaches based on next-generation sequencing have been worthwhile to better ascribe a specific subtype to each patient with young-onset diabetes. This guides the best appropriate treatment and clinical follow-up. Early etiological diagnosis of MD and individualized treatment are essential for achieving metabolic targets and avoiding long-term diabetes complications, as well as for drastically decreasing the financial and societal burden of diabetes-related healthcare. Genomic medicine-based practices help to optimize long-term clinical follow-up and patient care management.", - "journal_title": "Current diabetes reports", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/31385057/" - } - ], - "a63a6de1-9886-42a5-9572-e1743f6793c1": [ - { - "pub_id": "30229293", - "title": "The influence of paternal diet on sncRNA-mediated epigenetic inheritance.", - "authors": "Line Katrine Klastrup,Stine Thorhauge Bak,Anders Lade Nielsen", - "abstract": "The risk of developing metabolic diseases is conferred by genetic predisposition from risk genes and by environmental exposures that can manifest in epigenetic changes. The global rise in obesity and type II diabetes has motivated a search for the epigenetic factors underlying these diseases. The possibility of transgenerational inheritance of epigenetic changes raises questions regarding how spermatozoa transmit acquired epigenetic changes that affect the metabolic health of the next generation. The purpose of this review is to describe current key literature concerning small non-coding RNA (sncRNA), specifically (1) the effects of high-fat or low-protein diets on sncRNA presence in spermatozoa; (2) sncRNA transmission from father to offspring; and (3) the functional effects of inherited sncRNA on offspring metabolic phenotype. Current research has identified alterations in the content of sncRNA subtypes, including microRNA (miRNA), Piwi-interacting RNA (piRNA), and transferRNA (tRNA)-derived small non-coding RNA (tsncRNA), in spermatozoa in response to both high-fat diets and low-protein diets. The altered content of spermatozoa sncRNA due to high-fat diets was associated with a changed phenotype in offspring, with offspring displaying insulin resistance, altered body weight, and glucose intolerance. The altered sncRNA content of spermatozoa due to a low-protein diet was associated with altered levels of lipid metabolites in offspring and decreased expression of specific genes starting in two-cell embryos. The current literature suggests that sncRNAs mediate paternal intergenerational epigenetic inheritance and thus has a direct functional importance, as well as possess biomarker potential, for metabolic diseases. Further research is urgently required to identify the specific sncRNAs with the most profound impacts.", - "journal_title": "Molecular genetics and genomics : MGG", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/30229293/" - } - ], - "6910b508-6d25-4804-9e47-3590b57aa061": [ - { - "pub_id": "33568819", - "title": "Sequencing of 53,831 diverse genomes from the NHLBI TOPMed Program.", - "authors": "Daniel Taliun,Daniel N Harris,Michael D Kessler,Jedidiah Carlson,Zachary A Szpiech,Raul Torres,Sarah A Gagliano Taliun,Andr\u00e9 Corvelo,Stephanie M Gogarten,Hyun Min Kang,Achilleas N Pitsillides,Jonathon LeFaive,Seung-Been Lee,Xiaowen Tian,Brian L Browning,Sayantan Das,Anne-Katrin Emde,Wayne E Clarke,Douglas P Loesch,Amol C Shetty,Thomas W Blackwell,Albert V Smith,Quenna Wong,Xiaoming Liu,Matthew P Conomos,Dean M Bobo,Fran\u00e7ois Aguet,Christine Albert,Alvaro Alonso,Kristin G Ardlie,Dan E Arking,Stella Aslibekyan,Paul L Auer,John Barnard,R Graham Barr,Lucas Barwick,Lewis C Becker,Rebecca L Beer,Emelia J Benjamin,Lawrence F Bielak,John Blangero,Michael Boehnke,Donald W Bowden,Jennifer A Brody,Esteban G Burchard,Brian E Cade,James F Casella,Brandon Chalazan,Daniel I Chasman,Yii-Der Ida Chen,Michael H Cho,Seung Hoan Choi,Mina K Chung,Clary B Clish,Adolfo Correa,Joanne E Curran,Brian Custer,Dawood Darbar,Michelle Daya,Mariza de Andrade,Dawn L DeMeo,Susan K Dutcher,Patrick T Ellinor,Leslie S Emery,Celeste Eng,Diane Fatkin,Tasha Fingerlin,Lukas Forer,Myriam Fornage,Nora Franceschini,Christian Fuchsberger,Stephanie M Fullerton,Soren Germer,Mark T Gladwin,Daniel J Gottlieb,Xiuqing Guo,Michael E Hall,Jiang He,Nancy L Heard-Costa,Susan R Heckbert,Marguerite R Irvin,Jill M Johnsen,Andrew D Johnson,Robert Kaplan,Sharon L R Kardia,Tanika Kelly,Shannon Kelly,Eimear E Kenny,Douglas P Kiel,Robert Klemmer,Barbara A Konkle,Charles Kooperberg,Anna K\u00f6ttgen,Leslie A Lange,Jessica Lasky-Su,Daniel Levy,Xihong Lin,Keng-Han Lin,Chunyu Liu,Ruth J F Loos,Lori Garman,Robert Gerszten,Steven A Lubitz,Kathryn L Lunetta,Angel C Y Mak,Ani Manichaikul,Alisa K Manning,Rasika A Mathias,David D McManus,Stephen T McGarvey,James B Meigs,Deborah A Meyers,Julie L Mikulla,Mollie A Minear,Braxton D Mitchell,Sanghamitra Mohanty,May E Montasser,Courtney Montgomery,Alanna C Morrison,Joanne M Murabito,Andrea Natale,Pradeep Natarajan,Sarah C Nelson,Kari E North,Jeffrey R O'Connell,Nicholette D Palmer,Nathan Pankratz,Gina M Peloso,Patricia A Peyser,Jacob Pleiness,Wendy S Post,Bruce M Psaty,D C Rao,Susan Redline,Alexander P Reiner,Dan Roden,Jerome I Rotter,Ingo Ruczinski,Chlo\u00e9 Sarnowski,Sebastian Schoenherr,David A Schwartz,Jeong-Sun Seo,Sudha Seshadri,Vivien A Sheehan,Wayne H Sheu,M Benjamin Shoemaker,Nicholas L Smith,Jennifer A Smith,Nona Sotoodehnia,Adrienne M Stilp,Weihong Tang,Kent D Taylor,Marilyn Telen,Timothy A Thornton,Russell P Tracy,David J Van Den Berg,Ramachandran S Vasan,Karine A Viaud-Martinez,Scott Vrieze,Daniel E Weeks,Bruce S Weir,Scott T Weiss,Lu-Chen Weng,Cristen J Willer,Yingze Zhang,Xutong Zhao,Donna K Arnett,Allison E Ashley-Koch,Kathleen C Barnes,Eric Boerwinkle,Stacey Gabriel,Richard Gibbs,Kenneth M Rice,Stephen S Rich,Edwin K Silverman,Pankaj Qasba,Weiniu Gan, ,George J Papanicolaou,Deborah A Nickerson,Sharon R Browning,Michael C Zody,Sebastian Z\u00f6llner,James G Wilson,L Adrienne Cupples,Cathy C Laurie,Cashell E Jaquish,Ryan D Hernandez,Timothy D O'Connor,Gon\u00e7alo R Abecasis", - "abstract": "The Trans-Omics for Precision Medicine (TOPMed) programme seeks to elucidate the genetic architecture and biology of heart, lung, blood and sleep disorders, with the ultimate goal of improving diagnosis, treatment and prevention of these diseases. The initial phases of the programme focused on whole-genome sequencing of individuals with rich phenotypic data and diverse backgrounds. Here we describe the TOPMed goals and design as well as the available resources and early insights obtained from the sequence data. The resources include a variant browser, a genotype imputation server, and genomic and phenotypic data that are available through dbGaP (Database of Genotypes and Phenotypes)<sup>1</sup>. In the first 53,831 TOPMed samples, we detected more than 400\u00a0million single-nucleotide and insertion or deletion variants after alignment with the reference genome. Additional previously undescribed variants were detected through assembly of unmapped reads and customized analysis in highly variable loci. Among the more than 400\u00a0million detected variants, 97% have frequencies of less than 1% and 46% are singletons that are present in only one individual (53% among unrelated individuals). These rare variants provide insights into mutational processes and recent human evolutionary history. The extensive catalogue of genetic variation in TOPMed studies provides unique opportunities for exploring the contributions of rare and noncoding sequence variants to phenotypic variation. Furthermore, combining TOPMed haplotypes with modern imputation methods improves the power and reach of genome-wide association studies to include variants down to a frequency of approximately 0.01%.", - "journal_title": "Nature", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/33568819/" - } - ], - "87f80b4d-2904-4fdf-bb6f-1ee91ed53c03": [ - { - "pub_id": "26225775", - "title": "Where Next for Genetics and Genomics?", - "authors": "Chris Tyler-Smith,Huanming Yang,Laura F Landweber,Ian Dunham,Bartha M Knoppers,Peter Donnelly,Elaine R Mardis,Michael Snyder,Gil McVean", - "abstract": "The last few decades have utterly transformed genetics and genomics, but what might the next ten years bring? PLOS Biology asked eight leaders spanning a range of related areas to give us their predictions. Without exception, the predictions are for more data on a massive scale and of more diverse types. All are optimistic and predict enormous positive impact on scientific understanding, while a recurring theme is the benefit of such data for the transformation and personalization of medicine. Several also point out that the biggest changes will very likely be those that we don't foresee, even now.", - "journal_title": "PLoS biology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/26225775/" - } - ], - "2c132879-3bc2-4941-a082-042ee350b102": [ - { - "pub_id": "30459114", - "title": "Multivariate analysis of genome-wide data to identify potential pleiotropic genes for type 2 diabetes, obesity and coronary artery disease using MetaCCA.", - "authors": "XiaoCan Jia,YongLi Yang,YuanCheng Chen,Zhenhua Xia,Weiping Zhang,Yu Feng,Yifan Li,Jiebing Tan,Chao Xu,Qiang Zhang,Hongwen Deng,XueZhong Shi", - "abstract": "Although genome-wide association studies (GWAS) have been extensively applied in identifying SNP associated with metabolic diseases, the SNPs identified by this prevailing univariate approach only explain a small percentage of the genetic variance of traits. The extensive previous studies have repeatedly shown type2 diabetes (T2D), obesity and coronary artery disease (CAD) have common genetic mechanisms and the overlapping pathophysiological pathways. The genetic pleiotropy-informed metaCCA method was applied on summary statistics data from three independent meta-GWAS summary statistics to identify shared variants and pleiotropic effect between T2D, obesity and CAD. Furthermore, to refine all genes, we performed gene-based association analyses for these three diseases respectively using VEGAS2. Gene enrichment analysis was applied to explore the potential functional significance of the identified genes. After metaCCA analysis, 833 SNPs reached the Bonferroni corrected threshold (p\u202f<\u202f7.99\u202f\u00d7\u202f10<sup>-7</sup>) in the univariate SNP-multivariate phenotype analysis, and 327 genes with a significance threshold (p\u202f<\u202f3.73\u202f\u00d7\u202f10<sup>-6</sup>) were identified as potentially pleiotropic genes in the multivariate SNP-multivariate phenotype analysis. By screening the results of gene-based p-values, we identified 22 putative pleiotropic genes which achieved significance threshold in metaCCA analyses and were also associated with at least one disease in the VEGAS2 analyses. The metaCCA method identified novel variants associated with T2D, obesity and CAD by effectively incorporating information from different GWAS datasets. Our analyses may provide insights for some common therapeutic approaches of metabolic diseases based on the pleiotropic genes and common mechanisms identified.", - "journal_title": "International journal of cardiology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/30459114/" - } - ], - "5d933a9a-8b30-4cca-b09e-0f876df06ff7": [ - { - "pub_id": "32067423", - "title": "Role of Helicobacter pylori infection in the manifestation of old age-related diseases.", - "authors": "Abolfazl Zendehdel,Maryam Roham", - "abstract": "Helicobacter pylori is one of the most prevalent infection worldwide. It affects individuals of different age groups. Elderly people tend to resist eradication treatment and worsening of infection can lead to several gastric and non-gastric pathologies. Aging-associated cellular and molecular alteration can increase the risk of other pathologies such as osteoporosis, Alzheimer's disease, Parkinson's disease, respiratory and renal dysfunction, and cancer in geriatric patients, more than other age groups. This review article highlights some of the most common old age diseases and the role of H. pylori infection as a risk factor to worsen the conditions, presented by the molecular evidences of these associations. These studies can help clinicians to understand the underlying pathogenesis of the disease and identify high-risk patients, aiding clearer diagnosis and treatment.", - "journal_title": "Molecular genetics & genomic medicine", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/32067423/" - } - ], - "737d12b3-3805-4a4b-96c1-be39629950c3": [ - { - "pub_id": "29274115", - "title": "A novel desmin (DES) indel mutation causes severe atypical cardiomyopathy in combination with atrioventricular block and skeletal myopathy.", - "authors": "Ilona Schirmer,Mareike Dieding,B\u00e4rbel Klauke,Andreas Brodehl,Anna Gaertner-Rommel,Volker Walhorn,Jan Gummert,Uwe Schulz,Lech Paluszkiewicz,Dario Anselmetti,Hendrik Milting", - "abstract": "DES mutations cause different cardiac and skeletal myopathies. Most of them are missense mutations. Using a next-generation sequencing cardiac 174 gene panel, we identified a novel heterozygous in-frame indel mutation (DES-c.493_520del28insGCGT, p.Q165_A174delinsAS) in a Caucasian patient with cardiomyopathy in combination with atrioventricular block and skeletal myopathy. This indel mutation is located in the coding region of the first exon. Family anamnesis revealed a history of sudden cardiac death. We performed cell transfection experiments and in\u00a0vitro assembly experiments to prove the pathogenicity of this novel DES indel mutation. These experiments revealed a severe filament formation defect of mutant desmin supporting the pathogenicity. In addition, we labeled a skeletal muscle biopsy from the mutation carrier revealing cytoplasmic desmin positive protein aggregates. In summary, we identified and functionally characterized a pathogenic DES indel mutation causing cardiac and skeletal myopathy. Our study has relevance for the clinical and genetic interpretation of further DES indel mutations causing cardiac or skeletal myopathies and might be helpful for risk stratification.", - "journal_title": "Molecular genetics & genomic medicine", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/29274115/" - } - ], - "4be1d780-404a-4826-ba06-80b2c15e705b": [ - { - "pub_id": "27007718", - "title": "Genome-Wide Studies of Type 2 Diabetes and Lipid Traits in Hispanics.", - "authors": "Jennifer E Below,Esteban J Parra", - "abstract": "Although disproportionately affected by increasing rates of type 2 diabetes and dyslipidemias, Hispanic populations are underrepresented in efforts to understand genetic susceptibility to these disorders. Where research has been undertaken, these populations have provided substantial insight into identification of novel risk-associated genes and have aided in the ability to fine map previously described risk loci. Genome-wide analyses in Hispanic and trans-ethnic populations have resulted in identification of more than 40 replicated or novel genes with significant effects for type 2 diabetes or lipid traits. Initial investigations into rare variant effects have identified new risk-associated variants private to Hispanic populations, and preliminary results suggest metagenomic approaches in Hispanic populations, such as characterizing the gut microbiome, will enable the development of new predictive tools and therapeutic targets for type 2 diabetes. Future genome-wide studies in expanded cohorts of Hispanics are likely to result in new insights into the genetic etiology of metabolic health.", - "journal_title": "Current diabetes reports", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/27007718/" - } - ], - "dc17cd1d-f36c-46cd-9260-d9f1141851a1": [ - { - "pub_id": "27398621", - "title": "The genetic architecture of type 2 diabetes.", - "authors": "Christian Fuchsberger,Jason Flannick,Tanya M Teslovich,Anubha Mahajan,Vineeta Agarwala,Kyle J Gaulton,Clement Ma,Pierre Fontanillas,Loukas Moutsianas,Davis J McCarthy,Manuel A Rivas,John R B Perry,Xueling Sim,Thomas W Blackwell,Neil R Robertson,N William Rayner,Pablo Cingolani,Adam E Locke,Juan Fernandez Tajes,Heather M Highland,Josee Dupuis,Peter S Chines,Cecilia M Lindgren,Christopher Hartl,Anne U Jackson,Han Chen,Jeroen R Huyghe,Martijn van de Bunt,Richard D Pearson,Ashish Kumar,Martina M\u00fcller-Nurasyid,Niels Grarup,Heather M Stringham,Eric R Gamazon,Jaehoon Lee,Yuhui Chen,Robert A Scott,Jennifer E Below,Peng Chen,Jinyan Huang,Min Jin Go,Michael L Stitzel,Dorota Pasko,Stephen C J Parker,Tibor V Varga,Todd Green,Nicola L Beer,Aaron G Day-Williams,Teresa Ferreira,Tasha Fingerlin,Momoko Horikoshi,Cheng Hu,Iksoo Huh,Mohammad Kamran Ikram,Bong-Jo Kim,Yongkang Kim,Young Jin Kim,Min-Seok Kwon,Juyoung Lee,Selyeong Lee,Keng-Han Lin,Taylor J Maxwell,Yoshihiko Nagai,Xu Wang,Ryan P Welch,Joon Yoon,Weihua Zhang,Nir Barzilai,Benjamin F Voight,Bok-Ghee Han,Christopher P Jenkinson,Teemu Kuulasmaa,Johanna Kuusisto,Alisa Manning,Maggie C Y Ng,Nicholette D Palmer,Beverley Balkau,Alena Stan\u010d\u00e1kov\u00e1,Hanna E Abboud,Heiner Boeing,Vilmantas Giedraitis,Dorairaj Prabhakaran,Omri Gottesman,James Scott,Jason Carey,Phoenix Kwan,George Grant,Joshua D Smith,Benjamin M Neale,Shaun Purcell,Adam S Butterworth,Joanna M M Howson,Heung Man Lee,Yingchang Lu,Soo-Heon Kwak,Wei Zhao,John Danesh,Vincent K L Lam,Kyong Soo Park,Danish Saleheen,Wing Yee So,Claudia H T Tam,Uzma Afzal,David Aguilar,Rector Arya,Tin Aung,Edmund Chan,Carmen Navarro,Ching-Yu Cheng,Domenico Palli,Adolfo Correa,Joanne E Curran,Denis Rybin,Vidya S Farook,Sharon P Fowler,Barry I Freedman,Michael Griswold,Daniel Esten Hale,Pamela J Hicks,Chiea-Chuen Khor,Satish Kumar,Benjamin Lehne,Doroth\u00e9e Thuillier,Wei Yen Lim,Jianjun Liu,Yvonne T van der Schouw,Marie Loh,Solomon K Musani,Sobha Puppala,William R Scott,Lo\u00efc Yengo,Sian-Tsung Tan,Herman A Taylor,Farook Thameem,Gregory Wilson,Tien Yin Wong,P\u00e5l Rasmus Nj\u00f8lstad,Jonathan C Levy,Massimo Mangino,Lori L Bonnycastle,Thomas Schwarzmayr,Jo\u00e3o Fadista,Gabriela L Surdulescu,Christian Herder,Christopher J Groves,Thomas Wieland,Jette Bork-Jensen,Ivan Brandslund,Cramer Christensen,Heikki A Koistinen,Alex S F Doney,Leena Kinnunen,T\u00f5nu Esko,Andrew J Farmer,Liisa Hakaste,Dylan Hodgkiss,Jasmina Kravic,Valeriya Lyssenko,Mette Hollensted,Marit E J\u00f8rgensen,Torben J\u00f8rgensen,Claes Ladenvall,Johanne Marie Justesen,Annemari K\u00e4r\u00e4j\u00e4m\u00e4ki,Jennifer Kriebel,Wolfgang Rathmann,Lars Lannfelt,Torsten Lauritzen,Narisu Narisu,Allan Linneberg,Olle Melander,Lili Milani,Matt Neville,Marju Orho-Melander,Lu Qi,Qibin Qi,Michael Roden,Olov Rolandsson,Amy Swift,Anders H Rosengren,Kathleen Stirrups,Andrew R Wood,Evelin Mihailov,Christine Blancher,Mauricio O Carneiro,Jared Maguire,Ryan Poplin,Khalid Shakir,Timothy Fennell,Mark DePristo,Martin Hrab\u00e9 de Angelis,Panos Deloukas,Anette P Gjesing,Goo Jun,Peter Nilsson,Jacquelyn Murphy,Robert Onofrio,Barbara Thorand,Torben Hansen,Christa Meisinger,Frank B Hu,Bo Isomaa,Fredrik Karpe,Liming Liang,Annette Peters,Cornelia Huth,Stephen P O'Rahilly,Colin N A Palmer,Oluf Pedersen,Rainer Rauramaa,Jaakko Tuomilehto,Veikko Salomaa,Richard M Watanabe,Ann-Christine Syv\u00e4nen,Richard N Bergman,Dwaipayan Bharadwaj,Erwin P Bottinger,Yoon Shin Cho,Giriraj R Chandak,Juliana C N Chan,Kee Seng Chia,Mark J Daly,Shah B Ebrahim,Claudia Langenberg,Paul Elliott,Kathleen A Jablonski,Donna M Lehman,Weiping Jia,Ronald C W Ma,Toni I Pollin,Manjinder Sandhu,Nikhil Tandon,Philippe Froguel,In\u00eas Barroso,Yik Ying Teo,Eleftheria Zeggini,Ruth J F Loos,Kerrin S Small,Janina S Ried,Ralph A DeFronzo,Harald Grallert,Benjamin Glaser,Andres Metspalu,Nicholas J Wareham,Mark Walker,Eric Banks,Christian Gieger,Erik Ingelsson,Hae Kyung Im,Thomas Illig,Paul W Franks,Gemma Buck,Joseph Trakalo,David Buck,Inga Prokopenko,Reedik M\u00e4gi,Lars Lind,Yossi Farjoun,Katharine R Owen,Anna L Gloyn,Konstantin Strauch,Tiinamaija Tuomi,Jaspal Singh Kooner,Jong-Young Lee,Taesung Park,Peter Donnelly,Andrew D Morris,Andrew T Hattersley,Donald W Bowden,Francis S Collins,Gil Atzmon,John C Chambers,Timothy D Spector,Markku Laakso,Tim M Strom,Graeme I Bell,John Blangero,Ravindranath Duggirala,E Shyong Tai,Gilean McVean,Craig L Hanis,James G Wilson,Mark Seielstad,Timothy M Frayling,James B Meigs,Nancy J Cox,Rob Sladek,Eric S Lander,Stacey Gabriel,No\u00ebl P Burtt,Karen L Mohlke,Thomas Meitinger,Leif Groop,Goncalo Abecasis,Jose C Florez,Laura J Scott,Andrew P Morris,Hyun Min Kang,Michael Boehnke,David Altshuler,Mark I McCarthy", - "abstract": "The genetic architecture of common traits, including the number, frequency, and effect sizes of inherited variants that contribute to individual risk, has been long debated. Genome-wide association studies have identified scores of common variants associated with type 2 diabetes, but in aggregate, these explain only a fraction of the heritability of this disease. Here, to test the hypothesis that lower-frequency variants explain much of the remainder, the GoT2D and T2D-GENES consortia performed whole-genome sequencing in 2,657 European individuals with and without diabetes, and exome sequencing in 12,940 individuals from five ancestry groups. To increase statistical power, we expanded the sample size via genotyping and imputation in a further 111,548 subjects. Variants associated with type 2 diabetes after sequencing were overwhelmingly common and most fell within regions previously identified by genome-wide association studies. Comprehensive enumeration of sequence variation is necessary to identify functional alleles that provide important clues to disease pathophysiology, but large-scale sequencing does not support the idea that lower-frequency variants have a major role in predisposition to type 2 diabetes.", - "journal_title": "Nature", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/27398621/" - } - ], - "15b5c53c-d153-4932-9d24-9864e92a601d": [ - { - "pub_id": "36530175", - "title": "Damaging missense variants in <i>IGF1R</i> implicate a role for IGF-1 resistance in the etiology of type 2 diabetes.", - "authors": "Eugene J Gardner,Katherine A Kentistou,Stasa Stankovic,Samuel Lockhart,Eleanor Wheeler,Felix R Day,Nicola D Kerrison,Nicholas J Wareham,Claudia Langenberg,Stephen O'Rahilly,Ken K Ong,John R B Perry", - "abstract": "Type 2 diabetes (T2D) is a heritable metabolic disorder. While population studies have identified hundreds of common genetic variants associated with T2D, the role of rare (frequency\u00a0<\u00a00.1%) protein-coding variation is less clear. We performed exome sequence analysis in 418,436 (n\u00a0= 32,374 T2D cases) individuals in the UK Biobank. We identified previously reported genes (<i>GCK</i>, <i>GIGYF1</i>, <i>HNF1A</i>) in addition to missense variants in\u00a0<i>ZEB2</i> (n\u00a0= 31 carriers; odds ratio [OR]\u00a0= 5.5 [95% confidence interval\u00a0= 2.5-12.0]; p\u00a0= 6.4\u00a0\u00d7\u00a010<sup>-7</sup>), <i>MLXIPL</i> (n\u00a0= 245; OR\u00a0= 2.3 [1.6-3.2]; p\u00a0= 3.2\u00a0\u00d7\u00a010<sup>-7</sup>), and <i>IGF1R</i> (n\u00a0= 394; OR\u00a0= 2.4 [1.8-3.2]; p\u00a0= 1.3\u00a0\u00d7\u00a010<sup>-10</sup>). Carriers of damaging missense variants within <i>IGF1R</i> were also shorter (-2.2\u00a0cm [-1.8 to -2.7]; p\u00a0= 1.2\u00a0\u00d7\u00a010<sup>-19</sup>) and had higher circulating insulin-like growth factor-1 (IGF-1) protein levels (2.3\u00a0nmol/L [1.7-2.9]; p\u00a0= 2.8\u00a0\u00d7\u00a010<sup>-14</sup>), indicating relative IGF-1 resistance. A likely causal role of IGF-1 resistance was supported by Mendelian randomization analyses using common variants. These results increase understanding of the genetic architecture of T2D and highlight the growth hormone/IGF-1 axis as a potential therapeutic target.", - "journal_title": "Cell genomics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/36530175/" - } - ], - "faa23996-65fc-4bc6-938a-c959e981d493": [ - { - "pub_id": "30914061", - "title": "Developing a network view of type 2 diabetes risk pathways through integration of genetic, genomic and functional data.", - "authors": "Juan Fern\u00e1ndez-Tajes,Kyle J Gaulton,Martijn van de Bunt,Jason Torres,Matthias Thurner,Anubha Mahajan,Anna L Gloyn,Kasper Lage,Mark I McCarthy", - "abstract": "Genome-wide association studies (GWAS) have identified several hundred susceptibility loci for type 2 diabetes (T2D). One critical, but unresolved, issue concerns the extent to which the mechanisms through which these diverse signals influencing T2D predisposition converge on a limited set of biological processes. However, the causal variants identified by GWAS mostly fall into a non-coding sequence, complicating the task of defining the effector transcripts through which they operate. Here, we describe implementation of an analytical pipeline to address this question. First, we integrate multiple sources of genetic, genomic and biological data to assign positional candidacy scores to the genes that map to T2D GWAS signals. Second, we introduce genes with high scores as seeds within a network optimization algorithm (the asymmetric prize-collecting Steiner tree approach) which uses external, experimentally confirmed protein-protein interaction (PPI) data to generate high-confidence sub-networks. Third, we use GWAS data to test the T2D association enrichment of the \"non-seed\" proteins introduced into the network, as a measure of the overall functional connectivity of the network. We find (a) non-seed proteins in the T2D protein-interaction network so generated (comprising 705 nodes) are enriched for association to T2D (p\u2009=\u20090.0014) but not control traits, (b) stronger T2D-enrichment for islets than other tissues when we use RNA expression data to generate tissue-specific PPI networks and (c) enhanced enrichment (p\u2009=\u20093.9\u2009\u00d7\u200910<sup>-\u20095</sup>) when we combine the analysis of the islet-specific PPI network with a focus on the subset of T2D GWAS loci which act through defective insulin secretion. These analyses reveal a pattern of non-random functional connectivity between candidate causal genes at T2D GWAS loci and highlight the products of genes including YWHAG, SMAD4 or CDK2 as potential contributors to T2D-relevant islet dysfunction. The approach we describe can be applied to other complex genetic and genomic datasets, facilitating integration of diverse data types into disease-associated networks.", - "journal_title": "Genome medicine", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/30914061/" - } - ], - "4b5d79da-a618-424d-82aa-3024e4bca61d": [ - { - "pub_id": "32313152", - "title": "Mainstreaming genetics and genomics: a systematic review of the barriers and facilitators for nurses and physicians in secondary and tertiary care.", - "authors": "Stephanie White,Chris Jacobs,Jane Phillips", - "abstract": "Genetic and genomic health information increasingly informs routine clinical care and treatment. This systematic review aimed to identify the barriers and facilitators to integrating genetics and genomics into nurses' and physicians' usual practice (mainstreaming). A search of MEDLINE, EMBASE, CINAHL, and PsycINFO generated 7873 articles, of which 48 were included. Using narrative synthesis, barriers and facilitators were mapped to the Theoretical Domains Framework (TDF). Barriers were limitations to genetics knowledge and skill, low confidence initiating genetics discussions, lack of resources and guidelines, and concerns about discrimination and psychological harm. Facilitators were positive attitudes toward genetics, willingness to participate in discussions upon patient initiation, and intention to engage in genetics education. Nurses and physicians are largely underprepared to integrate genetic and genomic health information into routine clinical care. Ethical, legal, and psychological concerns surrounding genetic information can lead to avoidance of genetics discussions. The knowledge-practice gap could limit patients' and families' access to vital genetic information. Building the capacity of the current and next generation of nurses and physicians to integrate genetics and genomics into usual clinical practice is essential if opportunities afforded by precision medicine are to be fully realized.", - "journal_title": "Genetics in medicine : official journal of the American College of Medical Genetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/32313152/" - } - ], - "94e153f4-bc43-4e5b-99d4-6bb64ed24e4a": [ - { - "pub_id": "31816668", - "title": "Association of polymorphism in heat shock protein 70 genes with type 2 diabetes in Bangladeshi population.", - "authors": "Md Moniruzzaman,Irfan Ahmed,Saaimatul Huq,Md Shakur All Mahmud,Sonya Begum,U S Mahzabin Amin,Md Hadisur Rahman,Palash Kumar Sarker,Mohammad Uzzal Hossain,Keshob Chandra Das,Md Salimullah", - "abstract": "Type 2 diabetes mellitus (T2DM) is a chronic disorder of which stress is a major contributor. Under stressful condition, body synthesizes a family of molecular chaperone called Heat-shock proteins (HSPs). Current study assessed the frequency and association of HSP70-hom\u00a0+\u00a02,437\u00a0T/C polymorphism with T2DM risk among Bangladeshis. This polymorphism was selected through bioinformatics analyses and identified by PCR-RFLP method. Bioinformatics analysis identified this SNP as missense mutation which could destabilize the final HSP product. Heterozygous mutant (CT) genotype was significantly associated with T2DM incidence among the studied populations (p\u00a0=\u00a0.015). Further analysis revealed a strong association with female patients (p\u00a0=\u00a0.002), while the male group showed no association (p\u00a0=\u00a0.958). Moreover, the C allele was significantly associated among all diabetic patients (p\u00a0=\u00a0.016) and particularly in the female patient group (p\u00a0=\u00a0.001). However, under stressful condition, males with CT genotype were at high risk for T2DM incidence whereas, females with CT genotype showed no significant association. HSP70-hom\u00a0+\u00a02,437\u00a0T/C polymorphism was found to be significantly associated with T2DM incidence in the Bangladeshi population in both stress-dependent and independent manners.", - "journal_title": "Molecular genetics & genomic medicine", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/31816668/" - } - ], - "2d99dae0-a039-446e-82c7-434af2e5f421": [ - { - "pub_id": "34346195", - "title": "Exome sequencing identifies a disease variant of the mitochondrial ATP-Mg/Pi carrier SLC25A25 in two families with kidney stones.", - "authors": "M Reza Jabalameli,Fiona M Fitzpatrick,Roberto Colombo,Sarah A Howles,Gary Leggatt,Valerie Walker,Akira Wiberg,Edmund R S Kunji,Sarah Ennis", - "abstract": "Calcium kidney stones are common and recurrences are often not preventable by available empiric remedies. Their etiology is multifactorial and polygenic, and an increasing number of genes are implicated. Their identification will enable improved management. DNA from three stone-formers in a Southampton family (UK) and two from an Italian family were analyzed independently by whole exome sequencing and selected variants were genotyped across all available members of both pedigrees. A disease variant of SLC25A25 (OMIM 608745), encoding the mitochondrial ATP-Mg/Pi carrier 3 (APC3) was identified, and analyzed structurally and functionally with respect to its calcium-regulated transport activity. All five patients had a heterozygous dominant SLC25A25 variant (rs140777921; GRCh37.p13: chr 9 130868670 G>C; p.Gln349His; Reference Sequence NM_001006641.3). Non-stone formers also carried the variant indicating incomplete penetrance. Modeling suggests that the variant lacks a conserved polar interaction, which may cause structural instability. Calcium-regulated ATP transport was reduced to ~20% of the wild type, showing a large reduction in function. The transporter is important in regulating mitochondrial ATP production. This rare variant may increase urine lithogenicity through impaired provision of ATP for solute transport processes in the kidney, and/or for purinergic signaling. Variants found in other genes may compound this abnormality.", - "journal_title": "Molecular genetics & genomic medicine", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/34346195/" - } - ], - "949e5edc-c324-473e-85b4-f73d500572fb": [ - { - "pub_id": "33663937", - "title": "The oral microbiome of pregnant women facilitates gestational diabetes discrimination.", - "authors": "Xiaoqing Li,Jiayong Zheng,Xiuling Ma,Bing Zhang,Jinyang Zhang,Wenhuan Wang,Congcong Sun,Yeping Wang,Jianqiong Zheng,Haiying Chen,Jiejing Tao,Hai Wang,Fengyi Zhang,Jinfeng Wang,Hongping Zhang", - "abstract": "The oral microbiota plays an important role in the development of various diseases, whereas its association with gestational diabetes mellitus (GDM) remains largely unclear. The aim of this study is to identify biomarkers from the oral microbiota of GDM patients by analyzing the microbiome of the saliva and dental plaque samples of 111 pregnant women. We find that the microbiota of both types of oral samples in GDM patients exhibits differences and significantly varies from that of patients with periodontitis or dental caries. Using bacterial biomarkers from the oral microbiota, GDM classification models based on support vector machine and random forest algorithms are constructed. The area under curve (AUC) value of the classification model constructed by combination of Lautropia and Neisseria in dental plaque and Streptococcus in saliva reaches 0.83, and the value achieves a maximum value of 0.89 by adding clinical features. These findings suggest\u00a0that certain bacteria in either saliva or dental plaque can effectively distinguish women with GDM from healthy pregnant women, which provides evidence of oral microbiome as an informative source for developing noninvasive biomarkers of GDM.", - "journal_title": "Journal of genetics and genomics = Yi chuan xue bao", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/33663937/" - } - ], - "7b869773-8f84-497b-8462-8bf18bf25828": [ - { - "pub_id": "29220541", - "title": "Yoga for stroke rehabilitation.", - "authors": "Maggie Lawrence,Francisco T Celestino Junior,Hemilianna Hs Matozinho,Lindsay Govan,Jo Booth,Jane Beecher", - "abstract": "Stroke is a major health issue and cause of long-term disability and has a major emotional and socioeconomic impact. There is a need to explore options for long-term sustainable interventions that support stroke survivors to engage in meaningful activities to address life challenges after stroke. Rehabilitation focuses on recovery of function and cognition to the maximum level achievable, and may include a wide range of complementary strategies including yoga.Yoga is a mind-body practice that originated in India, and which has become increasingly widespread in the Western world. Recent evidence highlights the positive effects of yoga for people with a range of physical and psychological health conditions. A recent non-Cochrane systematic review concluded that yoga can be used as self-administered practice in stroke rehabilitation. To assess the effectiveness of yoga, as a stroke rehabilitation intervention, on recovery of function and quality of life (QoL). We searched the Cochrane Stroke Group Trials Register (last searched July 2017), Cochrane Central Register of Controlled Trials (CENTRAL) (last searched July 2017), MEDLINE (to July 2017), Embase (to July 2017), CINAHL (to July 2017), AMED (to July 2017), PsycINFO (to July 2017), LILACS (to July 2017), SciELO (to July 2017), IndMED (to July 2017), OTseeker (to July 2017) and PEDro (to July 2017). We also searched four trials registers, and one conference abstracts database. We screened reference lists of relevant publications and contacted authors for additional information. We included randomised controlled trials (RCTs) that compared yoga with a waiting-list control or no intervention control in stroke survivors. Two review authors independently extracted data from the included studies. We performed all analyses using Review Manager (RevMan). One review author entered the data into RevMan; another checked the entries. We discussed disagreements with a third review author until consensus was reached. We used the Cochrane 'Risk of bias' tool. Where we considered studies to be sufficiently similar, we conducted a meta-analysis by pooling the appropriate data. For outcomes for which it was inappropriate or impossible to pool quantitatively, we conducted a descriptive analysis and provided a narrative summary. We included two RCTs involving 72 participants. Sixty-nine participants were included in one meta-analysis (balance). Both trials assessed QoL, along with secondary outcomes measures relating to movement and psychological outcomes; one also measured disability.In one study the Stroke Impact Scale was used to measure QoL across six domains, at baseline and post-intervention. The effect of yoga on five domains (physical, emotion, communication, social participation, stroke recovery) was not significant; however, the effect of yoga on the memory domain was significant (mean difference (MD) 15.30, 95% confidence interval (CI) 1.29 to 29.31, P = 0.03), the evidence for this finding was very low grade. In the second study, QoL was assessed using the Stroke-Specifc QoL Scale; no significant effect was found.Secondary outcomes included movement, strength and endurance, and psychological variables, pain, and disability.Balance was measured in both studies using the Berg Balance Scale; the effect of intervention was not significant (MD 2.38, 95% CI -1.41 to 6.17, P = 0.22). Sensititivy analysis did not alter the direction of effect. One study measured balance self-efficacy, using the Activities-specific Balance Confidence Scale (MD 10.60, 95% CI -7.08,= to 28.28, P = 0.24); the effect of intervention was not significant; the evidence for this finding was very low grade.One study measured gait using the Comfortable Speed Gait Test (MD 1.32, 95% CI -1.35 to 3.99, P = 0.33), and motor function using the Motor Assessment Scale (MD -4.00, 95% CI -12.42 to 4.42, P = 0.35); no significant effect was found based on very low-grade evidence.One study measured disability using the modified Rankin Scale (mRS) but reported only whether participants were independent or dependent. No significant effect was found: (odds ratio (OR) 2.08, 95% CI 0.50 to 8.60, P = 0.31); the evidence for this finding was very low grade.Anxiety and depression were measured in one study. Three measures were used: the Geriatric Depression Scale-Short Form (GCDS15), and two forms of State Trait Anxiety Inventory (STAI, Form Y) to measure state anxiety (i.e. anxiety experienced in response to stressful situations) and trait anxiety (i.e. anxiety associated with chronic psychological disorders). No significant effect was found for depression (GDS15, MD -2.10, 95% CI -4.70 to 0.50, P = 0.11) or for trait anxiety (STAI-Y2, MD -6.70, 95% CI -15.35 to 1.95, P = 0.13), based on very low-grade evidence. However, a significant effect was found for state anxiety: STAI-Y1 (MD -8.40, 95% CI -16.74 to -0.06, P = 0.05); the evidence for this finding was very low grade.No adverse events were reported.Quality of the evidenceWe assessed the quality of the evidence using GRADE. Overall, the quality of the evidence was very low, due to the small number of trials included in the review both of which were judged to be at high risk of bias, particularly in relation to incompleteness of data and selective reporting, and especially regarding the representative nature of the sample in one study. Yoga has the potential for being included as part of patient-centred stroke rehabilitation. However, this review has identified insufficient information to confirm or refute the effectiveness or safety of yoga as a stroke rehabilitation treatment. Further large-scale methodologically robust trials are required to establish the effectiveness of yoga as a stroke rehabilitation treatment.", - "journal_title": "The Cochrane database of systematic reviews", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/29220541/" - } - ], - "4de29b20-8aad-4607-9b54-f13a62bbc3e7": [ - { - "pub_id": "30740423", - "title": "Results of the First Genome-Wide Association Study of Latent Autoimmune Diabetes in Adults further highlight the need for a novel diabetes classification system.", - "authors": "Theocharis Koufakis,Spyridon N Karras,Pantelis Zebekakis,Kalliopi Kotsa", - "abstract": "", - "journal_title": "Annals of translational medicine", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/30740423/" - } - ], - "ed473b21-b1e1-4b58-b48d-5e3be03b82f5": [ - { - "pub_id": "29310926", - "title": "Identification of non-HLA genes associated with development of islet autoimmunity and type 1 diabetes in the prospective TEDDY cohort.", - "authors": "Ashok Sharma,Xiang Liu,David Hadley,William Hagopian,Wei-Min Chen,Suna Onengut-Gumuscu,Carina T\u00f6rn,Andrea K Steck,Brigitte I Frohnert,Marian Rewers,Anette-G Ziegler,\u00c5ke Lernmark,Jorma Toppari,Jeffrey P Krischer,Beena Akolkar,Stephen S Rich,Jin-Xiong She, ", - "abstract": "Traditional linkage analysis and genome-wide association studies have identified HLA and a number of non-HLA genes as genetic factors for islet autoimmunity (IA) and type 1 diabetes (T1D). However, the relative risk associated with previously identified non-HLA genes is usually very small as measured in cases/controls from mixed populations. Genetic associations for IA and T1D may be more accurately assessed in prospective cohorts. In this study, 5806 subjects from the TEDDY (The Environmental Determinants of Diabetes in the Young) study, an international prospective cohort study, were genotyped for 176,586 SNPs on the ImmunoChip. Cox proportional hazards analyses were performed to discover the SNPs associated with the risk for IA, T1D, or both. Three regions were associated with the risk of developing any persistent confirmed islet autoantibody: one known region near SH2B3 (HR\u202f=\u202f1.35, p\u202f=\u202f3.58\u202f\u00d7\u202f10<sup>-7</sup>) with Bonferroni-corrected significance and another known region near PTPN22 (HR\u202f=\u202f1.46, p\u202f=\u202f2.17\u202f\u00d7\u202f10<sup>-6</sup>) and one novel region near PPIL2 (HR\u202f=\u202f2.47, p\u202f=\u202f9.64\u202f\u00d7\u202f10<sup>-7</sup>) with suggestive evidence (p\u202f<\u202f10<sup>-5</sup>). Two known regions (PTPN22: p\u202f=\u202f2.25\u202f\u00d7\u202f10<sup>-6</sup>, INS; p\u202f=\u202f1.32\u202f\u00d7\u202f10<sup>-7</sup>) and one novel region (PXK/PDHB: p\u202f=\u202f8.99\u202f\u00d7\u202f10<sup>-6</sup>) were associated with the risk for multiple islet autoantibodies. First appearing islet autoantibodies differ with respect to association. Two regions (INS: p\u202f=\u202f5.67\u202f\u00d7\u202f10<sup>-6</sup> and TTC34/PRDM16: 6.45\u202f\u00d7\u202f10<sup>-6</sup>) were associated if the fist appearing autoantibody was IAA and one region (RBFOX1: p\u202f=\u202f8.02\u202f\u00d7\u202f10<sup>-6</sup>) was associated if the first appearing autoantibody was GADA. The analysis of T1D identified one region already known to be associated with T1D (INS: p\u202f=\u202f3.13\u202f\u00d7\u202f10<sup>-7</sup>) and three novel regions (RNASET2, PLEKHA1, and PPIL2; 5.42\u202f\u00d7\u202f10<sup>-6</sup>\u202f>\u202fp\u202f>\u202f2.31\u202f\u00d7\u202f10<sup>-6</sup>). These results suggest that a number of low frequency variants influence the risk of developing IA and/or T1D and these variants can be identified by large prospective cohort studies using a survival analysis approach.", - "journal_title": "Journal of autoimmunity", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/29310926/" - } - ], - "3deff236-a94d-4e57-a6aa-bd432057bc8e": [ - { - "pub_id": "25997986", - "title": "iGWAS: Integrative Genome-Wide Association Studies of Genetic and Genomic Data for Disease Susceptibility Using Mediation Analysis.", - "authors": "Yen-Tsung Huang,Liming Liang,Miriam F Moffatt,William O C M Cookson,Xihong Lin", - "abstract": "Genome-wide association studies (GWAS) have been a standard practice in identifying single nucleotide polymorphisms (SNPs) for disease susceptibility. We propose a new approach, termed integrative GWAS (iGWAS) that exploits the information of gene expressions to investigate the mechanisms of the association of SNPs with a disease phenotype, and to incorporate the family-based design for genetic association studies. Specifically, the relations among SNPs, gene expression, and disease are modeled within the mediation analysis framework, which allows us to disentangle the genetic effect on a disease phenotype into two parts: an effect mediated through a gene expression (mediation effect, ME) and an effect through other biological mechanisms or environment-mediated mechanisms (alternative effect, AE). We develop omnibus tests for the ME and AE that are robust to underlying true disease models. Numerical studies show that the iGWAS approach is able to facilitate discovering genetic association mechanisms, and outperforms the SNP-only method for testing genetic associations. We conduct a family-based iGWAS of childhood asthma that integrates genetic and genomic data. The iGWAS approach identifies six novel susceptibility genes (MANEA, MRPL53, LYCAT, ST8SIA4, NDFIP1, and PTCH1) using the omnibus test with false discovery rate less than 1%, whereas no gene using SNP-only analyses survives with the same cut-off. The iGWAS analyses further characterize that genetic effects of these genes are mostly mediated through their gene expressions. In summary, the iGWAS approach provides a new analytic framework to investigate the mechanism of genetic etiology, and identifies novel susceptibility genes of childhood asthma that were biologically meaningful.", - "journal_title": "Genetic epidemiology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/25997986/" - } - ], - "e2d1d559-d48f-4e57-8372-04d31f0f9da3": [ - { - "pub_id": "26847670", - "title": "Gene targeting, genome editing: from Dolly to editors.", - "authors": "Wenfang Tan,Chris Proudfoot,Simon G Lillico,C Bruce A Whitelaw", - "abstract": "One of the most powerful strategies to investigate biology we have as scientists, is the ability to transfer genetic material in a controlled and deliberate manner between organisms. When applied to livestock, applications worthy of commercial venture can be devised. Although initial methods used to generate transgenic livestock resulted in random transgene insertion, the development of SCNT technology enabled homologous recombination gene targeting strategies to be used in livestock. Much has been accomplished using this approach. However, now we have the ability to change a specific base in the genome without leaving any other DNA mark, with no need for a transgene. With the advent of the genome editors this is now possible and like other significant technological leaps, the result is an even greater diversity of possible applications. Indeed, in merely 5\u00a0years, these 'molecular scissors' have enabled the production of more than 300 differently edited pigs, cattle, sheep and goats. The advent of genome editors has brought genetic engineering of livestock to a position where industry, the public and politicians are all eager to see real use of genetically engineered livestock to address societal needs. Since the first transgenic livestock reported just over three decades ago the field of livestock biotechnology has come a long way-but the most exciting period is just starting.", - "journal_title": "Transgenic research", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/26847670/" - } - ], - "44dfea31-ea1d-4a0a-bd33-eaa71160d089": [ - { - "pub_id": "33782414", - "title": "Gallstone disease, diabetes, calcium, triglycerides, smoking and alcohol consumption and pancreatitis risk: Mendelian randomization study.", - "authors": "Shuai Yuan,Edward L Giovannucci,Susanna C Larsson", - "abstract": "We conducted a Mendelian randomization study to determine the potential causal associations of gallstone disease, diabetes, serum calcium, triglyceride levels, smoking and alcohol consumption with acute and chronic pancreatitis. Genetic variants associated with the exposures at p\u2009<\u20095\u2009\u00d7\u200910<sup>-8</sup> were selected from corresponding genome-wide association studies. Summary-level data for pancreatitis were obtained from the FinnGen consortium and UK Biobank. Univariable and multivariable Mendelian randomization analyses were performed and results from FinnGen and UK Biobank were combined using the fixed-effects meta-analysis method. Genetic predisposition to gallstone disease, type 2 diabetes and smoking initiation was associated with an increased risk of acute pancreatitis. The combined odds ratios (ORs) were 1.74 (95% confidence interval (CI), 1.57, 1.93) for gallstone disease, 1.14 (95% CI, 1.06, 1.21) for type 2 diabetes and 1.56 (95% CI, 1.32, 1.83) for smoking initiation. The association for type 2 diabetes attenuated after adjustment for gallstone disease. Genetic predisposition to gallstone disease and smoking initiation as well as higher genetically predicted serum calcium and triglyceride levels were associated with an increased risk of chronic pancreatitis. The combined ORs of chronic pancreatitis were 1.27 (95% CI, 1.08, 1.50) for gallstone disease, 1.86 (95% CI, 1.43, 2.43) for smoking initiation, 2.20 (95% CI, 1.30, 3.72) for calcium and 1.47 (95% CI, 1.23, 1.76) for triglycerides. This study provides evidence in support that gallstone disease, type 2 diabetes, smoking and elevated calcium and triglyceride levels are causally associated with the risk of acute or chronic pancreatitis.", - "journal_title": "NPJ genomic medicine", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/33782414/" - } - ], - "c99adc1d-e48a-4175-b172-6db423609120": [ - { - "pub_id": "31822297", - "title": "Human genetics and genomics research in Ecuador: historical survey, current state, and future directions.", - "authors": "Marlon S Zambrano-Mila,Spiros N Agathos,Juergen K V Reichardt", - "abstract": "In South America, the history of human genetics is extensive and its beginnings go back to the onset of the twentieth century. In Ecuador, the historical record of human genetics and genomics research is limited. In this context, our work analyzes the current status and historical panorama of these fields, based on bibliographic searches in Scopus, Google Scholar, PubMed, and Web of Science. Our results determined that the oldest paper in human genetics coauthored by an Ecuadorian institution originates from the Central University of Ecuador in 1978. From a historical standpoint, the number of articles has increased since the 1990s. This growth has intensified and it is reflected in 137 manuscripts recorded from 2010 to 2019. Areas such as human population genetics, phylogeography, and forensic sciences are the core of genetics and genomics-associated research in Ecuador. Important advances have been made in the understanding of the bases of cancer, some genetic diseases, and congenital disorders. Fields such as pharmacogenetics and pharmacogenomics have begun to be explored during the last years. This work paints a comprehensive picture and provides additional insights into the future panorama of human genetic and genomic research in Ecuador as an example of an emerging, resource-limited country with interesting phylogeographic characteristics and public health implications.", - "journal_title": "Human genomics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/31822297/" - } - ], - "528babba-e50e-4d60-8f81-cb89f2ec7695": [ - { - "pub_id": "31070016", - "title": "Whole exome sequencing reveals novel LEPR frameshift mutation in severely obese children from Western India.", - "authors": "Arpan Bhatt,Charul Purani,Poonam Bhargava,Komal Patel,Tanvi Agarbattiwala,Apurvasinh Puvar,Krati Shah,Chaitanya G Joshi,Nidhi Dhamecha,Mukund Prabhakar,Madhvi Joshi", - "abstract": "Obesity, especially early onset of obesity is a serious health concern in both developed and developing countries. This is further associated with serious comorbidities like a fatty liver disease, cardiovascular diseases, type-2 diabetes, obstructive sleep apnea, renal complications and respiratory problems. Many times early onset of obesity is linked with heritable monogenic, polygenic and syndromic forms. Globally, studies on roles of genes involved in early onset of obesity are limited. Here in this study, a consanguineous family of Western Indian origin having four siblings, one unaffected and three affected with severe early onset of obesity was enrolled. Affected siblings also displayed comorbidities like mild to moderate obstructive sleep apnea, raised Renal Resistance Index, oliguria, and severe anemia. Whole Exome Sequencing (WES) of Trio with one affected and unaffected sibling was done. Data analysis was performed to check pathogenic mutation segregation in unaffected parents with affected and unaffected sibling. WES of trio identified novel frameshift mutation in the LEPR gene resulting in truncated leptin receptor (LEPR). The same mutation was confirmed in other affected siblings and two siblings of distant relatives by Sanger sequencing. The possible effects of truncating mutation in LEPR function by in silico analysis were also studied. Understanding genetic basis of obesity might provide\u00a0a clue for better management and treatment in times to come. This work demonstrates identification of novel mutation in LEPR gene resulting into early onset of obesity. Discovery of novel, population-specific genomics markers will help population screening programs in\u00a0creating base for possible therapeutic applications and prevention of this disease for next generations.", - "journal_title": "Molecular genetics & genomic medicine", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/31070016/" - } - ], - "065a4ead-3f3a-44a9-9dc2-41e579da1dae": [ - { - "pub_id": "27477082", - "title": "Genome-wide DNA methylation pattern in visceral adipose tissue differentiates insulin-resistant from insulin-sensitive obese subjects.", - "authors": "A B Crujeiras,A Diaz-Lagares,J M Moreno-Navarrete,J Sandoval,D Hervas,A Gomez,W Ricart,F F Casanueva,M Esteller,J M Fernandez-Real", - "abstract": "Elucidating the potential mechanisms involved in the detrimental effect of excess body weight on insulin action is an important priority in counteracting obesity-associated diseases. The present study aimed to disentangle the epigenetic basis of insulin resistance by performing a genome-wide epigenetic analysis in visceral adipose tissue (VAT) from morbidly obese patients depending on the insulin sensitivity evaluated by the clamp technique. The global human methylome screening performed in VAT from 7 insulin-resistant (IR) and 5 insulin-sensitive (IS) morbidly obese patients (discovery cohort) analyzed using the Infinium HumanMethylation450 BeadChip array identified 982 CpG sites able to perfectly separate the IR and IS samples. The identified sites represented 538 unique genes, 10% of which were diabetes-associated genes. The current work identified novel IR-related genes epigenetically regulated in VAT, such as COL9A1, COL11A2, CD44, MUC4, ADAM2, IGF2BP1, GATA4, TET1, ZNF714, ADCY9, TBX5, and HDACM. The gene with the largest methylation fold-change and mapped by 5 differentially methylated CpG sites located in island/shore and promoter region was ZNF714. This gene presented lower methylation levels in IR than in IS patients in association with increased transcription levels, as further reflected in a validation cohort (n\u00a0=\u00a024; 11 IR and 13 IS). This study reveals, for the first time, a potential epigenetic regulation involved in the dysregulation of VAT that could predispose patients to insulin resistance and future type 2 diabetes in morbid obesity, providing a potential therapeutic target and biomarkers for counteracting this process.", - "journal_title": "Translational research : the journal of laboratory and clinical medicine", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/27477082/" - } - ], - "2622ae0b-4cbf-468b-bb0f-afb4768968a6": [ - { - "pub_id": "31482010", - "title": "Genome-wide association study for proliferative diabetic retinopathy in Africans.", - "authors": "Chang Liu,Guanjie Chen,Amy R Bentley,Ayo Doumatey,Jie Zhou,Adebowale Adeyemo,Jinkui Yang,Charles Rotimi", - "abstract": "Proliferative diabetic retinopathy (PDR) is a sight-threatening complication of diabetes that is associated with longer duration of diabetes and poor glycemic control under a genetic susceptibility background. Although GWAS of PDR have been conducted in Europeans and Asians, none has been done in continental Africans, a population at increased risk for PDR. Here, we report a GWAS of PDR among Africans. PDR cases (<i>n</i>\u2009=\u200964) were T2D patients with neovascularization in the retina and/or retinal detachment. Controls (<i>n</i>\u2009=\u2009227) were T2D patients without listed eye complications despite high risk (T2D duration \u226510 years and fasting blood glucose >169\u2009mg/dl). Replication was assessed in African Americans enrolled in the ARIC study. We identified 4 significant loci: WDR72, HLA-B, GAP43/RP11-326J18.1, and AL713866.1. At WDR72 the most strongly associated SNPs were rs12906891 (MAF\u2009=\u20090.071; <i>p</i>\u2009=\u20099.68\u2009\u00d7\u200910-10; OR\u2009=\u20091.46, 95% CI [1.30,1.64]) and rs11070992 (MAF\u2009=\u20090.14; <i>p</i>\u2009=\u20094.23\u2009\u00d7\u200910<sup>-8</sup>; OR\u2009=\u20091.28, 95%CI [1.17-1.40]). rs11070992 replicated in African Americans (<i>p</i>\u2009=\u20090.04). Variants in this gene have been associated with diabetic retinopathy, glycemic control, revascularization, and kidney disease.", - "journal_title": "NPJ genomic medicine", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/31482010/" - } - ], - "fcc3cb07-5245-479e-a820-9ffba82a05e8": [ - { - "pub_id": "32113774", - "title": "Genetic and genomic analysis of long insemination interval in Israeli dairy cattle as an indicator of early abortions.", - "authors": "Moran Gershoni,Ephraim Ezra,Joel Ira Weller", - "abstract": "One of the causes of observed low fertility is embryo loss after fertilization. Previous findings suggested that more than half of fertilizations result in embryo loss before pregnancy is detected. We proposed reinsemination between 49 and 100 d after the first insemination as an indicator trait for early abortion (EA) in dairy cattle based on the mean estrus interval of 21 d. This trait was compared with conception rate from first insemination and conception status, computed as the inverse of the number of inseminations to conception. Animal model variance components were estimated by REML, including parents and grandparents of cows with records. First-parity heritability for first insemination conception rate was 3%. In the multitrait analysis of parities 1 to 3 for putative EA, heritabilities ranged from 8.9% for first parity to 10.4% for second parity. All genetic correlations were >0.9, whereas all environmental correlations were <0.12. The variance component for the service sire effect for putative EA rate was less than half the variance component for conception rate. Thus, genetic control of the 2 traits is clearly different, and analysis of EA rate by a single-trait animal model is justified. Genetic evaluation for putative EA was computed using this model, including all first- through third-parity cows with freshening dates from January 1, 1985, through December 31, 2016, that either became pregnant on first insemination or were reinseminated between 49 and 100 d after the first insemination. All known parents and grandparents of cows with records were included in the analysis. The regression of the breeding value for non-abortion rate on the cows' birth year was 0.083%/yr. The genetic correlation between first-parity EA and conception status was 0.995. The genetic correlations between first-parity EA and milk, fat, and protein production were all negative, whereas the genetic correlation between EA and herd life was 0.33. Inclusion of putative EA in the selection index instead of conception status resulted in 10 to 20% greater genetic gain for both fertility traits. In a genome-wide association study based on 1,200 dairy bulls with reliabilities >50% for abortion rate genotyped for 41,000 markers, 6 markers were found with nominal probabilities of <10<sup>-12</sup> to reject the null hypothesis of no effect on EA rate. The markers with the lowest probabilities for EA rate were also included among the markers with the lowest probabilities for female fertility, but not vice versa. The marker explaining the most variance for abortion rate is located within the ABCA9 gene, which is found within an ATP-binding cassette (ABC) genes cluster. The ABC family is the major class of primary active transporters in the placenta.", - "journal_title": "Journal of dairy science", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/32113774/" - } - ], - "ac00c552-7514-49d4-9e90-ab01c22472ae": [ - { - "pub_id": "30040732", - "title": "Neuro-Immuno-Gene- and Genome-Editing-Therapy for Alzheimer's Disease: Are We There Yet?", - "authors": "Sudhanshu P Raikwar,Ramasamy Thangavel,Iuliia Dubova,Mohammad Ejaz Ahmed,Pushpavathi Govindhasamy Selvakumar,Duraisamy Kempuraj,Smita Zaheer,Shankar Iyer,Asgar Zaheer", - "abstract": "Alzheimer's disease (AD) is a highly complex neurodegenerative disorder and the current treatment strategies are largely ineffective thereby leading to irreversible and progressive cognitive decline in AD patients. AD continues to defy successful treatment despite significant advancements in the field of molecular medicine. Repeatedly, early promising preclinical and clinical results have catapulted into devastating setbacks leading to multi-billion dollar losses not only to the top pharmaceutical companies but also to the AD patients and their families. Thus, it is very timely to review the progress in the emerging fields of gene therapy and stem cell-based precision medicine. Here, we have made sincere efforts to feature the ongoing progress especially in the field of AD gene therapy and stem cell-based regenerative medicine. Further, we also provide highlights in elucidating the molecular mechanisms underlying AD pathogenesis and describe novel AD therapeutic targets and strategies for the new drug discovery. We hope that the quantum leap in the scientific advancements and improved funding will bolster novel concepts that will propel the momentum toward a trajectory leading to a robust AD patient-specific next generation precision medicine with improved cognitive function and excellent life quality.", - "journal_title": "Journal of Alzheimer's disease : JAD", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/30040732/" - } - ], - "49320a63-b003-4018-b8c8-702f7966a43a": [ - { - "pub_id": "26066540", - "title": "Parents' experiences 12 years after newborn screening for genetic susceptibility to type 1 diabetes and their attitudes to whole-genome sequencing in newborns.", - "authors": "Nicola Kerruish", - "abstract": "The potential for utilizing whole-genome sequencing in newborn screening (NBS) has been recognized, but the ethical, legal, and social issues of this may require further analysis. This article begins to address the gap in the literature concerning psychosocial effects of \"genomic NBS,\" focusing on later effects of screening for genetic susceptibility to a single, complex disorder: type 1 diabetes (T1D). It also examines parental attitudes toward potential future expansions of NBS. Fifteen semistructured interviews were conducted with parents of children who had been tested for genetic susceptibility to T1D 12 years previously. Parents in this study were not psychologically burdened by knowledge of their child's genetic risk but perceived little benefit. Most of these parents disclosed the result to their child at age 12 years without obvious adverse impact. Parents were unenthusiastic about potential future expansions of NBS to include similar genomic tests. Absence of adverse psychosocial effects and ease of disclosure to the child represent initial positive findings, but they require replication and further evaluation in relation to uptake of prevention strategies. Attitudes of parents to \"genomic NBS\" are variable, suggesting that parental choice will be an important component of future screening programs.", - "journal_title": "Genetics in medicine : official journal of the American College of Medical Genetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/26066540/" - } - ], - "f52802b0-52ca-4c3c-8953-67bc70cd40c6": [ - { - "pub_id": "30735659", - "title": "Optimal Integration of Behavioral Medicine into Clinical Genetics and Genomics.", - "authors": "William M P Klein,Colleen M McBride,Caitlin G Allen,Elva M Arredondo,Cinnamon S Bloss,Kimberly A Kaphingst,Amy C Sturm,Catharine Wang", - "abstract": "Clinical genetics and genomics will exert their greatest population impact by leveraging the rich knowledge of human behavior that is central to the discipline of behavioral medicine. We contend that more concerted efforts are needed to integrate these fields synergistically, and accordingly, we consider barriers and potential actions to hasten such integration.", - "journal_title": "American journal of human genetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/30735659/" - } - ], - "bdf04fc4-cd77-4b20-a322-e524449a3108": [ - { - "pub_id": "34111113", - "title": "A genome-wide association study identifies 5 loci associated with frozen shoulder and implicates diabetes as a causal risk factor.", - "authors": "Harry D Green,Alistair Jones,Jonathan P Evans,Andrew R Wood,Robin N Beaumont,Jessica Tyrrell,Timothy M Frayling,Christopher Smith,Michael N Weedon", - "abstract": "Frozen shoulder is a painful condition that often requires surgery and affects up to 5% of individuals aged 40-60 years. Little is known about the causes of the condition, but diabetes is a strong risk factor. To begin to understand the biological mechanisms involved, we aimed to identify genetic variants associated with frozen shoulder and to use Mendelian randomization to test the causal role of diabetes. We performed a genome-wide association study (GWAS) of frozen shoulder in the UK Biobank using data from 10,104 cases identified from inpatient, surgical and primary care codes. We used data from FinnGen for replication and meta-analysis. We used one-sample and two-sample Mendelian randomization approaches to test for a causal association of diabetes with frozen shoulder. We identified five genome-wide significant loci. The most significant locus (lead SNP rs28971325; OR = 1.20, [95% CI: 1.16-1.24], p = 5x10-29) contained WNT7B. This variant was also associated with Dupuytren's disease (OR = 2.31 [2.24, 2.39], p<1x10-300) as were a further two of the frozen shoulder associated variants. The Mendelian randomization results provided evidence that type 1 diabetes is a causal risk factor for frozen shoulder (OR = 1.03 [1.02-1.05], p = 3x10-6). There was no evidence that obesity was causally associated with frozen shoulder, suggesting that diabetes influences risk of the condition through glycemic rather than mechanical effects. We have identified genetic loci associated with frozen shoulder. There is a large overlap with Dupuytren's disease associated loci. Diabetes is a likely causal risk factor. Our results provide evidence of biological mechanisms involved in this common painful condition.", - "journal_title": "PLoS genetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/34111113/" - } - ], - "af0ef613-cf39-45d3-a637-be6b2e9531b7": [ - { - "pub_id": "32477452", - "title": "Shared (epi)genomic background connecting neurodegenerative diseases and type 2 diabetes.", - "authors": "Valerio Caputo,Andrea Termine,Claudia Strafella,Emiliano Giardina,Raffaella Cascella", - "abstract": "The progressive aging of populations has resulted in an increased prevalence of chronic pathologies, especially of metabolic, neurodegenerative and movement disorders. In particular, type 2 diabetes (T2D), Alzheimer's disease (AD) and Parkinson's disease (PD) are among the most prevalent age-related, multifactorial pathologies that deserve particular attention, given their dramatic impact on patient quality of life, their economic and social burden as well the etiopathogenetic mechanisms, which may overlap in some cases. Indeed, the existence of common triggering factors reflects the contribution of mutual genetic, epigenetic and environmental features in the etiopathogenetic mechanisms underlying T2D and AD/PD. On this subject, this review will summarize the shared (epi)genomic features that characterize these complex pathologies. In particular, genetic variants and gene expression profiles associated with T2D and AD/PD will be discussed as possible contributors to determine the susceptibility and progression to these disorders. Moreover, potential shared epigenetic modifications and factors among T2D, AD and PD will also be illustrated. Overall, this review shows that findings from genomic studies still deserves further research to evaluate and identify genetic factors that directly contribute to the shared etiopathogenesis. Moreover, a common epigenetic background still needs to be investigated and characterized. The evidences discussed in this review underline the importance of integrating large-scale (epi)genomic data with additional molecular information and clinical and social background in order to finely dissect the complex etiopathogenic networks that build up the \"disease interactome\" characterizing T2D, AD and PD.", - "journal_title": "World journal of diabetes", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/32477452/" - } - ], - "77ffc55f-68a8-4c02-96a5-428b81bf6436": [ - { - "pub_id": "31086298", - "title": "Long-range enhancer-promoter contacts in gene expression control.", - "authors": "Stefan Schoenfelder,Peter Fraser", - "abstract": "Spatiotemporal gene expression programmes are orchestrated by transcriptional enhancers, which are key regulatory DNA elements that engage in physical contacts with their target-gene promoters, often bridging considerable genomic distances. Recent progress in genomics, genome editing and microscopy methodologies have enabled the genome-wide mapping of enhancer-promoter contacts and their functional dissection. In this Review, we discuss novel concepts on how enhancer-promoter interactions are established and maintained, how the 3D architecture of mammalian genomes both facilitates and constrains enhancer-promoter contacts, and the role they play in gene expression control during normal development and disease.", - "journal_title": "Nature reviews. Genetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/31086298/" - } - ], - "851e8543-425e-4217-834d-fcadaed4b3ec": [ - { - "pub_id": "34014961", - "title": "Genome-wide association study of vitamin D concentrations and bone mineral density in the African American-Diabetes Heart Study.", - "authors": "Nicholette D Palmer,Lingyi Lu,Thomas C Register,Leon Lenchik,J Jeffrey Carr,Pamela J Hicks,S Carrie Smith,Jianzhao Xu,Latchezar Dimitrov,Jacob Keaton,Meijian Guan,Maggie C Y Ng,Yii-der I Chen,Anthony J Hanley,Corinne D Engelman,Jill M Norris,Carl D Langefeld,Lynne E Wagenknecht,Donald W Bowden,Barry I Freedman,Jasmin Divers", - "abstract": "Relative to European Americans, African Americans have lower 25-hydroxyvitamin D (25OHD) and vitamin D binding protein (VDBP) concentrations, higher 1,25-dihydroxyvitamin D (1,25(OH)2D3) concentrations and bone mineral density (BMD), and paradoxically reduced burdens of calcified atherosclerotic plaque (subclinical atherosclerosis). To identify genetic factors contributing to vitamin D and BMD measures, association analysis of >14M variants was conducted in a maximum of 697 African American-Diabetes Heart Study participants with type 2 diabetes (T2D). The most significant association signals were detected for VDBP on chromosome 4; variants rs7041 (\u03b2 = 0.44, SE = 0.019, P = 9.4x10-86) and rs4588 (\u03b2 = 0.17, SE = 0.021, P = 3.5x10-08) in the group-specific component (vitamin D binding protein) gene (GC). These variants were found to be independently associated. In addition, rs7041 was also associated with bioavailable vitamin D (BAVD; \u03b2 = 0.16, SE = 0.02, P = 3.3x10-19). Six rare variants were significantly associated with 25OHD, including a non-synonymous variant in HSPG2 (rs116788687; \u03b2 = -1.07, SE = 0.17, P = 2.2x10-10) and an intronic variant in TNIK (rs143555701; \u03b2 = -1.01, SE = 0.18, P = 9.0x10-10), both biologically related to bone development. Variants associated with 25OHD failed to replicate in African Americans from the Insulin Resistance Atherosclerosis Family Study (IRASFS). Evaluation of vitamin D metabolism and bone mineral density phenotypes in an African American population enriched for T2D could provide insight into ethnic specific differences in vitamin D metabolism and bone mineral density.", - "journal_title": "PloS one", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/34014961/" - } - ], - "a41dae15-ad6c-4fb2-b146-a0f68b29ade3": [ - { - "pub_id": "32666640", - "title": "Identification of histone malonylation in the human fetal brain and implications for diabetes-induced neural tube defects.", - "authors": "Qin Zhang,Tanxi Cai,Zonghui Xiao,Dan Li,Chunlei Wan,Xiaodai Cui,Baoling Bai", - "abstract": "Neural tube defects (NTDs) are severe congenital malformations. Diabetes during pregnancy is a risk factor for NTDs, but its mechanism remains elusive. Emerging evidence suggests that protein malonylation is involved in diabetes. Here, we report the correlation between histone lysine malonylation in diabetes-induced NTDs. Nano-HPLC/MS/MS was used to screen the histone malonylation profile in human embryonic brain tissue. Then, the histone malonylation level was compared between the brains of normal control mice and mice with diabetes-induced NTDs. Finally, the histone malonylation level was compared under high glucose exposure in an E9 neuroepithelial cell line (NE4C). A total of 30 histone malonylation sites were identified in human embryonic brain tissue, including 18 novel sites. Furthermore, we found an increased histone malonylation level in brain tissues from mice with diabetes-induced NTDs. Finally, both the histone malonylation modified sites and the modified levels were proved to be increased in the NE4C treated with high glucose. Our results present a comprehensive map of histone malonylation in the human fetal brain. Furthermore, we provide experimental evidence supporting a relationship between histone malonylation and NTDs caused by high glucose-induced diabetes. These findings offer new insights into the pathological role of histone modifications in human NTDs.", - "journal_title": "Molecular genetics & genomic medicine", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/32666640/" - } - ], - "03110c8a-1232-40c2-8380-c9feb8b6468c": [ - { - "pub_id": "31993089", - "title": "The fine-scale genetic structure and selection signals of Chinese indigenous pigs.", - "authors": "Min Huang,Bin Yang,Hao Chen,Hui Zhang,Zhongping Wu,Huashui Ai,Jun Ren,Lusheng Huang", - "abstract": "Genome-wide SNP profiling has yielded insights into the genetic structure of China indigenous pigs, but has focused on a limited number of populations. Here, we present an analysis of population structure and signals of positive selection in 42 Chinese pig populations that represent the most extensive pig phenotypic diversity in China, using genotype data of 1.1 million SNPs on customized Beadchips. This unravels the fine-scale genetic diversity, phylogenic relationships, and population structure of these populations, which shows remarkably concordance between genetic clusters and geography with few exceptions. We also reveal the genetic contribution to North Chinese pigs from European modern pigs. Furthermore, we identify possible targets of selection in the Tibetan pig, including the well-characterized hypoxia gene (<i>EPAS1</i>) and several previously unrecognized candidates. Intriguingly, the selected haplotype in the <i>EPAS1</i> gene is associated with higher hemoglobin contents in Tibetan pigs, which is different from the protective role of <i>EPAS1</i> in the high-altitude adaptation in Tibetan dogs and their owners. Additionally, we present evidence for the causality between <i>EDNRB</i> variants and the two-end-black (TEB) coat color phenotype in all Chinese pig populations except the Jinhua pig. We hypothesize that distinct targets have been independently selected for the formation of the TEB phenotype in Chinese pigs of different geographic origins. This highlights the importance of characterizing population-specific genetic determinants for heritable phenotype in diverse pig populations.", - "journal_title": "Evolutionary applications", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/31993089/" - } - ], - "fa98be3a-0739-4dd1-90c6-2f47a133c0b1": [ - { - "pub_id": "28271161", - "title": "DNA methylation profiling reveals the presence of population-specific signatures correlating with phenotypic characteristics.", - "authors": "Anil K Giri,Soham Bharadwaj,Priyanka Banerjee,Shraddha Chakraborty,Vaisak Parekatt,Donaka Rajashekar,Abhishek Tomar,Aarthi Ravindran,Analabha Basu,Nikhil Tandon,Dwaipayan Bharadwaj", - "abstract": "Phenotypic characteristics are known to vary substantially among different ethnicities around the globe. These variations are mediated by number of stochastic events and cannot be attributed to genetic architecture alone. DNA methylation is a well-established mechanism that sculpts our epigenome influencing phenotypic variation including disease manifestation. Since DNA methylation is an important determinant for health issues of a population, it demands a thorough investigation of the natural differences in genome wide DNA methylation patterns across different ethnic groups. This study is based on comparative analyses of methylome from five different ethnicities with major focus on Indian subjects. The current study uses hierarchical clustering approaches, principal component analysis and locus specific differential methylation analysis on Illumina 450K methylation data to compare methylome of different ethnic subjects. Our data indicates that the variations in DNA methylation patterns of Indians are less among themselves compared to other global population. It empirically correlated with dietary, cultural and demographical divergences across different ethnic groups. Our work further suggests that Indians included in this study, despite their genetic similarity with the Caucasian population, are in close proximity with Japanese in terms of their methylation signatures.", - "journal_title": "Molecular genetics and genomics : MGG", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/28271161/" - } - ], - "7fe48b75-62e5-4459-913a-776bf6ccd764": [ - { - "pub_id": "29412141", - "title": "Integration of human pancreatic islet genomic data refines regulatory mechanisms at Type 2 Diabetes susceptibility loci.", - "authors": "Matthias Thurner,Martijn van de Bunt,Jason M Torres,Anubha Mahajan,Vibe Nylander,Amanda J Bennett,Kyle J Gaulton,Amy Barrett,Carla Burrows,Christopher G Bell,Robert Lowe,Stephan Beck,Vardhman K Rakyan,Anna L Gloyn,Mark I McCarthy", - "abstract": "Human genetic studies have emphasised the dominant contribution of pancreatic islet dysfunction to development of Type 2 Diabetes (T2D). However, limited annotation of the islet epigenome has constrained efforts to define the molecular mechanisms mediating the, largely regulatory, signals revealed by Genome-Wide Association Studies (GWAS). We characterised patterns of chromatin accessibility (ATAC-seq, n = 17) and DNA methylation (whole-genome bisulphite sequencing, n = 10) in human islets, generating high-resolution chromatin state maps through integration with established ChIP-seq marks. We found enrichment of GWAS signals for T2D and fasting glucose was concentrated in subsets of islet enhancers characterised by open chromatin and hypomethylation, with the former annotation predominant. At several loci (including <i>CDC123, ADCY5, KLHDC5</i>) the combination of fine-mapping genetic data and chromatin state enrichment maps, supplemented by allelic imbalance in chromatin accessibility pinpointed likely causal variants. The combination of increasingly-precise genetic and islet epigenomic information accelerates definition of causal mechanisms implicated in T2D pathogenesis.", - "journal_title": "eLife", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/29412141/" - } - ], - "f7072d9b-4e07-4541-bac7-13a25761f460": [ - { - "pub_id": "27693023", - "title": "A Single-Cell Transcriptome Atlas of the Human Pancreas.", - "authors": "Mauro J Muraro,Gitanjali Dharmadhikari,Dominic Gr\u00fcn,Nathalie Groen,Tim Dielen,Erik Jansen,Leon van Gurp,Marten A Engelse,Francoise Carlotti,Eelco J P de Koning,Alexander van Oudenaarden", - "abstract": "To understand organ function, it is important to have an inventory of its cell types and of their corresponding marker genes. This is a particularly challenging task for human tissues like the pancreas, because reliable markers are limited. Hence, transcriptome-wide studies are typically done on pooled islets of Langerhans, obscuring contributions from rare cell types and of potential subpopulations. To overcome this challenge, we developed an automated platform that uses FACS, robotics, and the CEL-Seq2 protocol to obtain the transcriptomes of thousands of single pancreatic cells from deceased organ donors, allowing in\u00a0silico purification of all main pancreatic cell types. We identify cell type-specific transcription factors and a subpopulation of REG3A-positive acinar cells. We also show that CD24 and TM4SF4 expression can be used to sort live alpha and beta cells with high purity. This resource will be useful for developing a deeper understanding of pancreatic biology and pathophysiology of diabetes mellitus.", - "journal_title": "Cell systems", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/27693023/" - } - ], - "697698d3-6959-48c5-9cb5-cac8dff223a8": [ - { - "pub_id": "34498060", - "title": "A systematic review of the validated monogenic causes of human male infertility: 2020 update and a discussion of emerging gene-disease relationships.", - "authors": "Brendan J Houston,Antoni Riera-Escamilla,Margot J Wyrwoll,Albert Salas-Huetos,Miguel J Xavier,Liina Nagirnaja,Corinna Friedrich,Don F Conrad,Kenneth I Aston,Csilla Krausz,Frank T\u00fcttelmann,Moira K O'Bryan,Joris A Veltman,Manon S Oud", - "abstract": "Human male infertility has a notable genetic component, including well-established diagnoses such as Klinefelter syndrome, Y-chromosome microdeletions and monogenic causes. Approximately 4% of all infertile men are now diagnosed with a genetic cause, but a majority (60-70%) remain without a clear diagnosis and are classified as unexplained. This is likely in large part due to a delay in the field adopting next-generation sequencing (NGS) technologies, and the absence of clear statements from field leaders as to what constitutes a validated cause of human male infertility (the current paper aims to address this). Fortunately, there has been a significant increase in the number of male infertility NGS studies. These have revealed a considerable number of novel gene-disease relationships (GDRs), which each require stringent assessment to validate the strength of genotype-phenotype associations. To definitively assess which of these GDRs are clinically relevant, the International Male Infertility Genomics Consortium (IMIGC) has identified the need for a systematic review and a comprehensive overview of known male infertility genes and an assessment of the evidence for reported GDRs. In 2019, the first standardised clinical validity assessment of monogenic causes of male infertility was published. Here, we provide a comprehensive update of the subsequent 1.5\u2009years, employing the joint expertise of the IMIGC to systematically evaluate all available evidence (as of 1 July 2020) for monogenic causes of isolated or syndromic male infertility, endocrine disorders or reproductive system abnormalities affecting the male sex organs. In addition, we systematically assessed the evidence for all previously reported possible monogenic causes of male infertility, using a framework designed for a more appropriate clinical interpretation of disease genes. We performed a literature search according to the PRISMA guidelines up until 1 July 2020 for publications in English, using search terms related to 'male infertility' in combination with the word 'genetics' in PubMed. Next, the quality and the extent of all evidence supporting selected genes were assessed using an established and standardised scoring method. We assessed the experimental quality, patient phenotype assessment and functional evidence based on gene expression, mutant in-vitro cell and in-vivo animal model phenotypes. A final score was used to determine the clinical validity of each GDR, across the following five categories: no evidence, limited, moderate, strong or definitive. Variants were also reclassified according to the American College of Medical Genetics and Genomics-Association for Molecular Pathology (ACMG-AMP) guidelines and were recorded in spreadsheets for each GDR, which are available at imigc.org. The primary outcome of this review was an overview of all known GDRs for monogenic causes of human male infertility and their clinical validity. We identified a total of 120 genes that were moderately, strongly or definitively linked to 104 infertility phenotypes. Our systematic review curates all currently available evidence to reveal the strength of GDRs in male infertility. The existing guidelines for genetic testing in male infertility cases are based on studies published 25\u2009years ago, and an update is far overdue. The identification of 104 high-probability 'human male infertility genes' is a 33% increase from the number identified in 2019. The insights generated in the current review will provide the impetus for an update of existing guidelines, will inform novel evidence-based genetic testing strategies used in clinics, and will identify gaps in our knowledge of male infertility genetics. We discuss the relevant international guidelines regarding research related to gene discovery and provide specific recommendations to the field of male infertility. Based on our findings, the IMIGC consortium recommend several updates to the genetic testing standards currently employed in the field of human male infertility, most important being the adoption of exome sequencing, or at least sequencing of the genes validated in this study, and expanding the patient groups for which genetic testing is recommended.", - "journal_title": "Human reproduction update", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/34498060/" - } - ], - "0b9235ba-bee0-4265-999b-b364b66066a8": [ - { - "pub_id": "29596946", - "title": "Genome-wide DNA methylation profiling in infants born to gestational diabetes mellitus.", - "authors": "Xiaoling Weng,Fatao Liu,Hong Zhang,Mengyuan Kan,Ting Wang,Minyue Dong,Yun Liu", - "abstract": "Offspring exposed to gestational diabetes mellitus (GDM) are at a high risk for metabolic diseases. The mechanisms behind the association between offspring exposed to GDM in utero and an increased risk of health consequences later in life remain unclear. The aim of this study was to clarify the changes in methylation levels in the foetuses of women with GDM and to explore the possible mechanisms linking maternal GDM with a high risk of metabolic diseases in offspring later in life. A genome-wide comparative methylome analysis on the umbilical cord blood of infants born to 30 women with GDM and 33 women with normal pregnancy was performed using Infinium HumanMethylation 450 BeadChip assays. A quantitative methylation analysis of 18 CpG dinucleotides was verified in the validation umbilical cord blood samples from 102 newborns exposed to GDM and 103 newborns who experienced normal pregnancy by MassARRAY EpiTYPER. A total of 4485 differentially methylated sites (DMSs), including 2150 hypermethylated sites and 2335 hypomethylated sites, with a mean \u03b2-value difference of >0.05, were identified by the 450k array. Good agreement was observed between the massarray validation data and the 450k array data (R<sup>2</sup>\u202f>\u202f0.99; P\u202f<\u202f0.0001). Thirty-seven CpGs (representing 20 genes) with a \u03b2-value difference of >\u202f0.15 between the GDM and healthy groups were identified and showed potential as clinical biomarkers for GDM. \"hsa04940: Type I diabetes mellitus\" was the most significant Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway, with a P-value\u202f=\u202f3.20E-07 and 1.36E-02 in the hypermethylated and hypomethylated genepathway enrichment analyses, respectively. In the Gene Ontology (GO) pathway analyses, immune MHC (major histocompatibility complex)-related pathways and neuron development-related pathways were significantly enriched. Our results suggest that GDM has epigenetic effects on genes that are preferentially involved in the Type I diabetes mellitus pathway, immune MHC-related pathways and neuron development-related pathways, with consequences on fetal growth and development, and provide supportive evidence that DNA methylation is involved in fetal metabolic programming.", - "journal_title": "Diabetes research and clinical practice", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/29596946/" - } - ], - "0ffd1f4d-683e-4e44-a6b2-8d2d9849c45d": [ - { - "pub_id": "26998692", - "title": "Genetic predisposition for beta cell fragility underlies type 1 and type 2 diabetes.", - "authors": "James Dooley,Lei Tian,Susann Schonefeldt,Viviane Delghingaro-Augusto,Josselyn E Garcia-Perez,Emanuela Pasciuto,Daniele Di Marino,Edward J Carr,Nikolay Oskolkov,Valeriya Lyssenko,Dean Franckaert,Vasiliki Lagou,Lut Overbergh,Jonathan Vandenbussche,Joke Allemeersch,Genevieve Chabot-Roy,Jane E Dahlstrom,D Ross Laybutt,Nikolai Petrovsky,Luis Socha,Kris Gevaert,Anton M Jetten,Diether Lambrechts,Michelle A Linterman,Chris C Goodnow,Christopher J Nolan,Sylvie Lesage,Susan M Schlenner,Adrian Liston", - "abstract": "Type 1 (T1D) and type 2 (T2D) diabetes share pathophysiological characteristics, yet mechanistic links have remained elusive. T1D results from autoimmune destruction of pancreatic beta cells, whereas beta cell failure in T2D is delayed and progressive. Here we find a new genetic component of diabetes susceptibility in T1D non-obese diabetic (NOD) mice, identifying immune-independent beta cell fragility. Genetic variation in Xrcc4 and Glis3 alters the response of NOD beta cells to unfolded protein stress, enhancing the apoptotic and senescent fates. The same transcriptional relationships were observed in human islets, demonstrating the role of beta cell fragility in genetic predisposition to diabetes.", - "journal_title": "Nature genetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/26998692/" - } - ], - "940283a4-b7e7-4bbe-ba34-c80c4717c15a": [ - { - "pub_id": "27155607", - "title": "Putting the Genome in Context: Gene-Environment Interactions in Type 2 Diabetes.", - "authors": "Paul W Franks,Guillaume Par\u00e9", - "abstract": "The genome is often the conduit through which environmental exposures convey their effects on health and disease. Whilst not all diseases act by directly perturbing the genome, the phenotypic responses are often genetically determined. Hence, whilst diseases are often defined has having differing degrees of genetic determination, genetic and environmental factors are, with few exceptions, inseparable features of most diseases, not least type 2 diabetes. It follows that to optimize diabetes, prevention and treatment will require that the etiological roles of genetic and environmental risk factors be jointly considered. As we discuss here, studies focused on quantifying gene-environment and gene-treatment interactions are gathering momentum and may eventually yield data that helps guide health-related choices and medical interventions for type 2 diabetes and other complex diseases.", - "journal_title": "Current diabetes reports", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/27155607/" - } - ], - "33f1abde-a821-483b-b8b4-785f499db09d": [ - { - "pub_id": "32784714", - "title": "Carrot Anthocyanins Genetics and Genomics: Status and Perspectives to Improve Its Application for the Food Colorant Industry.", - "authors": "Massimo Iorizzo,Julien Curaba,Marti Pottorff,Mario G Ferruzzi,Philipp Simon,Pablo F Cavagnaro", - "abstract": "Purple or black carrots (<i>Daucus carota</i> ssp. <i>sativus</i> var. <i>atrorubens</i> Alef) are characterized by their dark purple- to black-colored roots, owing their appearance to high anthocyanin concentrations. In recent years, there has been increasing interest in the use of black carrot anthocyanins as natural food dyes. Black carrot roots contain large quantities of mono-acylated anthocyanins, which impart a measure of heat-, light- and pH-stability, enhancing the color-stability of food products over their shelf-life. The genetic pathway controlling anthocyanin biosynthesis appears well conserved among land plants; however, different variants of anthocyanin-related genes between cultivars results in tissue-specific accumulations of purple pigments. Thus, broad genetic variations of anthocyanin profile, and tissue-specific distributions in carrot tissues and organs, can be observed, and the ratio of acylated to non-acylated anthocyanins varies significantly in the purple carrot germplasm. Additionally, anthocyanins synthesis can also be influenced by a wide range of external factors, such as abiotic stressors and/or chemical elicitors, directly affecting the anthocyanin yield and stability potential in food and beverage applications. In this study, we critically review and discuss the current knowledge on anthocyanin diversity, genetics and the molecular mechanisms controlling anthocyanin accumulation in carrots. We also provide a view of the current knowledge gaps and advancement needs as regards developing and applying innovative molecular tools to improve the yield, product performance and stability of carrot anthocyanin for use as a natural food colorant.", - "journal_title": "Genes", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/32784714/" - } - ], - "9b93b4eb-98c2-403f-aea2-6b24399501b8": [ - { - "pub_id": "30884193", - "title": "IRS1- rs10498210 G/A and CCR5-59029 A/G polymorphisms in patients with type 2 diabetes in Kurdistan.", - "authors": "Fatemeh Keshavarzi,Shadi Golsheh", - "abstract": "The insulin receptor substrate 1 (IRS1) is a critical factor in the signaling pathway for insulin, and mutations in this gene have been reported, which contribute to the ability to develop type 2 diabetes. The polymorphisms in the promoter region of C-C motif chemokine receptor5 (CCR5) are also being studied as candidates for susceptibility to develop type 2 diabetes. The aim of the current study was to determine the relationship between IRS1 and CCR5 polymorphisms with type 2 diabetes in the Kurdistan population. Genomic DNA was isolated from the blood by salt extraction method and the polymorphisms were examined using Restriction Fragment Length Polymorphism (RFLP) method. The results of current study indicated that the frequency of AA genotype in type 2 diabetic patients in both CCR5 (OR\u00a0=\u00a02.9, p\u00a0=\u00a00.04) and IRS1 (OR\u00a0=\u00a03.3, p\u00a0=\u00a00.036) were significantly more than controls. According to the results of this study, the presence of AA genotype in both CCR5 and IRS1 is associated with type 2 diabetes. There was no significant association between AG or GG genotypes with type 2 diabetes.", - "journal_title": "Molecular genetics & genomic medicine", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/30884193/" - } - ], - "459eafe2-cf00-4dad-8690-06bdd509afda": [ - { - "pub_id": "26704534", - "title": "Genome-wide association study of 25(OH) Vitamin D concentrations in Punjabi Sikhs: Results of the Asian Indian diabetic heart study.", - "authors": "Bishwa R Sapkota,Ruth Hopkins,Andrew Bjonnes,Sarju Ralhan,Gurpreet S Wander,Narinder K Mehra,Jai Rup Singh,Piers R Blackett,Richa Saxena,Dharambir K Sanghera", - "abstract": "Vitamin D deficiency is implicated in multiple disease conditions and accumulating evidence supports that the variation in serum vitamin D (25(OH)D) levels, including deficiency, is under strong genetic control. However, the underlying genetic mechanism associated with vitamin 25(OH)D concentrations is poorly understood. We earlier reported a very high prevalence of vitamin D deficiency associated with an increased risk for type 2 diabetes and obesity in a Punjabi Sikh diabetic cohort as part of the Asian Indian diabetic heart study (AIDHS). Here we have performed the first genome-wide association study (GWAS) of serum 25(OH)D on 3538 individuals from this Punjabi Sikh population. Our discovery GWAS comprised of 1387 subjects followed by validation of 24 putative SNPs (P<10(-4)) using an independent replication sample (n=2151) from the same population by direct genotyping. A novel locus at chromosome 20p11.21 represented by rs2207173 with minor allele frequency (MAF) 0.29, [\u03b2=-0.13, p=4.47\u00d710(-9)] between FOXA2 and SSTR4 was identified to be associated with 25(OH)D levels. Another suggestive association signal at rs11586313 (MAF 0.54) [\u03b2=0.90; p=1.36\u00d710(-6)] was found within the regulatory region of the IVL gene on chromosome 1q21.3. Additionally, our study replicated 3 of 5 known GWAS genes associated with 25(OH)D concentrations including GC (p=0.007) and CYP2R1 (p=0.019) reported in Europeans and the DAB1 (p=0.003), reported in Hispanics. Identification of novel association signals in biologically plausible regions with 25(OH)D metabolism will provide new molecular insights on genetic drivers of vitamin D status and its implications in health disparities.", - "journal_title": "The Journal of steroid biochemistry and molecular biology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/26704534/" - } - ], - "0b48022e-039a-4bf9-8a94-667c0ce77f3d": [ - { - "pub_id": "29029897", - "title": "Worldwide trends in body-mass index, underweight, overweight, and obesity from 1975 to 2016: a pooled analysis of 2416 population-based measurement studies in 128\u00b79 million children, adolescents, and adults.", - "authors": " ", - "abstract": "Underweight, overweight, and obesity in childhood and adolescence are associated with adverse health consequences throughout the life-course. Our aim was to estimate worldwide trends in mean body-mass index (BMI) and a comprehensive set of BMI categories that cover underweight to obesity in children and adolescents, and to compare trends with those of adults. We pooled 2416 population-based studies with measurements of height and weight on 128\u00b79 million participants aged 5 years and older, including 31\u00b75 million aged 5-19 years. We used a Bayesian hierarchical model to estimate trends from 1975 to 2016 in 200 countries for mean BMI and for prevalence of BMI in the following categories for children and adolescents aged 5-19 years: more than 2 SD below the median of the WHO growth reference for children and adolescents (referred to as moderate and severe underweight hereafter), 2 SD to more than 1 SD below the median (mild underweight), 1 SD below the median to 1 SD above the median (healthy weight), more than 1 SD to 2 SD above the median (overweight but not obese), and more than 2 SD above the median (obesity). Regional change in age-standardised mean BMI in girls from 1975 to 2016 ranged from virtually no change (-0\u00b701 kg/m<sup>2</sup> per decade; 95% credible interval -0\u00b742 to 0\u00b739, posterior probability [PP] of the observed decrease being a true decrease=0\u00b75098) in eastern Europe to an increase of 1\u00b700 kg/m<sup>2</sup> per decade (0\u00b769-1\u00b735, PP>0\u00b79999) in central Latin America and an increase of 0\u00b795 kg/m<sup>2</sup> per decade (0\u00b764-1\u00b725, PP>0\u00b79999) in Polynesia and Micronesia. The range for boys was from a non-significant increase of 0\u00b709 kg/m<sup>2</sup> per decade (-0\u00b733 to 0\u00b749, PP=0\u00b76926) in eastern Europe to an increase of 0\u00b777 kg/m<sup>2</sup> per decade (0\u00b750-1\u00b706, PP>0\u00b79999) in Polynesia and Micronesia. Trends in mean BMI have recently flattened in northwestern Europe and the high-income English-speaking and Asia-Pacific regions for both sexes, southwestern Europe for boys, and central and Andean Latin America for girls. By contrast, the rise in BMI has accelerated in east and south Asia for both sexes, and southeast Asia for boys. Global age-standardised prevalence of obesity increased from 0\u00b77% (0\u00b74-1\u00b72) in 1975 to 5\u00b76% (4\u00b78-6\u00b75) in 2016 in girls, and from 0\u00b79% (0\u00b75-1\u00b73) in 1975 to 7\u00b78% (6\u00b77-9\u00b71) in 2016 in boys; the prevalence of moderate and severe underweight decreased from 9\u00b72% (6\u00b70-12\u00b79) in 1975 to 8\u00b74% (6\u00b78-10\u00b71) in 2016 in girls and from 14\u00b78% (10\u00b74-19\u00b75) in 1975 to 12\u00b74% (10\u00b73-14\u00b75) in 2016 in boys. Prevalence of moderate and severe underweight was highest in India, at 22\u00b77% (16\u00b77-29\u00b76) among girls and 30\u00b77% (23\u00b75-38\u00b70) among boys. Prevalence of obesity was more than 30% in girls in Nauru, the Cook Islands, and Palau; and boys in the Cook Islands, Nauru, Palau, Niue, and American Samoa in 2016. Prevalence of obesity was about 20% or more in several countries in Polynesia and Micronesia, the Middle East and north Africa, the Caribbean, and the USA. In 2016, 75 (44-117) million girls and 117 (70-178) million boys worldwide were moderately or severely underweight. In the same year, 50 (24-89) million girls and 74 (39-125) million boys worldwide were obese. The rising trends in children's and adolescents' BMI have plateaued in many high-income countries, albeit at high levels, but have accelerated in parts of Asia, with trends no longer correlated with those of adults. Wellcome Trust, AstraZeneca Young Health Programme.", - "journal_title": "Lancet (London, England)", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/29029897/" - } - ], - "41a62819-a8b1-46c2-a191-20added5d81f": [ - { - "pub_id": "32133724", - "title": "Artificial intelligence in oncology.", - "authors": "Hideyuki Shimizu,Keiichi I Nakayama", - "abstract": "Artificial intelligence (AI) has contributed substantially to the resolution of a variety of biomedical problems, including cancer, over the past decade. Deep learning, a subfield of AI that is highly flexible and supports automatic feature extraction, is increasingly being applied in various areas of both basic and clinical cancer research. In this review, we describe numerous recent examples of the application of AI in oncology, including cases in which deep learning has efficiently solved problems that were previously thought to be unsolvable, and we address obstacles that must be overcome before such application can become more widespread. We also highlight resources and datasets that can help harness the power of AI for cancer research. The development of innovative approaches to and applications of AI will yield important insights in oncology in the coming decade.", - "journal_title": "Cancer science", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/32133724/" - } - ], - "6b6fd53a-8eee-4e52-9f02-9ae9da511e94": [ - { - "pub_id": "32383361", - "title": "Shortened consent forms for genome-wide sequencing: Parent and provider perspectives.", - "authors": "Emma C Hitchcock,Causes Study,Alison M Elliott", - "abstract": "Consent forms for exome and/or genome sequencing, collectively called genome-wide sequencing (GWS), frequently contain detailed information on complex topics such as sequencing analysis and incidental findings. Considering recent endeavors by the health care community to simplify GWS consent forms, it is important to gain stakeholders' perspectives on the content, length, and use of consent forms. Thematic analysis was conducted on data obtained from focus groups with two participant cohorts: parents who previously provided consent for trio-based GWS as part of the translational pediatric GWS CAUSES Study, and genetic health care providers (HCP) who provide pre-test counseling for GWS. Genetic HCP indicated that consent forms cannot replace pre-test counseling, and as such, a simplified consent form focusing on the implications of GWS would be beneficial to both patients and HCP. Although parents' primary concerns varied when considering GWS, they all highly valued information. Parents also indicated the need for community and support after the return of GWS results. Both participant cohorts recommended that consent forms be available online and include an appendix for supplementary information. It is important to include both parents and HCP in the design of GWS consent forms, and also, to help connect families who have a shared diagnosis after the post-test counseling session.", - "journal_title": "Molecular genetics & genomic medicine", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/32383361/" - } - ], - "5acc4c05-84a5-4bca-9d45-d8a0dfae7ac9": [ - { - "pub_id": "31368668", - "title": "Circulating miR-130 and its target PPAR-\u03b3 may be potential biomarkers in patients of coronary artery disease with type 2 diabetes mellitus.", - "authors": "Yonggang Yuan,Wanzhong Peng,Yongxing Liu,Zesheng Xu", - "abstract": "Patients of coronary artery disease (CAD) with type 2 diabetes mellitus (DM2) show increased mortality risk than CAD patients without DM2, while few biomarkers can be used to discriminate them. Fifty-nine patients of CAD with DM2 (DM2-CAD group), 79 patients of CAD without DM2 (CAD group), and 63 healthy control subjects were recruited. Circulating miR-130 (miR-130a and miR-130b) and PPAR-\u03b3 (peroxisome proliferator-activated receptor gamma) were measured and their Pearson correlation was analyzed. 3' UTR binding prediction and luciferase assay were used to determine the target relationship between miR-130 and PPAR-\u03b3. Receiver operating characteristics (ROC) analysis was performed to test the discrimination ability of miR-130 between DM2-CAD and CAD groups. miR-130a and miR-130b showed decreased expression in DM2-CAD group when compared with the CAD group and health control. Both bioinformatics and luciferase assays showed that miR-130 could bind the 3' UTR of PPAR-\u03b3. Furthermore, miR-130 negatively correlated with PPAR-\u03b3 in both CAD and DM2-CAD group in Pearson's coefficient analysis. Both miR-130a and miR-130b were able to discriminate DM2-CAD group from CAD group and control subjects. Circulating miR-130 may regulate the expression of PPAR-\u03b3 and can be used as a biomarker to discriminate DM2-CAD from CAD.", - "journal_title": "Molecular genetics & genomic medicine", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/31368668/" - } - ], - "b3fa4d11-72b9-4e6f-9c28-39efdaded492": [ - { - "pub_id": "30837372", - "title": "Overview of genomics and post-genomics research on type 2 diabetes mellitus: Future perspectives and a framework for further studies.", - "authors": "Battini Mohan Reddy,Rayabarapu Pranavchand,S A A Latheef", - "abstract": "In this review, we briefly outlined salient features of pathophysiology and results of the genetic association studies hitherto conducted on type 2 diabetes. Primarily focusing on the current status of genomic research, we briefly discussed the limited progress made during the post-genomic era and tried to identify the limitations of the post-genomic research strategies. We suggested reanalysis of the existing genomic data through advanced statistical and computational methods and recommended integrated genomics-metabolomics approaches for future studies to facilitate understanding of the gene-environment interactions in the manifestation of the disease. We also propose a framework for research that may be apt for determining the effects of urbanization and changing lifestyles in the manifestation of complex genetic disorders like type 2 diabetes in the Indian populations and offset the confounding effects of both genetic and environmental factors in the natural way.", - "journal_title": "Journal of biosciences", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/30837372/" - } - ], - "1ecd1047-39d1-44ea-b3a2-3d8472be3435": [ - { - "pub_id": "27245310", - "title": "Speech and language therapy for aphasia following stroke.", - "authors": "Marian C Brady,Helen Kelly,Jon Godwin,Pam Enderby,Pauline Campbell", - "abstract": "Aphasia is an acquired language impairment following brain damage that affects some or all language modalities: expression and understanding of speech, reading, and writing. Approximately one third of people who have a stroke experience aphasia. To assess the effects of speech and language therapy (SLT) for aphasia following stroke. We searched the Cochrane Stroke Group Trials Register (last searched 9 September 2015), CENTRAL (2015, Issue 5) and other Cochrane Library Databases (CDSR, DARE, HTA, to 22 September 2015), MEDLINE (1946 to September 2015), EMBASE (1980 to September 2015), CINAHL (1982 to September 2015), AMED (1985 to September 2015), LLBA (1973 to September 2015), and SpeechBITE (2008 to September 2015). We also searched major trials registers for ongoing trials including ClinicalTrials.gov (to 21 September 2015), the Stroke Trials Registry (to 21 September 2015), Current Controlled Trials (to 22 September 2015), and WHO ICTRP (to 22 September 2015). In an effort to identify further published, unpublished, and ongoing trials we also handsearched the International Journal of Language and Communication Disorders (1969 to 2005) and reference lists of relevant articles, and we contacted academic institutions and other researchers. There were no language restrictions. Randomised controlled trials (RCTs) comparing SLT (a formal intervention that aims to improve language and communication abilities, activity and participation) versus no SLT; social support or stimulation (an intervention that provides social support and communication stimulation but does not include targeted therapeutic interventions); or another SLT intervention (differing in duration, intensity, frequency, intervention methodology or theoretical approach). We independently extracted the data and assessed the quality of included trials. We sought missing data from investigators. We included 57 RCTs (74 randomised comparisons) involving 3002 participants in this review (some appearing in more than one comparison). Twenty-seven randomised comparisons (1620 participants) assessed SLT versus no SLT; SLT resulted in clinically and statistically significant benefits to patients' functional communication (standardised mean difference (SMD) 0.28, 95% confidence interval (CI) 0.06 to 0.49, P = 0.01), reading, writing, and expressive language, but (based on smaller numbers) benefits were not evident at follow-up. Nine randomised comparisons (447 participants) assessed SLT with social support and stimulation; meta-analyses found no evidence of a difference in functional communication, but more participants withdrew from social support interventions than SLT. Thirty-eight randomised comparisons (1242 participants) assessed two approaches to SLT. Functional communication was significantly better in people with aphasia that received therapy at a high intensity, high dose, or over a long duration compared to those that received therapy at a lower intensity, lower dose, or over a shorter period of time. The benefits of a high intensity or a high dose of SLT were confounded by a significantly higher dropout rate in these intervention groups. Generally, trials randomised small numbers of participants across a range of characteristics (age, time since stroke, and severity profiles), interventions, and outcomes. Our review provides evidence of the effectiveness of SLT for people with aphasia following stroke in terms of improved functional communication, reading, writing, and expressive language compared with no therapy. There is some indication that therapy at high intensity, high dose or over a longer period may be beneficial. HIgh-intensity and high dose interventions may not be acceptable to all.", - "journal_title": "The Cochrane database of systematic reviews", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/27245310/" - } - ], - "bd834094-7504-4fc5-bc9d-78e6a9e719f0": [ - { - "pub_id": "30938100", - "title": "Association of PTPN22 polymorphism and its correlation with Graves' disease susceptibility in Polish adult population-A preliminary study.", - "authors": "Natalia Wawrusiewicz-Kurylonek,Olga Martyna Koper-Lenkiewicz,Joanna Go\u015bcik,Janusz My\u015bliwiec,Przemys\u0142aw Paw\u0142owski,Adam Jacek Kr\u0119towski", - "abstract": "Susceptibility to Graves' disease (GD) is determined by various genetic factors; the gene encoding protein tyrosine phosphatase (PTPN22) may be one of those associated with higher risk of GD. The aim was to estimate the association of the PTPN22 gene polymorphism rs2476601:c.C>T (c.1858C>T) with the predisposition to GD within the adult north-eastern Polish population. PTPN22 gene polymorphism was analyzed in individuals with clinical GD history (n\u00a0=\u00a0166) and healthy subjects (n\u00a0=\u00a0154). The presence of different variants of the investigated gene polymorphism was estimated using the DNA Sanger sequencing method. Patients with GD had a more frequent occurrence of the T gene allele of PTPN22 gene compared to the control group, however, it was not significant (p\u00a0=\u00a00.257). Analysis of genotype distribution showed significantly more frequent occurrence of TT homozygote in GD patients compared to control individuals (p\u00a0=\u00a00.016, OR\u00a0=\u00a09.28). Patients with ophthalmopathy had a less frequent occurrence of the T gene allele of PTPN22 gene compared to patients without ophthalmopathy, however, it was not significant (p\u00a0=\u00a00.12). Occurrence of the T gene allele of PTPN22 gene in GD manifestation in those under 40-year old was more frequent compared to individuals over 40, but the obtained difference was also not significant (p\u00a0=\u00a00.75). Our preliminary study suggest that PTPN22:c.1858C>T gene polymorphism may be associated with a predisposition to GD within the adult north-eastern Polish population. The studied polymorphism of the PTPN22 gene did not significantly affect the risk of ophthalmopathy developing and disease manifestation before the age of 40.", - "journal_title": "Molecular genetics & genomic medicine", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/30938100/" - } - ], - "953e74d0-0fbd-461c-bec1-66c9da2eb900": [ - { - "pub_id": "27125457", - "title": "In\u00a0vitro CRISPR-Cas9-mediated efficient Ad5 vector modification.", - "authors": "Lichun Tang,Mengmeng Gong,Pumin Zhang", - "abstract": "The CRISPR-Cas9 genome editing system has been widely used in multiple cells and organisms. Here we developed a CRISPR-Cas9 based in\u00a0vitro large DNA vector editing system, using the Ad5-based vector as an example. We demonstrate use of this system to generate targeted mutations, in-frame gene deletion, and gene replacement. This in\u00a0vitro CRISPR editing system exhibits high efficiency and accuracy. We believe this system can be applied in a variety of experimental settings.", - "journal_title": "Biochemical and biophysical research communications", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/27125457/" - } - ], - "db8194b1-837f-42da-b7e9-3272e25c3560": [ - { - "pub_id": "28420700", - "title": "Diabetes, Associated Clinical Spectrum, Long-term Prognosis, and Genotype/Phenotype Correlations in 201 Adult Patients With Hepatocyte Nuclear Factor 1B (<i>HNF1B</i>) Molecular Defects.", - "authors": "Dani\u00e8le Dubois-Laforgue,Erika Cornu,C\u00e9cile Saint-Martin,Jo\u00ebl Coste,Christine Bellann\u00e9-Chantelot,Jos\u00e9 Timsit, ", - "abstract": "Molecular defects of hepatocyte nuclear factor 1B (<i>HNF1B</i>) are associated with a multiorgan disease, including diabetes (maturity-onset diabetes of the young 5) and kidney abnormalities. The HNF1B syndrome is related to <i>HNF1B</i> mutations or to a 17q12 deletion spanning 15 genes, including <i>HNF1B</i>. Here, we described HNF1B-related diabetes and associated phenotypes and assessed genotype/phenotype correlations at diagnosis and in the long-term. This multicenter retrospective cohort study included 201 patients, aged 18 years or older at follow-up, with <i>HNF1B</i> mutations (<i>n</i> = 101) or deletion (<i>n</i> = 100). Diabetes was present in 159 patients. At diagnosis, clinical symptoms of diabetes were present in 67 of 144 patients and HNF1B renal disease in 64 of 102. Although responsiveness to sulfonylureas/repaglinide was observed in 29 of the 51 tested, 111 of 140 patients (79%) were treated with insulin at follow-up. Diabetic retinopathy and/or neuropathy were present in 46 of 114 patients. Renal cysts were present in 122 of 166 patients, chronic kidney disease stages 3-4 (CKD3-4) in 75 of 169 (44%), and end-stage renal disease (ESRD) in 36 of 169 (21%). Compared with the patients with mutations, those with <i>HNF1B</i> deletion less often had CKD3-4/ESRD at diagnosis (11 of 43 vs. 27 of 35, <i>P</i> < 10<sup>-4</sup>) and in the long term (40 of 78 vs. 71 of 91, <i>P</i> = 0.0003). They were leaner and more frequently treated with insulin. In patients with HNF1B syndrome, diabetes complications, cardiovascular risk factors, CKD3-4, and ESRD are highly prevalent. At diabetes diagnosis, the presence of morphological and/or functional kidney disease may help etiological diagnosis. Genotype/phenotype correlations may have implications for the care and the prognosis of these patients.", - "journal_title": "Diabetes care", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/28420700/" - } - ], - "230022b2-931e-42ab-b100-5e9776483d1a": [ - { - "pub_id": "31958216", - "title": "Identification of novel differentially expressed genes in retinas of STZ-induced long-term diabetic rats through RNA sequencing.", - "authors": "Xindan Xing,Yan Jiang,Hanying Wang,Yuan Zhang,Tian Niu,Yuan Qu,Chingyi Wang,Haiyan Wang,Kun Liu", - "abstract": "The aim of this research was to investigate the retinal transcriptome changes in long-term streptozotocin (STZ)-induced rats' retinas using RNA sequencing (RNA-seq), to explore the molecular mechanisms of diabetic retinopathy (DR), and to identify novel targets for the treatment of DR by comparing the gene expression profile we obtained. In this study, 6 healthy male SD rats were randomly divided into wild-type (WT) group and streptozotocin (STZ)-induced group, 3 rats each group. After 6\u00a0months, 3 normal retina samples and 3 DM retina samples (2 retinas from the same rat were considered as 1 sample) were tested and differentially expressed genes (DEGs) were measured by RNA-seq technology. Then, we did Gene Ontology (GO) enrichment analysis and KEGG (Kyoto Encyclopedia of Genes and Genomes) pathway analysis and validated the results of RNA-seq through qRT-PCR. A total of 118 DEGs were identified, of which 72 were up-regulated and 46 were down-regulated. The enriched GO terms showed that 3 most significant enrichment terms were binding (molecular function), cell part (cellular component), and biological regulation (biological process). The results of the KEGG pathway analysis revealed a significant enrichment in cell adhesion molecules, PI3K-Akt signaling pathway, and allograft rejection, etc. CONCLUSION: Our research has identified specific DEGs and also speculated their potential functions, which will provide novel targets to explore the molecular mechanisms of DR.", - "journal_title": "Molecular genetics & genomic medicine", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/31958216/" - } - ], - "d9b4a93b-2fb8-46e6-bccf-18dbc4ec8024": [ - { - "pub_id": "34874954", - "title": "A genome-wide association study identifies novel candidate genes for susceptibility to diabetes mellitus in non-obese cats.", - "authors": "Yaiza Forcada,Mike Boursnell,Brian Catchpole,David B Church", - "abstract": "Diabetes mellitus (DM) is a common feline endocrinopathy, which is similar to human type 2 diabetes (T2DM) in terms of its pathophysiology. T2DM occurs due to peripheral insulin resistance and/or \u03b2-cell dysfunction. Several studies have identified genetic and environmental factors that contribute to susceptibility to human T2DM. In cats, environmental factors such as obesity and physical inactivity have been linked with DM, although to date, the only genetic association that has been demonstrated is with a polymorphism in the feline MC4R gene. The aim of this study was to perform a genome-wide association study (GWAS) to identify polymorphisms associated with feline DM. Illumina Infinium 63k iSelect DNA arrays were used to analyse genomic DNA samples from 200 diabetic domestic shorthair cats and 399 non-diabetic control cats. Data was analysed using PLINK whole genome data analysis toolset. A linear model analysis, EMMAX, was done to test for population structure and HAPLOVIEW was used to identify haplotype blocks surrounding the significant SNPs to assist with candidate gene nomination. A total of 47,497 SNPs were available for analysis. Four SNPs were identified with genome-wide significance: chrA2.4150731 (praw = 9.94 x10-8); chrUn17.115508 (praw = 6.51 x10-8); chrUn17.394136 (praw = 2.53 x10-8); chrUn17.314128 (praw = 2.53 x10-8) as being associated with DM. The first SNP is located within chromosome A2, less than 4kb upstream of the dipeptidyl-peptidase-9 (DPP9) gene, a peptidase involved in incretin inactivation. The remaining three SNPs are located within a haplotype block towards the end of chromosome A3; within this region, genes of interest include TMEM18 and ACP1, both previously associated with T2DM. This study indicates a polygenic component to susceptibility to DM in cats and has highlighted several loci and candidate genes worthy of further investigation.", - "journal_title": "PloS one", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/34874954/" - } - ], - "85c3da22-2afa-4a31-814d-b293f9caf6f9": [ - { - "pub_id": "33608049", - "title": "Development of genome-wide polygenic risk scores for lipid traits and clinical applications for dyslipidemia, subclinical atherosclerosis, and diabetes cardiovascular complications among East Asians.", - "authors": "Claudia H T Tam,Cadmon K P Lim,Andrea O Y Luk,Alex C W Ng,Heung-Man Lee,Guozhi Jiang,Eric S H Lau,Baoqi Fan,Raymond Wan,Alice P S Kong,Wing-Hung Tam,Risa Ozaki,Elaine Y K Chow,Ka-Fai Lee,Shing-Chung Siu,Grace Hui,Chiu-Chi Tsang,Kam-Piu Lau,Jenny Y Y Leung,Man-Wo Tsang,Grace Kam,Ip-Tim Lau,June K Y Li,Vincent T F Yeung,Emmy Lau,Stanley Lo,Samuel Fung,Yuk-Lun Cheng,Chun-Chung Chow,Miao Hu,Weichuan Yu,Stephen K W Tsui,Yu Huang,Huiyao Lan,Cheuk-Chun Szeto,Nelson L S Tang,Maggie C Y Ng,Wing-Yee So,Brian Tomlinson,Juliana C N Chan,Ronald C W Ma, , ", - "abstract": "The clinical utility of personal genomic information in identifying individuals at increased risks for dyslipidemia and cardiovascular diseases remains unclear. We used data from Biobank Japan (n\u2009=\u200970,657-128,305) and developed novel East Asian-specific genome-wide polygenic risk scores (PRSs) for four lipid traits. We validated (n\u2009=\u20094271) and subsequently tested associations of these scores with 3-year lipid changes in adolescents (n\u2009=\u2009620), carotid intima-media thickness (cIMT) in adult women (n\u2009=\u2009781), dyslipidemia (n\u2009=\u20097723), and coronary heart disease (CHD) (n\u2009=\u20092374 cases and 6246 controls) in type 2 diabetes (T2D) patients. Our PRSs aggregating 84-549 genetic variants (0.251\u2009<\u2009correlation coefficients (r)\u2009<\u20090.272) had comparably stronger association with lipid variations than the typical PRSs derived based on the genome-wide significant variants (0.089\u2009<\u2009r\u2009<\u20090.240). Our PRSs were robustly associated with their corresponding lipid levels (7.5\u2009\u00d7\u200910<sup>-\u2009103</sup>\u2009<\u2009P\u2009<\u20091.3\u2009\u00d7\u200910<sup>-\u200975</sup>) and 3-year lipid changes (1.4\u2009\u00d7\u200910<sup>-\u20096</sup>\u2009<\u2009P\u2009<\u20090.0130) which started to emerge in childhood and adolescence. With the adjustments for principal components (PCs), sex, age, and body mass index, there was an elevation of 5.3% in TC (\u03b2\u2009\u00b1\u2009SE\u2009=\u20090.052\u2009\u00b1\u20090.002), 11.7% in TG (\u03b2\u2009\u00b1\u2009SE\u2009=\u20090.111\u2009\u00b1\u20090.006), 5.8% in HDL-C (\u03b2\u2009\u00b1\u2009SE\u2009=\u20090.057\u2009\u00b1\u20090.003), and 8.4% in LDL-C (\u03b2\u2009\u00b1\u2009SE\u2009=\u20090.081\u2009\u00b1\u20090.004) per one standard deviation increase in the corresponding PRS. However, their predictive power was attenuated in T2D patients (0.183\u2009<\u2009r\u2009<\u20090.231). When we included each PRS (for TC, TG, and LDL-C) in addition to the clinical factors and PCs, the AUC for dyslipidemia was significantly increased by 0.032-0.057 in the general population (7.5\u2009\u00d7\u200910<sup>-\u20093</sup>\u2009<\u2009P\u2009<\u20090.0400) and 0.029-0.069 in T2D patients (2.1\u2009\u00d7\u200910<sup>-\u200910</sup>\u2009<\u2009P\u2009<\u20090.0428). Moreover, the quintile of TC-related PRS was moderately associated with cIMT in adult women (\u03b2\u2009\u00b1\u2009SE\u2009=\u20090.011\u2009\u00b1\u20090.005, P<sub>trend</sub>\u2009=\u20090.0182). Independent of conventional risk factors, the quintile of PRSs for TC [OR (95% CI)\u2009=\u20091.07 (1.03-1.11)], TG [OR (95% CI)\u2009=\u20091.05 (1.01-1.09)], and LDL-C [OR (95% CI)\u2009=\u20091.05 (1.01-1.09)] were significantly associated with increased risk of CHD in T2D patients (4.8\u2009\u00d7\u200910<sup>-\u20094</sup>\u2009<\u2009P\u2009<\u20090.0197). Further adjustment for baseline lipid drug use notably attenuated the CHD association. The PRSs derived and validated here highlight the potential for early genomic screening and personalized risk assessment for cardiovascular disease.", - "journal_title": "Genome medicine", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/33608049/" - } - ], - "e4a469d8-5c4f-48aa-9175-eba55767e8f4": [ - { - "pub_id": "30474315", - "title": "Gene coexpression network analysis identified potential biomarkers in gestational diabetes mellitus progression.", - "authors": "Xiaomin Zhao,Wen Li", - "abstract": "Gestational diabetes mellitus (GDM) is one of the most common problems during pregnancy. Lack of international consistent diagnostic procedures has limit improvement of current therapeutic effectiveness. Here, we aimed to screen potential gene biomarkers that might play vital roles in GDM progression for assistance of its diagnostic and treatment. Gene expression profiles in four GDM placentae at first trimester, four GDM placentae at second trimester, and four normal placentae were obtained from the publicly available Gene Expression Omnibus (GEO). Weighted gene coexpression network analysis (WGCNA) indicated two gene modules, that is, black and brown module, that was significantly positively and negatively correlated with GDM progression time points, respectively. Additionally, a significant positive correlation between module membership (MM) and degree in protein-protein interaction network of brown module genes was observed. KIF2C, CENPE, CCNA2, AURKB, MAD2L1, CCNB2, CDC20, PLK1, CCNB1, and CDK1 all have degree larger than 50 and MM larger than 0.9, so they might be valuable biomarkers in GDM. Gene set enrichment analysis inferred tight relations between carbohydrate metabolism or steroid biosynthesis-related processes and GDM progression. All in all, our study should provide several novel references for GDM diagnosis and therapeutic.", - "journal_title": "Molecular genetics & genomic medicine", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/30474315/" - } - ], - "2bef9608-4bd6-4252-9fbd-2413b2cad4f8": [ - { - "pub_id": "34732801", - "title": "Gene-level analysis of rare variants in 379,066 whole exome sequences identifies an association of GIGYF1 loss of function with type 2 diabetes.", - "authors": "Aimee M Deaton,Margaret M Parker,Lucas D Ward,Alexander O Flynn-Carroll,Lucas BonDurant,Gregory Hinkle,Parsa Akbari,Luca A Lotta, , ,Aris Baras,Paul Nioi", - "abstract": "Sequencing of large cohorts offers an unprecedented opportunity to identify rare genetic variants and to find novel contributors to human disease. We used gene-based collapsing tests to identify genes associated with glucose, HbA1c and type 2 diabetes (T2D) diagnosis in 379,066 exome-sequenced participants in the UK Biobank. We identified associations for variants in GCK, HNF1A and PDX1, which are known to be involved in Mendelian forms of diabetes. Notably, we uncovered novel associations for GIGYF1, a gene not previously implicated by human genetics in diabetes. GIGYF1 predicted loss of function (pLOF) variants associated with increased levels of glucose (0.77\u00a0mmol/L increase, p\u2009=\u20094.42\u2009\u00d7\u200910<sup>-12</sup>) and HbA1c (4.33\u00a0mmol/mol, p\u2009=\u20091.28\u2009\u00d7\u200910<sup>-14</sup>) as well as T2D diagnosis (OR\u2009=\u20094.15, p\u2009=\u20096.14\u2009\u00d7\u200910<sup>-11</sup>). Multiple rare variants contributed to these associations, including singleton variants. GIGYF1 pLOF also associated with decreased cholesterol levels as well as an increased risk of hypothyroidism. The association of GIGYF1 pLOF with T2D diagnosis replicated in an independent cohort from the Geisinger Health System. In addition, a common variant association for glucose and T2D was identified at the GIGYF1 locus. Our results highlight the role of GIGYF1 in regulating insulin signaling and protecting from diabetes.", - "journal_title": "Scientific reports", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/34732801/" - } - ], - "4a71cebc-a7ab-4fa3-9dc0-8982ee77ecec": [ - { - "pub_id": "29765977", - "title": "Systems Pharmacology-Based Approach of Connecting Disease Genes in Genome-Wide Association Studies with Traditional Chinese Medicine.", - "authors": "Jihye Kim,Minjae Yoo,Jimin Shin,Hyunmin Kim,Jaewoo Kang,Aik Choon Tan", - "abstract": "Traditional Chinese medicine (TCM) originated in ancient China has been practiced over thousands of years for treating various symptoms and diseases. However, the molecular mechanisms of TCM in treating these diseases remain unknown. In this study, we employ a systems pharmacology-based approach for connecting GWAS diseases with TCM for potential drug repurposing and repositioning. We studied 102 TCM components and their target genes by analyzing microarray gene expression experiments. We constructed disease-gene networks from 2558 GWAS studies. We applied a systems pharmacology approach to prioritize disease-target genes. Using this bioinformatics approach, we analyzed 14,713 GWAS disease-TCM-target gene pairs and identified 115 disease-gene pairs with <i>q</i> value\u2009<\u20090.2. We validated several of these GWAS disease-TCM-target gene pairs with literature evidence, demonstrating that this computational approach could reveal novel indications for TCM. We also develop TCM-Disease web application to facilitate the traditional Chinese medicine drug repurposing efforts. Systems pharmacology is a promising approach for connecting GWAS diseases with TCM for potential drug repurposing and repositioning. The computational approaches described in this study could be easily expandable to other disease-gene network analysis.", - "journal_title": "International journal of genomics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/29765977/" - } - ], - "6c0a5d18-6bb2-4483-8e5d-4285043fc51f": [ - { - "pub_id": "34002096", - "title": "Genome-wide association study of more than 40,000 bipolar disorder cases provides new insights into the underlying biology.", - "authors": "Niamh Mullins,Andreas J Forstner,Kevin S O'Connell,Brandon Coombes,Jonathan R I Coleman,Zhen Qiao,Thomas D Als,Tim B Bigdeli,Sigrid B\u00f8rte,Julien Bryois,Alexander W Charney,Ole Kristian Drange,Michael J Gandal,Saskia P Hagenaars,Masashi Ikeda,Nolan Kamitaki,Minsoo Kim,Kristi Krebs,Georgia Panagiotaropoulou,Brian M Schilder,Laura G Sloofman,Stacy Steinberg,Vassily Trubetskoy,Bendik S Winsvold,Hong-Hee Won,Liliya Abramova,Kristina Adorjan,Esben Agerbo,Mariam Al Eissa,Diego Albani,Ney Alliey-Rodriguez,Adebayo Anjorin,Verneri Antilla,Anastasia Antoniou,Swapnil Awasthi,Ji Hyun Baek,Marie B\u00e6kvad-Hansen,Nicholas Bass,Michael Bauer,Eva C Beins,Sarah E Bergen,Armin Birner,Carsten B\u00f8cker Pedersen,Erlend B\u00f8en,Marco P Boks,Rosa Bosch,Murielle Brum,Ben M Brumpton,Nathalie Brunkhorst-Kanaan,Monika Budde,Jonas Bybjerg-Grauholm,William Byerley,Murray Cairns,Miquel Casas,Pablo Cervantes,Toni-Kim Clarke,Cristiana Cruceanu,Alfredo Cuellar-Barboza,Julie Cunningham,David Curtis,Piotr M Czerski,Anders M Dale,Nina Dalkner,Friederike S David,Franziska Degenhardt,Srdjan Djurovic,Amanda L Dobbyn,Athanassios Douzenis,Torbj\u00f8rn Elvs\u00e5shagen,Valentina Escott-Price,I Nicol Ferrier,Alessia Fiorentino,Tatiana M Foroud,Liz Forty,Josef Frank,Oleksandr Frei,Nelson B Freimer,Louise Fris\u00e9n,Katrin Gade,Julie Garnham,Joel Gelernter,Marianne Gi\u00f8rtz Pedersen,Ian R Gizer,Scott D Gordon,Katherine Gordon-Smith,Tiffany A Greenwood,Jakob Grove,Jos\u00e9 Guzman-Parra,Kyooseob Ha,Magnus Haraldsson,Martin Hautzinger,Urs Heilbronner,Dennis Hellgren,Stefan Herms,Per Hoffmann,Peter A Holmans,Laura Huckins,St\u00e9phane Jamain,Jessica S Johnson,Janos L Kalman,Yoichiro Kamatani,James L Kennedy,Sarah Kittel-Schneider,James A Knowles,Manolis Kogevinas,Maria Koromina,Thorsten M Kranz,Henry R Kranzler,Michiaki Kubo,Ralph Kupka,Steven A Kushner,Catharina Lavebratt,Jacob Lawrence,Markus Leber,Heon-Jeong Lee,Phil H Lee,Shawn E Levy,Catrin Lewis,Calwing Liao,Susanne Lucae,Martin Lundberg,Donald J MacIntyre,Sigurdur H Magnusson,Wolfgang Maier,Adam Maihofer,Dolores Malaspina,Eirini Maratou,Lina Martinsson,Manuel Mattheisen,Steven A McCarroll,Nathaniel W McGregor,Peter McGuffin,James D McKay,Helena Medeiros,Sarah E Medland,Vincent Millischer,Grant W Montgomery,Jennifer L Moran,Derek W Morris,Thomas W M\u00fchleisen,Niamh O'Brien,Claire O'Donovan,Loes M Olde Loohuis,Lilijana Oruc,Sergi Papiol,Antonio F Pardi\u00f1as,Amy Perry,Andrea Pfennig,Evgenia Porichi,James B Potash,Digby Quested,Towfique Raj,Mark H Rapaport,J Raymond DePaulo,Eline J Regeer,John P Rice,Fabio Rivas,Margarita Rivera,Julian Roth,Panos Roussos,Douglas M Ruderfer,Cristina S\u00e1nchez-Mora,Eva C Schulte,Fanny Senner,Sally Sharp,Paul D Shilling,Engilbert Sigurdsson,Lea Sirignano,Claire Slaney,Olav B Smeland,Daniel J Smith,Janet L Sobell,Christine S\u00f8holm Hansen,Maria Soler Artigas,Anne T Spijker,Dan J Stein,John S Strauss,Beata \u015awi\u0105tkowska,Chikashi Terao,Thorgeir E Thorgeirsson,Claudio Toma,Paul Tooney,Evangelia-Eirini Tsermpini,Marquis P Vawter,Helmut Vedder,James T R Walters,Stephanie H Witt,Simon Xi,Wei Xu,Jessica Mei Kay Yang,Allan H Young,Hannah Young,Peter P Zandi,Hang Zhou,Lea Zillich, ,Rolf Adolfsson,Ingrid Agartz,Martin Alda,Lars Alfredsson,Gulja Babadjanova,Lena Backlund,Bernhard T Baune,Frank Bellivier,Susanne Bengesser,Wade H Berrettini,Douglas H R Blackwood,Michael Boehnke,Anders D B\u00f8rglum,Gerome Breen,Vaughan J Carr,Stanley Catts,Aiden Corvin,Nicholas Craddock,Udo Dannlowski,Dimitris Dikeos,T\u00f5nu Esko,Bruno Etain,Panagiotis Ferentinos,Mark Frye,Janice M Fullerton,Micha Gawlik,Elliot S Gershon,Fernando S Goes,Melissa J Green,Maria Grigoroiu-Serbanescu,Joanna Hauser,Frans Henskens,Jan Hillert,Kyung Sue Hong,David M Hougaard,Christina M Hultman,Kristian Hveem,Nakao Iwata,Assen V Jablensky,Ian Jones,Lisa A Jones,Ren\u00e9 S Kahn,John R Kelsoe,George Kirov,Mikael Land\u00e9n,Marion Leboyer,Cathryn M Lewis,Qingqin S Li,Jolanta Lissowska,Christine Lochner,Carmel Loughland,Nicholas G Martin,Carol A Mathews,Fermin Mayoral,Susan L McElroy,Andrew M McIntosh,Francis J McMahon,Ingrid Melle,Patricia Michie,Lili Milani,Philip B Mitchell,Gunnar Morken,Ole Mors,Preben Bo Mortensen,Bryan Mowry,Bertram M\u00fcller-Myhsok,Richard M Myers,Benjamin M Neale,Caroline M Nievergelt,Merete Nordentoft,Markus M N\u00f6then,Michael C O'Donovan,Ketil J Oedegaard,Tomas Olsson,Michael J Owen,Sara A Paciga,Chris Pantelis,Carlos Pato,Michele T Pato,George P Patrinos,Roy H Perlis,Danielle Posthuma,Josep Antoni Ramos-Quiroga,Andreas Reif,Eva Z Reininghaus,Marta Ribas\u00e9s,Marcella Rietschel,Stephan Ripke,Guy A Rouleau,Takeo Saito,Ulrich Schall,Martin Schalling,Peter R Schofield,Thomas G Schulze,Laura J Scott,Rodney J Scott,Alessandro Serretti,Cynthia Shannon Weickert,Jordan W Smoller,Hreinn Stefansson,Kari Stefansson,Eystein Stordal,Fabian Streit,Patrick F Sullivan,Gustavo Turecki,Arne E Vaaler,Eduard Vieta,John B Vincent,Irwin D Waldman,Thomas W Weickert,Thomas Werge,Naomi R Wray,John-Anker Zwart,Joanna M Biernacka,John I Nurnberger,Sven Cichon,Howard J Edenberg,Eli A Stahl,Andrew McQuillin,Arianna Di Florio,Roel A Ophoff,Ole A Andreassen", - "abstract": "Bipolar disorder is a heritable mental illness with complex etiology. We performed a genome-wide association study of 41,917 bipolar disorder cases and 371,549 controls of European ancestry, which identified 64 associated genomic loci. Bipolar disorder risk alleles were enriched in genes in synaptic signaling pathways and brain-expressed genes, particularly those with high specificity of expression in neurons of the prefrontal cortex and hippocampus. Significant signal enrichment was found in genes encoding targets of antipsychotics, calcium channel blockers, antiepileptics and anesthetics. Integrating expression quantitative trait locus data implicated 15 genes robustly linked to bipolar disorder via gene expression, encoding druggable targets such as HTR6, MCHR1, DCLK3 and FURIN. Analyses of bipolar disorder subtypes indicated high but imperfect genetic correlation between bipolar disorder type I and II and identified additional associated loci. Together, these results advance our understanding of the biological etiology of bipolar disorder, identify novel therapeutic leads and prioritize genes for functional follow-up studies.", - "journal_title": "Nature genetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/34002096/" - } - ], - "ccb4bb6f-7d39-4e26-aec1-c99128af1ff2": [ - { - "pub_id": "31131548", - "title": "Role of genomics literacy in reducing the burden of common genetic diseases in Africa.", - "authors": "Gerald Mboowa,Ivan Sserwadda", - "abstract": "In Africa, health practitioners and the current knowledge of the public on genetics and genomics is still very low and yet this has potential to reduce the burden of common genetic diseases. Many initiatives have promoted genomic research, infrastructure, and capacity building in Africa. What remains to be done is to improve genomics literacy among populations and communities while utilizing an array of strategies. Genomic literacy and awareness are key in the management of genetic diseases which includes diagnosis, prevention of complications and therapy. Africa is characterized by great cultural and language diversity thereby requiring a multidisciplinary approach to improving public and community genomics literacy and engagement. However, this is further complicated by having the fact that sub-Saharan Africa is comprised of countries with the lowest literacy rates in the world. We applied the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines to review genomic literacy in Africa using PubMed database. We found very limited evidence of genomics literacy for genetic diseases in Africa. We propose a number of approaches that if adopted will significantly increase the genomic literacy and reduce the burden of genetic diseases in Africa.", - "journal_title": "Molecular genetics & genomic medicine", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/31131548/" - } - ], - "d01eef0b-9e5b-4d97-a114-60edbce93671": [ - { - "pub_id": "30130595", - "title": "Pilot genome-wide association study identifying novel risk loci for type 2 diabetes in a Maya population.", - "authors": "Miriam Givisay Dom\u00ednguez-Cruz,Mar\u00eda de Lourdes Mu\u00f1oz,Armando Totomoch-Serra,Mar\u00eda Guadalupe Garc\u00eda-Escalante,Juan Burgue\u00f1o,Nina Valadez-Gonz\u00e1lez,Doris Pinto-Escalantes,\u00c1lvaro D\u00edaz-Badillo", - "abstract": "Type 2 diabetes mellitus (T2D) is one of the two leading causes of mortality in Mexico. However, most studies have focused on Caucasians or Asians, and there are a small number of studies investigating Maya populations. Furthermore, to the best of our knowledge, there is no information on isolated Maya communities with T2D frequencies of 20% that are primarily attributed to ethnicity. Consequently, this study focused on assessing which genetic risk variants could be involved in the high rates of T2D in 92 individuals with Maya ancestry; 47 were diagnosed with T2D, and 45 were classified as healthy individuals. A pilot genome-wide association study was performed using the Affymetrix Axiom Genome-wide LAT1 array. The population structure was determined with the ADMIXTURE software using 1289 Latin American selected polymorphisms, and 39 polymorphisms associated with T2D were included for replication. Association tests were performed using the Statistical Analysis System (SAS) using the allelic, genotype and Armitage trend tests. The results indicated that population structure analysis displayed no differences between T2D patients and healthy individuals; 24 loci located were identified for probable association with T2D (p\u202f>\u202f1.288\u202f\u00d7\u202f10<sup>-7</sup> and p\u202f<\u202f1.348\u202f\u00d7\u202f10<sup>-4</sup>); the polymorphism AGTR2 rs1914711 in chromosome X was identified by the allele test (OR\u202f=\u202f6.824; p\u202f=\u202f1.448\u202f\u00d7\u202f10<sup>-9</sup>) as a candidate gene for association with T2D; and ARL15 rs4311394 was associated as a T2D protector by genotype and the Armitage trend test (OR\u202f=\u202f0.318; p\u202f=\u202f0.001). In conclusion, this study proposes 24 candidate SNPs associated with T2D for replication studies and one for protective association with T2D.", - "journal_title": "Gene", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/30130595/" - } - ], - "7ebf3dcf-0e9a-44d7-bd1c-1c49004d0753": [ - { - "pub_id": "29387902", - "title": "Lnc-ing non-coding RNAs with metabolism and diabetes: roles of lncRNAs.", - "authors": "Neha Goyal,Devesh Kesharwani,Malabika Datta", - "abstract": "Type 2 diabetes is a complex metabolic disorder characterized by insulin resistance and pancreatic \u03b2-cell dysfunction. Deregulated glucose and lipid metabolism are the primary underlying manifestations associated with this disease and its complications. Long non-coding RNAs (lncRNAs) are a novel class of functional RNAs that regulate a variety of biological processes by a diverse interplay of mechanisms including recruitment of epigenetic modifiers, transcriptional and post-transcriptional regulation, control of mRNA decay, and sequestration of transcription factors. Although the underlying causes that define the diabetic phenotype are extremely intricate, most of the studies in the last decades were mostly centered on protein-coding genes. However, current opinion in the recent past has authenticated the contributions of diverse lncRNAs as critical regulatory players during the manifestation of diabetes. The current review will highlight the importance of lncRNAs in regulating cellular processes that govern metabolic homeostasis in key metabolic tissues. A more in-depth understanding of lncRNAs may enable their exploitation as biomarkers or for therapeutic applications during diabetes and its associated complications.", - "journal_title": "Cellular and molecular life sciences : CMLS", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/29387902/" - } - ], - "31588831-61b3-4018-9962-bd6985c3061b": [ - { - "pub_id": "27459454", - "title": "Contribution of the Nurses' Health Studies to Uncovering Risk Factors for Type 2 Diabetes: Diet, Lifestyle, Biomarkers, and Genetics.", - "authors": "Sylvia H Ley,Andres V Ardisson Korat,Qi Sun,Deirdre K Tobias,Cuilin Zhang,Lu Qi,Walter C Willett,JoAnn E Manson,Frank B Hu", - "abstract": "To review the contribution of the Nurses' Health Study (NHS) and the NHS II to addressing hypotheses regarding risk factors for type 2 diabetes. We carried out a narrative review of 1976 to 2016 NHS and NHS II publications. The NHS and NHS II have uncovered important roles in type 2 diabetes for individual nutrients, foods, dietary patterns, and physical activity independent of excess body weight. Up to 90% of type 2 diabetes cases are potentially preventable if individuals follow a healthy diet and lifestyle. The NHS investigations have also identified novel biomarkers for diabetes, including adipokines, inflammatory cytokines, nutrition metabolites, and environmental pollutants, offering new insights into the pathophysiology of the disease. Global collaborative efforts have uncovered many common genetic variants associated with type 2 diabetes and improved our understanding of gene-environment interactions. Continued efforts to identify epigenetic, metagenomic, and metabolomic risk factors for type 2 diabetes have the potential to reveal new pathways and improve prediction and prevention. Over the past several decades, the NHS and NHS II have made major contributions to public health recommendations and strategies designed to reduce the global burden of diabetes.", - "journal_title": "American journal of public health", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/27459454/" - } - ], - "232dc4fe-6c33-4ec6-ad51-6c2bd95d0bea": [ - { - "pub_id": "29025893", - "title": "Disease-specific biases in alternative splicing and tissue-specific dysregulation revealed by multitissue profiling of lymphocyte gene expression in type 1 diabetes.", - "authors": "Jeremy R B Newman,Ana Conesa,Matthew Mika,Felicia N New,Suna Onengut-Gumuscu,Mark A Atkinson,Stephen S Rich,Lauren M McIntyre,Patrick Concannon", - "abstract": "Genome-wide association studies (GWAS) have identified multiple, shared allelic associations with many autoimmune diseases. However, the pathogenic contributions of variants residing in risk loci remain unresolved. The location of the majority of shared disease-associated variants in noncoding regions suggests they contribute to risk of autoimmunity through effects on gene expression in the immune system. In the current study, we test this hypothesis by applying RNA sequencing to CD4<sup>+</sup>, CD8<sup>+</sup>, and CD19<sup>+</sup> lymphocyte populations isolated from 81 subjects with type 1 diabetes (T1D). We characterize and compare the expression patterns across these cell types for three gene sets: all genes, the set of genes implicated in autoimmune disease risk by GWAS, and the subset of these genes specifically implicated in T1D. We performed RNA sequencing and aligned the reads to both the human reference genome and a catalog of all possible splicing events developed from the genome, thereby providing a comprehensive evaluation of the roles of gene expression and alternative splicing (AS) in autoimmunity. Autoimmune candidate genes displayed greater expression specificity in the three lymphocyte populations relative to other genes, with significantly increased levels of splicing events, particularly those predicted to have substantial effects on protein isoform structure and function (e.g., intron retention, exon skipping). The majority of single-nucleotide polymorphisms within T1D-associated loci were also associated with one or more <i>cis</i>-expression quantitative trait loci (<i>cis</i>-eQTLs) and/or splicing eQTLs. Our findings highlight a substantial, and previously underrecognized, role for AS in the pathogenesis of autoimmune disorders and particularly for T1D.", - "journal_title": "Genome research", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/29025893/" - } - ], - "48fa92f3-edad-4ee6-91aa-a6801571e4af": [ - { - "pub_id": "34604815", - "title": "Genetic discovery and risk characterization in type 2 diabetes across diverse populations.", - "authors": "Linda M Polfus,Burcu F Darst,Heather Highland,Xin Sheng,Maggie C Y Ng,Jennifer E Below,Lauren Petty,Stephanie Bien,Xueling Sim,Wei Wang,Pierre Fontanillas,Yesha Patel, , , ,Michael Preuss,Claudia Schurmann,Zhaohui Du,Yingchang Lu,Suhn K Rhie,Joseph M Mercader,Teresa Tusie-Luna,Clicerio Gonz\u00e1lez-Villalpando,Lorena Orozco,Cassandra N Spracklen,Brian E Cade,Richard A Jensen,Meng Sun,Yoonjung Yoonie Joo,Ping An,Lisa R Yanek,Lawrence F Bielak,Salman Tajuddin,Aude Nicolas,Guanjie Chen,Laura Raffield,Xiuqing Guo,Wei-Min Chen,Girish N Nadkarni,Mariaelisa Graff,Ran Tao,James S Pankow,Martha Daviglus,Qibin Qi,Eric A Boerwinkle,Simin Liu,Lawrence S Phillips,Ulrike Peters,Chris Carlson,Lynne R Wikens,Loic Le Marchand,Kari E North,Steven Buyske,Charles Kooperberg,Ruth J F Loos,Daniel O Stram,Christopher A Haiman", - "abstract": "Genomic discovery and characterization of risk loci for type 2 diabetes (T2D) have been conducted primarily in individuals of European ancestry. We conducted a multiethnic genome-wide association study of T2D among 53,102 cases and 193,679 control subjects from African, Hispanic, Asian, Native Hawaiian, and European population groups in the Population Architecture Genomics and Epidemiology (PAGE) and Diabetes Genetics Replication and Meta-analysis (DIAGRAM) Consortia. In individuals of African ancestry, we discovered a risk variant in the <i>TGFB1</i> gene (rs11466334, risk allele frequency (RAF) = 6.8%, odds ratio [OR] = 1.27, p = 2.06 \u00d7 10<sup>-8</sup>), which replicated in independent studies of African ancestry (p = 6.26 \u00d7 10<sup>-23</sup>). We identified a multiethnic risk variant in the <i>BACE2</i> gene (rs13052926, RAF = 14.1%, OR = 1.08, p = 5.75 \u00d7 10<sup>-9</sup>), which also replicated in independent studies (p = 3.45 \u00d7 10<sup>-4</sup>). We also observed a significant difference in the performance of a multiethnic genetic risk score (GRS) across population groups (p<sub>heterogeneity</sub> = 3.85 \u00d7 10<sup>-20</sup>). Comparing individuals in the top GRS risk category (40%-60%), the OR was highest in Asians (OR = 3.08) and European (OR = 2.94) ancestry populations, followed by Hispanic (OR = 2.39), Native Hawaiian (OR = 2.02), and African ancestry (OR = 1.57) populations. These findings underscore the importance of genetic discovery and risk characterization in diverse populations and the urgent need to further increase representation of non-European ancestry individuals in genetics research to improve genetic-based risk prediction across populations.", - "journal_title": "HGG advances", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/34604815/" - } - ], - "68c109d7-cfef-4a50-8f22-f0b16a5cb52c": [ - { - "pub_id": "33039572", - "title": "DNA methylation methods: Global DNA methylation and methylomic analyses.", - "authors": "Shizhao Li,Trygve O Tollefsbol", - "abstract": "DNA methylation provides a pivotal layer of epigenetic regulation in eukaryotes that has significant involvement for numerous biological processes in health and disease. The function of methylation of cytosine bases in DNA was originally proposed as a \"silencing\" epigenetic marker and focused on promoter regions of genes for decades. Improved technologies and accumulating studies have been extending our understanding of the roles of DNA methylation to various genomic contexts including gene bodies, repeat sequences and transcriptional start sites. The demand for comprehensively describing DNA methylation patterns spawns a diversity of DNA methylation profiling technologies that target its genomic distribution. These approaches have enabled the measurement of cytosine methylation from specific loci at restricted regions to single-base-pair resolution on a genome-scale level. In this review, we discuss the different DNA methylation analysis technologies primarily based on the initial treatments of DNA samples: bisulfite conversion, endonuclease digestion and affinity enrichment, involving methodology evolution, principles, applications, and their relative merits. This review may offer referable information for the selection of various platforms for genome-wide analysis of DNA methylation.", - "journal_title": "Methods (San Diego, Calif.)", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/33039572/" - } - ], - "657de620-10e3-4b82-ad93-a0b6a775aca4": [ - { - "pub_id": "26782299", - "title": "Hypomethylation within gene promoter regions and type 1 diabetes in discordant monozygotic twins.", - "authors": "Emon Elboudwarej,Michael Cole,Farren B S Briggs,Alexandra Fouts,Pamela R Fain,Hong Quach,Diana Quach,Elizabeth Sinclair,Lindsey A Criswell,Julie A Lane,Andrea K Steck,Lisa F Barcellos,Janelle A Noble", - "abstract": "Genetic susceptibility to type 1 diabetes (T1D) is well supported by epidemiologic evidence; however, disease risk cannot be entirely explained by established genetic variants identified so far. This study addresses the question of whether epigenetic modification of the inherited DNA sequence may contribute to T1D susceptibility. Using the Infinium HumanMethylation450 BeadChip array (450k), a total of seven long-term disease-discordant monozygotic (MZ) twin pairs and five pairs of HLA-identical, disease-discordant non-twin siblings (NTS) were examined for associations between DNA methylation (DNAm) and T1D. Strong evidence for global hypomethylation of CpG sites within promoter regions in MZ twins with TID compared to twins without T1D was observed. DNA methylation data were then grouped into three categories of CpG sites for further analysis, including those within: 1) the major histocompatibility complex (MHC) region, 2) non-MHC genes with reported T1D association through genome wide association studies (GWAS), and 3) the epigenome, or remainder of sites that did not include MHC and T1D associated genes. Initial results showed modest methylation differences between discordant MZ twins for the MHC region and T1D-associated CpG sites, BACH2, INS-IGF2, and CLEC16A (DNAm difference range: 2.2%-5.0%). In the epigenome CpG set, the greatest methylation differences were observed in MAGI2, FANCC, and PCDHB16, (DNAm difference range: 6.9%-16.1%). These findings were not observed in the HLA-identical NTS pairs. Targeted pyrosequencing of five candidate CpG loci identified using the 450k array in the original discordant MZ twins produced similar results using control DNA samples, indicating strong agreement between the two DNA methylation profiling platforms. However, findings for the top five candidate CpG loci were not replicated in six additional T1D-discordant MZ twin pairs. Our results indicate global DNA hypomethylation within gene promoter regions may contribute to T1D; however, findings do not support the involvement of large DNAm differences at single CpG sites alone in T1D.", - "journal_title": "Journal of autoimmunity", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/26782299/" - } - ], - "588bca6b-82c0-4ac1-9c7e-dc09af1d49b0": [ - { - "pub_id": "29913182", - "title": "The genetic architecture of type 1 diabetes mellitus.", - "authors": "Denis M Nyaga,Mark H Vickers,Craig Jefferies,Jo K Perry,Justin M O'Sullivan", - "abstract": "Type 1 diabetes mellitus (T1D) is a complex autoimmune disorder characterised by loss of the insulin-producing pancreatic beta cells in genetically predisposed individuals, ultimately resulting in insulin deficiency and hyperglycaemia. T1D is most common among children and young adults, and the incidence is on the rise across the world. The aetiology of T1D is hypothesized to involve genetic and environmental factors that result in the T-cell mediated destruction of pancreatic beta cells. There is a strong genetic risk to T1D; with genome-wide association studies (GWAS) identifying over 60 susceptibility regions within the human genome which are marked by single nucleotide polymorphisms (SNPs). Here, we review what is currently known about the genetics of T1D. We argue that advancing our understanding of the aetiology and pathogenesis of T1D will require the integration of genome biology (omics-data) with GWAS data, thereby making it possible to elucidate the putative gene regulatory networks modulated by disease-associated SNPs. This approach has a potential to revolutionize clinical management of T1D in an era of precision medicine.", - "journal_title": "Molecular and cellular endocrinology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/29913182/" - } - ], - "cf022812-00a2-42ba-88fb-5c2014c86c43": [ - { - "pub_id": "31322649", - "title": "Genetic Risk Scores for Diabetes Diagnosis and Precision Medicine.", - "authors": "Miriam S Udler,Mark I McCarthy,Jose C Florez,Anubha Mahajan", - "abstract": "During the last decade, there have been substantial advances in the identification and characterization of DNA sequence variants associated with individual predisposition to type 1 and type 2 diabetes. As well as providing insights into the molecular, cellular, and physiological mechanisms involved in disease pathogenesis, these risk variants, when combined into a polygenic score, capture information on individual patterns of disease predisposition that have the potential to influence clinical management. In this review, we describe the various opportunities that polygenic scores provide: to predict diabetes risk, to support differential diagnosis, and to understand phenotypic and clinical heterogeneity. We also describe the challenges that will need to be overcome if this potential is to be fully realized.", - "journal_title": "Endocrine reviews", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/31322649/" - } - ], - "07e78308-be06-4330-b61c-34628ba78633": [ - { - "pub_id": "33335512", - "title": "Genetics and Epigenetics: New Insight on Gestational Diabetes Mellitus.", - "authors": "Maria Grazia Dalfr\u00e0,Silvia Burlina,Gloria Giovanna Del Vescovo,Annunziata Lapolla", - "abstract": "Gestational diabetes mellitus (GDM) is the most common metabolic complication of pregnancy, with a prevalence that has increased significantly in the last decade, coming to affect 12-18% of all pregnancies. GDM is believed to be the result of a combination of genetic, epigenetic and environmental factors. Following the identification of susceptibility genes for type 2 diabetes by means of genome-wide association studies, an association has also been demonstrated between some type 2 diabetes susceptibility genes and GDM, suggesting a partial similarity of the genetic architecture behind the two forms of diabetes. More recent genome-wide association studies, focusing on maternal metabolism during pregnancy, have demonstrated an overlap in the genes associated with metabolic traits in gravid and non-gravid populations, as well as in genes apparently unique to pregnancy. Epigenetic changes-such as DNA methylation, histone modifications and microRNA gene silencing-have also been identified in GDM patients. Metabolomics has been used to profile the metabolic state of women during pregnancy, based on the measurement of numerous low-molecular-weight metabolites. Measuring amino acids and conventional metabolites has revealed changes in pregnant women with a higher insulin resistance and high blood glucose levels that resemble the changes seen in non-gravid, insulin-resistant populations. This would suggest similarities in the metabolic profiles typical of insulin resistance and hyperglycemia whether individuals are pregnant or not. Future studies combining data obtained using multiple technologies will enable an integrated systems biology approach to maternal metabolism during a pregnancy complicated by GDM. This review highlights the recent knowledge on the impact of genetics and epigenetics in the pathophysiology of GDM and the maternal and fetal complications associated with this pathology condition.", - "journal_title": "Frontiers in endocrinology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/33335512/" - } - ], - "f136ebbc-afe9-4773-ac22-451dce7f438e": [ - { - "pub_id": "27124316", - "title": "A Genome-Wide Association Study Provides New Evidence That CACNA1C Gene is Associated With Diabetic Cataract.", - "authors": "Cheng Chang,Kaida Zhang,Abirami Veluchamy,Harry L H\u00e9bert,Helen C Looker,Helen M Colhoun,Colin N A Palmer,Weihua Meng", - "abstract": "Diabetic cataract is one of the major eye complications of diabetes. It was reported that cataract occurs two to five times more frequently in patients with diabetes compared with those with no diabetes. The purpose of this study was to identify genetic contributors of diabetic cataract based on a genome-wide association approach using a well-defined Scottish diabetic cohort. We adapted linked e-health records to define diabetic cataract. A diabetic cataract case in this study was defined as a type 2 diabetic patient who has ever been recorded in the linked e-health records to have cataracts in both eyes or who had previous cataract extraction surgeries in at least one eye. A control in this study was defined as a type 2 diabetic individual who has never been diagnosed as cataract in the linked e-health records and had no history of cataract surgeries. A standard genome-wide association approach was applied. Overall, we have 2341 diabetic cataract cases and 2878 controls in the genetics of diabetes audit and research in Tayside Scotland (GoDARTS) dataset. We found that the P value of rs2283290 in the CACNA1C gene was 8.81 \u00d7 10(-10), which has reached genome-wide significance. We also identified that the blood calcium level was statistically different between diabetic cataract cases and controls. We identified supporting evidence that CACNA1C gene is associated with diabetic cataract. The role of calcium in the cataractogenesis needs to be reevaluated in future studies.", - "journal_title": "Investigative ophthalmology & visual science", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/27124316/" - } - ], - "8909aa39-da1c-49fc-aa39-2be2db686ddc": [ - { - "pub_id": "27310578", - "title": "Replication and Relevance of Multiple Susceptibility Loci Discovered from Genome Wide Association Studies for Type 2 Diabetes in an Indian Population.", - "authors": "Nagaraja M Phani,Prabha Adhikari,Shivashankara K Nagri,Sydney C D'Souza,Kapaettu Satyamoorthy,Padmalatha S Rai", - "abstract": "Several genetic variants for type 2 diabetes (T2D) have been identified through genome wide association studies (GWAS) from Caucasian population; however replication studies were not consistent across various ethnicities. Objective of the current study is to examine the possible correlation of 9 most significant GWAS single nucleotide polymorphisms (SNPs) for T2D susceptibility as well as the interactive effect of these variants on the risk of T2D in an Indian population. Case-control cohorts of 1156 individuals were genotyped for 9 SNPs from an Indian population. Association analyses were performed using logistic regression after adjusting for covariates. Multifactor dimensionality reduction (MDR) analysis was adopted to determine gene-gene interactions and discriminatory power of combined SNP effect was assessed by grouping individuals based on the number of risk alleles and by calculating area under the receiver-operator characteristic curve (AUC). We confirm the association of TCF7L2 (rs7903146) and SLC30A8 (rs13266634) with T2D. MDR analysis showed statistically significant interactions among four SNPs of SLC30A8 (rs13266634), IGF2BP2 (rs4402960), HHEX (rs1111875) and CDKN2A (rs10811661) genes. Cumulative analysis showed an increase in odds ratio against the baseline group of individuals carrying 5 to 6 risk alleles and discriminatory power of genetic test based on 9 variants showed higher AUC value when analyzed along with body mass index (BMI). These results provide a strong evidence for independent association between T2D and SNPs for in TCF7L2 and SLC30A8. MDR analysis demonstrates that independently non-significant variants may interact with one another resulting in increased disease susceptibility in the population tested.", - "journal_title": "PloS one", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/27310578/" - } - ], - "69f1f8e6-4acb-4988-a778-d1a9b524fc62": [ - { - "pub_id": "31500825", - "title": "Biomarkers for type 2 diabetes.", - "authors": "Markku Laakso", - "abstract": "The prevalence and incidence of type 2 diabetes (T2D), representing >90% of all cases of diabetes, are increasing rapidly worldwide. Identification of individuals at high risk of developing diabetes is of great importance as early interventions might delay or even prevent full-blown disease. T2D is a complex disease caused by multiple genetic loci in interplay with lifestyle and environmental factors. Recently over 400 distinct association signals were published; these explain 18% of the risk of T2D. In this review there is a major focus on risk factors and genetic and non-genetic biomarkers for the risk of T2D identified especially in large prospective population-based studies, and studies testing causality of the biomarkers for T2D in Mendelian randomization studies. Another focus is on understanding genome-phenome interplay in the classification of individuals with T2D into subgroups. Several recent large population-based studies and their meta-analyses have identified multiple potential genetic and non-genetic biomarkers for the risk of T2D. Combination of genetic variants and physiologically characterized pathways improves the classification of individuals with T2D into subgroups, and is also paving the way to a precision medicine approach, in T2D.", - "journal_title": "Molecular metabolism", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/31500825/" - } - ], - "c1a4379a-6413-4328-8b83-d0a0bb21c2b2": [ - { - "pub_id": "30104762", - "title": "Genome-wide polygenic scores for common diseases identify individuals with risk equivalent to monogenic mutations.", - "authors": "Amit V Khera,Mark Chaffin,Krishna G Aragam,Mary E Haas,Carolina Roselli,Seung Hoan Choi,Pradeep Natarajan,Eric S Lander,Steven A Lubitz,Patrick T Ellinor,Sekar Kathiresan", - "abstract": "A key public health need is to identify individuals at high risk for a given disease to enable enhanced screening or preventive therapies. Because most common diseases have a genetic component, one important approach is to stratify individuals based on inherited DNA variation<sup>1</sup>. Proposed clinical applications have largely focused on finding carriers of rare monogenic mutations at several-fold increased risk. Although most disease risk is polygenic in nature<sup>2-5</sup>, it has not yet been possible to use polygenic predictors to identify individuals at risk comparable to monogenic mutations. Here, we develop and validate genome-wide polygenic scores for five common diseases. The approach identifies 8.0, 6.1, 3.5, 3.2, and 1.5% of the population at greater than threefold increased risk for coronary artery disease, atrial fibrillation, type 2 diabetes, inflammatory bowel disease, and breast cancer, respectively. For coronary artery disease, this prevalence is 20-fold higher than the carrier frequency of rare monogenic mutations conferring comparable risk<sup>6</sup>. We propose that it is time to contemplate the inclusion of polygenic risk prediction in clinical care, and discuss relevant issues.", - "journal_title": "Nature genetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/30104762/" - } - ], - "143fe896-0f3e-49d2-98f8-2af585d5070e": [ - { - "pub_id": "30686584", - "title": "Epilepsy in adults.", - "authors": "Roland D Thijs,Rainer Surges,Terence J O'Brien,Josemir W Sander", - "abstract": "Epilepsy is one of the most common serious brain conditions, affecting over 70 million people worldwide. Its incidence has a bimodal distribution with the highest risk in infants and older age groups. Progress in genomic technology is exposing the complex genetic architecture of the common types of epilepsy, and is driving a paradigm shift. Epilepsy is a symptom complex with multiple risk factors and a strong genetic predisposition rather than a condition with a single expression and cause. These advances have resulted in the new classification of epileptic seizures and epilepsies. A detailed clinical history and a reliable eyewitness account of a seizure are the cornerstones of the diagnosis. Ancillary investigations can help to determine cause and prognosis. Advances in brain imaging are helping to identify the structural and functional causes and consequences of the epilepsies. Comorbidities are increasingly recognised as important aetiological and prognostic markers. Antiseizure medication might suppress seizures in up to two-thirds of all individuals but do not alter long-term prognosis. Epilepsy surgery is the most effective way to achieve long-term seizure freedom in selected individuals with drug-resistant focal epilepsy, but it is probably not used enough. With improved understanding of the gradual development of epilepsy, epigenetic determinants, and pharmacogenomics comes the hope for better, disease-modifying, or even curative, pharmacological and non-pharmacological treatment strategies. Other developments are clinical implementation of seizure detection devices and new neuromodulation techniques, including responsive neural stimulation.", - "journal_title": "Lancet (London, England)", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/30686584/" - } - ], - "eea5f67b-edf7-4ec1-b874-461b49914480": [ - { - "pub_id": "33866450", - "title": "PPAR\u03b3 and Diabetes: Beyond the Genome and Towards Personalized Medicine.", - "authors": "Simona Cataldi,Valerio Costa,Alfredo Ciccodicola,Marianna Aprile", - "abstract": "Full and partial synthetic agonists targeting the transcription factor PPAR\u03b3 are contained in FDA-approved insulin-sensitizing drugs and used for the treatment of metabolic syndrome-related dysfunctions. Here, we discuss the association between PPARG genetic variants and drug efficacy, as well as the role of alternative splicing and post-translational modifications as contributors to the complexity of PPAR\u03b3 signaling and to the effects of synthetic PPAR\u03b3 ligands. PPAR\u03b3 regulates the transcription of several target genes governing adipocyte differentiation and glucose and lipid metabolism, as well as insulin sensitivity and inflammatory pathways. These pleiotropic functions confer great relevance to PPAR\u03b3 in physiological regulation of whole-body metabolism, as well as in the etiology of metabolic disorders. Accordingly, PPARG gene mutations, nucleotide variations, and post-translational modifications have been associated with adipose tissue disorders and the related risk of insulin resistance and type 2 diabetes (T2D). Moreover, PPAR\u03b3 alternative splicing isoforms-generating dominant-negative isoforms mainly expressed in human adipose tissue-have been related to impaired PPAR\u03b3 activity and adipose tissue dysfunctions. Thus, multiple regulatory levels that contribute to PPAR\u03b3 signaling complexity may account for the beneficial as well as adverse effects of PPAR\u03b3 agonists. Further targeted analyses, taking into account all these aspects, are needed for better deciphering the role of PPAR\u03b3 in human pathophysiology, especially in insulin resistance and T2D. The therapeutic potential of full and partial PPAR\u03b3 synthetic agonists underlines the clinical significance of this nuclear receptor. PPARG mutations, polymorphisms, alternative splicing isoforms, and post-translational modifications may contribute to the pathogenesis of metabolic disorders, also influencing the responsiveness of pharmacological therapy. Therefore, in the context of the current evidence-based trend to personalized diabetes management, we highlight the need to decipher the intricate regulation of PPAR\u03b3 signaling to pave the way to tailored therapies in patients with insulin resistance and T2D.", - "journal_title": "Current diabetes reports", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/33866450/" - } - ], - "1854d678-f8ac-4669-8dc4-aad5769bb183": [ - { - "pub_id": "27586139", - "title": "Genetics and Genomics of Coronary Artery Disease.", - "authors": "Milos Pjanic,Clint L Miller,Robert Wirka,Juyong B Kim,Daniel M DiRenzo,Thomas Quertermous", - "abstract": "Coronary artery disease (or coronary heart disease), is the leading cause of mortality in many of the developing as well as the developed countries of the world. Cholesterol-enriched plaques in the heart's blood vessels combined with inflammation lead to the lesion expansion, narrowing of blood vessels, reduced blood flow, and may subsequently cause lesion rupture and a heart attack. Even though several environmental risk factors have been established, such as high LDL-cholesterol, diabetes, and high blood pressure, the underlying genetic composition may substantially modify the disease risk; hence, genome composition and gene-environment interactions may be critical for disease progression. Ongoing scientific efforts have seen substantial advancements related to the fields of genetics and genomics, with the major breakthroughs yet to come. As genomics is the most rapidly advancing field in the life sciences, it is important to present a comprehensive overview of current efforts. Here, we present a summary of various genetic and genomics assays and approaches applied to coronary artery disease research.", - "journal_title": "Current cardiology reports", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/27586139/" - } - ], - "52839835-a0ac-4056-b762-f60ded1a9619": [ - { - "pub_id": "33392712", - "title": "Genomic risk score provides predictive performance for type 2 diabetes in the UK biobank.", - "authors": "Xiaolu Chen,Congcong Liu,Shucheng Si,Yunxia Li,Wenchao Li,Tonghui Yuan,Fuzhong Xue", - "abstract": "Type 2 diabetes (T2D) is affected by a combination of genetic and environmental factors. However, the comprehensive genomic risk scores (GRSs) for T2D prediction have not been evaluated. Using a meta-scoring approach, we developed a metaGRS for T2D; T2D-related traits consist of 1,692 genetic variants in the UK Biobank training set (n\u2009=\u200940,423\u2009+\u20097,558 events) and evaluate this score in the validation set (n\u2009=\u2009303,053). The hazard ratio (HR) for T2D was 1.32 (95% confidence interval [CI]: 1.29-1.35) per standard deviation of metaGRS and was larger than previously published T2D-GRS. Individuals, in the top 25% of metaGRS, have an HR of 2.08 (95%CI: 1.93-2.23) compared with those in the bottom 25%. The addition of metaGRS to all conventional risk factors significantly increased the AUC (P\u2009<\u20090.001). Adding metaGRS to all conventional risk factors significantly improved the reclassification accuracy (continuous net reclassification improvement\u2009=\u200911.8%, 95%CI: 9.2%-14.2%). All analyses adjusted for age, sex, and 10PCs. The metaGRS significantly improves T2D prediction ability.", - "journal_title": "Acta diabetologica", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/33392712/" - } - ], - "5c91b83f-4d0f-400a-b266-6f3ff97d48aa": [ - { - "pub_id": "30412241", - "title": "Genome-wide association study of cervical cancer suggests a role for ARRDC3 gene in human papillomavirus infection.", - "authors": "Fumihiko Takeuchi,Iwao Kukimoto,Zhiqiang Li,Shuang Li,Ni Li,Zhibin Hu,Atsushi Takahashi,Shusaku Inoue,Sana Yokoi,Jianhua Chen,Dong Hang,Makoto Kuroda,Fumihiko Matsuda,Mika Mizuno,Seiichiro Mori,Peng Wu,Naotake Tanaka,Keitaro Matsuo,Yoichiro Kamatani,Michiaki Kubo,Ding Ma,Yongyong Shi", - "abstract": "The development of cervical cancer is initiated by human papillomavirus (HPV) infection and involves both viral and host genetic factors. Genome-wide association studies (GWAS) of cervical cancer have identified associations in the HLA locus and two loci outside HLA, but the principal genes that control infection and pathogenesis have not been identified. In the present study, we performed GWAS of cervical cancer in East Asian populations, involving 2609 cases and 4712 controls in the discovery stage and 1461 cases and 3295 controls in the follow-up stage. We identified novel-significant associations at 5q14 with the lead single nucleotide polymorphism (SNP) rs59661306 (P\u00a0=\u00a02.4\u00a0\u00d7\u00a010-11) and at 7p11 with the lead SNP rs7457728 (P\u00a0=\u00a01.2\u00a0\u00d7\u00a010-8). In 5q14, the chromatin region of the GWAS-significant SNPs was found to be in contact with the promoter of the ARRDC3 (arrestin domain-containing 3) gene. In our functional studies, ARRDC3 knockdown in HeLa cells caused significant reductions in both cell growth and susceptibility to HPV16 pseudovirion infection, suggesting that ARRDC3 is involved in the infectious entry of HPV into the cell. Our study advances the understanding of host genes that are responsible for cervical cancer susceptibility and guides future research on HPV infection and cancer development.", - "journal_title": "Human molecular genetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/30412241/" - } - ], - "9923e77c-5ae5-4330-ba35-1725f27da331": [ - { - "pub_id": "31766143", - "title": "Candidate Gene and Genome-Wide Association Studies for Circulating Leptin Levels Reveal Population and Sex-Specific Associations in High Cardiovascular Risk Mediterranean Subjects.", - "authors": "Carolina Ortega-Azor\u00edn,Oscar Coltell,Eva M Asensio,Jose V Sorl\u00ed,Jos\u00e9 I Gonz\u00e1lez,Olga Portol\u00e9s,Carmen Saiz,Ramon Estruch,Judith B Ram\u00edrez-Sabio,Alejandro P\u00e9rez-Fidalgo,Jose M Ordovas,Dolores Corella", - "abstract": "Leptin is a hormone crucial in the regulation of food intake and body-weight maintenance. However, the genes and gene variants that influence its plasma levels are still not well known. Results of studies investigating polymorphisms in candidate genes have been inconsistent, and, in addition, very few genome-wide association studies (GWAS) have been undertaken. Our aim was to investigate the genes and gene variants most associated with plasma leptin concentrations in a high-cardiovascular-risk Mediterranean population. We measured plasma leptin in 1011 men and women, and analyzed the genetic factors associated using three approaches: (1) Analyzing the single nucleotide polymorphisms (SNPs) reported in a GWAS meta-analysis in other populations (including an SNP in/near each of these LEP, SLC32A1, GCKR, CCNL, COBLL1, and FTO genes); (2) Investigating additional SNPs in/near those genes, also including the RLEP gene; and (3) Undertaking a GWAS to discover new genes. We did not find any statistically significant associations between the previously published SNPs and plasma leptin (Ln) in the whole population adjusting for sex and age. However, on undertaking an extensive screening of other gene variants in those genes to capture a more complete set of SNPs, we found more associations. Outstanding among the findings was the heterogeneity per sex. We detected several statistically significant interaction terms with sex for these SNPs in the candidate genes. The gene most associated with plasma leptin levels was the FTO gene in men (specifically the rs1075440 SNP) and the LEPR in women (specifically the rs12145690 SNP). In the GWAS on the whole population, we found several new associations at the <i>p</i> < 1 \u00d7 10<sup>-5</sup> level, among them with the rs245908-CHN2 SNP (<i>p</i> = 1.6 \u00d7 10<sup>-6</sup>). We also detected a SNP*sex interaction at the GWAS significance level (<i>p</i> < 5 \u00d7 10<sup>-8</sup>), involving the SLIT3 gene, a gene regulated by estrogens. In conclusion, our study shows that the SNPs selected as relevant for plasma leptin levels in other populations, are not good markers for this Mediterranean population, so supporting those studies claiming a bias when generalizing GWAS results to different populations. These population-specific differences may include not only genetic characteristics, but also age, health status, and the influence of other environmental variables. In addition, we have detected several sex-specific effects. These results suggest that genomic analyses, involving leptin, should be estimated by sex and consider population-specificity for more precise estimations.", - "journal_title": "Nutrients", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/31766143/" - } - ], - "4ad6da14-56a3-48ab-a587-42761ceac238": [ - { - "pub_id": "35047865", - "title": "From karyotypes to precision genomics in 9p deletion and duplication syndromes.", - "authors": "Eleanor I Sams,Jeffrey K Ng,Victoria Tate,Ying-Chen Claire Hou,Yang Cao,Lucinda Antonacci-Fulton,Khadija Belhassan,Julie Neidich,Robi D Mitra,F Sessions Cole,Patricia Dickson,Jeffrey Milbrandt,Tychele N Turner", - "abstract": "While 9p deletion and duplication syndromes have been studied for several years, small sample sizes and minimal high-resolution data have limited a comprehensive delineation of genotypic and phenotypic characteristics. In this study, we examined genetic data from 719 individuals in the worldwide 9p Network Cohort: a cohort seven to nine times larger than any previous study of 9p. Most breakpoints occur in bands 9p22 and 9p24, accounting for 35% and 38% of all breakpoints, respectively. Bands 9p11 and 9p12 have the fewest breakpoints, with each accounting for 0.6% of all breakpoints. The most common phenotype in 9p deletion and duplication syndromes is developmental delay, and we identified eight known neurodevelopmental disorder genes in 9p22 and 9p24. Since it has been previously reported that some individuals have a secondary structural variant related to the 9p variant, we examined our cohort for these variants and found 97 events. The top secondary variant involved 9q in 14 individuals (1.9%), including ring chromosomes and inversions. We identified a gender bias with significant enrichment for females (p = 0.0006) that may arise from a sex reversal in some individuals with 9p deletions. Genes on 9p were characterized regarding function, constraint metrics, and protein-protein interactions, resulting in a prioritized set of genes for further study. Finally, we achieved precision genomics in one child with a complex 9p structural variation using modern genomic technologies, demonstrating that long-read sequencing will be integral for some cases. Our study is the largest ever on 9p-related syndromes and provides key insights into genetic factors involved in these syndromes.", - "journal_title": "HGG advances", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/35047865/" - } - ], - "801c9288-70c9-4d14-b8bc-13ee6708803a": [ - { - "pub_id": "34012068", - "title": "ACMG SF v3.0 list for reporting of secondary findings in clinical exome and genome sequencing: a policy statement of the American College of Medical Genetics and Genomics (ACMG).", - "authors": "David T Miller,Kristy Lee,Wendy K Chung,Adam S Gordon,Gail E Herman,Teri E Klein,Douglas R Stewart,Laura M Amendola,Kathy Adelman,Sherri J Bale,Michael H Gollob,Steven M Harrison,Ray E Hershberger,Kent McKelvey,C Sue Richards,Christopher N Vlangos,Michael S Watson,Christa Lese Martin, ", - "abstract": "", - "journal_title": "Genetics in medicine : official journal of the American College of Medical Genetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/34012068/" - } - ], - "77a3661f-21e0-4def-8cb6-4f39f303212e": [ - { - "pub_id": "32385877", - "title": "The role of inflammation and genetics in periodontal disease.", - "authors": "Bruno G Loos,Thomas E Van Dyke", - "abstract": "Periodontitis is a complex disease: (a) various causative factors play a role simultaneously and interact with each other; and (b) the disease is episodic in nature, and bursts of disease activity can be recognized, ie, the disease develops and cycles in a nonlinear fashion. We recognize that various causative factors determine the immune blueprint and, consequently, the immune fitness of a subject. Normally, the host lives in a state of homeostasis or symbiosis with the oral microbiome; however, disturbances in homeostatic balance can occur, because of an aberrant host response (inherited and/or acquired during life). This imbalance results from hyper- or hyporesponsiveness and/or lack of sufficient resolution of inflammation, which in turn is responsible for much of the disease destruction seen in periodontitis. The control of this destruction by anti-inflammatory processes and proresolution processes limits the destruction to the tissues surrounding the teeth. The local inflammatory processes can also become systemic, which in turn affect organs such as the heart. Gingival inflammation also elicits changes in the ecology of the subgingival environment providing optimal conditions for the outgrowth of gram-negative, anaerobic species, which become pathobionts and can propagate periodontal inflammation and can further negatively impact immune fitness. The factors that determine immune fitness are often the same factors that determine the response to the resident biofilm, and are clustered as follows: (a) genetic and epigenetic factors; (b) lifestyle factors, such as smoking, diet, and psychosocial conditions; (c) comorbidities, such as diabetes; and (d) local and dental factors, as well as randomly determined factors (stochasticity). Of critical importance are the pathobionts in a dysbiotic biofilm that drive the viscious cycle. Focusing on genetic factors, currently variants in at least 65 genes have been suggested as being associated with periodontitis based on genome-wide association studies and candidate gene case control studies. These studies have found pleiotropy between periodontitis and cardiovascular diseases. Most of these studies point to potential pathways in the pathogenesis of periodontal disease. Also, most contribute to a small portion of the total risk profile of periodontitis, often limited to specific racial and ethnic groups. To date, 4 genetic loci are shared between atherosclerotic cardiovascular diseases and periodontitis, ie, CDKN2B-AS1(ANRIL), a conserved noncoding element within CAMTA1 upstream of VAMP3, PLG, and a haplotype block at the VAMP8 locus. The shared genes suggest that periodontitis is not causally related to atherosclerotic diseases, but rather both conditions are sequelae of similar (the same?) aberrant inflammatory pathways. In addition to variations in genomic sequences, epigenetic modifications of DNA can affect the genetic blueprint of the host responses. This emerging field will yield new valuable information about susceptibility to periodontitis and subsequent persisting inflammatory reactions in periodontitis. Further studies are required to verify and expand our knowledge base before final cause and effect conclusions about the role of inflammation and genetic factors in periodontitis can be made.", - "journal_title": "Periodontology 2000", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/32385877/" - } - ], - "7f69403c-5bb3-4a3c-889b-6d6c9f144bdd": [ - { - "pub_id": "33203707", - "title": "Plasma Vitamin C and Type 2 Diabetes: Genome-Wide Association Study and Mendelian Randomization Analysis in European Populations.", - "authors": "Ju-Sheng Zheng,Jian'an Luan,Eleni Sofianopoulou,Fumiaki Imamura,Isobel D Stewart,Felix R Day,Maik Pietzner,Eleanor Wheeler,Luca A Lotta,Thomas E Gundersen,Pilar Amiano,Eva Ardanaz,Mar\u00eda-Dolores Chirlaque,Guy Fagherazzi,Paul W Franks,Rudolf Kaaks,Nasser Laouali,Francesca Romana Mancini,Peter M Nilsson,N Charlotte Onland-Moret,Anja Olsen,Kim Overvad,Salvatore Panico,Domenico Palli,Fulvio Ricceri,Olov Rolandsson,Annemieke M W Spijkerman,Mar\u00eda-Jos\u00e9 S\u00e1nchez,Matthias B Schulze,N\u00faria Sala,Sabina Sieri,Anne Tj\u00f8nneland,Rosario Tumino,Yvonne T van der Schouw,Elisabete Weiderpass,Elio Riboli,John Danesh,Adam S Butterworth,Stephen J Sharp,Claudia Langenberg,Nita G Forouhi,Nicholas J Wareham", - "abstract": "Higher plasma vitamin C levels are associated with lower type 2 diabetes risk, but whether this association is causal is uncertain. To investigate this, we studied the association of genetically predicted plasma vitamin C with type 2 diabetes. We conducted genome-wide association studies of plasma vitamin C among 52,018 individuals of European ancestry to discover novel genetic variants. We performed Mendelian randomization analyses to estimate the association of genetically predicted differences in plasma vitamin C with type 2 diabetes in up to 80,983 case participants and 842,909 noncase participants. We compared this estimate with the observational association between plasma vitamin C and incident type 2 diabetes, including 8,133 case participants and 11,073 noncase participants. We identified 11 genomic regions associated with plasma vitamin C (<i>P</i> < 5 \u00d7 10<sup>-8</sup>), with the strongest signal at <i>SLC23A1</i>, and 10 novel genetic loci including <i>SLC23A3</i>, <i>CHPT1</i>, <i>BCAS3</i>, <i>SNRPF</i>, <i>RER1</i>, <i>MAF</i>, <i>GSTA5</i>, <i>RGS14</i>, <i>AKT1</i>, and <i>FADS1</i>. Plasma vitamin C was inversely associated with type 2 diabetes (hazard ratio per SD 0.88; 95% CI 0.82, 0.94), but there was no association between genetically predicted plasma vitamin C (excluding <i>FADS1</i> variant due to its apparent pleiotropic effect) and type 2 diabetes (1.03; 95% CI 0.96, 1.10). These findings indicate discordance between biochemically measured and genetically predicted plasma vitamin C levels in the association with type 2 diabetes among European populations. The null Mendelian randomization findings provide no strong evidence to suggest the use of vitamin C supplementation for type 2 diabetes prevention.", - "journal_title": "Diabetes care", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/33203707/" - } - ], - "1c18e524-0f4e-4024-b937-aef9edccee80": [ - { - "pub_id": "30809045", - "title": "Characteristics and quality of genetics and genomics mobile apps: a systematic review.", - "authors": "Divya Talwar,Yu-Lyu Yeh,Wei-Ju Chen,Lei-Shih Chen", - "abstract": "Mobile applications (apps) have been increasingly utilized to access the latest and abundant information related to genetics/genomics for resources, risk assessments, and individualized recommendations. Nevertheless, the number and quality of the current apps in genetics/genomics remain unknown. Thus, in this review, we aimed to identify existing genetic/genomic apps, summarize their characteristics, and examine their quality. A systematic search of genetics/genomics apps was conducted on Apple Store and Google Play. We adapted a validated evaluation scale, Mobile App Rating Scale (MARS), to examine the quality of genetics/genomics apps. Eighty-eight genetics/genomics apps, with the cost ranging from free to $49.99, formed the final sample. Findings showed that the majority of the apps had reference/resource as a feature (95.5%), had health professional students as the target audience (86.4%), and did not focus on specific diseases (78.5%). Only 21.6% of the apps were developed by reliable or authoritative agencies, and the apps' overall quality was slightly above average based on the criteria of the MARS. Therefore, while genetics/genomics mobile apps might be useful resources, their quality still needs improvement, especially with respect to the credibility and evidence-based items of app information as well as the customization items of app engagement; caution must be taken when using those apps.", - "journal_title": "European journal of human genetics : EJHG", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/30809045/" - } - ], - "d2ae7a22-e865-4927-885f-2f024b350fa5": [ - { - "pub_id": "30394782", - "title": "Precision behavioral medicine: Implications of genetic and genomic discoveries for behavioral weight loss treatment.", - "authors": "Jeanne M McCaffery", - "abstract": "This article reviews the concept of precision behavioral medicine and the progress toward applying genetics and genomics as tools to optimize weight management intervention. We discuss genetic, epigenetic, and genomic markers, as well as interactions between genetics and the environment as they relate to obesity and behavioral weight loss to date. Recommendations for the conditions under which genetics and genomics could be incorporated to support clinical decision-making in behavioral weight loss are outlined and illustrative scenarios of how this approach could improve clinical outcomes are provided. It is concluded that there is not yet sufficient evidence to leverage genetics or genomics to aid the treatment of obesity but the foundations are being laid. (PsycINFO Database Record (c) 2018 APA, all rights reserved).", - "journal_title": "The American psychologist", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/30394782/" - } - ], - "22125d3d-2da9-4e8e-aac4-559d9a7cf99c": [ - { - "pub_id": "26487741", - "title": "Identifying Novel Gene Variants in Coronary Artery Disease and Shared Genes With Several Cardiovascular Risk Factors.", - "authors": "Marissa LeBlanc,Verena Zuber,Bettina Kulle Andreassen,Aree Witoelar,Lingyao Zeng,Francesco Bettella,Yunpeng Wang,Linda K McEvoy,Wesley K Thompson,Andrew J Schork,Sjur Reppe,Elizabeth Barrett-Connor,Symen Ligthart,Abbas Dehghan,Kaare M Gautvik,Christopher P Nelson,Heribert Schunkert,Nilesh J Samani, ,Paul M Ridker,Daniel I Chasman,P\u00e5l Aukrust,Srdjan Djurovic,Arnoldo Frigessi,Rahul S Desikan,Anders M Dale,Ole A Andreassen", - "abstract": "Coronary artery disease (CAD) is a critical determinant of morbidity and mortality. Previous studies have identified several cardiovascular disease risk factors, which may partly arise from a shared genetic basis with CAD, and thus be useful for discovery of CAD genes. We aimed to improve discovery of CAD genes and inform the pathogenic relationship between CAD and several cardiovascular disease risk factors using a shared polygenic signal-informed statistical framework. Using genome-wide association studies summary statistics and shared polygenic pleiotropy-informed conditional and conjunctional false discovery rate methodology, we systematically investigated genetic overlap between CAD and 8 traits related to cardiovascular disease risk factors: low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, triglycerides, type 2 diabetes mellitus, C-reactive protein, body mass index, systolic blood pressure, and type 1 diabetes mellitus. We found significant enrichment of single-nucleotide polymorphisms associated with CAD as a function of their association with low-density lipoprotein, high-density lipoprotein, triglycerides, type 2 diabetes mellitus, C-reactive protein, body mass index, systolic blood pressure, and type 1 diabetes mellitus. Applying the conditional false discovery rate method to the enriched phenotypes, we identified 67 novel loci associated with CAD (overall conditional false discovery rate <0.01). Furthermore, we identified 53 loci with significant effects in both CAD and at least 1 of low-density lipoprotein, high-density lipoprotein, triglycerides, type 2 diabetes mellitus, C-reactive protein, systolic blood pressure, and type 1 diabetes mellitus. The observed polygenic overlap between CAD and cardiometabolic risk factors indicates a pathogenic relation that warrants further investigation. The new gene loci identified implicate novel genetic mechanisms related to CAD.", - "journal_title": "Circulation research", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/26487741/" - } - ], - "6a8362f1-8572-4f6f-97d4-1d783c1937c7": [ - { - "pub_id": "31500827", - "title": "(Epi)genomic heterogeneity of pancreatic islet function and failure in type 2 diabetes.", - "authors": "Nathan Lawlor,Michael L Stitzel", - "abstract": "Pancreatic Islets of Langerhans are heterogeneous tissues consisting of multiple endocrine cell types that carry out distinct yet coordinated roles to regulate blood glucose homeostasis. Islet dysfunction and specifically failure of the beta cells to secrete adequate insulin are known precursors to type 2 diabetes (T2D) onset. However, the exact genetic, (epi)genomic, and environmental mechanisms that contribute to islet failure, and ultimately to T2D pathogenesis, require further elucidation. This review summarizes efforts and advances in dissection of the complex genetic underpinnings of islet function and resilience in T2D pathogenesis. In this review, we will highlight results of the latest T2D genome-wide association study (GWAS) and discuss how these data are being combined with clinical measures in patients to uncover putative T2D subtypes and with functional (epi)genomic studies in islets to understand the genetic programming of islet cell identity, function, and adaptation. Finally, we discuss new and important opportunities to address major knowledge gaps in our understanding of islet (dys)function in T2D risk and progression. Genetic variation exerts clear effects on the islet epigenome, regulatory element usage, and gene expression. Future (epi)genomic comparative analyses between T2D and normal islets should incorporate genetics to distinguish patient-specific from disease-specific differences. Incorporating genotype information into future analyses and studies will also enable more precise insights into the molecular genetics of islet deficiency and failure in T2D risk, and should ultimately contribute to a stratified view of T2D and more precise treatment strategies. Islet cellular heterogeneity continues to remain a challenge for understanding the associations between islet failure and T2D development. Further efforts to obtain purified islet cell type populations and determine the specific genetic and environmental effects on each will help address this. Beyond observation of islets at steady state conditions, more research of islet stress and stimulation responses are needed to understand the transition of these tissues from a healthy to diseased state. Together, focusing on these objectives will provide more opportunities to prevent, treat, and manage T2D.", - "journal_title": "Molecular metabolism", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/31500827/" - } - ], - "c49a1138-407c-4ee7-bdd3-83e1e86f5f48": [ - { - "pub_id": "27323467", - "title": "Genetics and Genomics of Pathogens: Fighting Infections with Genome-Sequencing Technology.", - "authors": "Alexandra Plavskin", - "abstract": "Discussions of clinical genetics and genomics often focus on screening for disease-causing genes in humans and the promise of targeted therapies. Another important area of research is analysis of pathogen genomes. Genetics and genomics-based approaches, such as population genomics and phylogenetics, provide insight into mechanisms of resistance, sources of infections, and pathogen transmission routes.", - "journal_title": "Medsurg nursing : official journal of the Academy of Medical-Surgical Nurses", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/27323467/" - } - ], - "66948d59-a372-4efc-8610-f2fa6fd0c66c": [ - { - "pub_id": "33419004", - "title": "Genetics and Genomics of <i>SOST</i>: Functional Analysis of Variants and Genomic Regulation in Osteoblasts.", - "authors": "N\u00faria Mart\u00ednez-Gil,Neus Roca-Ayats,M\u00f3nica Cozar,Nat\u00e0lia Garcia-Giralt,Diana Ovejero,Xavier Nogu\u00e9s,Daniel Grinberg,Susanna Balcells", - "abstract": "<i>SOST</i> encodes the sclerostin protein, which acts as a key extracellular inhibitor of the canonical Wnt pathway in bone, playing a crucial role in skeletal development and bone homeostasis. The objective of this work was to assess the functionality of two variants previously identified (the rare variant rs570754792 and the missense variant p.Val10Ile) and to investigate the physical interactors of the <i>SOST</i> proximal promoter region in bone cells. Through a promoter luciferase reporter assay we show that the minor allele of rs570754792, a variant located in the extended TATA box motif, displays a significant decrease in promoter activity. Likewise, through western blot studies of extracellular and intracellular sclerostin, we observe a reduced expression of the p.Val10Ile mutant protein. Finally, using a circular chromosome conformation capture assay (4C-seq) in 3 bone cell types (MSC, hFOB, Saos-2), we have detected physical interactions between the <i>SOST</i> proximal promoter and the <i>ECR5</i> enhancer, several additional enhancers located between <i>EVT4</i> and <i>MEOX1</i> and a distant region containing exon 18 of <i>DHX8</i>. In conclusion, <i>SOST</i> presents functional regulatory and missense variants that affect its expression and displays physical contacts with far reaching genomic sequences, which may play a role in its regulation within bone cells.", - "journal_title": "International journal of molecular sciences", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/33419004/" - } - ], - "42e06cda-627e-46f2-a289-c4c1fb6af8f2": [ - { - "pub_id": "27681254", - "title": "Differentially expressed microRNAs in the corpus cavernosum from a murine model with type 2 diabetes mellitus-associated erectile dysfunction.", - "authors": "Feng Pan,Jinwei You,Yuan Liu,Xuefeng Qiu,Wen Yu,Jiehua Ma,Lianjun Pan,Aixia Zhang,Qipeng Zhang", - "abstract": "To better understand the molecular aetiology of type 2 diabetes mellitus-associated erectile dysfunction (T2DMED) and to provide candidates for further study of its diagnosis and treatment, this study was designed to investigate differentially expressed microRNAs (miRNAs) in the corpus cavernosum (CC) of mice with T2DMED using GeneChip array techniques (Affymetrix miRNA 4.0 Array) and to predict target genes and signalling pathways regulated by these miRNAs based on bioinformatic analysis using TargetScan, the DAIAN web platform and DAVID. In the initial screening, 21 miRNAs appeared distinctly expressed in the T2DMED group (fold change \u22653, p\u00a0\u2264\u00a00.01). Among them, the differential expression of miR-18a, miR-206, miR-122, and miR-133 were confirmed by qRT-PCR (p\u00a0<\u00a00.05 and FDR <5\u00a0%). According to bioinformatic analysis, the four miRNAs were speculated to play potential roles in the mechanisms of T2DMED via regulating 28 different genes and several pathways, including apoptosis, fibrosis, eNOS/cGMP/PKG, and vascular smooth muscle contraction processes, which mainly focused on influencing the functions of the endothelium and smooth muscle in the CC. IGF-1, as one of the target genes, was verified to decrease in the CCs of T2DMED animals via ELISA and was confirmed as the target of miR-18a or miR-206 via luciferase assay. Finally, these four miRNAs deserve further confirmation as biomarkers of T2DMED in larger studies. Additionally, miR-18a and/or miR-206 may provide new preventive/therapeutic targets for ED management by targeting IGF-1.", - "journal_title": "Molecular genetics and genomics : MGG", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/27681254/" - } - ], - "54812135-0ef6-4654-afe9-8ee40336238e": [ - { - "pub_id": "35638288", - "title": "A genome-wide functional genomics approach uncovers genetic determinants of immune phenotypes in type 1 diabetes.", - "authors": "Xiaojing Chu,Anna W M Janssen,Hans Koenen,Linzhung Chang,Xuehui He,Irma Joosten,Rinke Stienstra,Yunus Kuijpers,Cisca Wijmenga,Cheng-Jian Xu,Mihai G Netea,Cees J Tack,Yang Li", - "abstract": "The large inter-individual variability in immune-cell composition and function determines immune responses in general and susceptibility o immune-mediated diseases in particular. While much has been learned about the genetic variants relevant for type 1 diabetes (T1D), the pathophysiological mechanisms through which these variations exert their effects remain unknown. Blood samples were collected from 243 patients with T1D of Dutch descent. We applied genetic association analysis on >200 immune-cell traits and >100 cytokine production profiles in response to stimuli measured to identify genetic determinants of immune function, and compared the results obtained in T1D to healthy controls. Genetic variants that determine susceptibility to T1D significantly affect T cell composition. Specifically, the CCR5+ regulatory T cells associate with T1D through the CCR region, suggesting a shared genetic regulation. Genome-wide quantitative trait loci (QTLs) mapping analysis of immune traits revealed 15 genetic loci that influence immune responses in T1D, including 12 that have never been reported in healthy population studies, implying a disease-specific genetic regulation. This study provides new insights into the genetic factors that affect immunological responses in T1D. This work was supported by an ERC starting grant (no. 948207) and a Radboud University Medical Centre Hypatia grant (2018) to YL and an ERC advanced grant (no. 833247) and a Spinoza grant of the Netherlands Association for Scientific Research to MGN CT received funding from the Perspectief Biomarker Development Center Research Programme, which is (partly) financed by the Netherlands Organisation for Scientific Research (NWO). AJ was funded by a grant from the European Foundation for the Study of Diabetes (EFSD/AZ Macrovascular Programme 2015). XC was supported by the China Scholarship Council (201706040081).", - "journal_title": "eLife", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/35638288/" - } - ], - "ba4df6c3-8d2c-4b96-8fae-e5b5072eb1c7": [ - { - "pub_id": "26912320", - "title": "Systematic Evaluation of Genes and Genetic Variants Associated with Type 1 Diabetes Susceptibility.", - "authors": "Ramesh Ram,Munish Mehta,Quang T Nguyen,Irma Larma,Bernhard O Boehm,Flemming Pociot,Patrick Concannon,Grant Morahan", - "abstract": "Genome-wide association studies have found >60 loci that confer genetic susceptibility to type 1 diabetes (T1D). Many of these are defined only by anonymous single nucleotide polymorphisms: the underlying causative genes, as well as the molecular bases by which they mediate susceptibility, are not known. Identification of how these variants affect the complex mechanisms contributing to the loss of tolerance is a challenge. In this study, we performed systematic analyses to characterize these variants. First, all known genes in strong linkage disequilibrium (r(2) > 0.8) with the reported single nucleotide polymorphisms for each locus were tested for commonly occurring nonsynonymous variations. We found only a total of 22 candidate genes at 16 T1D loci with common nonsynonymous alleles. Next, we performed functional studies to examine the effect of non-HLA T1D risk alleles on regulating expression levels of genes in four different cell types: EBV-transformed B cell lines (resting and 6 h PMA stimulated) and purified CD4(+) and CD8(+) T cells. We mapped cis-acting expression quantitative trait loci and found 24 non-HLA loci that affected the expression of 31 transcripts significantly in at least one cell type. Additionally, we observed 25 loci that affected 38 transcripts in trans. In summary, our systems genetics analyses defined the effect of T1D risk alleles on levels of gene expression and provide novel insights into the complex genetics of T1D, suggesting that most of the T1D risk alleles mediate their effect by influencing expression of multiple nearby genes.", - "journal_title": "Journal of immunology (Baltimore, Md. : 1950)", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/26912320/" - } - ], - "a4b0655d-895c-4368-9401-ee2903b15d42": [ - { - "pub_id": "36739136", - "title": "A 12-gene pharmacogenetic panel to prevent adverse drug reactions: an open-label, multicentre, controlled, cluster-randomised crossover implementation study.", - "authors": "Jesse J Swen,Cathelijne H van der Wouden,Lisanne En Manson,Heshu Abdullah-Koolmees,Kathrin Blagec,Tanja Blagus,Stefan B\u00f6hringer,Anne Cambon-Thomsen,Erika Cecchin,Ka-Chun Cheung,Vera Hm Deneer,Mathilde Dupui,Magnus Ingelman-Sundberg,Siv Jonsson,Candace Joefield-Roka,Katja S Just,Mats O Karlsson,Lidija Konta,Rudolf Koopmann,Marjolein Kriek,Thorsten Lehr,Christina Mitropoulou,Emmanuelle Rial-Sebbag,Victoria Rollinson,Rossana Roncato,Matthias Samwald,Elke Schaeffeler,Maria Skokou,Matthias Schwab,Daniela Steinberger,Julia C Stingl,Roman Tremmel,Richard M Turner,Mandy H van Rhenen,Cristina L D\u00e1vila Fajardo,Vita Dol\u017ean,George P Patrinos,Munir Pirmohamed,Gere Sunder-Plassmann,Giuseppe Toffoli,Henk-Jan Guchelaar, ", - "abstract": "The benefit of pharmacogenetic testing before starting drug therapy has been well documented for several single gene-drug combinations. However, the clinical utility of a pre-emptive genotyping strategy using a pharmacogenetic panel has not been rigorously assessed. We conducted an open-label, multicentre, controlled, cluster-randomised, crossover implementation study of a 12-gene pharmacogenetic panel in 18 hospitals, nine community health centres, and 28 community pharmacies in seven European countries (Austria, Greece, Italy, the Netherlands, Slovenia, Spain, and the UK). Patients aged 18 years or older receiving a first prescription for a drug clinically recommended in the guidelines of the Dutch Pharmacogenetics Working Group (ie, the index drug) as part of routine care were eligible for inclusion. Exclusion criteria included previous genetic testing for a gene relevant to the index drug, a planned duration of treatment of less than 7 consecutive days, and severe renal or liver insufficiency. All patients gave written informed consent before taking part in the study. Participants were genotyped for 50 germline variants in 12 genes, and those with an actionable variant (ie, a drug-gene interaction test result for which the Dutch Pharmacogenetics Working Group [DPWG] recommended a change to standard-of-care drug treatment) were treated according to DPWG recommendations. Patients in the control group received standard treatment. To prepare clinicians for pre-emptive pharmacogenetic testing, local teams were educated during a site-initiation visit and online educational material was made available. The primary outcome was the occurrence of clinically relevant adverse drug reactions within the 12-week follow-up period. Analyses were irrespective of patient adherence to the DPWG guidelines. The primary analysis was done using a gatekeeping analysis, in which outcomes in people with an actionable drug-gene interaction in the study group versus the control group were compared, and only if the difference was statistically significant was an analysis done that included all of the patients in the study. Outcomes were compared between the study and control groups, both for patients with an actionable drug-gene interaction test result (ie, a result for which the DPWG recommended a change to standard-of-care drug treatment) and for all patients who received at least one dose of index drug. The safety analysis included all participants who received at least one dose of a study drug. This study is registered with ClinicalTrials.gov, NCT03093818 and is closed to new participants. Between March 7, 2017, and June 30, 2020, 41\u2008696 patients were assessed for eligibility and 6944 (51\u00b74 % female, 48\u00b76% male; 97\u00b77% self-reported European, Mediterranean, or Middle Eastern ethnicity) were enrolled and assigned to receive genotype-guided drug treatment (n=3342) or standard care (n=3602). 99 patients (52 [1\u00b76%] of the study group and 47 [1\u00b73%] of the control group) withdrew consent after group assignment. 652 participants (367 [11\u00b70%] in the study group and 285 [7\u00b79%] in the control group) were lost to follow-up. In patients with an actionable test result for the index drug (n=1558), a clinically relevant adverse drug reaction occurred in 152 (21\u00b70%) of 725 patients in the study group and 231 (27\u00b77%) of 833 patients in the control group (odds ratio [OR] 0\u00b770 [95% CI 0\u00b754-0\u00b791]; p=0\u00b70075), whereas for all patients, the incidence was 628 (21\u00b75%) of 2923 patients in the study group and 934 (28\u00b76%) of 3270 patients in the control group (OR 0\u00b770 [95% CI 0\u00b761-0\u00b779]; p <0\u00b70001). Genotype-guided treatment using a 12-gene pharmacogenetic panel significantly reduced the incidence of clinically relevant adverse drug reactions and was feasible across diverse European health-care system organisations and settings. Large-scale implementation could help to make drug therapy increasingly safe. European Union Horizon 2020.", - "journal_title": "Lancet (London, England)", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/36739136/" - } - ], - "35e2839e-4c74-4d5e-8321-dba5a74380a4": [ - { - "pub_id": "27687163", - "title": "Embracing an \"African Ethos\" to facilitate African immigrants participation in medical genetics and genomics research.", - "authors": "Aaron G Buseh,Patricia E Stevens,Sandra Millon-Underwood,Sheryl T Kelber,Leolia Townsend", - "abstract": "Limited published research exists on perceptions and potentials for black African immigrants' participation in medical genetics and genomics research. This study explores the inclination and disinclination of African immigrants\u00a0to be involved in genetics and genomics research. In-depth qualitative interviews were employed in which a sample of black African immigrants 18\u00a0years and older (n = 34) were interviewed. Barriers included contrary beliefs and customs about disease and the human body that differs from Western conceptions, and lack of genuine connection to the health care system. Facilitators included promotion of an \"African ethos,\" wherein Africans unite with one another in a communal extension of self and robust community involvement across the life span of genetic studies. It is important for researchers and genetic counselors to understand the sociocultural underpinnings of African immigrants about genetics and genomics research as an initial step to encouraging their participation.", - "journal_title": "Nursing outlook", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/27687163/" - } - ], - "ec830735-113b-489f-bbd9-4127790b41c1": [ - { - "pub_id": "31006638", - "title": "Strain- and Species-Level Variation in the Microbiome of Diabetic Wounds Is Associated with Clinical Outcomes and Therapeutic Efficacy.", - "authors": "Lindsay R Kalan,Jacquelyn S Meisel,Michael A Loesche,Joseph Horwinski,Ioana Soaita,Xiaoxuan Chen,Aayushi Uberoi,Sue E Gardner,Elizabeth A Grice", - "abstract": "Chronic wounds are a major complication of diabetes associated with high morbidity and health care expenditures. To investigate the role of colonizing microbiota\u00a0in diabetic wound healing, clinical outcomes, and response to interventions, we conducted a longitudinal, prospective study of patients with neuropathic diabetic foot ulcers (DFU). Metagenomic shotgun sequencing revealed that strain-level variation of Staphylococcus aureus and genetic signatures of biofilm formation were associated with poor outcomes. Cultured wound isolates of S.\u00a0aureus elicited differential phenotypes in mouse models that corresponded with patient outcomes, while wound \"bystanders\" such as Corynebacterium striatum and Alcaligenes faecalis, typically considered commensals or contaminants, also significantly impacted wound severity and healing. Antibiotic resistance genes were widespread, and debridement, rather than antibiotic treatment, significantly shifted the DFU microbiota in patients with more favorable outcomes. These findings suggest that the DFU microbiota may be a marker for clinical outcomes and response to therapeutic interventions.", - "journal_title": "Cell host & microbe", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/31006638/" - } - ], - "d343a1b9-f9d3-49e3-a13b-a41eead992c4": [ - { - "pub_id": "34059833", - "title": "The trans-ancestral genomic architecture of glycemic traits.", - "authors": "Ji Chen,Cassandra N Spracklen,Ga\u00eblle Marenne,Arushi Varshney,Laura J Corbin,Jian'an Luan,Sara M Willems,Ying Wu,Xiaoshuai Zhang,Momoko Horikoshi,Thibaud S Boutin,Reedik M\u00e4gi,Johannes Waage,Ruifang Li-Gao,Kei Hang Katie Chan,Jie Yao,Mila D Anasanti,Audrey Y Chu,Annique Claringbould,Jani Heikkinen,Jaeyoung Hong,Jouke-Jan Hottenga,Shaofeng Huo,Marika A Kaakinen,Tin Louie,Winfried M\u00e4rz,Hortensia Moreno-Macias,Anne Ndungu,Sarah C Nelson,Ilja M Nolte,Kari E North,Chelsea K Raulerson,Debashree Ray,Rebecca Rohde,Denis Rybin,Claudia Schurmann,Xueling Sim,Lorraine Southam,Isobel D Stewart,Carol A Wang,Yujie Wang,Peitao Wu,Weihua Zhang,Tarunveer S Ahluwalia,Emil V R Appel,Lawrence F Bielak,Jennifer A Brody,No\u00ebl P Burtt,Claudia P Cabrera,Brian E Cade,Jin Fang Chai,Xiaoran Chai,Li-Ching Chang,Chien-Hsiun Chen,Brian H Chen,Kumaraswamy Naidu Chitrala,Yen-Feng Chiu,Hugoline G de Haan,Graciela E Delgado,Ayse Demirkan,Qing Duan,Jorgen Engmann,Segun A Fatumo,Javier Gay\u00e1n,Franco Giulianini,Jung Ho Gong,Stefan Gustafsson,Yang Hai,Fernando P Hartwig,Jing He,Yoriko Heianza,Tao Huang,Alicia Huerta-Chagoya,Mi Yeong Hwang,Richard A Jensen,Takahisa Kawaguchi,Katherine A Kentistou,Young Jin Kim,Marcus E Kleber,Ishminder K Kooner,Shuiqing Lai,Leslie A Lange,Carl D Langefeld,Marie Lauzon,Man Li,Symen Ligthart,Jun Liu,Marie Loh,Jirong Long,Valeriya Lyssenko,Massimo Mangino,Carola Marzi,May E Montasser,Abhishek Nag,Masahiro Nakatochi,Damia Noce,Raymond Noordam,Giorgio Pistis,Michael Preuss,Laura Raffield,Laura J Rasmussen-Torvik,Stephen S Rich,Neil R Robertson,Rico Rueedi,Kathleen Ryan,Serena Sanna,Richa Saxena,Katharina E Schraut,Bengt Sennblad,Kazuya Setoh,Albert V Smith,Thomas Spars\u00f8,Rona J Strawbridge,Fumihiko Takeuchi,Jingyi Tan,Stella Trompet,Erik van den Akker,Peter J van der Most,Niek Verweij,Mandy Vogel,Heming Wang,Chaolong Wang,Nan Wang,Helen R Warren,Wanqing Wen,Tom Wilsgaard,Andrew Wong,Andrew R Wood,Tian Xie,Mohammad Hadi Zafarmand,Jing-Hua Zhao,Wei Zhao,Najaf Amin,Zorayr Arzumanyan,Arne Astrup,Stephan J L Bakker,Damiano Baldassarre,Marian Beekman,Richard N Bergman,Alain Bertoni,Matthias Bl\u00fcher,Lori L Bonnycastle,Stefan R Bornstein,Donald W Bowden,Qiuyin Cai,Archie Campbell,Harry Campbell,Yi Cheng Chang,Eco J C de Geus,Abbas Dehghan,Shufa Du,Gudny Eiriksdottir,Aliki Eleni Farmaki,Mattias Fr\u00e5nberg,Christian Fuchsberger,Yutang Gao,Anette P Gjesing,Anuj Goel,Sohee Han,Catharina A Hartman,Christian Herder,Andrew A Hicks,Chang-Hsun Hsieh,Willa A Hsueh,Sahoko Ichihara,Michiya Igase,M Arfan Ikram,W Craig Johnson,Marit E J\u00f8rgensen,Peter K Joshi,Rita R Kalyani,Fouad R Kandeel,Tomohiro Katsuya,Chiea Chuen Khor,Wieland Kiess,Ivana Kolcic,Teemu Kuulasmaa,Johanna Kuusisto,Kristi L\u00e4ll,Kelvin Lam,Deborah A Lawlor,Nanette R Lee,Rozenn N Lemaitre,Honglan Li, ,Shih-Yi Lin,Jaana Lindstr\u00f6m,Allan Linneberg,Jianjun Liu,Carlos Lorenzo,Tatsuaki Matsubara,Fumihiko Matsuda,Geltrude Mingrone,Simon Mooijaart,Sanghoon Moon,Toru Nabika,Girish N Nadkarni,Jerry L Nadler,Mari Nelis,Matt J Neville,Jill M Norris,Yasumasa Ohyagi,Annette Peters,Patricia A Peyser,Ozren Polasek,Qibin Qi,Dennis Raven,Dermot F Reilly,Alex Reiner,Fernando Rivideneira,Kathryn Roll,Igor Rudan,Charumathi Sabanayagam,Kevin Sandow,Naveed Sattar,Annette Sch\u00fcrmann,Jinxiu Shi,Heather M Stringham,Kent D Taylor,Tanya M Teslovich,Betina Thuesen,Paul R H J Timmers,Elena Tremoli,Michael Y Tsai,Andre Uitterlinden,Rob M van Dam,Diana van Heemst,Astrid van Hylckama Vlieg,Jana V van Vliet-Ostaptchouk,Jagadish Vangipurapu,Henrik Vestergaard,Tao Wang,Ko Willems van Dijk,Tatijana Zemunik,Gon\u00e7alo R Abecasis,Linda S Adair,Carlos Alberto Aguilar-Salinas,Marta E Alarc\u00f3n-Riquelme,Ping An,Larissa Aviles-Santa,Diane M Becker,Lawrence J Beilin,Sven Bergmann,Hans Bisgaard,Corri Black,Michael Boehnke,Eric Boerwinkle,Bernhard O B\u00f6hm,Klaus B\u00f8nnelykke,D I Boomsma,Erwin P Bottinger,Thomas A Buchanan,Micka\u00ebl Canouil,Mark J Caulfield,John C Chambers,Daniel I Chasman,Yii-Der Ida Chen,Ching-Yu Cheng,Francis S Collins,Adolfo Correa,Francesco Cucca,H Janaka de Silva,George Dedoussis,S\u00f6lve Elmst\u00e5hl,Michele K Evans,Ele Ferrannini,Luigi Ferrucci,Jose C Florez,Paul W Franks,Timothy M Frayling,Philippe Froguel,Bruna Gigante,Mark O Goodarzi,Penny Gordon-Larsen,Harald Grallert,Niels Grarup,Sameline Grimsgaard,Leif Groop,Vilmundur Gudnason,Xiuqing Guo,Anders Hamsten,Torben Hansen,Caroline Hayward,Susan R Heckbert,Bernardo L Horta,Wei Huang,Erik Ingelsson,Pankow S James,Marjo-Ritta Jarvelin,Jost B Jonas,J Wouter Jukema,Pontiano Kaleebu,Robert Kaplan,Sharon L R Kardia,Norihiro Kato,Sirkka M Keinanen-Kiukaanniemi,Bong-Jo Kim,Mika Kivimaki,Heikki A Koistinen,Jaspal S Kooner,Antje K\u00f6rner,Peter Kovacs,Diana Kuh,Meena Kumari,Zoltan Kutalik,Markku Laakso,Timo A Lakka,Lenore J Launer,Karin Leander,Huaixing Li,Xu Lin,Lars Lind,Cecilia Lindgren,Simin Liu,Ruth J F Loos,Patrik K E Magnusson,Anubha Mahajan,Andres Metspalu,Dennis O Mook-Kanamori,Trevor A Mori,Patricia B Munroe,Inger Nj\u00f8lstad,Jeffrey R O'Connell,Albertine J Oldehinkel,Ken K Ong,Sandosh Padmanabhan,Colin N A Palmer,Nicholette D Palmer,Oluf Pedersen,Craig E Pennell,David J Porteous,Peter P Pramstaller,Michael A Province,Bruce M Psaty,Lu Qi,Leslie J Raffel,Rainer Rauramaa,Susan Redline,Paul M Ridker,Frits R Rosendaal,Timo E Saaristo,Manjinder Sandhu,Jouko Saramies,Neil Schneiderman,Peter Schwarz,Laura J Scott,Elizabeth Selvin,Peter Sever,Xiao-Ou Shu,P Eline Slagboom,Kerrin S Small,Blair H Smith,Harold Snieder,Tamar Sofer,Thorkild I A S\u00f8rensen,Tim D Spector,Alice Stanton,Claire J Steves,Michael Stumvoll,Liang Sun,Yasuharu Tabara,E Shyong Tai,Nicholas J Timpson,Anke T\u00f6njes,Jaakko Tuomilehto,Teresa Tusie,Matti Uusitupa,Pim van der Harst,Cornelia van Duijn,Veronique Vitart,Peter Vollenweider,Tanja G M Vrijkotte,Lynne E Wagenknecht,Mark Walker,Ya X Wang,Nick J Wareham,Richard M Watanabe,Hugh Watkins,Wen B Wei,Ananda R Wickremasinghe,Gonneke Willemsen,James F Wilson,Tien-Yin Wong,Jer-Yuarn Wu,Anny H Xiang,Lisa R Yanek,Lo\u00efc Yengo,Mitsuhiro Yokota,Eleftheria Zeggini,Wei Zheng,Alan B Zonderman,Jerome I Rotter,Anna L Gloyn,Mark I McCarthy,Jos\u00e9e Dupuis,James B Meigs,Robert A Scott,Inga Prokopenko,Aaron Leong,Ching-Ti Liu,Stephen C J Parker,Karen L Mohlke,Claudia Langenberg,Eleanor Wheeler,Andrew P Morris,In\u00eas Barroso, ", - "abstract": "Glycemic traits are used to diagnose and monitor type 2 diabetes and cardiometabolic health. To date, most genetic studies of glycemic traits have focused on individuals of European ancestry. Here we aggregated genome-wide association studies comprising up to 281,416 individuals without diabetes (30% non-European ancestry) for whom fasting glucose, 2-h glucose after an oral glucose challenge, glycated hemoglobin and fasting insulin data were available. Trans-ancestry and single-ancestry meta-analyses identified 242\u2009loci (99 novel; P\u2009<\u20095\u2009\u00d7\u200910<sup>-8</sup>), 80% of which had no significant evidence of between-ancestry heterogeneity. Analyses restricted to individuals of European ancestry with equivalent sample size would have led to 24 fewer new loci. Compared with single-ancestry analyses, equivalent-sized trans-ancestry fine-mapping reduced the number of estimated variants in 99% credible sets by a median of 37.5%. Genomic-feature, gene-expression and gene-set analyses revealed distinct biological signatures for each trait, highlighting different underlying biological pathways. Our results increase our understanding of diabetes pathophysiology by using trans-ancestry studies for improved power and resolution.", - "journal_title": "Nature genetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/34059833/" - } - ], - "d1be871a-23b7-4666-a06c-51cf18a2b653": [ - { - "pub_id": "35708486", - "title": "Novel genes and sex differences in COVID-19 severity.", - "authors": "Raquel Cruz,Silvia Diz-de Almeida,Miguel L\u00f3pez de Heredia,In\u00e9s Quintela,Francisco C Ceballos,Guillermo Pita,Jos\u00e9 M Lorenzo-Salazar,Rafaela Gonz\u00e1lez-Montelongo,Manuela Gago-Dom\u00ednguez,Marta Sevilla Porras,Jair Antonio Tenorio Casta\u00f1o,Julian Nevado,Jose Mar\u00eda Aguado,Carlos Aguilar,Sergio Aguilera-Albesa,Virginia Almadana,Berta Almoguera,Nuria Alvarez,\u00c1lvaro Andreu-Bernabeu,Eunate Arana-Arri,Celso Arango,Mar\u00eda J Arranz,Maria-Jesus Artiga,Ra\u00fal C Baptista-Rosas,Mar\u00eda Barreda-S\u00e1nchez,Moncef Belhassen-Garcia,Joao F Bezerra,Marcos A C Bezerra,Luc\u00eda Boix-Palop,Mar\u00eda Brion,Ram\u00f3n Brugada,Matilde Bustos,Enrique J Calder\u00f3n,Cristina Carbonell,Luis Castano,Jose E Castelao,Rosa Conde-Vicente,M Lourdes Cordero-Lorenzana,Jose L Cortes-Sanchez,Marta Corton,M Teresa Darnaude,Alba De Martino-Rodr\u00edguez,Victor Del Campo-P\u00e9rez,Aranzazu Diaz de Bustamante,Elena Dom\u00ednguez-Garrido,Andre D Luchessi,Roc\u00edo Eiros,Gladys Mercedes Estigarribia Sanabria,Mar\u00eda Carmen Fari\u00f1as,Ux\u00eda Fern\u00e1ndez-Robelo,Amanda Fern\u00e1ndez-Rodr\u00edguez,Tania Fern\u00e1ndez-Villa,Bel\u00e9n Gil-Fournier,Javier G\u00f3mez-Arrue,Beatriz Gonz\u00e1lez \u00c1lvarez,Fernan Gonzalez Bernaldo de Quir\u00f3s,Javier Gonz\u00e1lez-Pe\u00f1as,Juan F Guti\u00e9rrez-Bautista,Mar\u00eda Jos\u00e9 Herrero,Antonio Herrero-Gonzalez,Mar\u00eda A Jimenez-Sousa,Mar\u00eda Claudia Lattig,Anabel Liger Borja,Rosario Lopez-Rodriguez,Esther Mancebo,Caridad Mart\u00edn-L\u00f3pez,Vicente Mart\u00edn,Oscar Martinez-Nieto,Iciar Martinez-Lopez,Michel F Martinez-Resendez,Angel Martinez-Perez,Juliana F Mazzeu,Eleuterio Merayo Mac\u00edas,Pablo Minguez,Victor Moreno Cuerda,Vivian N Silbiger,Silviene F Oliveira,Eva Ortega-Paino,Mara Parellada,Estela Paz-Artal,Ney P C Santos,Patricia P\u00e9rez-Matute,Patricia Perez,M Elena P\u00e9rez-Tom\u00e1s,Teresa Perucho,Mel Lina Pinsach-Abuin,Ericka N Pompa-Mera,Gloria L Porras-Hurtado,Aurora Pujol,Soraya Ramiro Le\u00f3n,Salvador Resino,Marianne R Fernandes,Emilio Rodr\u00edguez-Ruiz,Fernando Rodriguez-Artalejo,Jos\u00e9 A Rodriguez-Garcia,Francisco Ruiz Cabello,Javier Ruiz-Hornillos,Pablo Ryan,Jos\u00e9 Manuel Soria,Juan Carlos Souto,Eduardo Tamayo,Alvaro Tamayo-Velasco,Juan Carlos Taracido-Fernandez,Alejandro Teper,Lilian Torres-Tobar,Miguel Urioste,Juan Valencia-Ramos,Zuleima Y\u00e1\u00f1ez,Ruth Zarate,Tomoko Nakanishi,Sara Pigazzini,Frauke Degenhardt,Guillaume Butler-Laporte,Douglas Maya-Miles,Luis Bujanda,Youssef Bouysran,Adriana Palom,David Ellinghaus,Manuel Mart\u00ednez-Bueno,Selina Rolker,Sara Amitrano,Luisa Roade,Francesca Fava,Christoph D Spinner,Daniele Prati,David Bernardo,Federico Garcia,Gilles Darcis,Israel Fern\u00e1ndez-Cadenas,Jan Cato Holter,Jesus M Banales,Robert Frithiof,Stefano Duga,Rosanna Asselta,Alexandre C Pereira,Manuel Romero-G\u00f3mez,Beatriz Nafr\u00eda-Jim\u00e9nez,Johannes R Hov,Isabelle Migeotte,Alessandra Renieri,Anna M Planas,Kerstin U Ludwig,Maria Buti,Souad Rahmouni,Marta E Alarc\u00f3n-Riquelme,Eva C Schulte,Andre Franke,Tom H Karlsen,Luca Valenti,Hugo Zeberg,Brent Richards,Andrea Ganna,Merc\u00e8 Boada,Itziar de Rojas,Agust\u00edn Ruiz,Pascual S\u00e1nchez-Juan,Luis Miguel Real, , , ,Encarna Guillen-Navarro,Carmen Ayuso,Anna Gonz\u00e1lez-Neira,Jos\u00e9 A Riancho,Augusto Rojas-Martinez,Carlos Flores,Pablo Lapunzina,Angel Carracedo", - "abstract": "Here, we describe the results of a genome-wide study conducted in 11\u2009939 coronavirus disease 2019 (COVID-19) positive cases with an extensive clinical information that were recruited from 34 hospitals across Spain (SCOURGE consortium). In sex-disaggregated genome-wide association studies for COVID-19 hospitalization, genome-wide significance (P\u2009<\u20095\u2009\u00d7\u200910-8) was crossed for variants in 3p21.31 and 21q22.11 loci only among males (P\u2009=\u00a01.3\u2009\u00d7\u200910-22 and P\u2009=\u00a08.1\u2009\u00d7\u200910-12, respectively), and for variants in 9q21.32 near TLE1 only among females (P\u2009=\u00a04.4\u2009\u00d7\u200910-8). In a second phase, results were combined with an independent Spanish cohort (1598 COVID-19 cases and 1068 population controls), revealing in the overall analysis two novel risk loci in 9p13.3 and 19q13.12, with fine-mapping prioritized variants functionally associated with AQP3 (P\u2009=\u00a02.7\u2009\u00d7\u200910-8) and ARHGAP33 (P\u2009=\u00a01.3\u2009\u00d7\u200910-8), respectively. The meta-analysis of both phases with four European studies stratified by sex from the Host Genetics Initiative (HGI) confirmed the association of the 3p21.31 and 21q22.11 loci predominantly in males and replicated a recently reported variant in 11p13 (ELF5, P\u2009=\u20094.1\u2009\u00d7\u200910-8). Six of the COVID-19 HGI discovered loci were replicated and an HGI-based genetic risk score predicted the severity strata in SCOURGE. We also found more SNP-heritability and larger heritability differences by age (<60 or \u226560\u00a0years) among males than among females. Parallel genome-wide screening of inbreeding depression in SCOURGE also showed an effect of homozygosity in COVID-19 hospitalization and severity and this effect was stronger among older males. In summary, new candidate genes for COVID-19 severity and evidence supporting genetic disparities among sexes are provided.", - "journal_title": "Human molecular genetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/35708486/" - } - ], - "e9fe3604-5c5a-41e1-ab6c-3aa69a138823": [ - { - "pub_id": "30356183", - "title": "The human gut microbiome in early-onset type 1 diabetes from the TEDDY study.", - "authors": "Tommi Vatanen,Eric A Franzosa,Randall Schwager,Surya Tripathi,Timothy D Arthur,Kendra Vehik,\u00c5ke Lernmark,William A Hagopian,Marian J Rewers,Jin-Xiong She,Jorma Toppari,Anette-G Ziegler,Beena Akolkar,Jeffrey P Krischer,Christopher J Stewart,Nadim J Ajami,Joseph F Petrosino,Dirk Gevers,Harri L\u00e4hdesm\u00e4ki,Hera Vlamakis,Curtis Huttenhower,Ramnik J Xavier", - "abstract": "Type 1 diabetes (T1D) is an autoimmune disease that targets pancreatic islet beta cells and incorporates genetic and environmental factors<sup>1</sup>, including complex genetic elements<sup>2</sup>, patient exposures<sup>3</sup> and the gut microbiome<sup>4</sup>. Viral infections<sup>5</sup> and broader gut dysbioses<sup>6</sup> have been identified as potential causes or contributing factors; however, human studies have not yet identified microbial compositional or functional triggers that are predictive of islet autoimmunity or T1D. Here we analyse 10,913 metagenomes in stool samples from 783 mostly white, non-Hispanic children. The samples were collected monthly from three months of age until the clinical end point (islet autoimmunity or T1D) in the The Environmental Determinants of Diabetes in the Young (TEDDY) study, to characterize the natural history of the early gut microbiome in connection to islet autoimmunity, T1D diagnosis, and other common early life events such as antibiotic treatments and probiotics. The microbiomes of control children contained more genes that were related to fermentation and the biosynthesis of short-chain fatty acids, but these were not consistently associated with particular taxa across geographically diverse clinical centres, suggesting that microbial factors associated with T1D are taxonomically diffuse but functionally more coherent. When we investigated the broader establishment and development of the infant microbiome, both taxonomic and functional profiles were dynamic and highly individualized, and dominated in the first year of life by one of three largely exclusive Bifidobacterium species (B. bifidum, B. breve or B. longum) or by the phylum Proteobacteria. In particular, the strain-specific carriage of genes for the utilization of human milk oligosaccharide within a subset of B. longum was present specifically in breast-fed infants. These analyses of TEDDY gut metagenomes provide, to our knowledge, the largest and most detailed longitudinal functional profile of the developing gut microbiome in relation to islet autoimmunity, T1D and other early childhood events. Together with existing evidence from human cohorts<sup>7,8</sup> and a T1D mouse model<sup>9</sup>, these data support the protective effects of short-chain fatty acids in early-onset human T1D.", - "journal_title": "Nature", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/30356183/" - } - ], - "2d3ddef3-a947-4991-8c8a-abb2cee94500": [ - { - "pub_id": "27979720", - "title": "Neurodevelopmental disorders.", - "authors": "Anita Thapar,Miriam Cooper,Michael Rutter", - "abstract": "Neurodevelopmental disorders such as attention deficit hyperactivity disorder (ADHD) and autism spectrum disorder, although most commonly considered in childhood, can be lifelong conditions. In this Personal View that is shaped by clinical experience and research, we adopt a conceptual approach. First, we discuss what disorders are neurodevelopmental and why such a grouping is useful. We conclude that both distinction and grouping are helpful and that it is important to take into account the strong overlap across neurodevelopmental disorders. Then we highlight some challenges in bridging research and clinical practice. We discuss the complexity of clinical phenotypes and the importance of the social context. We also argue the importance of viewing neurodevelopmental disorders as traits but highlight that this is not the only approach to use. Finally, we consider developmental change across the life-span. Overall, we argue strongly for a flexible approach in clinical practice that takes into consideration the high level of heterogeneity and overlap in neurodevelopmental disorders and for research to link more closely to what is observed in real-life practice.", - "journal_title": "The lancet. Psychiatry", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/27979720/" - } - ], - "72ebb953-2408-4967-bd33-f36e5789587f": [ - { - "pub_id": "32090477", - "title": "Waist circumference increases risk of coronary heart disease: Evidence from a Mendelian randomization study.", - "authors": "Qinchang Chen,Lingling Li,Junzhe Yi,Kai Huang,Runnan Shen,Ridong Wu,Chen Yao", - "abstract": "This study investigated whether expanding waist circumference (WC) is causally associated with an elevated risk of coronary heart disease (CHD), using a two-sample Mendelian randomization (MR) study through integrating summarized data from genome-wide association study. The data included in this analysis were mainly from the Genetic Investigation of ANthropometric Traits (GIANT), Consortium and Coronary Artery Disease Genome wide Replication, and Meta-analysis plus the Coronary Artery Disease (C4D) Genetics (CARDIoGRAMplusC4D) Consortium. Three statistical approaches, inverse-variance weighted (IVW), weighted median, and MR-Egger regression method were conducted to assess the casual relationship. The exposure was WC, measured by 46 single-nucleotide polymorphisms from GIANT and the outcome was the risk of CHD. Then, we used the genetic data from Neale Lab and TAG to infer whether WC causally affected the established risk factors of CHD. The IVW method presented that genetically predicted WC was positively casually associated with CHD (odds ratio [OR]: 1.57, 95% CI\u00a0=\u00a01.33-1.84; p\u00a0=\u00a04.81e-08), which was consistent with the result of weighted median and MR-Egger regression. MR-Egger regression indicated that there was no directional horizontal pleiotropy to violate the MR assumption. Additionally, expanded WC was also associated with higher risk of hypertension and diabetes, higher cholesterol, more smoking intensity, and decreased frequency of physical activity. Our analysis provided strong evidence to indicate a causal relationship between WC and increased risk of CHD.", - "journal_title": "Molecular genetics & genomic medicine", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/32090477/" - } - ], - "2a94ec9f-6fb6-4ce3-8e33-1a8859470be9": [ - { - "pub_id": "28838971", - "title": "A Loss-of-Function Splice Acceptor Variant in <i>IGF2</i> Is Protective for Type 2 Diabetes.", - "authors": "Josep M Mercader,Rachel G Liao,Avery D Bell,Zachary Dymek,Karol Estrada,Taru Tukiainen,Alicia Huerta-Chagoya,Hortensia Moreno-Mac\u00edas,Kathleen A Jablonski,Robert L Hanson,Geoffrey A Walford,Ignasi Moran,Ling Chen,Vineeta Agarwala,Mar\u00eda Luisa Ordo\u00f1ez-S\u00e1nchez,Rosario Rodr\u00edguez-Guillen,Maribel Rodr\u00edguez-Torres,Yayoi Segura-Kato,Humberto Garc\u00eda-Ortiz,Federico Centeno-Cruz,Francisco Barajas-Olmos,Lizz Caulkins,Sobha Puppala,Pierre Fontanillas,Amy L Williams,S\u00edlvia Bon\u00e0s-Guarch,Chris Hartl,Stephan Ripke, ,Katherine Tooley,Jacqueline Lane,Carlos Zerrweck,Ang\u00e9lica Mart\u00ednez-Hern\u00e1ndez,Emilio J C\u00f3rdova,Elvia Mendoza-Caamal,Cecilia Contreras-Cubas,Mar\u00eda E Gonz\u00e1lez-Villalpando,Ivette Cruz-Bautista,Liliana Mu\u00f1oz-Hern\u00e1ndez,Donaji G\u00f3mez-Velasco,Ulises Alvirde,Brian E Henderson,Lynne R Wilkens,Loic Le Marchand,Olimpia Arellano-Campos,Laura Riba,Maegan Harden, ,Stacey Gabriel, ,Hanna E Abboud,Maria L Cortes,Cristina Revilla-Monsalve,Sergio Islas-Andrade,Xavier Soberon,Joanne E Curran,Christopher P Jenkinson,Ralph A DeFronzo,Donna M Lehman,Craig L Hanis,Graeme I Bell,Michael Boehnke,John Blangero,Ravindranath Duggirala,Richa Saxena,Daniel MacArthur,Jorge Ferrer,Steven A McCarroll,David Torrents,William C Knowler,Leslie J Baier,Noel Burtt,Clicerio Gonz\u00e1lez-Villalpando,Christopher A Haiman,Carlos A Aguilar-Salinas,Teresa Tusi\u00e9-Luna,Jason Flannick,Suzanne B R Jacobs,Lorena Orozco,David Altshuler,Jose C Florez, ", - "abstract": "Type 2 diabetes (T2D) affects more than 415 million people worldwide, and its costs to the health care system continue to rise. To identify common or rare genetic variation with potential therapeutic implications for T2D, we analyzed and replicated genome-wide protein coding variation in a total of 8,227 individuals with T2D and 12,966 individuals without T2D of Latino descent. We identified a novel genetic variant in the <i>IGF2</i> gene associated with \u223c20% reduced risk for T2D. This variant, which has an allele frequency of 17% in the Mexican population but is rare in Europe, prevents splicing between <i>IGF2</i> exons 1 and 2. We show in vitro and in human liver and adipose tissue that the variant is associated with a specific, allele-dosage-dependent reduction in the expression of <i>IGF2</i> isoform 2. In individuals who do not carry the protective allele, expression of <i>IGF2</i> isoform 2 in adipose is positively correlated with both incidence of T2D and increased plasma glycated hemoglobin in individuals without T2D, providing support that the protective effects are mediated by reductions in <i>IGF2</i> isoform 2. Broad phenotypic examination of carriers of the protective variant revealed no association with other disease states or impaired reproductive health. These findings suggest that reducing <i>IGF2</i> isoform 2 expression in relevant tissues has potential as a new therapeutic strategy for T2D, even beyond the Latin American population, with no major adverse effects on health or reproduction.", - "journal_title": "Diabetes", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/28838971/" - } - ], - "fbcdf388-2f26-4be9-8c92-d6a030c45689": [ - { - "pub_id": "33966626", - "title": "COVID-19 one year into the pandemic: from genetics and genomics to therapy, vaccination, and policy.", - "authors": "Giuseppe Novelli,Michela Biancolella,Ruty Mehrian-Shai,Vito Luigi Colona,Anderson F Brito,Nathan D Grubaugh,Vasilis Vasiliou,Lucio Luzzatto,Juergen K V Reichardt", - "abstract": "COVID-19 has engulfed the world and it will accompany us all for some time to come. Here, we review the current state at the milestone of 1 year into the pandemic, as declared by the WHO (World Health Organization). We review several aspects of the on-going pandemic, focusing first on two major topics: viral variants and the human genetic susceptibility to disease severity. We then consider recent and exciting new developments in therapeutics, such as monoclonal antibodies, and in prevention strategies, such as vaccines. We also briefly discuss how advances in basic science and in biotechnology, under the threat of a worldwide emergency, have accelerated to an unprecedented degree of the transition from the laboratory to clinical applications. While every day we acquire more and more tools to deal with the on-going pandemic, we are aware that the path will be arduous and it will require all of us being community-minded. In this respect, we lament past delays in timely full investigations, and we call for bypassing local politics in the interest of humankind on all continents.", - "journal_title": "Human genomics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/33966626/" - } - ], - "aa33df5e-983b-433c-8ebc-34d10fbc1ce3": [ - { - "pub_id": "32493714", - "title": "Phenotypic and Genetic Characterization of Lower LDL Cholesterol and Increased Type 2 Diabetes Risk in the UK Biobank.", - "authors": "Yann C Klimentidis,Amit Arora,Michelle Newell,Jin Zhou,Jose M Ordovas,Benjamin J Renquist,Alexis C Wood", - "abstract": "Although hyperlipidemia is traditionally considered a risk factor for type 2 diabetes (T2D), evidence has emerged from statin trials and candidate gene investigations suggesting that lower LDL cholesterol (LDL-C) increases T2D risk. We thus sought to more comprehensively examine the phenotypic and genotypic relationships of LDL-C with T2D. Using data from the UK Biobank, we found that levels of circulating LDL-C were negatively associated with T2D prevalence (odds ratio 0.41 [95% CI 0.39, 0.43] per mmol/L unit of LDL-C), despite positive associations of circulating LDL-C with HbA<sub>1c</sub> and BMI. We then performed the first genome-wide exploration of variants simultaneously associated with lower circulating LDL-C and increased T2D risk, using data on LDL-C from the UK Biobank (<i>n</i> = 431,167) and the Global Lipids Genetics Consortium (<i>n</i> = 188,577), and data on T2D from the Diabetes Genetics Replication and Meta-Analysis consortium (<i>n</i> = 898,130). We identified 31 loci associated with lower circulating LDL-C and increased T2D, capturing several potential mechanisms. Seven of these loci have previously been identified for this dual phenotype, and nine have previously been implicated in nonalcoholic fatty liver disease. These findings extend our current understanding of the higher T2D risk among individuals with low circulating LDL-C and of the underlying mechanisms, including those responsible for the diabetogenic effect of LDL-C-lowering medications.", - "journal_title": "Diabetes", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/32493714/" - } - ], - "561f13ee-3b5d-49bf-9196-6aea8219ce0d": [ - { - "pub_id": "27353450", - "title": "The genetic regulatory signature of type 2 diabetes in human skeletal muscle.", - "authors": "Laura J Scott,Michael R Erdos,Jeroen R Huyghe,Ryan P Welch,Andrew T Beck,Brooke N Wolford,Peter S Chines,John P Didion,Narisu Narisu,Heather M Stringham,D Leland Taylor,Anne U Jackson,Swarooparani Vadlamudi,Lori L Bonnycastle,Leena Kinnunen,Jouko Saramies,Jouko Sundvall,Ricardo D'Oliveira Albanus,Anna Kiseleva,John Hensley,Gregory E Crawford,Hui Jiang,Xiaoquan Wen,Richard M Watanabe,Timo A Lakka,Karen L Mohlke,Markku Laakso,Jaakko Tuomilehto,Heikki A Koistinen,Michael Boehnke,Francis S Collins,Stephen C J Parker", - "abstract": "Type 2 diabetes (T2D) results from the combined effects of genetic and environmental factors on multiple tissues over time. Of the >100 variants associated with T2D and related traits in genome-wide association studies (GWAS), >90% occur in non-coding regions, suggesting a strong regulatory component to T2D risk. Here to understand how T2D status, metabolic traits and genetic variation influence gene expression, we analyse skeletal muscle biopsies from 271 well-phenotyped Finnish participants with glucose tolerance ranging from normal to newly diagnosed T2D. We perform high-depth strand-specific mRNA-sequencing and dense genotyping. Computational integration of these data with epigenome data, including ATAC-seq on skeletal muscle, and transcriptome data across diverse tissues reveals that the tissue-specific genetic regulatory architecture of skeletal muscle is highly enriched in muscle stretch/super enhancers, including some that overlap T2D GWAS variants. In one such example, T2D risk alleles residing in a muscle stretch/super enhancer are linked to increased expression and alternative splicing of muscle-specific isoforms of ANK1.", - "journal_title": "Nature communications", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/27353450/" - } - ], - "2da9b10b-fac7-45c5-96d4-6569aa0be00b": [ - { - "pub_id": "32588561", - "title": "Determination of mutations in iron regulating genes of beta thalassemia major patients of Khyber Pakhtunkhwa, Pakistan.", - "authors": "Maryam Shah,Lubna Danish,Najeeb U Khan,Fakhar Zaman,Muhammad Ismail,Mehfooz Hussain,Ruqiya Pervaiz,Aqib Iqbal", - "abstract": "Hepcidin and hemochromatosis (HFE) are iron regulatory proteins that are encoded by HAMP and HFE genes. Mutation in either HAMP gene or HFE gene causes Hepcidin protein deficiency that can lead to iron overload in beta thalassemia patients. The aim of this research work was to study the presence of G71D mutation of HAMP gene and H63D mutation of HFE gene in beta thalassemia major and minor group to check the association of these mutations with serum ferritin level of beta thalassemia patients. The study was conducted on 42 beta thalassemia major and 20 beta thalassemia minor samples along with 20 control samples. The genotyping of both mutations has done by ARM-PCR technique with specific set of primers. Significant effect of G71D and H63D mutations was observed on serum ferritin level of thalassemia major group. The risk allele of HAMP G71D and HFE H63D was found with high frequency (48% and 49%, respectively) in beta thalassemia major than in control group. High genotypic frequency of HAMP and HFE gene mutation gene mutation was observed in beta thalassemia major than beta thalassemia minor and control group (7% and 9%, respectively). It can be concluded that both HAMP and HFE gene mutations show high frequency in beta thalassemia major patients and mean significant association between mutations and high serum ferritin level of beta thalassemia major patients but the nonsignificant results of Odd ratios showed that both mutations do not act as major risk factor in beta thalassemia major.", - "journal_title": "Molecular genetics & genomic medicine", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/32588561/" - } - ], - "82012b1c-332a-4b23-94ec-5e3536302173": [ - { - "pub_id": "30050001", - "title": "High-Throughput Approaches onto Uncover (Epi)Genomic Architecture of Type 2 Diabetes.", - "authors": "Anna Dziewulska,Aneta M Dobosz,Agnieszka Dobrzyn", - "abstract": "Type 2 diabetes (T2D) is a complex disorder that is caused by a combination of genetic, epigenetic, and environmental factors. High-throughput approaches have opened a new avenue toward a better understanding of the molecular bases of T2D. A genome-wide association studies (GWASs) identified a group of the most common susceptibility genes for T2D (i.e., <i>TCF7L2</i>, <i>PPARG</i>, <i>KCNJ1</i>, <i>HNF1A</i>, <i>PTPN1</i>, and <i>CDKAL1</i>) and illuminated novel disease-causing pathways. Next-generation sequencing (NGS)-based techniques have shed light on rare-coding genetic variants that account for an appreciable fraction of T2D heritability (<i>KCNQ1</i> and <i>ADRA2A</i>) and population risk of T2D (<i>SLC16A11</i>, <i>TPCN2</i>, <i>PAM</i>, and <i>CCND2</i>). Moreover, single-cell sequencing of human pancreatic islets identified gene signatures that are exclusive to \u03b1-cells (<i>GCG</i>, <i>IRX2</i>, and <i>IGFBP2</i>) and \u03b2-cells (<i>INS</i>, <i>ADCYAP1</i>, <i>INS-IGF2</i>, and <i>MAFA</i>). Ongoing epigenome-wide association studies (EWASs) have progressively defined links between epigenetic markers and the transcriptional activity of T2D target genes. Differentially methylated regions were found in <i>TCF7L2</i>, <i>THADA</i>, <i>KCNQ1</i>, <i>TXNIP</i>, <i>SOCS3</i>, <i>SREBF1</i>, and <i>KLF14</i> loci that are related to T2D. Additionally, chromatin state maps in pancreatic islets were provided and several non-coding RNAs (ncRNA) that are key to T2D pathogenesis were identified (i.e., miR-375). The present review summarizes major progress that has been made in mapping the (epi)genomic landscape of T2D within the last few years.", - "journal_title": "Genes", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/30050001/" - } - ], - "e2badd5b-39b8-41c4-827a-19c6f686b9f3": [ - { - "pub_id": "29969661", - "title": "Genetic variants of resistin and its plasma levels: Association with obesity and dyslipidemia related to type 2 diabetes susceptibility.", - "authors": "Nirali Rathwa,Roma Patel,Sayantani Pramanik Palit,A V Ramachandran,Rasheedunnisa Begum", - "abstract": "Resistin, an adipokine, is involved in obesity and Type 2 Diabetes (T2D). The current study evaluates the association between RETN polymorphisms (-638\u202fG/A, -420C/G & -358\u202fG/A) and the risk towards T2D. Controls and T2D patients were enrolled from Gujarat, India. Polymorphisms of RETN were genotyped by Polymerase Chain Reaction-Restriction Fragment Length Polymorphism. For the genotype-phenotype correlation analysis Fasting Blood Glucose (FBG), Body Mass Index (BMI) and plasma lipid profile were used. Plasma levels of resistin were assayed by ELISA. Our study suggests an association of RETN -420C/G polymorphism with T2D risk. The CC genotype of RETN -420C/G polymorphism was found to be associated with FBG, BMI, and total cholesterol. Plasma resistin levels were found to be significantly increased in diabetic patients as compared to controls. Our findings suggest -420C/G polymorphism of RETN as an important factor which could pose a powerful risk towards T2D susceptibility.", - "journal_title": "Genomics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/29969661/" - } - ], - "0d249cf0-9457-473d-a04b-cdeab34d7fb5": [ - { - "pub_id": "27287034", - "title": "TRPV1 Gene Polymorphisms Are Associated with Type 2 Diabetes by Their Interaction with Fat Consumption in the Korean Genome Epidemiology Study.", - "authors": "Sunmin Park,Xin Zhang,Na Ra Lee,Hyun-Seok Jin", - "abstract": "Different transient receptor potential vanilloid 1 (TRPV1) variants may be differently activated by noxious stimuli. We investigated how TRPV1 variants modulated the prevalence of type 2 diabetes and specific gene-nutrient interactions. Among 8,842 adults aged 40-69 years in the Korean Genome Epidemiology Study, the associations between TRPV1 genotypes and the prevalence of type 2 diabetes as well as their gene-nutrient interactions were investigated after adjusting for the covariates of age, gender, residence area, body mass index, daily energy intake, and total activity. The TRPV1 rs161364 and rs8065080 minor alleles lowered HOMA-IR and the risk of type 2 diabetes after adjusting for covariates. There were gene-nutrient interactions between TRPV1 variants rs161364 and rs8065080 and preference for oily taste, intake of oily foods, and fat intake after adjusting for covariates. Among subjects with the minor alleles of TRPV1 rs161364 and rs8065080, the group with a high preference for oily foods had a lower odds ratio for type 2 diabetes. Consistent with the preference for taste, among subjects with the minor alleles, the group with high fat intake from oily foods also exhibited a lower risk of type 2 diabetes than subjects with the major alleles. People with the minor alleles of the TRPV1 single nucleotide polymorphisms rs161364 and rs8065080 have a lower risk of diabetes with a high-fat diet, but people with the major alleles are at a higher risk of type 2 diabetes when consuming high-fat diets. The majority of people should be careful about a high fat intake.", - "journal_title": "Journal of nutrigenetics and nutrigenomics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/27287034/" - } - ], - "b5ed7f1a-cabd-435b-9f36-8436b82dddff": [ - { - "pub_id": "31170205", - "title": "Characterization of bovine (Bos taurus) imprinted genes from genomic to amino acid attributes by data mining approaches.", - "authors": "Keyvan Karami,Saeed Zerehdaran,Ali Javadmanesh,Mohammad Mahdi Shariati,Hossein Fallahi", - "abstract": "Genomic imprinting results in monoallelic expression of genes in mammals and flowering plants. Understanding the function of imprinted genes improves our knowledge of the regulatory processes in the genome. In this study, we have employed classification and clustering algorithms with attribute weighting to specify the unique attributes of both imprinted (monoallelic) and biallelic expressed genes. We have obtained characteristics of 22 known monoallelically expressed (imprinted) and 8 biallelic expressed genes that have been experimentally validated alongside 208 randomly selected genes in bovine (Bos taurus). Attribute weighting methods and various supervised and unsupervised algorithms in machine learning were applied. Unique characteristics were discovered and used to distinguish mono and biallelic expressed genes from each other in bovine. To obtain the accuracy of classification, 10-fold cross-validation with concerning each combination of attribute weighting (feature selection) and machine learning algorithms, was used. Our approach was able to accurately predict mono and biallelic genes using the genomics and proteomics attributes.", - "journal_title": "PloS one", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/31170205/" - } - ], - "5c1e50c0-3545-490c-8430-c199fd84db97": [ - { - "pub_id": "36344967", - "title": "A haplotype-resolved genome assembly of the Nile rat facilitates exploration of the genetic basis of diabetes.", - "authors": "Huishi Toh,Chentao Yang,Giulio Formenti,Kalpana Raja,Lily Yan,Alan Tracey,William Chow,Kerstin Howe,Lucie A Bergeron,Guojie Zhang,Bettina Haase,Jacquelyn Mountcastle,Olivier Fedrigo,John Fogg,Bogdan Kirilenko,Chetan Munegowda,Michael Hiller,Aashish Jain,Daisuke Kihara,Arang Rhie,Adam M Phillippy,Scott A Swanson,Peng Jiang,Dennis O Clegg,Erich D Jarvis,James A Thomson,Ron Stewart,Mark J P Chaisson,Yury V Bukhman", - "abstract": "The Nile rat (Avicanthis niloticus) is an important animal model because of its robust diurnal rhythm, a cone-rich retina, and a propensity to develop diet-induced diabetes without chemical or genetic modifications. A closer similarity to humans in these aspects, compared to the widely used Mus musculus and Rattus norvegicus models, holds the promise of better translation of research findings to the clinic. We report a 2.5 Gb, chromosome-level reference genome assembly with fully resolved parental haplotypes, generated with the Vertebrate Genomes Project (VGP). The assembly is highly contiguous, with contig N50 of 11.1 Mb, scaffold N50 of 83 Mb, and 95.2% of the sequence assigned to chromosomes. We used a novel workflow to identify 3613 segmental duplications and quantify duplicated genes. Comparative analyses revealed unique genomic features of the Nile rat, including some that affect genes associated with type 2 diabetes and metabolic dysfunctions. We discuss 14 genes that are heterozygous in the Nile rat or highly diverged from the house mouse. Our findings reflect the exceptional level of genomic resolution present in this assembly, which will greatly expand the potential of the Nile rat as a model organism.", - "journal_title": "BMC biology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/36344967/" - } - ], - "1e5eee34-b4c8-47be-ba2c-6d14d13d49bf": [ - { - "pub_id": "33892786", - "title": "Identification of ZBTB18 as a novel colorectal tumor suppressor gene through genome-wide promoter hypermethylation analysis.", - "authors": "Sarah Bazzocco,Higinio Dopeso,\u00c1gueda Mart\u00ednez-Barriocanal,Estefan\u00eda Anguita,Roc\u00edo Nieto,Jing Li,Elia Garc\u00eda-Vidal,Valentina Maggio,Paulo Rodrigues,Priscila Guimar\u00e3es de Marcondes,Simo Schwartz,Lauri A Aaltonen,Alex S\u00e1nchez,John M Mariadason,Diego Arango", - "abstract": "Cancer initiation and progression are driven by genetic and epigenetic changes. Although genome/exome sequencing has significantly contributed to the characterization of the genetic driver alterations, further investigation is required to systematically identify cancer driver genes regulated by promoter hypermethylation. Using genome-wide analysis of promoter methylation in 45 colorectal cancer cell lines, we found that higher overall methylation levels were associated with microsatellite instability (MSI), faster proliferation and absence of APC mutations. Because epigenetically silenced genes could represent important oncogenic drivers, we used mRNA expression profiling of colorectal cancer cell lines and primary tumors to identify a subset of 382 (3.9%) genes for which promoter methylation was negatively associated with gene expression. Remarkably, a significant enrichment in zinc finger proteins was observed, including the transcriptional repressor ZBTB18. Re-introduction of ZBTB18 in colon cancer cells significantly reduced proliferation in vitro and in a subcutaneous xenograft mouse model. Moreover, immunohistochemical analysis revealed that ZBTB18 is frequently lost or reduced in colorectal tumors, and reduced ZBTB18 expression was found to be associated with lymph node metastasis and shorter survival of patients with locally advanced colorectal cancer. We identified a set of 382 genes putatively silenced by promoter methylation in colorectal cancer that could significantly contribute to the oncogenic process. Moreover, as a proof of concept, we demonstrate that the epigenetically silenced gene ZBTB18 has tumor suppressor activity and is a novel prognostic marker for patients with locally advanced colorectal cancer.", - "journal_title": "Clinical epigenetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/33892786/" - } - ], - "c500b56a-3606-4a5e-b0c2-29eaa631cb16": [ - { - "pub_id": "34782789", - "title": "Responsible use of polygenic risk scores in the clinic: potential benefits, risks and gaps.", - "authors": " ", - "abstract": "Polygenic risk scores (PRSs) aggregate the many small effects of alleles across the human genome to estimate the risk of a disease or disease-related trait for an individual. The potential benefits of PRSs include cost-effective enhancement of primary disease prevention, more refined diagnoses and improved precision when prescribing medicines. However, these must be weighed against the potential risks, such as uncertainties and biases in PRS performance, as well as potential misunderstanding and misuse of these within medical practice and in wider society. By addressing key issues including gaps in best practices, risk communication and regulatory frameworks, PRSs can be used responsibly to improve human health. Here, the International Common Disease Alliance's PRS Task Force, a multidisciplinary group comprising expertise in genetics, law, ethics, behavioral science and more, highlights recent research to provide a comprehensive summary of the state of polygenic score research, as well as the needs and challenges as PRSs move closer to widespread use in the clinic.", - "journal_title": "Nature medicine", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/34782789/" - } - ], - "59c5ad68-6524-466f-a037-1cc1dff592d8": [ - { - "pub_id": "31473834", - "title": "Association of IGF1 and VEGFA polymorphisms with diabetic retinopathy in Pakistani population.", - "authors": "Netasha Khan,Andrew D Paterson,Delnaz Roshandel,Ali Raza,Muhammad Ajmal,Nadia K Waheed,Maleeha Azam,Raheel Qamar", - "abstract": "The incidence of microvascular complications, including diabetic retinopathy (DR), increases with duration of type 2 diabetes (T2D). Meta-GWAS have reported numerous single-nucleotide polymorphisms (SNPs) associated with T2D; however, no loci, achieving genome-wide significance has been reported for DR. Vascular endothelial growth factor A (VEGFA) and insulin-like growth factor 1 (IGF1) are considered as potential genetic candidates involved in T2D and DR progression. Moreover, the association of serum levels of these proteins with diabetes-related traits is controversial. Therefore, the current study was designed to evaluate the possible genetic predisposition and role of these circulating growth factors in serum in the pathophysiology of T2D and DR. A cohort of 1126 individuals with T2D was collected including those without retinopathy (DNR\u2009=\u2009573), non-progressive diabetic retinopathy (NPDR\u2009=\u2009301) and progressive diabetic retinopathy (PDR\u2009=\u2009252), and 348 healthy controls. Genomic DNA was isolated, and six SNPs: rs833061, rs13207351, rs1570360, rs2010963, rs5742632 and rs6214, were genotyped and results statistically analyzed. ELISA was performed on a subset of the samples to measure serum levels of IGF1 and VEGFA. The minor allele of rs6214 was associated with T2D [OR\u2009=\u20091.67 (95% CI\u2009\u20091.39-2.01, p\u2009=\u20094.9E-8)], rs13207351 was associated with NPDR [OR\u2009=\u20091.97 (95% CI\u2009 1.28-3.03, p\u2009=\u20099.0E-3)]when compared with DNR, and rs5742632 showed positive association with PDR [OR\u2009=\u20091.66 (95% CI\u2009\u20091.33-2.05, p\u2009=\u20091.0E-4)] compared to DNR. Lowered IGF1 serum levels were found to be associated with T2D, NPDR and PDR. IGF1 was found to increase the T2DM susceptibility as well as advanced DR, i.e., PDR, while VEGFA was found to be associated with early DR stage, i.e., NPDR.", - "journal_title": "Acta diabetologica", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/31473834/" - } - ], - "6fb02215-e24d-4878-86cf-54d8b68eeac5": [ - { - "pub_id": "29178640", - "title": "Expanding the mutational spectrum in Johanson-Blizzard syndrome: identification of whole exon deletions and duplications in the UBR1 gene by multiplex ligation-dependent probe amplification analysis.", - "authors": "Maja Sukalo,Eva Sch\u00e4flein,Ina Schanze,David B Everman,Nima Rezaei,Jes\u00fas Argente,Isabel Lorda-Sanchez,Charu Deshpande,Tsutomu Takahashi,Alexander Kleger,Martin Zenker", - "abstract": "Johanson-Blizzard syndrome (JBS, MIM #243800) is a very rare autosomal recessive disorder characterized by exocrine pancreatic insufficiency, nasal wing hypoplasia, hypodontia, and other abnormalities. JBS is caused by mutations of the UBR1 gene (MIM *605981), encoding a ubiquitin ligase of the N-end rule pathway. Molecular findings in a total of 65 unrelated patients with a clinical diagnosis of JBS who were previously screened for UBR1 mutations by Sanger sequencing were reviewed and cases lacking a disease-causing UBR1 mutation on either one or both alleles were included in this study. In order to discover mutations that are not detectable by Sanger sequencing, we designed a probe set for multiplex ligation-dependent probe amplification (MLPA) analysis of the UBR1 gene and analyzed the copy number status of all 47 UBR1 exons. Our previous studies using Sanger sequencing could detect mutations in 93.1% of 130 disease-associated UBR1 alleles. Six patients with a highly suggestive clinical diagnosis of JBS and unsolved genotype were included in this study. MLPA analysis detected six alleles harboring exon deletions/duplications, thereby raising the mutation detection rate in the entire cohort to 97.7% (127/130 alleles). We conclude that single or multi-exon deletions or duplications account for a substantial proportion of JBS-associated UBR1 mutations.", - "journal_title": "Molecular genetics & genomic medicine", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/29178640/" - } - ], - "1cebda9b-a727-4bfd-8521-cf61903235cc": [ - { - "pub_id": "32099086", - "title": "Insights into pancreatic islet cell dysfunction from type 2 diabetes mellitus genetics.", - "authors": "Nicole A J Krentz,Anna L Gloyn", - "abstract": "Type 2 diabetes mellitus (T2DM) is an increasingly prevalent multifactorial disease that has both genetic and environmental risk factors, resulting in impaired glucose homeostasis. Genome-wide association studies (GWAS) have identified over 400 genetic signals that are associated with altered risk of T2DM. Human physiology and epigenomic data support a central role for the pancreatic islet in the pathogenesis of T2DM. This Review focuses on the promises and challenges of moving from genetic associations to molecular mechanisms and highlights efforts to identify the causal variant and effector transcripts at T2DM GWAS susceptibility loci. In addition, we examine current human models that are used to study both \u03b2-cell development and function, including EndoC-\u03b2 cell lines and human induced pluripotent stem cell-derived \u03b2-like cells. We use examples of four T2DM susceptibility loci (CDKAL1, MTNR1B, SLC30A8 and PAM) to emphasize how a holistic approach involving genetics, physiology, and cellular and developmental biology can disentangle disease mechanisms at T2DM GWAS signals.", - "journal_title": "Nature reviews. Endocrinology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/32099086/" - } - ], - "773837e0-371c-4ba2-bdc0-02c4996b534d": [ - { - "pub_id": "34031597", - "title": "Genetics and genomics of arrhythmic risk: current and future strategies to prevent sudden cardiac death.", - "authors": "Chiara Scrocco,Connie R Bezzina,Michael J Ackerman,Elijah R Behr", - "abstract": "A genetic risk of sudden cardiac arrest and sudden death due to an arrhythmic cause, known as sudden cardiac death (SCD), has become apparent from epidemiological studies in the general population and in patients with ischaemic heart disease. However, genetic susceptibility to sudden death is greatest in young people and is associated with uncommon, monogenic forms of heart disease. Despite comprehensive pathology and genetic evaluations, SCD remains unexplained in a proportion of young people and is termed sudden arrhythmic death syndrome, which poses challenges to the identification of relatives from affected families who might be at risk of SCD. In this Review, we assess the current understanding of the epidemiology and causes of SCD and evaluate both the monogenic and the polygenic contributions to the risk of SCD in the young and SCD associated with drug therapy. Finally, we analyse the potential clinical role of genomic testing in the prevention of SCD in the general population.", - "journal_title": "Nature reviews. Cardiology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/34031597/" - } - ], - "18a35699-873a-4542-b35a-3a4a14edd628": [ - { - "pub_id": "29387042", - "title": "Type 2 Diabetes Mellitus and Cardiovascular Disease: Genetic and Epigenetic Links.", - "authors": "Salvatore De Rosa,Biagio Arcidiacono,Eusebio Chiefari,Antonio Brunetti,Ciro Indolfi,Daniela P Foti", - "abstract": "Type 2 diabetes mellitus (DM) is a common metabolic disorder predisposing to diabetic cardiomyopathy and atherosclerotic cardiovascular disease (CVD), which could lead to heart failure through a variety of mechanisms, including myocardial infarction and chronic pressure overload. Pathogenetic mechanisms, mainly linked to hyperglycemia and chronic sustained hyperinsulinemia, include changes in metabolic profiles, intracellular signaling pathways, energy production, redox status, increased susceptibility to ischemia, and extracellular matrix remodeling. The close relationship between type 2 DM and CVD has led to the common soil hypothesis, postulating that both conditions share common genetic and environmental factors influencing this association. However, although the common risk factors of both CVD and type 2 DM, such as obesity, insulin resistance, dyslipidemia, inflammation, and thrombophilia, can be identified in the majority of affected patients, less is known about how these factors influence both conditions, so that efforts are still needed for a more comprehensive understanding of this relationship. The genetic, epigenetic, and environmental backgrounds of both type 2 DM and CVD have been more recently studied and updated. However, the underlying pathogenetic mechanisms have seldom been investigated within the broader shared background, but rather studied in the specific context of type 2 DM or CVD, separately. As the precise pathophysiological links between type 2 DM and CVD are not entirely understood and many aspects still require elucidation, an integrated description of the genetic, epigenetic, and environmental influences involved in the concomitant development of both diseases is of paramount importance to shed new light on the interlinks between type 2 DM and CVD. This review addresses the current knowledge of overlapping genetic and epigenetic aspects in type 2 DM and CVD, including microRNAs and long non-coding RNAs, whose abnormal regulation has been implicated in both disease conditions, either etiologically or as cause for their progression. Understanding the links between these disorders may help to drive future research toward an integrated pathophysiological approach and to provide future directions in the field.", - "journal_title": "Frontiers in endocrinology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/29387042/" - } - ], - "8051a2ea-ac83-4204-a439-13d4f105be45": [ - { - "pub_id": "32753378", - "title": "Polygenic inheritance, GWAS, polygenic risk scores, and the search for functional variants.", - "authors": "Daniel J M Crouch,Walter F Bodmer", - "abstract": "The reconciliation between Mendelian inheritance of discrete traits and the genetically based correlation between relatives for quantitative traits was Fisher's infinitesimal model of a large number of genetic variants, each with very small effects, whose causal effects could not be individually identified. The development of genome-wide genetic association studies (GWAS) raised the hope that it would be possible to identify single polymorphic variants with identifiable functional effects on complex traits. It soon became clear that, with larger and larger GWAS on more and more complex traits, most of the significant associations had such small effects, that identifying their individual functional effects was essentially hopeless. Polygenic risk scores that provide an overall estimate of the genetic propensity to a trait at the individual level have been developed using GWAS data. These provide useful identification of groups of individuals with substantially increased risks, which can lead to recommendations of medical treatments or behavioral modifications to reduce risks. However, each such claim will require extensive investigation to justify its practical application. The challenge now is to use limited genetic association studies to find individually identifiable variants of significant functional effect that can help to understand the molecular basis of complex diseases and traits, and so lead to improved disease prevention and treatment. This can best be achieved by 1) the study of rare variants, often chosen by careful candidate assessment, and 2) the careful choice of phenotypes, often extremes of a quantitative variable, or traits with relatively high heritability.", - "journal_title": "Proceedings of the National Academy of Sciences of the United States of America", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/32753378/" - } - ], - "f6baaabe-5856-4be5-8fe5-cd2b935ebacf": [ - { - "pub_id": "34853355", - "title": "The tale of TILs in breast cancer: A report from The International Immuno-Oncology Biomarker Working Group.", - "authors": "Khalid El Bairi,Harry R Haynes,Elizabeth Blackley,Susan Fineberg,Jeffrey Shear,Sophia Turner,Juliana Ribeiro de Freitas,Daniel Sur,Luis Claudio Amendola,Masoumeh Gharib,Amine Kallala,Indu Arun,Farid Azmoudeh-Ardalan,Luciana Fujimoto,Luz F Sua,Shi-Wei Liu,Huang-Chun Lien,Pawan Kirtani,Marcelo Balancin,Hicham El Attar,Prerna Guleria,Wenxian Yang,Emad Shash,I-Chun Chen,Veronica Bautista,Jose Fernando Do Prado Moura,Bernardo L Rapoport,Carlos Castaneda,Eunice Spengler,Gabriela Acosta-Haab,Isabel Frahm,Joselyn Sanchez,Miluska Castillo,Najat Bouchmaa,Reena R Md Zin,Ruohong Shui,Timothy Onyuma,Wentao Yang,Zaheed Husain,Karen Willard-Gallo,An Coosemans,Edith A Perez,Elena Provenzano,Paula Gonzalez Ericsson,Eduardo Richardet,Ravi Mehrotra,Sandra Sarancone,Anna Ehinger,David L Rimm,John M S Bartlett,Giuseppe Viale,Carsten Denkert,Akira I Hida,Christos Sotiriou,Sibylle Loibl,Stephen M Hewitt,Sunil Badve,William Fraser Symmans,Rim S Kim,Giancarlo Pruneri,Shom Goel,Prudence A Francis,Gloria Inurrigarro,Rin Yamaguchi,Hernan Garcia-Rivello,Hugo Horlings,Said Afqir,Roberto Salgado,Sylvia Adams,Marleen Kok,Maria Vittoria Dieci,Stefan Michiels,Sandra Demaria,Sherene Loi, ", - "abstract": "The advent of immune-checkpoint inhibitors (ICI) in modern oncology has significantly improved survival in several cancer settings. A subgroup of women with breast cancer (BC) has immunogenic infiltration of lymphocytes with expression of programmed death-ligand 1 (PD-L1). These patients may potentially benefit from ICI targeting the programmed death 1 (PD-1)/PD-L1 signaling axis. The use of tumor-infiltrating lymphocytes (TILs) as predictive and prognostic biomarkers has been under intense examination. Emerging data suggest that TILs are associated with response to both cytotoxic treatments and immunotherapy, particularly for patients with triple-negative BC. In this review from The International Immuno-Oncology Biomarker Working Group, we discuss (a) the biological understanding of TILs, (b) their analytical and clinical validity and efforts toward the clinical utility in BC, and (c) the current status of PD-L1 and TIL testing across different continents, including experiences from low-to-middle-income countries, incorporating also the view of a patient advocate. This information will help set the stage for future approaches to optimize the understanding and clinical utilization of TIL analysis in patients with BC.", - "journal_title": "NPJ breast cancer", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/34853355/" - } - ], - "ca89a942-79a6-4677-9519-3dd0b7d6400b": [ - { - "pub_id": "33016646", - "title": "Atypical juvenile hereditary hemochromatosis onset with positive pancreatic islet autoantibodies diabetes caused by novel mutations in HAMP and overall clinical management.", - "authors": "Hui-Xuan Wu,Jun-Ying Liu,De-Wen Yan,Long Li,Xiang-Hua Zhuang,Hai-Yan Li,Zhi-Guang Zhou,Hou-De Zhou", - "abstract": "Atypical clinical symptoms of juvenile hereditary hemochromatosis (JHH) often leads to misdiagnosis and underdiagnosis bringing ominous outcomes, even death. The whole exome was sequenced and interpreted. A literature review assisted to analyze and verify the phenotype-genotype relationships. We revealed the entire process of diagnosis, treatments, and outcome of two diabetic onset of JHH families to provide new insights for genotype-phenotype relation with novel compound heterozygous mutations in the hepcidin antimicrobial peptide (HAMP, OMIM: 606464). Two probands were diagnosed and treated as type 1 diabetes initially because of specific symptoms and positive islet autoantibodies. Poor control of hyperglycemia and progressive symptoms occurred. Sequencing informed that the compound heterozygous and homozygous mutations c.166C>G and c.223C>T in HAMP caused type 1 diabetic-onset JHH. The two patients accessed irregular phlebotomy treatments, and then, experienced poor prognosis. We summarized the process of overall clinical management of reported 26 cases comparing to our novel atypical diabetic onsets Juvenile Hereditary Hemochromatosis cases. It was first reported that positive pancreatic islet autoantibodies diabetes onset of JHH resulted from loss-of-function mutations of HAMP, of which the atypical JHH should be differentially diagnosed with type 1 diabetes at the onset. Early administration of phlebotomy and vital organs protection and surveillance might be important for the treatment of atypical JHH.", - "journal_title": "Molecular genetics & genomic medicine", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/33016646/" - } - ], - "0b9c1e0f-54bc-47f2-a083-ecf9d607335d": [ - { - "pub_id": "32546605", - "title": "Genome-Wide Gene-Diabetes and Gene-Obesity Interaction Scan in 8,255 Cases and 11,900 Controls from PanScan and PanC4 Consortia.", - "authors": "Hongwei Tang,Lai Jiang,Rachael Z Stolzenberg-Solomon,Alan A Arslan,Laura E Beane Freeman,Paige M Bracci,Paul Brennan,Federico Canzian,Mengmeng Du,Steven Gallinger,Graham G Giles,Phyllis J Goodman,Charles Kooperberg,Lo\u00efc Le Marchand,Rachel E Neale,Xiao-Ou Shu,Kala Visvanathan,Emily White,Wei Zheng,Demetrius Albanes,Gabriella Andreotti,Ana Babic,William R Bamlet,Sonja I Berndt,Amanda Blackford,Bas Bueno-de-Mesquita,Julie E Buring,Daniele Campa,Stephen J Chanock,Erica Childs,Eric J Duell,Charles Fuchs,J Michael Gaziano,Michael Goggins,Patricia Hartge,Manal H Hassam,Elizabeth A Holly,Robert N Hoover,Rayjean J Hung,Robert C Kurtz,I-Min Lee,N\u00faria Malats,Roger L Milne,Kimmie Ng,Ann L Oberg,Irene Orlow,Ulrike Peters,Miquel Porta,Kari G Rabe,Nathaniel Rothman,Ghislaine Scelo,Howard D Sesso,Debra T Silverman,Ian M Thompson,Anne Tj\u00f8nneland,Antonia Trichopoulou,Jean Wactawski-Wende,Nicolas Wentzensen,Lynne R Wilkens,Herbert Yu,Anne Zeleniuch-Jacquotte,Laufey T Amundadottir,Eric J Jacobs,Gloria M Petersen,Brian M Wolpin,Harvey A Risch,Nilanjan Chatterjee,Alison P Klein,Donghui Li,Peter Kraft,Peng Wei", - "abstract": "Obesity and diabetes are major modifiable risk factors for pancreatic cancer. Interactions between genetic variants and diabetes/obesity have not previously been comprehensively investigated in pancreatic cancer at the genome-wide level. We conducted a gene-environment interaction (GxE) analysis including 8,255 cases and 11,900 controls from four pancreatic cancer genome-wide association study (GWAS) datasets (Pancreatic Cancer Cohort Consortium I-III and Pancreatic Cancer Case Control Consortium). Obesity (body mass index \u226530 kg/m<sup>2</sup>) and diabetes (duration \u22653 years) were the environmental variables of interest. Approximately 870,000 SNPs (minor allele frequency \u22650.005, genotyped in at least one dataset) were analyzed. Case-control (CC), case-only (CO), and joint-effect test methods were used for SNP-level GxE analysis. As a complementary approach, gene-based GxE analysis was also performed. Age, sex, study site, and principal components accounting for population substructure were included as covariates. Meta-analysis was applied to combine individual GWAS summary statistics. No genome-wide significant interactions (departures from a log-additive odds model) with diabetes or obesity were detected at the SNP level by the CC or CO approaches. The joint-effect test detected numerous genome-wide significant GxE signals in the GWAS main effects top hit regions, but the significance diminished after adjusting for the GWAS top hits. In the gene-based analysis, a significant interaction of diabetes with variants in the <i>FAM63A</i> (family with sequence similarity 63 member A) gene (significance threshold <i>P</i> < 1.25 \u00d7 10<sup>-6</sup>) was observed in the meta-analysis (<i>P</i> <sub>GxE</sub> = 1.2 \u00d710<sup>-6</sup>, <i>P</i> <sub>Joint</sub> = 4.2 \u00d710<sup>-7</sup>). This analysis did not find significant GxE interactions at the SNP level but found one significant interaction with diabetes at the gene level. A larger sample size might unveil additional genetic factors via GxE scans. This study may contribute to discovering the mechanism of diabetes-associated pancreatic cancer.", - "journal_title": "Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/32546605/" - } - ], - "7e809821-000d-4fff-971d-264650e3612b": [ - { - "pub_id": "26297071", - "title": "The progress in understanding and treatment of diabetic retinopathy.", - "authors": "Alan W Stitt,Timothy M Curtis,Mei Chen,Reinhold J Medina,Gareth J McKay,Alicia Jenkins,Thomas A Gardiner,Timothy J Lyons,Hans-Peter Hammes,Rafael Sim\u00f3,Noemi Lois", - "abstract": "Diabetic retinopathy is the most frequently occurring complication of diabetes mellitus and remains a leading cause of vision loss globally. Its aetiology and pathology have been extensively studied for half a century, yet there are disappointingly few therapeutic options. Although some new treatments have been introduced for diabetic macular oedema (DMO) (e.g. intravitreal vascular endothelial growth factor inhibitors ('anti-VEGFs') and new steroids), up to 50% of patients fail to respond. Furthermore, for people with proliferative diabetic retinopathy (PDR), laser photocoagulation remains a mainstay therapy, even though it is an inherently destructive procedure. This review summarises the clinical features of diabetic retinopathy and its risk factors. It describes details of retinal pathology and how advances in our understanding of pathogenesis have led to identification of new therapeutic targets. We emphasise that although there have been significant advances, there is still a pressing need for a better understanding basic mechanisms enable development of reliable and robust means to identify patients at highest risk, and to intervene effectively before vision loss occurs.", - "journal_title": "Progress in retinal and eye research", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/26297071/" - } - ], - "50c72e55-b5fe-42a6-b837-64c28620a4c0": [ - { - "pub_id": "27081110", - "title": "Cardiovascular Disease in Women: Clinical Perspectives.", - "authors": "Mariana Garcia,Sharon L Mulvagh,C Noel Bairey Merz,Julie E Buring,JoAnn E Manson", - "abstract": "Cardiovascular disease continues to be the leading cause of death among women in the United States, accounting for \u22481 of every 3 female deaths. Sex-specific data focused on cardiovascular disease have been increasing steadily, yet is not routinely collected nor translated into practice. This comprehensive review focuses on novel and unique aspects of cardiovascular health in women and sex differences as they relate to clinical practice in the prevention, diagnosis, and treatment of cardiovascular disease. This review also provides current approaches to the evaluation and treatment of acute coronary syndromes that are more prevalent in women, including myocardial infarction associated with nonobstructive coronary arteries, spontaneous coronary artery dissection, and stress-induced cardiomyopathy (Takotsubo Syndrome). Other cardiovascular disease entities with higher prevalence or unique considerations in women, such as heart failure with preserved ejection fraction, peripheral arterial disease, and abdominal aortic aneurysms, are also briefly reviewed. Finally, recommendations for cardiac rehabilitation are addressed.", - "journal_title": "Circulation research", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/27081110/" - } - ], - "717d8dcc-543b-438c-9660-b72a1354fbd0": [ - { - "pub_id": "34485958", - "title": "Defining nosocomial transmission of <i>Escherichia coli</i> and antimicrobial resistance genes: a genomic surveillance study.", - "authors": "Catherine Ludden,Francesc Coll,Theodore Gouliouris,Olivier Restif,Beth Blane,Grace A Blackwell,Narender Kumar,Plamena Naydenova,Charles Crawley,Nicholas M Brown,Julian Parkhill,Sharon J Peacock", - "abstract": "<i>Escherichia coli</i> is a leading cause of bloodstream infections. Developing interventions to reduce <i>E coli</i> infections requires an understanding of the frequency of nosocomial transmission, but the available evidence is scarce. We aimed to detect and characterise transmission of <i>E coli</i> and associated plasmids in a hospital setting. In this prospective observational cohort study, patients were admitted to two adult haematology wards at the Cambridge University Hospitals NHS Foundation Trust in England. Patients aged 16 years and older who were treated for haematological malignancies were included. Stool samples were collected from study participants on admission, once per week, and at discharge. We sequenced multiple <i>E coli</i> isolates (both extended spectrum \u03b2-lactamase [ESBL]-producing and non-ESBL-producing) from each stool sample. A genetic threshold to infer <i>E coli</i> transmission was defined by maximum within-host single nucleotide polymorphism (SNP) diversity and the probability of drawing observed pairs of between-patient isolates at different SNP thresholds. Putative transmission clusters were identified when sequences were less than the genetic threshold. Epidemiological links for each transmission event were investigated. We sequenced all <i>E coli</i> positive blood samples from the two adult haematology wards. We recruited 174 (51%) of 338 adult patients admitted to the wards between May 13 and Nov 13, 2015. We obtained and cultured 376 stool samples from 149 patients, of which 152 samples from 97 (65%) patients grew <i>E coli</i>. Whole-genome sequencing was done on 970 isolates. We identified extensive diversity in the bacterial population (90 sequence types) and mixed <i>E coli</i> sequence type carriage. 24 (26%) patients carried two sequence types, 12 (13%) carried three, and six (6%) patients carried four or more sequence types. Using a 17 SNP cutoff we identified ten clusters in 20 patients. The largest cluster contained seven patients, whereas four patients were included in multiple clusters. Strong epidemiological links were found between patients in seven clusters. 17 (11%) of 149 patients had stool samples positive for ESBL-producing <i>E coli</i>, the most common of which was associated with <i>bla</i> <sub>CTX-M-15</sub> (12 [71%] of 17). Long-read sequencing revealed that <i>bla</i> <sub>CTX-M-15</sub> was often integrated into the chromosome, with little evidence for plasmid transmission. Seven patients developed <i>E coli</i> bloodstream infection, four with identical strains to those in their stool; two of these had documented nosocomial acquisition. We provide evidence of bacterial transmission and endogenous infection during routine care by integrating genomic and epidemiological data and by determining a genetic cutoff informed by within-host diversity in the studied population. Our findings challenge single colony-based investigations, and the widely accepted notion of plasmid spread. UK Department of Health, Wellcome Trust, UK National Institute for Health Research.", - "journal_title": "The Lancet. Microbe", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/34485958/" - } - ], - "e3eebb84-4eac-4dc7-86a6-0d859fa094e7": [ - { - "pub_id": "27019060", - "title": "Maternal genome-wide DNA methylation profiling in gestational diabetes shows distinctive disease-associated changes relative to matched healthy pregnancies.", - "authors": "Pensee Wu,William E Farrell,Kim E Haworth,Richard D Emes,Mark O Kitchen,John R Glossop,Fahmy W Hanna,Anthony A Fryer", - "abstract": "Several recent reports have described associations between gestational diabetes (GDM) and changes to the epigenomic landscape where the DNA samples were derived from either cord or placental sources. We employed genome-wide 450K array analysis to determine changes to the epigenome in a unique cohort of maternal blood DNA from 11 pregnant women prior to GDM development relative to matched controls. Hierarchical clustering segregated the samples into 2 distinct clusters comprising GDM and healthy pregnancies. Screening identified 100 CpGs with a mean \u03b2-value difference of \u22650.2 between cases and controls. Using stringent criteria, 5 CpGs (within COPS8, PIK3R5, HAAO, CCDC124, and C5orf34 genes) demonstrated potentials to be clinical biomarkers as revealed by differential methylation in 8 of 11 women who developed GDM relative to matched controls. We identified, for the first time, maternal methylation changes prior to the onset of GDM that may prove useful as biomarkers for early therapeutic intervention.", - "journal_title": "Epigenetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/27019060/" - } - ], - "a8bfdaff-7e26-4038-a572-501c13b27197": [ - { - "pub_id": "25561578", - "title": "APOL1 nephropathy: from gene to mechanisms of kidney injury.", - "authors": "Etty Kruzel-Davila,Walter G Wasser,Sharon Aviram,Karl Skorecki", - "abstract": "The contribution of African ancestry to the risk of focal segmental glomerulosclerosis and chronic kidney disease has been partially explained by the recently described chromosome 22q variants in the gene apolipoprotein L1 (APOL1). The APOL1 variants appear at a high allele frequency in populations of West African ancestry as a result of apparent adaptive selection of the heterozygous state. Heterozygosity protects from infection with Trypanosoma brucei rhodesiense. This review will describe the role of the approaches in population genetics for the description of APOL1-associated nephropathies and draw inferences as to the biologic mechanisms from genetic epidemiology findings to date. Modifier loci can influence APOL1 risk for the development of kidney disease. 'Second hits', both viral and non-viral, may explain the discrepancy between the remarkably high odds ratios and the low lifetime risks of kidney disease in two allele carriers of APOL1 risk variants. Therapeutic strategies for APOL1-associated nephropathies will require the prevention and treatment of these 'second hits' and the development of drugs to protect the APOL1 downstream renal injury pathways.", - "journal_title": "Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/25561578/" - } - ], - "afd09e9d-5017-41e0-9145-e973cd826308": [ - { - "pub_id": "29122391", - "title": "Genetics and epigenetics of NAFLD and NASH: Clinical impact.", - "authors": "Mohammed Eslam,Luca Valenti,Stefano Romeo", - "abstract": "Non-alcoholic fatty liver disease (NAFLD) is now recognised as the most common liver disease worldwide. It encompasses a broad spectrum of conditions, from simple steatosis, through non-alcoholic steatohepatitis, to fibrosis and ultimately cirrhosis and hepatocellular carcinoma. A hallmark of NAFLD is the substantial inter-patient variation in disease progression. NAFLD is considered a complex disease trait such that interactions between the environment and a susceptible polygenic host background determine disease phenotype and influence progression. Recent years have witnessed multiple genome-wide association and large candidate gene studies, which have enriched our understanding of the genetic basis of NAFLD. Notably, the I148M PNPLA3 variant has been identified as the major common genetic determinant of NAFLD. Variants with moderate effect size in TM6SF2, MBOAT7 and GCKR have also been shown to have a significant contribution. The premise for this review is to discuss the status of research into important genetic and epigenetic modifiers of NAFLD progression. The potential to translate the accumulating wealth of genetic data into the design of novel therapeutics and the clinical implementation of diagnostic/prognostic biomarkers will be explored. Finally, personalised medicine and the opportunities for future research and challenges in the immediate post genetics era will be illustrated and discussed.", - "journal_title": "Journal of hepatology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/29122391/" - } - ], - "5f119e74-d364-4f7b-bbdd-6fd19427e5a8": [ - { - "pub_id": "31520524", - "title": "Metformin treatment in young children with fragile X syndrome.", - "authors": "Hazel Maridith B Biag,Laura A Potter,Victoria Wilkins,Sumra Afzal,Alexis Rosvall,Maria Jimena Salcedo-Arellano,Akash Rajaratnam,Ramiro Manzano-Nunez,Andrea Schneider,Flora Tassone,Susan M Rivera,Randi J Hagerman", - "abstract": "Metformin is a drug commonly used in individuals with type 2 diabetes, obesity, and impaired glucose tolerance. It has a strong safety profile in both children and adults. Studies utilizing the Drosophila model and knock out mouse model of fragile X syndrome (FXS) have found metformin to rescue memory, social novelty deficits, and neuroanatomical abnormalities. These studies provided preliminary evidence that metformin could be used as a targeted treatment for the cognitive and behavioral problems associated with FXS. Previously, a case series of children and adults with FXS treated with metformin demonstrated improvements in irritability, social responsiveness, language, and hyperactivity. Here, we present nine children with FXS between 2 and 7\u00a0years of age who were treated clinically with metformin and monitored for behavioral and metabolic changes. Parent reports and developmental testing before and after metformin are presented. There were improvements in language development and behavior (such as lethargy and stereotypy) in most of the patients. These results support the need for a controlled trial of metformin in children with FXS under 7\u00a0years old whose brains are in a critical developmental window and thus may experience a greater degree of clinical benefit from metformin.", - "journal_title": "Molecular genetics & genomic medicine", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/31520524/" - } - ], - "22a0a8a3-18c1-46f9-aca2-1391c5524431": [ - { - "pub_id": "31595705", - "title": "Targeted sequencing identifies novel variants in common and rare MODY genes.", - "authors": "Lucas S de Santana,Lilian A Caetano,Aline D Costa-Riquetto,Pedro C Franco,Renata P Dotto,Andr\u00e9 F Reis,Let\u00edcia S Weinert,Sandra P Silveiro,Marcio F Vendramini,Flaviene A do Prado,Giovanna C P Abrah\u00e3o,Ana Greg\u00f3ria F P de Almeida,Maria da G Rodrigues Tavares,Wagner Rodrigo B Gon\u00e7alves,Augusto C Santomauro Junior,Bruno Halpern,Alexander A L Jorge,Marcia Nery,Milena G Teles", - "abstract": "Maturity-onset diabetes of the young (MODY) is a form of monogenic diabetes with autosomal dominant inheritance. To date, mutations in 11 genes have been frequently associated with this phenotype. In Brazil, few cohorts have been screened for MODY, all using a candidate gene approach, with a high prevalence of undiagnosed cases (MODY-X). We conducted a next-generation sequencing target panel (tNGS) study to investigate, for the first time, a Brazilian cohort of MODY patients with a negative prior genetic analysis. One hundred and two patients were selected, of which 26 had an initial clinical suspicion of MODY-GCK and 76 were non-GCK MODY. After excluding all benign and likely benign variants and variants of uncertain significance, we were able to assign a genetic cause for 12.7% (13/102) of the probands. Three rare MODY subtypes were identified (PDX1/NEUROD1/ABCC8), and eight variants had not been previously described/mapped in genomic databases. Important clinical findings were evidenced in some cases after genetic diagnosis, such as MODY-PDX1/HNF1B. A multiloci genetic approach allowed the identification of rare MODY subtypes, reducing the large percentage of MODY-X in Brazilian cases and contributing to a better clinical, therapeutic, and prognostic characterization of these rare phenotypes.", - "journal_title": "Molecular genetics & genomic medicine", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/31595705/" - } - ], - "05ac6648-5523-41c7-86c7-8240f0bf7e14": [ - { - "pub_id": "34004484", - "title": "Circulating ceramides as biomarkers of cardiovascular disease: Evidence from phenotypic and genomic studies.", - "authors": "Kathryn A McGurk,Bernard D Keavney,Anna Nicolaou", - "abstract": "There is a need for new biomarkers of atherosclerotic cardiovascular disease (ACVD), the main cause of death globally. Ceramides, a class of potent bioactive lipid mediators, have signalling roles in apoptosis, cellular stress and inflammation. Recent studies have highlighted circulating ceramides as novel biomarkers of coronary artery disease, type-2 diabetes and insulin resistance. Ceramides are highly regulated by enzymatic reactions throughout the body in terms of their activity and metabolism, including production, degradation and transport. The genetic studies that have been completed to date on the main ceramide species found in circulation are described, highlighting the importance of DNA variants in genes involved in ceramide biosynthesis as key influencers of heritable, circulating ceramide levels. We also review studies of disease associations with ceramides and discuss mechanistic insights deriving from recent genomic studies. The signalling activities of ceramides in vascular inflammation and apoptosis, associations between circulating ceramides and coronary artery disease risk, type-2 diabetes and insulin resistance, and the potential importance of ceramides with regard to ACVD risk factors, such as blood pressure, lipoproteins and lifestyle factors, are also discussed.", - "journal_title": "Atherosclerosis", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/34004484/" - } - ], - "7e83b0ad-8950-48e1-8e5c-7b048be228bb": [ - { - "pub_id": "30892943", - "title": "Genomic Research Through an Indigenous Lens: Understanding the Expectations.", - "authors": "Nanibaa' A Garrison,M\u0101ui Hudson,Leah L Ballantyne,Ibrahim Garba,Andrew Martinez,Maile Taualii,Laura Arbour,Nadine R Caron,Stephanie Carroll Rainie", - "abstract": "Indigenous scholars are leading initiatives to improve access to genetic and genomic research and health care based on their unique cultural contexts and within sovereign-based governance models created and accepted by their peoples. In the past, Indigenous peoples' engagement with genomicresearch was hampered by a lack of standardized guidelines and institutional partnerships, resulting in group harms. This article provides a comparative analysis of research guidelines from Canada, New Zealand, Australia, and the United States that pertain to Indigenous peoples. The goals of the analysis are to identify areas that need attention, support Indigenous-led governance, and promote the development of a model research policy framework for genomic research and health care that has international relevance for Indigenous peoples.", - "journal_title": "Annual review of genomics and human genetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/30892943/" - } - ], - "ff69cd83-ab79-4c24-8bc5-fd9009aa259b": [ - { - "pub_id": "33188205", - "title": "Genome-wide association analysis of type 2 diabetes in the EPIC-InterAct study.", - "authors": "Lina Cai,Eleanor Wheeler,Nicola D Kerrison,Jian'an Luan,Panos Deloukas,Paul W Franks,Pilar Amiano,Eva Ardanaz,Catalina Bonet,Guy Fagherazzi,Leif C Groop,Rudolf Kaaks,Jos\u00e9 Mar\u00eda Huerta,Giovanna Masala,Peter M Nilsson,Kim Overvad,Valeria Pala,Salvatore Panico,Miguel Rodriguez-Barranco,Olov Rolandsson,Carlotta Sacerdote,Matthias B Schulze,Annemieke M W Spijkerman,Anne Tjonneland,Rosario Tumino,Yvonne T van der Schouw,Stephen J Sharp,Nita G Forouhi,Elio Riboli,Mark I McCarthy,In\u00eas Barroso,Claudia Langenberg,Nicholas J Wareham", - "abstract": "Type 2 diabetes (T2D) is a global public health challenge. Whilst the advent of genome-wide association studies has identified >400 genetic variants associated with T2D, our understanding of its biological mechanisms and translational insights is still limited. The EPIC-InterAct project, centred in 8 countries in the European Prospective Investigations into Cancer and Nutrition study, is one of the largest prospective studies of T2D. Established as a nested case-cohort study to investigate the interplay between genetic and lifestyle behavioural factors on the risk of T2D, a total of 12,403 individuals were identified as incident T2D cases, and a representative sub-cohort of 16,154 individuals was selected from a larger cohort of 340,234 participants with a follow-up time of 3.99 million person-years. We describe the results from a genome-wide association analysis between more than 8.9 million SNPs and T2D risk among 22,326 individuals (9,978 cases and 12,348 non-cases) from the EPIC-InterAct study. The summary statistics to be shared provide a valuable resource to facilitate further investigations into the genetics of T2D.", - "journal_title": "Scientific data", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/33188205/" - } - ], - "370075cf-8288-43e0-97ed-74046648e8bc": [ - { - "pub_id": "30291341", - "title": "The Global State of the Genetic Counseling Profession.", - "authors": "MaryAnn Abacan,Lamia Alsubaie,Kristine Barlow-Stewart,Beppy Caanen,Christophe Cordier,Eliza Courtney,Emeline Davoine,Janice Edwards,Niby J Elackatt,Kate Gardiner,Yue Guan,Lian-Hua Huang,Charlotta Ingvoldstad Malmgren,Sahil Kejriwal,Hyon J Kim,Deborah Lambert,Paulina Araceli Lantigua-Cruz,Juliana M H Lee,Marianne Lodahl,\u00c5shild Lunde,Shelley Macaulay,Ivan Macciocca,Sonia Margarit,Anna Middleton,Ramona Moldovan,Joanne Ngeow,Alexandra J Obregon-Tito,Kelly E Ormond,Milena Paneque,Karen Powell,Kunal Sanghavi,Diana Scotcher,Jenna Scott,Clara Serra Juh\u00e9,Shiri Shkedi-Rafid,Tina-Mari\u00e9 Wessels,Sook-Yee Yoon,Catherine Wicklund", - "abstract": "The profession of genetic counseling (also called genetic counselling in many countries) began nearly 50 years ago in the United States, and has grown internationally in the past 30 years. While there have been many papers describing the profession of genetic counseling in individual countries or regions, data remains incomplete and has been published in diverse journals with limited access. As a result of the 2016 Transnational Alliance of Genetic Counseling (TAGC) conference in Barcelona, Spain, and the 2017 World Congress of Genetic Counselling in the UK, we endeavor to describe as fully as possible the global state of genetic counseling as a profession. We estimate that in 2018 there are nearly 7000 genetic counselors with the profession established or developing in no less than 28 countries.", - "journal_title": "European journal of human genetics : EJHG", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/30291341/" - } - ], - "60c26184-f85d-4a99-afbd-877884f37900": [ - { - "pub_id": "26788538", - "title": "Allelic variants of the Melanocortin 4 receptor (MC4R) gene in a South African study group.", - "authors": "Murray Logan,Maria-Teresa Van der Merwe,Tyren M Dodgen,Renier Myburgh,Arinda Eloff,Marco Alessandrini,Michael S Pepper", - "abstract": "Obesity is a global epidemic that results in significant morbidity and mortality. Mutations in the melanocortin 4 receptor (MC4R) gene, which codes for a G-protein-coupled receptor responsible for postprandial satiety signaling, have been associated with monogenic obesity. The prevalence of obesity is on the increase in South Africa, and it is hypothesized that mutations in MC4R are a contributing factor. The aim of this study was to perform a retrospective assessment of the relationship between allelic variants of MC4R and BMI in a South African study cohort. DNA was isolated from a demographically representative cohort of 297 individuals and the entire MC4R gene sequenced by Sanger sequencing. Eight previously reported MC4R variants were identified in 42 of the 297 (14.1%) study participants. The most frequently observed MC4R alleles were V103I (4.0%), I170V (1.5%), and I198I (1.2%), while the remaining five variants together constituted 1.18%. Five compound heterozygotes were also detected. Although MC4R variants were rare, the majority of variation was observed in individuals of Black African ancestry. No statistically significant associations with BMI were reported. Given that lifestyle interventions have limited success in decreasing obesity, there is an urgent need to perform large-scale population studies to further elucidate the molecular underpinnings of this disease.", - "journal_title": "Molecular genetics & genomic medicine", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/26788538/" - } - ], - "681624d8-c652-4088-92d9-46f542cbc304": [ - { - "pub_id": "29093303", - "title": "Quantitative Relationship Between Cumulative Risk Alleles Based on Genome-Wide Association Studies and Type 2 Diabetes Mellitus: A Systematic Review and Meta-analysis.", - "authors": "Satoru Kodama,Kazuya Fujihara,Hajime Ishiguro,Chika Horikawa,Nobumasa Ohara,Yoko Yachi,Shiro Tanaka,Hitoshi Shimano,Kiminori Kato,Osamu Hanyu,Hirohito Sone", - "abstract": "Many epidemiological studies have assessed the genetic risk of having undiagnosed or of developing type 2 diabetes mellitus (T2DM) using several single nucleotide polymorphisms (SNPs) based on findings of genome-wide association studies (GWAS). However, the quantitative association of cumulative risk alleles (RAs) of such SNPs with T2DM risk has been unclear. The aim of this meta-analysis is to review the strength of the association between cumulative RAs and T2DM risk. Systematic literature searches were conducted for cross-sectional or longitudinal studies that examined odds ratios (ORs) for T2DM in relation to genetic profiles. Logarithm of the estimated OR (log OR) of T2DM for 1 increment in RAs carried (1-\u0394RA) in each study was pooled using a random-effects model. There were 46 eligible studies that included 74,880 cases among 249,365 participants. In 32 studies with a cross-sectional design, the pooled OR for T2DM morbidity for 1-\u0394RA was 1.16 (95% confidence interval [CI], 1.13-1.19). In 15 studies that had a longitudinal design, the OR for incident T2DM was 1.10 (95% CI, 1.08-1.13). There was large heterogeneity in the magnitude of log OR (P < 0.001 for both cross-sectional studies and longitudinal studies). The top 10 commonly used genes significantly explained the variance in the log OR (P = 0.04 for cross-sectional studies; P = 0.006 for longitudinal studies). The current meta-analysis indicated that carrying 1-\u0394RA in T2DM-associated SNPs was associated with a modest risk of prevalent or incident T2DM, although the heterogeneity in the used genes among studies requires us to interpret the results with caution.", - "journal_title": "Journal of epidemiology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/29093303/" - } - ], - "e6682821-7729-4cbe-a817-51c4ce641e01": [ - { - "pub_id": "32602265", - "title": "SHORT syndrome in two Chinese girls: A case report and review of the literature.", - "authors": "Yanhong Zhang,Baolan Ji,Jinsheng Li,Yanying Li,Mei Zhang,Bo Ban", - "abstract": "SHORT syndrome is a rare inherited multisystem disease that includes characteristic facial features, growth retardation, and metabolic anomalies and is related to heterozygous mutations in the PIK3R1 gene. However, it is difficult to ascertain the relationship between the phenotype and the genotype quickly and efficiently. We report two Chinese girls with SHORT syndrome who presented with growth retardation, dysmorphic features, insulin resistance, and diabetes. Comprehensive medical evaluations were collected, including anthropometric measurements, laboratory measurements, and imaging examinations. Whole exome and Sanger sequencing was performed to detect and confirm the underlying genetic mutations in these patients. We prescribed metformin for the patients. The patients both presented diabetes, insulin resistance, short stature, lipodystrophy, and characteristic facial dysmorphic features. A heterozygous mutation was detected in the PIK3R1 gene (c.1615_1617del) of Patient 1. The analysis of patient 2 revealed another PIK3R1 mutation (c.1945C>T). After family validation, neither their parents nor their brothers had similar clinical presentations or carried the same mutation. We identified two de novo heterozygous mutations in PIK3R1 as the cause of SHORT syndrome in two Chinese girls. Additionally, in terms of diabetes control, metformin works well in the early treatment stage.", - "journal_title": "Molecular genetics & genomic medicine", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/32602265/" - } - ], - "7b8b3e82-ff68-4997-bec4-c0ce0789da92": [ - { - "pub_id": "27185156", - "title": "Increased Melatonin Signaling Is a Risk Factor for Type 2 Diabetes.", - "authors": "Tiinamaija Tuomi,Cecilia L F Nagorny,Pratibha Singh,Hedvig Bennet,Qian Yu,Ida Alenkvist,Bo Isomaa,Bjarne \u00d6stman,Johan S\u00f6derstr\u00f6m,Anu-Katriina Pesonen,Silja Martikainen,Katri R\u00e4ikk\u00f6nen,Tom Fors\u00e9n,Liisa Hakaste,Peter Almgren,Petter Storm,Olof Asplund,Liliya Shcherbina,Malin Fex,Jo\u00e3o Fadista,Anders Tengholm,Nils Wierup,Leif Groop,Hindrik Mulder", - "abstract": "Type 2 diabetes (T2D) is a global pandemic. Genome-wide association studies (GWASs) have identified >100 genetic variants associated with the disease, including a common variant in the melatonin receptor 1\u00a0b gene (MTNR1B). Here, we demonstrate increased MTNR1B expression in human islets from risk G-allele carriers, which likely leads to a reduction in insulin release, increasing T2D risk. Accordingly, in\u00a0insulin-secreting cells, melatonin reduced cAMP levels, and MTNR1B overexpression exaggerated the inhibition of insulin release exerted by melatonin. Conversely, mice with a disruption of\u00a0the receptor secreted more insulin. Melatonin treatment in a human recall-by-genotype study reduced insulin secretion and raised glucose levels more extensively in risk G-allele carriers. Thus, our data support a model where enhanced melatonin signaling in islets reduces insulin secretion, leading to hyperglycemia and greater future risk of T2D. The findings also imply\u00a0that melatonin physiologically serves to inhibit nocturnal insulin release.", - "journal_title": "Cell metabolism", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/27185156/" - } - ], - "dbf417f2-617f-418d-a155-8f12385656e9": [ - { - "pub_id": "28672053", - "title": "A genome-wide association study suggests that MAPK14 is associated with diabetic foot ulcers.", - "authors": "W Meng,A Veluchamy,H L H\u00e9bert,A Campbell,H M Colhoun,C N A Palmer", - "abstract": "Diabetic foot ulcers (DFUs) are a devastating complication of diabetes. To identify genetic contributors to the development of DFUs in the presence of peripheral neuropathy in a Scottish cohort with diabetes using a genome-wide association study. A genome-wide association approach was applied. A case was defined as a person with diabetes (type 1 or type 2) who had ever had a foot ulcer (current or previous) in at least one foot, as well as a positive monofilament test result (i.e. evidence of peripheral neuropathy) recorded in their longitudinal e-health records. A control was defined as an individual with diabetes (type 1 or type 2) who has never been recorded as having a foot ulcer in either foot but who had a positive monofilament test result recorded in either foot in their longitudinal e-health records. There were 699 DFU cases and 2695 controls in the Genetics of Diabetes Audit and Research in Tayside Scotland (GoDARTS) dataset. The single-nucleotide polymorphism rs80028505 (Chr6p21\u00b731) in MAPK14 reached genome-wide significance with a lowest P-value of 2\u00b745 \u00d7 10<sup>-8</sup> . The narrow-sense heritability of this phenotype is 0\u00b706. We suggest that MAPK14 is associated with DFUs.", - "journal_title": "The British journal of dermatology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/28672053/" - } - ], - "7d5b12ef-7b17-4b49-8da2-1a4179601520": [ - { - "pub_id": "31228163", - "title": "Genomic Research in Rat Models of Kidney Disease.", - "authors": "Yoram Yagil,Ronen Levi-Varadi,Chana Yagil", - "abstract": "Current understanding of the mechanisms underlying renal disease in humans is incomplete. Consequently, our ability to prevent the occurrence of renal disease or treat established kidney disease is limited. Investigating kidney disease directly in humans poses objective difficulties, which has led investigators to seek experimental animal models that simulate renal disease in humans. Animal models have thus become a tool of major importance in the study of renal physiology and have been crucial in shedding light on the complex mechanisms involved in kidney function and in our current understanding of the pathophysiology of renal disease. Among animal models, the rat has been the preferred and most commonly used species for the investigation of renal disease. This chapter reviews what has been achieved over the years, using the rat as a tool for the investigation of renal disease in humans, focusing on the contribution of rat genetics and genomics to the elucidation of the mechanisms underlying the pathophysiology of the major types of renal disease, including primary and secondary renal diseases.", - "journal_title": "Methods in molecular biology (Clifton, N.J.)", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/31228163/" - } - ], - "e14d92cf-d1ff-4a75-beee-b3312defeffd": [ - { - "pub_id": "31613576", - "title": "Postpartum Care: An Approach to the Fourth Trimester.", - "authors": "Heather L Paladine,Carol E Blenning,Yorgos Strangas", - "abstract": "The postpartum period, defined as the 12 weeks after delivery, is an important time for a new mother and her family and can be considered a fourth trimester. Outpatient postpartum care should be initiated within three weeks after delivery in person or by phone, and may require multiple contacts with the patient to fully address needs and concerns. A full assessment is recommended within 12 weeks. Care should initially focus on acute needs and risks for morbidity and mortality and then transition to care for chronic conditions and health maintenance. Complications of pregnancy, such as hypertensive disorders and gestational diabetes mellitus, affect a woman's long-term health and require specific attention. Women diagnosed with gestational diabetes should receive a 75-g two-hour fasting oral glucose tolerance test between four and 12 weeks postpartum. Patients with hypertensive disorders of pregnancy should have a blood pressure check performed within seven days of delivery. All women should have a biopsychosocial assessment (e.g., depression, intimate partner violence) screening in the postpartum period, and preventive counseling should be offered to women at high risk. Additional patient concerns may include urinary incontinence, constipation, breastfeeding, sexuality, and contraception. Treating these issues during the postpartum period is important to the new mother's immediate and long-term health.", - "journal_title": "American family physician", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/31613576/" - } - ], - "24c79e24-1b2a-4e5c-bcb8-f966f29b60c8": [ - { - "pub_id": "36055208", - "title": "Addressing underrepresentation in genomics research through community engagement.", - "authors": "Amy A Lemke,Edward D Esplin,Aaron J Goldenberg,Claudia Gonzaga-Jauregui,Neil A Hanchard,Julie Harris-Wai,Justin E Ideozu,Rosario Isasi,Andrew P Landstrom,Anya E R Prince,Erin Turbitt,Maya Sabatello,Samantha A Schrier Vergano,Matthew R G Taylor,Joon-Ho Yu,Kyle B Brothers,Nanibaa' A Garrison", - "abstract": "The vision of the American Society of Human Genetics (ASHG) is that people everywhere will realize the benefits of human genetics and genomics. Implicit in that vision is the importance of ensuring that the benefits of human genetics and genomics research are realized in ways that minimize harms and maximize benefits, a goal that can only be achieved through focused efforts to address health inequities and increase the representation of underrepresented communities in genetics and genomics research. This guidance is intended to advance community engagement as an approach that can be used across the research lifecycle. Community engagement uniquely offers researchers in human genetics and genomics an opportunity to pursue that vision successfully, including by addressing underrepresentation in genomics research.", - "journal_title": "American journal of human genetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/36055208/" - } - ], - "e2c1cfb0-9cfc-4a59-9df6-8599708b25ed": [ - { - "pub_id": "32561617", - "title": "Precision Medicine in Diabetes: A Consensus Report From the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD).", - "authors": "Wendy K Chung,Karel Erion,Jose C Florez,Andrew T Hattersley,Marie-France Hivert,Christine G Lee,Mark I McCarthy,John J Nolan,Jill M Norris,Ewan R Pearson,Louis Philipson,Allison T McElvaine,William T Cefalu,Stephen S Rich,Paul W Franks", - "abstract": "The convergence of advances in medical science, human biology, data science, and technology has enabled the generation of new insights into the phenotype known as \"diabetes.\" Increased knowledge of this condition has emerged from populations around the world, illuminating the differences in how diabetes presents, its variable prevalence, and how best practice in treatment varies between populations. In parallel, focus has been placed on the development of tools for the application of precision medicine to numerous conditions. This Consensus Report presents the American Diabetes Association (ADA) Precision Medicine in Diabetes Initiative in partnership with the European Association for the Study of Diabetes (EASD), including its mission, the current state of the field, and prospects for the future. Expert opinions are presented on areas of precision diagnostics and precision therapeutics (including prevention and treatment), and key barriers to and opportunities for implementation of precision diabetes medicine, with better care and outcomes around the globe, are highlighted. Cases where precision diagnosis is already feasible and effective (i.e., monogenic forms of diabetes) are presented, while the major hurdles to the global implementation of precision diagnosis of complex forms of diabetes are discussed. The situation is similar for precision therapeutics, in which the appropriate therapy will often change over time owing to the manner in which diabetes evolves within individual patients. This Consensus Report describes a foundation for precision diabetes medicine, while highlighting what remains to be done to realize its potential. This, combined with a subsequent, detailed evidence-based review (due 2022), will provide a roadmap for precision medicine in diabetes that helps improve the quality of life for all those with diabetes.", - "journal_title": "Diabetes care", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/32561617/" - } - ], - "a4e27158-1e54-4ee2-9cc1-049489a628bc": [ - { - "pub_id": "30637094", - "title": "Minimal information for studies of extracellular vesicles 2018 (MISEV2018): a position statement of the International Society for Extracellular Vesicles and update of the MISEV2014 guidelines.", - "authors": "Clotilde Th\u00e9ry,Kenneth W Witwer,Elena Aikawa,Maria Jose Alcaraz,Johnathon D Anderson,Ramaroson Andriantsitohaina,Anna Antoniou,Tanina Arab,Fabienne Archer,Georgia K Atkin-Smith,D Craig Ayre,Jean-Marie Bach,Daniel Bachurski,Hossein Baharvand,Leonora Balaj,Shawn Baldacchino,Natalie N Bauer,Amy A Baxter,Mary Bebawy,Carla Beckham,Apolonija Bedina Zavec,Abderrahim Benmoussa,Anna C Berardi,Paolo Bergese,Ewa Bielska,Cherie Blenkiron,Sylwia Bobis-Wozowicz,Eric Boilard,Wilfrid Boireau,Antonella Bongiovanni,Francesc E Borr\u00e0s,Steffi Bosch,Chantal M Boulanger,Xandra Breakefield,Andrew M Breglio,Meadhbh \u00c1 Brennan,David R Brigstock,Alain Brisson,Marike Ld Broekman,Jacqueline F Bromberg,Paulina Bryl-G\u00f3recka,Shilpa Buch,Amy H Buck,Dylan Burger,Sara Busatto,Dominik Buschmann,Benedetta Bussolati,Edit I Buz\u00e1s,James Bryan Byrd,Giovanni Camussi,David Rf Carter,Sarah Caruso,Lawrence W Chamley,Yu-Ting Chang,Chihchen Chen,Shuai Chen,Lesley Cheng,Andrew R Chin,Aled Clayton,Stefano P Clerici,Alex Cocks,Emanuele Cocucci,Robert J Coffey,Anabela Cordeiro-da-Silva,Yvonne Couch,Frank Aw Coumans,Beth Coyle,Rossella Crescitelli,Miria Ferreira Criado,Crislyn D'Souza-Schorey,Saumya Das,Amrita Datta Chaudhuri,Paola de Candia,Eliezer F De Santana,Olivier De Wever,Hernando A Del Portillo,Tanguy Demaret,Sarah Deville,Andrew Devitt,Bert Dhondt,Dolores Di Vizio,Lothar C Dieterich,Vincenza Dolo,Ana Paula Dominguez Rubio,Massimo Dominici,Mauricio R Dourado,Tom Ap Driedonks,Filipe V Duarte,Heather M Duncan,Ramon M Eichenberger,Karin Ekstr\u00f6m,Samir El Andaloussi,Celine Elie-Caille,Uta Erdbr\u00fcgger,Juan M Falc\u00f3n-P\u00e9rez,Farah Fatima,Jason E Fish,Miguel Flores-Bellver,Andr\u00e1s F\u00f6rs\u00f6nits,Annie Frelet-Barrand,Fabia Fricke,Gregor Fuhrmann,Susanne Gabrielsson,Ana G\u00e1mez-Valero,Chris Gardiner,Kathrin G\u00e4rtner,Raphael Gaudin,Yong Song Gho,Bernd Giebel,Caroline Gilbert,Mario Gimona,Ilaria Giusti,Deborah Ci Goberdhan,Andr\u00e9 G\u00f6rgens,Sharon M Gorski,David W Greening,Julia Christina Gross,Alice Gualerzi,Gopal N Gupta,Dakota Gustafson,Aase Handberg,Reka A Haraszti,Paul Harrison,Hargita Hegyesi,An Hendrix,Andrew F Hill,Fred H Hochberg,Karl F Hoffmann,Beth Holder,Harry Holthofer,Baharak Hosseinkhani,Guoku Hu,Yiyao Huang,Veronica Huber,Stuart Hunt,Ahmed Gamal-Eldin Ibrahim,Tsuneya Ikezu,Jameel M Inal,Mustafa Isin,Alena Ivanova,Hannah K Jackson,Soren Jacobsen,Steven M Jay,Muthuvel Jayachandran,Guido Jenster,Lanzhou Jiang,Suzanne M Johnson,Jennifer C Jones,Ambrose Jong,Tijana Jovanovic-Talisman,Stephanie Jung,Raghu Kalluri,Shin-Ichi Kano,Sukhbir Kaur,Yumi Kawamura,Evan T Keller,Delaram Khamari,Elena Khomyakova,Anastasia Khvorova,Peter Kierulf,Kwang Pyo Kim,Thomas Kislinger,Mikael Klingeborn,David J Klinke,Miroslaw Kornek,Maja M Kosanovi\u0107,\u00c1rp\u00e1d Ferenc Kov\u00e1cs,Eva-Maria Kr\u00e4mer-Albers,Susanne Krasemann,Mirja Krause,Igor V Kurochkin,Gina D Kusuma,S\u00f6ren Kuypers,Saara Laitinen,Scott M Langevin,Lucia R Languino,Joanne Lannigan,Cecilia L\u00e4sser,Louise C Laurent,Gregory Lavieu,Elisa L\u00e1zaro-Ib\u00e1\u00f1ez,Soazig Le Lay,Myung-Shin Lee,Yi Xin Fiona Lee,Debora S Lemos,Metka Lenassi,Aleksandra Leszczynska,Isaac Ts Li,Ke Liao,Sten F Libregts,Erzsebet Ligeti,Rebecca Lim,Sai Kiang Lim,Aija Lin\u0113,Karen Linnemannst\u00f6ns,Alicia Llorente,Catherine A Lombard,Magdalena J Lorenowicz,\u00c1kos M L\u00f6rincz,Jan L\u00f6tvall,Jason Lovett,Michelle C Lowry,Xavier Loyer,Quan Lu,Barbara Lukomska,Taral R Lunavat,Sybren Ln Maas,Harmeet Malhi,Antonio Marcilla,Jacopo Mariani,Javier Mariscal,Elena S Martens-Uzunova,Lorena Martin-Jaular,M Carmen Martinez,Vilma Regina Martins,Mathilde Mathieu,Suresh Mathivanan,Marco Maugeri,Lynda K McGinnis,Mark J McVey,David G Meckes,Katie L Meehan,Inge Mertens,Valentina R Minciacchi,Andreas M\u00f6ller,Malene M\u00f8ller J\u00f8rgensen,Aizea Morales-Kastresana,Jess Morhayim,Fran\u00e7ois Mullier,Maurizio Muraca,Luca Musante,Veronika Mussack,Dillon C Muth,Kathryn H Myburgh,Tanbir Najrana,Muhammad Nawaz,Irina Nazarenko,Peter Nejsum,Christian Neri,Tommaso Neri,Rienk Nieuwland,Leonardo Nimrichter,John P Nolan,Esther Nm Nolte-'t Hoen,Nicole Noren Hooten,Lorraine O'Driscoll,Tina O'Grady,Ana O'Loghlen,Takahiro Ochiya,Martin Olivier,Alberto Ortiz,Luis A Ortiz,Xabier Osteikoetxea,Ole \u00d8stergaard,Matias Ostrowski,Jaesung Park,D Michiel Pegtel,Hector Peinado,Francesca Perut,Michael W Pfaffl,Donald G Phinney,Bartijn Ch Pieters,Ryan C Pink,David S Pisetsky,Elke Pogge von Strandmann,Iva Polakovicova,Ivan Kh Poon,Bonita H Powell,Ilaria Prada,Lynn Pulliam,Peter Quesenberry,Annalisa Radeghieri,Robert L Raffai,Stefania Raimondo,Janusz Rak,Marcel I Ramirez,Gra\u00e7a Raposo,Morsi S Rayyan,Neta Regev-Rudzki,Franz L Ricklefs,Paul D Robbins,David D Roberts,Silvia C Rodrigues,Eva Rohde,Sophie Rome,Kasper Ma Rouschop,Aurelia Rughetti,Ashley E Russell,Paula Sa\u00e1,Susmita Sahoo,Edison Salas-Huenuleo,Catherine S\u00e1nchez,Julie A Saugstad,Meike J Saul,Raymond M Schiffelers,Raphael Schneider,Tine Hiorth Sch\u00f8yen,Aaron Scott,Eriomina Shahaj,Shivani Sharma,Olga Shatnyeva,Faezeh Shekari,Ganesh Vilas Shelke,Ashok K Shetty,Kiyotaka Shiba,Pia R-M Siljander,Andreia M Silva,Agata Skowronek,Orman L Snyder,Rodrigo Pedro Soares,Barbara W S\u00f3dar,Carolina Soekmadji,Javier Sotillo,Philip D Stahl,Willem Stoorvogel,Shannon L Stott,Erwin F Strasser,Simon Swift,Hidetoshi Tahara,Muneesh Tewari,Kate Timms,Swasti Tiwari,Rochelle Tixeira,Mercedes Tkach,Wei Seong Toh,Richard Tomasini,Ana Claudia Torrecilhas,Juan Pablo Tosar,Vasilis Toxavidis,Lorena Urbanelli,Pieter Vader,Bas Wm van Balkom,Susanne G van der Grein,Jan Van Deun,Martijn Jc van Herwijnen,Kendall Van Keuren-Jensen,Guillaume van Niel,Martin E van Royen,Andre J van Wijnen,M Helena Vasconcelos,Ivan J Vechetti,Tiago D Veit,Laura J Vella,\u00c9milie Velot,Frederik J Verweij,Beate Vestad,Jose L Vi\u00f1as,Tam\u00e1s Visnovitz,Krisztina V Vukman,Jessica Wahlgren,Dionysios C Watson,Marca Hm Wauben,Alissa Weaver,Jason P Webber,Viktoria Weber,Ann M Wehman,Daniel J Weiss,Joshua A Welsh,Sebastian Wendt,Asa M Wheelock,Zolt\u00e1n Wiener,Leonie Witte,Joy Wolfram,Angeliki Xagorari,Patricia Xander,Jing Xu,Xiaomei Yan,Mar\u00eda Y\u00e1\u00f1ez-M\u00f3,Hang Yin,Yuana Yuana,Valentina Zappulli,Jana Zarubova,Vytautas \u017d\u0117kas,Jian-Ye Zhang,Zezhou Zhao,Lei Zheng,Alexander R Zheutlin,Antje M Zickler,Pascale Zimmermann,Angela M Zivkovic,Davide Zocco,Ewa K Zuba-Surma", - "abstract": "The last decade has seen a sharp increase in the number of scientific publications describing physiological and pathological functions of extracellular vesicles (EVs), a collective term covering various subtypes of cell-released, membranous structures, called exosomes, microvesicles, microparticles, ectosomes, oncosomes, apoptotic bodies, and many other names. However, specific issues arise when working with these entities, whose size and amount often make them difficult to obtain as relatively pure preparations, and to characterize properly. The International Society for Extracellular Vesicles (ISEV) proposed Minimal Information for Studies of Extracellular Vesicles (\"MISEV\") guidelines for the field in 2014. We now update these \"MISEV2014\" guidelines based on evolution of the collective knowledge in the last four years. An important point to consider is that ascribing a specific function to EVs in general, or to subtypes of EVs, requires reporting of specific information beyond mere description of function in a crude, potentially contaminated, and heterogeneous preparation. For example, claims that exosomes are endowed with exquisite and specific activities remain difficult to support experimentally, given our still limited knowledge of their specific molecular machineries of biogenesis and release, as compared with other biophysically similar EVs. The MISEV2018 guidelines include tables and outlines of suggested protocols and steps to follow to document specific EV-associated functional activities. Finally, a checklist is provided with summaries of key points.", - "journal_title": "Journal of extracellular vesicles", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/30637094/" - } - ], - "ef684dbd-c0f9-4f5d-a370-2b4a9386e436": [ - { - "pub_id": "31132961", - "title": "Genome-wide DNA methylation profiling of human diabetic peripheral neuropathy in subjects with type 2 diabetes mellitus.", - "authors": "Kai Guo,Sarah Elzinga,Stephanie Eid,Claudia Figueroa-Romero,Lucy M Hinder,Crystal Pacut,Eva L Feldman,Junguk Hur", - "abstract": "DNA methylation is an epigenetic mechanism important for the regulation of gene expression, which plays a vital role in the interaction between genetic and environmental factors. Aberrant epigenetic changes are implicated in the pathogenesis of diabetes and diabetic complications, but the role of DNA methylation in diabetic peripheral neuropathy (DPN) is not well understood. Therefore, our aim in this study was to explore the role of DNA methylation in the progression of DPN in type 2 diabetes. We compared genome-wide DNA methylation profiles of human sural nerve biopsies from subjects with stable or improving nerve fibre counts to biopsies from subjects with progressive loss of nerve fibres. Nerve fibre counts were determined by comparing myelinated nerve fibre densities between an initial and repeat biopsy separated by 52 weeks. Subjects with significant nerve regeneration (regenerators) and subjects with significant nerve degeneration (degenerators) represent the two extreme DPN phenotypes. Using reduced representation bisulfite sequencing, we identified 3,460 differentially methylated CpG dinucleotides between the two groups. The genes associated with differentially methylated CpGs were highly enriched in biological processes that have previously been implicated in DPN such as nervous system development, neuron development, and axon guidance, as well as glycerophospholipid metabolism and mitogen-activated protein kinase (MAPK) signalling. These findings are the first to provide a comprehensive analysis of DNA methylation profiling in human sural nerves of subjects with DPN and suggest that epigenetic regulation has an important role in the progression of this prevalent diabetic complication.", - "journal_title": "Epigenetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/31132961/" - } - ], - "88dde947-5255-40e1-92d5-afde089b517b": [ - { - "pub_id": "33164750", - "title": "Integration of genomics and transcriptomics predicts diabetic retinopathy susceptibility genes.", - "authors": "Andrew D Skol,Segun C Jung,Ana Marija Sokovic,Siquan Chen,Sarah Fazal,Olukayode Sosina,Poulami P Borkar,Amy Lin,Maria Sverdlov,Dingcai Cao,Anand Swaroop,Ionut Bebu, ,Barbara E Stranger,Michael A Grassi", - "abstract": "We determined differential gene expression in response to high glucose in lymphoblastoid cell lines derived from matched individuals with type 1 diabetes with and without retinopathy. Those genes exhibiting the largest difference in glucose response were assessed for association with diabetic retinopathy in a genome-wide association study meta-analysis. Expression quantitative trait loci (eQTLs) of the glucose response genes were tested for association with diabetic retinopathy. We detected an enrichment of the eQTLs from the glucose response genes among small association p-values and identified folliculin (<i>FLCN</i>) as a susceptibility gene for diabetic retinopathy. Expression of <i>FLCN</i> in response to glucose was greater in individuals with diabetic retinopathy. Independent cohorts of individuals with diabetes revealed an association of <i>FLCN</i> eQTLs with diabetic retinopathy. Mendelian randomization confirmed a direct positive effect of increased <i>FLCN</i> expression on retinopathy. Integrating genetic association with gene expression implicated <i>FLCN</i> as a disease gene for diabetic retinopathy.", - "journal_title": "eLife", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/33164750/" - } - ], - "8c2184e3-fbe4-4337-97b6-b9ab10e8412e": [ - { - "pub_id": "27411435", - "title": "Effects of the genome on immune regulation in type 1 diabetes.", - "authors": "Flemming Pociot,Simranjeet Kaur,Lotte B Nielsen", - "abstract": "Type 1 diabetes (T1DM) is a complex disease, arising through the interaction of an incompletely defined combination of genetic susceptibility and environmental factors. It is well accepted that T1DM results from selective immune-mediated destruction of the insulin-producing \u03b2 cells in the islets of langerhans. Genetic studies of T1DM have identified several regions of susceptibility and identified major networks and pathways contributing to risk. In this study, we have taken advantages of the Immunochip fine-mapping genotyping data to address different aspects of immune regulation in relation to T1DM. First, we confirm that dense single nucleotide polymorphism (SNP) genotyping of the major histocompatibility complex/human leukocyte antigen (MHC/HLA) region capture the complex genetic contribution of this region to disease risk. Furthermore, it is shown that Immunochip genotyping can translate into a limited number of DRB1 and DQB1 amino acid residues that account for most of the HLA-risk. Second, we use the Immunochip data to look for functional significance by correlation to circulating levels of chemokines and demonstrate that genetic variation at chromosome 2, 3, and 6 correlates with circulating CCL2 and CCL4 in recent onset T1DM patients. Finally, we report that genetic variants predict autoantibody positivity in T1DM cases.", - "journal_title": "Pediatric diabetes", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/27411435/" - } - ], - "581fb26a-8391-433b-afc2-d5694f5344fd": [ - { - "pub_id": "36113507", - "title": "Global incidence, prevalence, and mortality of type 1 diabetes in 2021 with projection to 2040: a modelling study.", - "authors": "Gabriel A Gregory,Thomas I G Robinson,Sarah E Linklater,Fei Wang,Stephen Colagiuri,Carine de Beaufort,Kim C Donaghue, ,Dianna J Magliano,Jayanthi Maniam,Trevor J Orchard,Priyanka Rai,Graham D Ogle", - "abstract": "Accurate data on type 1 diabetes prevalence, incidence, associated mortality and life expectancy are crucial to inform public health policy, but these data are scarce. We therefore developed a model based on available data to estimate these values for 201 countries for the year 2021 and estimate the projected prevalent cases in 2040. We fitted a discrete-time illness-death model (Markov model) to data on type 1 diabetes incidence and type 1 diabetes-associated mortality to produce type 1 diabetes prevalence, incidence, associated mortality and life expectancy in all countries. Type 1 diabetes incidence and mortality data were available from 97 and 37 countries respectively. Diagnosis rates were estimated using data from an expert survey. Mortality was modelled using random-forest regression of published type 1 diabetes mortality data, and life expectancy was calculated accordingly using life tables. Estimates were validated against observed prevalence data for 15 countries. We also estimated missing prevalence (the number of additional people who would be alive with type 1 diabetes if their mortality matched general population rates). In 2021, there were about 8\u00b74 (95% uncertainty interval 8\u00b71-8\u00b78) million individuals worldwide with type 1 diabetes: of these 1\u00b75 million (18%) were younger than 20 years, 5\u00b74 million (64%) were aged 20-59 years, and 1\u00b76 million (19%) were aged 60 years or older. In that year there were 0\u00b75 million new cases diagnosed (median age of onset 39 years), about 35\u2009000 non-diagnosed individuals died within 12 months of symptomatic onset. One fifth (1\u00b78 million) of individuals with type 1 diabetes were in low-income and lower-middle-income countries. Remaining life expectancy of a 10-year-old diagnosed with type 1 diabetes in 2021 ranged from a mean of 13 years in low-income countries to 65 years in high-income countries. Missing prevalent cases in 2021 were estimated at 3\u00b77 million. In 2040, we predict an increase in prevalent cases to 13\u00b75-17\u00b74 million (60-107% higher than in 2021) with the largest relative increase versus 2021 in low-income and lower-middle-income countries. The burden of type 1 diabetes in 2021 is vast and is expected to increase rapidly, especially in resource-limited countries. Most incident and prevalent cases are adults. The substantial missing prevalence highlights the premature mortality of type 1 diabetes and an opportunity to save and extend lives of people with type 1 diabetes. Our new model, which will be made publicly available as the Type 1 Diabetes Index model, will be an important tool to support health delivery, advocacy, and funding decisions for type 1 diabetes. JDRF International.", - "journal_title": "The lancet. Diabetes & endocrinology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/36113507/" - } - ], - "fb01b51c-3558-4133-a2f1-66c37bb5594e": [ - { - "pub_id": "35721735", - "title": "Genome-Wide Placental Gene Methylations in Gestational Diabetes Mellitus, Fetal Growth and Metabolic Health Biomarkers in Cord Blood.", - "authors": "Wen-Juan Wang,Rong Huang,Tao Zheng,Qinwen Du,Meng-Nan Yang,Ya-Jie Xu,Xin Liu,Min-Yi Tao,Hua He,Fang Fang,Fei Li,Jian-Gao Fan,Jun Zhang,Laurent Briollais,Fengxiu Ouyang,Zhong-Cheng Luo", - "abstract": "Gestational diabetes mellitus (GDM) \"program\" an elevated risk of metabolic syndrome in the offspring. Epigenetic alterations are a suspected mechanism. GDM has been associated with placental DNA methylation changes in some epigenome-wide association studies. It remains unclear which genes or pathways are affected, and whether any placental differential gene methylations are correlated to fetal growth or circulating metabolic health biomarkers. In an epigenome-wide association study using the Infinium MethylationEPIC Beadchip, we sought to identify genome-wide placental differentially methylated genes and enriched pathways in GDM, and to assess the correlations with fetal growth and metabolic health biomarkers in cord blood. The study samples were 30 pairs of term placentas in GDM vs. euglycemic pregnancies (controls) matched by infant sex and gestational age at delivery in the Shanghai Birth Cohort. Cord blood metabolic health biomarkers included insulin, C-peptide, proinsulin, IGF-I, IGF-II, leptin and adiponectin. Adjusting for maternal age, pre-pregnancy BMI, parity, mode of delivery and placental cell type heterogeneity, 256 differentially methylated positions (DMPs,130 hypermethylated and 126 hypomethylated) were detected between GDM and control groups accounting for multiple tests with false discovery rate <0.05 and beta-value difference >0.05. WSCD2 was identified as a differentially methylated gene in both site- and region-level analyses. We validated 7 hypermethylated (CYP1A2, GFRA1, HDAC4, LIMS2, NAV3, PAX6, UPK1B) and 10 hypomethylated (DPP10, CPLX1, CSMD2, GPR133, NRXN1, PCSK9, PENK, PRDM16, PTPRN2, TNXB) genes reported in previous epigenome-wide association studies. We did not find any enriched pathway accounting for multiple tests. DMPs in 11 genes (CYP2D7P1, PCDHB15, ERG, SIRPB1, DKK2, RAPGEF5, CACNA2D4, PCSK9, TSNARE1, CADM2, KCNAB2) were correlated with birth weight (z score) accounting for multiple tests. There were no significant correlations between placental gene methylations and cord blood biomarkers. In conclusions, GDM was associated with DNA methylation changes in a number of placental genes, but these placental gene methylations were uncorrelated to the observed metabolic health biomarkers (fetal growth factors, leptin and adiponectin) in cord blood. We validated 17 differentially methylated placental genes in GDM, and identified 11 differentially methylated genes relevant to fetal growth.", - "journal_title": "Frontiers in endocrinology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/35721735/" - } - ], - "f1c8cd32-f4f0-49b2-a2c7-125769cc02b3": [ - { - "pub_id": "30006586", - "title": "Care of adults with neurofibromatosis type 1: a clinical practice resource of the American College of Medical Genetics and Genomics (ACMG).", - "authors": "Douglas R Stewart,Bruce R Korf,Katherine L Nathanson,David A Stevenson,Kaleb Yohay", - "abstract": "This practice resource is designed primarily as an educational resource for medical geneticists and other clinicians to help them provide quality medical services. Adherence to this practice resource is completely voluntary and does not necessarily assure a successful medical outcome. This practice resource should not be considered inclusive of all proper procedures and tests or exclusive of other procedures and tests that are reasonably directed to obtaining the same results. In determining the propriety of any specific procedure or test, the clinician should apply his or her own professional judgment to the specific clinical circumstances presented by the individual patient or specimen. Clinicians are encouraged to document the reasons for the use of a particular procedure or test, whether or not it is in conformance with this practice resource. Clinicians also are advised to take notice of the date this practice resource was adopted, and to consider other medical and scientific information that becomes available after that date. It also would be prudent to consider whether intellectual property interests may restrict the performance of certain tests and other procedures. Neurofibromatosis type 1 (NF1) is an autosomal dominant disorder that is caused by a heterozygous loss-of-function variant in the tumor suppressor gene NF1; it affects ~1/1,900-1/3,500 people worldwide. The disorder is associated with an 8-15-year reduction in average life expectancy in both men and women, primarily due to malignant neoplasms and cardiovascular causes. A work group of experts sought to determine the prevalence, morbidity and mortality, and available treatments of common and emerging NF1-related clinical problems in adults. Work-group members identified peer-reviewed publications from PubMed. Publications derived from populations and multi-institution cohorts were prioritized. Recommendations for management arose by consensus from this literature and the collective expertise of the authors. Malignant peripheral nerve sheath tumor (MPNST), breast cancer, cutaneous neurofibromas, and significant psychiatric and neurologic diagnoses are common problems in patients with NF1. Patient education and sensitization to worrisome signs and symptoms such as progressive severe pain (MPNST), changes in tumor volume (MPNST), new, unexplained neurologic symptoms (MPNST, brain tumors), and diaphoresis/palpitations (pheochromocytoma) are important. Although many issues in adults with NF1 can be managed by an internist or family physician, we strongly encourage evaluation by, and care coordination with, a specialized NF1 clinic.", - "journal_title": "Genetics in medicine : official journal of the American College of Medical Genetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/30006586/" - } - ], - "9f386bdd-fa6f-476f-9b9d-b2602957284f": [ - { - "pub_id": "33261667", - "title": "Whole blood co-expression modules associate with metabolic traits and type 2 diabetes: an IMI-DIRECT study.", - "authors": "Valborg Gudmundsdottir,Helle Krogh Pedersen,Gianluca Mazzoni,Kristine H Allin,Anna Artati,Joline W Beulens,Karina Banasik,Caroline Brorsson,Henna Cederberg,Elizaveta Chabanova,Federico De Masi,Petra J Elders,Ian Forgie,Giuseppe N Giordano,Harald Grallert,Ramneek Gupta,Mark Haid,Torben Hansen,Tue H Hansen,Andrew T Hattersley,Alison Heggie,Mun-Gwan Hong,Angus G Jones,Robert Koivula,Tarja Kokkola,Markku Laakso,Peter L\u00f8ngreen,Anubha Mahajan,Andrea Mari,Timothy J McDonald,Donna McEvoy,Petra B Musholt,Imre Pavo,Cornelia Prehn,Hartmut Ruetten,Martin Ridderstr\u00e5le,Femke Rutters,Sapna Sharma,Roderick C Slieker,Ali Syed,Juan Fernandez Tajes,Cecilia Engel Thomas,Henrik S Thomsen,Jagadish Vangipurapu,Henrik Vestergaard,Ana Vi\u00f1uela,Agata Wesolowska-Andersen,Mark Walker,Jerzy Adamski,Jochen M Schwenk,Mark I McCarthy,Ewan Pearson,Emmanouil Dermitzakis,Paul W Franks,Oluf Pedersen,S\u00f8ren Brunak", - "abstract": "The rising prevalence of type 2 diabetes (T2D) poses a major global challenge. It remains unresolved to what extent transcriptomic signatures of metabolic dysregulation and T2D can be observed in easily accessible tissues such as blood. Additionally, large-scale human studies are required to further our understanding of the putative inflammatory component of insulin resistance and T2D. Here we used transcriptomics data from individuals with (n\u2009=\u2009789) and without (n\u2009=\u20092127) T2D from the IMI-DIRECT cohorts to describe the co-expression structure of whole blood that mainly reflects processes and cell types of the immune system, and how it relates to metabolically relevant clinical traits and T2D. Clusters of co-expressed genes were identified in the non-diabetic IMI-DIRECT cohort and evaluated with regard to stability, as well as preservation and rewiring in the cohort of individuals with T2D. We performed functional and immune cell signature enrichment analyses, and a genome-wide association study to describe the genetic regulation of the modules. Phenotypic and trans-omics associations of the transcriptomic modules were investigated across both IMI-DIRECT cohorts. We identified 55 whole blood co-expression modules, some of which clustered in larger super-modules. We identified a large number of associations between these transcriptomic modules and measures of insulin action and glucose tolerance. Some of the metabolically linked modules reflect neutrophil-lymphocyte ratio in blood while others are independent of white blood cell estimates, including a module of genes encoding neutrophil granule proteins with antibacterial properties for which the strongest associations with clinical traits and T2D status were observed. Through the integration of genetic and multi-omics data, we provide a holistic view of the regulation and molecular context of whole blood transcriptomic modules. We furthermore identified an overlap between genetic signals for T2D and co-expression modules involved in type II interferon signaling. Our results offer a large-scale map of whole blood transcriptomic modules in the context of metabolic disease and point to novel biological candidates for future studies related to T2D.", - "journal_title": "Genome medicine", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/33261667/" - } - ], - "a40877bb-3362-45fb-9943-8aae0cbb8734": [ - { - "pub_id": "26600078", - "title": "The severity of nonalcoholic fatty liver disease is associated with gut dysbiosis and shift in the metabolic function of the gut microbiota.", - "authors": "J\u00e9r\u00f4me Boursier,Olaf Mueller,Matthieu Barret,Mariana Machado,Lionel Fizanne,Felix Araujo-Perez,Cynthia D Guy,Patrick C Seed,John F Rawls,Lawrence A David,Gilles Hunault,Fr\u00e9d\u00e9ric Oberti,Paul Cal\u00e8s,Anna Mae Diehl", - "abstract": "Several animal studies have emphasized the role of gut microbiota in nonalcoholic fatty liver disease (NAFLD). However, data about gut dysbiosis in human NAFLD remain scarce in the literature, especially studies including the whole spectrum of NAFLD lesions. We aimed to evaluate the association between gut dysbiosis and severe NAFLD lesions, that is, nonalcoholic steatohepatitis (NASH) and fibrosis, in a well-characterized population of adult NAFLD. Fifty-seven patients with biopsy-proven NAFLD were enrolled. Taxonomic composition of gut microbiota was determined using 16S ribosomal RNA gene sequencing of stool samples. Thirty patients had F0/F1 fibrosis stage at liver biopsy (10 with NASH), and 27 patients had significant F\u22652 fibrosis (25 with NASH). Bacteroides abundance was significantly increased in NASH and F\u22652 patients, whereas Prevotella abundance was decreased. Ruminococcus abundance was significantly higher in F\u22652 patients. By multivariate analysis, Bacteroides abundance was independently associated with NASH and Ruminococcus with F\u22652 fibrosis. Stratification according to the abundance of these two bacteria generated three patient subgroups with increasing severity of NAFLD lesions. Based on imputed metagenomic profiles, Kyoto Encyclopedia of Genes and Genomes pathways significantly related to NASH and fibrosis F\u22652 were mostly related to carbohydrate, lipid, and amino acid metabolism. NAFLD severity associates with gut dysbiosis and a shift in metabolic function of the gut microbiota. We identified Bacteroides as independently associated with NASH and Ruminococcus with significant fibrosis. Thus, gut microbiota analysis adds information to classical predictors of NAFLD severity and suggests novel metabolic targets for pre-/probiotics therapies.", - "journal_title": "Hepatology (Baltimore, Md.)", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/26600078/" - } - ], - "e2e4550c-6004-4911-aa83-fde6ed6d872c": [ - { - "pub_id": "28167949", - "title": "Exploration of Genetic and Genomic Resources for Abiotic and Biotic Stress Tolerance in Pearl Millet.", - "authors": "Radha Shivhare,Charu Lata", - "abstract": "Pearl millet is one of the most important small-grained C<sub>4</sub> Panicoid crops with a large genome size (\u223c2352 Mb), short life cycle and outbreeding nature. It is highly resilient to areas with scanty rain and high temperature. Pearl millet is a nutritionally superior staple crop for people inhabiting hot, drought-prone arid and semi-arid regions of South Asia and Africa where it is widely grown and used for food, hay, silage, bird feed, building material, and fuel. Having excellent nutrient composition and exceptional buffering capacity against variable climatic conditions and pathogen attack makes pearl millet a wonderful model crop for stress tolerance studies. Pearl millet germplasm show a large range of genotypic and phenotypic variations including tolerance to abiotic and biotic stresses. Conventional breeding for enhancing abiotic and biotic stress resistance in pearl millet have met with considerable success, however, in last few years various novel approaches including functional genomics and molecular breeding have been attempted in this crop for augmenting yield under adverse environmental conditions, and there is still a lot of scope for further improvement using genomic tools. Discovery and use of various DNA-based markers such as EST-SSRs, DArT, CISP, and SSCP-SNP in pearl millet not only help in determining population structure and genetic diversity but also prove to be important for developing strategies for crop improvement at a faster rate and greater precision. Molecular marker-based genetic linkage maps and identification of genomic regions determining yield under abiotic stresses particularly terminal drought have paved way for marker-assisted selection and breeding of pearl millet cultivars. Reference collections and marker-assisted backcrossing have also been used to improve biotic stress resistance in pearl millet specifically to downy mildew. Whole genome sequencing of pearl millet genome will give new insights for processing of functional genes and assist in crop improvement programs through molecular breeding approaches. This review thus summarizes the exploration of pearl millet genetic and genomic resources for improving abiotic and biotic stress resistance and development of cultivars superior in stress tolerance.", - "journal_title": "Frontiers in plant science", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/28167949/" - } - ], - "13ad1128-9df0-4956-9606-2d5b936bf204": [ - { - "pub_id": "27103245", - "title": "Test-Retest Reliability of the Genetics and Genomics in Nursing Practice Survey Instrument.", - "authors": "Kathleen A Calzone,Stacey Culp,Jean Jenkins,Sarah Caskey,Pamela B Edwards,Mary Ann Fuchs,Amber Reints,Brita Stange,Janice Questad,Laurie Badzek", - "abstract": "Assessment of nursing genomic competency is critical given increasing genomic applications to health care. The study aims were to determine the test-retest reliability of the Genetics and Genomics in Nursing Practice Survey (GGNPS), which measures this competency, and to revise the survey accordingly. Registered nurses (n = 232) working at 2 Magnet-designated hospitals participating in a multiinstitutional genomic competency study completed the GGNPS. Cohen's kappa and weighted kappa were used to measure the agreement of item responses between Time 1 and Time 2. Survey items were revised based on the results. Mean agreement for the instrument was 0.407 (range = 0.150-1.000). Moderate agreement or higher was achieved in 39% of the items. GGNPS test-retest reliability was not optimal, and the instrument was refined based on the study findings. Further testing of the revised instrument is planned to assess the instrument performance.", - "journal_title": "Journal of nursing measurement", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/27103245/" - } - ], - "8dcc3eab-8ddd-45f8-a3ef-266253b51e15": [ - { - "pub_id": "29948331", - "title": "Whole-exome sequencing in maya indigenous families: variant in PPP1R3A is associated with type 2 diabetes.", - "authors": "Katy S\u00e1nchez-Pozos,Mar\u00eda Guadalupe Ort\u00edz-L\u00f3pez,B\u00e1rbara I Pe\u00f1a-Espinoza,Mar\u00eda de Los \u00c1ngeles Granados-Silvestre,Ver\u00f3nica Jim\u00e9nez-Jacinto,J\u00e9r\u00f4me Verleyen,Fasil Tekola-Ayele,Alejandro Sanchez-Flores,Marta Menjivar", - "abstract": "It has been presumed that increased susceptibility in Mexicans to type 2 diabetes (T2D) is attributed to the Native American genetic ancestry. Nonetheless, it is not known if there are private genetic variants that confer susceptibility to develop T2D in our population. The Maya indigenous group has the highest proportion of Native American ancestry (98%) which makes it a representative group of the original peoples of Mexico. Thus, the aim of the present study is to identify new genetic variants associated with T2D in Maya families. Whole-exome sequencing was performed on DNA samples from Maya families with a third-generation family history of T2D only in one parental line. Four variants were identified for APOB, PPP1R3A, TPPP2, and GPR1 genes, and were further tested for association with T2D in 600 unrelated Maya in a case-control study. For the first time, rs1799999 in PPP1R3A was associated with risk of T2D in Mayan Mexican individuals (OR\u2009=\u20091.625, P\u2009=\u20090.014). Interestingly, carriers of rs1799999 presented increased values of HOMA-IR. In addition, rs1801702 in APOB was associated with total cholesterol and LDL-C (P\u2009=\u20090.019 and P\u2009=\u20090.020, respectively) in normoglycemic individuals; rs3732083 in GPR1 with HOMA-IR (P\u2009=\u20090.016) and rs9624 in TPPP2 with total cholesterol and triglycerides (P\u2009=\u20090.002 and P\u2009=\u20090.005, respectively) in T2D subjects. Overall, these findings support the idea that there are other genetic variants yet to be described, involved in T2D development in Maya population, being insulin resistance and lipid metabolism the main mechanisms implicated. Thus, these results can contribute to the understanding of diabetes genetic background in Mexican population.", - "journal_title": "Molecular genetics and genomics : MGG", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/29948331/" - } - ], - "031710f4-7b49-40d8-8568-682d86ed3b99": [ - { - "pub_id": "30093963", - "title": "MicroRNA profiling and their pathways in South African individuals with prediabetes and newly diagnosed type 2 diabetes mellitus.", - "authors": "Tandi E Matsha,Andre P Kengne,Stanton Hector,Desiree L Mbu,Yandiswa Y Yako,Rajiv T Erasmus", - "abstract": "Early identification of individuals with elevated risk of developing diabetes mellitus, followed by the implementation of effective prevention interventions can delay the onset of the disease and related complications. In this regard, recent studies have shown that miRNAs are useful as early markers of certain disease types, including diabetes. We used high throughput sequencing to assess miRNA expression profiles from whole blood of 12 individuals with screen-detected diabetes, 12 with prediabetes and 12 with normal glucose tolerance, matched for age, blood pressure, smoking and body mass index. We identified a total of 261 (57 novel) differentially expressed miRNA profiles between the study groups. Comparison of the miRNA expression profiles between prediabetess and diabetes revealed 25 common miRNA, but highlighted some interesting differences. For instance, three miRNAs (miR-126-3p, miR-28-3p miR-486-5p) were dysregulated in prediabetes compared to screen-detected diabetes. Target gene analysis showed thousands of potential genes and KEGG pathway analysis revealed 107 significant pathways of which some are involved signal transduction, cell-cell communications, cell growth and death, immune response, endocrine system and metabolic diseases. This first detailed African study has shown both known and novel differentially expressed miRNAs in relation to glucose tolerance.", - "journal_title": "Oncotarget", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/30093963/" - } - ], - "5943d77b-0724-4617-89eb-e5c9a54eab15": [ - { - "pub_id": "35047833", - "title": "Lessons learned from the eMERGE Network: balancing genomics in discovery and practice.", - "authors": " ", - "abstract": "The Electronic Medical Records and Genomics (eMERGE) Network, established in 2007, is a consortium of academic and integrated health systems conducting discovery and implementation research in translational genomics. Here, we outline the history of the network, highlight major impacts and lessons learned, and present the tools and resources developed for large-scale genomic analyses and translation into a clinical setting. The network developed methods to extract phenotypes from the electronic medical record to perform genome-wide and phenome-wide association studies. Recruited cohorts were clinically sequenced off a custom panel for targeted sequencing of variants and monogenic disease risks and returned to participants to investigate the impact of return of genomic results. After generating a 105,000 participant-imputed genome-wide association study (GWAS) dataset for discovery, the network enrolled and sequenced 24,998 participants. Integration of these results into the medical record and the effects of results on participants provided key lessons to the field. These learned lessons inform genetic research in diverse populations and provide insights into the clinical impact of return and implementation of genomic medicine using the electronic medical record. The lessons produced by the eMERGE Network can be utilized by other consortia as translational genomic medicine research evolves.", - "journal_title": "HGG advances", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/35047833/" - } - ], - "b6bbc3ee-60b8-4a4b-8feb-e93e7645e364": [ - { - "pub_id": "28384471", - "title": "Sleep and Human Aging.", - "authors": "Bryce A Mander,Joseph R Winer,Matthew P Walker", - "abstract": "Older adults do not sleep as well as younger adults. Why? What alterations in sleep quantity and quality occur as we age, and are there functional consequences? What are the underlying neural mechanisms that explain age-related sleep disruption? This review tackles these questions. First, we describe canonical changes in human sleep quantity and quality in cognitively normal older adults. Second, we explore the underlying neurobiological mechanisms that may account for these human sleep alterations. Third, we consider the functional consequences of age-related sleep disruption, focusing on memory impairment as an exemplar. We conclude with a discussion of a still-debated question: do older adults simply need less sleep, or rather, are they unable to generate the sleep that they still need?", - "journal_title": "Neuron", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/28384471/" - } - ], - "a7b79952-6e33-4859-9225-1d632daeb758": [ - { - "pub_id": "33529164", - "title": "Monogenic diabetes: a gateway to precision medicine in diabetes.", - "authors": "Haichen Zhang,Kevin Colclough,Anna L Gloyn,Toni I Pollin", - "abstract": "Monogenic diabetes refers to diabetes mellitus (DM) caused by a mutation in a single gene and accounts for approximately 1%-5% of diabetes. Correct diagnosis is clinically critical for certain types of monogenic diabetes, since the appropriate treatment is determined by the etiology of the disease (e.g., oral sulfonylurea treatment of HNF1A/HNF4A-diabetes vs. insulin injections in type 1 diabetes). However, achieving a correct diagnosis requires genetic testing, and the overlapping of the clinical features of monogenic diabetes with those of type 1 and type 2 diabetes has frequently led to misdiagnosis. Improvements in sequencing technology are increasing opportunities to diagnose monogenic diabetes, but challenges remain. In this Review, we describe the types of monogenic diabetes, including common and uncommon types of maturity-onset diabetes of the young, multiple causes of neonatal DM, and syndromic diabetes such as Wolfram syndrome and lipodystrophy. We also review methods of prioritizing patients undergoing genetic testing, and highlight existing challenges facing sequence data interpretation that can be addressed by forming collaborations of expertise and by pooling cases.", - "journal_title": "The Journal of clinical investigation", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/33529164/" - } - ], - "8b0bd019-d86b-4c7d-bfa1-e8016d283e56": [ - { - "pub_id": "31441606", - "title": "The clinical and genetic characteristics of permanent neonatal diabetes (PNDM) in the state of Qatar.", - "authors": "Sara Al-Khawaga,Idris Mohammed,Saras Saraswathi,Basma Haris,Reem Hasnah,Amira Saeed,Hakeem Almabrazi,Najeeb Syed,Puthen Jithesh,Ahmed El Awwa,Amal Khalifa,Fawziya AlKhalaf,Goran Petrovski,Essam M Abdelalim,Khalid Hussain", - "abstract": "Neonatal diabetes mellitus (NDM) is a rare condition that occurs within the first six months of life. Permanent NDM (PNDM) is caused by mutations in specific genes that are known for their expression at early and/or late stages of pancreatic beta- cell development, and are either involved in beta-cell survival, insulin processing, regulation, and release. The native population in Qatar continues to practice consanguineous marriages that lead to a high level of homozygosity. To our knowledge, there is no previous report on the genomics of NDM among the Qatari population. The aims of the current study are to identify patients with NDM diagnosed between 2001 and 2016, and examine their clinical and genetic characteristics. To calculate the incidence of PNDM, all patients with PNDM diagnosed between 2001 and 2016 were compared to the total number of live births over the 16-year-period. Whole Genome Sequencing (WGS) was used to investigate the genetic etiology in the PNDM cohort. PNDM was diagnosed in nine (n\u00a0=\u00a09) patients with an estimated incidence rate of 1:22,938 live births among the indigenous Qatari. Seven different mutations in six genes (PTF1A, GCK, SLC2A2, EIF2AK3, INS, and HNF1B) were identified. In the majority of cases, the genetic etiology was part of a previously identified autosomal recessive disorder. Two novel de novo mutations were identified in INS and HNF1B. Qatar has the second highest reported incidence of PNDM worldwide. A majority of PNDM cases present as rare familial autosomal recessive disorders. Pancreas associated transcription factor 1a (PTF1A) enhancer deletions are the most common cause of PNDM in Qatar, with only a few previous cases reported in the literature.", - "journal_title": "Molecular genetics & genomic medicine", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/31441606/" - } - ], - "1d36ca52-e275-4788-93a4-a2143184e513": [ - { - "pub_id": "31786155", - "title": "Gut Microbiome Fermentation Determines the Efficacy of Exercise for Diabetes Prevention.", - "authors": "Yan Liu,Yao Wang,Yueqiong Ni,Cynthia K Y Cheung,Karen S L Lam,Yu Wang,Zhengyuan Xia,Dewei Ye,Jiao Guo,Michael Andrew Tse,Gianni Panagiotou,Aimin Xu", - "abstract": "Exercise is an effective strategy for diabetes management but is limited by the phenomenon of exercise resistance (i.e., the lack of or the adverse response to exercise on metabolic health). Here, in 39 medication-naive men with prediabetes, we found that exercise-induced alterations in the gut microbiota correlated closely with improvements in glucose homeostasis and insulin sensitivity (clinicaltrials.gov entry NCT03240978). The microbiome of responders exhibited an enhanced capacity for biosynthesis of short-chain fatty acids and catabolism of branched-chain amino acids, whereas those of non-responders were characterized by increased production of metabolically detrimental compounds. Fecal microbial transplantation from responders, but not non-responders, mimicked the effects of exercise on alleviation of insulin resistance in obese mice. Furthermore, a machine-learning algorithm integrating baseline microbial signatures accurately predicted personalized glycemic response to exercise in an additional 30 subjects. These findings raise the possibility of maximizing the benefits of exercise by targeting the gut microbiota.", - "journal_title": "Cell metabolism", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/31786155/" - } - ], - "fdb1fd2e-2bf6-4a25-a78d-f8002ce466fc": [ - { - "pub_id": "29632382", - "title": "Refining the accuracy of validated target identification through coding variant fine-mapping in type 2 diabetes.", - "authors": "Anubha Mahajan,Jennifer Wessel,Sara M Willems,Wei Zhao,Neil R Robertson,Audrey Y Chu,Wei Gan,Hidetoshi Kitajima,Daniel Taliun,N William Rayner,Xiuqing Guo,Yingchang Lu,Man Li,Richard A Jensen,Yao Hu,Shaofeng Huo,Kurt K Lohman,Weihua Zhang,James P Cook,Bram Peter Prins,Jason Flannick,Niels Grarup,Vassily Vladimirovich Trubetskoy,Jasmina Kravic,Young Jin Kim,Denis V Rybin,Hanieh Yaghootkar,Martina M\u00fcller-Nurasyid,Karina Meidtner,Ruifang Li-Gao,Tibor V Varga,Jonathan Marten,Jin Li,Albert Vernon Smith,Ping An,Symen Ligthart,Stefan Gustafsson,Giovanni Malerba,Ayse Demirkan,Juan Fernandez Tajes,Valgerdur Steinthorsdottir,Matthias Wuttke,C\u00e9cile Lecoeur,Michael Preuss,Lawrence F Bielak,Marielisa Graff,Heather M Highland,Anne E Justice,Dajiang J Liu,Eirini Marouli,Gina Marie Peloso,Helen R Warren, , , ,Saima Afaq,Shoaib Afzal,Emma Ahlqvist,Peter Almgren,Najaf Amin,Lia B Bang,Alain G Bertoni,Cristina Bombieri,Jette Bork-Jensen,Ivan Brandslund,Jennifer A Brody,No\u00ebl P Burtt,Micka\u00ebl Canouil,Yii-Der Ida Chen,Yoon Shin Cho,Cramer Christensen,Sophie V Eastwood,Kai-Uwe Eckardt,Krista Fischer,Giovanni Gambaro,Vilmantas Giedraitis,Megan L Grove,Hugoline G de Haan,Sophie Hackinger,Yang Hai,Sohee Han,Anne Tybj\u00e6rg-Hansen,Marie-France Hivert,Bo Isomaa,Susanne J\u00e4ger,Marit E J\u00f8rgensen,Torben J\u00f8rgensen,Annemari K\u00e4r\u00e4j\u00e4m\u00e4ki,Bong-Jo Kim,Sung Soo Kim,Heikki A Koistinen,Peter Kovacs,Jennifer Kriebel,Florian Kronenberg,Kristi L\u00e4ll,Leslie A Lange,Jung-Jin Lee,Benjamin Lehne,Huaixing Li,Keng-Hung Lin,Allan Linneberg,Ching-Ti Liu,Jun Liu,Marie Loh,Reedik M\u00e4gi,Vasiliki Mamakou,Roberta McKean-Cowdin,Girish Nadkarni,Matt Neville,Sune F Nielsen,Ioanna Ntalla,Patricia A Peyser,Wolfgang Rathmann,Kenneth Rice,Stephen S Rich,Line Rode,Olov Rolandsson,Sebastian Sch\u00f6nherr,Elizabeth Selvin,Kerrin S Small,Alena Stan\u010d\u00e1kov\u00e1,Praveen Surendran,Kent D Taylor,Tanya M Teslovich,Barbara Thorand,Gudmar Thorleifsson,Adrienne Tin,Anke T\u00f6njes,Anette Varbo,Daniel R Witte,Andrew R Wood,Pranav Yajnik,Jie Yao,Lo\u00efc Yengo,Robin Young,Philippe Amouyel,Heiner Boeing,Eric Boerwinkle,Erwin P Bottinger,Rajiv Chowdhury,Francis S Collins,George Dedoussis,Abbas Dehghan,Panos Deloukas,Marco M Ferrario,Jean Ferri\u00e8res,Jose C Florez,Philippe Frossard,Vilmundur Gudnason,Tamara B Harris,Susan R Heckbert,Joanna M M Howson,Martin Ingelsson,Sekar Kathiresan,Frank Kee,Johanna Kuusisto,Claudia Langenberg,Lenore J Launer,Cecilia M Lindgren,Satu M\u00e4nnist\u00f6,Thomas Meitinger,Olle Melander,Karen L Mohlke,Marie Moitry,Andrew D Morris,Alison D Murray,Ren\u00e9e de Mutsert,Marju Orho-Melander,Katharine R Owen,Markus Perola,Annette Peters,Michael A Province,Asif Rasheed,Paul M Ridker,Fernando Rivadineira,Frits R Rosendaal,Anders H Rosengren,Veikko Salomaa,Wayne H-H Sheu,Rob Sladek,Blair H Smith,Konstantin Strauch,Andr\u00e9 G Uitterlinden,Rohit Varma,Cristen J Willer,Matthias Bl\u00fcher,Adam S Butterworth,John Campbell Chambers,Daniel I Chasman,John Danesh,Cornelia van Duijn,Jos\u00e9e Dupuis,Oscar H Franco,Paul W Franks,Philippe Froguel,Harald Grallert,Leif Groop,Bok-Ghee Han,Torben Hansen,Andrew T Hattersley,Caroline Hayward,Erik Ingelsson,Sharon L R Kardia,Fredrik Karpe,Jaspal Singh Kooner,Anna K\u00f6ttgen,Kari Kuulasmaa,Markku Laakso,Xu Lin,Lars Lind,Yongmei Liu,Ruth J F Loos,Jonathan Marchini,Andres Metspalu,Dennis Mook-Kanamori,B\u00f8rge G Nordestgaard,Colin N A Palmer,James S Pankow,Oluf Pedersen,Bruce M Psaty,Rainer Rauramaa,Naveed Sattar,Matthias B Schulze,Nicole Soranzo,Timothy D Spector,Kari Stefansson,Michael Stumvoll,Unnur Thorsteinsdottir,Tiinamaija Tuomi,Jaakko Tuomilehto,Nicholas J Wareham,James G Wilson,Eleftheria Zeggini,Robert A Scott,In\u00eas Barroso,Timothy M Frayling,Mark O Goodarzi,James B Meigs,Michael Boehnke,Danish Saleheen,Andrew P Morris,Jerome I Rotter,Mark I McCarthy", - "abstract": "We aggregated coding variant data for 81,412 type 2 diabetes cases and 370,832 controls of diverse ancestry, identifying 40 coding variant association signals (P\u2009<\u20092.2\u2009\u00d7\u200910<sup>-7</sup>); of these, 16 map outside known risk-associated loci. We make two important observations. First, only five of these signals are driven by low-frequency variants: even for these, effect sizes are modest (odds ratio \u22641.29). Second, when we used large-scale genome-wide association data to fine-map the associated variants in their regional context, accounting for the global enrichment of complex trait associations in coding sequence, compelling evidence for coding variant causality was obtained for only 16 signals. At 13 others, the associated coding variants clearly represent 'false leads' with potential to generate erroneous mechanistic inference. Coding variant associations offer a direct route to biological insight for complex diseases and identification of validated therapeutic targets; however, appropriate mechanistic inference requires careful specification of their causal contribution to disease predisposition.", - "journal_title": "Nature genetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/29632382/" - } - ], - "e904332c-5d6e-4c01-b58f-5d992422a513": [ - { - "pub_id": "32207560", - "title": "Functional informed genome-wide interaction analysis of body mass index, diabetes and colorectal cancer risk.", - "authors": "Zhiyu Xia,Yu-Ru Su,Paneen Petersen,Lihong Qi,Andre E Kim,Jane C Figueiredo,Yi Lin,Hongmei Nan,Lori C Sakoda,Demetrius Albanes,Sonja I Berndt,St\u00e9phane B\u00e9zieau,Stephanie Bien,Daniel D Buchanan,Graham Casey,Andrew T Chan,David V Conti,David A Drew,Steven J Gallinger,W James Gauderman,Graham G Giles,Stephen B Gruber,Marc J Gunter,Michael Hoffmeister,Mark A Jenkins,Amit D Joshi,Loic Le Marchand,Juan P Lewinger,Li Li,Noralane M Lindor,Victor Moreno,Neil Murphy,Rami Nassir,Polly A Newcomb,Shuji Ogino,Gad Rennert,Mingyang Song,Xiaoliang Wang,Alicja Wolk,Michael O Woods,Hermann Brenner,Emily White,Martha L Slattery,Edward L Giovannucci,Jenny Chang-Claude,Paul D P Pharoah,Li Hsu,Peter T Campbell,Ulrike Peters", - "abstract": "Body mass index (BMI) and diabetes are established risk factors for colorectal cancer (CRC), likely through perturbations in metabolic traits (e.g. insulin resistance and glucose homeostasis). Identification of interactions between variation in genes and these metabolic risk factors may identify novel biologic insights into CRC etiology. To improve statistical power and interpretation for gene-environment interaction (G\u00a0\u00d7\u00a0E) testing, we tested genetic variants that regulate expression of a gene together for interaction with BMI (kg/m<sup>2</sup> ) and diabetes on CRC risk among 26\u00a0017 cases and 20\u00a0692 controls. Each variant was weighted based on PrediXcan analysis of gene expression data from colon tissue generated in the Genotype-Tissue Expression Project for all genes with heritability \u22651%. We used a mixed-effects model to jointly measure the G\u00a0\u00d7\u00a0E interaction in a gene by partitioning the interactions into the predicted gene expression levels (fixed effects), and residual G\u00a0\u00d7\u00a0E effects (random effects). G\u00a0\u00d7\u00a0BMI analyses were stratified by sex as BMI-CRC associations differ by sex. We used false discovery rates to account for multiple comparisons and reported all results with FDR <0.2. Among 4839 genes tested, genetically predicted expressions of FOXA1 (P\u00a0=\u00a03.15\u00a0\u00d7\u00a010<sup>-5</sup> ), PSMC5 (P\u00a0=\u00a04.51\u00a0\u00d7\u00a010<sup>-4</sup> ) and CD33 (P\u00a0=\u00a02.71\u00a0\u00d7\u00a010<sup>-4</sup> ) modified the association of BMI on CRC risk for men; KIAA0753 (P\u00a0=\u00a02.29\u00a0\u00d7\u00a010<sup>-5</sup> ) and SCN1B (P\u00a0=\u00a02.76\u00a0\u00d7\u00a010<sup>-4</sup> ) modified the association of BMI on CRC risk for women; and PTPN2 modified the association between diabetes and CRC risk in both sexes (P\u00a0=\u00a02.31\u00a0\u00d7\u00a010<sup>-5</sup> ). Aggregating G\u00a0\u00d7\u00a0E interactions and incorporating functional information, we discovered novel genes that may interact with BMI and diabetes on CRC risk.", - "journal_title": "Cancer medicine", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/32207560/" - } - ], - "38c95330-afa3-42a5-9c51-d1b5a91cdb51": [ - { - "pub_id": "33589840", - "title": "Genome-wide meta-analysis, fine-mapping and integrative prioritization implicate new Alzheimer's disease risk genes.", - "authors": "Jeremy Schwartzentruber,Sarah Cooper,Jimmy Z Liu,Inigo Barrio-Hernandez,Erica Bello,Natsuhiko Kumasaka,Adam M H Young,Robin J M Franklin,Toby Johnson,Karol Estrada,Daniel J Gaffney,Pedro Beltrao,Andrew Bassett", - "abstract": "Genome-wide association studies have discovered numerous genomic loci associated with Alzheimer's disease (AD); yet the causal genes and variants are incompletely identified. We performed an updated genome-wide AD meta-analysis, which identified 37 risk loci, including new associations near CCDC6, TSPAN14, NCK2 and SPRED2. Using three SNP-level fine-mapping methods, we identified 21 SNPs with >50% probability each of being causally involved in AD risk and others strongly suggested by functional annotation. We followed this with colocalization analyses across 109 gene expression quantitative trait loci datasets and prioritization of genes by using protein interaction networks and tissue-specific expression. Combining this information into a quantitative score, we found that evidence converged on likely causal genes, including the above four genes, and those at previously discovered AD loci, including BIN1, APH1B, PTK2B, PILRA and CASS4.", - "journal_title": "Nature genetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/33589840/" - } - ], - "02a9d5a9-41a4-4d70-b828-c4bda13fa01c": [ - { - "pub_id": "27686049", - "title": "An endoplasmic reticulum stress-regulated lncRNA hosting a microRNA megacluster induces early features of diabetic nephropathy.", - "authors": "Mitsuo Kato,Mei Wang,Zhuo Chen,Kirti Bhatt,Hyung Jung Oh,Linda Lanting,Supriya Deshpande,Ye Jia,Jennifer Y C Lai,Christopher L O'Connor,YiFan Wu,Jeffrey B Hodgin,Robert G Nelson,Markus Bitzer,Rama Natarajan", - "abstract": "It is important to find better treatments for diabetic nephropathy (DN), a debilitating renal complication. Targeting early features of DN, including renal extracellular matrix accumulation (ECM) and glomerular hypertrophy, can prevent disease progression. Here we show that a megacluster of nearly 40 microRNAs and their host long non-coding RNA transcript (lnc-MGC) are coordinately increased in the glomeruli of mouse models of DN, and mesangial cells treated with transforming growth factor-\u03b21 (TGF- \u03b21) or high glucose. Lnc-MGC is regulated by an endoplasmic reticulum (ER) stress-related transcription factor, CHOP. Cluster microRNAs and lnc-MGC are decreased in diabetic Chop<sup>-/-</sup> mice that showed protection from DN. Target genes of megacluster microRNAs have functions related to protein synthesis and ER stress. A chemically modified oligonucleotide targeting lnc-MGC inhibits cluster microRNAs, glomerular ECM and hypertrophy in diabetic mice. Relevance to human DN is also demonstrated. These results demonstrate the translational implications of targeting lnc-MGC for controlling DN progression.", - "journal_title": "Nature communications", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/27686049/" - } - ], - "fd36ceb0-07e9-4bd1-b6ac-bc50f29f6bc4": [ - { - "pub_id": "35140703", - "title": "Causal Relationship Between Gut Microbiota and Autoimmune Diseases: A Two-Sample Mendelian Randomization Study.", - "authors": "Qian Xu,Jing-Jing Ni,Bai-Xue Han,Shan-Shan Yan,Xin-Tong Wei,Gui-Juan Feng,Hong Zhang,Lei Zhang,Bin Li,Yu-Fang Pei", - "abstract": "Growing evidence has shown that alterations in gut microbiota composition are associated with multiple autoimmune diseases (ADs). However, it is unclear whether these associations reflect a causal relationship. To reveal the causal association between gut microbiota and AD, we conducted a two-sample Mendelian randomization (MR) analysis. We assessed genome-wide association study (GWAS) summary statistics for gut microbiota and six common ADs, namely, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, multiple sclerosis, type 1 diabetes (T1D), and celiac disease (CeD), from published GWASs. Two-sample MR analyses were first performed to identify causal bacterial taxa for ADs in discovery samples. Significant bacterial taxa were further replicated in independent replication outcome samples. A series of sensitivity analyses was performed to validate the robustness of the results. Finally, a reverse MR analysis was performed to evaluate the possibility of reverse causation. Combining the results from the discovery and replication stages, we identified one causal bacterial genus, <i>Bifidobacterium</i>. A higher relative abundance of the <i>Bifidobacterium</i> genus was associated with a higher risk of T1D [odds ratio (OR): 1.605; 95% CI, 1.339-1.922; <i>P<sub>FDR</sub></i> = 4.19 \u00d7 10<sup>-7</sup>] and CeD (OR: 1.401; 95% CI, 1.139-1.722; <i>P<sub>FDR</sub></i> = 2.03 \u00d7 10<sup>-3</sup>), respectively. Further sensitivity analyses validated the robustness of the above associations. The results of reverse MR analysis showed no evidence of reverse causality from T1D and CeD to the <i>Bifidobacterium</i> genus. This study implied a causal relationship between the <i>Bifidobacterium</i> genus and T1D and CeD, thus providing novel insights into the gut microbiota-mediated development mechanism of ADs.", - "journal_title": "Frontiers in immunology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/35140703/" - } - ], - "6eb4f17d-ef52-4c1d-a71f-42414f97f21e": [ - { - "pub_id": "34187551", - "title": "Genome-wide association studies identify 137 genetic loci for DNA methylation biomarkers of aging.", - "authors": "Daniel L McCartney,Josine L Min,Rebecca C Richmond,Ake T Lu,Maria K Sobczyk,Gail Davies,Linda Broer,Xiuqing Guo,Ayoung Jeong,Jeesun Jung,Silva Kasela,Seyma Katrinli,Pei-Lun Kuo,Pamela R Matias-Garcia,Pashupati P Mishra,Marianne Nygaard,Teemu Palviainen,Amit Patki,Laura M Raffield,Scott M Ratliff,Tom G Richardson,Oliver Robinson,Mette Soerensen,Dianjianyi Sun,Pei-Chien Tsai,Matthijs D van der Zee,Rosie M Walker,Xiaochuan Wang,Yunzhang Wang,Rui Xia,Zongli Xu,Jie Yao,Wei Zhao,Adolfo Correa,Eric Boerwinkle,Pierre-Antoine Dugu\u00e9,Peter Durda,Hannah R Elliott,Christian Gieger, ,Eco J C de Geus,Sarah E Harris,Gibran Hemani,Medea Imboden,Mika K\u00e4h\u00f6nen,Sharon L R Kardia,Jacob K Kresovich,Shengxu Li,Kathryn L Lunetta,Massimo Mangino,Dan Mason,Andrew M McIntosh,Jonas Mengel-From,Ann Zenobia Moore,Joanne M Murabito, ,Miina Ollikainen,James S Pankow,Nancy L Pedersen,Annette Peters,Silvia Polidoro,David J Porteous,Olli Raitakari,Stephen S Rich,Dale P Sandler,Elina Sillanp\u00e4\u00e4,Alicia K Smith,Melissa C Southey,Konstantin Strauch,Hemant Tiwari,Toshiko Tanaka,Therese Tillin,Andre G Uitterlinden,David J Van Den Berg,Jenny van Dongen,James G Wilson,John Wright,Idil Yet,Donna Arnett,Stefania Bandinelli,Jordana T Bell,Alexandra M Binder,Dorret I Boomsma,Wei Chen,Kaare Christensen,Karen N Conneely,Paul Elliott,Luigi Ferrucci,Myriam Fornage,Sara H\u00e4gg,Caroline Hayward,Marguerite Irvin,Jaakko Kaprio,Deborah A Lawlor,Terho Lehtim\u00e4ki,Falk W Lohoff,Lili Milani,Roger L Milne,Nicole Probst-Hensch,Alex P Reiner,Beate Ritz,Jerome I Rotter,Jennifer A Smith,Jack A Taylor,Joyce B J van Meurs,Paolo Vineis,Melanie Waldenberger,Ian J Deary,Caroline L Relton,Steve Horvath,Riccardo E Marioni", - "abstract": "Biological aging estimators derived from DNA methylation data are heritable and correlate with morbidity and mortality. Consequently, identification of genetic and environmental contributors to the variation in these measures in populations has become a major goal in the field. Leveraging DNA methylation and SNP data from more than 40,000 individuals, we identify 137 genome-wide significant loci, of which 113 are novel, from genome-wide association study (GWAS) meta-analyses of four epigenetic clocks and epigenetic surrogate markers for granulocyte proportions and plasminogen activator inhibitor 1 levels, respectively. We find evidence for shared genetic loci associated with the Horvath clock and expression of transcripts encoding genes linked to lipid metabolism and immune function. Notably, these loci are independent of those reported to regulate DNA methylation levels at constituent clock CpGs. A polygenic score for GrimAge acceleration showed strong associations with adiposity-related traits, educational attainment, parental longevity, and C-reactive protein levels. This study illuminates the genetic architecture underlying epigenetic aging and its shared genetic contributions with lifestyle factors and longevity.", - "journal_title": "Genome biology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/34187551/" - } - ], - "bc40ff4f-794d-4ad2-9780-73cf06903a3a": [ - { - "pub_id": "29216683", - "title": "Human perforin gene variation is geographically distributed.", - "authors": "Robin C Willenbring,Yasuhiro Ikeda,Larry R Pease,Aaron J Johnson", - "abstract": "Deleterious mutations in PRF1 result in lethal, childhood disease, familial hemophagocytic lymphohistiocytosis type 2 (FHL 2). However, not all mutations in PRF1 are deleterious and result in FHL 2. Currently, these nondeleterious mutations are being investigated in the onset of numerous disorders, such as lymphomas and diabetes. Yet, there is still an overwhelmingly large amount of PRF1 mutations that are not associated with disease. We conducted a post hoc analysis of the PRF1 mutations in the coding region using the recently published Exome Aggregation Consortium genomes, Leiden Open Variation Database, NCBI SNP database, and primary literature to better understand PRF1 variation in the human population. This study catalogs 460 PRF1 mutations in the coding region, and demonstrates PRF1 is more variant then previously predicted. We identify key PRF1 mutations with high allelic frequency and are only found in certain populations. Additionally, we define PRF1 SNVs are geographically distributed. This study concludes with a novel hypothesis that nondeleterious mutation in PRF1, which decreases perforin expression and/or activity, may be an example of selective advantage in the context of environmental stressors prevalent near the equator. Our studies illustrate how perforin deficiency can be protective from injuries resulting in blood-brain barrier (BBB) disruption.", - "journal_title": "Molecular genetics & genomic medicine", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/29216683/" - } - ], - "b1ff2990-cb5b-48a0-b502-7dc277186b2e": [ - { - "pub_id": "36315135", - "title": "Genetic Testing to Inform Epilepsy Treatment Management From an International Study of Clinical Practice.", - "authors": "Dianalee McKnight,Ana Morales,Kathryn E Hatchell,Sara L Bristow,Joshua L Bonkowsky,Michael Scott Perry,Anne T Berg,Felippe Borlot,Edward D Esplin,Chad Moretz,Katie Angione,Loreto R\u00edos-Pohl,Robert L Nussbaum,Swaroop Aradhya, ,Chad R Haldeman-Englert,Rebecca J Levy,Venu G Parachuri,Guillermo Lay-Son,David J D\u00e1vila-Ortiz de Montellano,Miguel Angel Ramirez-Garcia,Edmar O Ben\u00edtez Alonso,Julie Ziobro,Adela Chirita-Emandi,Temis M Felix,Dianne Kulasa-Luke,Andre Megarbane,Shefali Karkare,Sarah L Chagnon,Jennifer B Humberson,Melissa J Assaf,Sebastian Silva,Katherine Zarroli,Oksana Boyarchuk,Gary R Nelson,Rachel Palmquist,Katherine C Hammond,Sean T Hwang,Susan B Boutlier,Melinda Nolan,Kaitlin Y Batley,Devraj Chavda,Carlos Alberto Reyes-Silva,Oleksandr Miroshnikov,Britton Zuccarelli,Louise Amlie-Wolf,James W Wheless,Syndi Seinfeld,Manoj Kanhangad,Jeremy L Freeman,Susana Monroy-Santoyo,Natalia Rodriguez-Vazquez,Monique M Ryan,Michelle Machie,Patricio Guerra,Muhammad Jawad Hassan,Meghan S Candee,Caleb P Bupp,Kristen L Park,Eric Muller,Pamela Lupo,Robert C Pedersen,Amir M Arain,Andrea Murphy,Krista Schatz,Weiyi Mu,Paige M Kalika,Lautaro Plaza,Marissa A Kellogg,Evelyn G Lora,Robert P Carson,Victoria Svystilnyk,Viviana Venegas,Rebecca R Luke,Huiyuan Jiang,Tetiana Stetsenko,Milagros M Due\u00f1as-Roque,Joseph Trasmonte,Rebecca J Burke,Anna C E Hurst,Douglas M Smith,Lauren J Massingham,Laura Pisani,Carrie E Costin,Betsy Ostrander,Francis M Filloux,Amitha L Ananth,Ismail S Mohamed,Alla Nechai,Jasmin M Dao,Michael C Fahey,Ermal Aliu,Stephen Falchek,Craig A Press,Lauren Treat,Krista Eschbach,Angela Starks,Ryan Kammeyer,Joshua J Bear,Mona Jacobson,Veronika Chernuha,Bailey Meibos,Kristen Wong,Matthew T Sweney,A Chris Espinoza,Colin B Van Orman,Arie Weinstock,Ashutosh Kumar,Claudia Soler-Alfonso,Danielle A Nolan,Muhammad Raza,Miguel David Rojas Carrion,Geetha Chari,Eric D Marsh,Yael Shiloh-Malawsky,Sumit Parikh,Ernesto Gonzalez-Giraldo,Stephen Fulton,Yoshimi Sogawa,Kaitlyn Burns,Myroslava Malets,Johnny David Montiel Blanco,Christa W Habela,Carey A Wilson,Guillermo G Guzm\u00e1n,Mariia Pavliuk", - "abstract": "It is currently unknown how often and in which ways a genetic diagnosis given to a patient with epilepsy is associated with clinical management and outcomes. To evaluate how genetic diagnoses in patients with epilepsy are associated with clinical management and outcomes. This was a retrospective cross-sectional study of patients referred for multigene panel testing between March 18, 2016, and August 3, 2020, with outcomes reported between May and November 2020. The study setting included a commercial genetic testing laboratory and multicenter clinical practices. Patients with epilepsy, regardless of sociodemographic features, who received a pathogenic/likely pathogenic (P/LP) variant were included in the study. Case report forms were completed by all health care professionals. Genetic test results. Clinical management changes after a genetic diagnosis (ie, 1 P/LP variant in autosomal dominant and X-linked diseases; 2 P/LP variants in autosomal recessive diseases) and subsequent patient outcomes as reported by health care professionals on case report forms. Among 418 patients, median (IQR) age at the time of testing was 4 (1-10) years, with an age range of 0 to 52 years, and 53.8% (n = 225) were female individuals. The mean (SD) time from a genetic test order to case report form completion was 595\u2009(368) days (range, 27-1673 days). A genetic diagnosis was associated with changes in clinical management for 208 patients (49.8%) and usually (81.7% of the time) within 3 months of receiving the result. The most common clinical management changes were the addition of a new medication (78 [21.7%]), the initiation of medication (51 [14.2%]), the referral of a patient to a specialist (48 [13.4%]), vigilance for subclinical or extraneurological disease features (46 [12.8%]), and the cessation of a medication (42 [11.7%]). Among 167 patients with follow-up clinical information available (mean [SD] time, 584\u2009[365] days), 125 (74.9%) reported positive outcomes, 108 (64.7%) reported reduction or elimination of seizures, 37 (22.2%) had decreases in the severity of other clinical signs, and 11 (6.6%) had reduced medication adverse effects. A few patients reported worsening of outcomes, including a decline in their condition (20 [12.0%]), increased seizure frequency (6 [3.6%]), and adverse medication effects (3 [1.8%]). No clinical management changes were reported for 178 patients (42.6%). Results of this cross-sectional study suggest that genetic testing of individuals with epilepsy may be materially associated with clinical decision-making and improved patient outcomes.", - "journal_title": "JAMA neurology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/36315135/" - } - ], - "36db242b-65d4-4f06-818a-a3043cdabb05": [ - { - "pub_id": "28322352", - "title": "Gene-based genome-wide association study identified 19p13.3 for lean body mass.", - "authors": "Shu Ran,Lei Zhang,Lu Liu,An-Ping Feng,Yu-Fang Pei,Lei Zhang,Ying-Ying Han,Yong Lin,Xiao Li,Wei-Wen Kong,Xin-Yi You,Wen Zhao,Qing Tian,Hui Shen,Yong-Hong Zhang,Hong-Wen Deng", - "abstract": "Lean body mass (LBM) is a complex trait for human health. To identify genomic loci underlying LBM, we performed a gene-based genome-wide association study of lean mass index (LMI) in 1000 unrelated Caucasian subjects, and replicated in 2283 unrelated Caucasians subjects. Gene-based association analyses highlighted the significant associations of three genes UQCR, TCF3 and MBD3 in one single locus 19p13.3 (discovery p\u2009=\u20096.10\u2009\u00d7\u200910<sup>-5</sup>, 1.65\u2009\u00d7\u200910<sup>-4</sup> and 1.10\u2009\u00d7\u200910<sup>-4</sup>; replication p\u2009=\u20092.21\u2009\u00d7\u200910<sup>-3</sup>, 1.84\u2009\u00d7\u200910<sup>-3</sup> and 6.95\u2009\u00d7\u200910<sup>-3</sup>; combined p\u2009=\u20092.26\u2009\u00d7\u200910<sup>-6</sup>, 4.86\u2009\u00d7\u200910<sup>-6</sup> and 1.15\u2009\u00d7\u200910<sup>-5</sup>, respectively). These results, together with the known functional relevance of the three genes to LMI, suggested that the 19p13.3 region containing UQCR, TCF3 and MBD3 genes was a novel locus underlying lean mass variation.", - "journal_title": "Scientific reports", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/28322352/" - } - ], - "71e5be87-28c0-41dc-9d6a-e181e42fa6ab": [ - { - "pub_id": "31757015", - "title": "Altered Genome-Wide DNA Methylation in Peripheral Blood of South African Women with Gestational Diabetes Mellitus.", - "authors": "Stephanie Dias,Sumaiya Adam,Paul Rheeder,Johan Louw,Carmen Pheiffer", - "abstract": "Increasing evidence implicate altered DNA methylation in the pathophysiology of gestational diabetes mellitus (GDM). This exploratory study probed the association between GDM and peripheral blood DNA methylation patterns in South African women. Genome-wide DNA methylation profiling was conducted in women with (<i>n</i> = 12) or without (<i>n</i> = 12) GDM using the Illumina Infinium HumanMethylationEPIC BeadChip array. Functional analysis of differentially methylated genes was conducted using Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses. A total of 1046 CpG sites (associated with 939 genes) were differentially methylated between GDM and non-GDM groups. Enriched pathways included GDM-related pathways such as insulin resistance, glucose metabolism and inflammation. DNA methylation of the top five CpG loci showed distinct methylation patterns in GDM and non-GDM groups and was correlated with glucose concentrations. Of these, one CpG site mapped to the calmodulin-binding transcription activator 1 (<i>CAMTA1</i>) gene, which have been shown to regulate insulin production and secretion and may offer potential as an epigenetic biomarker in our population. Further validation using pyrosequencing and conducting longitudinal studies in large sample sizes and in different populations are required to investigate their candidacy as biomarkers of GDM.", - "journal_title": "International journal of molecular sciences", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/31757015/" - } - ], - "36858807-1395-4b2f-a3ee-e054f9b0149d": [ - { - "pub_id": "32556999", - "title": "A novel gene in early childhood diabetes: EDEM2 silencing decreases SLC2A2 and PXD1 expression, leading to impaired insulin secretion.", - "authors": "Yazeid Alhaidan,Henrik Thybo Christesen,Kurt H\u00f8jlund,Mohammed A Al Balwi,Klaus Brusgaard", - "abstract": "Monogenic diabetes is a rare type of diabetes resulting from mutations in a single gene. To date, most cases remain genetically unexplained, posing a challenge for accurate diabetes treatment, which leads to on a molecular diagnosis. Therefore, a trio exome scan was performed in a lean, nonsyndromic Caucasian girl with diabetes onset at 2\u00bd years who was negative for autoantibodies. The lean father had diabetes from age 11\u00a0years. A novel heterozygous mutation in EDEM2, c.1271G\u2009>\u2009A; p.Arg424His, was found in the proband and father. Downregulation of Edem2 in rat RIN-m \u03b2-cells resulted in a decrease in insulin genes Ins1 to 67.9% (p\u2009=\u20090.006) and Ins2 to 16.8% (p\u2009<\u20090.001) and reduced insulin secretion by 60.4% (p\u2009=\u20090.0003). Real-time PCR revealed a major disruption of endocrine pancreas-specific genes, including Glut2 and Pxd1, with mRNA suppression to 54% (p\u2009<\u20090.001) and 85.7% (p\u2009=\u20090.01), respectively. No other expression changes related to stress or apoptotic genes were observed. Extended clinical follow-up involving ten family members showed that two healthy individuals carried the same mutation with no sign of diabetes in the clinical screen except for a slight increase in IA-2 antibody in one of them, suggesting incomplete penetrance. In conclusion, we describe EDEM2 as a likely/potential novel diabetes gene, in which inhibition in vitro reduces the expression of \u03b2-cell genes involved in the glucose-stimulated insulin secretion (GSIS) pathway, leading to an overall suppression of insulin secretion but not apoptosis.", - "journal_title": "Molecular genetics and genomics : MGG", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/32556999/" - } - ], - "efe72885-181b-4765-8fe1-ab623372ab70": [ - { - "pub_id": "35136969", - "title": "Susac syndrome: challenges in the diagnosis and treatment.", - "authors": "Mariano Marrodan,Marcela P Fiol,Jorge Correale", - "abstract": "Susac syndrome is a disorder thought to be mediated by an autoimmune response towards endothelial cells, leading to a characteristic clinical triad of encephalopathy, visual disturbances due to branch arterial occlusions and sensorineural hearing impairment. Although it is a rare disease, three reasons make it important. First, given its variable presentation, Susac syndrome is underdiagnosed. Second, it is considered an important differential diagnosis in different neurological, psychiatric, ophthalmological and hearing disorders, and consequently is frequently misdiagnosed. Third, in many cases, Susac syndrome is diagnosed and treated late, with significant irreversible sequelae including dementia, blindness and hearing loss. Neuropathology findings derived from both Susac syndrome patient tissue and novel transgenic mouse models indicate cytotoxic CD8+ T cells adhere to microvessels, inducing endothelial cell swelling, vascular narrowing and occlusion, causing microinfarcts. Anti-endothelial cell antibodies are present in serum in 25% of Susac syndrome patients, but it is unclear whether they are aetiologically related to the disease, or an epiphenomenon. The clinical triad comprising encephalopathy, branch arterial occlusions, and sensorineural hearing impairment is considered pathognomonic, although great variability is found in presentation and natural course of disease. At first evaluation, only 13-30% of patients exhibit the full clinical triad, making diagnosis difficult. Retinal fluorescein angiography, optic coherence tomography, MRI and tonal audiometry are helpful methods for diagnosing and monitoring disease activity during treatment. By contrast, there are no reliable objective immune markers to monitor disease activity. Immunosuppression is the current treatment, with high-dose corticosteroid therapy as the mainstay, but additional therapies such as intravenous immunoglobulins, cyclophosphamide, rituximab and mycophenolate mofetil are often necessary, because the disease can be devastating, causing irreversible organ damage. Unfortunately, low rates of disease, variability in presentation and paucity of objective biomarkers make prospective controlled clinical trials for Susac syndrome treatment difficult. Current immunosuppressive treatments are therefore based on empirical evidence, mainly from retrospective case series and expert opinion. In this review, we draw attention to the need to take consider Susac syndrome in the differential diagnosis of different neurological, psychiatric, ophthalmological and hearing disorders. Furthermore, we summarize our current knowledge of this syndrome, in reference to its pathophysiology, diagnosis and management, emphasizing the need for prospective and controlled studies that allow a better therapeutic approach.", - "journal_title": "Brain : a journal of neurology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/35136969/" - } - ], - "f1c14ecb-5bef-457e-a381-531616566173": [ - { - "pub_id": "32656703", - "title": "MTNR1B gene on susceptibility to gestational diabetes mellitus: a two-stage hospital-based study in Southern China.", - "authors": "Yulong Jia,Yi Shen,Xiuying Shi,Xuefeng Gu,Peng Zhang,Yuanlin Liu,Aiyong Zhu,Liying Jiang", - "abstract": "Large-scale studies on genetic risk loci for melatonin receptor 1B (MTNR1B) gene and GDM risk have not been well generalized to the Chinese population. In this study, we performed two-stage case-control study: 1.429 pregnant women: 753 GDM/676 controls in the Southern Chinese population by genotyping 5 SNPs (rs10830963, rs1387153, rs2166706, rs1447352, and rs4753426) in MTNR1B. Genotypes were determined using the Sequenom MassARRAY platform and TaqMan allelic discrimination assay. Interactions between genetic variants and age/BMI as predictors of GDM risk were evaluated under the logistic regression model. In the first stage, the SNP rs10830963 was discovered to be potentially related to GDM risk (additive model: OR\u2009=\u20091.27, 95%CI\u2009=\u20091.05-1.55, P\u2009=\u20090.025), which was further confirmed in the second stage with a similar effect (additive model: OR\u2009=\u20091.53, 95%CI\u2009=\u20091.19-1.98, P\u2009=\u20090.005). In the combined stage, the G allele of rs10830963 was potentially associated with GDM risk (additive model: OR\u2009=\u20091.36, 95%CI\u2009=\u20091.17-1.59, P\u2009<\u20090.001; dominant model: OR\u2009=\u20091.45, 95%CI\u2009=\u20091.15-1.83, P\u2009=\u20090.005). The rs10830963 interacted with age and BMI to contribute to GDM risk in the combined participants. And, the similar interactive effects for the other four SNPs also exist. These findings offer the potential to improve our understanding of the etiology of GDM, and particularly of biological mechanisms.", - "journal_title": "Molecular genetics and genomics : MGG", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/32656703/" - } - ], - "c3a664f0-9689-485d-a9db-d97bd0664e95": [ - { - "pub_id": "26643952", - "title": "Epigenome-wide association study identifies TXNIP gene associated with type 2 diabetes mellitus and sustained hyperglycemia.", - "authors": "Carolina Soriano-T\u00e1rraga,Jordi Jim\u00e9nez-Conde,Eva Giralt-Steinhauer,Marina Mola-Caminal,Rosa M Vivanco-Hidalgo,Angel Ois,Ana Rodr\u00edguez-Campello,Elisa Cuadrado-Godia,Sergi Sayols-Baixeras,Roberto Elosua,Jaume Roquer, ", - "abstract": "Type 2 diabetes mellitus (DM) is an established risk factor for a wide range of vascular diseases, including ischemic stroke (IS). Glycated hemoglobin A1c (HbA1c), a marker for average blood glucose levels over the previous 12 weeks, is used as a measure of glycemic control and also as a diagnostic criterion for diabetes (HbA1c levels \u2265 6.5%). Epigenetic mechanisms, such as DNA methylation, may be associated with aging processes and with modulation of the risk of various pathologies, such as DM. Specifically, DNA methylation could be one of the mechanisms mediating the relation between DM and environmental exposures. Our goal was to identify new CpG methylation sites associated with DM. We performed a genome-wide methylation study in whole-blood DNA from an IS patient cohorts. Illumina HumanMethylation450 BeadChip array was used to measure DNA methylation in CpG sites. All statistical analyses were adjusted for sex, age, hyperlipidemia, body mass index (BMI), smoking habit and cell count. Findings were replicated in two independent cohorts, an IS cohort and a population-based cohort, using the same array. In the discovery phase (N = 355), we identified a CpG site, cg19693031 (located in the TXNIP gene) that was associated with DM (P = 1.17 \u00d7 10(-12)); this CpG was replicated in two independent cohorts (N = 167 and N = 645). Methylation of TXNIP was inversely and intensely associated with HbA1c levels (P = 7.3 \u00d7 10(-16)), specifically related to diabetic patients with poor control of glucose levels. We identified an association between the TXNIP gene and DM through epigenetic mechanisms, related to sustained hyperglycemia levels (HbA1c \u2265 7%).", - "journal_title": "Human molecular genetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/26643952/" - } - ], - "7a9c869f-5a48-4751-b915-ce6737231d41": [ - { - "pub_id": "30894700", - "title": "Epigenetics and epigenomics in diabetic kidney disease and metabolic memory.", - "authors": "Mitsuo Kato,Rama Natarajan", - "abstract": "The development and progression of diabetic kidney disease (DKD), a highly prevalent\u00a0complication of diabetes mellitus, are influenced by both genetic and environmental factors. DKD is an important contributor to the morbidity of patients with diabetes mellitus, indicating a\u00a0clear need for an improved understanding of disease aetiology to inform the development of\u00a0more efficacious treatments. DKD is characterized by an accumulation of extracellular matrix,\u00a0hypertrophy and fibrosis in kidney glomerular and tubular cells. Increasing evidence shows that\u00a0genes associated with these features of DKD are regulated not only by classical signalling pathways but also by epigenetic mechanisms involving chromatin histone modifications, DNA\u00a0methylation and non-coding RNAs. These mechanisms can respond to\u00a0changes in the environment and, importantly, might mediate the persistent long-term expression\u00a0of DKD-related genes and phenotypes induced by prior glycaemic exposure despite\u00a0subsequent glycaemic control, a phenomenon called metabolic memory. Detection of\u00a0epigenetic events during the early stages of DKD could be valuable for timely diagnosis and\u00a0prompt treatment to prevent progression to end-stage renal disease. Identification of epigenetic signatures of DKD via epigenome-wide association studies might also inform precision medicine approaches. Here, we highlight the\u00a0emerging role of epigenetics and epigenomics in DKD and the translational potential of\u00a0candidate epigenetic factors and\u00a0non-coding RNAs as biomarkers and drug targets for\u00a0DKD.", - "journal_title": "Nature reviews. Nephrology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/30894700/" - } - ], - "55f4c3f7-b278-4390-acde-e50574044d39": [ - { - "pub_id": "34586716", - "title": "Heritability and genome-wide association study of blood pressure in Chinese adult twins.", - "authors": "Jiahao Chen,Weijing Wang,Zhaoying Li,Chunsheng Xu,Xiaocao Tian,Dongfeng Zhang", - "abstract": "Blood pressure (BP) is an independent and important factor for chronic diseases such as cardiovascular diseases and diabetes. We firstly conducted twin modeling analyses to explore the heritability of BP, including systolic blood pressure (SBP), diastolic blood pressure (DBP), pulse pressure (PP) and mean arterial pressure (MAP), and then performed genome-wide association studies to explore the associated genomic loci, genes, and pathways. A total of 380 Chinese twin pairs were included. The AE model containing additive genetic parameter (A) and unique/non-shared environmental parameter (E) was the best fit model, with A accounting for 53.7%, 50.1%, 48.1%, and 53.3% for SBP, DBP, PP and MAP, respectively. No SNP was found to reach the genome-wide significance level (p\u00a0<\u00a05\u00a0\u00d7\u00a010<sup>-8</sup> ), however, three, four, 14 and nine SNPs were found to exceed suggestive significance level (p\u00a0<\u00a01\u00a0\u00d7\u00a010<sup>-5</sup> ) for SBP, DBP, PP, and MAP, respectively. And after imputation, 46, 37, 91 and 61 SNPs were found to exceed the suggestive significance level for SBP, DBP, PP, and MAP, respectively. In gene-based analysis, 53 common genes were found among SBP, DBP, PP, and MAP. In pathway enrichment analysis, 672, 706, 701, and 596 biological pathways were associated with SBP, DBP, PP, and MAP, respectively (p\u00a0<\u00a00.05). Our study suggests that BP is moderately heritable in the Chinese population and could be mediated by a series of genomic loci, genes, and pathways. Future larger-scale studies are needed to confirm our findings.", - "journal_title": "Molecular genetics & genomic medicine", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/34586716/" - } - ], - "d3680301-01e7-47cf-8d48-8e48d7f90c3f": [ - { - "pub_id": "32854766", - "title": "Correction to: Genome-wide profiling of DNA methylation and gene expression identifies candidate genes for human diabetic neuropathy.", - "authors": "Kai Guo,Stephanie A Eid,Sarah E Elzinga,Crystal Pacut,Eva L Feldman,Junguk Hur", - "abstract": "An amendment to this paper has been published and can be accessed via the original article.", - "journal_title": "Clinical epigenetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/32854766/" - } - ], - "53742f18-da70-4774-b687-f4db964974b4": [ - { - "pub_id": "29849136", - "title": "Publisher Correction: Re-analysis of public genetic data reveals a rare X-chromosomal variant associated with type 2 diabetes.", - "authors": "S\u00edlvia Bon\u00e0s-Guarch,Marta Guindo-Mart\u00ednez,Irene Miguel-Escalada,Niels Grarup,David Sebastian,Elias Rodriguez-Fos,Friman S\u00e1nchez,Merc\u00e8 Planas-F\u00e8lix,Paula Cortes-S\u00e1nchez,Santi Gonz\u00e1lez,Pascal Timshel,Tune H Pers,Claire C Morgan,Ignasi Moran,Goutham Atla,Juan R Gonz\u00e1lez,Montserrat Puiggros,Jonathan Mart\u00ed,Ehm A Andersson,Carlos D\u00edaz,Rosa M Badia,Miriam Udler,Aaron Leong,Varindepal Kaur,Jason Flannick,Torben J\u00f8rgensen,Allan Linneberg,Marit E J\u00f8rgensen,Daniel R Witte,Cramer Christensen,Ivan Brandslund,Emil V Appel,Robert A Scott,Jian'an Luan,Claudia Langenberg,Nicholas J Wareham,Oluf Pedersen,Antonio Zorzano,Jose C Florez,Torben Hansen,Jorge Ferrer,Josep Maria Mercader,David Torrents", - "abstract": "In the originally published version of this Article, the affiliation details for Santi Gonz\u00e1lez, Jian'an Luan and Claudia Langenberg were inadvertently omitted. Santi Gonz\u00e1lez should have been affiliated with 'Barcelona Supercomputing Center (BSC), Joint BSC-CRG-IRB Research Program in Computational Biology, 08034 Barcelona, Spain', and Jian'an Luan and Claudia Langenberg should have been affiliated with 'MRC Epidemiology Unit, University of Cambridge School of Clinical Medicine, Cambridge Biomedical Campus, Cambridge CB2 0QQ, UK'. Furthermore, the abstract contained an error in the SNP ID for the rare variant in chromosome Xq23, which was incorrectly given as rs146662057 and should have been rs146662075. These errors have now been corrected in both the PDF and HTML versions of the Article.", - "journal_title": "Nature communications", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/29849136/" - } - ], - "424a3a92-022d-4dab-8b21-6cf07204f4ad": [ - { - "pub_id": "34601942", - "title": "Genome-Wide Association Study of Peripheral Artery Disease.", - "authors": "Natalie R van Zuydam,Alexander Stiby,Moustafa Abdalla,Erin Austin,Emma H Dahlstr\u00f6m,Stela McLachlan,Efthymia Vlachopoulou,Emma Ahlqvist,Chen Di Liao,Niina Sandholm,Carol Forsblom,Anubha Mahajan,Neil R Robertson,N William Rayner,Eero Lindholm,Juha Sinisalo,Markus Perola,Milla Kallio,Emily Weiss,Jackie Price,Andrew Paterson,Barbara Klein,Veikko Salomaa,Colin N A Palmer,Per-Henrik Groop,Leif Groop,Mark I McCarthy,Mariza de Andrade,Andrew P Morris,Jemma C Hopewell,Helen M Colhoun,Iftikhar J Kullo, ", - "abstract": "Peripheral artery disease (PAD) affects >200 million people worldwide and is associated with high mortality and morbidity. We sought to identify genomic variants associated with PAD overall and in the contexts of diabetes and smoking status. We identified genetic variants associated with PAD and then meta-analyzed with published summary statistics from the Million Veterans Program and UK Biobank to replicate their findings. Next, we ran stratified genome-wide association analysis in ever smokers, never smokers, individuals with diabetes, and individuals with no history of diabetes and corresponding interaction analyses, to identify variants that modify the risk of PAD by diabetic or smoking status. We identified 5 genome-wide significant (<i>P</i><sub><i>association</i></sub> \u22645\u00d710<sup>-8</sup>) associations with PAD in 449\u2009548 (N<sub>cases</sub>=12\u2009086) individuals of European ancestry near <i>LPA (lipoprotein [a]), CDKN2BAS1 (CDKN2B antisense RNA 1), SH2B3 (SH2B adaptor protein 3) - PTPN11 (protein tyrosine phosphatase non-receptor type 11), HDAC9 (histone deacetylase 9), and CHRNA3 (cholinergic receptor nicotinic alpha 3 subunit</i>) loci (which overlapped previously reported associations). Meta-analysis with variants previously associated with PAD showed that 18 of 19 published variants remained genome-wide significant. In individuals with diabetes, rs116405693 at the <i>CCSER1 (coiled-coil serine rich protein 1</i>) locus was associated with PAD (odds ratio [95% CI], 1.51 [1.32-1.74], <i>P</i><sub><i>diabetes</i></sub>=2.5\u00d710<sup>-9</sup>, <i>P</i><sub><i>interactionwithdiabetes</i></sub>=5.3\u00d710<sup>-7</sup>). Furthermore, in smokers, rs12910984 at the <i>CHRNA3</i> locus was associated with PAD (odds ratio [95% CI], 1.15 [1.11-1.19], <i>P</i><sub><i>smokers</i></sub>=9.3\u00d710<sup>-10</sup>, <i>P</i><sub><i>interactionwithsmoking</i></sub>=3.9\u00d710<sup>-5</sup>). Our analyses confirm the published genetic associations with PAD and identify novel variants that may influence susceptibility to PAD in the context of diabetes or smoking status.", - "journal_title": "Circulation. Genomic and precision medicine", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/34601942/" - } - ], - "53b0490d-1234-48de-b688-69a297427bc3": [ - { - "pub_id": "31399846", - "title": "Comparative genomic and functional analysis of Akkermansia muciniphila and closely related species.", - "authors": "Juyuan Xing,Xiaobo Li,Yingjiao Sun,Juanjuan Zhao,Shaohua Miao,Qin Xiong,Yonggang Zhang,Guishan Zhang", - "abstract": "Akkermansia muciniphila is an important bacterium that resides on the mucus layer of the intestinal tract. Akkermansia muciniphila has a high abundance in human feces and plays an important role in human health. In this article, 23 whole genome sequences of the Akkermansia genus were comparatively studied. Phylogenetic trees were constructed with three methods: All amino acid sequences of each strain were used to construct the first phylogenetic tree using the web server of Composition Vector Tree Version 3. The matrix of Genome-to-Genome Distances which were obtained from GGDC 2.0 was used to construct the second phylogenetic tree using FastME. The concatenated single-copy core gene-based phylogenetic tree was generated through MEGA. The single-copy genes were obtained using OrthoMCL. Population structure was assessed by STRUCTURE\u00a02.3.4 using the SNPs in core genes. PROKKA and Roary were used to do pan-genome analyses. The biosynthetic gene clusters were predicted using antiSMASH 4.0. IalandViewer 4 was used to detect the genomic islands. The results of comparative genomic analysis revealed that: (1) The 23 Akkermansia strains formed 4 clades in phylogenetic trees. The A. muciniphila strains isolated from different geographic regions and ecological niches, formed a closely related clade. (2) The 23 Akkermansia strains were divided into 4 species based on digital DNA-DNA hybridization (dDDH) values. (3) Pan-genome of A. muciniphila is in an open state and increases with addition of new sequenced genomes. (4) SNPs were not evenly distributed throughout the A. muciniphila genomes. The genes in regions with high SNP density are related to metabolism and cell wall/membrane envelope biogenesis. (5) The thermostable outer-membrane protein, Amuc_1100, was conserved in the Akkermansia genus, except for Akkermansia glycaniphila Pyt<sup>T</sup>. Overall, applying comparative genomic and pan-genomic analyses, we classified and illuminated the phylogenetic relationship of the 23 Akkermansia strains. Insights of the evolutionary, population structure, gene clusters and genome islands of Akkermansia provided more information about the possible physiological and probiotic mechanisms of the Akkermansia strains, and gave some instructions for the in-depth researches about the use of Akkermansia as a gut probiotic in the future.", - "journal_title": "Genes & genomics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/31399846/" - } - ], - "a9fe781e-7c73-4c98-827a-120b563d2b46": [ - { - "pub_id": "31700163", - "title": "Laboratory screening and diagnosis of open neural tube defects, 2019 revision: a technical standard of the American College of Medical Genetics and Genomics (ACMG).", - "authors": "Glenn E Palomaki,Caleb Bupp,Anthony R Gregg,Mary E Norton,Devin Oglesbee,Robert G Best, ", - "abstract": "Open neural tube defects (ONTDs) include open spina bifida (OSB) and anencephaly. These defects are caused by incomplete closure of the neural tube at about 4 weeks of pregnancy. Levels of early second-trimester maternal serum (ms) alpha-fetoprotein (AFP) are sufficiently elevated in affected pregnancies to be used as a population-based screening test. The basic screening methodology was described in the late 1970s and screening programs were active a few years later. By identifying pregnancies with the highest msAFP levels, about 80% of OSB and 95% of anencephaly can be identified as early as 16 weeks gestation. The interpretation of msAFP levels is complicated by the need to consider multiple factors such as gestational age, maternal weight, maternal race, multiple gestations, and more. Testing for AFP and acetylcholinesterase in amniotic fluid and/or identification of the lesion by targeted ultrasound is considered diagnostic of ONTD. When a diagnosis is made, options include termination, surgery after delivery, or in utero surgery, depending on factors such as location and size of the defect, and the presence of any additional anomalies. Screening for ONTD should be performed as part of a comprehensive program linking primary obstetrical care providers, laboratorians, and high-risk clinicians.", - "journal_title": "Genetics in medicine : official journal of the American College of Medical Genetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/31700163/" - } - ], - "b72eb0d1-50e3-4def-94bc-abf77891f519": [ - { - "pub_id": "33162936", - "title": "Functional Genomics in Pancreatic \u03b2 Cells: Recent Advances in Gene Deletion and Genome Editing Technologies for Diabetes Research.", - "authors": "Ming Hu,Ines Cherkaoui,Shivani Misra,Guy A Rutter", - "abstract": "The inheritance of variants that lead to coding changes in, or the mis-expression of, genes critical to pancreatic beta cell function can lead to alterations in insulin secretion and increase the risk of both type 1 and type 2 diabetes. Recently developed clustered regularly interspaced short palindromic repeats (CRISPR/Cas9) gene editing tools provide a powerful means of understanding the impact of identified variants on cell function, growth, and survival and might ultimately provide a means, most likely after the transplantation of genetically \"corrected\" cells, of treating the disease. Here, we review some of the disease-associated genes and variants whose roles have been probed up to now. Next, we survey recent exciting developments in CRISPR/Cas9 technology and their possible exploitation for \u03b2 cell functional genomics. Finally, we will provide a perspective as to how CRISPR/Cas9 technology may find clinical application in patients with diabetes.", - "journal_title": "Frontiers in endocrinology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/33162936/" - } - ], - "e0cb390f-a0b5-475c-8ebe-69d640bd0193": [ - { - "pub_id": "35470713", - "title": "Heme oxygenase-1 and hemopexin gene polymorphisms and the risk of anti-tuberculosis drug-induced hepatotoxicity in China.", - "authors": "Wenpei Liu,Lihuan Lu,Hongqiu Pan,Xiaomin He,Meiling Zhang,Nannan Wang,Jia Zhu,Honggang Yi,Shaowen Tang", - "abstract": "<b>Objective:</b> To assess whether the risk of anti-tuberculosis drug-induced hepatotoxicity (ATDH) might be influenced by heme oxygenase-1 (<i>HMOX1</i>) and hemopexin (<i>HPX</i>) gene polymorphisms. <b>Methods:</b> A dynamic anti-tuberculosis treatment cohort was constructed, and the 1:4 matched nested case-control study was analysed. Eight single-nucleotide polymorphisms (SNPs) of the two genes were selected for genotyping\u00a0and Bonferroni correction was performed to correct for multiple comparison. <b>Results:</b> Overall, 7.8% of patients developed ATDH. SNP rs1807714 in the <i>HMOX1</i> gene had decreased effects on the risk of moderate and severe hepatotoxicity under the dominant and additive models, and hepatocellular injury under the additive model. SNP rs2682099 in the <i>HPX</i> gene had increased effects on the risk of moderate and severe hepatotoxicity under the recessive model. However, these associations disappeared after Bonferroni correction. <b>Conclusion:</b><i>HMOX1</i> and <i>HPX</i> gene polymorphisms might not be associated with susceptibility to ATDH in the Chinese population.", - "journal_title": "Pharmacogenomics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/35470713/" - } - ], - "c3c83137-5643-491b-845e-5af845d9fe4a": [ - { - "pub_id": "30181159", - "title": "Type 2 Diabetes-Associated Genetic Variants Regulate Chromatin Accessibility in Human Islets.", - "authors": "Shubham Khetan,Romy Kursawe,Ahrim Youn,Nathan Lawlor,Alexandria Jillette,Eladio J Marquez,Duygu Ucar,Michael L Stitzel", - "abstract": "Type 2 diabetes (T2D) is a complex disorder in which both genetic and environmental risk factors contribute to islet dysfunction and failure. Genome-wide association studies (GWAS) have linked single nucleotide polymorphisms (SNPs), most of which are noncoding, in >200 loci to islet dysfunction and T2D. Identification of the putative causal variants and their target genes and whether they lead to gain or loss of function remains challenging. Here, we profiled chromatin accessibility in pancreatic islet samples from 19 genotyped individuals and identified 2,949 SNPs associated with in vivo <i>cis</i>-regulatory element use (i.e., chromatin accessibility quantitative trait loci [caQTL]). Among the caQTLs tested (<i>n</i> = 13) using luciferase reporter assays in MIN6 \u03b2-cells, more than half exhibited effects on enhancer activity that were consistent with in vivo chromatin accessibility changes. Importantly, islet caQTL analysis nominated putative causal SNPs in 13 T2D-associated GWAS loci, linking 7 and 6 T2D risk alleles, respectively, to gain or loss of in vivo chromatin accessibility. By investigating the effect of genetic variants on chromatin accessibility in islets, this study is an important step forward in translating T2D-associated GWAS SNP into functional molecular consequences.", - "journal_title": "Diabetes", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/30181159/" - } - ], - "787e2a2c-be24-4970-94b1-0f872a8cd684": [ - { - "pub_id": "30968599", - "title": "HDAC4 mutations cause diabetes and induce \u03b2-cell FoxO1 nuclear exclusion.", - "authors": "Maolian Gong,Yong Yu,Lei Liang,Dogus Vuralli,Sebastian Froehler,Peter Kuehnen,Philipp Du Bois,Jingjing Zhang,Aidi Cao,Yuantao Liu,Khalid Hussain,Jens Fielitz,Shiqi Jia,Wei Chen,Klemens Raile", - "abstract": "Studying patients with rare Mendelian diabetes has uncovered molecular mechanisms regulating \u03b2-cell pathophysiology. Previous studies have shown that Class IIa histone deacetylases (HDAC4, 5, 7, and 9) modulate mammalian pancreatic endocrine cell function and glucose homeostasis. We performed exome sequencing in one adolescent nonautoimmune diabetic patient and detected one de novo predicted disease-causing HDAC4 variant (p.His227Arg). We screened our pediatric diabetes cohort with unknown etiology using Sanger sequencing. In mouse pancreatic \u03b2-cell lines (Min6 and SJ cells), we performed insulin secretion assay and quantitative RT-PCR to measure the \u03b2-cell function transfected with the detected HDAC4 variants and wild type. We carried out immunostaining and Western blot to investigate if the detected HDAC4 variants affect the cellular translocation and acetylation status of Forkhead box protein O1 (FoxO1) in the pancreatic \u03b2-cells. We discovered three HDAC4 mutations (p.His227Arg, p.Asp234Asn, and p.Glu374Lys) in unrelated individuals who had nonautoimmune diabetes with various degrees of \u03b2-cell loss. In mouse pancreatic \u03b2-cell lines, we found that these three HDAC4 mutations decrease insulin secretion, down-regulate \u03b2-cell-specific transcriptional factors, and cause nuclear exclusion of acetylated FoxO1. Mutations in HDAC4 disrupt the deacetylation of FoxO1, subsequently decrease the \u03b2-cell function including insulin secretion, resulting in diabetes.", - "journal_title": "Molecular genetics & genomic medicine", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/30968599/" - } - ], - "b21bbbce-b53f-416b-8378-b635f4270ace": [ - { - "pub_id": "28721436", - "title": "Age at natural menopause and risk of type 2 diabetes: a prospective cohort study.", - "authors": "Taulant Muka,Eralda Asllanaj,Naim Avazverdi,Loes Jaspers,Najada Stringa,Jelena Milic,Symen Ligthart,M Arfan Ikram,Joop S E Laven,Maryam Kavousi,Abbas Dehghan,Oscar H Franco", - "abstract": "In this study, we aimed to examine the association between age at natural menopause and risk of type 2 diabetes, and to assess whether this association is independent of potential mediators. We included 3639 postmenopausal women from the prospective, population-based Rotterdam Study. Age at natural menopause was self-reported retrospectively and was treated as a continuous variable and in categories (premature, <40\u00a0years; early, 40-44\u00a0years; normal, 45-55\u00a0years; and late menopause, >55\u00a0years [reference]). Type 2 diabetes events were diagnosed on the basis of medical records and glucose measurements from Rotterdam Study visits. HRs and 95% CIs were calculated using Cox proportional hazards models, adjusted for confounding factors; in another model, they were additionally adjusted for potential mediators, including obesity, C-reactive protein, glucose and insulin, as well as for levels of total oestradiol and androgens. During a median follow-up of 9.2\u00a0years, we identified 348 individuals with incident type 2 diabetes. After adjustment for confounders, HRs for type 2 diabetes were 3.7 (95% CI 1.8, 7.5), 2.4 (95% CI 1.3, 4.3) and 1.60 (95% CI 1.0, 2.8) for women with premature, early and normal menopause, respectively, relative to those with late menopause (p <sub>trend</sub>\u00a0<0.001). The HR for type 2 diabetes per 1\u00a0year older at menopause was 0.96 (95% CI 0.94, 0.98). Further adjustment for BMI, glycaemic traits, metabolic risk factors, C-reactive protein, endogenous sex hormone levels or shared genetic factors did not affect this association. Early onset of natural menopause is an independent marker for type 2 diabetes in postmenopausal women.", - "journal_title": "Diabetologia", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/28721436/" - } - ], - "c9fda811-1e12-480c-b432-987fa1d24fce": [ - { - "pub_id": "26965507", - "title": "Telomere length change plateaus at 4\u00a0years of age in Latino children: associations with baseline length and maternal change.", - "authors": "Janet M Wojcicki,Stephen Shiboski,Melvin B Heyman,Deena Elwan,Jue Lin,Elizabeth Blackburn,Elissa Epel", - "abstract": "Telomeres are the protective complexes at the end of chromosomes, required for genomic stability. Little is known about predictors of attrition in young children or the relationship between parental and child patterns of telomere change. Telomere length was assessed twice over one year, at 4 and at 5\u00a0years of age, in Latino preschool children (n\u00a0=\u00a077) and their mothers (n\u00a0=\u00a070) in whole blood leukocytes. Maternal and child rates of attrition during the same time period were compared in 70 mother-child pairs. More children showed lengthened telomeres over one year compared to their mothers and very few children showed attrition (2.6\u00a0%). Approximately 31\u00a0% of children and 16\u00a0% of mothers displayed lengthening over one year while 66\u00a0% of children showed maintenance in contrast with 74\u00a0% of mothers. The strongest predictor for child telomere length change was child's baseline telomere length (r\u00a0=\u00a0-0.61, p\u00a0<\u00a00.01). Maternal rate of change was associated with child rate of change (r\u00a0=\u00a00.33, p\u00a0<\u00a00.01). After controlling for child baseline telomere length, the relationship between child and maternal rate of change trended towards significance (Coeff\u00a0=\u00a00.20, 95\u00a0% CI -0.03 to 0.43; p\u00a0=\u00a00.08). We found primarily maintenance and lengthening from 4 to 5\u00a0years of age in children, with minimal telomere attrition, indicating that most of the telomere loss happens in the first 4\u00a0years, plateauing by age 4. Lastly, we found close to 10\u00a0% of the variance in rate of change in children shared by mothers. While some of this shared variance is genetic, there are likely environmental factors that need to be further identified that impact rate of telomere length change.", - "journal_title": "Molecular genetics and genomics : MGG", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/26965507/" - } - ], - "155c2238-a2ca-44a5-aacc-6aeb8664bff1": [ - { - "pub_id": "26902266", - "title": "Genome wide association study of uric acid in Indian population and interaction of identified variants with Type 2 diabetes.", - "authors": "Anil K Giri,Priyanka Banerjee,Shraddha Chakraborty,Yasmeen Kauser,Aditya Undru,Suki Roy,Vaisak Parekatt,Saurabh Ghosh,Nikhil Tandon,Dwaipayan Bharadwaj", - "abstract": "Abnormal level of Serum Uric Acid (SUA) is an important marker and risk factor for complex diseases including Type 2 Diabetes. Since genetic determinant of uric acid in Indians is totally unexplored, we tried to identify common variants associated with SUA in Indians using Genome Wide Association Study (GWAS). Association of five known variants in SLC2A9 and SLC22A11 genes with SUA level in 4,834 normoglycemics (1,109 in discovery and 3,725 in validation phase) was revealed with different effect size in Indians compared to other major ethnic population of the world. Combined analysis of 1,077 T2DM subjects (772 in discovery and 305 in validation phase) and normoglycemics revealed additional GWAS signal in ABCG2 gene. Differences in effect sizes of ABCG2 and SLC2A9 gene variants were observed between normoglycemics and T2DM patients. We identified two novel variants near long non-coding RNA genes AL356739.1 and AC064865.1 with nearly genome wide significance level. Meta-analysis and in silico replication in 11,745 individuals from AUSTWIN consortium improved association for rs12206002 in AL356739.1 gene to sub-genome wide association level. Our results extends association of SLC2A9, SLC22A11 and ABCG2 genes with SUA level in Indians and enrich the assemblages of evidence for SUA level and T2DM interrelationship.", - "journal_title": "Scientific reports", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/26902266/" - } - ], - "40c30ce7-909d-4f40-9848-9e225f902bc1": [ - { - "pub_id": "32124004", - "title": "33rd international mammalian genome conference: meeting highlights.", - "authors": "Lauren J Tracey,Kelsey E Noll,Xavier Montagutelli", - "abstract": "Scientists from 12 countries met at the International Mammalian Genome Conference (IMGC) to share advances in mammalian genetics and genomics research. The event was held in Strasbourg, France and represents the city's second time hosting the IMGC. A diverse attendance of pre-doctoral and post-doctoral trainees, young investigators, established researchers, clinicians, bioinformaticians, and computational biologists enjoyed a rich scientific program of 63 oral presentations, 65 posters, and 5 workshops in the fields of epigenetics, system genetics, developmental biology, cancer, human disease modeling, technical advances, and bioinformatics. This report presents selected highlights of this meeting which illustrate how recent advances in mammalian genetic approaches have improved our ability to decipher complex biological mechanisms.", - "journal_title": "Mammalian genome : official journal of the International Mammalian Genome Society", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/32124004/" - } - ], - "843f216d-8278-4505-8e40-cc1597e1e4e9": [ - { - "pub_id": "34302125", - "title": "Correction to: Direct-to-consumer prenatal testing for multigenic or polygenic disorders: a position statement of the American College of Medical Genetics and Genomics (ACMG).", - "authors": " ", - "abstract": "", - "journal_title": "Genetics in medicine : official journal of the American College of Medical Genetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/34302125/" - } - ], - "dcd88798-0248-45e0-8d45-8614c7697266": [ - { - "pub_id": "30487263", - "title": "Multiethnic Genome-Wide Association Study of Diabetic Retinopathy Using Liability Threshold Modeling of Duration of Diabetes and Glycemic Control.", - "authors": "Samuela Pollack,Robert P Igo,Richard A Jensen,Mark Christiansen,Xiaohui Li,Ching-Yu Cheng,Maggie C Y Ng,Albert V Smith,Elizabeth J Rossin,Ayellet V Segr\u00e8,Samaneh Davoudi,Gavin S Tan,Yii-Der Ida Chen,Jane Z Kuo,Latchezar M Dimitrov,Lynn K Stanwyck,Weihua Meng,S Mohsen Hosseini,Minako Imamura,Darryl Nousome,Jihye Kim,Yang Hai,Yucheng Jia,Jeeyun Ahn,Aaron Leong,Kaanan Shah,Kyu Hyung Park,Xiuqing Guo,Eli Ipp,Kent D Taylor,Sharon G Adler,John R Sedor,Barry I Freedman, ,I-Te Lee,Wayne H-H Sheu,Michiaki Kubo,Atsushi Takahashi,Samy Hadjadj,Michel Marre,David-Alexandre Tregouet,Roberta Mckean-Cowdin,Rohit Varma,Mark I McCarthy,Leif Groop,Emma Ahlqvist,Valeriya Lyssenko,Elisabet Agardh,Andrew Morris,Alex S F Doney,Helen M Colhoun,Iiro Toppila,Niina Sandholm,Per-Henrik Groop,Shiro Maeda,Craig L Hanis,Alan Penman,Ching J Chen,Heather Hancock,Paul Mitchell,Jamie E Craig,Emily Y Chew,Andrew D Paterson,Michael A Grassi,Colin Palmer,Donald W Bowden,Brian L Yaspan,David Siscovick,Mary Frances Cotch,Jie Jin Wang,Kathryn P Burdon,Tien Y Wong,Barbara E K Klein,Ronald Klein,Jerome I Rotter,Sudha K Iyengar,Alkes L Price,Lucia Sobrin", - "abstract": "To identify genetic variants associated with diabetic retinopathy (DR), we performed a large multiethnic genome-wide association study. Discovery included eight European cohorts (<i>n</i> = 3,246) and seven African American cohorts (<i>n</i> = 2,611). We meta-analyzed across cohorts using inverse-variance weighting, with and without liability threshold modeling of glycemic control and duration of diabetes. Variants with a <i>P</i> value <1 \u00d7 10<sup>-5</sup> were investigated in replication cohorts that included 18,545 European, 16,453 Asian, and 2,710 Hispanic subjects. After correction for multiple testing, the C allele of rs142293996 in an intron of nuclear VCP-like (<i>NVL</i>) was associated with DR in European discovery cohorts (<i>P</i> = 2.1 \u00d7 10<sup>-9</sup>), but did not reach genome-wide significance after meta-analysis with replication cohorts. We applied the Disease Association Protein-Protein Link Evaluator (DAPPLE) to our discovery results to test for evidence of risk being spread across underlying molecular pathways. One protein-protein interaction network built from genes in regions associated with proliferative DR was found to have significant connectivity (<i>P</i> = 0.0009) and corroborated with gene set enrichment analyses. These findings suggest that genetic variation in <i>NVL,</i> as well as variation within a protein-protein interaction network that includes genes implicated in inflammation, may influence risk for DR.", - "journal_title": "Diabetes", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/30487263/" - } - ], - "f28818ac-fb82-496a-b46f-86138fdcd107": [ - { - "pub_id": "34471717", - "title": "Adiponectin gene polymorphisms associated with diabetes mellitus: A descriptive review.", - "authors": "Mithu Howlader,Mst Irin Sultana,Farzana Akter,Md Murad Hossain", - "abstract": "Diabetes is currently a growing concern of the age. Prevention and treatment of diabetes is a global health priority. Adiponectin is an adipocyte derived protein hormone that enhances insulin sensitivity and ameliorates diabetes by enhancing fatty acid oxidation and glucose uptake in skeletal muscle and reducing glucose production in the liver. Low serum adiponectin concentrations are associated with diabetes, central obesity, insulin resistance and metabolic syndrome. Adiponectin gene is located on chromosome 3q27, where a locus of susceptibility to diabetes was mapped. Several cross-sectional studies showed that single nucleotide polymorphisms (SNPs) in adiponectin gene (ADIPOQ) were associated with diabetes. SNPs in ADIPOQ help in assessing the association of common variants with levels of adiponectin and the risk of diabetes. Two common SNPs, rs2241766 and rs1501299, have been linked significantly to type 1 diabetes mellitus which endow the world with a block of haplotypes. Experimental evidences also suggest that rs1501299, rs2241766, rs266729, rs17366743, rs17300539, rs182052, rs822396, rs17846866, rs3774261 and rs822393 are significantly associated with type 2 diabetes mellitus which is the predominant form of the disease. In addition, rs2241766 and rs266729 are extensively associated with gestational diabetes, a condition that develops in women during pregnancy. Therefore not a particular single mutation but a number of SNPs in adiponectin gene could be a risk factor for developing diabetes among the individuals worldwide. This study firmly suggests that adiponectin plays a crucial role in the pathogenesis of type 1, type 2 and gestational diabetes mellitus.", - "journal_title": "Heliyon", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/34471717/" - } - ], - "ab32e261-658c-4a8b-94fc-857826b29f5a": [ - { - "pub_id": "29503172", - "title": "Novel subgroups of adult-onset diabetes and their association with outcomes: a data-driven cluster analysis of six variables.", - "authors": "Emma Ahlqvist,Petter Storm,Annemari K\u00e4r\u00e4j\u00e4m\u00e4ki,Mats Martinell,Mozhgan Dorkhan,Annelie Carlsson,Petter Vikman,Rashmi B Prasad,Dina Mansour Aly,Peter Almgren,Ylva Wessman,Nael Shaat,Peter Sp\u00e9gel,Hindrik Mulder,Eero Lindholm,Olle Melander,Ola Hansson,Ulf Malmqvist,\u00c5ke Lernmark,Kaj Lahti,Tom Fors\u00e9n,Tiinamaija Tuomi,Anders H Rosengren,Leif Groop", - "abstract": "Diabetes is presently classified into two main forms, type 1 and type 2 diabetes, but type 2 diabetes in particular is highly heterogeneous. A refined classification could provide a powerful tool to individualise treatment regimens and identify individuals with increased risk of complications at diagnosis. We did data-driven cluster analysis (k-means and hierarchical clustering) in patients with newly diagnosed diabetes (n=8980) from the Swedish All New Diabetics in Scania cohort. Clusters were based on six variables (glutamate decarboxylase antibodies, age at diagnosis, BMI, HbA<sub>1c</sub>, and homoeostatic model assessment 2 estimates of \u03b2-cell function and insulin resistance), and were related to prospective data from patient records on development of complications and prescription of medication. Replication was done in three independent cohorts: the Scania Diabetes Registry (n=1466), All New Diabetics in Uppsala (n=844), and Diabetes Registry Vaasa (n=3485). Cox regression and logistic regression were used to compare time to medication, time to reaching the treatment goal, and risk of diabetic complications and genetic associations. We identified five replicable clusters of patients with diabetes, which had significantly different patient characteristics and risk of diabetic complications. In particular, individuals in cluster 3 (most resistant to insulin) had significantly higher risk of diabetic kidney disease than individuals in clusters 4 and 5, but had been prescribed similar diabetes treatment. Cluster 2 (insulin deficient) had the highest risk of retinopathy. In support of the clustering, genetic associations in the clusters differed from those seen in traditional type 2 diabetes. We stratified patients into five subgroups with differing disease progression and risk of diabetic complications. This new substratification might eventually help to tailor and target early treatment to patients who would benefit most, thereby representing a first step towards precision medicine in diabetes. Swedish Research Council, European Research Council, Vinnova, Academy of Finland, Novo Nordisk Foundation, Scania University Hospital, Sigrid Juselius Foundation, Innovative Medicines Initiative 2 Joint Undertaking, Vasa Hospital district, Jakobstadsnejden Heart Foundation, Folkh\u00e4lsan Research Foundation, Ollqvist Foundation, and Swedish Foundation for Strategic Research.", - "journal_title": "The lancet. Diabetes & endocrinology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/29503172/" - } - ], - "3db3cae6-93e8-4424-82e6-81c4c3f33395": [ - { - "pub_id": "31092297", - "title": "Genome-wide association study identifies novel loci for type 2 diabetes-attributed end-stage kidney disease in African Americans.", - "authors": "Meijian Guan,Jacob M Keaton,Latchezar Dimitrov,Pamela J Hicks,Jianzhao Xu,Nicholette D Palmer,Lijun Ma,Swapan K Das,Yii-Der I Chen,Josef Coresh,Myriam Fornage,Nora Franceschini,Holly Kramer,Carl D Langefeld,Josyf C Mychaleckyj,Rulan S Parekh,Wendy S Post,Laura J Rasmussen-Torvik,Stephen S Rich,Jerome I Rotter,John R Sedor,Denyse Thornley-Brown,Adrienne Tin,James G Wilson,Barry I Freedman,Donald W Bowden,Maggie C Y Ng, ", - "abstract": "End-stage kidney disease (ESKD) is a significant public health concern disproportionately affecting African Americans (AAs). Type 2 diabetes (T2D) is the leading cause of ESKD in the USA, and efforts to uncover genetic susceptibility to diabetic kidney disease (DKD) have had limited success. A prior genome-wide association study (GWAS) in AAs with T2D-ESKD was expanded with additional AA cases and controls and genotypes imputed to the higher density 1000 Genomes reference panel. The discovery analysis included 3432 T2D-ESKD cases and 6977 non-diabetic non-nephropathy controls (N\u2009=\u200910,409), followed by a discrimination analysis in 2756 T2D non-nephropathy controls to exclude T2D-associated variants. Six independent variants located in or near RND3/RBM43, SLITRK3, ENPP7, GNG7, and APOL1 achieved genome-wide significant association (P\u2009<\u20095\u2009\u00d7\u200910<sup>-8</sup>) with T2D-ESKD. Following extension analyses in 1910 non-diabetic ESKD cases and 908 non-diabetic non-nephropathy controls, a meta-analysis of 5342 AA all-cause ESKD cases and 6977 AA non-diabetic non-nephropathy controls revealed an additional novel all-cause ESKD locus at EFNB2 (rs77113398; P\u2009=\u20099.84\u2009\u00d7\u200910<sup>-9</sup>; OR\u2009=\u20091.94). Exclusion of APOL1 renal-risk genotype carriers identified two additional genome-wide significant T2D-ESKD-associated loci at GRAMD3 and MGAT4C. A second variant at GNG7 (rs373971520; P\u2009=\u20092.17\u2009\u00d7\u200910<sup>-8</sup>, OR\u2009=\u20091.46) remained associated with all-cause ESKD in the APOL1-negative analysis. Findings provide further evidence for genetic factors associated with advanced kidney disease in AAs with T2D.", - "journal_title": "Human genomics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/31092297/" - } - ], - "d93a7f4b-2704-4515-9a8b-1975578f89b3": [ - { - "pub_id": "32162118", - "title": "Identification of novel functional CpG-SNPs associated with type 2 diabetes and coronary artery disease.", - "authors": "Zun Wang,Chuan Qiu,Xu Lin,Lan-Juan Zhao,Yong Liu,Xinrui Wu,Qian Wang,Wei Liu,Kelvin Li,Hong-Wen Deng,Si-Yuan Tang,Hui Shen", - "abstract": "Genome-wide association studies (GWASs) have identified hundreds of single nucleotide polymorphisms (SNPs) associated with type 2 diabetes (T2D) and coronary artery disease (CAD), respectively. Nevertheless, these studies were generally performed for single-trait/disease and failed to assess the pleiotropic role of the identified variants. To identify novel functional loci and the pleiotropic relationship between CAD and T2D, the targeted cFDR analysis on CpG-SNPs was performed by integrating two independent large and multi-centered GWASs with summary statistics of T2D (26,676 cases and 132,532 controls) and CAD (60,801 cases and 123,504 controls). Applying the cFDR significance threshold of 0.05, we observed a pleiotropic enrichment between T2D and CAD by incorporating pleiotropic effects into a conditional analysis framework. We identified 79 novel CpG-SNPs for T2D, 61 novel CpG-SNPs for CAD, and 18 novel pleiotropic loci for both traits. Among these novel CpG-SNPs, 33 of them were annotated as methylation quantitative trait locus (meQTL) in whole blood, and ten of them showed expression QTL (eQTL), meQTL, and metabolic QTL (metaQTL) effects simultaneously. To the best of our knowledge, we performed the first targeted cFDR analysis on CpG-SNPs, and our findings provided novel insights into the shared biological mechanisms and overlapped genetic heritability between T2D and CAD.", - "journal_title": "Molecular genetics and genomics : MGG", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/32162118/" - } - ], - "d38ac31f-45c8-476a-b7d9-2fcd845cb010": [ - { - "pub_id": "31056336", - "title": "Phenotypic relationships, genetic parameters, genome-wide associations, and identification of potential candidate genes for ketosis and fat-to-protein ratio in German Holstein cows.", - "authors": "S-L Klein,C Scheper,K Br\u00fcgemann,H H Swalve,S K\u00f6nig", - "abstract": "Energy demand for milk production in early lactation exceeds energy intake, especially in high-yielding Holstein cows. Energy deficiency causes increasing susceptibility to metabolic disorders. In addition to several blood parameters, the fat-to-protein ratio (FPR) is suggested as an indicator for ketosis, because a FPR >1.5 refers to high lipolysis. The aim of this study was to analyze phenotypic, quantitative genetic, and genomic associations between FPR and ketosis. In this regard, 8,912 first-lactation Holstein cows were phenotyped for ketosis according to a veterinarian diagnosis key. Ketosis was diagnosed if the cow showed an abnormal carbohydrate metabolism with increased content of ketone bodies in the blood or urine. At least one entry for ketosis in the first 6 wk after calving implied a score = 1 (diseased); otherwise, a score = 0 (healthy) was assigned. The FPR from the first test-day was defined as a Gaussian distributed trait (FPRgauss), and also as a binary response trait (FPRbin), considering a threshold of FPR = 1.5. After imputation and quality controls, 45,613 SNP markers from the 8,912 genotyped cows were used for genomic studies. Phenotypically, an increasing ketosis incidence was associated with significantly higher FPR, and vice versa. Hence, from a practical trait recording perspective, first test-day FPR is suggested as an indicator for ketosis. The ketosis heritability was slightly larger when modeling the pedigree-based relationship matrix (pedigree-based: 0.17; SNP-based: 0.11). For FPRbin, heritabilities were larger when modeling the genomic relationship matrix (pedigree-based: 0.09; SNP-based: 0.15). For FPRgauss, heritabilities were almost identical for both pedigree and genomic relationship matrices (pedigree-based: 0.14; SNP-based: 0.15). Genetic correlations between ketosis with FPRbin and FPRgauss using either pedigree- or genomic-based relationship matrices were in a moderate range from 0.39 to 0.71. Applying genome-wide association studies, we identified the specific SNP rs109896020 (BTA 5, position: 115,456,438 bp) significantly contributing to ketosis. The identified potential candidate gene PARVB in close chromosomal distance is associated with nonalcoholic fatty liver disease in humans. The most important SNP contributing to FPRbin was located within the DGAT1 gene. Different SNP significantly contributed to ketosis and FPRbin, indicating different mechanisms for both traits genomically.", - "journal_title": "Journal of dairy science", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/31056336/" - } - ], - "1918a20b-a594-463e-819a-d1be14405ff5": [ - { - "pub_id": "34873335", - "title": "Common and rare variant association analyses in amyotrophic lateral sclerosis identify 15 risk loci with distinct genetic architectures and neuron-specific biology.", - "authors": "Wouter van Rheenen,Rick A A van der Spek,Mark K Bakker,Joke J F A van Vugt,Paul J Hop,Ramona A J Zwamborn,Niek de Klein,Harm-Jan Westra,Olivier B Bakker,Patrick Deelen,Gemma Shireby,Eilis Hannon,Matthieu Moisse,Denis Baird,Restuadi Restuadi,Egor Dolzhenko,Annelot M Dekker,Klara Gawor,Henk-Jan Westeneng,Gijs H P Tazelaar,Kristel R van Eijk,Maarten Kooyman,Ross P Byrne,Mark Doherty,Mark Heverin,Ahmad Al Khleifat,Alfredo Iacoangeli,Aleksey Shatunov,Nicola Ticozzi,Johnathan Cooper-Knock,Bradley N Smith,Marta Gromicho,Siddharthan Chandran,Suvankar Pal,Karen E Morrison,Pamela J Shaw,John Hardy,Richard W Orrell,Michael Sendtner,Thomas Meyer,Nazli Ba\u015fak,Anneke J van der Kooi,Antonia Ratti,Isabella Fogh,Cinzia Gellera,Giuseppe Lauria,Stefania Corti,Cristina Cereda,Daisy Sproviero,Sandra D'Alfonso,Gianni Sorar\u00f9,Gabriele Siciliano,Massimiliano Filosto,Alessandro Padovani,Adriano Chi\u00f2,Andrea Calvo,Cristina Moglia,Maura Brunetti,Antonio Canosa,Maurizio Grassano,Ettore Beghi,Elisabetta Pupillo,Giancarlo Logroscino,Beatrice Nefussy,Alma Osmanovic,Angelica Nordin,Yossef Lerner,Michal Zabari,Marc Gotkine,Robert H Baloh,Shaughn Bell,Patrick Vourc'h,Philippe Corcia,Philippe Couratier,St\u00e9phanie Millecamps,Vincent Meininger,Fran\u00e7ois Salachas,Jesus S Mora Pardina,Abdelilah Assialioui,Ricardo Rojas-Garc\u00eda,Patrick A Dion,Jay P Ross,Albert C Ludolph,Jochen H Weishaupt,David Brenner,Axel Freischmidt,Gilbert Bensimon,Alexis Brice,Alexandra Durr,Christine A M Payan,Safa Saker-Delye,Nicholas W Wood,Simon Topp,Rosa Rademakers,Lukas Tittmann,Wolfgang Lieb,Andre Franke,Stephan Ripke,Alice Braun,Julia Kraft,David C Whiteman,Catherine M Olsen,Andre G Uitterlinden,Albert Hofman,Marcella Rietschel,Sven Cichon,Markus M N\u00f6then,Philippe Amouyel, , , , ,Bryan J Traynor,Andrew B Singleton,Miguel Mitne Neto,Ruben J Cauchi,Roel A Ophoff,Martina Wiedau-Pazos,Catherine Lomen-Hoerth,Vivianna M van Deerlin,Julian Grosskreutz,Annekathrin Roediger,Nayana Gaur,Alexander J\u00f6rk,Tabea Barthel,Erik Theele,Benjamin Ilse,Beatrice Stubendorff,Otto W Witte,Robert Steinbach,Christian A H\u00fcbner,Caroline Graff,Lev Brylev,Vera Fominykh,Vera Demeshonok,Anastasia Ataulina,Boris Rogelj,Bla\u017e Koritnik,Janez Zidar,Metka Ravnik-Glava\u010d,Damjan Glava\u010d,Zorica Stevi\u0107,Vivian Drory,Monica Povedano,Ian P Blair,Matthew C Kiernan,Beben Benyamin,Robert D Henderson,Sarah Furlong,Susan Mathers,Pamela A McCombe,Merrilee Needham,Shyuan T Ngo,Garth A Nicholson,Roger Pamphlett,Dominic B Rowe,Frederik J Steyn,Kelly L Williams,Karen A Mather,Perminder S Sachdev,Anjali K Henders,Leanne Wallace,Mamede de Carvalho,Susana Pinto,Susanne Petri,Markus Weber,Guy A Rouleau,Vincenzo Silani,Charles J Curtis,Gerome Breen,Jonathan D Glass,Robert H Brown,John E Landers,Christopher E Shaw,Peter M Andersen,Ewout J N Groen,Michael A van Es,R Jeroen Pasterkamp,Dongsheng Fan,Fleur C Garton,Allan F McRae,George Davey Smith,Tom R Gaunt,Michael A Eberle,Jonathan Mill,Russell L McLaughlin,Orla Hardiman,Kevin P Kenna,Naomi R Wray,Ellen Tsai,Heiko Runz,Lude Franke,Ammar Al-Chalabi,Philip Van Damme,Leonard H van den Berg,Jan H Veldink", - "abstract": "Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with a lifetime risk of one in 350 people and an unmet need for disease-modifying therapies. We conducted a cross-ancestry genome-wide association study (GWAS) including 29,612 patients with ALS and 122,656 controls, which identified 15 risk loci. When combined with 8,953 individuals with whole-genome sequencing (6,538 patients, 2,415 controls) and a large cortex-derived expression quantitative trait locus (eQTL) dataset (MetaBrain), analyses revealed locus-specific genetic architectures in which we prioritized genes either through rare variants, short tandem repeats or regulatory effects. ALS-associated risk loci were shared with multiple traits within the neurodegenerative spectrum but with distinct enrichment patterns across brain regions and cell types. Of the environmental and lifestyle risk factors obtained from the literature, Mendelian randomization analyses indicated a causal role for high cholesterol levels. The combination of all ALS-associated signals reveals a role for perturbations in vesicle-mediated transport and autophagy and provides evidence for cell-autonomous disease initiation in glutamatergic neurons.", - "journal_title": "Nature genetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/34873335/" - } - ], - "a80fdb7f-4ba9-43a0-a423-9df9b83da372": [ - { - "pub_id": "27787193", - "title": "The Role of Host Genetics (and Genomics) in Tuberculosis.", - "authors": "Vivek Naranbhai", - "abstract": "Familial risk of tuberculosis (TB) has been recognized for centuries. Largely through studies of mono- and dizygotic twin concordance rates, studies of families with Mendelian susceptibility to mycobacterial disease, and candidate gene studies performed in the 20th century, it was recognized that susceptibility to TB disease has a substantial host genetic component. Limitations in candidate gene studies and early linkage studies made the robust identification of specific loci associated with disease challenging, and few loci have been convincingly associated across multiple populations. Genome-wide and transcriptome-wide association studies, based on microarray (commonly known as genechip) technologies, conducted in the past decade have helped shed some light on pathogenesis but only a handful of new pathways have been identified. This apparent paradox, of high heritability but few replicable associations, has spurred a new wave of collaborative global studies. This review aims to comprehensively review the heritability of TB, critically review the host genetic and transcriptomic correlates of disease, and highlight current studies and future prospects in the study of host genomics in TB. An implicit goal of elucidating host genetic correlates of susceptibility to Mycobacterium tuberculosis infection or TB disease is to identify pathophysiological features amenable to translation to new preventive, diagnostic, or therapeutic interventions. The translation of genomic insights into new clinical tools is therefore also discussed.", - "journal_title": "Microbiology spectrum", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/27787193/" - } - ], - "af69cd19-2155-43b9-a866-da6957156662": [ - { - "pub_id": "29691896", - "title": "Genome-wide interaction with the insulin secretion locus MTNR1B reveals CMIP as a novel type 2 diabetes susceptibility gene in African Americans.", - "authors": "Jacob M Keaton,Chuan Gao,Meijian Guan,Jacklyn N Hellwege,Nicholette D Palmer,James S Pankow,Myriam Fornage,James G Wilson,Adolfo Correa,Laura J Rasmussen-Torvik,Jerome I Rotter,Yii-Der I Chen,Kent D Taylor,Stephen S Rich,Lynne E Wagenknecht,Barry I Freedman,Maggie C Y Ng,Donald W Bowden", - "abstract": "Although type 2 diabetes (T2D) results from metabolic defects in insulin secretion and insulin sensitivity, most of the genetic risk loci identified to date relates to insulin secretion. We reported that T2D loci influencing insulin sensitivity may be identified through interactions with insulin secretion loci, thereby leading to T2D. Here, we hypothesize that joint testing of variant main effects and interaction effects with an insulin secretion locus increases power to identify genetic interactions leading to T2D. We tested this hypothesis with an intronic MTNR1B SNP, rs10830963, which is associated with acute insulin response to glucose, a dynamic measure of insulin secretion. rs10830963 was tested for interaction and joint (main + interaction) effects with genome-wide data in African Americans (2,452 cases and 3,772 controls) from five cohorts. Genome-wide genotype data (Affymetrix Human Genome 6.0 array) was imputed to a 1000 Genomes Project reference panel. T2D risk was modeled using logistic regression with rs10830963 dosage, age, sex, and principal component as predictors. Joint effects were captured using the Kraft two degrees of freedom test. Genome-wide significant (P\u00a0<\u00a05\u00a0\u00d7\u00a010<sup>-8</sup> ) interaction with MTNR1B and joint effects were detected for CMIP intronic SNP rs17197883 (P<sub>interaction\u00a0</sub> =\u00a01.43\u00a0\u00d7\u00a010<sup>-8</sup> ; P<sub>joint\u00a0</sub> =\u00a04.70\u00a0\u00d7\u00a010<sup>-8</sup> ). CMIP variants have been nominally associated with T2D, fasting glucose, and adiponectin in individuals of East Asian ancestry, with high-density lipoprotein, and with waist-to-hip ratio adjusted for body mass index in Europeans. These data support the hypothesis that additional genetic factors contributing to T2D risk, including insulin sensitivity loci, can be identified through interactions with insulin secretion loci.", - "journal_title": "Genetic epidemiology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/29691896/" - } - ], - "0df24827-df9f-46ee-a43d-dc5465c62f0d": [ - { - "pub_id": "29627041", - "title": "Obesity and asthma.", - "authors": "Ubong Peters,Anne E Dixon,Erick Forno", - "abstract": "Obesity is a vast public health problem and both a major risk factor and disease modifier for asthma in children and adults. Obese subjects have increased asthma risk, and obese asthmatic patients have more symptoms, more frequent and severe exacerbations, reduced response to several asthma medications, and decreased quality of life. Obese asthma is a complex syndrome, including different phenotypes of disease that are just beginning to be understood. We examine the epidemiology and characteristics of this syndrome in children and adults, as well as the changes in lung function seen in each age group. We then discuss the better recognized factors and mechanisms involved in disease pathogenesis, focusing particularly on diet and nutrients, the microbiome, inflammatory and metabolic dysregulation, and the genetics/genomics of obese asthma. Finally, we describe current evidence on the effect of weight loss and mention some important future directions for research in the field.", - "journal_title": "The Journal of allergy and clinical immunology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/29627041/" - } - ], - "b8377494-6c44-41b4-8b1a-24724a9d4c2c": [ - { - "pub_id": "30900398", - "title": "Polymorphism of MTHFR 1298A>C in relation to adverse pregnancy outcomes in Chinese populations.", - "authors": "Hui Mo,Meng Rao,Gang Wang,Yan-Xi Long,Hua-Wei Wang,Li Tang", - "abstract": "Adverse pregnancy outcomes (APOs) are involved in a series of abnormal pregnancies like embryo growth arrest, spontaneous abortion, premature birth, stillbirth, fetal malformation, birth defects and other pathological pregnancy, and childbirth complications. Polymorphism of methylenetetrahydrofolate reductase gene (MTHFR, 607093) is one of the main genetic causes of APO. However, there is still debate on whether MTHFR 1298A>C, rs1801131, polymorphism is related to APO. For the lack of extensive research in the Chinese population at present, the study aim to investigate the relationship between MTHFR 1298A>C polymorphism with APO through a large number of data. A total of 241 samples from patients with APO and 117 healthy controls in Yunnan province were used for MTHFR gene polymorphism analysis, with double fluorescence quantitative polymerase chain reaction (PCR). In consideration of the low frequency of MTHFR 1298C/C genotype, which might affect the statistic results, further datasets of MTHFR 1298A>C polymorphism were collected from literature and analyzed. No statistical difference was detected in the frequency of MTHFR1298A>C polymorphism between two groups in Yunnan. Our data showed that the frequency of MTHFR 1298A/A genotype had the decreasing tendency among Chinese population from northern to southern, as well as eastern to western of China. The frequency of MTHFR 1298A/C and 1298C/C genotypes had the adverse tendency. The frequency of MTHFR 1298C/C genotype was significantly different between two groups in Chinese populations. The significant difference was also observed in the frequency of MTHFR 1298C/C polymorphism between two groups from central China and southern China. In summary, our data showed that MTHFR 1298C/C genotype was one of the important genetic factors of APO in China.", - "journal_title": "Molecular genetics & genomic medicine", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/30900398/" - } - ], - "d56f56c8-ae7e-49e1-9d32-15e981d51d5f": [ - { - "pub_id": "30459394", - "title": "Laboratory analysis of amino acids, 2018 revision: a technical standard of the American College of Medical Genetics and Genomics (ACMG).", - "authors": "J Daniel Sharer,Irene De Biase,Dietrich Matern,Sarah Young,Michael J Bennett,Adviye A Tolun, ", - "abstract": "Amino acid abnormalities are observed in a broad spectrum of inherited metabolic diseases, such as disorders of amino acid metabolism and transport, organic acidemias, and ureagenesis defects. Comprehensive analysis of physiologic amino acids in blood, urine, and cerebrospinal fluid is typically performed in the following clinical settings: evaluation of symptomatic patients in whom a diagnosis is not known; evaluation of previously diagnosed patients to monitor treatment efficacy; evaluation of asymptomatic or presymptomatic (at-risk) relatives of known patients; follow-up testing for an abnormal newborn screen; and assessment of dietary protein adequacy or renal function in general patient populations. Currently, the most common analytical method to quantify amino acids is based on ion exchange chromatography using post-column derivatization with ninhydrin and spectrophotometric detection. Newer methodologies are based on liquid chromatographic separation with detection by mass spectrometry or spectrophotometry. Amino acid analysis by nonseparation methods, such as the flow injection-tandem mass spectrometric (MS/MS) method used for newborn screening, is considered inadequate for the diagnosis of at-risk patients. The purpose of this document is to provide a technical standard for amino acid analysis as applied to the diagnosis and management of inborn errors of metabolism.", - "journal_title": "Genetics in medicine : official journal of the American College of Medical Genetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/30459394/" - } - ], - "6002ff5b-83b0-4118-8de6-8fe7d778ffa8": [ - { - "pub_id": "32578026", - "title": "Nutrigenetics/Nutrigenomics, Personalized Nutrition, and Precision Healthcare.", - "authors": "James A Marcum", - "abstract": "The purposes of the present review are to examine the emergence of nutrigenetics/nutrigenomics, to analyze the relationship between nutrigenetics and nutrigenomics, to explore the impact of nutrigenetics/nutrigenomics on healthcare with respect to noncommunicable diseases, and to discuss the challenges facing the implementation of nutrigenetics/nutrigenomics within healthcare. Nutrigenetics/nutrigenomics is certainly a thriving specialty given the sharp increase of publications over the last two decades. The relationship between nutrigenetics and nutrigenomics is proposed as complementary. The current clinical and research literature supports the significant impact nutrigenetics/nutrigenomics has on treating and preventing noncommunicable diseases. Although several challenges face the implementation of nutrigenetics/nutrigenomics into healthcare, they are not insurmountable. Nutrigenetics/nutrigenomics plays an important role not only in treating diseases and illnesses but also in promoting health and wellness through both basic and clinical research; and it is critical for the future of both personalized nutrition and precision healthcare.", - "journal_title": "Current nutrition reports", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/32578026/" - } - ], - "78886d26-b31a-460d-9a7c-6046b020518d": [ - { - "pub_id": "31254375", - "title": "Identification of rare copy number variations reveals PJA2, APCS, SYNPO, and TAC1 as novel candidate genes in Autism Spectrum Disorders.", - "authors": "Tania Bitar,Walid Hleihel,Sylviane Marouillat,Sandrine Vonwill,Marie-Laure Vuillaume,Michel Soufia,Patrick Vourc'h,Frederic Laumonnier,Christian R Andres", - "abstract": "There is a strong evidence for genetic factors as the main causes of Autism Spectrum Disorders (ASD). To date, hundreds of genes have been identified either by copy number variations (CNVs) and/or single nucleotide variations. However, despite all the findings, the genetics of these disorders have not been totally explored. Thus, the aim of our work was to identify rare CNVs and genes present in these regions in ASD children, using a high-resolution comparative genomic hybridization technique and quantitative PCR (qPCR) approach. Our results have shown 60-70 chromosomal aberrations per patient. We have initially selected 66 CNVs that have been further assessed using qPCR. Finally, we have validated 22 CNVs including 11 deletions and 11 duplications. Ten CNVs are de novo, 11 are inherited and one of unknown origin of transmission. Among the CNVs detected, novel ASD candidate genes PJA2, SYNPO, APCS, and TAC1 have been identified in our group of Lebanese patients. In addition, previously described CNVs have been identified containing genes such as SHANK3, MBP, CHL1, and others. Our study broadens the population spectrum of studied ASD patients and adds new candidates at the list of genes contributing to these disorders.", - "journal_title": "Molecular genetics & genomic medicine", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/31254375/" - } - ], - "38f00352-359f-4efb-aa5c-4a434e384324": [ - { - "pub_id": "26661414", - "title": "Genetic variations in the PSMA3, PSMA6 and PSMC6 genes are associated with type 1 diabetes in Latvians and with expression level of number of UPS-related and T1DM-susceptible genes in HapMap individuals.", - "authors": "Tatjana Sjakste,Natalia Paramonova,Kristine Osina,Kristine Dokane,Jelizaveta Sokolovska,Nikolajs Sjakste", - "abstract": "The ubiquitin-proteasome system (UPS), a key player of proteostasis network in the body, was implicated in type 1 diabetes mellitus (T1DM) pathogenesis. Polymorphisms in genes encoding proteasome subunits may potentially affect system efficiency. However, data in this field are still limited. To fulfil this gap, single nucleotide polymorphisms in the PSMB5 (rs11543947), PSMA6 (rs2277460, rs1048990), PSMC6 (rs2295826, rs2295827) and PSMA3 (rs2348071) genes were genotyped on susceptibility to T1DM in Latvians. The rs11543947 was found to be neutral and other loci manifested disease susceptibility, with rs1048990 and rs2348071 being the most significantly associated (P < 0.001; OR 2.042 [1.376-3.032] and OR 2.096 [1.415-3.107], respectively). Risk effect was associated with female phenotype for rs2277460 and family history for rs2277460, rs2295826 and rs2295827. Five-locus genotypes being at risk simultaneously at any two or more loci showed strong (P < 0.0001) T1DM association. The T1DM protective effects (P < 0.001) were shown for five-locus genotype and haplotype homozygous on common alleles and composed of common alleles, respectively. Using SNPexp data set, correlations have been revealed between the rs1048990, rs2295826, rs2295827 and rs2348071 T1DM risk genotypes and expression levels of 14 genes related to the UPS and 42 T1DM-susceptible genes encoding proteins involved in innate and adaptive immunity, antiviral response, insulin signalling, glucose-energy metabolism and other pathways implicated in T1DM pathogenesis. Genotype-phenotype and genotype-genotype clusterings support genotyping results. Our results provide evidence on new T1DM-susceptible loci in the PSMA3, PSMA6 and PSMC6 proteasome genes and give a new insight into the T1DM pathogenesis.", - "journal_title": "Molecular genetics and genomics : MGG", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/26661414/" - } - ], - "000ed756-21e2-422e-9455-87932bb5916c": [ - { - "pub_id": "30743315", - "title": "Methylation of HIF3A promoter CpG islands contributes to insulin resistance in gestational diabetes mellitus.", - "authors": "Yinghong Zhang,Yangyang Chen,Hongmei Qu,Yuanli Wang", - "abstract": "Gestational diabetes mellitus (GDM) is defined as any degree of glucose intolerance during pregnancy, and will lead to high risk of diabetes even after pregnancy. Hypoxia-inducible factor (HIF) family proteins are transcriptional factors that are highly correlated with methylation, which might be involved in the regulation of GDM. Baseline clinical characteristics of the GDM patients and healthy women were analyzed. Omental tissue from GDM patients and control groups were collected and detected for the expression levels of HIF1A, HIF2A, and HIF3A. The CpG islands of HIF3A promoter were predicted by \"methprimer\" software, and the methylation level of CpG islands was detected by bisulfite sequencing PCR. HIF3A was downregulated in the omental tissue from GDM patients, whereas HIF1A and HIF2A were not affected. Furthermore, HIF3A expression was positively correlated with levels of estrogen receptor \u03b1 (ESR1) and solute carrier family 2 member 4 (SLC2A4). Moreover, CpG islands of HIF3A promoter were highly methylated in GDM patients. In addition, methylation level of CpG islands could be upregulated by Estradiol (E2) treatment, since high dose of E2 reduced HIF3A mRNA expression in 3T3-L1 adipocytes. Our findings demonstrate that the expression level of HIF3A, but not HIF1A or HIF2A, is downregulated in GDM patients. The methylation status of HIF3A promoter region is highly correlated with GDM, which could be a novel therapeutic target for GDM treatment.", - "journal_title": "Molecular genetics & genomic medicine", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/30743315/" - } - ], - "c86752e6-aada-4a1e-9182-abfa5b298889": [ - { - "pub_id": "31897802", - "title": "Genetic variants associated with exercise performance in both moderately trained and highly trained individuals.", - "authors": "N R Harvey,S Voisin,P J Dunn,H Sutherland,X Yan,M Jacques,I D Papadimitriou,L J Haseler,K J Ashton,L M Haupt,N Eynon,L R Griffiths", - "abstract": "Adaptation to exercise training is a complex trait that may be influenced by genetic variants. We identified 36 single nucleotide polymorphisms (SNPs) that had been previously associated with endurance or strength performance, exercise-related phenotypes or exercise intolerant disorders. A MassARRAY multiplex genotyping assay was designed to identify associations with these SNPs against collected endurance fitness phenotype parameters obtained from two exercise cohorts (Gene SMART study; n\u2009=\u200958 and Hawaiian Ironman Triathlon 2008; n\u2009=\u2009115). These parameters included peak power output (PP), a time trial (TT), lactate threshold (LT), maximal oxygen uptake (VO<sub>2</sub> max) in recreationally active individuals and a triathlon time-to-completion (Hawaiian Ironman Triathlon cohort only). A nominal significance threshold of \u03b1\u2009<\u20090.05 was used to identify 17 variants (11 in the Gene SMART population and six in the Hawaiian Ironman Triathlon cohort) which were significantly associated with performance gains in highly trained individuals. The variant rs1474347 located in Interleukin 6 (IL6) was the only variant with a false discovery rate\u2009<\u20090.05 and was found to be associated with gains in VO<sub>2</sub> max (additional 4.016\u00a0mL/(kg\u00a0min) for each G allele inherited) after training in the Gene SMART cohort. In summary, this study found further evidence to suggest that genetic variance can influence training response in a moderately trained cohort and provides an example of the potential application of genomic research in the assessment of exercise trait response.", - "journal_title": "Molecular genetics and genomics : MGG", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/31897802/" - } - ], - "83a34294-d942-476f-be2f-ff8d7ec3dec4": [ - { - "pub_id": "33179336", - "title": "Genome-wide search for genes affecting the age at diagnosis of type 1 diabetes.", - "authors": "A Syreeni,N Sandholm,C Sidore,F Cucca,J Haukka,V Harjutsalo,P-H Groop, ", - "abstract": "Type 1 diabetes (T1D) is an autoimmune disease affecting individuals in the early years of life. Although previous studies have identified genetic loci influencing T1D diagnosis age, these studies did not investigate the genome with high resolution. We performed a genome-wide meta-analysis for age at diagnosis with cohorts from Finland (Finnish Diabetic Nephropathy Study), the United Kingdom (UK Genetic Resource Investigating Diabetes) and Sardinia. Through SNP associations, transcriptome-wide association analysis linked T1D diagnosis age and gene expression. We identified two chromosomal regions associated with T1D diagnosis age: multiple independent variants in the HLA region on chromosome 6 and a locus on chromosome 17q12. We performed gene-level association tests with transcriptome prediction models from two whole blood datasets, lymphocyte cell line, spleen, pancreas and small intestine tissues. Of the non-HLA genes, lower PNMT expression in whole blood, and higher IKZF3 and ZPBP2, and lower ORMDL3 and GSDMB transcription levels in multiple tissues were associated with lower T1D diagnosis age (FDR\u00a0=\u00a00.05). These genes lie on chr17q12 which is associated with T1D, other autoimmune diseases, and childhood asthma. Additionally, higher expression of PHF20L1, a gene not previously implicated in T1D, was associated with lower diagnosis age in lymphocytes, pancreas, and spleen. Altogether, the non-HLA associations were enriched in open chromatin in various blood cells, blood vessel tissues and foetal thymus tissue. Multiple genes on chr17q12 and PHF20L1 on chr8 were associated with T1D diagnosis age and only further studies may elucidate the role of these genes for immunity and T1D onset.", - "journal_title": "Journal of internal medicine", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/33179336/" - } - ], - "4c1adf85-c06e-43ef-90e5-9a80ba7d6392": [ - { - "pub_id": "27070700", - "title": "Long Noncoding RNAs in Cancer Pathways.", - "authors": "Adam M Schmitt,Howard Y Chang", - "abstract": "Genome-wide cancer mutation analyses are revealing an extensive landscape of functional mutations within the noncoding genome, with profound effects on the expression of long noncoding RNAs (lncRNAs). While the exquisite regulation of lncRNA transcription can provide signals of malignant transformation, we now understand that lncRNAs drive many important cancer phenotypes through their interactions with other cellular macromolecules including DNA, protein, and RNA. Recent advancements in surveying lncRNA molecular mechanisms are now providing the tools to functionally annotate these cancer-associated transcripts, making these molecules attractive targets for therapeutic intervention in the fight against cancer.", - "journal_title": "Cancer cell", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/27070700/" - } - ], - "c8404542-9eac-43e4-9331-e3c9066f3cd4": [ - { - "pub_id": "27802415", - "title": "Genome-Wide and Gene-Based Meta-Analyses Identify Novel Loci Influencing Blood Pressure Response to Hydrochlorothiazide.", - "authors": "Erika Salvi,Zhiying Wang,Federica Rizzi,Yan Gong,Caitrin W McDonough,Sandosh Padmanabhan,Timo P Hiltunen,Chiara Lanzani,Roberta Zaninello,Martina Chittani,Kent R Bailey,Antti-Pekka Sarin,Matteo Barcella,Olle Melander,Arlene B Chapman,Paolo Manunta,Kimmo K Kontula,Nicola Glorioso,Daniele Cusi,Anna F Dominiczak,Julie A Johnson,Cristina Barlassina,Eric Boerwinkle,Rhonda M Cooper-DeHoff,Stephen T Turner", - "abstract": "This study aimed to identify novel loci influencing the antihypertensive response to hydrochlorothiazide monotherapy. A genome-wide meta-analysis of blood pressure (BP) response to hydrochlorothiazide was performed in 1739 white hypertensives from 6 clinical trials within the International Consortium for Antihypertensive Pharmacogenomics Studies, making it the largest study to date of its kind. No signals reached genome-wide significance (P<5\u00d710<sup>-</sup><sup>8</sup>), and the suggestive regions (P<10<sup>-5</sup>) were cross-validated in 2 black cohorts treated with hydrochlorothiazide. In addition, a gene-based analysis was performed on candidate genes with previous evidence of involvement in diuretic response, in BP regulation, or in hypertension susceptibility. Using the genome-wide meta-analysis approach, with validation in blacks, we identified 2 suggestive regulatory regions linked to gap junction protein \u03b11 gene (GJA1) and forkhead box A1 gene (FOXA1), relevant for cardiovascular and kidney function. With the gene-based approach, we identified hydroxy-delta-5-steroid dehydrogenase, 3 \u03b2- and steroid \u03b4-isomerase 1 gene (HSD3B1) as significantly associated with BP response (P<2.28\u00d710<sup>-<sup>4</sup></sup> ). HSD3B1 encodes the 3\u03b2-hydroxysteroid dehydrogenase enzyme and plays a crucial role in the biosynthesis of aldosterone and endogenous ouabain. By amassing all of the available pharmacogenomic studies of BP response to hydrochlorothiazide, and using 2 different analytic approaches, we identified 3 novel loci influencing BP response to hydrochlorothiazide. The gene-based analysis, never before applied to pharmacogenomics of antihypertensive drugs to our knowledge, provided a powerful strategy to identify a locus of interest, which was not identified in the genome-wide meta-analysis because of high allelic heterogeneity. These data pave the way for future investigations on new pathways and drug targets to enhance the current understanding of personalized antihypertensive treatment.", - "journal_title": "Hypertension (Dallas, Tex. : 1979)", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/27802415/" - } - ], - "27ed8ba4-ec5a-40a0-b839-a3bc5fe5f554": [ - { - "pub_id": "31879237", - "title": "The genetics and genomics of cystic fibrosis.", - "authors": "N Sharma,G R Cutting", - "abstract": "Genetics is the branch of biology concerned with study of individual genes and how they work whereas genomics is involved with the analysis of all genes and their interactions. Both of these approaches have been applied extensively to CF. Identification of the CFTR gene initiated the dissection of CF genetics at the molecular level. Subsequently, thousands of variants were found in the gene and the functional consequences of a subset have been studied in detail. The completion of the human genome ushered in a new phase of study where the role of genes beyond CFTR could be evaluated for their contribution to the severity of CF. This will be a brief overview of the contribution of these complementary methods to our understanding of CF pathogenesis.", - "journal_title": "Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/31879237/" - } - ], - "c406e629-b6a3-4f24-8300-7192cdfb0ba9": [ - { - "pub_id": "37400433", - "title": "Causal associations between cardiorespiratory fitness and type 2 diabetes.", - "authors": "Lina Cai,Tomas Gonzales,Eleanor Wheeler,Nicola D Kerrison,Felix R Day,Claudia Langenberg,John R B Perry,Soren Brage,Nicholas J Wareham", - "abstract": "Higher cardiorespiratory fitness is associated with lower risk of type 2 diabetes. However, the causality of this relationship and the biological mechanisms that underlie it are unclear. Here, we examine genetic determinants of cardiorespiratory fitness in 450k European-ancestry individuals in UK Biobank, by leveraging the genetic overlap between fitness measured by an exercise test and resting heart rate. We identified 160 fitness-associated loci which we validated in an independent cohort, the Fenland study. Gene-based analyses prioritised candidate genes, such as CACNA1C, SCN10A, MYH11 and MYH6, that are enriched in biological processes related to cardiac muscle development and muscle contractility. In a Mendelian Randomisation framework, we demonstrate that higher genetically predicted fitness is causally associated with lower risk of type 2 diabetes independent of adiposity. Integration with proteomic data identified N-terminal pro B-type natriuretic peptide, hepatocyte growth factor-like protein and sex hormone-binding globulin as potential mediators of this relationship. Collectively, our findings provide insights into the biological mechanisms underpinning cardiorespiratory fitness and highlight the importance of improving fitness for diabetes prevention.", - "journal_title": "Nature communications", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/37400433/" - } - ], - "e5cf067c-8be0-4b0a-b376-7882cdc9d96c": [ - { - "pub_id": "35643086", - "title": "Exploring and exploiting genetics and genomics for sweetpotato improvement: Status and perspectives.", - "authors": "Mengxiao Yan,Haozhen Nie,Yunze Wang,Xinyi Wang,Robert Jarret,Jiamin Zhao,Hongxia Wang,Jun Yang", - "abstract": "Sweetpotato (Ipomoea batatas (L.) Lam.) is one of the most important root crops cultivated worldwide. Because of its adaptability, high yield potential, and nutritional value, sweetpotato has become an important food crop, particularly in developing countries. To ensure adequate crop yields to meet increasing demand, it is essential to enhance the tolerance of sweetpotato to environmental stresses and other yield-limiting factors. The highly heterozygous hexaploid genome of I.\u00a0batatas complicates genetic studies and limits improvement of sweetpotato through traditional breeding. However, application of next-generation sequencing\u00a0and high-throughput genotyping and phenotyping technologies to sweetpotato genetics and genomics research has provided new tools and resources for crop improvement. In this review, we discuss the genomics resources that are available for sweetpotato, including the current reference genome, databases, and available bioinformatics tools. We systematically review the current state of knowledge on the polyploid genetics of sweetpotato, including studies of its origin and germplasm diversity and the associated mapping of important agricultural traits. We then outline the conventional and molecular breeding approaches that have been applied to sweetpotato. Finally, we discuss future goals for genetic studies of sweetpotato and crop improvement via breeding in combination with state-of-the-art multi-omics approaches such as genomic selection and gene editing. These approaches will advance and accelerate genetic improvement of this important root crop and facilitate its sustainable global production.", - "journal_title": "Plant communications", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/35643086/" - } - ], - "d093aecb-9fe1-41b9-802c-21b75bcffb9b": [ - { - "pub_id": "35197629", - "title": "Low-dose metformin targets the lysosomal AMPK pathway through PEN2.", - "authors": "Teng Ma,Xiao Tian,Baoding Zhang,Mengqi Li,Yu Wang,Chunyan Yang,Jianfeng Wu,Xiaoyan Wei,Qi Qu,Yaxin Yu,Shating Long,Jin-Wei Feng,Chun Li,Cixiong Zhang,Changchuan Xie,Yaying Wu,Zheni Xu,Junjie Chen,Yong Yu,Xi Huang,Ying He,Luming Yao,Lei Zhang,Mingxia Zhu,Wen Wang,Zhi-Chao Wang,Mingliang Zhang,Yuqian Bao,Weiping Jia,Shu-Yong Lin,Zhiyun Ye,Hai-Long Piao,Xianming Deng,Chen-Song Zhang,Sheng-Cai Lin", - "abstract": "Metformin, the most prescribed antidiabetic medicine, has shown other benefits such as anti-ageing and anticancer effects<sup>1-4</sup>. For clinical doses of metformin, AMP-activated protein kinase (AMPK) has a major role in its mechanism of action<sup>4,5</sup>; however, the direct molecular target of metformin remains unknown. Here we show that clinically relevant concentrations of metformin inhibit the lysosomal proton pump v-ATPase, which is a central node for AMPK activation following glucose starvation<sup>6</sup>. We synthesize a photoactive metformin probe and identify PEN2, a subunit of \u03b3-secretase<sup>7</sup>, as a binding partner of metformin with a dissociation constant at micromolar levels. Metformin-bound PEN2 forms a complex with ATP6AP1, a subunit of the v-ATPase<sup>8</sup>, which leads to the inhibition of v-ATPase and the activation of AMPK without effects on cellular AMP levels. Knockout of PEN2 or re-introduction of a PEN2 mutant that does not bind ATP6AP1 blunts AMPK activation. In vivo, liver-specific knockout of Pen2 abolishes metformin-mediated reduction of hepatic fat content, whereas intestine-specific knockout of Pen2 impairs its glucose-lowering effects. Furthermore, knockdown of pen-2 in Caenorhabditis elegans abrogates metformin-induced extension of lifespan. Together, these findings reveal that metformin binds PEN2 and initiates a signalling route that intersects, through ATP6AP1, the lysosomal glucose-sensing pathway for AMPK activation. This ensures that metformin exerts its therapeutic benefits in patients without substantial adverse effects.", - "journal_title": "Nature", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/35197629/" - } - ], - "246946ff-3b83-4c39-8146-3d48b5d498f6": [ - { - "pub_id": "29404672", - "title": "Meta-genome-wide association studies identify a locus on chromosome 1 and multiple variants in the MHC region for serum C-peptide in type 1 diabetes.", - "authors": "Delnaz Roshandel,Rose Gubitosi-Klug,Shelley B Bull,Angelo J Canty,Marcus G Pezzolesi,George L King,Hillary A Keenan,Janet K Snell-Bergeon,David M Maahs,Ronald Klein,Barbara E K Klein,Trevor J Orchard,Tina Costacou,Michael N Weedon, ,Richard A Oram,Andrew D Paterson", - "abstract": "The aim of this study was to identify genetic variants associated with beta cell function in type 1 diabetes, as measured by serum C-peptide levels, through meta-genome-wide association studies (meta-GWAS). We performed a meta-GWAS to combine the results from five studies in type 1 diabetes with cross-sectionally measured stimulated, fasting or random C-peptide levels, including 3479 European participants. The p values across studies were combined, taking into account sample size and direction of effect. We also performed separate meta-GWAS for stimulated (n\u2009=\u20091303), fasting (n\u2009=\u20092019) and random (n\u2009=\u20091497) C-peptide levels. In the meta-GWAS for stimulated/fasting/random C-peptide levels, a SNP on chromosome 1, rs559047 (Chr1:238753916, T>A, minor allele frequency [MAF] 0.24-0.26), was associated with C-peptide (p\u2009=\u20094.13\u2009\u00d7\u200910<sup>-8</sup>), meeting the genome-wide significance threshold (p\u2009<\u20095\u2009\u00d7\u200910<sup>-8</sup>). In the same meta-GWAS, a locus in the MHC region (rs9260151) was close to the genome-wide significance threshold (Chr6:29911030, C>T, MAF 0.07-0.10, p\u2009=\u20098.43\u2009\u00d7\u200910<sup>-8</sup>). In the stimulated C-peptide meta-GWAS, rs61211515 (Chr6:30100975, T/-, MAF 0.17-0.19) in the MHC region was associated with stimulated C-peptide (\u03b2 [SE]\u2009=\u2009-\u20090.39 [0.07], p\u2009=\u20099.72\u2009\u00d7\u200910<sup>-8</sup>). rs61211515 was also associated with the rate of stimulated C-peptide decline over time in a subset of individuals (n\u2009=\u2009258) with annual repeated measures for up to 6\u00a0years (p\u2009=\u20090.02). In the meta-GWAS of random C-peptide, another MHC region, SNP rs3135002 (Chr6:32668439, C>A, MAF 0.02-0.06), was associated with C-peptide (p\u2009=\u20093.49\u2009\u00d7\u200910<sup>-8</sup>). Conditional analyses suggested that the three identified variants in the MHC region were independent of each other. rs9260151 and rs3135002 have been associated with type 1 diabetes, whereas rs559047 and rs61211515 have not been associated with a risk of developing type 1 diabetes. We identified a locus on chromosome 1 and multiple variants in the MHC region, at least some of which were distinct from type 1 diabetes risk loci, that were associated with C-peptide, suggesting partly non-overlapping mechanisms for the development and progression of type 1 diabetes. These associations need to be validated in independent populations. Further investigations could provide insights into mechanisms of beta cell loss and opportunities to preserve beta cell function.", - "journal_title": "Diabetologia", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/29404672/" - } - ], - "497ff4e6-aae7-45ec-a752-c850f5f06f94": [ - { - "pub_id": "15082592", - "title": "Absence of PRSS1 mutations and association of SPINK1 trypsin inhibitor mutations in hereditary and non-hereditary chronic pancreatitis.", - "authors": "G R Chandak,M M Idris,D N Reddy,K R Mani,S Bhaskar,G V Rao,L Singh", - "abstract": "Mutations in the cationic trypsinogen (protease, serine, 1 (trypsin 1); PRSS1) gene are causally associated with recurrent acute and chronic pancreatitis. We investigated whether mutations in the PRSS1 gene are associated with hereditary and non-hereditary pancreatitis. As a modifier role has been proposed for trypsin inhibitor (serine protease inhibitor, Kazal type I; SPINK1) mutations, the role of SPINK1 mutations in these patients was also analysed. The coding regions of PRSS1 and SPINK1 genes were sequenced in 290 controls and 198 patients, of whom 120 were diagnosed as idiopathic (ICP), 41 as alcoholic (ACP), and 37 as hereditary pancreatitis (HP). Twenty four unaffected relatives of HP probands were also analysed and genotype-phenotype correlations and statistical analyses were performed. No mutations in the PRSS1 gene were detected in any of the patients, including HP patients, while the N34S mutation was observed in the SPINK1 gene in the majority of HP patients (73%). Similarly, 26.8% of ACP (11 of 41) and 32.5% (39 of 120) of ICP patients also had SPINK1 mutations. The N34S mutation was observed in both homozygous and heterozygous conditions. In comparison, only 2.76% of the control population had the N34S allele (p<0.001). The P55S mutation was observed in one ICP and one ACP patient, and in three normal individuals. Genotype-phenotype correlations did not suggest any significant difference in the age of onset, severity of disease, or pancreatic endocrine insufficiency in patients with or without mutated SPINK1 and irrespective of the allelic status of N34S SPINK1. Irrespective of the aetiology, mutations in the PRSS1 gene are not associated with chronic pancreatitis, including HP. In contrast, the N34S mutation in the SPINK1 gene shows a significant correlation in these patients. A comparable phenotype in terms of age of onset, diabetes mellitus, and other phenotypic features in patients with or without SPINK1 mutations and N34S homozygotes and heterozygotes suggests that there may still be involvement of other genetic or environmental factors.", - "journal_title": "Gut", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/15082592/" - } - ], - "5a72ab80-edf3-4f7d-a049-3951c6ca99f9": [ - { - "pub_id": "35765100", - "title": "Development and validation of a trans-ancestry polygenic risk score for type 2 diabetes in diverse populations.", - "authors": "Tian Ge,Marguerite R Irvin,Amit Patki,Vinodh Srinivasasainagendra,Yen-Feng Lin,Hemant K Tiwari,Nicole D Armstrong,Barbara Benoit,Chia-Yen Chen,Karmel W Choi,James J Cimino,Brittney H Davis,Ozan Dikilitas,Bethany Etheridge,Yen-Chen Anne Feng,Vivian Gainer,Hailiang Huang,Gail P Jarvik,Christopher Kachulis,Eimear E Kenny,Atlas Khan,Krzysztof Kiryluk,Leah Kottyan,Iftikhar J Kullo,Christoph Lange,Niall Lennon,Aaron Leong,Edyta Malolepsza,Ayme D Miles,Shawn Murphy,Bahram Namjou,Renuka Narayan,Mark J O'Connor,Jennifer A Pacheco,Emma Perez,Laura J Rasmussen-Torvik,Elisabeth A Rosenthal,Daniel Schaid,Maria Stamou,Miriam S Udler,Wei-Qi Wei,Scott T Weiss,Maggie C Y Ng,Jordan W Smoller,Matthew S Lebo,James B Meigs,Nita A Limdi,Elizabeth W Karlson", - "abstract": "Type 2 diabetes (T2D) is a worldwide scourge caused by both genetic and environmental risk factors that disproportionately afflicts communities of color. Leveraging existing large-scale genome-wide association studies (GWAS), polygenic risk scores (PRS) have shown promise to complement established clinical risk factors and intervention paradigms, and improve early diagnosis and prevention of T2D. However, to date, T2D PRS have been most widely developed and validated in individuals of European descent. Comprehensive assessment of T2D PRS in non-European populations is critical for equitable deployment of PRS to clinical practice that benefits global populations. We integrated T2D GWAS in European, African, and East Asian populations to construct a trans-ancestry T2D PRS using a newly developed Bayesian polygenic modeling method, and assessed the prediction accuracy of the PRS in the multi-ethnic Electronic Medical Records and Genomics (eMERGE) study (11,945 cases; 57,694 controls), four Black cohorts (5137 cases; 9657 controls), and the Taiwan Biobank (4570 cases; 84,996 controls). We additionally evaluated a post hoc ancestry adjustment method that can express the polygenic risk on the same scale across ancestrally diverse individuals and facilitate the clinical implementation of the PRS in prospective cohorts. The trans-ancestry PRS was significantly associated with T2D status across the ancestral groups examined. The top 2% of the PRS distribution can identify individuals with an approximately 2.5-4.5-fold of increase in T2D risk, which corresponds to the increased risk of T2D for first-degree relatives. The post hoc ancestry adjustment method eliminated major distributional differences in the PRS across ancestries without compromising its predictive performance. By integrating T2D GWAS from multiple populations, we developed and validated a trans-ancestry PRS, and demonstrated its potential as a meaningful index of risk among diverse patients in clinical settings. Our efforts represent the first step towards the implementation of the T2D PRS into routine healthcare.", - "journal_title": "Genome medicine", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/35765100/" - } - ], - "f9b65334-56b7-43e9-9fda-b778c18c1c67": [ - { - "pub_id": "36553074", - "title": "Using Recurrent Neural Networks for Predicting Type-2 Diabetes from Genomic and Tabular Data.", - "authors": "Parvathaneni Naga Srinivasu,Jana Shafi,T Balamurali Krishna,Canavoy Narahari Sujatha,S Phani Praveen,Muhammad Fazal Ijaz", - "abstract": "The development of genomic technology for smart diagnosis and therapies for various diseases has lately been the most demanding area for computer-aided diagnostic and treatment research. Exponential breakthroughs in artificial intelligence and machine intelligence technologies could pave the way for identifying challenges afflicting the healthcare industry. Genomics is paving the way for predicting future illnesses, including cancer, Alzheimer's disease, and diabetes. Machine learning advancements have expedited the pace of biomedical informatics research and inspired new branches of computational biology. Furthermore, knowing gene relationships has resulted in developing more accurate models that can effectively detect patterns in vast volumes of data, making classification models important in various domains. Recurrent Neural Network models have a memory that allows them to quickly remember knowledge from previous cycles and process genetic data. The present work focuses on type 2 diabetes prediction using gene sequences derived from genomic DNA fragments through automated feature selection and feature extraction procedures for matching gene patterns with training data. The suggested model was tested using tabular data to predict type 2 diabetes based on several parameters. The performance of neural networks incorporating Recurrent Neural Network (RNN) components, Long Short-Term Memory (LSTM), and Gated Recurrent Units (GRU) was tested in this research. The model's efficiency is assessed using the evaluation metrics such as Sensitivity, Specificity, Accuracy, F1-Score, and Mathews Correlation Coefficient (MCC). The suggested technique predicted future illnesses with fair Accuracy. Furthermore, our research showed that the suggested model could be used in real-world scenarios and that input risk variables from an end-user Android application could be kept and evaluated on a secure remote server.", - "journal_title": "Diagnostics (Basel, Switzerland)", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/36553074/" - } - ], - "42268e13-e204-46d5-ae9c-0d87f3f4c553": [ - { - "pub_id": "35047847", - "title": "Identification of 90 NAFLD GWAS loci and establishment of NAFLD PRS and causal role of NAFLD in coronary artery disease.", - "authors": "Zong Miao,Kristina M Garske,David Z Pan,Amogha Koka,Dorota Kaminska,Ville M\u00e4nnist\u00f6,Janet S Sinsheimer,Jussi Pihlajam\u00e4ki,P\u00e4ivi Pajukanta", - "abstract": "The prevalence of non-alcoholic fatty liver disease (NAFLD), now also known as metabolic dysfunction-associated fatty liver disease (MAFLD), is rapidly increasing worldwide due to the ongoing obesity epidemic. However, currently the NALFD diagnosis requires non-readily available imaging technologies or liver biopsy, which has drastically limited the sample sizes of NAFLD studies and hampered the discovery of its genetic component. Here we utilized the large UK Biobank (UKB) to accurately estimate the NAFLD status in UKB based on common serum traits and anthropometric measures. Scoring all individuals in UKB for NAFLD risk resulted in 28,396 NAFLD cases and 108,652 healthy individuals at a >90% confidence level. Using this imputed NAFLD status to perform the largest NAFLD genome-wide association study (GWAS) to date, we identified 94 independent (R<sup>2</sup> < 0.2) NAFLD GWAS loci, of which 90 have not been identified before; built a polygenic risk score (PRS) model to predict the genetic risk of NAFLD; and used the GWAS variants of imputed NAFLD for a tissue-aware Mendelian randomization analysis that discovered a significant causal effect of NAFLD on coronary artery disease (CAD). In summary, we accurately estimated the NAFLD status in UKB using common serum traits and anthropometric measures, which empowered us to identify 90 GWAS NAFLD loci, build NAFLD PRS, and discover a significant causal effect of NAFLD on CAD.", - "journal_title": "HGG advances", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/35047847/" - } - ], - "90015638-c92d-4506-95b5-b789f08d613a": [ - { - "pub_id": "28843612", - "title": "Genomic regulation of type 2 diabetes endophenotypes: Contribution from genetic studies in the Goto-Kakizaki rat.", - "authors": "Marie-Th\u00e9r\u00e8se Bihoreau,Marc-Emmanuel Dumas,Mark Lathrop,Dominique Gauguier", - "abstract": "The inbred Goto-Kakizaki (GK) rat strain is a unique model of spontaneous type 2 diabetes mellitus caused by naturally occurring genetic variants that have been selectively isolated from an outbred colony of Wistar rats. Genetic and genomic studies in experimental crosses and congenic strains of the GK have shed light on the complex etiopathogenesis of diabetes phenotypes in this model. Diabetes-related phenotypes in the GK are under polygenic control and distinct genetic loci regulate glucose tolerance, insulin secretion, \u03b2-cell mass and plasma lipids. Metabolome and transcriptome profiling data in GK crosses and congenics, combined with GK genome resequencing, have resulted in a comprehensive landscape of genomic regulations of metabolism that can disentangle causal relationships between GK variants and diabetes phenotypes. Application of systems biology and systems genetics in the GK has contributed to improve our understanding of the fundamental mechanisms regulating metabolism. The wealth of physiological, genetic and genomic information in this strain makes it one of the most powerful model systems to improve our understanding of genetic regulations of metabolism and for testing therapeutic solutions for diabetes.", - "journal_title": "Biochimie", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/28843612/" - } - ], - "634e46d2-d778-447e-a6d8-3850d7c08687": [ - { - "pub_id": "35550244", - "title": "Development of a Field Guide for Assessing Readiness to Implement Evidence-Based Cancer Screening Interventions in Primary Care Clinics.", - "authors": "Sarah D Hohl,Stephanie Melillo,Thuy T Vu,Cam Escoffery,Amy DeGroff,Dara Schlueter,Leslie W Ross,Annette E Maxwell,Krishna P Sharma,Jennifer Boehm,Djenaba Joseph,Peggy A Hannon", - "abstract": "Evidence-based interventions, including provider assessment and feedback, provider reminders, patient reminders, and reduction of structural barriers, improve colorectal cancer screening rates. Assessing primary care clinics' readiness to implement these interventions can help clinics use strengths, identify barriers, and plan for success. However, clinics may lack tools to assess readiness and use findings to plan for successful implementation. To address this need, we developed the Field Guide for Assessing Readiness to Implement Evidence-Based Cancer Screening Interventions (Field Guide) for the Centers for Disease Control and Prevention's (CDC's) Colorectal Cancer Control Program (CRCCP). We conducted a literature review of evidence and existing tools to measure implementation readiness, reviewed readiness tools from selected CRCCP award recipients (n = 35), and conducted semi-structured interviews with key informants (n = 8). We sought feedback from CDC staff and recipients to inform the final document. The Field Guide, which is publicly available online, outlines 4 assessment phases: 1) convene team members and determine assessment activities, 2) design and administer the readiness assessment, 3) evaluate assessment data, and 4) develop an implementation plan. Assessment activities and tools are included to facilitate completion of each phase. The Field Guide integrates implementation science and practical experience into a relevant tool to bolster clinic capacity for implementation, increase potential for intervention sustainability, and improve colorectal cancer screening rates, with a focus on patients served in safety net clinic settings. Although this tool was developed for use in primary care clinics for cancer screening, the Field Guide may have broader application for clinics and their partners for other chronic diseases.", - "journal_title": "Preventing chronic disease", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/35550244/" - } - ], - "030ceea6-139c-4917-b4a9-6e615a083a31": [ - { - "pub_id": "33453057", - "title": "Valuing genetic and genomic testing in France: current challenges and latest evidence.", - "authors": "Catherine Lejeune,Ines F Amado, ", - "abstract": "High-throughput next-generation sequencing technologies have seen an increase in use in most developed countries. The translation of genomic testing into clinical practice challenges the traditional model of medical care in France and raises numerous medical, legal, ethical, organizational, and financial issues. In order to allow the population to use this revolution to its advantage, France has conceived the French Plan for Genomic Medicine 2025. Its aim is to improve health and quality of life, to organize new pathways of care and counseling, and to make decisions about insurance coverage. It has also been designed to drive innovation and promote economic growth in France by incorporating genomic medicine into the French health care system. These issues can be addressed through evaluations developed to aid the decision-making process in the context of resource scarcity. Health economists can help to resolve these resource allocation challenges by measuring the impact of this technological revolution on patients, caregivers, providers, and the health care system. In this paper, we will review challenges associated with implementing genomic testing in France. One of the pilot studies of the French Plan for Genomic Medicine 2025 will be presented as an illustration of the role of health economists in overcoming some of the challenges of this technological revolution.", - "journal_title": "Journal of community genetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/33453057/" - } - ], - "e34eb78b-2998-4f94-8893-8fca1fedc4d9": [ - { - "pub_id": "35729161", - "title": "Islet autoantibody seroconversion in type-1 diabetes is associated with metagenome-assembled genomes in infant gut microbiomes.", - "authors": "Li Zhang,Karen R Jonscher,Zuyuan Zhang,Yi Xiong,Ryan S Mueller,Jacob E Friedman,Chongle Pan", - "abstract": "The immune system of some genetically susceptible children can be triggered by certain environmental factors to produce islet autoantibodies (IA) against pancreatic \u03b2 cells, which greatly increases their risk for Type-1 diabetes. An environmental factor under active investigation is the gut microbiome due to its important role in immune system education. Here, we study gut metagenomes that are de-novo-assembled in 887 at-risk children in the Environmental Determinants of Diabetes in the Young (TEDDY) project. Our results reveal a small set of core protein families, present in >50% of the subjects, which account for 64% of the sequencing reads. Time-series binning generates 21,536 high-quality metagenome-assembled genomes (MAGs) from 883 species, including 176 species that hitherto have no MAG representation in previous comprehensive human microbiome surveys. IA seroconversion is positively associated with 2373 MAGs and negatively with 1549 MAGs. Comparative genomics analysis identifies lipopolysaccharides biosynthesis in Bacteroides MAGs\u00a0and sulfate reduction in Anaerostipes MAGs as functional signatures of MAGs with positive IA-association. The functional signatures in the MAGs with negative IA-association include carbohydrate degradation in lactic acid bacteria MAGs and nitrate reduction in Escherichia MAGs. Overall, our results show a distinct set of gut microorganisms associated with IA seroconversion and uncovered the functional genomics signatures of these IA-associated microorganisms.", - "journal_title": "Nature communications", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/35729161/" - } - ], - "f97246cb-7a71-409b-bb1a-dd01a5ef5c5e": [ - { - "pub_id": "37705676", - "title": "Guideline for allergological diagnosis of drug hypersensitivity reactions: S2k Guideline of the German Society for Allergology and Clinical Immunology (DGAKI) in cooperation with the German Dermatological Society (DDG), the Association of German Allergologists (\u00c4DA), the German Society for Pediatric Allergology (GPA), the German Contact Dermatitis Research Group (DKG), the German Society for Pneumology (DGP), the German Society of Otorhinolaryngology, Head and Neck Surgery, the Austrian Society of Allergology and Immunology (\u00d6GAI), the Austrian Society of Dermatology and Venereology (\u00d6GDV), the German Academy of Allergology and Environmental Medicine (DAAU), and the German Documentation Center for Severe Skin Reactions (dZh).", - "authors": "Knut Brockow,Gerda Wurpts,Axel Trautmann,Wolfgang Pf\u00fctzner,Regina Treudler,Andreas J Bircher,Randolph Brehler,Timo Buhl,Heinrich Dickel,Thomas Fuchs,Thilo Jakob,Julia Kurz,Burkhard Kreft,Lars Lange,Hans F Merk,Maja Mockenhaupt,Norbert M\u00fclleneisen,Hagen Ott,Johannes Ring,Franziska Ru\u00ebff,Bernhardt Sachs,Helmut Sitter,Bettina Wedi,Stefan W\u00f6hrl,Margitta Worm,Torsten Zuberbier", - "abstract": "Not available.", - "journal_title": "Allergologie select", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/37705676/" - } - ], - "398fe5a6-f3f8-41e7-9d3e-9f5f2d055485": [ - { - "pub_id": "35047859", - "title": "Novel pathogenic variants and quantitative phenotypic analyses of Robinow syndrome: WNT signaling perturbation and phenotypic variability.", - "authors": "Chaofan Zhang,Angad Jolly,Brian J Shayota,Juliana F Mazzeu,Haowei Du,Moez Dawood,Patricia Celestino Soper,Ariadne Ramalho de Lima,B\u00e1rbara Merfort Ferreira,Zeynep Coban-Akdemir,Janson White,Deborah Shears,Fraser Robert Thomson,Sarah Louise Douglas,Andrew Wainwright,Kathryn Bailey,Paul Wordsworth,Mike Oldridge,Tracy Lester,Alistair D Calder,Katja Dumic,Siddharth Banka,Dian Donnai,Shalini N Jhangiani,Lorraine Potocki,Wendy K Chung,Sara Mora,Hope Northrup,Myla Ashfaq,Jill A Rosenfeld,Kati Mason,Lynda C Pollack,Allyn McConkie-Rosell,Wei Kelly,Marie McDonald,Natalie S Hauser,Peter Leahy,Cynthia M Powell,Raquel Boy,Rachel Sayuri Honjo,Fernando Kok,Lucia R Martelli,Vicente Odone Filho, Genomics England Research Consortium,Donna M Muzny,Richard A Gibbs,Jennifer E Posey,Pengfei Liu,James R Lupski,V Reid Sutton,Claudia M B Carvalho", - "abstract": "Robinow syndrome (RS) is a genetically heterogeneous disorder with six genes that converge on the WNT/planar cell polarity (PCP) signaling pathway implicated (<i>DVL1</i>, <i>DVL3</i>, <i>FZD2</i>, <i>NXN</i>, <i>ROR2</i>, and <i>WNT5A</i>). RS is characterized by skeletal dysplasia and distinctive facial and physical characteristics. To further explore the genetic heterogeneity, paralog contribution, and phenotypic variability of RS, we investigated a cohort of 22 individuals clinically diagnosed with RS from 18 unrelated families. Pathogenic or likely pathogenic variants in genes associated with RS or RS phenocopies were identified in all 22 individuals, including the first variant to be reported in <i>DVL2</i>. We retrospectively collected medical records of 16 individuals from this cohort and extracted clinical descriptions from 52 previously published cases. We performed Human Phenotype Ontology (HPO) based quantitative phenotypic analyses to dissect allele-specific phenotypic differences. Individuals with <i>FZD2</i> variants clustered into two groups with demonstrable phenotypic differences between those with missense and truncating alleles. Probands with biallelic <i>NXN</i> variants clustered together with the majority of probands carrying <i>DVL1</i>, <i>DVL2</i>, and <i>DVL3</i> variants, demonstrating no phenotypic distinction between the <i>NXN</i>-autosomal recessive and dominant forms of RS. While phenotypically similar diseases on the RS differential matched through HPO analysis, clustering using phenotype similarity score placed RS-associated phenotypes in a unique cluster containing <i>WNT5A</i>, <i>FZD2</i>, and <i>ROR2</i> apart from non-RS-associated paralogs. Through human phenotype analyses of this RS cohort and OMIM clinical synopses of Mendelian disease, this study begins to tease apart specific biologic roles for non-canonical WNT-pathway proteins.", - "journal_title": "HGG advances", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/35047859/" - } - ], - "82353dbc-bbd0-4bcf-a5d4-81cd909969de": [ - { - "pub_id": "18325640", - "title": "Detecting AIDS restriction genes: from candidate genes to genome-wide association discovery.", - "authors": "H B Hutcheson,J A Lautenberger,G W Nelson,J U Pontius,B D Kessing,C A Winkler,M W Smith,R Johnson,R Stephens,J Phair,J J Goedert,S Donfield,S J O'Brien", - "abstract": "The screening of common genetic polymorphisms among candidate genes for AIDS pathology in HIV exposed cohort populations has led to the description of 20 AIDS restriction genes (ARGs), variants that affect susceptibility to HIV infection or to AIDS progression. The combination of high-throughput genotyping platforms and the recent HapMap annotation of some 3 million human SNP variants has been developed for and applied to gene discovery in complex and multi-factorial diseases. Here, we explore novel computational approaches to ARG discovery which consider interacting analytical models, various genetic influences, and SNP-haplotype/LD structure in AIDS cohort populations to determine if these ARGs could have been discovered using an unbiased genome-wide association approach. The procedures were evaluated by tracking the performance of haplotypes and SNPs within ARG regions to detect genetic association in the same AIDS cohort populations in which the ARGs were originally discovered. The methodology captures the signals of multiple non-independent AIDS-genetic association tests of different disease stages and uses association signal strength (odds ratio or relative hazard), statistical significance (p-values), gene influence, internal replication, and haplotype structure together as a multi-facetted approach to identifying important genetic associations within a deluge of genotyping/test data. The complementary approaches perform rather well and predict the detection of a variety of undiscovered ARGs that affect different stages of HIV/AIDS pathogenesis using genome-wide association analyses.", - "journal_title": "Vaccine", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/18325640/" - } - ], - "d793d0ae-9b2d-4f54-8be2-3dfa76127217": [ - { - "pub_id": "34751383", - "title": "Genetic and genomic architecture in eight strains of the laboratory opossum Monodelphis domestica.", - "authors": "Xiao Xiong,Paul B Samollow,Wenqi Cao,Richard Metz,Chao Zhang,Ana C Leandro,John L VandeBerg,Xu Wang", - "abstract": "The gray short-tailed opossum (Monodelphis domestica) is an established laboratory-bred marsupial model for biomedical research. It is a critical species for comparative genomics research, providing the pivotal phylogenetic outgroup for studies of derived vs ancestral states of genomic/epigenomic characteristics for eutherian mammal lineages. To characterize the current genetic profile of this laboratory marsupial, we examined 79 individuals from eight established laboratory strains. Double digest restriction site-associated DNA sequencing and whole-genome resequencing experiments were performed to investigate the genetic architecture in these strains. A total of 66,640 high-quality single nucleotide polymorphisms (SNPs) were identified. We analyzed SNP density, average heterozygosity, nucleotide diversity, and population differentiation parameter Fst within and between the eight strains. Principal component and population structure analysis clearly resolve the strains at the level of their ancestral founder populations, and the genetic architecture of these strains correctly reflects their breeding history. We confirmed the successful establishment of the first inbred laboratory opossum strain LSD (inbreeding coefficient F\u2009>\u20090.99) and a nearly inbred strain FD2M1 (0.98\u2009<\u2009F\u2009<\u20090.99), each derived from a different ancestral background. These strains are suitable for various experimental protocols requiring controlled genetic backgrounds and for intercrosses and backcrosses that can generate offspring with informative SNPs for studying a variety of genetic and epigenetic processes. Together with recent advances in reproductive manipulation and CRISPR/Cas9 techniques for Monodelphis domestica, the existence of distinctive inbred strains will enable genome editing on different genetic backgrounds, greatly expanding the utility of this marsupial model for biomedical research.", - "journal_title": "G3 (Bethesda, Md.)", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/34751383/" - } - ], - "16e272af-f687-4261-99cf-8125a9e7cdc7": [ - { - "pub_id": "17703236", - "title": "Genome-wide association studies provide new insights into type 2 diabetes aetiology.", - "authors": "Timothy M Frayling", - "abstract": "Human geneticists are currently in the middle of a race. Thanks to a new technology in the form of 'genome-wide chips', investigators can potentially find many novel disease genes in one large experiment. Type 2 diabetes has been hot out of the blocks with six recent publications that together provide convincing evidence for six new gene regions involved in the condition. Together with candidate approaches, these studies have identified 11 confirmed genomic regions that alter the risk of type 2 diabetes in the European population. One of these regions, the fat mass and obesity associated gene (FTO), represents by far the best example of an association between common variation and fat mass in the general population.", - "journal_title": "Nature reviews. Genetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/17703236/" - } - ], - "4f709611-ea0b-4bcc-a634-df5d518ccb54": [ - { - "pub_id": "32025007", - "title": "Pan-cancer analysis of whole genomes.", - "authors": " ", - "abstract": "Cancer is driven by genetic change, and the advent of massively parallel sequencing has enabled systematic documentation of this variation at the whole-genome scale<sup>1-3</sup>. Here we report the integrative analysis of 2,658\u00a0whole-cancer genomes and their matching normal tissues across 38 tumour types from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA). We describe the generation of the PCAWG resource, facilitated by international data sharing using compute clouds. On average, cancer genomes contained 4-5\u00a0driver mutations when combining coding and non-coding genomic elements; however, in around 5% of cases no drivers were identified, suggesting that cancer driver discovery is not yet complete. Chromothripsis, in which many clustered structural variants arise in a single catastrophic event, is frequently an early event in tumour evolution; in acral melanoma, for example, these events precede most somatic point mutations and affect several cancer-associated genes simultaneously. Cancers with abnormal telomere maintenance often originate from tissues with low replicative activity and show several mechanisms of preventing telomere attrition to critical levels. Common and rare germline variants affect patterns of somatic mutation, including point mutations, structural variants and somatic retrotransposition. A collection of papers from the PCAWG Consortium describes non-coding mutations that drive cancer beyond those in the TERT promoter<sup>4</sup>; identifies new signatures of mutational processes that cause base substitutions, small insertions and deletions and structural variation<sup>5,6</sup>; analyses timings and patterns of tumour evolution<sup>7</sup>; describes the diverse transcriptional consequences of somatic mutation on splicing, expression levels, fusion genes and promoter activity<sup>8,9</sup>; and evaluates a range of more-specialized features of cancer genomes<sup>8,10-18</sup>.", - "journal_title": "Nature", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/32025007/" - } - ], - "4d8353a9-d4b0-4a49-ba3f-7fbab75b520b": [ - { - "pub_id": "29221444", - "title": "Genome-wide association study of coronary artery calcified atherosclerotic plaque in African Americans with type 2 diabetes.", - "authors": "Jasmin Divers,Nicholette D Palmer,Carl D Langefeld,W Mark Brown,Lingyi Lu,Pamela J Hicks,S Carrie Smith,Jianzhao Xu,James G Terry,Thomas C Register,Lynne E Wagenknecht,John S Parks,Lijun Ma,Gary C Chan,Sarah G Buxbaum,Adolfo Correa,Solomon Musani,James G Wilson,Herman A Taylor,Donald W Bowden,John Jeffrey Carr,Barry I Freedman", - "abstract": "Coronary artery calcified atherosclerotic plaque (CAC) predicts cardiovascular disease (CVD). Despite exposure to more severe conventional CVD risk factors, African Americans (AAs) are less likely to develop CAC, and when they do, have markedly lower levels than European Americans. Genetic factors likely contribute to the observed ethnic differences. To identify genes associated with CAC in AAs with type 2 diabetes (T2D), a genome-wide association study (GWAS) was performed using the Illumina 5\u00a0M chip in 691 African American-Diabetes Heart Study participants (AA-DHS), with replication in 205 Jackson Heart Study (JHS) participants with T2D. Genetic association tests were performed on the genotyped and 1000 Genomes-imputed markers separately for each study, and combined in a meta-analysis. Single nucleotide polymorphisms (SNPs), rs11353135 (2q22.1), rs16879003 (6p22.3), rs5014012, rs58071836 and rs10244825 (all on chromosome 7), rs10918777 (9q31.2), rs13331874 (16p13.3) and rs4459623 (18q12.1) were associated with presence and/or quantity of CAC in the AA-DHS and JHS, with meta-analysis p-values \u22648.0\u2009\u00d7\u200910<sup>-7</sup>. The strongest result in AA-DHS alone was rs6491315 in the 13q32.1 region (parameter estimate (SE)\u2009=\u2009-1.14 (0.20); p-value\u2009=\u20099.1\u2009\u00d7\u200910<sup>-9</sup>). This GWAS peak replicated a previously reported AA-DHS CAC admixture signal (rs7492028, LOD score 2.8). Genetic association between SNPs on chromosomes 2, 6, 7, 9, 16 and 18 and CAC were detected in AAs with T2D from AA-DHS and replicated in the JHS. These data support a role for genetic variation on these chromosomes as contributors to CAC in AAs with T2D, as well as to variation in CAC between populations of African and European ancestry.", - "journal_title": "BMC genetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/29221444/" - } - ], - "e0252c29-4a8b-4b51-bd9d-e7a5de5b558a": [ - { - "pub_id": "23209562", - "title": "Wiki-pi: a web-server of annotated human protein-protein interactions to aid in discovery of protein function.", - "authors": "Naoki Orii,Madhavi K Ganapathiraju", - "abstract": "Protein-protein interactions (PPIs) are the basis of biological functions. Knowledge of the interactions of a protein can help understand its molecular function and its association with different biological processes and pathways. Several publicly available databases provide comprehensive information about individual proteins, such as their sequence, structure, and function. There also exist databases that are built exclusively to provide PPIs by curating them from published literature. The information provided in these web resources is protein-centric, and not PPI-centric. The PPIs are typically provided as lists of interactions of a given gene with links to interacting partners; they do not present a comprehensive view of the nature of both the proteins involved in the interactions. A web database that allows search and retrieval based on biomedical characteristics of PPIs is lacking, and is needed. We present Wiki-Pi (read Wiki-\u03c0), a web-based interface to a database of human PPIs, which allows users to retrieve interactions by their biomedical attributes such as their association to diseases, pathways, drugs and biological functions. Each retrieved PPI is shown with annotations of both of the participant proteins side-by-side, creating a basis to hypothesize the biological function facilitated by the interaction. Conceptually, it is a search engine for PPIs analogous to PubMed for scientific literature. Its usefulness in generating novel scientific hypotheses is demonstrated through the study of IGSF21, a little-known gene that was recently identified to be associated with diabetic retinopathy. Using Wiki-Pi, we infer that its association to diabetic retinopathy may be mediated through its interactions with the genes HSPB1, KRAS, TMSB4X and DGKD, and that it may be involved in cellular response to external stimuli, cytoskeletal organization and regulation of molecular activity. The website also provides a wiki-like capability allowing users to describe or discuss an interaction. Wiki-Pi is available publicly and freely at http://severus.dbmi.pitt.edu/wiki-pi/.", - "journal_title": "PloS one", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/23209562/" - } - ], - "07b2ec5d-6b36-4ce5-8af1-21835e405ef3": [ - { - "pub_id": "28175964", - "title": "Painting a new picture of personalised medicine for diabetes.", - "authors": "Mark I McCarthy", - "abstract": "The current focus on delivery of personalised (or precision) medicine reflects the expectation that developments in genomics, imaging and other domains will extend our diagnostic and prognostic capabilities, and enable more effective targeting of current and future preventative and therapeutic options. The clinical benefits of this approach are already being realised in rare diseases and cancer but the impact on management of complex diseases, such as type 2 diabetes, remains limited. This may reflect reliance on inappropriate models of disease architecture, based around rare, high-impact genetic and environmental exposures that are poorly suited to our emerging understanding of type 2 diabetes. This review proposes an alternative 'palette' model, centred on a molecular taxonomy that focuses on positioning an individual with respect to the major pathophysiological processes that contribute to diabetes risk and progression. This model anticipates that many individuals with diabetes will have multiple parallel defects that affect several of these processes. One corollary of this model is that research efforts should, at least initially, be targeted towards identifying and characterising individuals whose adverse metabolic trajectory is dominated by perturbation in a restricted set of processes.", - "journal_title": "Diabetologia", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/28175964/" - } - ], - "28e57dda-9fc6-4cbd-a83e-4c87946bccc8": [ - { - "pub_id": "36686442", - "title": "Asprosin in health and disease, a new glucose sensor with central and peripheral metabolic effects.", - "authors": "Mariam Farrag,Djedjiga Ait Eldjoudi,Mar\u00eda Gonz\u00e1lez-Rodr\u00edguez,Alfonso Cordero-Barreal,Clara Ruiz-Fern\u00e1ndez,Maurizio Capuozzo,Miguel Angel Gonz\u00e1lez-Gay,Antonio Mera,Francisca Lago,Ahmed Soffar,Amina Essawy,Jesus Pino,Yousof Farrag,Oreste Gualillo", - "abstract": "Adipose tissue malfunction leads to altered adipokine secretion which might consequently contribute to an array of metabolic diseases spectrum including obesity, diabetes mellitus, and cardiovascular disorders. Asprosin is a novel diabetogenic adipokine classified as a caudamin hormone protein. This adipokine is released from white adipose tissue during fasting and elicits glucogenic and orexigenic effects. Although white adipose tissue is the dominant source for this multitask adipokine, other tissues also may produce asprosin such as salivary glands, pancreatic B-cells, and cartilage. Significantly, plasma asprosin levels link to glucose metabolism, lipid profile, insulin resistance (IR), and \u03b2-cell function. Indeed, asprosin exhibits a potent role in the metabolic process, induces hepatic glucose production, and influences appetite behavior. Clinical and preclinical research showed dysregulated levels of circulating asprosin in several metabolic diseases including obesity, type 2 diabetes mellitus (T2DM), polycystic ovarian syndrome (PCOS), non-alcoholic fatty liver (NAFLD), and several types of cancer. This review provides a comprehensive overview of the asprosin role in the etiology and pathophysiological manifestations of these conditions. Asprosin could be a promising candidate for both novel pharmacological treatment strategies and diagnostic tools, although developing a better understanding of its function and signaling pathways is still needed.", - "journal_title": "Frontiers in endocrinology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/36686442/" - } - ], - "56f184b6-f5d7-4246-bf52-2c6e6dc5af56": [ - { - "pub_id": "35610036", - "title": "PiER: web-based facilities tailored for genetic target prioritisation harnessing human disease genetics, functional genomics and protein interactions.", - "authors": "Hai Fang", - "abstract": "Integrative prioritisation promotes translational use of disease genetic findings\u00a0in target discovery. I report 'PiER' (http://www.genetictargets.com/PiER), web-based facilities that support ab initio and real-time genetic target prioritisation through integrative use of human disease genetics, functional genomics and protein interactions. By design, the PiER features two facilities: elementary and combinatory. The elementary facility is designed to perform specific tasks, including three online tools: eV2CG, utilising functional genomics to link disease-associated variants (particularly located at the non-coding genome) to core genes likely responsible for genetic associations in disease; eCG2PG, using knowledge of protein interactions to 'network' core genes and additional peripheral genes, producing a ranked list of core and peripheral genes; and eCrosstalk, exploiting the information of pathway-derived interactions to identify highly-ranked genes mediating crosstalk between molecular pathways. Each of elementary tasks giving results is sequentially piped to the next one. By chaining together elementary tasks, the combinatory facility automates genetics-led and network-based integrative prioritisation for genetic targets at the gene level (cTGene) and at the crosstalk level (cTCrosstalk). Together with a tutorial-like booklet describing instructions on how to use, the PiER facilities meet\u00a0multi-tasking needs to\u00a0accelerate computational translational medicine that leverages human disease genetics and genomics for early-stage\u00a0target discovery and drug repurposing.", - "journal_title": "Nucleic acids research", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/35610036/" - } - ], - "2e306ac0-ccbe-4503-9b9a-4656d8588ddf": [ - { - "pub_id": "36753304", - "title": "Role of the Gut-Brain Axis in the Shared Genetic Etiology Between Gastrointestinal Tract Diseases and Psychiatric Disorders: A Genome-Wide Pleiotropic Analysis.", - "authors": "Weiming Gong,Ping Guo,Yuanming Li,Lu Liu,Ran Yan,Shuai Liu,Shukang Wang,Fuzhong Xue,Xiang Zhou,Zhongshang Yuan", - "abstract": "Comorbidities and genetic correlations between gastrointestinal tract diseases and psychiatric disorders have been widely reported, with the gut-brain axis (GBA) hypothesized as a potential biological basis. However, the degree to which the shared genetic determinants are involved in these associations underlying the GBA is unclear. To investigate the shared genetic etiology between gastrointestinal tract diseases and psychiatric disorders and to identify shared genomic loci, genes, and pathways. This genome-wide pleiotropic association study using genome-wide association summary statistics from publicly available data sources was performed with various statistical genetic approaches to sequentially investigate the pleiotropic associations from genome-wide single-nucleotide variation (SNV; formerly single-nucleotide polymorphism [SNP]), and gene levels and biological pathways to disentangle the underlying shared genetic etiology between 4 gastrointestinal tract diseases (inflammatory bowel disease, irritable bowel syndrome, peptic ulcer disease, and gastroesophageal reflux disease) and 6 psychiatric disorders (schizophrenia, bipolar disorder, major depressive disorder, attention-deficit/hyperactivity disorder, posttraumatic stress disorder, and anorexia nervosa). Data were collected from March 10, 2021, to August 25, 2021, and analysis was performed from January 8 through May 30, 2022. The primary outcomes consisted of a list of genetic loci, genes, and pathways shared between gastrointestinal tract diseases and psychiatric disorders. Extensive genetic correlations and genetic overlaps were found among 22 of 24 trait pairs. Pleiotropic analysis under a composite null hypothesis identified 2910 significant potential pleiotropic SNVs in 19 trait pairs, with 83 pleiotropic loci and 24 colocalized loci detected. Gene-based analysis found 158 unique candidate pleiotropic genes, which were highly enriched in certain GBA-related phenotypes and tissues, whereas pathway enrichment analysis further highlighted biological pathways primarily involving cell adhesion, synaptic structure and function, and immune cell differentiation. Several identified pleiotropic loci also shared causal variants with gut microbiomes. Mendelian randomization analysis further illustrated vertical pleiotropy across 8 pairwise traits. Notably, many pleiotropic loci were identified for multiple pairwise traits, such as 1q32.1 (INAVA), 19q13.33 (FUT2), 11q23.2 (NCAM1), and 1p32.3 (LRP8). These findings suggest that the pleiotropic genetic determinants between gastrointestinal tract diseases and psychiatric disorders are extensively distributed across the genome. These findings not only support the shared genetic basis underlying the GBA but also have important implications for intervention and treatment targets of these diseases simultaneously.", - "journal_title": "JAMA psychiatry", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/36753304/" - } - ], - "8c526a48-6b4a-42a7-b27e-550a4fbc6e26": [ - { - "pub_id": "18437207", - "title": "Defining the role of the MHC in autoimmunity: a review and pooled analysis.", - "authors": "Michelle M A Fernando,Christine R Stevens,Emily C Walsh,Philip L De Jager,Philippe Goyette,Robert M Plenge,Timothy J Vyse,John D Rioux", - "abstract": "The major histocompatibility complex (MHC) is one of the most extensively studied regions in the human genome because of the association of variants at this locus with autoimmune, infectious, and inflammatory diseases. However, identification of causal variants within the MHC for the majority of these diseases has remained difficult due to the great variability and extensive linkage disequilibrium (LD) that exists among alleles throughout this locus, coupled with inadequate study design whereby only a limited subset of about 20 from a total of approximately 250 genes have been studied in small cohorts of predominantly European origin. We have performed a review and pooled analysis of the past 30 years of research on the role of the MHC in six genetically complex disease traits - multiple sclerosis (MS), type 1 diabetes (T1D), systemic lupus erythematosus (SLE), ulcerative colitis (UC), Crohn's disease (CD), and rheumatoid arthritis (RA) - in order to consolidate and evaluate the current literature regarding MHC genetics in these common autoimmune and inflammatory diseases. We corroborate established MHC disease associations and identify predisposing variants that previously have not been appreciated. Furthermore, we find a number of interesting commonalities and differences across diseases that implicate both general and disease-specific pathogenetic mechanisms in autoimmunity.", - "journal_title": "PLoS genetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/18437207/" - } - ], - "96f13e8e-633e-4728-853f-81ffbad6c58a": [ - { - "pub_id": "27895219", - "title": "Primer in Genetics and Genomics, Article 1: DNA, Genes, and Chromosomes.", - "authors": "Janice S Dorman,Mandy J Schmella,Susan W Wesmiller", - "abstract": "Precision medicine refers to the practice of determining a patient's unique genetic, biomarker, and other characteristics for the purpose of improving his or her clinical outcomes. Not all patients with the same clinical diagnosis respond equally to identical treatment regimens. By examining patients at the molecular level, health-care providers will be better able to apply the most effective therapies that each individual requires. To understand precision medicine, nurses must have a solid understanding of genomics and proteomics. The purpose of this article is to (1) provide a historical review of what and how we have learned about the genome, particularly in the past century, (2) explain the processes whereby genetic information in cellular DNA is transcribed to messenger RNA and translated to protein, and (3) introduce genetic and epigenetic mechanisms that regulate gene expression.", - "journal_title": "Biological research for nursing", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/27895219/" - } - ], - "635d1b7f-81d6-46ec-9ed1-28aea38e28e9": [ - { - "pub_id": "29263820", - "title": "Ranking factors involved in diabetes remission after bariatric surgery using machine-learning integrating clinical and genomic biomarkers.", - "authors": "Helle Krogh Pedersen,Valborg Gudmundsdottir,Mette Krogh Pedersen,Caroline Brorsson,S\u00f8ren Brunak,Ramneek Gupta", - "abstract": "As weight-loss surgery is an effective treatment for the glycaemic control of type 2 diabetes in obese patients, yet not all patients benefit, it is valuable to find predictive factors for this diabetic remission. This will help elucidating possible mechanistic insights and form the basis for prioritising obese patients with dysregulated diabetes for surgery where diabetes remission is of interest. In this study, we combine both clinical and genomic factors using heuristic methods, informed by prior biological knowledge in order to rank factors that would have a role in predicting diabetes remission, and indeed in identifying patients who may have low likelihood in responding to bariatric surgery for improved glycaemic control. Genetic variants from the Illumina CardioMetaboChip were prioritised through single-association tests and then seeded a larger selection from protein-protein interaction networks. Artificial neural networks allowing nonlinear correlations were trained to discriminate patients with and without surgery-induced diabetes remission, and the importance of each clinical and genetic parameter was evaluated. The approach highlighted insulin treatment, baseline HbA1c levels, use of insulin-sensitising agents and baseline serum insulin levels, as the most informative variables with a decent internal validation performance (74% accuracy, area under the curve (AUC) 0.81). Adding information for the eight top-ranked single nucleotide polymorphisms (SNPs) significantly boosted classification performance to 84% accuracy (AUC 0.92). The eight SNPs mapped to eight genes - <i>ABCA1, ARHGEF12, CTNNBL1, GLI3, PROK2, RYBP, SMUG1</i> and <i>STXBP5</i> - three of which are known to have a role in insulin secretion, insulin sensitivity or obesity, but have not been indicated for diabetes remission after bariatric surgery before.", - "journal_title": "NPJ genomic medicine", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/29263820/" - } - ], - "d18e1df5-afd9-4ded-8ead-ba5a704d6a38": [ - { - "pub_id": "36208799", - "title": "Genome-wide association and Mendelian randomization study of fibroblast growth factor 21 reveals causal associations with hyperlipidemia and possibly NASH.", - "authors": "Susanna C Larsson,Karl Micha\u00eblsson,Marina Mola-Caminal,Jonas H\u00f6ijer,Christos S Mantzoros", - "abstract": "Fibroblast growth factor 21 (FGF21) is a hepatokine that produces metabolic benefits, such as improvements of lipid profile. We performed a genome-wide association study (GWAS) to identify genetic variants associated with circulating FGF21 and investigated the causal effects of FGF21 on pertinent outcomes using Mendelian randomization (MR). We conducted a GWAS testing \u223c7.8 million DNA sequence variants with circulating FGF21 in a discovery cohort of 6259 Swedish adults with replication in 4483 Swedish women. We then performed two-sample MR analyses of genetically predicted circulating FGF21 in relation to alcohol and nutrient intake, cardiovascular and metabolic biomarkers and diseases, and liver function biomarkers using publicly available GWAS summary statistics data. Our GWAS identified multiple single-nucleotide polymorphisms with genome-wide significant associations (P\u00a0<\u00a05\u00a0\u00d7\u00a010<sup>-8</sup>) with circulating FGF21 on chromosomes 2 and 19 in or near the GCKR and FGF21 genes, respectively. The strongest signal at the FGF21 locus (rs2548957, \u03b2\u00a0=\u00a00.181, P\u00a0<\u00a02.18\u00a0\u00d7\u00a010<sup>-42</sup>) displayed in two-sample MR analyses robust associations with lower alcohol intake, lower circulating low-density lipoprotein cholesterol, apolipoprotein B, C-reactive protein, gamma-glutamyl transferase, and galectin-3 concentrations, and higher circulating insulin-like growth factor-I and alkaline phosphatase concentrations after correcting for multiple testing (P\u00a0<\u00a00.0018) whereas associations with fat mass, type 2 diabetes, and cardiovascular disease were largely null. We identified robust associations of certain genetic variants in or near the GCKR and FGF21 genes with circulating FGF21 concentrations. Furthermore, our results support a strong causal effect of FGF21 on improved lipid profile, reduced alcohol consumption and C-reactive protein concentrations, and liver function biomarkers including fibrosis. We found largely null or weak positive associations with fat mass, diabetes, and cardiovascular disease as well as higher insulin-like growth factor-I concentrations, which could indicate a compensatory increase to regulate the above FGF21 resistant states in humans.", - "journal_title": "Metabolism: clinical and experimental", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/36208799/" - } - ], - "4de8b42d-a983-4b52-a582-edee07dbaa61": [ - { - "pub_id": "35199043", - "title": "Stability of polygenic scores across discovery genome-wide association studies.", - "authors": "Laura M Schultz,Alison K Merikangas,Kosha Ruparel,S\u00e9bastien Jacquemont,David C Glahn,Raquel E Gur,Ran Barzilay,Laura Almasy", - "abstract": "Polygenic scores (PGS) are commonly evaluated in terms of their predictive accuracy at the population level by the proportion of phenotypic variance they explain. To be useful for precision medicine applications, they also need to be evaluated at the individual level when phenotypes are not necessarily already known. We investigated the stability of PGS in European American (EUR) and African American (AFR)-ancestry individuals from the Philadelphia Neurodevelopmental Cohort and the Adolescent Brain Cognitive Development study using different discovery genome-wide association study (GWAS) results for post-traumatic stress disorder (PTSD), type 2 diabetes (T2D), and height. We found that pairs of EUR-ancestry GWAS for the same trait had genetic correlations >0.92. However, PGS calculated from pairs of same-ancestry and different-ancestry GWAS had correlations that ranged from <0.01 to 0.74. PGS stability was greater for height than for PTSD or T2D. A series of height GWAS in the UK Biobank suggested that correlation between PGS is strongly dependent on the extent of sample overlap between the discovery GWAS. Focusing on the upper end of the PGS distribution, different discovery GWAS do not consistently identify the same individuals in the upper quantiles, with the best case being 60% of individuals above the 80th percentile of PGS overlapping from one height GWAS to another. The degree of overlap decreases sharply as higher quantiles, less heritable traits, and different-ancestry GWAS are considered. PGS computed from different discovery GWAS have only modest correlation at the individual level, underscoring the need to proceed cautiously with integrating PGS into precision medicine applications.", - "journal_title": "HGG advances", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/35199043/" - } - ], - "0af8f2bf-8caf-4459-823b-06e22e637cc8": [ - { - "pub_id": "22328972", - "title": "A Database of Gene-Environment Interactions Pertaining to Blood Lipid Traits, Cardiovascular Disease and Type 2 Diabetes.", - "authors": "Yu-Chi Lee,Chao-Qiang Lai,Jose M Ordovas,Laurence D Parnell", - "abstract": "As the role of the environment - diet, exercise, alcohol and tobacco use and sleep among others - is accorded a more prominent role in modifying the relationship between genetic variants and clinical measures of disease, consideration of gene-environment (GxE) interactions is a must. To facilitate incorporation of GxE interactions into single-gene and genome-wide association studies, we have compiled from the literature a database of GxE interactions relevant to nutrition, blood lipids, cardiovascular disease and type 2 diabetes. Over 550 such interactions have been incorporated into a single database, along with over 1430 instances where a lack of statistical significance was found. This database will serve as an important resource to researchers in genetics and nutrition in order to gain an understanding of which points in the human genome are sensitive to variations in diet, physical activity and alcohol use, among other lifestyle choices. Furthermore, this GxE database has been designed with future integration into a larger database of nutritional phenotypes in mind.", - "journal_title": "Journal of data mining in genomics & proteomics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/22328972/" - } - ], - "eabd3649-6fa6-4c1c-966a-0d9d5309c158": [ - { - "pub_id": "35094288", - "title": "The relationship between polymorphism of insulin-like growth factor I gene and susceptibility to type 2 diabetes in Uygur population, Xinjiang, China.", - "authors": "Tingting Wang,Gulixiati Maimaitituersun,Haonan Shi,Cheng Chen,Qi Ma,Yinxia Su,Hua Yao,Jia Zhu", - "abstract": "Type 2 diabetes (T2DM) susceptibility varies among different populations and is affected by gene single nucleotide polymorphism (SNP). Insulin-like growth factor (IGF)-1 gene, which has many SNP loci, is involved in T2DM pathogenesis. However, the relationship of IGF-1 gene polymorphism with T2DM in Uyghur population is less studied. To investigate the relationship between T2DM susceptibility and polymorphism of IGF-1 gene in Uyghur population of Xinjiang, China. This study enrolled 220 cases (122 males (55.46%) and 98 females (44.54%); mean age of 53.40\u2009\u00b1\u200910.94\u00a0years) of T2DM patients (T2DM group) and 229 (124 males (54.15%) and 105 females (45.85%); mean age of 51.64\u2009\u00b1\u200910.48\u00a0years) healthy controls (control group). Biochemical indexes were determined. IGF-1 gene polymorphism was analyzed by SNP genotyping. The levels of TG, HDL, LDL, BUN, and Cr were statistically significant between the T2DM group and the control group. In terms of IGF-1 polymorphism, T2DM group had higher frequency of AA genotype (OR\u2009=\u20092.40, 95% CI\u2009=\u20091.19-4.84) and allele A (OR\u2009=\u20091.55, 95% CI\u2009=\u20091.17-2.06) of rs35767 loci, suggesting that rs35767 is related to the occurrence of T2DM. A total of 5 gene interaction models was obtained through analyzing the interaction of 5 SNP loci with the GMDR method. Among them, the two-factor model that included rs35767 locus and rs5742694 locus had statistical difference with a large cross-validation consistency (10/10). The combination of GG/CC, GA/AA, AA/AA, and AA/AC genotype was in high-risk group, whereas the combination of GG/AA, GG/AC, GA/AC and GA/CC genotype was in the low-risk group. The risk of T2DM in the high-risk group was 2.165 times than that of the low-risk group (OR\u2009=\u20092.165, 95% CI\u2009=\u20091.478-3.171). TG, HDL, LDL, BUN, and Cr are influencing factors of T2DM in Uyghur population. The rs35767 locus of IGF-1 gene may be associated with T2DM in Uyghur population. The high-risk group composing of rs35767 locus and rs5742694 locus has a higher risk of T2DM.", - "journal_title": "Genes & genomics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/35094288/" - } - ], - "2a2a279f-ecbc-46e3-9d4e-76d4a0a4c678": [ - { - "pub_id": "35763030", - "title": "Genome-wide meta-analysis and omics integration identifies novel genes associated with diabetic kidney disease.", - "authors": "Niina Sandholm,Joanne B Cole,Viji Nair,Xin Sheng,Hongbo Liu,Emma Ahlqvist,Natalie van Zuydam,Emma H Dahlstr\u00f6m,Damian Fermin,Laura J Smyth,Rany M Salem,Carol Forsblom,Erkka Valo,Valma Harjutsalo,Eoin P Brennan,Gareth J McKay,Darrell Andrews,Ross Doyle,Helen C Looker,Robert G Nelson,Colin Palmer,Amy Jayne McKnight,Catherine Godson,Alexander P Maxwell,Leif Groop,Mark I McCarthy,Matthias Kretzler,Katalin Susztak,Joel N Hirschhorn,Jose C Florez,Per-Henrik Groop, ", - "abstract": "Diabetic kidney disease (DKD) is the leading cause of kidney failure and has a substantial genetic component. Our aim was to identify novel genetic factors and genes contributing to DKD by performing meta-analysis of previous genome-wide association studies (GWAS) on DKD and by integrating the results with renal transcriptomics datasets. We performed GWAS meta-analyses using ten phenotypic definitions of DKD, including nearly 27,000 individuals with diabetes. Meta-analysis results were integrated with estimated quantitative trait locus data from human glomerular (N=119) and tubular (N=121) samples to perform transcriptome-wide association study. We also performed gene aggregate tests to jointly test all available common genetic markers within a gene, and combined the results with various kidney omics datasets. The meta-analysis identified a novel intronic variant (rs72831309) in the TENM2 gene associated with a lower risk of the combined chronic kidney disease (eGFR<60 ml/min per 1.73 m<sup>2</sup>) and DKD (microalbuminuria or worse) phenotype (p=9.8\u00d710<sup>-9</sup>; although not withstanding correction for multiple testing, p>9.3\u00d710<sup>-9</sup>). Gene-level analysis identified ten genes associated with DKD (COL20A1, DCLK1, EIF4E, PTPRN-RESP18, GPR158, INIP-SNX30, LSM14A and MFF; p<2.7\u00d710<sup>-6</sup>). Integration of GWAS with human glomerular and tubular expression data demonstrated higher tubular AKIRIN2 gene expression in individuals with vs without DKD (p=1.1\u00d710<sup>-6</sup>). The lead SNPs within six loci significantly altered DNA methylation of a nearby CpG site in kidneys (p<1.5\u00d710<sup>-11</sup>). Expression of lead genes in kidney tubules or glomeruli correlated with relevant pathological phenotypes (e.g. TENM2 expression correlated positively with eGFR [p=1.6\u00d710<sup>-8</sup>] and negatively with tubulointerstitial fibrosis [p=2.0\u00d710<sup>-9</sup>], tubular DCLK1 expression correlated positively with fibrosis [p=7.4\u00d710<sup>-16</sup>], and SNX30 expression correlated positively with eGFR [p=5.8\u00d710<sup>-14</sup>] and negatively with fibrosis [p<2.0\u00d710<sup>-16</sup>]). Altogether, the results point to novel genes contributing to the pathogenesis of DKD. The GWAS meta-analysis results can be accessed via the type 1 and type 2 diabetes (T1D and T2D, respectively) and Common Metabolic Diseases (CMD) Knowledge Portals, and downloaded on their respective download pages ( https://t1d.hugeamp.org/downloads.html ; https://t2d.hugeamp.org/downloads.html ; https://hugeamp.org/downloads.html ).", - "journal_title": "Diabetologia", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/35763030/" - } - ], - "d98495dc-25c4-4e1a-b7e4-017c96951ef0": [ - { - "pub_id": "35408874", - "title": "Genomics and Epigenomics of Gestational Diabetes Mellitus: Understanding the Molecular Pathways of the Disease Pathogenesis.", - "authors": "Nadia Abu Samra,Herbert F Jelinek,Habiba Alsafar,Farah Asghar,Muhieddine Seoud,Shahad M Hussein,Hisham M Mubarak,Siddiq Anwar,Mashal Memon,Nariman Afify,Ridda Manzoor,Zahrah Al-Homedi,Wael Osman", - "abstract": "One of the most common complications during pregnancy is gestational diabetes mellitus (GDM), hyperglycemia that occurs for the first time during pregnancy. The condition is multifactorial, caused by an interaction between genetic, epigenetic, and environmental factors. However, the underlying mechanisms responsible for its pathogenesis remain elusive. Moreover, in contrast to several common metabolic disorders, molecular research in GDM is lagging. It is important to recognize that GDM is still commonly diagnosed during the second trimester of pregnancy using the oral glucose tolerance test (OGGT), at a time when both a fetal and maternal pathophysiology is already present, demonstrating the increased blood glucose levels associated with exacerbated insulin resistance. Therefore, early detection of metabolic changes and associated epigenetic and genetic factors that can lead to an improved prediction of adverse pregnancy outcomes and future cardio-metabolic pathologies in GDM women and their children is imperative. Several genomic and epigenetic approaches have been used to identify the genes, genetic variants, metabolic pathways, and epigenetic modifications involved in GDM to determine its etiology. In this article, we explore these factors as well as how their functional effects may contribute to immediate and future pathologies in women with GDM and their offspring from birth to adulthood. We also discuss how these approaches contribute to the changes in different molecular pathways that contribute to the GDM pathogenesis, with a special focus on the development of insulin resistance.", - "journal_title": "International journal of molecular sciences", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/35408874/" - } - ], - "be6abf85-9214-4c7e-ac2d-450dfb53a268": [ - { - "pub_id": "34927100", - "title": "Transethnic analysis of psoriasis susceptibility in South Asians and Europeans enhances fine-mapping in the MHC and genomewide.", - "authors": "Philip E Stuart,Lam C Tsoi,Rajan P Nair,Manju Ghosh,Madhulika Kabra,Pakeeza A Shaiq,Ghazala K Raja,Raheel Qamar,B K Thelma,Matthew T Patrick,Anita Parihar,Sonam Singh,Sujay Khandpur,Uma Kumar,Michael Wittig,Frauke Degenhardt,Trilokraj Tejasvi,John J Voorhees,Stephan Weidinger,Andre Franke,Goncalo R Abecasis,Vinod K Sharma,James T Elder", - "abstract": "Because transethnic analysis may facilitate prioritization of causal genetic variants, we performed a genomewide association study (GWAS) of psoriasis in South Asians (SAS), consisting of 2,590 cases and 1,720 controls. Comparison with our existing European-origin (EUR) GWAS showed that effect sizes of known psoriasis signals were highly correlated in SAS and EUR (Spearman \u03c1 = 0.78; <i>p</i> < 2 \u00d7 10<sup>-14</sup>). Transethnic meta-analysis identified two non-MHC psoriasis loci (1p36.22 and 1q24.2) not previously identified in EUR, which may have regulatory roles. For these two loci, the transethnic GWAS provided higher genetic resolution and reduced the number of potential causal variants compared to using the EUR sample alone. We then explored multiple strategies to develop reference panels for accurately imputing MHC genotypes in both SAS and EUR populations and conducted a fine-mapping of MHC psoriasis associations in SAS and the largest such effort for EUR. <i>HLA-C*06</i> was the top-ranking MHC locus in both populations but was even more prominent in SAS based on odds ratio, disease liability, model fit and predictive power. Transethnic modeling also substantially boosted the probability that the <i>HLA-C*06</i> protein variant is causal. Secondary MHC signals included coding variants of <i>HLA-C</i> and <i>HLA-B</i>, but also potential regulatory variants of these two genes as well as <i>HLA-A</i> and several HLA class II genes, with effects on both chromatin accessibility and gene expression. This study highlights the shared genetic basis of psoriasis in SAS and EUR populations and the value of transethnic meta-analysis for discovery and fine-mapping of susceptibility loci.", - "journal_title": "HGG advances", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/34927100/" - } - ], - "1e175ac4-bbe7-4673-9185-33a73ba35d68": [ - { - "pub_id": "27908689", - "title": "PCSK9 genetic variants and risk of type 2 diabetes: a mendelian randomisation study.", - "authors": "Amand F Schmidt,Daniel I Swerdlow,Michael V Holmes,Riyaz S Patel,Zammy Fairhurst-Hunter,Donald M Lyall,Fernando Pires Hartwig,Bernardo Lessa Horta,Elina Hypp\u00f6nen,Christine Power,Max Moldovan,Erik van Iperen,G Kees Hovingh,Ilja Demuth,Kristina Norman,Elisabeth Steinhagen-Thiessen,Juri Demuth,Lars Bertram,Tian Liu,Stefan Coassin,Johann Willeit,Stefan Kiechl,Karin Willeit,Dan Mason,John Wright,Richard Morris,Goya Wanamethee,Peter Whincup,Yoav Ben-Shlomo,Stela McLachlan,Jackie F Price,Mika Kivimaki,Catherine Welch,Adelaida Sanchez-Galvez,Pedro Marques-Vidal,Andrew Nicolaides,Andrie G Panayiotou,N Charlotte Onland-Moret,Yvonne T van der Schouw,Giuseppe Matullo,Giovanni Fiorito,Simonetta Guarrera,Carlotta Sacerdote,Nicholas J Wareham,Claudia Langenberg,Robert Scott,Jian'an Luan,Martin Bobak,Sofia Malyutina,Andrzej Paj\u0105k,Ruzena Kubinova,Abdonas Tamosiunas,Hynek Pikhart,Lise Lotte Nystrup Husemoen,Niels Grarup,Oluf Pedersen,Torben Hansen,Allan Linneberg,Kenneth Starup Simonsen,Jackie Cooper,Steve E Humphries,Murray Brilliant,Terrie Kitchner,Hakon Hakonarson,David S Carrell,Catherine A McCarty,H Lester Kirchner,Eric B Larson,David R Crosslin,Mariza de Andrade,Dan M Roden,Joshua C Denny,Cara Carty,Stephen Hancock,John Attia,Elizabeth Holliday,Martin O'Donnell,Salim Yusuf,Michael Chong,Guillaume Pare,Pim van der Harst,M Abdullah Said,Ruben N Eppinga,Niek Verweij,Harold Snieder, ,Tim Christen,Dennis O Mook-Kanamori,Stefan Gustafsson,Lars Lind,Erik Ingelsson,Raha Pazoki,Oscar Franco,Albert Hofman,Andre Uitterlinden,Abbas Dehghan,Alexander Teumer,Sebastian Baumeister,Marcus D\u00f6rr,Markus M Lerch,Uwe V\u00f6lker,Henry V\u00f6lzke,Joey Ward,Jill P Pell,Daniel J Smith,Tom Meade,Anke H Maitland-van der Zee,Ekaterina V Baranova,Robin Young,Ian Ford,Archie Campbell,Sandosh Padmanabhan,Michiel L Bots,Diederick E Grobbee,Philippe Froguel,Doroth\u00e9e Thuillier,Beverley Balkau,Am\u00e9lie Bonnefond,Bertrand Cariou,Melissa Smart,Yanchun Bao,Meena Kumari,Anubha Mahajan,Paul M Ridker,Daniel I Chasman,Alex P Reiner,Leslie A Lange,Marylyn D Ritchie,Folkert W Asselbergs,Juan-Pablo Casas,Brendan J Keating,David Preiss,Aroon D Hingorani, ,Naveed Sattar", - "abstract": "Statin treatment and variants in the gene encoding HMG-CoA reductase are associated with reductions in both the concentration of LDL cholesterol and the risk of coronary heart disease, but also with modest hyperglycaemia, increased bodyweight, and modestly increased risk of type 2 diabetes, which in no way offsets their substantial benefits. We sought to investigate the associations of LDL cholesterol-lowering PCSK9 variants with type 2 diabetes and related biomarkers to gauge the likely effects of PCSK9 inhibitors on diabetes risk. In this mendelian randomisation study, we used data from cohort studies, randomised controlled trials, case control studies, and genetic consortia to estimate associations of PCSK9 genetic variants with LDL cholesterol, fasting blood glucose, HbA<sub>1c</sub>, fasting insulin, bodyweight, waist-to-hip ratio, BMI, and risk of type 2 diabetes, using a standardised analysis plan, meta-analyses, and weighted gene-centric scores. Data were available for more than 550\u2008000 individuals and 51\u2008623 cases of type 2 diabetes. Combined analyses of four independent PCSK9 variants (rs11583680, rs11591147, rs2479409, and rs11206510) scaled to 1 mmol/L lower LDL cholesterol showed associations with increased fasting glucose (0\u00b709 mmol/L, 95% CI 0\u00b702 to 0\u00b715), bodyweight (1\u00b703 kg, 0\u00b724 to 1\u00b782), waist-to-hip ratio (0\u00b7006, 0\u00b7003 to 0\u00b7010), and an odds ratio for type diabetes of 1\u00b729 (1\u00b711 to 1\u00b750). Based on the collected data, we did not identify associations with HbA<sub>1c</sub> (0\u00b703%, -0\u00b701 to 0\u00b708), fasting insulin (0\u00b700%, -0\u00b706 to 0\u00b707), and BMI (0\u00b711 kg/m<sup>2</sup>, -0\u00b709 to 0\u00b730). PCSK9 variants associated with lower LDL cholesterol were also associated with circulating higher fasting glucose concentration, bodyweight, and waist-to-hip ratio, and an increased risk of type 2 diabetes. In trials of PCSK9 inhibitor drugs, investigators should carefully assess these safety outcomes and quantify the risks and benefits of PCSK9 inhibitor treatment, as was previously done for statins. British Heart Foundation, and University College London Hospitals NHS Foundation Trust (UCLH) National Institute for Health Research (NIHR) Biomedical Research Centre.", - "journal_title": "The lancet. Diabetes & endocrinology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/27908689/" - } - ], - "ab545ee2-3aff-45a2-a4e8-088cd79deeac": [ - { - "pub_id": "36866468", - "title": "Childhood adiposity and novel subtypes of diabetes in adults: a Mendelian randomisation and genome-wide genetic correlation study.", - "authors": "Yuxia Wei,Yiqiang Zhan,Sofia Carlsson", - "abstract": "Five novel subtypes of adult-onset diabetes were identified in 2018. We aimed to investigate whether childhood adiposity increases the risks of these subtypes using a Mendelian randomisation design, and to explore genetic overlaps between body size (self-reported perceived body size [ie, thinner, about average, or plumper] in childhood, and BMI measured in adulthood) and these subtypes. The Mendelian randomisation and genetic correlation analyses were based on summary statistics from European genome-wide association studies of childhood body size (n=453\u2008169), adult BMI (n=359\u2008983), latent autoimmune diabetes in adults (n=8581), severe insulin-deficient diabetes (n=3937), severe insulin-resistant diabetes (n=3874), mild obesity-related diabetes (n=4118), and mild age-related diabetes (n=5605). We identified 267 independent genetic variants as instrumental variables for childhood body size in the Mendelian randomisation analysis of latent autoimmune diabetes in adults and 258 independent genetic variants as instrumental variables for other diabetes subtypes. The inverse variance-weighted method was used as the primary estimator in the Mendelian randomisation analysis, supplemented by other Mendelian randomisation estimators. We calculated overall genetic correlations (rg) between childhood or adult adiposity and different subtypes using linkage disequilibrium score regression. A large childhood body size was associated with increased risk of latent autoimmune diabetes in adults (odds ratio [OR] 1\u00b762, 95% CI 1\u00b795-2\u00b752), severe insulin-deficient diabetes (OR 2\u00b745, 1\u00b735-4\u00b746), severe insulin-resistant diabetes (OR 3\u00b708, 1\u00b773-5\u00b750), and mild obesity-related diabetes (OR 7\u00b770, 4\u00b732-13\u00b77), but not mild age-related diabetes in the main Mendelian randomisation analysis. Other Mendelian randomisation estimators gave similar results and did not support the existence of horizontal pleiotropy. There was genetic overlap between childhood body size and mild obesity-related diabetes (rg 0\u00b7282; p=0\u00b70003), and between adult BMI and all diabetes subtypes. This study provides genetic evidence that higher childhood adiposity is a risk factor for all subtypes of adult-onset diabetes, except mild age-related diabetes. It is therefore important to prevent and intervene in childhood overweight or obesity. There is shared genetic contribution to childhood obesity and mild obesity-related diabetes. The study was supported by the China Scholarship Council, the Swedish Research Council (grant number 2018-03035), Research Council for Health, Working Life and Welfare (grant number 2018-00337), and Novo Nordisk Foundation (grant number NNF19OC0057274).", - "journal_title": "The Lancet. Global health", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/36866468/" - } - ], - "2a44f131-be1d-4566-affa-1966fa3029f6": [ - { - "pub_id": "36333501", - "title": "Multi-ancestry genome-wide association analyses identify novel genetic mechanisms in rheumatoid arthritis.", - "authors": "Kazuyoshi Ishigaki,Saori Sakaue,Chikashi Terao,Yang Luo,Kyuto Sonehara,Kensuke Yamaguchi,Tiffany Amariuta,Chun Lai Too,Vincent A Laufer,Ian C Scott,Sebastien Viatte,Meiko Takahashi,Koichiro Ohmura,Akira Murasawa,Motomu Hashimoto,Hiromu Ito,Mohammed Hammoudeh,Samar Al Emadi,Basel K Masri,Hussein Halabi,Humeira Badsha,Imad W Uthman,Xin Wu,Li Lin,Ting Li,Darren Plant,Anne Barton,Gisela Orozco,Suzanne M M Verstappen,John Bowes,Alexander J MacGregor,Suguru Honda,Masaru Koido,Kohei Tomizuka,Yoichiro Kamatani,Hiroaki Tanaka,Eiichi Tanaka,Akari Suzuki,Yuichi Maeda,Kenichi Yamamoto,Satoru Miyawaki,Gang Xie,Jinyi Zhang,Christopher I Amos,Edward Keystone,Gertjan Wolbink,Irene van der Horst-Bruinsma,Jing Cui,Katherine P Liao,Robert J Carroll,Hye-Soon Lee,So-Young Bang,Katherine A Siminovitch,Niek de Vries,Lars Alfredsson,Solbritt Rantap\u00e4\u00e4-Dahlqvist,Elizabeth W Karlson,Sang-Cheol Bae,Robert P Kimberly,Jeffrey C Edberg,Xavier Mariette,Tom Huizinga,Philippe Dieud\u00e9,Matthias Schneider,Martin Kerick,Joshua C Denny, ,Koichi Matsuda,Keitaro Matsuo,Tsuneyo Mimori,Fumihiko Matsuda,Keishi Fujio,Yoshiya Tanaka,Atsushi Kumanogoh,Matthew Traylor,Cathryn M Lewis,Stephen Eyre,Huji Xu,Richa Saxena,Thurayya Arayssi,Yuta Kochi,Katsunori Ikari,Masayoshi Harigai,Peter K Gregersen,Kazuhiko Yamamoto,S Louis Bridges,Leonid Padyukov,Javier Martin,Lars Klareskog,Yukinori Okada,Soumya Raychaudhuri", - "abstract": "Rheumatoid arthritis (RA) is a highly heritable complex disease with unknown etiology. Multi-ancestry genetic research of RA promises to improve power to detect genetic signals, fine-mapping resolution and performances of polygenic risk scores (PRS). Here, we present a large-scale genome-wide association study (GWAS) of RA, which includes 276,020 samples from five ancestral groups. We conducted a multi-ancestry meta-analysis and identified 124 loci (P\u2009<\u20095\u2009\u00d7\u200910<sup>-8</sup>), of which 34 are novel. Candidate genes at the novel loci suggest essential roles of the immune system (for example, TNIP2 and TNFRSF11A) and joint tissues (for example, WISP1) in RA etiology. Multi-ancestry fine-mapping identified putatively causal variants with biological insights (for example, LEF1). Moreover, PRS based on multi-ancestry GWAS outperformed PRS based on single-ancestry GWAS and had comparable performance between populations of European and East Asian ancestries. Our study provides several insights into the etiology of RA and improves the genetic predictability of RA.", - "journal_title": "Nature genetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/36333501/" - } - ], - "ed74a165-fd2c-456c-ae68-1a4d824cf3c8": [ - { - "pub_id": "28116330", - "title": "Identification and functional analysis of c.422_423InsT, a novel mutation of the <i>HNF1A</i> gene in a patient with diabetes.", - "authors": "Jes\u00fas Miguel Maga\u00f1a-Cerino,Juan P Luna-Arias,Mar\u00eda Luisa Labra-Barrios,Bartolo Avenda\u00f1o-Borromeo,Xavier Miguel Boldo-Le\u00f3n,Mirian Carolina Mart\u00ednez-L\u00f3pez", - "abstract": "<i>HNF1A</i> gene regulates liver-specific genes, and genes that have a role in glucose metabolism, transport, and secretion of insulin. <i>HNF1A</i> gene mutations are frequently associated with type 2 diabetes. HNF1A protein has three domains: the dimerization domain, the DNA-binding domain, and the trans-activation domain. Some mutations in the dimerization or DNA-binding domains have no influence on the normal allele, while others have dominant negative effects. The I27L, A98V, and S487N polymorphisms are common variants of the <i>HNF1A</i> gene; they have been found in T2D and non-diabetic subjects. We searched for mutations in the first three exons of the <i>HNF1A</i> gen in an Amerindian population of 71 diabetic patients. DNA sequencing revealed the previously reported I27L polymorphism (c.79A>C) in 53% of diabetic patients and in 67% of the control group. Thus, the I27L/L27L polymorphism might be a marker of Amerindians. In addition, we found the c.422_423InsT mutation in the <i>HNF1A</i> gene of one patient, which had not been previously reported. This mutation resulted in a frame shift of the open reading frame and a new translation stop in codon 187, leading to a truncated polypeptide of 186 amino acids (Q141Hfs*47). This novel mutation affects the DNA-binding capacity of the mutant HNF1A protein by EMSA; its intracellular localization by fluorescence and confocal microscopy, and a dominant-negative effect affecting the DNA-binding capacity of the normal HNF1A by EMSA. We also studied the homology modeling structure to understand the effect of this mutation on its DNA-binding capacity and its dominant negative effect. The HNF1A Q141Hfs*47 mutant polypeptide has no DNA-binding capacity and exerts a dominant negative effect on the HNF1A protein. Therefore, it might produce severe phenotypic effects on the expression levels of a set of <i>\u03b2</i>-cell genes. Consequently, its screening should be included in the genetic analysis of diabetic patients after more functional studies are performed.", - "journal_title": "Molecular genetics & genomic medicine", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/28116330/" - } - ], - "b514440a-128c-41a3-9b93-6f23354dc859": [ - { - "pub_id": "36632916", - "title": "Peripheral and central control of obesity by primary cilia.", - "authors": "Yue Wu,Jun Zhou,Yunfan Yang", - "abstract": "Primary cilia are hair-like structures that protrude from the cell surface. They are capable of sensing external cues and conveying a vast array of signals into cells to regulate a variety of physiological activities. Mutations in cilium-associated genes are linked to a group of diseases with overlapping clinical manifestations, collectively known as ciliopathies. A significant proportion of human ciliopathy cases are accompanied by metabolic disorders such as obesity and type 2 diabetes. Nevertheless, the mechanisms through which dysfunction of primary cilia contributes to obesity are complex. In this review, we present an overview of primary cilia and highlight obesity-related ciliopathies. We also discuss the potential role of primary cilia in peripheral organs, with a focus on adipose tissues. In addition, we emphasize the significance of primary cilia in the central regulation of obesity, especially the involvement of ciliary signaling in the hypothalamic control of feeding behavior. This review therefore proposes a framework of both peripheral and central regulation of obesity by primary cilia, which may benefit further exploration of the ciliary role in metabolic regulation.", - "journal_title": "Journal of genetics and genomics = Yi chuan xue bao", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/36632916/" - } - ], - "4a593a09-25f6-4caf-8ed5-f120bf56cdd8": [ - { - "pub_id": "34862199", - "title": "Recessive Genome-Wide Meta-analysis Illuminates Genetic Architecture of Type 2 Diabetes.", - "authors": "Mark J O'Connor,Philip Schroeder,Alicia Huerta-Chagoya,Paula Cort\u00e9s-S\u00e1nchez,Silv\u00eda Bon\u00e0s-Guarch,Marta Guindo-Mart\u00ednez,Joanne B Cole,Varinderpal Kaur,David Torrents,Kumar Veerapen,Niels Grarup,Mitja Kurki,Carsten F Rundsten,Oluf Pedersen,Ivan Brandslund,Allan Linneberg,Torben Hansen,Aaron Leong,Jose C Florez,Josep M Mercader", - "abstract": "Most genome-wide association studies (GWAS) of complex traits are performed using models with additive allelic effects. Hundreds of loci associated with type 2 diabetes have been identified using this approach. Additive models, however, can miss loci with recessive effects, thereby leaving potentially important genes undiscovered. We conducted the largest GWAS meta-analysis using a recessive model for type 2 diabetes. Our discovery sample included 33,139 case subjects and 279,507 control subjects from 7 European-ancestry cohorts, including the UK Biobank. We identified 51 loci associated with type 2 diabetes, including five variants undetected by prior additive analyses. Two of the five variants had minor allele frequency of <5% and were each associated with more than a doubled risk in homozygous carriers. Using two additional cohorts, FinnGen and a Danish cohort, we replicated three of the variants, including one of the low-frequency variants, rs115018790, which had an odds ratio in homozygous carriers of 2.56 (95% CI 2.05-3.19; P = 1 \u00d7 10-16) and a stronger effect in men than in women (for interaction, P = 7 \u00d7 10-7). The signal was associated with multiple diabetes-related traits, with homozygous carriers showing a 10% decrease in LDL cholesterol and a 20% increase in triglycerides; colocalization analysis linked this signal to reduced expression of the nearby PELO gene. These results demonstrate that recessive models, when compared with GWAS using the additive approach, can identify novel loci, including large-effect variants with pathophysiological consequences relevant to type 2 diabetes.", - "journal_title": "Diabetes", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/34862199/" - } - ], - "9fe2f814-3375-45c1-b9e1-6ac5a6ecccb8": [ - { - "pub_id": "29154141", - "title": "Novel genes associated with amyotrophic lateral sclerosis: diagnostic and clinical implications.", - "authors": "Ruth Chia,Adriano Chi\u00f2,Bryan J Traynor", - "abstract": "The disease course of amyotrophic lateral sclerosis (ALS) is rapid and, because its pathophysiology is unclear, few effective treatments are available. Genetic research aims to understand the underlying mechanisms of ALS and identify potential therapeutic targets. The first gene associated with ALS was SOD1, identified in 1993 and, by early 2014, more than 20 genes had been identified as causative of, or highly associated with, ALS. These genetic discoveries have identified key disease pathways that are therapeutically testable and could potentially lead to the development of better treatments for people with ALS. Since 2014, seven additional genes have been associated with ALS (MATR3, CHCHD10, TBK1, TUBA4A, NEK1, C21orf2, and CCNF), all of which were identified by genome-wide association studies, whole genome studies, or exome sequencing technologies. Each of the seven novel genes code for proteins associated with one or more molecular pathways known to be involved in ALS. These pathways include dysfunction in global protein homoeostasis resulting from abnormal protein aggregation or a defect in the protein clearance pathway, mitochondrial dysfunction, altered RNA metabolism, impaired cytoskeletal integrity, altered axonal transport dynamics, and DNA damage accumulation due to defective DNA repair. Because these novel genes share common disease pathways with other genes implicated in ALS, therapeutics targeting these pathways could be useful for a broad group of patients stratified by genotype. However, the effects of these novel genes have not yet been investigated in animal models, which will be a key step to translating these findings into clinical practice. WHERE NEXT?: The identification of these seven novel genes has been important in unravelling the molecular mechanisms underlying ALS. However, our understanding of what causes ALS is not complete, and further genetic research will provide additional detail about its causes. Increased genetic knowledge will also identify potential therapeutic targets and could lead to the development of individualised medicine for patients with ALS. These developments will have a direct effect on clinical practice when genome sequencing becomes a routine and integral part of disease diagnosis and management.", - "journal_title": "The Lancet. Neurology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/29154141/" - } - ], - "185c1bd4-711e-4a41-947f-f82e2dbf6e94": [ - { - "pub_id": "2079966", - "title": "Extrachromosomal circular DNAs and genomic sequence plasticity in eukaryotic cells.", - "authors": "J W Gaubatz", - "abstract": "The ability of eukaryotic organisms of the same genotype to vary in developmental pattern or in phenotype according to varying environmental conditions is frequently associated with changes in extrachromosomal circular DNA (eccDNA) sequences. Although variable in size, sequence complexity, and copy number, the best characterized of these eccDNAs contain sequences homologous to chromosomal DNA which indicates that they might arise from genetic rearrangements, such as homologous recombination. The abundance of repetitive sequence families in eccDNAs is consistent with the notion that tandem repeats and dispersed repetitive elements participate in intrachromosomal recombination events. There is also evidence that a fraction of this DNA has characteristics similar to retrotransposons. It has been suggested that eccDNAs could reflect altered patterns of gene expression or an instability of chromosomal sequences during development and aging. This article reviews some of the findings and concepts regarding eccDNAs and sequence plasticity in eukaryotic genomes.", - "journal_title": "Mutation research", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/2079966/" - } - ], - "2561a7c9-cf43-43cd-bc5f-a8b37c5e959e": [ - { - "pub_id": "1660054", - "title": "Detection of Epstein-Barr virus genomes in Hodgkin's disease: relation to age.", - "authors": "R F Jarrett,A Gallagher,D B Jones,F E Alexander,A S Krajewski,A Kelsey,J Adams,B Angus,S Gledhill,D H Wright", - "abstract": "An investigation as to whether any particular subgroup of patients with Hodgkin's disease was particularly likely to be Epstein-Barr virus (EBV) genome positive was made on samples from 95 patients. These were grouped according to age and Hodgkin's disease subtype, and analysed using Southern blot analysis. Most samples from children or adults aged 50 years or over contained detectable EBV genomes; samples from young adults were only rarely positive. The differences in EBV positivity by age were highly significant, but there was no significant association between EBV and histological subtype after allowing for the effect of age. The results support the hypothesis that Hodgkin's disease in different age groups may have different aetiologies, and suggest that EBV does have a pathogenetic role in Hodgkin's disease in children and older age groups.", - "journal_title": "Journal of clinical pathology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/1660054/" - } - ], - "a733a920-9896-4ca4-910d-d6f0184a0777": [ - { - "pub_id": "2687102", - "title": "Genetic instability and aging: theories, facts, and future perspectives.", - "authors": "P E Slagboom,J Vijg", - "abstract": "The fundamental mechanisms involved in the physiological deterioration observed with age in mammalian organisms have not yet been elucidated. It appears that random alterations in informational biomolecules and in their synthesis could be the basis of such physiological changes. There is, however, a lack of knowledge with respect to the frequency and characteristics of changes introduced in the cellular molecular machinery. Moreover, the driving force initiating the generation of such alterations and the order of events in which they occur are unknown at present. In this article, data concerning the hypothesis that the aging process is associated with widespread genetic instability are reviewed in the context of the complex interactions between the three major informational biomolecules, DNA, RNA, and protein. We conclude that the results obtained to date do not rule out the possibility that genetic instability in a wide sense is a major causal factor in a number of age-related phenomena. However, it appears that new strategies based on a new technology are ultimately necessary to elucidate the alterations in the intricately interwoven patterns of molecular control that could underlie the various aspects of the aging process. A first attempt is made to formulate the problems in this field and to provide some solutions.", - "journal_title": "Genome", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/2687102/" - } - ], - "32461927-8022-462a-b1a0-13c11dbf6862": [ - { - "pub_id": "7835898", - "title": "Marked changes in mitochondrial DNA deletion levels in Alzheimer brains.", - "authors": "M Corral-Debrinski,T Horton,M T Lott,J M Shoffner,A C McKee,M F Beal,B H Graham,D C Wallace", - "abstract": "Levels of the common 4977 nucleotide pair (np) mitochondrial DNA (mtDNA) deletion (mtDNA4977) were quantitated in the cortex, putamen, and cerebellum of patients with Alzheimer disease (AD) and compared to age-matched controls. Although cerebellum deletion levels were comparably low in AD patients and controls of all ages, cortical deletion levels were clearly different. The levels of mtDNA deletions in control brains started low, but rose markedly after age 75, while those of AD patients started high and declined to low levels by age 80. Choosing age 75 to arbitrarily delineate between younger and older subjects, younger patients had 15 times more mtDNA deletions than younger controls, while older patients had one-fifth the deletion level of older controls. Younger AD patients also had fourfold more deletions than older AD patients. These results support the hypothesis that OXPHOS defects resulting from somatic mtDNA mutations may play a role in AD pathophysiology.", - "journal_title": "Genomics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/7835898/" - } - ], - "75b6122b-213d-4fc6-a779-c7a44c74ec9d": [ - { - "pub_id": "8530074", - "title": "Decreased cytochrome-c oxidase activity and lack of age-related accumulation of mitochondrial DNA deletions in the brains of schizophrenics.", - "authors": "L Cavelier,E E Jazin,I Eriksson,J Prince,U B\u00e5ve,L Oreland,U Gyllensten", - "abstract": "Defects in mitochondrial energy production have been implicated in several neurodegenerative disorders, such as Parkinson disease and amyotrophic lateral sclerosis. To study the contribution of mitochondrial defects to Alzheimer disease and schizophrenia, cytochrome-c oxidase (COX) activity and levels of the mtDNA4977 deletion in postmortem brain tissue specimens of patients were compared with those of asymptomatic age-matched controls. No difference in COX activity was observed between Alzheimer patients and controls in any of five brain regions investigated. In contrast, schizophrenic patients had a 63% reduction of the COX activity in the nucleus caudatus (P < 0.0001) and a 43% reduction in the cortex gyrus frontalis (P < 0.05) as compared to controls. The average levels of the mtDNA4977 deletion did not differ significantly between Alzheimer patients and controls, and the deletion followed similar modes of accumulation with age in the two groups. In contrast, no age-related accumulation of mtDNA deletions was found in schizophrenic patients. The reduction in COX activity in schizophrenic patients did not correlate with changes in the total amount of mtDNA or levels of the mtDNA4977 deletion. The lack of age-related accumulation of the mtDNA4977 deletion and reduction in COX activity suggest that a mitochondrial dysfunction may be involved in the pathogenesis of schizophrenia.", - "journal_title": "Genomics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/8530074/" - } - ], - "0af83a97-18ef-47f4-9f0c-872633ca3414": [ - { - "pub_id": "35379992", - "title": "New insights into the genetic etiology of Alzheimer's disease and related dementias.", - "authors": "C\u00e9line Bellenguez,Fahri K\u00fc\u00e7\u00fckali,Iris E Jansen,Luca Kleineidam,Sonia Moreno-Grau,Najaf Amin,Adam C Naj,Rafael Campos-Martin,Benjamin Grenier-Boley,Victor Andrade,Peter A Holmans,Anne Boland,Vincent Damotte,Sven J van der Lee,Marcos R Costa,Teemu Kuulasmaa,Qiong Yang,Itziar de Rojas,Joshua C Bis,Amber Yaqub,Ivana Prokic,Julien Chapuis,Shahzad Ahmad,Vilmantas Giedraitis,Dag Aarsland,Pablo Garcia-Gonzalez,Carla Abdelnour,Emilio Alarc\u00f3n-Mart\u00edn,Daniel Alcolea,Montserrat Alegret,Ignacio Alvarez,Victoria \u00c1lvarez,Nicola J Armstrong,Anthoula Tsolaki,Carmen Ant\u00fanez,Ildebrando Appollonio,Marina Arcaro,Silvana Archetti,Alfonso Arias Pastor,Beatrice Arosio,Lavinia Athanasiu,Henri Bailly,Nerisa Banaj,Miquel Baquero,Sandra Barral,Alexa Beiser,Ana Bel\u00e9n Pastor,Jennifer E Below,Penelope Benchek,Luisa Benussi,Claudine Berr,C\u00e9line Besse,Valentina Bessi,Giuliano Binetti,Alessandra Bizarro,Rafael Blesa,Merc\u00e8 Boada,Eric Boerwinkle,Barbara Borroni,Silvia Boschi,Paola Boss\u00f9,Geir Br\u00e5then,Jan Bressler,Catherine Bresner,Henry Brodaty,Keeley J Brookes,Luis Ignacio Brusco,Dolores Buiza-Rueda,Katharina B\u00fbrger,Vanessa Burholt,William S Bush,Miguel Calero,Laura B Cantwell,Genevi\u00e8ve Chene,Jaeyoon Chung,Michael L Cuccaro,\u00c1ngel Carracedo,Roberta Cecchetti,Laura Cervera-Carles,Camille Charbonnier,Hung-Hsin Chen,Caterina Chillotti,Simona Ciccone,Jurgen A H R Claassen,Christopher Clark,Elisa Conti,Ana\u00efs Corma-G\u00f3mez,Emanuele Costantini,Carlo Custodero,Delphine Daian,Maria Carolina Dalmasso,Antonio Daniele,Efthimios Dardiotis,Jean-Fran\u00e7ois Dartigues,Peter Paul de Deyn,Katia de Paiva Lopes,Lot D de Witte,St\u00e9phanie Debette,J\u00fcrgen Deckert,Teodoro Del Ser,Nicola Denning,Anita DeStefano,Martin Dichgans,Janine Diehl-Schmid,M\u00f3nica Diez-Fairen,Paolo Dionigi Rossi,Srdjan Djurovic,Emmanuelle Duron,Emrah D\u00fczel,Carole Dufouil,Gudny Eiriksdottir,Sebastiaan Engelborghs,Valentina Escott-Price,Ana Espinosa,Michael Ewers,Kelley M Faber,Tagliavini Fabrizio,Sune Fallgaard Nielsen,David W Fardo,Lucia Farotti,Chiara Fenoglio,Marta Fern\u00e1ndez-Fuertes,Raffaele Ferrari,Catarina B Ferreira,Evelyn Ferri,Bertrand Fin,Peter Fischer,Tormod Fladby,Klaus Flie\u00dfbach,Bernard Fongang,Myriam Fornage,Juan Fortea,Tatiana M Foroud,Silvia Fostinelli,Nick C Fox,Emlio Franco-Mac\u00edas,Mar\u00eda J Bullido,Ana Frank-Garc\u00eda,Lutz Froelich,Brian Fulton-Howard,Daniela Galimberti,Jose Maria Garc\u00eda-Alberca,Pablo Garc\u00eda-Gonz\u00e1lez,Sebastian Garcia-Madrona,Guillermo Garcia-Ribas,Roberta Ghidoni,Ina Giegling,Giaccone Giorgio,Alison M Goate,Oliver Goldhardt,Duber Gomez-Fonseca,Antonio Gonz\u00e1lez-P\u00e9rez,Caroline Graff,Giulia Grande,Emma Green,Timo Grimmer,Edna Gr\u00fcnblatt,Michelle Grunin,Vilmundur Gudnason,Tamar Guetta-Baranes,Annakaisa Haapasalo,Georgios Hadjigeorgiou,Jonathan L Haines,Kara L Hamilton-Nelson,Harald Hampel,Olivier Hanon,John Hardy,Annette M Hartmann,Lucrezia Hausner,Janet Harwood,Stefanie Heilmann-Heimbach,Seppo Helisalmi,Michael T Heneka,Isabel Hern\u00e1ndez,Martin J Herrmann,Per Hoffmann,Clive Holmes,Henne Holstege,Raquel Huerto Vilas,Marc Hulsman,Jack Humphrey,Geert Jan Biessels,Xueqiu Jian,Charlotte Johansson,Gyungah R Jun,Yuriko Kastumata,John Kauwe,Patrick G Kehoe,Lena Kilander,Anne Kinhult St\u00e5hlbom,Miia Kivipelto,Anne Koivisto,Johannes Kornhuber,Mary H Kosmidis,Walter A Kukull,Pavel P Kuksa,Brian W Kunkle,Amanda B Kuzma,Carmen Lage,Erika J Laukka,Lenore Launer,Alessandra Lauria,Chien-Yueh Lee,Jenni Lehtisalo,Ondrej Lerch,Alberto Lle\u00f3,William Longstreth,Oscar Lopez,Adolfo Lopez de Munain,Seth Love,Malin L\u00f6wemark,Lauren Luckcuck,Kathryn L Lunetta,Yiyi Ma,Juan Mac\u00edas,Catherine A MacLeod,Wolfgang Maier,Francesca Mangialasche,Marco Spallazzi,Marta Marqui\u00e9,Rachel Marshall,Eden R Martin,Angel Mart\u00edn Montes,Carmen Mart\u00ednez Rodr\u00edguez,Carlo Masullo,Richard Mayeux,Simon Mead,Patrizia Mecocci,Miguel Medina,Alun Meggy,Shima Mehrabian,Silvia Mendoza,Manuel Men\u00e9ndez-Gonz\u00e1lez,Pablo Mir,Susanne Moebus,Merel Mol,Laura Molina-Porcel,Laura Montrreal,Laura Morelli,Fermin Moreno,Kevin Morgan,Thomas Mosley,Markus M N\u00f6then,Carolina Muchnik,Shubhabrata Mukherjee,Benedetta Nacmias,Tiia Ngandu,Gael Nicolas,B\u00f8rge G Nordestgaard,Robert Olaso,Adelina Orellana,Michela Orsini,Gemma Ortega,Alessandro Padovani,Caffarra Paolo,Goran Papenberg,Lucilla Parnetti,Florence Pasquier,Pau Pastor,Gina Peloso,Alba P\u00e9rez-Cord\u00f3n,Jordi P\u00e9rez-Tur,Pierre Pericard,Oliver Peters,Yolande A L Pijnenburg,Juan A Pineda,Gerard Pi\u00f1ol-Ripoll,Claudia Pisanu,Thomas Polak,Julius Popp,Danielle Posthuma,Josef Priller,Raquel Puerta,Olivier Quenez,In\u00e9s Quintela,Jesper Qvist Thomassen,Alberto R\u00e1bano,Innocenzo Rainero,Farid Rajabli,Inez Ramakers,Luis M Real,Marcel J T Reinders,Christiane Reitz,Dolly Reyes-Dumeyer,Perry Ridge,Steffi Riedel-Heller,Peter Riederer,Natalia Roberto,Eloy Rodriguez-Rodriguez,Arvid Rongve,Irene Rosas Allende,Mait\u00e9e Rosende-Roca,Jose Luis Royo,Elisa Rubino,Dan Rujescu,Mar\u00eda Eugenia S\u00e1ez,Paraskevi Sakka,Ingvild Saltvedt,\u00c1ngela Sanabria,Mar\u00eda Bernal S\u00e1nchez-Arjona,Florentino Sanchez-Garcia,Pascual S\u00e1nchez Juan,Raquel S\u00e1nchez-Valle,Sigrid B Sando,Chlo\u00e9 Sarnowski,Claudia L Satizabal,Michela Scamosci,Nikolaos Scarmeas,Elio Scarpini,Philip Scheltens,Norbert Scherbaum,Martin Scherer,Matthias Schmid,Anja Schneider,Jonathan M Schott,Geir Selb\u00e6k,Davide Seripa,Manuel Serrano,Jin Sha,Alexey A Shadrin,Olivia Skrobot,Susan Slifer,Gijsje J L Snijders,Hilkka Soininen,Vincenzo Solfrizzi,Alina Solomon,Yeunjoo Song,Sandro Sorbi,Oscar Sotolongo-Grau,Gianfranco Spalletta,Annika Spottke,Alessio Squassina,Eystein Stordal,Juan Pablo Tartan,Llu\u00eds T\u00e1rraga,Niccolo Tes\u00ed,Anbupalam Thalamuthu,Tegos Thomas,Giuseppe Tosto,Latchezar Traykov,Lucio Tremolizzo,Anne Tybj\u00e6rg-Hansen,Andre Uitterlinden,Abbe Ullgren,Ingun Ulstein,Sergi Valero,Otto Valladares,Christine Van Broeckhoven,Jeffery Vance,Badri N Vardarajan,Aad van der Lugt,Jasper Van Dongen,Jeroen van Rooij,John van Swieten,Rik Vandenberghe,Frans Verhey,Jean-S\u00e9bastien Vidal,Jonathan Vogelgsang,Martin Vyhnalek,Michael Wagner,David Wallon,Li-San Wang,Ruiqi Wang,Leonie Weinhold,Jens Wiltfang,Gill Windle,Bob Woods,Mary Yannakoulia,Habil Zare,Yi Zhao,Xiaoling Zhang,Congcong Zhu,Miren Zulaica, , , , , , , , , ,Lindsay A Farrer,Bruce M Psaty,Mohsen Ghanbari,Towfique Raj,Perminder Sachdev,Karen Mather,Frank Jessen,M Arfan Ikram,Alexandre de Mendon\u00e7a,Jakub Hort,Magda Tsolaki,Margaret A Pericak-Vance,Philippe Amouyel,Julie Williams,Ruth Frikke-Schmidt,Jordi Clarimon,Jean-Fran\u00e7ois Deleuze,Giacomina Rossi,Sudha Seshadri,Ole A Andreassen,Martin Ingelsson,Mikko Hiltunen,Kristel Sleegers,Gerard D Schellenberg,Cornelia M van Duijn,Rebecca Sims,Wiesje M van der Flier,Agust\u00edn Ruiz,Alfredo Ramirez,Jean-Charles Lambert", - "abstract": "Characterization of the genetic landscape of Alzheimer's disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/'proxy' AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE \u03b54 allele.", - "journal_title": "Nature genetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/35379992/" - } - ], - "03a4f57c-3a11-4d3d-a1e9-6d0d8bdb7cb7": [ - { - "pub_id": "11701657", - "title": "The genetics of aging.", - "authors": "C E Finch,G Ruvkun", - "abstract": "The genetic analysis of life span has only begun in mammals, invertebrates, such as Caenorhabditis elegans and Drosophila, and yeast. Even at this primitive stage of the genetic analysis of aging, the physiological observations that rate of metabolism is intimately tied to life span is supported. In many examples from mice to worms to flies to yeast, genetic variants that affect life span also modify metabolism. Insulin signaling regulates life span coordinately with reproduction, metabolism, and free radical protective gene regulation in C. elegans. This may be related to the findings that caloric restriction also regulates mammalian aging, perhaps via the modulation of insulin-like signaling pathways. The nervous system has been implicated as a key tissue where insulin-like signaling and free radical protective pathways regulate life span in C. elegans and Drosophila. Genes that determine the life span could act in neuroendocrine cells in diverse animals. The involvement of insulin-like hormones suggests that the plasticity in life spans evident in animal phylogeny may be due to variation in the timing of release of hormones that control vitality and mortality as well as variation in the response to those hormones. Pedigree analysis of human aging may reveal variations in the orthologs of the insulin pathway genes and coupled pathways that regulate invertebrate aging. Thus, genetic approaches may identify a set of circuits that was established in ancestral metazoans to regulate their longevity.", - "journal_title": "Annual review of genomics and human genetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/11701657/" - } - ], - "e02ea82c-1e15-4f06-a0fc-18943799559c": [ - { - "pub_id": "11743069", - "title": "Plant systematics in the age of genomics.", - "authors": "D C Daly,K M Cameron,D W Stevenson", - "abstract": "", - "journal_title": "Plant physiology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/11743069/" - } - ], - "38aaad4f-c06c-4e64-9962-a69b7ffb9b15": [ - { - "pub_id": "12902548", - "title": "Molecular mechanisms of reduced beta-adrenergic signaling in the aged heart as revealed by genomic profiling.", - "authors": "James G Dobson,John Fray,Jack L Leonard,Richard E Pratt", - "abstract": "Myocardial aging leads to a reduction of beta-adrenergic receptor-induced metabolic and contractile responsiveness. We hypothesize that a change in the patterns of gene expression is important in these age-related events. To test this, hearts were harvested from young and aged male rats (3-4 and 20-22 mo, respectively). Total mRNA was extracted and prepared for hybridization to Affymetrix U34A GeneChips. Filtering criteria, involving fold change and a statistical significance cutoff were employed, yielding 263 probe pairs exhibiting differential signals. Of the 163 annotated genes, at least 56 (34%) were classified as signaling/cell communication. Of these 56, approximately half were directly involved in G protein-coupled receptor signaling pathways. We next determined which of these changes might be involved in anti-adrenergic activity and identified 19 potentially important gene products. Importantly, we observed a decrease in beta1-adrenergic receptor and adenylyl cyclase mRNAs, whereas the mRNA encoding beta-arrestin increased. Furthermore, the results demonstrate an increase in mRNAs encoding the adenosine A1 receptor and phospholipase D, which could increase anti-adrenergic effects. Moreover, the mRNAs encoding the muscarinic M3 receptor, nicotinic acetylcholine receptor beta3, and nicotinic acetylcholine receptor-related protein were increased as was the mRNA encoding guanylate kinase-associated protein. Interestingly, we also observed eight mRNAs whose abundance changed three- to sixfold with aging that could be considered as being compensatory. Although these results do not prove causality, they demonstrate that cardiac aging is associated with changes in the profiles of gene expression and that many of these changes may contribute to reduced adrenergic signaling.", - "journal_title": "Physiological genomics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/12902548/" - } - ], - "98676960-3cef-42df-8143-faa4da1be8a3": [ - { - "pub_id": "11479155", - "title": "Comet-assay analysis identifies genomic damage in lymphocytes of uremic patients.", - "authors": "H Stopper,F Boullay,A Heidland,J Vienken,U Bahner", - "abstract": "This study investigates genomic damage in peripheral lymphocytes from patients with moderate to severe chronic renal insufficiency and those on long-term maintenance hemodialysis (MHD) and hemodiafiltration therapy. As a measure for genomic damage, the comet assay (single-cell gel electrophoresis) was applied. This test detects single- and double-strand breaks and alkali labile sites through electrophoretic mobility of the resulting fragments. The average damage (percentage of DNA in the tail region of the comet) observed in cells of the control group of 21 healthy subjects was 10.5% +/- 0.8%. There was a significant increase to 14.7% +/- 3.5% in cells of 23 patients with chronic renal failure, and a further increase to 17.1% +/- 3.5% in the subgroup of 12 patients with serum creatinine values greater than 6 mg/dL. Damage was 16.7% +/- 4.2% in cells of the MHD group (26 patients) and 20.1% +/- 3.0% in the subgroup with MHD therapy longer than 10 years (8 patients). Cellular DNA damage in the group of 15 maintenance hemodiafiltration patients was 15.6% +/- 2.1%, ranging between predialysis and MHD patients, and did not seem to increase with treatment time. These results, together with previously observed elevated frequencies of micronuclei, decreased DNA repair, and increased cancer incidence described for these patient groups, emphasize the need to further optimize the current therapy for reducing the degree of genomic damage.", - "journal_title": "American journal of kidney diseases : the official journal of the National Kidney Foundation", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/11479155/" - } - ], - "ec8e3403-5bf0-47b2-8a36-f5058617f73f": [ - { - "pub_id": "9675914", - "title": "Microarrays: biotechnology's discovery platform for functional genomics.", - "authors": "M Schena,R A Heller,T P Theriault,K Konrad,E Lachenmeier,R W Davis", - "abstract": "Advances in microarray technology enable massive parallel mining of biological data, with biological chips providing hybridization-based expression monitoring, polymorphism detection and genotyping on a genomic scale. Microarrays containing sequences representative of all human genes may soon permit the expression analysis of the entire human genome in a single reaction. These 'genome chips' will provide unprecedented access to key areas of human health, including disease prognosis and diagnosis, drug discovery, toxicology, aging, and mental illness. Microarray technology is rapidly becoming a central platform for functional genomics.", - "journal_title": "Trends in biotechnology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/9675914/" - } - ], - "a2e92c37-e0f3-41d8-950c-0dcaceeed7e9": [ - { - "pub_id": "12368240", - "title": "Retroelement distributions in the human genome: variations associated with age and proximity to genes.", - "authors": "Patrik Medstrand,Louie N van de Lagemaat,Dixie L Mager", - "abstract": "Remnants of more than 3 million transposable elements, primarily retroelements, comprise nearly half of the human genome and have generated much speculation concerning their evolutionary significance. We have exploited the draft human genome sequence to examine the distributions of retroelements on a genome-wide scale. Here we show that genomic densities of 10 major classes of human retroelements are distributed differently with respect to surrounding GC content and also show that the oldest elements are preferentially found in regions of lower GC compared with their younger relatives. In addition, we determined whether retroelement densities with respect to genes could be accurately predicted based on surrounding GC content or if genes exert independent effects on the density distributions. This analysis revealed that all classes of long terminal repeat (LTR) retroelements and L1 elements, particularly those in the same orientation as the nearest gene, are significantly underrepresented within genes and older LTR elements are also underrepresented in regions within 5 kb of genes. Thus, LTR elements have been excluded from gene regions, likely because of their potential to affect gene transcription. In contrast, the density of Alu sequences in the proximity of genes is significantly greater than that predicted based on the surrounding GC content. Furthermore, we show that the previously described density shift of Alu repeats with age to domains of higher GC was markedly delayed on the Y chromosome, suggesting that recombination between chromosome pairs greatly facilitates genomic redistributions of retroelements. These findings suggest that retroelements can be removed from the genome, possibly through recombination resulting in re-creation of insert-free alleles. Such a process may provide an explanation for the shifting distributions of retroelements with time.", - "journal_title": "Genome research", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/12368240/" - } - ], - "1f65141c-40f9-426f-bb15-adebacf4d3a4": [ - { - "pub_id": "9556024", - "title": "Neurodegeneration and aging: role of the second genome.", - "authors": "M B Graeber,E Grasbon-Frodl,U V Eitzen,S K\u00f6sel", - "abstract": "The latest Health Report of the World Health Organization predicts a significant increase in the age of human populations over the next two decades. In the developed world, at least 20% of the population will be older than 65 years. This development together with the as yet unknown etiology of many neurodegenerative disorders has caused an increased interest in the biology and pathophysiology of mitochondria. Dysfunction of mitochondria has been linked to both normal aging and neurodegenerative disorders, with the latter occurring much more frequently at higher age. Specifically, genetic defects in mitochondria have been shown to accumulate during life, and certain mutations of mitochondrial genes have been implicated in the etiology of Parkinson's and Alzheimer's diseases. In addition, a large number of new mitochondrial diseases have been identified following the first description of mitochondrial mutations 10 years ago. While there can be little doubt that DNA defects of mitochondria play a role in aging, specific mutations of mitochondrial genes underlying Parkinson's or Alzheimer's diseases remain to be identified. There is evidence, however, that mutations of the mitochondrial genome may increase the susceptibility to neurodegeneration.", - "journal_title": "Journal of neuroscience research", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/9556024/" - } - ], - "e5a6191f-6682-4abb-80b3-38a5b6f4ca5f": [ - { - "pub_id": "7668249", - "title": "Rearranged mitochondrial genomes are present in human oocytes.", - "authors": "X Chen,R Prosser,S Simonetti,J Sadlock,G Jagiello,E A Schon", - "abstract": "Using quantitative PCR, we have determined that a human oocyte contains approximately 100,000 mitochondrial genomes (mtDNAs). We have also found that some oocytes harbor measurable levels (up to 0.1%) of the so-called common deletion, an mtDNA molecule containing a 4,977-bp rearrangement that is present in high amounts in many patients with \"sporadic\" Kearns-Sayre syndrome (KSS) and progressive external ophthalmoplegia (PEO). This is the first demonstration that rearranged mtDNAs are present in human oocytes, and it provides experimental support for the supposition that pathogenic deletions associated with the ontogeny of sporadic KSS and PEO can be transmitted in the female germ line, from mother to child. The relevance of these finding to the accumulation of extremely low levels of deleted mtDNAs in both somatic and germ-line tissues during normal human aging is also discussed.", - "journal_title": "American journal of human genetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/7668249/" - } - ], - "d95b7bec-b4a7-4600-9a38-859dede780df": [ - { - "pub_id": "11223402", - "title": "Mitochondrial genome instability in human cancers.", - "authors": "N O Bianchi,M S Bianchi,S M Richard", - "abstract": "Malfunction of mismatch repair (MMR) genes produces nuclear genome instability (NGI) and plays an important role in the origin of some hereditary and sporadic human cancers. The appearance of non-inherited microsatellite alleles in tumor cells (microsatellite instability, MSI) is one of the expressions of NGI. We present here data showing mitochondrial genome instability (mtGI) in most of the human cancers analyzed so far. The mtDNA markers used were point mutations, length-tract instability of mono- or dinucleotide repeats, mono- or dinucleotide insertions or deletions, and long deletions. Comparison of normal and tumoral tissues from the same individual reveals that mt-mutations may show as homoplasmic (all tumor cells have the same variant haplotype) or as heteroplasmic (tumor cells are a mosaic of inherited and acquired variant haplotypes). Breast, colorectal, gastric and kidney cancers exhibit mtGI with a pattern of mt-mutations specific for each tumor. No correlation between NGI and mtGI was found in breast, colorectal or kidney cancers, while a positive correlation was found in gastric cancer. Conversely, germ cell testicular cancers lack mtGI. Damage by reactive oxygen species (ROS), slipped-strand mispairing (SSM) and deficient repair are the causes explaining the appearance of mtGI. The replication and repair of mtDNA are controlled by nuclear genes. So far, there is no clear evidence linking MMR gene malfunction with mtGI. Polymerase gamma (POLgamma) carries out the mtDNA synthesis. Since this process is error-prone due to a deficiency in the proofreading activity of POLgamma, this enzyme has been assumed to be involved in the origin of mt-mutations. Somatic cells have hundreds to thousands of mtDNA molecules with a very high rate of spontaneous mutations. Accordingly, most somatic cells probably have a low frequency of randomly mutated mtDNA molecules. Most cancers are of monoclonal origin. Hence, to explain the appearance of mtGI in tumors we have to explain why a given variant mt-haplotype expands and replaces part of (heteroplasmy) or all (homoplasmy) wild mt-haplotypes in cancer cells. Selective and/or replicative advantage of some mutations combined with a severe bottleneck during the mitochondrial segregation accompanying mitosis are the mechanisms probably involved in the origin of mtGI.", - "journal_title": "Mutation research", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/11223402/" - } - ], - "75638595-32f5-4b2c-a7dd-bbe64f95728c": [ - { - "pub_id": "11701823", - "title": "THE CAENORHABDITIS ELEGANS GENOME: A Guide in The Post Genomics Age.", - "authors": "D M Bird,C H Opperman,S J Jones,D L Baillie", - "abstract": "The completion of the entire genome sequence of the free-living nematode, Caenorhabditis elegans is a tremendous milestone in modern biology. Not only will scientists be poring over data mined from this resource, but techniques and methodologies developed along the way have changed the way we can approach biological questions. The completion of the C. elegans genomic sequence will be of particular importance to scientists working on parasitic nematodes. In many cases, these nematode species present intractable challenges to those interested in their biology and genetics. The data already compared from parasites to the C. elegans database reveals a wealth of opportunities for parasite biologists. It is likely that many of the same genes will be present in parasites and that these genes will have similar functions. Additional information regarding differences between free-living and parasitic species will provide insight into the evolution and nature of parasitism. Finally, genetic and genomic approaches to the study of parasitic nematodes now have a clearly marked path to follow.", - "journal_title": "Annual review of phytopathology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/11701823/" - } - ], - "6005d141-8758-44b5-9baa-d553da68d167": [ - { - "pub_id": "12618000", - "title": "Functional genomics of ageing.", - "authors": "Jan Vijg,Yousin Suh", - "abstract": "Ageing is the most complex phenotype currently known, since it becomes manifest in all organs and tissues, affects an organism's entire physiology, impacts function at all levels and increases susceptibility to all major chronic diseases. Insight into the molecular and cellular targets of the ageing process would offer the unprecedented opportunity to postpone and prevent some, if not all, of its deteriorative aspects by preventive and therapeutic means. Thus far, our understanding of the causes of ageing is limited. To an important extent this is due to our inability, in the past, to study ageing systems. Instead, ample information has been gathered about individual cellular components at various ages, but this has not allowed a clear understanding of the integrated genomic circuits that control mechanisms of ageing, survival and stress responses. With the emergence of functional genomics, we finally have the opportunity to study ageing in a comprehensive manner, as a function of the dynamic network of genes that determines the physiology of an individual organism over time.", - "journal_title": "Mechanisms of ageing and development", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/12618000/" - } - ], - "a12388bc-0a2c-4cf4-aa39-39eebabe9a7e": [ - { - "pub_id": "9922103", - "title": "The bottleneck: mitochondrial imperatives in oogenesis and ovarian follicular fate.", - "authors": "R P Jansen,K de Boer", - "abstract": "Molecular geneticists and ovarian physiologists today face the challenge of defining and reconciling two major biological imperatives that each center on oogenesis, folliculogenesis and competition between ovarian follicles: (1), defining how the mitochondrial genome--important in both aging and a number of serious mitochondrial diseases--is refreshed and purified as it passes, via the oocyte's cytoplasm, from one generation to the next; and (2), endeavouring to discover what cytoplasmic factor(s) it is that permits some eggs but not others to produce viable embryos and ongoing pregnancies. We review here in detail the passage of mitochondria through the female germ cell line. For mitochondria, the processes of oogenesis, follicle formation and loss constitute a restriction/amplification/constraint event of the kind predicted by L. Chao for purification and refinement of a haploid genome. We argue that maintaining the integrity of mitochondrial inheritance is such a strong evolutionary imperative that we should expect at least some features of ovarian follicular formation, function and loss to be primarily adapted to this specific purpose. We predict, moreover, that to prevent accumulation of mild mitochondrial genomes in the population there is a need for physiological female sterility prior to total depletion of ovarian oocytes, a phenomenon for which there is empirical evidence and which we term the o\u00f6pause.", - "journal_title": "Molecular and cellular endocrinology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/9922103/" - } - ], - "ddc57e64-2b93-41e5-baac-6bdb52e7b6e6": [ - { - "pub_id": "12409452", - "title": "Human mitochondrial DNA with large deletions repopulates organelles faster than full-length genomes under relaxed copy number control.", - "authors": "Francisca Diaz,Maria Pilar Bayona-Bafaluy,Michele Rana,Marialejandra Mora,Huiling Hao,Carlos T Moraes", - "abstract": "Partially-deleted mitochondrial DNA (DeltamtDNA) accumulates during aging of postmitotic tissues. This accumulation has been linked to decreased metabolic activity, increased reactive oxygen species formation and the aging process. Taking advantage of cell lines with heteroplasmic mtDNA mutations, we showed that, after severe mtDNA depletion, organelles are quickly and predominantly repopulated with DeltamtDNA, whereas repopulation with the wild-type counterpart is slower. This behavior was not observed for full-length genomes with pathogenic point mutations. The faster repopulation of smaller molecules was supported by metabolic labeling of mtDNA with [3H]thymidine during relaxed copy number control conditions. We also showed that hybrid cells containing two defective mtDNA haplotypes tend to retain the smaller one as they adjust their normal mtDNA copy number. Taken together, our results indicate that, under relaxed copy number control, DeltamtDNAs repopulate mitochondria more efficiently than full-length genomes.", - "journal_title": "Nucleic acids research", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/12409452/" - } - ], - "4406f0d4-9983-47d6-b7e3-1620ae09654d": [ - { - "pub_id": "12044939", - "title": "Large genome rearrangements as a primary cause of aging.", - "authors": "Jan Vijg,Martijn E T Doll\u00e9", - "abstract": "In his introductory chapter of the Mutation Research special issue on 'Genetic Instability and Aging', the late Bernard Strehler provided some historical perspectives on the long-standing hypothesis that aging is primarily caused by changes in the genome of somatic cells (Strehler, 1995, Mutat. Res. 338 (1995) 3). Based on his own findings of a loss of ribosomal RNA gene copies in postmitotic tissues of dogs as well as humans during aging, his main conclusion was that deletional mutations are more likely than point mutations to be a main causal factor in aging. To directly assess the levels of different types of spontaneous mutations in organs and tissues during aging, we have used a mouse model harboring a chromosomally integrated cluster of lacZ-containing plasmids that can be recovered and analyzed in Escherichia coli. Our results indicate the accumulation of mutations in some but not all organs of the mouse with significant differences in mutational spectra. In addition to point mutations, genome rearrangements involving up to 66 Mb of genomic DNA appeared to be a major component of the mutational spectra. Physical characterization of the breakpoints of such rearrangements indicated their possible origin by erroneous, non-homologous DNA double-strand break repair. Based on their increased occurrence during aging in some tissues and their often very large size, we have designed a model for an aging tissue in terms of a cellular mosaic with a gradual increase in genome rearrangements that leads to functional senescence, neoplastic transformation or death of individual cells by disrupting nuclear architecture and patterns of gene regulation.", - "journal_title": "Mechanisms of ageing and development", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/12044939/" - } - ], - "5f434783-db8a-409e-a1c6-1dc1c5e2ba1c": [ - { - "pub_id": "29930110", - "title": "Analysis of shared heritability in common disorders of the brain.", - "authors": " ,Verneri Anttila,Brendan Bulik-Sullivan,Hilary K Finucane,Raymond K Walters,Jose Bras,Laramie Duncan,Valentina Escott-Price,Guido J Falcone,Padhraig Gormley,Rainer Malik,Nikolaos A Patsopoulos,Stephan Ripke,Zhi Wei,Dongmei Yu,Phil H Lee,Patrick Turley,Benjamin Grenier-Boley,Vincent Chouraki,Yoichiro Kamatani,Claudine Berr,Luc Letenneur,Didier Hannequin,Philippe Amouyel,Anne Boland,Jean-Fran\u00e7ois Deleuze,Emmanuelle Duron,Badri N Vardarajan,Christiane Reitz,Alison M Goate,Matthew J Huentelman,M Ilyas Kamboh,Eric B Larson,Ekaterina Rogaeva,Peter St George-Hyslop,Hakon Hakonarson,Walter A Kukull,Lindsay A Farrer,Lisa L Barnes,Thomas G Beach,F Yesim Demirci,Elizabeth Head,Christine M Hulette,Gregory A Jicha,John S K Kauwe,Jeffrey A Kaye,James B Leverenz,Allan I Levey,Andrew P Lieberman,Vernon S Pankratz,Wayne W Poon,Joseph F Quinn,Andrew J Saykin,Lon S Schneider,Amanda G Smith,Joshua A Sonnen,Robert A Stern,Vivianna M Van Deerlin,Linda J Van Eldik,Denise Harold,Giancarlo Russo,David C Rubinsztein,Anthony Bayer,Magda Tsolaki,Petra Proitsi,Nick C Fox,Harald Hampel,Michael J Owen,Simon Mead,Peter Passmore,Kevin Morgan,Markus M N\u00f6then,Martin Rossor,Michelle K Lupton,Per Hoffmann,Johannes Kornhuber,Brian Lawlor,Andrew McQuillin,Ammar Al-Chalabi,Joshua C Bis,Agustin Ruiz,Merc\u00e8 Boada,Sudha Seshadri,Alexa Beiser,Kenneth Rice,Sven J van der Lee,Philip L De Jager,Daniel H Geschwind,Matthias Riemenschneider,Steffi Riedel-Heller,Jerome I Rotter,Gerhard Ransmayr,Bradley T Hyman,Carlos Cruchaga,Montserrat Alegret,Bendik Winsvold,Priit Palta,Kai-How Farh,Ester Cuenca-Leon,Nicholas Furlotte,Tobias Kurth,Lannie Ligthart,Gisela M Terwindt,Tobias Freilinger,Caroline Ran,Scott D Gordon,Guntram Borck,Hieab H H Adams,Terho Lehtim\u00e4ki,Juho Wedenoja,Julie E Buring,Markus Sch\u00fcrks,Maria Hrafnsdottir,Jouke-Jan Hottenga,Brenda Penninx,Ville Artto,Mari Kaunisto,Salli Veps\u00e4l\u00e4inen,Nicholas G Martin,Grant W Montgomery,Mitja I Kurki,Eija H\u00e4m\u00e4l\u00e4inen,Hailiang Huang,Jie Huang,Cynthia Sandor,Caleb Webber,Bertram Muller-Myhsok,Stefan Schreiber,Veikko Salomaa,Elizabeth Loehrer,Hartmut G\u00f6bel,Alfons Macaya,Patricia Pozo-Rosich,Thomas Hansen,Thomas Werge,Jaakko Kaprio,Andres Metspalu,Christian Kubisch,Michel D Ferrari,Andrea C Belin,Arn M J M van den Maagdenberg,John-Anker Zwart,Dorret Boomsma,Nicholas Eriksson,Jes Olesen,Daniel I Chasman,Dale R Nyholt,Andreja Avbersek,Larry Baum,Samuel Berkovic,Jonathan Bradfield,Russell J Buono,Claudia B Catarino,Patrick Cossette,Peter De Jonghe,Chantal Depondt,Dennis Dlugos,Thomas N Ferraro,Jacqueline French,Helle Hjalgrim,Jennifer Jamnadas-Khoda,Reetta K\u00e4lvi\u00e4inen,Wolfram S Kunz,Holger Lerche,Costin Leu,Dick Lindhout,Warren Lo,Daniel Lowenstein,Mark McCormack,Rikke S M\u00f8ller,Anne Molloy,Ping-Wing Ng,Karen Oliver,Michael Privitera,Rodney Radtke,Ann-Kathrin Ruppert,Thomas Sander,Steven Schachter,Christoph Schankin,Ingrid Scheffer,Susanne Schoch,Sanjay M Sisodiya,Philip Smith,Michael Sperling,Pasquale Striano,Rainer Surges,G Neil Thomas,Frank Visscher,Christopher D Whelan,Federico Zara,Erin L Heinzen,Anthony Marson,Felicitas Becker,Hans Stroink,Fritz Zimprich,Thomas Gasser,Raphael Gibbs,Peter Heutink,Maria Martinez,Huw R Morris,Manu Sharma,Mina Ryten,Kin Y Mok,Sara Pulit,Steve Bevan,Elizabeth Holliday,John Attia,Thomas Battey,Giorgio Boncoraglio,Vincent Thijs,Wei-Min Chen,Braxton Mitchell,Peter Rothwell,Pankaj Sharma,Cathie Sudlow,Astrid Vicente,Hugh Markus,Christina Kourkoulis,Joana Pera,Miriam Raffeld,Scott Silliman,Vesna Boraska Perica,Laura M Thornton,Laura M Huckins,N William Rayner,Cathryn M Lewis,Monica Gratacos,Filip Rybakowski,Anna Keski-Rahkonen,Anu Raevuori,James I Hudson,Ted Reichborn-Kjennerud,Palmiero Monteleone,Andreas Karwautz,Katrin Mannik,Jessica H Baker,Julie K O'Toole,Sara E Trace,Oliver S P Davis,Sietske G Helder,Stefan Ehrlich,Beate Herpertz-Dahlmann,Unna N Danner,Annemarie A van Elburg,Maurizio Clementi,Monica Forzan,Elisa Docampo,Jolanta Lissowska,Joanna Hauser,Alfonso Tortorella,Mario Maj,Fragiskos Gonidakis,Konstantinos Tziouvas,Hana Papezova,Zeynep Yilmaz,Gudrun Wagner,Sarah Cohen-Woods,Stefan Herms,Antonio Juli\u00e0,Raquel Rabionet,Danielle M Dick,Samuli Ripatti,Ole A Andreassen,Thomas Espeseth,Astri J Lundervold,Vidar M Steen,Dalila Pinto,Stephen W Scherer,Harald Aschauer,Alexandra Schosser,Lars Alfredsson,Leonid Padyukov,Katherine A Halmi,James Mitchell,Michael Strober,Andrew W Bergen,Walter Kaye,Jin Peng Szatkiewicz,Bru Cormand,Josep Antoni Ramos-Quiroga,Cristina S\u00e1nchez-Mora,Marta Ribas\u00e9s,Miguel Casas,Amaia Hervas,Maria Jes\u00fas Arranz,Jan Haavik,Tetyana Zayats,Stefan Johansson,Nigel Williams,Astrid Dempfle,Aribert Rothenberger,Jonna Kuntsi,Robert D Oades,Tobias Banaschewski,Barbara Franke,Jan K Buitelaar,Alejandro Arias Vasquez,Alysa E Doyle,Andreas Reif,Klaus-Peter Lesch,Christine Freitag,Olga Rivero,Haukur Palmason,Marcel Romanos,Kate Langley,Marcella Rietschel,Stephanie H Witt,Soeren Dalsgaard,Anders D B\u00f8rglum,Irwin Waldman,Beth Wilmot,Nikolas Molly,Claiton H D Bau,Jennifer Crosbie,Russell Schachar,Sandra K Loo,James J McGough,Eugenio H Grevet,Sarah E Medland,Elise Robinson,Lauren A Weiss,Elena Bacchelli,Anthony Bailey,Vanessa Bal,Agatino Battaglia,Catalina Betancur,Patrick Bolton,Rita Cantor,Patr\u00edcia Celestino-Soper,Geraldine Dawson,Silvia De Rubeis,Frederico Duque,Andrew Green,Sabine M Klauck,Marion Leboyer,Pat Levitt,Elena Maestrini,Shrikant Mane,Daniel Moreno- De-Luca,Jeremy Parr,Regina Regan,Abraham Reichenberg,Sven Sandin,Jacob Vorstman,Thomas Wassink,Ellen Wijsman,Edwin Cook,Susan Santangelo,Richard Delorme,Bernadette Rog\u00e9,Tiago Magalhaes,Dan Arking,Thomas G Schulze,Robert C Thompson,Jana Strohmaier,Keith Matthews,Ingrid Melle,Derek Morris,Douglas Blackwood,Andrew McIntosh,Sarah E Bergen,Martin Schalling,St\u00e9phane Jamain,Anna Maaser,Sascha B Fischer,C\u00e9line S Reinbold,Janice M Fullerton,Jos\u00e9 Guzman-Parra,Fermin Mayoral,Peter R Schofield,Sven Cichon,Thomas W M\u00fchleisen,Franziska Degenhardt,Johannes Schumacher,Michael Bauer,Philip B Mitchell,Elliot S Gershon,John Rice,James B Potash,Peter P Zandi,Nick Craddock,I Nicol Ferrier,Martin Alda,Guy A Rouleau,Gustavo Turecki,Roel Ophoff,Carlos Pato,Adebayo Anjorin,Eli Stahl,Markus Leber,Piotr M Czerski,Cristiana Cruceanu,Ian R Jones,Danielle Posthuma,Till F M Andlauer,Andreas J Forstner,Fabian Streit,Bernhard T Baune,Tracy Air,Grant Sinnamon,Naomi R Wray,Donald J MacIntyre,David Porteous,Georg Homuth,Margarita Rivera,Jakob Grove,Christel M Middeldorp,Ian Hickie,Michele Pergadia,Divya Mehta,Johannes H Smit,Rick Jansen,Eco de Geus,Erin Dunn,Qingqin S Li,Matthias Nauck,Robert A Schoevers,Aartjan Tf Beekman,James A Knowles,Alexander Viktorin,Paul Arnold,Cathy L Barr,Gabriel Bedoya-Berrio,O Joseph Bienvenu,Helena Brentani,Christie Burton,Beatriz Camarena,Carolina Cappi,Danielle Cath,Maria Cavallini,Daniele Cusi,Sabrina Darrow,Damiaan Denys,Eske M Derks,Andrea Dietrich,Thomas Fernandez,Martijn Figee,Nelson Freimer,Gloria Gerber,Marco Grados,Erica Greenberg,Gregory L Hanna,Andreas Hartmann,Matthew E Hirschtritt,Pieter J Hoekstra,Alden Huang,Chaim Huyser,Cornelia Illmann,Michael Jenike,Samuel Kuperman,Bennett Leventhal,Christine Lochner,Gholson J Lyon,Fabio Macciardi,Marcos Madruga-Garrido,Irene A Malaty,Athanasios Maras,Lauren McGrath,Eur\u00edpedes C Miguel,Pablo Mir,Gerald Nestadt,Humberto Nicolini,Michael S Okun,Andrew Pakstis,Peristera Paschou,John Piacentini,Christopher Pittenger,Kerstin Plessen,Vasily Ramensky,Eliana M Ramos,Victor Reus,Margaret A Richter,Mark A Riddle,Mary M Robertson,Veit Roessner,Maria Ros\u00e1rio,Jack F Samuels,Paul Sandor,Dan J Stein,Fotis Tsetsos,Filip Van Nieuwerburgh,Sarah Weatherall,Jens R Wendland,Tomasz Wolanczyk,Yulia Worbe,Gwyneth Zai,Fernando S Goes,Nicole McLaughlin,Paul S Nestadt,Hans-Jorgen Grabe,Christel Depienne,Anuar Konkashbaev,Nuria Lanzagorta,Ana Valencia-Duarte,Elvira Bramon,Nancy Buccola,Wiepke Cahn,Murray Cairns,Siow A Chong,David Cohen,Benedicto Crespo-Facorro,James Crowley,Michael Davidson,Lynn DeLisi,Timothy Dinan,Gary Donohoe,Elodie Drapeau,Jubao Duan,Lieuwe Haan,David Hougaard,Sena Karachanak-Yankova,Andrey Khrunin,Janis Klovins,Vaidutis Ku\u010dinskas,Jimmy Lee Chee Keong,Svetlana Limborska,Carmel Loughland,Jouko L\u00f6nnqvist,Brion Maher,Manuel Mattheisen,Colm McDonald,Kieran C Murphy,Igor Nenadic,Jim van Os,Christos Pantelis,Michele Pato,Tracey Petryshen,Digby Quested,Panos Roussos,Alan R Sanders,Ulrich Schall,Sibylle G Schwab,Kang Sim,Hon-Cheong So,Elisabeth St\u00f6gmann,Mythily Subramaniam,Draga Toncheva,John Waddington,James Walters,Mark Weiser,Wei Cheng,Robert Cloninger,David Curtis,Pablo V Gejman,Frans Henskens,Morten Mattingsdal,Sang-Yun Oh,Rodney Scott,Bradley Webb,Gerome Breen,Claire Churchhouse,Cynthia M Bulik,Mark Daly,Martin Dichgans,Stephen V Faraone,Rita Guerreiro,Peter Holmans,Kenneth S Kendler,Bobby Koeleman,Carol A Mathews,Alkes Price,Jeremiah Scharf,Pamela Sklar,Julie Williams,Nicholas W Wood,Chris Cotsapas,Aarno Palotie,Jordan W Smoller,Patrick Sullivan,Jonathan Rosand,Aiden Corvin,Benjamin M Neale,Jonathan M Schott,Richard Anney,Josephine Elia,Maria Grigoroiu-Serbanescu,Howard J Edenberg,Robin Murray", - "abstract": "Disorders of the brain can exhibit considerable epidemiological comorbidity and often share symptoms, provoking debate about their etiologic overlap. We quantified the genetic sharing of 25 brain disorders from genome-wide association studies of 265,218 patients and 784,643 control participants and assessed their relationship to 17 phenotypes from 1,191,588 individuals. Psychiatric disorders share common variant risk, whereas neurological disorders appear more distinct from one another and from the psychiatric disorders. We also identified significant sharing between disorders and a number of brain phenotypes, including cognitive measures. Further, we conducted simulations to explore how statistical power, diagnostic misclassification, and phenotypic heterogeneity affect genetic correlations. These results highlight the importance of common genetic variation as a risk factor for brain disorders and the value of heritability-based methods in understanding their etiology.", - "journal_title": "Science (New York, N.Y.)", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/29930110/" - } - ], - "a280f957-98e0-4098-bc4b-fa3bdc25558d": [ - { - "pub_id": "11595044", - "title": "Statistical tests of selective neutrality in the age of genomics.", - "authors": "R Nielsen", - "abstract": "Examining genomic data for traces of selection provides a powerful tool for identifying genomic regions of functional importance. Many methods for identifying such regions have focused on conserved sites. However, positive selection may also be an indication of functional importance. This article provides a brief review of some of the statistical methods used to detect selection using DNA sequence data or other molecular data. Statistical tests based on allelic distributions or levels of variability often depend on strong assumptions regarding population demographics. In contrast, tests based on comparisons of the level of variability in nonsynonymous and synonymous sites can be constructed without demographic assumptions. Such tests appear to be useful for identifying specific regions or specific sites targeted by selection.", - "journal_title": "Heredity", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/11595044/" - } - ], - "63be1ce8-c2cc-48e5-96e5-e905d8791e37": [ - { - "pub_id": "12421750", - "title": "Signatures of domain shuffling in the human genome.", - "authors": "Henrik Kaessmann,Sebastian Z\u00f6llner,Anton Nekrutenko,Wen-Hsiung Li", - "abstract": "To elucidate the role of exon shuffling in shaping the complexity of the human genome/proteome, we have systematically analyzed intron phase distributions in the coding sequence of human protein domains. We found that introns at the boundaries of domains show high excess of symmetrical phase combinations (i.e., 0-0, 1-1, and 2-2), whereas nonboundary introns show no excess symmetry. This suggests that exon shuffling has primarily involved rearrangement of structural and functional domains as a whole. Furthermore, we found that domains flanked by phase 1 introns have dramatically expanded in the human genome due to domain shuffling and that 1-1 symmetrical domains and domain families are nonrandomly distributed with respect to their age. The predominance and extracellular location of 1-1 symmetrical domains among domains specific to metazoans suggests that they are associated with the rise of multicellularity. On the other hand, 0-0 symmetrical domains tend to be over-represented among ancient protein domains that are shared between the eukaryotic and prokaryotic kingdoms, which is compatible with the suggestion of primordial domain shuffling in the progenote. To see whether the human data reflect general genomic patterns of metazoans, similar analyses were done for the nematode Caenorhabditis elegans. Although the C. elegans data generally concur with the human patterns, we identified fewer intron-bounded domains in this organism, consistent with the lower complexity of C. elegans genes. [The following individuals kindly provided reagents, samples, or unpublished information as indicated in the paper: Z. Gu and R. Stevens.]", - "journal_title": "Genome research", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/12421750/" - } - ], - "9df1e17a-a45c-4946-b532-18a3d26f303f": [ - { - "pub_id": "9689094", - "title": "Molecular archaeology of the Escherichia coli genome.", - "authors": "J G Lawrence,H Ochman", - "abstract": "The availability of the complete sequence of Escherichia coli strain MG1655 provides the first opportunity to assess the overall impact of horizontal genetic transfer on the evolution of bacterial genomes. We found that 755 of 4,288 ORFs (547.8 kb) have been introduced into the E. coli genome in at least 234 lateral transfer events since this species diverged from the Salmonella lineage 100 million years (Myr) ago. The average age of introduced genes was 14.4 Myr, yielding a rate of transfer 16 kb/Myr/lineage since divergence. Although most of the acquired genes subsequently were deleted, the sequences that have persisted ( approximately 18% of the current chromosome) have conferred properties permitting E. coli to explore otherwise unreachable ecological niches.", - "journal_title": "Proceedings of the National Academy of Sciences of the United States of America", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/9689094/" - } - ], - "98ce73c6-a53b-486f-8326-4b0bd47ec22e": [ - { - "pub_id": "11462233", - "title": "Using linked markers to infer the age of a mutation.", - "authors": "B Rannala,G Bertorelle", - "abstract": "Advances in sequencing and genotyping technologies over the last decade have enabled geneticists to easily characterize genetic variation at the nucleotide level. Hundreds of genes harboring mutations associated with genetic disease have now been identified by positional cloning. Using variation at closely linked genetic markers, it is possible to predict the times in the past at which particular mutations arose. Such studies suggest that many of the rare mutations underlying human genetic disorders are relatively young. Studies of variation at genetic markers linked to particular mutations can provide insights into human geographic history, and historical patterns of natural selection and disease, that are not available from other sources. We review two approaches for estimating allele age using variation at linked genetic markers. A phylogenetic approach aims to reconstruct the gene tree underlying a sample of chromosomes carrying a particular mutation, obtaining a \"direct\" estimate of allele age from the age of the root of this tree. A population genetic approach relies on models of demography, mutation, and/or recombination to estimate allele age without explicitly reconstructing the gene tree. Phylogenetic methods are best suited for studies of ancient mutations, while population genetic methods are better suited for studies of recent mutations. Methods that rely on recombination to infer the ages of alleles can be fine-tuned by choosing linked markers at optimal map distances to maximize the information available about allele age. A limitation of methods that rely on recombination is the frequent lack of a fine-scale linkage map. Maximum likelihood and Bayesian methods for estimating allele age that rely on intensive numerical computation are described, as well as \"composite\" likelihood and moment-based methods that lead to simple estimators. The former provide more accurate estimates (particularly for large samples of chromosomes) and should be employed if computationally practical.", - "journal_title": "Human mutation", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/11462233/" - } - ], - "010bb1e3-60aa-48d5-8aaa-83ae33a8de14": [ - { - "pub_id": "12209020", - "title": "Influence of age, sex, and strength training on human muscle gene expression determined by microarray.", - "authors": "Stephen M Roth,Robert E Ferrell,David G Peters,E Jeffrey Metter,Ben F Hurley,Marc A Rogers", - "abstract": "The purpose of this study was to determine the influence of age, sex, and strength training (ST) on large-scale gene expression patterns in vastus lateralis muscle biopsies using high-density cDNA microarrays and quantitative PCR. Muscle samples from sedentary young (20-30 yr) and older (65-75 yr) men and women (5 per group) were obtained before and after a 9-wk unilateral heavy resistance ST program. RNA was hybridized to cDNA filter microarrays representing approximately 4,000 known human genes and comparisons were made among arrays to determine differential gene expression as a result of age and sex differences, and/or response to ST. Sex had the strongest influence on muscle gene expression, with differential expression (>1.7-fold) observed for approximately 200 genes between men and women (approximately 75% with higher expression in men). Age contributed to differential expression as well, as approximately 50 genes were identified as differentially expressed (>1.7-fold) in relation to age, representing structural, metabolic, and regulatory gene classes. Sixty-nine genes were identified as being differentially expressed (>1.7-fold) in all groups in response to ST, and the majority of these were downregulated. Quantitative PCR was employed to validate expression levels for caldesmon, SWI/SNF (BAF60b), and four-and-a-half LIM domains 1. These significant differences suggest that in the analysis of skeletal muscle gene expression issues of sex, age, and habitual physical activity must be addressed, with sex being the most critical variable.", - "journal_title": "Physiological genomics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/12209020/" - } - ], - "1d5ad0c4-29bb-45d7-b599-c561703e6d3d": [ - { - "pub_id": "10814715", - "title": "A full genome scan for age-related maculopathy.", - "authors": "D E Weeks,Y P Conley,T S Mah,T O Paul,L Morse,J Ngo-Chang,J P Dailey,R E Ferrell,M B Gorin", - "abstract": "Age-related macular degeneration or age-related maculopathy (ARM) is a major public health issue, as it is the leading cause of irreversible vision loss in the elderly in the Western world. Using three diagnostic models, we have genotyped markers in 16 plausible candidate regions and have carried out a genome-wide screen for ARM susceptibility loci. A panel of 225 ARM families comprising up to 212 affected sib pairs was genotyped for 386 markers. Under our most stringent diagnostic model, the regions with the strongest evidence of linkage were on chromosome 9 near D9S301 and on 10 near D10S1230, with peak multipoint heterogeneity LOD scores (HLOD) of 1.87 and 1. 42 and peak GeneHunter-Plus non-parametric LOD scores (GHP LOD) of 1. 69 and 1.83. After expanding our initial set of families to 364 ARM families with up to 329 affected sib pairs, the linkage signal on chromosome 9 vanished, while the chromosome 10 signal decreased to a GHP LOD of about 1.0, with a SimIBD P -value of 0.008 under the broadest diagnostic model with marker D10S1236. After error filtration, the GHP LOD increased to 1.27 under our most stringent model and 1.42 under our broadest model, peaking near D10S1236. This peak was seen consistently across all three diagnostic models. Our analyses also excluded up to nine different candidate regions and identified a few other regions of potential linkage, suitable for further studies. Of particular interest was the region on chromosome 5 near D5S1480, where a reasonable candidate gene, glutathione peroxidase 3, resides.", - "journal_title": "Human molecular genetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/10814715/" - } - ], - "d3d37b06-8621-424e-9de5-462e4b28adf6": [ - { - "pub_id": "12610534", - "title": "Epigenetic regulation of gene expression: how the genome integrates intrinsic and environmental signals.", - "authors": "Rudolf Jaenisch,Adrian Bird", - "abstract": "Cells of a multicellular organism are genetically homogeneous but structurally and functionally heterogeneous owing to the differential expression of genes. Many of these differences in gene expression arise during development and are subsequently retained through mitosis. Stable alterations of this kind are said to be 'epigenetic', because they are heritable in the short term but do not involve mutations of the DNA itself. Research over the past few years has focused on two molecular mechanisms that mediate epigenetic phenomena: DNA methylation and histone modifications. Here, we review advances in the understanding of the mechanism and role of DNA methylation in biological processes. Epigenetic effects by means of DNA methylation have an important role in development but can also arise stochastically as animals age. Identification of proteins that mediate these effects has provided insight into this complex process and diseases that occur when it is perturbed. External influences on epigenetic processes are seen in the effects of diet on long-term diseases such as cancer. Thus, epigenetic mechanisms seem to allow an organism to respond to the environment through changes in gene expression. The extent to which environmental effects can provoke epigenetic responses represents an exciting area of future research.", - "journal_title": "Nature genetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/12610534/" - } - ], - "a40987df-f8c9-49ce-a985-acb6744dd6dc": [ - { - "pub_id": "8765750", - "title": "Isolation and characterization of genomic and cDNA clones encoding mouse senescence marker protein-30 (SMP30).", - "authors": "T Fujita,T Shirasawa,N Maruyama", - "abstract": "We isolated and characterized genomic and cDNA clones encoding mouse senescence marker protein-30 (SMP30), the protein amounts of which are known to decrease with aging in the livers of rats. This decrease in the expression of SMP30 is independent of androgen. SMP30 is a calcium binding protein also called regucalcin. The expression of SMP30 in aged mouse liver and 5' flanking sequence of the genome were also characterized. The cDNA contained an open reading frame encoding 299 amino acids with a calculated molecular weight of 33-404. The amino acid sequence of mouse SMP30 showed 94% similarity to rat SMP30 and 89% to human SMP30. Northern blot analysis specifically detected mouse SMP30 transcript in the liver and also confirmed its significant decrease with aging. Analysis of the murine genomic clone revealed that SMP30 was organized by seven exons and six introns, spanning approx. 17.5 kb. Primer extension analysis revealed that two major transcription initiation sites were localized at 101 bp and 102 bp upstream from ATG translation initiation codon. The nucleotide (nt) sequence of 5' flanking region showed a TATA-like sequence, a CAAT box, and SP-1 sites at nt -29, -72 and -169 in the promoter region, respectively. Interestingly, we found two classes of C/EBP sites which are highly and constantly expressed in the liver, in addition to AP-2, AP-1, GATA-1, AP-1/GRE and GAGA sites. These results provide important clues for understanding the regulatory mechanism of SMP30 gene expression and its relationship to aging.", - "journal_title": "Biochimica et biophysica acta", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/8765750/" - } - ], - "80dab45e-186d-4a72-b0fe-31d13ea5b8ab": [ - { - "pub_id": "11154284", - "title": "From cot curves to genomics. How gene cloning established new concepts in plant biology.", - "authors": "R B Goldberg", - "abstract": "", - "journal_title": "Plant physiology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/11154284/" - } - ], - "672bff43-055b-4b7d-bc8f-3b1688584b98": [ - { - "pub_id": "11707900", - "title": "From life to death--the struggle between chemistry and biology during aging: the Maillard reaction as an amplifier of genomic damage.", - "authors": "J W Baynes", - "abstract": "Biogerontology is the study of the aging of biological systems. This review addresses the relationship between chemistry and biology during aging, proposing that chemistry is responsible for the aging of biological systems. In the continuing struggle between chemistry and biology, chemistry is always the short-term, tactical winner--death of the individual is inevitable. However, barring the extinction of species, biology is the long-term, strategic victor--life survives, and the struggle continues. The rate of random chemical damage to the genome is considered the major factor determining lifespan of species. Oxidative stress and reactive oxygen species are recognized as a primary source of damage in aging and chronic disease. The Maillard reaction, involving nonenzymatic, oxidative reactions of carbohydrate and lipid substrates, is seen as an amplifier of reactive oxygen damage. Maillard reaction products in protein are viewed as integrators of cumulative damage by reactive oxygen, and possibly as initiators of protective responses, but the primary factor affecting lifespan is identified as silent cumulative damage to the genome, resulting from imperfect repair. Maillard reaction inhibitors show promise for treatment of chronic diseases, such as diabetes and atherosclerosis, and also have a positive effect on health in normal animals. Future studies should focus on evaluation of the effects of these inhibitors on genomic damage and lifespan extension.", - "journal_title": "Biogerontology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/11707900/" - } - ], - "711ef37f-d365-4d14-b6f4-8967d8c5ab7c": [ - { - "pub_id": "16925525", - "title": "Mechanisms of RecQ helicases in pathways of DNA metabolism and maintenance of genomic stability.", - "authors": "Sudha Sharma,Kevin M Doherty,Robert M Brosh", - "abstract": "Helicases are molecular motor proteins that couple the hydrolysis of NTP to nucleic acid unwinding. The growing number of DNA helicases implicated in human disease suggests that their vital specialized roles in cellular pathways are important for the maintenance of genome stability. In particular, mutations in genes of the RecQ family of DNA helicases result in chromosomal instability diseases of premature aging and/or cancer predisposition. We will discuss the mechanisms of RecQ helicases in pathways of DNA metabolism. A review of RecQ helicases from bacteria to human reveals their importance in genomic stability by their participation with other proteins to resolve DNA replication and recombination intermediates. In the light of their known catalytic activities and protein interactions, proposed models for RecQ function will be summarized with an emphasis on how this distinct class of enzymes functions in chromosomal stability maintenance and prevention of human disease and cancer.", - "journal_title": "The Biochemical journal", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/16925525/" - } - ], - "430d5170-6200-40e8-a697-fc72dde0b8a5": [ - { - "pub_id": "32424353", - "title": "Genome-wide association study identifies 32 novel breast cancer susceptibility loci from overall and subtype-specific analyses.", - "authors": "Haoyu Zhang,Thomas U Ahearn,Julie Lecarpentier,Daniel Barnes,Jonathan Beesley,Guanghao Qi,Xia Jiang,Tracy A O'Mara,Ni Zhao,Manjeet K Bolla,Alison M Dunning,Joe Dennis,Qin Wang,Zumuruda Abu Ful,Kristiina Aittom\u00e4ki,Irene L Andrulis,Hoda Anton-Culver,Volker Arndt,Kristan J Aronson,Banu K Arun,Paul L Auer,Jacopo Azzollini,Daniel Barrowdale,Heiko Becher,Matthias W Beckmann,Sabine Behrens,Javier Benitez,Marina Bermisheva,Katarzyna Bialkowska,Ana Blanco,Carl Blomqvist,Natalia V Bogdanova,Stig E Bojesen,Bernardo Bonanni,Davide Bondavalli,Ake Borg,Hiltrud Brauch,Hermann Brenner,Ignacio Briceno,Annegien Broeks,Sara Y Brucker,Thomas Br\u00fcning,Barbara Burwinkel,Saundra S Buys,Helen Byers,Trinidad Cald\u00e9s,Maria A Caligo,Mariarosaria Calvello,Daniele Campa,Jose E Castelao,Jenny Chang-Claude,Stephen J Chanock,Melissa Christiaens,Hans Christiansen,Wendy K Chung,Kathleen B M Claes,Christine L Clarke,Sten Cornelissen,Fergus J Couch,Angela Cox,Simon S Cross,Kamila Czene,Mary B Daly,Peter Devilee,Orland Diez,Susan M Domchek,Thilo D\u00f6rk,Miriam Dwek,Diana M Eccles,Arif B Ekici,D Gareth Evans,Peter A Fasching,Jonine Figueroa,Lenka Foretova,Florentia Fostira,Eitan Friedman,Debra Frost,Manuela Gago-Dominguez,Susan M Gapstur,Judy Garber,Jos\u00e9 A Garc\u00eda-S\u00e1enz,Mia M Gaudet,Simon A Gayther,Graham G Giles,Andrew K Godwin,Mark S Goldberg,David E Goldgar,Anna Gonz\u00e1lez-Neira,Mark H Greene,Jacek Gronwald,Pascal Gu\u00e9nel,Lothar H\u00e4berle,Eric Hahnen,Christopher A Haiman,Christopher R Hake,Per Hall,Ute Hamann,Elaine F Harkness,Bernadette A M Heemskerk-Gerritsen,Peter Hillemanns,Frans B L Hogervorst,Bernd Holleczek,Antoinette Hollestelle,Maartje J Hooning,Robert N Hoover,John L Hopper,Anthony Howell,Hanna Huebner,Peter J Hulick,Evgeny N Imyanitov, , ,Claudine Isaacs,Louise Izatt,Agnes Jager,Milena Jakimovska,Anna Jakubowska,Paul James,Ramunas Janavicius,Wolfgang Janni,Esther M John,Michael E Jones,Audrey Jung,Rudolf Kaaks,Pooja Middha Kapoor,Beth Y Karlan,Renske Keeman,Sofia Khan,Elza Khusnutdinova,Cari M Kitahara,Yon-Dschun Ko,Irene Konstantopoulou,Linetta B Koppert,Stella Koutros,Vessela N Kristensen,Anne-Vibeke Laenkholm,Diether Lambrechts,Susanna C Larsson,Pierre Laurent-Puig,Conxi Lazaro,Emilija Lazarova,Flavio Lejbkowicz,Goska Leslie,Fabienne Lesueur,Annika Lindblom,Jolanta Lissowska,Wing-Yee Lo,Jennifer T Loud,Jan Lubinski,Alicja Lukomska,Robert J MacInnis,Arto Mannermaa,Mehdi Manoochehri,Siranoush Manoukian,Sara Margolin,Maria Elena Martinez,Laura Matricardi,Lesley McGuffog,Catriona McLean,Noura Mebirouk,Alfons Meindl,Usha Menon,Austin Miller,Elvira Mingazheva,Marco Montagna,Anna Marie Mulligan,Claire Mulot,Taru A Muranen,Katherine L Nathanson,Susan L Neuhausen,Heli Nevanlinna,Patrick Neven,William G Newman,Finn C Nielsen,Liene Nikitina-Zake,Jesse Nodora,Kenneth Offit,Edith Olah,Olufunmilayo I Olopade,H\u00e5kan Olsson,Nick Orr,Laura Papi,Janos Papp,Tjoung-Won Park-Simon,Michael T Parsons,Bernard Peissel,Ana Peixoto,Beth Peshkin,Paolo Peterlongo,Julian Peto,Kelly-Anne Phillips,Marion Piedmonte,Dijana Plaseska-Karanfilska,Karolina Prajzendanc,Ross Prentice,Darya Prokofyeva,Brigitte Rack,Paolo Radice,Susan J Ramus,Johanna Rantala,Muhammad U Rashid,Gad Rennert,Hedy S Rennert,Harvey A Risch,Atocha Romero,Matti A Rookus,Matthias R\u00fcbner,Thomas R\u00fcdiger,Emmanouil Saloustros,Sarah Sampson,Dale P Sandler,Elinor J Sawyer,Maren T Scheuner,Rita K Schmutzler,Andreas Schneeweiss,Minouk J Schoemaker,Ben Sch\u00f6ttker,Peter Sch\u00fcrmann,Leigha Senter,Priyanka Sharma,Mark E Sherman,Xiao-Ou Shu,Christian F Singer,Snezhana Smichkoska,Penny Soucy,Melissa C Southey,John J Spinelli,Jennifer Stone,Dominique Stoppa-Lyonnet, , ,Anthony J Swerdlow,Csilla I Szabo,Rulla M Tamimi,William J Tapper,Jack A Taylor,Manuel R Teixeira,MaryBeth Terry,Mads Thomassen,Darcy L Thull,Marc Tischkowitz,Amanda E Toland,Rob A E M Tollenaar,Ian Tomlinson,Diana Torres,Melissa A Troester,Th\u00e9r\u00e8se Truong,Nadine Tung,Michael Untch,Celine M Vachon,Ans M W van den Ouweland,Lizet E van der Kolk,Elke M van Veen,Elizabeth J vanRensburg,Ana Vega,Barbara Wappenschmidt,Clarice R Weinberg,Jeffrey N Weitzel,Hans Wildiers,Robert Winqvist,Alicja Wolk,Xiaohong R Yang,Drakoulis Yannoukakos,Wei Zheng,Kristin K Zorn,Roger L Milne,Peter Kraft,Jacques Simard,Paul D P Pharoah,Kyriaki Michailidou,Antonis C Antoniou,Marjanka K Schmidt,Georgia Chenevix-Trench,Douglas F Easton,Nilanjan Chatterjee,Montserrat Garc\u00eda-Closas", - "abstract": "Breast cancer susceptibility variants frequently show heterogeneity in associations by tumor subtype<sup>1-3</sup>. To identify novel loci, we performed a genome-wide association study including 133,384 breast cancer cases and 113,789 controls, plus 18,908 BRCA1 mutation carriers (9,414 with breast cancer) of European ancestry, using both standard and novel methodologies that account for underlying tumor heterogeneity by estrogen receptor, progesterone receptor and human epidermal growth factor receptor 2 status and tumor grade. We identified 32 novel susceptibility loci (P\u2009<\u20095.0\u2009\u00d7\u200910<sup>-8</sup>), 15 of which showed evidence for associations with at least one tumor feature (false discovery rate\u2009<\u20090.05). Five loci showed associations (P\u2009<\u20090.05) in opposite directions between luminal and non-luminal subtypes. In silico analyses showed that these five loci contained cell-specific enhancers that differed between normal luminal and basal mammary cells. The genetic correlations between five intrinsic-like subtypes ranged from 0.35 to 0.80. The proportion of genome-wide chip heritability explained by all known susceptibility loci was 54.2% for luminal A-like disease and 37.6% for triple-negative disease. The odds ratios of polygenic risk scores, which included 330 variants, for the highest 1% of quantiles compared with middle quantiles were 5.63 and 3.02 for luminal A-like and triple-negative disease, respectively. These findings provide an improved understanding of genetic predisposition to breast cancer subtypes and will inform the development of subtype-specific polygenic risk scores.", - "journal_title": "Nature genetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/32424353/" - } - ], - "aff67cef-4bf7-42dc-826b-2a259722008d": [ - { - "pub_id": "17689905", - "title": "The skin as a mirror of the aging process in the human organism--state of the art and results of the aging research in the German National Genome Research Network 2 (NGFN-2).", - "authors": "Evgenia Makrantonaki,Christos C Zouboulis, ", - "abstract": "As our society is growing older, the consequences of aging have begun to gain particular attention. Improvement of quality of life at old age and prevention of age-associated diseases have become the main focus of the aging research. The process of aging in humans is complex and underlies multiple influences, with the probable involvement of heritable and various environmental factors. In particular, hormones are decisively involved in the generation of aging. Over time, important circulating hormones decline due to a reduced secretion of the pituitary, the adrenal glands and the gonads or due to an intercurrent disease. Among them, serum levels of growth factors and sexual steroids show significant aging-associated changes. Within the scope of the Explorative Project 'Genetic aetiology of human longevity' supported by the German National Genome Research Network 2 (NGFN-2) an in vitro model of human hormonal aging has been developed. Human SZ95 sebocytes were maintained under a hormone-substituted environment consisting of growth factors and sexual steroids in concentrations corresponding to those circulating in 20- and in 60-year-old women. Eight hundred and ninety-nine genes showed a differential expression in SZ95 sebocytes maintained under the 20- and 60-year-old hormone mixture, respectively. Among them genes were regulated which are involved in biological processes which are all hallmarks of aging. The most significantly altered signaling pathway identified was that of the transforming growth factor-beta (TGF-beta). A disturbed function of this cascade has been associated with tumorigenesis, i.e. in pancreatic, prostate, intestine, breast, and uterine cancer. Interestingly, genes expressed in signaling pathways operative in age-associated diseases such as Huntington's disease (HD), dentatorubral-pallidoluysian atrophy (DRPLA), and amyotrophic lateral sclerosis (ALS) were also identified. These data demonstrate that skin and its appendages may represent an adequate model for aging research. Hormones interact in a complex fashion, and aging may be partly attributed to the changes in their circulating blood levels. Furthermore, a disturbed hormone status may partially act towards the manifestation of neurodegenerative diseases. Thus, these results could be a basis for an integrated and interdisciplinary approach to the analysis of the aging process.", - "journal_title": "Experimental gerontology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/17689905/" - } - ], - "36664800-972c-4f1a-9b58-673dd69365a5": [ - { - "pub_id": "17630829", - "title": "Evolutionary history of mammalian transposons determined by genome-wide defragmentation.", - "authors": "Joti Giordano,Yongchao Ge,Yevgeniy Gelfand,Gy\u00f6rgy Abrus\u00e1n,Gary Benson,Peter E Warburton", - "abstract": "The constant bombardment of mammalian genomes by transposable elements (TEs) has resulted in TEs comprising at least 45% of the human genome. Because of their great age and abundance, TEs are important in comparative phylogenomics. However, estimates of TE age were previously based on divergence from derived consensus sequences or phylogenetic analysis, which can be unreliable, especially for older more diverged elements. Therefore, a novel genome-wide analysis of TE organization and fragmentation was performed to estimate TE age independently of sequence composition and divergence or the assumption of a constant molecular clock. Analysis of TEs in the human genome revealed approximately 600,000 examples where TEs have transposed into and fragmented other TEs, covering >40% of all TEs or approximately 542 Mbp of genomic sequence. The relative age of these TEs over evolutionary time is implicit in their organization, because newer TEs have necessarily transposed into older TEs that were already present. A matrix of the number of times that each TE has transposed into every other TE was constructed, and a novel objective function was developed that derived the chronological order and relative ages of human TEs spanning >100 million years. This method has been used to infer the relative ages across all four major TE classes, including the oldest, most diverged elements. Analysis of DNA transposons over the history of the human genome has revealed the early activity of some MER2 transposons, and the relatively recent activity of MER1 transposons during primate lineages. The TEs from six additional mammalian genomes were defragmented and analyzed. Pairwise comparison of the independent chronological orders of TEs in these mammalian genomes revealed species phylogeny, the fact that transposons shared between genomes are older than species-specific transposons, and a subset of TEs that were potentially active during periods of speciation.", - "journal_title": "PLoS computational biology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/17630829/" - } - ], - "2f6a5948-c165-44b6-904b-72b54cac2b65": [ - { - "pub_id": "12408962", - "title": "Ahl2, a second locus affecting age-related hearing loss in mice.", - "authors": "Kenneth R Johnson,Qing Yin Zheng", - "abstract": "Inbred mouse strains with age-related hearing loss (AHL) provide valuable models for studying the genetic basis of human presbycusis. Here we report the genetic mapping of a second AHL locus in mice (designated Ahl2) that is a major contributor to the 8- to 10-month difference in hearing loss onset times between NOD/LtJ and C57BL/6J mice. A whole-genome linkage scan of 110 progeny from a (C57BL/6JxNOD/LtJ)xNOD/LtJ backcross revealed statistically significant associations of ABR thresholds with markers on chromosome 5, with a peak lod score of 5.5 for D5Mit309. At 6 months of age, backcross progeny that inherited two copies of the recessive NOD/LtJ-derived allele at this locus (genotype ahl2/ahl2) exhibited ABR thresholds that were on average 26 decibels above those of heterozygous mice. Analysis of a (CAST/EixNOD/LtJ)xNOD/LtJ backcross, which segregates strain-specific alleles at both Ahl2 and the Ahl locus on chromosome 10, showed that the hearing loss attributable to Ahl2 is dependent on a predisposing Ahl genotype. The statistically significant effect of Ahl2 observed in crosses with NOD/LtJ was not seen in crosses involving three other strains with early onset AHL: A/J, BUB/BnJ, and SKH2/J.", - "journal_title": "Genomics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/12408962/" - } - ], - "f377428d-564d-4d5b-b86c-515b9325134f": [ - { - "pub_id": "17227869", - "title": "Cdc42 GTPase-activating protein deficiency promotes genomic instability and premature aging-like phenotypes.", - "authors": "Lei Wang,Linda Yang,Marcella Debidda,David Witte,Yi Zheng", - "abstract": "Cdc42 is a member of the Rho GTPase family known to regulate cell actin cytoskeleton organization, polarity, and growth, but its function in mammalian organismal physiology remains unclear. We found that natural aging of WT mice is marked with increased Cdc42 activity in various tissues. Among the negative regulators of Cdc42, gene targeting of Cdc42 GTPase-activating protein (Cdc42GAP) results in constitutively elevated Cdc42-GTP level in diverse tissues of adult mice; significantly shortened life span of the animals; and multiple premature aging-like phenotypes, including a reduction in body mass, a loss of subdermal adipose tissue, severe lordokyphosis, muscle atrophy, osteoporosis, and reduction of reepithelialization ability in wound-healing. Cdc42GAP-/- mouse embryonic fibroblasts and/or tissues display reduced population doubling, significantly dampened DNA damage repair activity after DNA-damaging agent treatment, accumulated genomic abnormalities, and induction of p53, p16Ink4a, p21Cip1, and senescence-associated beta-galactosidase expressions. Furthermore, Cdc42 activation is sufficient to promote a premature cellular senescence phenotype that depends on p53. These results suggest a role of Cdc42 activity in regulating mammalian genomic stability and aging-related physiology.", - "journal_title": "Proceedings of the National Academy of Sciences of the United States of America", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/17227869/" - } - ], - "7d451e79-b698-4744-aeb2-ff319f430d96": [ - { - "pub_id": "20798392", - "title": "Age-dependent chromosomal distribution of male-biased genes in Drosophila.", - "authors": "Yong E Zhang,Maria D Vibranovski,Benjamin H Krinsky,Manyuan Long", - "abstract": "We investigated the correlation between the chromosomal location and age distribution of new male-biased genes formed by duplications via DNA intermediates (DNA-level) or by de novo origination in Drosophila. Our genome-wide analysis revealed an excess of young X-linked male-biased genes. The proportion of X-linked male-biased genes then diminishes through time, leading to an autosomal excess of male-biased genes. The switch between X-linked and autosomal enrichment of male-biased genes was also present in the distribution of both protein-coding genes on the D. pseudoobscura neo-X chromosome and microRNA genes of D. melanogaster. These observations revealed that the evolution of male-biased genes is more complicated than the previously detected one-step X\u2192A gene traffic and the enrichment of the male-biased genes on autosomes. The pattern we detected suggests that the interaction of various evolutionary forces such as the meiotic sex chromosome inactivation (MSCI), faster-X effect, and sexual antagonism in the male germline might have shaped the chromosomal distribution of male-biased genes on different evolutionary time scales.", - "journal_title": "Genome research", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/20798392/" - } - ], - "bc9b208a-126d-44a3-b5b8-0d40c562bc38": [ - { - "pub_id": "15202522", - "title": "Risk factors for Hodgkin's lymphoma by EBV status and significance of detection of EBV genomes in serum of patients with EBV-associated Hodgkin's lymphoma.", - "authors": "Ruth F Jarrett", - "abstract": "Epstein Barr virus (EBV) is associated with around one-third of Hodgkin's lymphoma (HL) cases and this association is believed to be causal. In these EBV-associated cases, there is a clonal EBV infection within tumors, and EBV genomes and gene products are detectable in Hodgkin and Reed-Sternberg (HRS) cells. The proportion of EBV-associated HL in any population varies with age, sex, ethnicity and histologic subtype. Two population-based epidemiologic studies have examined risk factor profiles in HL with cases stratified according to EBV status. For EBV-associated HL cases, there is a small peak in incidence in young adults (15-24 years) and a second larger peak in older adults. By contrast, HL that is not associated with EBV (EBV-negative HL) accounts for the major part of the young adult incidence peak after which the incidence of this disease entity then declines. Prior infectious mononucleosis (IM) is associated with an increased risk of developing HL, and there is a specific, probably causal, association between previous IM and young adult EBV-associated HL. We therefore believe that the small peak in the incidence of EBV-associated HL in young adults is real and related to late infection by EBV. EBV-associated HL in childhood and young adults, therefore, appears to follow primary infection by the virus. At the time of diagnosis, EBV-associated HL patients have an increased frequency of circulating EBV-infected cells compared to patients with EBV-negative HL and normal controls. The EBV is present in memory B cells and most probably reflects increased viral replication at another site, such as the oropharynx. EBV genomes are detectable in the serum and plasma of EBV-associated HL cases. The origin of EBV genomes in serum/plasma differs in different disease states; in HL viral genomes are present as naked DNA and are probably shed from tumors. EBV genome copy number in serum/plasma may provide an indication of tumor burden and may prove to be a useful marker for monitoring HL patients. The etiology of EBV-negative HL remains unknown and, while the involvement of an infectious agent may be suspected, none has yet been identified. Overall, epidemiologic studies support the idea that HL can be divided into two etiologic subgroups on the basis of EBV status and suggest that EBV-associated cases can be further divided into three groups related to age at diagnosis.", - "journal_title": "Leukemia & lymphoma", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/15202522/" - } - ], - "9716cfe1-4885-4c16-92c8-87fead7cb6a9": [ - { - "pub_id": "20145203", - "title": "Distinctive patterns of age-dependent hypomethylation in interspersed repetitive sequences.", - "authors": "Pornrutsami Jintaridth,Apiwat Mutirangura", - "abstract": "Interspersed repetitive sequences (IRSs) are a major contributor to genome size and may contribute to cellular functions. IRSs are subdivided according to size and functionally related structures into short interspersed elements, long interspersed elements (LINEs), DNA transposons, and LTR-retrotransposons. Many IRSs may produce RNA and regulate genes by a variety of mechanisms. The majority of DNA methylation occurs in IRSs and is believed to suppress IRS activities. Global hypomethylation, or the loss of genome-wide methylation, is a common epigenetic event not only in senescent cells but also in cancer cells. Loss of LINE-1 methylation has been characterized in many cancers. Here, we evaluated the methylation levels of peripheral blood mononuclear cells of LINE-1, Alu, and human endogenous retrovirus K (HERV-K) in 177 samples obtained from volunteers between 20 and 88 yr of age. Age was negatively associated with methylation levels of Alu (r = -0.452, P < 10(-3)) and HERV-K (r = -0.326, P < 10(-3)) but not LINE-1 (r = 0.145, P = 0.055). Loss of methylation of Alu occurred during ages 34-68 yr, and loss of methylation of HERV-K occurred during ages 40-63 yr and again during ages 64-83 yr. Interestingly, methylation of Alu and LINE-1 are directly associated, particularly at ages 49 yr and older (r = 0.49, P < 10(-3)). Therefore, only some types of IRSs lose methylation at certain ages. Moreover, Alu and HERV-K become hypomethylated differently. Finally, there may be several mechanisms of global methylation. However, not all of these mechanisms are age-dependent. This finding may lead to a better understanding of not only the biological causes and consequences of genome-wide hypomethylation but also the role of IRSs in the aging process.", - "journal_title": "Physiological genomics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/20145203/" - } - ], - "bee76c7e-f8e1-42b5-bd14-0c3958e74553": [ - { - "pub_id": "19812666", - "title": "Finding the missing heritability of complex diseases.", - "authors": "Teri A Manolio,Francis S Collins,Nancy J Cox,David B Goldstein,Lucia A Hindorff,David J Hunter,Mark I McCarthy,Erin M Ramos,Lon R Cardon,Aravinda Chakravarti,Judy H Cho,Alan E Guttmacher,Augustine Kong,Leonid Kruglyak,Elaine Mardis,Charles N Rotimi,Montgomery Slatkin,David Valle,Alice S Whittemore,Michael Boehnke,Andrew G Clark,Evan E Eichler,Greg Gibson,Jonathan L Haines,Trudy F C Mackay,Steven A McCarroll,Peter M Visscher", - "abstract": "Genome-wide association studies have identified hundreds of genetic variants associated with complex human diseases and traits, and have provided valuable insights into their genetic architecture. Most variants identified so far confer relatively small increments in risk, and explain only a small proportion of familial clustering, leading many to question how the remaining, 'missing' heritability can be explained. Here we examine potential sources of missing heritability and propose research strategies, including and extending beyond current genome-wide association approaches, to illuminate the genetics of complex diseases and enhance its potential to enable effective disease prevention or treatment.", - "journal_title": "Nature", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/19812666/" - } - ], - "1b0ceedf-6500-47d1-a9e9-195f81f35ab3": [ - { - "pub_id": "15485344", - "title": "Nutritional genomics.", - "authors": "Jose M Ordovas,Dolores Corella", - "abstract": "Nutritional genomics has tremendous potential to change the future of dietary guidelines and personal recommendations. Nutrigenetics will provide the basis for personalized dietary recommendations based on the individual's genetic make up. This approach has been used for decades for certain monogenic diseases; however, the challenge is to implement a similar concept for common multifactorial disorders and to develop tools to detect genetic predisposition and to prevent common disorders decades before their manifestation. The preliminary results involving gene-diet interactions for cardiovascular diseases and cancer are promising, but mostly inconclusive. Success in this area will require the integration of different disciplines and investigators working on large population studies designed to adequately investigate gene-environment interactions. Despite the current difficulties, preliminary evidence strongly suggests that the concept should work and that we will be able to harness the information contained in our genomes to achieve successful aging using behavioral changes; nutrition will be the cornerstone of this endeavor.", - "journal_title": "Annual review of genomics and human genetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/15485344/" - } - ], - "67ec2631-aa17-436e-800b-1bc046fb5b19": [ - { - "pub_id": "9098100", - "title": "Age-associated alterations of the mitochondrial genome.", - "authors": "C M Lee,R Weindruch,J M Aiken", - "abstract": "Age-associated alterations of the mitochondrial genome occur in several different species; however, their physiological relevance remains unclear. The age-associated changes of mitochondrial DNA (mtDNA) include nucleotide point mutations and modifications, as well as deletions. In this review, we summarize the current literature on age-associated mtDNA mutations and deletions and comment on their abundance. A clear need exists for a more thorough evaluation of the total damage to the mitochondrial genome that accumulates in aged tissues.", - "journal_title": "Free radical biology & medicine", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/9098100/" - } - ], - "b4b65968-74b4-4130-9cb3-c0aee689595c": [ - { - "pub_id": "30478036", - "title": "Biparental Inheritance of Mitochondrial DNA in Humans.", - "authors": "Shiyu Luo,C Alexander Valencia,Jinglan Zhang,Ni-Chung Lee,Jesse Slone,Baoheng Gui,Xinjian Wang,Zhuo Li,Sarah Dell,Jenice Brown,Stella Maris Chen,Yin-Hsiu Chien,Wuh-Liang Hwu,Pi-Chuan Fan,Lee-Jun Wong,Paldeep S Atwal,Taosheng Huang", - "abstract": "Although there has been considerable debate about whether paternal mitochondrial DNA (mtDNA) transmission may coexist with maternal transmission of mtDNA, it is generally believed that mitochondria and mtDNA are exclusively maternally inherited in humans. Here, we identified three unrelated multigeneration families with a high level of mtDNA heteroplasmy (ranging from 24 to 76%) in a total of 17 individuals. Heteroplasmy of mtDNA was independently examined by high-depth whole mtDNA sequencing analysis in our research laboratory and in two Clinical Laboratory Improvement Amendments and College of American Pathologists-accredited laboratories using multiple approaches. A comprehensive exploration of mtDNA segregation in these families shows biparental mtDNA transmission with an autosomal dominantlike inheritance mode. Our results suggest that, although the central dogma of maternal inheritance of mtDNA remains valid, there are some exceptional cases where paternal mtDNA could be passed to the offspring. Elucidating the molecular mechanism for this unusual mode of inheritance will provide new insights into how mtDNA is passed on from parent to offspring and may even lead to the development of new avenues for the therapeutic treatment for pathogenic mtDNA transmission.", - "journal_title": "Proceedings of the National Academy of Sciences of the United States of America", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/30478036/" - } - ], - "a2462fad-e20d-498c-8dd2-0e7214e08e38": [ - { - "pub_id": "16322484", - "title": "Genome-wide scan for white matter hyperintensity: the Framingham Heart Study.", - "authors": "Anita L DeStefano,Larry D Atwood,Joseph M Massaro,Nancy Heard-Costa,Alexa Beiser,Rhoda Au,Philip A Wolf,Charles DeCarli", - "abstract": "White matter hyperintensity (WMH) volume is associated with aging and cerebrovascular disease and has been demonstrated to have a high heritability in the Framingham Heart Study as well as in other studies. We performed a genome-wide linkage analysis to identify chromosomal regions that may harbor genes influencing WMH in a family-based sample of the Framingham Heart Study. Brain magnetic resonance scans were performed, and WMH and total cranial volume (TCV) were quantified as previously described on 2259 cohort and offspring participants. The outcome used for linkage analysis was an age specific (within 10-year age groups) z-score for the natural logarithm of the ratio of WMH to TCV. This z-score was based on 2230 individuals after excluding 26 participants with neurological conditions other than stroke and 3 individuals whose ages were out of range. Variance component linkage analysis included 747 individuals (mean age=62.16+/-12.43 years) with both magnetic resonance measure and genotype information in 237 families. Mean percent WMH to TCV was 0.098+/-0.175 with a range of 0.00025% to 1.37% in the linkage analysis subjects. A maximum multipoint logarithm of the odds (LOD) score=3.69, which indicates significant evidence of linkage, was observed at 4 cM on chromosome 4. A suggestive peak with LOD=1.78 was observed at 95 cM on chromosome 17. We have significant evidence that a gene influencing WMH volume is located on chromosome 4 of the human genome.", - "journal_title": "Stroke", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/16322484/" - } - ], - "a0fcfb05-6fb2-4359-b849-a5f2b515ef2e": [ - { - "pub_id": "19774229", - "title": "The relationship of DNA methylation with age, gender and genotype in twins and healthy controls.", - "authors": "Marco P Boks,Eske M Derks,Daniel J Weisenberger,Erik Strengman,Esther Janson,Iris E Sommer,Ren\u00e9 S Kahn,Roel A Ophoff", - "abstract": "Cytosine-5 methylation within CpG dinucleotides is a potentially important mechanism of epigenetic influence on human traits and disease. In addition to influences of age and gender, genetic control of DNA methylation levels has recently been described. We used whole blood genomic DNA in a twin set (23 MZ twin-pairs and 23 DZ twin-pairs, N = 92) as well as healthy controls (N = 96) to investigate heritability and relationship with age and gender of selected DNA methylation profiles using readily commercially available GoldenGate bead array technology. Despite the inability to detect meaningful methylation differences in the majority of CpG loci due to tissue type and locus selection issues, we found replicable significant associations of DNA methylation with age and gender. We identified associations of genetically heritable single nucleotide polymorphisms with large differences in DNA methylation levels near the polymorphism (cis effects) as well as associations with much smaller differences in DNA methylation levels elsewhere in the human genome (trans effects). Our results demonstrate the feasibility of array-based approaches in studies of DNA methylation and highlight the vast differences between individual loci. The identification of CpG loci of which DNA methylation levels are under genetic control or are related to age or gender will facilitate further studies into the role of DNA methylation and disease.", - "journal_title": "PloS one", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/19774229/" - } - ], - "c10ff8e0-81ff-4ac2-b1cc-2fdc89640166": [ - { - "pub_id": "16759788", - "title": "Profile of chromosomal aberrations in different gestational age spontaneous abortions detected by comparative genomic hybridization.", - "authors": "Dimitar N Azmanov,Tania V Milachich,Boriana M Zaharieva,Gergana I Michailova,Violeta G Dimitrova,Zivka H Karagiozova,Valentina T Maznejkova,Todor A Chernev,Draga I Toncheva", - "abstract": "To determine the frequency and type of chromosomal aberrations in different gestational age spontaneous abortions. In the study, 106 spontaneous abortions (SAs) were studied by comparative genomic hybridization. The frequency of detected chromosomal aberrations was 37.7%. Numerical chromosomal aberrations were disclosed in 82.5% of the aberrant cases, while structural chromosomal aberrations-in 17.5%. Highest frequency of aberrations was detected in the blighted ovum specimens (62.5%) compared to missed and second trimester SAs (respectively, 36.0% and 34.8%). With regard to structural aberrations, the difference in the frequencies between blighted ovum specimens and second trimester SAs nearly reached statistical significance (p=0.0847). However, due to the low number of blighted ovum specimens analyzed (n=8), this result should be interpreted with due caution. The most frequently affected chromosomal arms were Xp and Xq (13.7% of aberrant chromosomal arms, each), followed by 16p (8.4%), 16q (8.4%), 15q (4.2%) and 19q (4.2%). We describe for the first time a profile of chromosomal aberrations in SAs from different gestational ages, detected by CGH. Our results showed highest frequency of chromosome aberrations in blighted ovum specimens compared to other types of spontaneous abortions, higher rate of structural aberrations than reported before (17.5%) and some aberrations that so far were not found by CGH.", - "journal_title": "European journal of obstetrics, gynecology, and reproductive biology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/16759788/" - } - ], - "6bf4ca4d-b158-49fd-a7d1-7955e4dd78f6": [ - { - "pub_id": "15705954", - "title": "The rice nuclear genome continuously integrates, shuffles, and eliminates the chloroplast genome to cause chloroplast-nuclear DNA flux.", - "authors": "Mitsuhiro Matsuo,Yuki Ito,Ryo Yamauchi,Junichi Obokata", - "abstract": "Plastid DNA fragments are often found in the plant nuclear genome, and DNA transfer from plastids to the nucleus is ongoing. However, successful gene transfer is rare. What happens to compensate for this? To address this question, we analyzed nuclear-localized plastid DNA (nupDNA) fragments throughout the rice (Oryza sativa ssp japonica) genome, with respect to their age, size, structure, and integration sites on chromosomes. The divergence of nupDNA sequences from the sequence of the present plastid genome strongly suggests that plastid DNA has been transferred repeatedly to the nucleus in rice. Age distribution profiles of the nupDNA population, together with the size and structural characteristics of each fragment, revealed that once plastid DNAs are integrated into the nuclear genome, they are rapidly fragmented and vigorously shuffled, and surprisingly, 80% of them are eliminated from the nuclear genome within a million years. Large nupDNA fragments preferentially localize to the pericentromeric region of the chromosomes, where integration and elimination frequencies are markedly higher. These data indicate that the plant nuclear genome is in equilibrium between frequent integration and rapid elimination of the chloroplast genome and that the pericentromeric regions play a significant role in facilitating the chloroplast-nuclear DNA flux.", - "journal_title": "The Plant cell", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/15705954/" - } - ], - "63308275-a453-415d-8814-6f2932148ecd": [ - { - "pub_id": "18541911", - "title": "Intraspecific phylogenetic analysis of Siberian woolly mammoths using complete mitochondrial genomes.", - "authors": "M Thomas P Gilbert,Daniela I Drautz,Arthur M Lesk,Simon Y W Ho,Ji Qi,Aakrosh Ratan,Chih-Hao Hsu,Andrei Sher,Love Dal\u00e9n,Anders G\u00f6therstr\u00f6m,Lynn P Tomsho,Snjezana Rendulic,Michael Packard,Paula F Campos,Tatyana V Kuznetsova,Fyodor Shidlovskiy,Alexei Tikhonov,Eske Willerslev,Paola Iacumin,Bernard Buigues,Per G P Ericson,Mietje Germonpr\u00e9,Pavel Kosintsev,Vladimir Nikolaev,Malgosia Nowak-Kemp,James R Knight,Gerard P Irzyk,Clotilde S Perbost,Karin M Fredrikson,Timothy T Harkins,Sharon Sheridan,Webb Miller,Stephan C Schuster", - "abstract": "We report five new complete mitochondrial DNA (mtDNA) genomes of Siberian woolly mammoth (Mammuthus primigenius), sequenced with up to 73-fold coverage from DNA extracted from hair shaft material. Three of the sequences present the first complete mtDNA genomes of mammoth clade II. Analysis of these and 13 recently published mtDNA genomes demonstrates the existence of two apparently sympatric mtDNA clades that exhibit high interclade divergence. The analytical power afforded by the analysis of the complete mtDNA genomes reveals a surprisingly ancient coalescence age of the two clades, approximately 1-2 million years, depending on the calibration technique. Furthermore, statistical analysis of the temporal distribution of the (14)C ages of these and previously identified members of the two mammoth clades suggests that clade II went extinct before clade I. Modeling of protein structures failed to indicate any important functional difference between genomes belonging to the two clades, suggesting that the loss of clade II more likely is due to genetic drift than a selective sweep.", - "journal_title": "Proceedings of the National Academy of Sciences of the United States of America", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/18541911/" - } - ], - "2d3b74ec-9aff-42c7-9afb-74fc93d212f3": [ - { - "pub_id": "18937294", - "title": "Genome-wide association scan of the time to onset of attention deficit hyperactivity disorder.", - "authors": "Jessica Lasky-Su,Richard J L Anney,Benjamin M Neale,Barbara Franke,Kaixin Zhou,Julian B Maller,Alejandro Arias Vasquez,Wai Chen,Philip Asherson,Jan Buitelaar,Tobias Banaschewski,Richard Ebstein,Michael Gill,Ana Miranda,Fernando Mulas,Robert D Oades,Herbert Roeyers,Aribert Rothenberger,Joseph Sergeant,Edmund Sonuga-Barke,Hans Christoph Steinhausen,Eric Taylor,Mark Daly,Nan Laird,Christoph Lange,Stephen V Faraone", - "abstract": "A time-to-onset analysis for family-based samples was performed on the genomewide association (GWAS) data for attention deficit hyperactivity disorder (ADHD) to determine if associations exist with the age at onset of ADHD. The initial dataset consisted of 958 parent-offspring trios that were genotyped on the Perlegen 600,000 SNP array. After data cleaning procedures, 429,981 autosomal SNPs and 930 parent-offspring trios were used found suitable for use and a family-based logrank analysis was performed using that age at first ADHD symptoms as the quantitative trait of interest. No SNP achieved genome-wide significance, and the lowest P-values had a magnitude of 10(-7). Several SNPs among a pre-specified list of candidate genes had nominal associations including SLC9A9, DRD1, ADRB2, SLC6A3, NFIL3, ADRB1, SYT1, HTR2A, ARRB2, and CHRNA4. Of these findings SLC9A9 stood out as a promising candidate, with nominally significant SNPs in six distinct regions of the gene.", - "journal_title": "American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/18937294/" - } - ], - "5c814c02-7157-40db-968d-98ac062744d6": [ - { - "pub_id": "15743672", - "title": "Cancer and aging: the importance of telomeres in genome maintenance.", - "authors": "Francis Rodier,Sahn-Ho Kim,Tarlochan Nijjar,Paul Yaswen,Judith Campisi", - "abstract": "Telomeres are the specialized DNA-protein structures that cap the ends of linear chromosomes, thereby protecting them from degradation and fusion by cellular DNA repair processes. In vertebrate cells, telomeres consist of several kilobase pairs of DNA having the sequence TTAGGG, a few hundred base pairs of single-stranded DNA at the 3' end of the telomeric DNA tract, and a host of proteins that organize the telomeric double and single-stranded DNA into a protective structure. Functional telomeres are essential for maintaining the integrity and stability of genomes. When combined with loss of cell cycle checkpoint controls, telomere dysfunction can lead to genomic instability, a common cause and hallmark of cancer. Consequently, normal mammalian cells respond to dysfunctional telomeres by undergoing apoptosis (programmed cell death) or cellular senescence (permanent cell cycle arrest), two cellular tumor suppressor mechanisms. These tumor suppressor mechanisms are potent suppressors of cancer, but recent evidence suggests that they can antagonistically also contribute to aging phenotypes. Here, we review what is known about the structure and function of telomeres in mammalian cells, particularly human cells, and how telomere dysfunction may arise and contribute to cancer and aging phenotypes.", - "journal_title": "The international journal of biochemistry & cell biology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/15743672/" - } - ], - "ac98b39e-2526-4f1b-a07e-fa2d42470fba": [ - { - "pub_id": "19881911", - "title": "Epigenetic Control of MicroRNA Expression and Aging.", - "authors": "Ruqiang Liang,David J Bates,Eugenia Wang", - "abstract": "MicroRNAs are a major category among the noncoding RNA fraction that negatively regulate gene expression at the post-transcriptional level, by either degrading the target messages or inhibiting their translation. MicroRNAs may be referred to as 'dimmer switches' of gene expression, because of their ability to repress gene expression without completely silencing it. Whether through up-regulating specific groups of microRNAs to suppress unwanted gene expressions, or by down-regulating other microRNAs whose target genes' expression is necessary for cellular function, such as cell proliferation, apoptosis, or differentiation, these regulatory RNAs play pivotal roles in a wide variety of cellular processes. The equilibrium between these two groups of microRNA expressions largely determines the function of particular cell types. Our recent results with several model systems show that upon aging, there is a trend of up-regulation of microRNA expression, with concomitant inverse down-regulation of target genes. This review addresses molecular mechanisms that may provide the underlying control for this up-regulating trend, focusing on activation by various microRNAs' own promoters, through binding with pivotal transcription factors, stress response, methylation of clustered DNA domains, etc. Thus, epigenomic control of aging may be due in part to heightened promoter activation of unwanted microRNA expressions, which in turn down-regulate their target gene products. Overriding and dampening the activation of these noncoding RNAs may prove to be a new frontier for future research, to delay aging and extend healthy life-span.", - "journal_title": "Current genomics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/19881911/" - } - ], - "19306130-17a1-4689-b986-bae15b111bf6": [ - { - "pub_id": "11880029", - "title": "Toward high-throughput synthesis of complex natural product-like compounds in the genomics and proteomics age.", - "authors": "Prabhat Arya,Reni Joseph,Doug T H Chou", - "abstract": "In the age of high-throughput biology, novel genes and proteins are emerging quickly. The need for developing organic synthesis-derived methods that allow rapid access to polyfunctional, complex natural product-like compounds is growing constantly, largely because these small-molecule-based compounds serve as smart, powerful tools both in understanding the roles and functions of emerging biological targets and in validating their biological responses. Developing asymmetric synthesis-derived organic reactions on solid phase allows the synthesis of complex natural product-like compounds in a high-throughput manner. Solid phase organic synthesis is now commonly utilized in the library synthesis of rather simple compounds (i.e., compounds with no multiple stereogenic centers). With few exceptions, the synthesis of complex natural product-like derivatives is still in its infancy. Some recent efforts made in this area indicate opportunities yet to be explored.", - "journal_title": "Chemistry & biology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/11880029/" - } - ], - "5935ecaa-13ed-4d45-9707-67e1268a040c": [ - { - "pub_id": "12067572", - "title": "Micronutrients and genomic stability: a new paradigm for recommended dietary allowances (RDAs).", - "authors": "M Fenech", - "abstract": "Diet as a key factor in determining genomic stability is more important than previously imagined because we now know that it impacts on all relevant pathways, namely exposure to dietary carcinogens, activation/detoxification of carcinogens, DNA repair, DNA synthesis and apoptosis. Current recommended dietary allowances for vitamins and minerals are based largely on the prevention of diseases of deficiency such as scurvy in the case of vitamin C. Because diseases of development, degenerative disease and aging itself are partly caused by damage to DNA it seems logical that we should focus better our attention on defining optimal requirements of key minerals and vitamins for preventing damage to both nuclear and mitochondrial DNA. To date, our knowledge on optimal micronutrient levels for genomic stability is scanty and disorganised. However, there is already sufficient evidence to suggest that marginal deficiencies in folate, vitamin B12, niacin and zinc impact significantly on spontaneous chromosome damage rate. The recent data for folate and vitamin B12 in humans with respect to micronucleus formation in blood and epithelial cells provide compelling evidence of the important role of these micronutrients in maintenance of genome integrity and the need to revise current RDAs for these micronutrients based on minimisation of DNA damage. Appropriately designed in vitro studies and in vivo placebo controlled trials with dose responses using a complementary array of DNA damage biomarkers are required to define recommended dietary allowances for genomic stability. Furthermore these studies would have to be targeted to individuals with common genetic polymorphisms that alter the bioavailability of specific micronutrients and the affinity of specific key enzymes involved in DNA metabolism for their micronutrient co-factor. That there is a need for an international collaborative effort to establish RDAs for genomic stability is self-evident.", - "journal_title": "Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/12067572/" - } - ], - "3f62c6ad-37c6-45ed-92ac-fafaf86a08d3": [ - { - "pub_id": "15980864", - "title": "Genomic instability in laminopathy-based premature aging.", - "authors": "Baohua Liu,Jianming Wang,Kui Ming Chan,Wai Mui Tjia,Wen Deng,Xinyuan Guan,Jian-dong Huang,Kai Man Li,Pui Yin Chau,David J Chen,Duanqing Pei,Alberto M Pendas,Juan Cadi\u00f1anos,Carlos L\u00f3pez-Ot\u00edn,Hung Fat Tse,Chris Hutchison,Junjie Chen,Yihai Cao,Kathryn S E Cheah,Karl Tryggvason,Zhongjun Zhou", - "abstract": "Premature aging syndromes often result from mutations in nuclear proteins involved in the maintenance of genomic integrity. Lamin A is a major component of the nuclear lamina and nuclear skeleton. Truncation in lamin A causes Hutchinson-Gilford progerial syndrome (HGPS), a severe form of early-onset premature aging. Lack of functional Zmpste24, a metalloproteinase responsible for the maturation of prelamin A, also results in progeroid phenotypes in mice and humans. We found that Zmpste24-deficient mouse embryonic fibroblasts (MEFs) show increased DNA damage and chromosome aberrations and are more sensitive to DNA-damaging agents. Bone marrow cells isolated from Zmpste24-/- mice show increased aneuploidy and the mice are more sensitive to DNA-damaging agents. Recruitment of p53 binding protein 1 (53BP1) and Rad51 to sites of DNA lesion is impaired in Zmpste24-/- MEFs and in HGPS fibroblasts, resulting in delayed checkpoint response and defective DNA repair. Wild-type MEFs ectopically expressing unprocessible prelamin A show similar defects in checkpoint response and DNA repair. Our results indicate that unprocessed prelamin A and truncated lamin A act dominant negatively to perturb DNA damage response and repair, resulting in genomic instability which might contribute to laminopathy-based premature aging.", - "journal_title": "Nature medicine", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/15980864/" - } - ], - "abe4a37a-4aee-41fa-8b0b-b88bb5d6aa89": [ - { - "pub_id": "27501488", - "title": "The aging population: demographics and the biology of aging.", - "authors": "Eleni Kanasi,Srinivas Ayilavarapu,Judith Jones", - "abstract": "Epidemiologic studies show that 11% of the world's population is over 60\u00a0years of age; this is projected to increase, by 2050, to 22% of the population. Oral aging is a current focus of several organizations including the Federation Dentaire Internationale, the World Health Organization and the American and Japanese Dental Associations. In their Tokyo Declaration, the Japanese Association identified the elderly population as one of its main target groups. One of the WHO goals is for each person to retain more than 20 teeth by age 80, despite the fact that the prevalence of periodontal disease is continuously rising as the population is aging. Every species has its own characteristic lifespan, which is determined by its evolutionary history and is modified by multiple diverse factors, including biological mechanisms. In humans, the gradual accumulation of products of cellular metabolism and extensive DNA damage contribute to the aging process. Aging is thought to be associated with a low-grade inflammatory phenotype in mammals, called 'inflammaging', and is the result of autophagic capacity impairing so-called 'housekeeping activities' in the cells, resulting in protein aggregation, mitochondrial dysfunction and oxidative stress. Delayed stem-cell proliferation, associated with aging, may impact the maintenance and survival of a living being, but excessive proliferation could also result in depleted reserves of stem cells. Studies are needed to address the association of delayed cell proliferation and wound healing with the onset of periodontal diseases and response to treatment. The effects of systemic diseases, medications, psychological effects and decreased interest or ability in performing oral-hygiene practices are thought to result in periodontal diseases, and ultimately in tooth loss, in aged individuals. Together with an aging population comes a responsibility for 'healthy' and 'successful' aging. This article describes the changing global demographic profile and the effects of an aging society on the prevalence and incidence of periodontal diseases. We review the definitions of normal and successful aging, the principles of geriatric medicine and the highlights of biological aging at cellular, tissue and systems levels.", - "journal_title": "Periodontology 2000", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/27501488/" - } - ], - "7291ceb2-482a-4f9b-a116-2b68ff24854f": [ - { - "pub_id": "15031306", - "title": "Genome-wide scan for a healthy aging phenotype provides support for a locus near D4S1564 promoting healthy aging.", - "authors": "Terry Reed,Danielle M Dick,Sean K Uniacke,Tatiana Foroud,William C Nichols", - "abstract": "Living to a late age without suffering any major health problems is a genetically influenced trait. To identify the genes contributing to this important phenotype, a 10 cM genome screen was performed in 95 pairs of male fraternal twins concordant for healthy aging. Individuals meeting these criteria were defined as those attaining the age of 70 free of cardiovascular disease (coronary surgery, diabetes, heart attack, and stroke) and prostate cancer. Six chromosomal regions were identified with logarithm of odds (LOD) scores greater than 1.2 (p<.01). A region on chromosome 4 at marker D4S1564 produced a LOD score of 1.67; this was the same marker previously linked to extreme longevity segregating as an autosomal dominant trait in centenarian families. Our results provide independent evidence that a locus on the long arm of chromosome 4 is associated with better physical aging and/or longevity.", - "journal_title": "The journals of gerontology. Series A, Biological sciences and medical sciences", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/15031306/" - } - ], - "76711672-61e4-4988-90a7-ddfd34bf22d7": [ - { - "pub_id": "10568741", - "title": "Functional genomics and rat models.", - "authors": "H J Jacob", - "abstract": "", - "journal_title": "Genome research", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/10568741/" - } - ], - "f3b66ba6-48f5-440b-b5e1-6d83468db425": [ - { - "pub_id": "20798317", - "title": "Genomic comparison of the ants Camponotus floridanus and Harpegnathos saltator.", - "authors": "Roberto Bonasio,Guojie Zhang,Chaoyang Ye,Navdeep S Mutti,Xiaodong Fang,Nan Qin,Greg Donahue,Pengcheng Yang,Qiye Li,Cai Li,Pei Zhang,Zhiyong Huang,Shelley L Berger,Danny Reinberg,Jun Wang,J\u00fcrgen Liebig", - "abstract": "The organized societies of ants include short-lived worker castes displaying specialized behavior and morphology and long-lived queens dedicated to reproduction. We sequenced and compared the genomes of two socially divergent ant species: Camponotus floridanus and Harpegnathos saltator. Both genomes contained high amounts of CpG, despite the presence of DNA methylation, which in non-Hymenoptera correlates with CpG depletion. Comparison of gene expression in different castes identified up-regulation of telomerase and sirtuin deacetylases in longer-lived H. saltator reproductives, caste-specific expression of microRNAs and SMYD histone methyltransferases, and differential regulation of genes implicated in neuronal function and chemical communication. Our findings provide clues on the molecular differences between castes in these two ants and establish a new experimental model to study epigenetics in aging and behavior.", - "journal_title": "Science (New York, N.Y.)", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/20798317/" - } - ], - "70b52a1e-834b-43c0-9e6a-3010bc3a06ae": [ - { - "pub_id": "18852196", - "title": "Genome-wide association studies: past, present and future.", - "authors": "Mark I McCarthy,Joel N Hirschhorn", - "abstract": "", - "journal_title": "Human molecular genetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/18852196/" - } - ], - "bd0f30e8-81e1-4553-bf88-762bc49197a3": [ - { - "pub_id": "10767343", - "title": "Transgenic mice carrying large human genomic sequences with expanded CTG repeat mimic closely the DM CTG repeat intergenerational and somatic instability.", - "authors": "H Seznec,A S Lia-Baldini,C Duros,C Fouquet,C Lacroix,H Hofmann-Radvanyi,C Junien,G Gourdon", - "abstract": "Myotonic dystrophy (DM) is caused by a CTG repeat expansion in the 3'UTR of the DM protein kinase (DMPK) gene. A very high level of instability is observed through successive generations and the size of the repeat is generally correlated with the severity of the disease and with age at onset. Furthermore, tissues from DM patients exhibit somatic mosaicism that increases with age. We generated transgenic mice carrying large human genomic sequences with 20, 55 or >300 CTG, cloned from patients from the same affected DM family. Using large human flanking sequences and a large amplification, we demonstrate that the intergenerational CTG repeat instability is reproduced in mice, with a strong bias towards expansions and with the same sex- and size-dependent characteristics as in humans. Moreover, a high level of instability, increasing with age, can be observed in tissues and in sperm. Although we did not observe dramatic expansions (or 'big jumps' over several hundred CTG repeats) as in congenital forms of DM, our model carrying >300 CTG is the first to show instability so close to the human DM situation. Our three models carrying different sizes of CTG repeat provide insight on the different factors modulating the CTG repeat instability.", - "journal_title": "Human molecular genetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/10767343/" - } - ], - "f08c0391-2d72-491c-a472-5db71bf11ac8": [ - { - "pub_id": "12817446", - "title": "Telomeres in the chicken: genome stability and chromosome ends.", - "authors": "M E Delany,L M Daniels,S E Swanberg,H A Taylor", - "abstract": "Telomeres are the complex nucleoprotein structures at the termini of linear chromosomes. Telomeric DNA consists of a highly conserved hexanucleotide arranged in tandem repeats. Telomerase, a ribonucleoprotein of the reverse transcriptase family, specifies the sequence of telomeric DNA and maintains telomere array length. Numerous studies in model organisms established the significance of telomere structure and function in regulating genome stability, cellular aging, and oncogenesis. Our overall research objectives are to understand the organization of the telomere arrays in chicken in the context of the unusual organization and specialized features of this higher vertebrate genome (which include a compact genome, numerous microchromosomes, and high recombination rate) and to elucidate the role telomeres play in genome stability impacting cell function and life span. Recent studies found that the chicken genome contains three overlapping size classes of telomere arrays that differ in location and age-related stability: Class I 0.5 to 10 kb, Class II 10 to 40 kb, and Class III 40 kb to 2 Mb. Some notable features of chicken telomere biology are that the chicken genome contains ten times more telomeric DNA than the human genome and the Class III telomere arrays are the largest described for any vertebrate species. In vivo, chicken telomeres (Class II) shorten in an age-related fashion and telomerase activity is high in early stage embryos and developing organs but down-regulates during late embryogenesis or postnatally in most somatic tissues. In vitro, chicken cells down-regulate telomerase activity unless transformed. Knowledge of chicken telomere biology contributes information relevant to present and future biotechnology applications of chickens in vivo and chicken cells in vitro.", - "journal_title": "Poultry science", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/12817446/" - } - ], - "ecc1326c-4239-48a6-afff-7a8d06c4b123": [ - { - "pub_id": "17425718", - "title": "From seedling to mature plant: arabidopsis plastidial genome copy number, RNA accumulation and transcription are differentially regulated during leaf development.", - "authors": "Reimo Zoschke,Karsten Liere,Thomas B\u00f6rner", - "abstract": "Little is known about DNA and RNA metabolism during leaf development and aging in the model organism Arabidopsis. Therefore we examined the nuclear and plastidial DNA content of tissue ranging in age from 2-day-old cotyledons to 37-day-old senescent rosette leaves. Flow-cytometric analysis showed an increase in nuclear DNA ploidy levels of up to 128 genome copies per nucleus in older leaves. The copy numbers of nuclear 18S-rRNA genes were determined to be 700 +/- 60 per haploid genome. Adjusted to the average level of nuclear DNA polyploidism per cell, plastome copy numbers varied from about 1000 to 1700 per cell without significant variation during development from young to old rosette leaves. The transcription activity of all studied plastid genes was significantly reduced in older rosette leaves in comparison to that in young leaves. In contrast, levels of plastidial transcript accumulation showed different patterns. In the case of psbA, transcripts accumulated to even higher levels in older leaves, indicating that differential regulation of plastidial gene expression occurs during leaf development. Examination of promoter activity from clpP and rrn16 genes by primer extension analyses revealed that two RNA polymerases (NEP and PEP) transcribe these genes in cotyledons as well as in young and senescent leaves. However, PEP may have a more prominent role in older rosette leaves than in young cotyledons. We conclude that in cotyledons or leaves of different ages plastidial gene expression is regulated at the transcriptional and post-transcriptional levels, but not by plastome copy number.", - "journal_title": "The Plant journal : for cell and molecular biology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/17425718/" - } - ], - "09af1dfa-d131-4ad5-84e6-b120200d0dcb": [ - { - "pub_id": "15268757", - "title": "Genome-scale expression profiling of Hutchinson-Gilford progeria syndrome reveals widespread transcriptional misregulation leading to mesodermal/mesenchymal defects and accelerated atherosclerosis.", - "authors": "Antonei B Csoka,Sangeeta B English,Carl P Simkevich,David G Ginzinger,Atul J Butte,Gerald P Schatten,Frank G Rothman,John M Sedivy", - "abstract": "Hutchinson-Gilford progeria syndrome (HGPS) is a rare genetic disease with widespread phenotypic features resembling premature aging. HGPS was recently shown to be caused by dominant mutations in the LMNA gene, resulting in the in-frame deletion of 50 amino acids near the carboxyl terminus of the encoded lamin A protein. Children with this disease typically succumb to myocardial infarction or stroke caused by severe atherosclerosis at an average age of 13 years. To elucidate further the molecular pathogenesis of this disease, we compared the gene expression patterns of three HGPS fibroblast cell strains heterozygous for the LMNA mutation with three normal, age-matched cell strains. We defined a set of 361 genes (1.1% of the approximately 33,000 genes analysed) that showed at least a 2-fold, statistically significant change. The most prominent categories encode transcription factors and extracellular matrix proteins, many of which are known to function in the tissues severely affected in HGPS. The most affected gene, MEOX2/GAX, is a homeobox transcription factor implicated as a negative regulator of mesodermal tissue proliferation. Thus, at the gene expression level, HGPS shows the hallmarks of a developmental disorder affecting mesodermal and mesenchymal cell lineages. The identification of a large number of genes implicated in atherosclerosis is especially valuable, because it provides clues to pathological processes that can now be investigated in HGPS patients or animal models.", - "journal_title": "Aging cell", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/15268757/" - } - ], - "4b091b62-13fe-4996-8866-e8764610ac15": [ - { - "pub_id": "18067683", - "title": "Transcriptional profiling of MnSOD-mediated lifespan extension in Drosophila reveals a species-general network of aging and metabolic genes.", - "authors": "Christina Curtis,Gary N Landis,Donna Folk,Nancy B Wehr,Nicholas Hoe,Morris Waskar,Diana Abdueva,Dmitriy Skvortsov,Daniel Ford,Allan Luu,Ananth Badrinath,Rodney L Levine,Timothy J Bradley,Simon Tavar\u00e9,John Tower", - "abstract": "Several interventions increase lifespan in model organisms, including reduced insulin/insulin-like growth factor-like signaling (IIS), FOXO transcription factor activation, dietary restriction, and superoxide dismutase (SOD) over-expression. One question is whether these manipulations function through different mechanisms, or whether they intersect on common processes affecting aging. A doxycycline-regulated system was used to over-express manganese-SOD (MnSOD) in adult Drosophila, yielding increases in mean and maximal lifespan of 20%. Increased lifespan resulted from lowered initial mortality rate and required MnSOD over-expression in the adult. Transcriptional profiling indicated that the expression of specific genes was altered by MnSOD in a manner opposite to their pattern during normal aging, revealing a set of candidate biomarkers of aging enriched for carbohydrate metabolism and electron transport genes and suggesting a true delay in physiological aging, rather than a novel phenotype. Strikingly, cross-dataset comparisons indicated that the pattern of gene expression caused by MnSOD was similar to that observed in long-lived Caenorhabditis elegans insulin-like signaling mutants and to the xenobiotic stress response, thus exposing potential conserved longevity promoting genes and implicating detoxification in Drosophila longevity. The data suggest that MnSOD up-regulation and a retrograde signal of reactive oxygen species from the mitochondria normally function as an intermediate step in the extension of lifespan caused by reduced insulin-like signaling in various species. The results implicate a species-conserved net of coordinated genes that affect the rate of senescence by modulating energetic efficiency, purine biosynthesis, apoptotic pathways, endocrine signals, and the detoxification and excretion of metabolites.", - "journal_title": "Genome biology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/18067683/" - } - ], - "b1832c4f-ed59-42e7-b787-a83b37263aa2": [ - { - "pub_id": "19430479", - "title": "Genome-wide association study of blood pressure and hypertension.", - "authors": "Daniel Levy,Georg B Ehret,Kenneth Rice,Germaine C Verwoert,Lenore J Launer,Abbas Dehghan,Nicole L Glazer,Alanna C Morrison,Andrew D Johnson,Thor Aspelund,Yurii Aulchenko,Thomas Lumley,Anna K\u00f6ttgen,Ramachandran S Vasan,Fernando Rivadeneira,Gudny Eiriksdottir,Xiuqing Guo,Dan E Arking,Gary F Mitchell,Francesco U S Mattace-Raso,Albert V Smith,Kent Taylor,Robert B Scharpf,Shih-Jen Hwang,Eric J G Sijbrands,Joshua Bis,Tamara B Harris,Santhi K Ganesh,Christopher J O'Donnell,Albert Hofman,Jerome I Rotter,Josef Coresh,Emelia J Benjamin,Andr\u00e9 G Uitterlinden,Gerardo Heiss,Caroline S Fox,Jacqueline C M Witteman,Eric Boerwinkle,Thomas J Wang,Vilmundur Gudnason,Martin G Larson,Aravinda Chakravarti,Bruce M Psaty,Cornelia M van Duijn", - "abstract": "Blood pressure is a major cardiovascular disease risk factor. To date, few variants associated with interindividual blood pressure variation have been identified and replicated. Here we report results of a genome-wide association study of systolic (SBP) and diastolic (DBP) blood pressure and hypertension in the CHARGE Consortium (n = 29,136), identifying 13 SNPs for SBP, 20 for DBP and 10 for hypertension at P < 4 \u00d7 10(-7). The top ten loci for SBP and DBP were incorporated into a risk score; mean BP and prevalence of hypertension increased in relation to the number of risk alleles carried. When ten CHARGE SNPs for each trait were included in a joint meta-analysis with the Global BPgen Consortium (n = 34,433), four CHARGE loci attained genome-wide significance (P < 5 \u00d7 10(-8)) for SBP (ATP2B1, CYP17A1, PLEKHA7, SH2B3), six for DBP (ATP2B1, CACNB2, CSK-ULK3, SH2B3, TBX3-TBX5, ULK4) and one for hypertension (ATP2B1). Identifying genes associated with blood pressure advances our understanding of blood pressure regulation and highlights potential drug targets for the prevention or treatment of hypertension.", - "journal_title": "Nature genetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/19430479/" - } - ], - "04405b2b-901a-423c-9f08-418f5514c535": [ - { - "pub_id": "17059877", - "title": "Characterization of a bidirectional promoter shared between two human genes related to aging: SIRT3 and PSMD13.", - "authors": "D Bellizzi,S Dato,P Cavalcante,G Covello,F Di Cianni,G Passarino,G Rose,G De Benedictis", - "abstract": "The human SIRT3 gene contains an intronic VNTR enhancer whose variability is correlated with life span. The SIRT3 5' flanking region encompasses the PSMD13 gene encoding the p40.5 regulator subunit of the 26S proteasome. Proteasome is a multicatalytic proteinase whose function declines with aging. SIRT3 and PSMD13 are linked in a head-to-head configuration (788-bp intergenic region). The molecular configuration of two genes that are both related to aging prompted us to search for shared regulatory mechanisms between them. Transfection experiments carried out in HeLa cells by deletion mutants of the PSMD13-SIRT3 intergenic region showed a complex pathway of coregulation acting in both directions. Furthermore, linkage disequilibrium (LD) analyses carried out in a sample of 710 subjects (18-108 years of age) screened for A21631G (marker of PSMD13), and for G477T and VNTR(intron5) (markers of SIRT3), revealed high LD, with significantly different PSMD13-SIRT3 haplotype pools between samples of centenarians and younger people.", - "journal_title": "Genomics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/17059877/" - } - ], - "cf41dd3c-1f6d-4800-84a0-868a2bcb54f4": [ - { - "pub_id": "16131528", - "title": "Growth, metabolism, and blood pressure disturbances during aging in transgenic rats with altered brain renin-angiotensin systems.", - "authors": "Sherry O Kasper,Christy S Carter,Carlos M Ferrario,Detlev Ganten,Leon F Ferder,William E Sonntag,Patricia E Gallagher,Debra I Diz", - "abstract": "Transgenic rats with targeted decreased glial expression of angiotensinogen (ASrAogen rats) did not show an increase in systolic pressure compared with Sprague-Dawley (SD) rats during aging (15-69 wk of age). ASrAogen animals had lower body weights throughout the study, similar to reports for animals with systemic knockout of angiotensinogen or treated long term with renin-angiotensin system (RAS) blockers. Further characterization of indexes of growth and metabolism in ASrAogen rats compared with (mRen2)27 and SD rats, which express elevated versus normal brain and tissue angiotensin II levels, respectively, revealed that serum leptin was 100-200% higher in SD and (mRen2)27 rats at 46 wk and 69 wk of age. Consistent with low serum leptin, ASrAogen rats had higher food intake (73%) compared with SD or (mRen2)27 rats. (mRen2)27 rats had higher resting insulin levels than ASrAogen rats at all ages. Insulin levels were constant during aging in ASrAogen rats, whereas an increase occurred in SD rats, leading to higher insulin levels at 46 and 69 wk of age compared with ASrAogen rats. IGF-1 was comparable among strains at all ages, but (mRen2)27 rats had longer and ASrAogen rats had shorter tail lengths versus SD rats at 15 wk of age. In conclusion, reduced expression of glial angiotensinogen blunts the age-dependent rise in insulin levels and weight gain, findings that mimic the effects of long-term systemic blockade of the RAS or systemic knockout of angiotensinogen. These data implicate glial angiotensinogen in the regulation of body metabolism as well as hormonal mechanisms regulating blood pressure.", - "journal_title": "Physiological genomics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/16131528/" - } - ], - "81341f40-5066-4944-af85-21a96ca3bb22": [ - { - "pub_id": "19557197", - "title": "NRXN3 is a novel locus for waist circumference: a genome-wide association study from the CHARGE Consortium.", - "authors": "Nancy L Heard-Costa,M Carola Zillikens,Keri L Monda,Asa Johansson,Tamara B Harris,Mao Fu,Talin Haritunians,Mary F Feitosa,Thor Aspelund,Gudny Eiriksdottir,Melissa Garcia,Lenore J Launer,Albert V Smith,Braxton D Mitchell,Patrick F McArdle,Alan R Shuldiner,Suzette J Bielinski,Eric Boerwinkle,Fred Brancati,Ellen W Demerath,James S Pankow,Alice M Arnold,Yii-Der Ida Chen,Nicole L Glazer,Barbara McKnight,Bruce M Psaty,Jerome I Rotter,Najaf Amin,Harry Campbell,Ulf Gyllensten,Cristian Pattaro,Peter P Pramstaller,Igor Rudan,Maksim Struchalin,Veronique Vitart,Xiaoyi Gao,Aldi Kraja,Michael A Province,Qunyuan Zhang,Larry D Atwood,Jos\u00e9e Dupuis,Joel N Hirschhorn,Cashell E Jaquish,Christopher J O'Donnell,Ramachandran S Vasan,Charles C White,Yurii S Aulchenko,Karol Estrada,Albert Hofman,Fernando Rivadeneira,Andr\u00e9 G Uitterlinden,Jacqueline C M Witteman,Ben A Oostra,Robert C Kaplan,Vilmundur Gudnason,Jeffrey R O'Connell,Ingrid B Borecki,Cornelia M van Duijn,L Adrienne Cupples,Caroline S Fox,Kari E North", - "abstract": "Central abdominal fat is a strong risk factor for diabetes and cardiovascular disease. To identify common variants influencing central abdominal fat, we conducted a two-stage genome-wide association analysis for waist circumference (WC). In total, three loci reached genome-wide significance. In stage 1, 31,373 individuals of Caucasian descent from eight cohort studies confirmed the role of FTO and MC4R and identified one novel locus associated with WC in the neurexin 3 gene [NRXN3 (rs10146997, p = 6.4x10(-7))]. The association with NRXN3 was confirmed in stage 2 by combining stage 1 results with those from 38,641 participants in the GIANT consortium (p = 0.009 in GIANT only, p = 5.3x10(-8) for combined analysis, n = 70,014). Mean WC increase per copy of the G allele was 0.0498 z-score units (0.65 cm). This SNP was also associated with body mass index (BMI) [p = 7.4x10(-6), 0.024 z-score units (0.10 kg/m(2)) per copy of the G allele] and the risk of obesity (odds ratio 1.13, 95% CI 1.07-1.19; p = 3.2x10(-5) per copy of the G allele). The NRXN3 gene has been previously implicated in addiction and reward behavior, lending further evidence that common forms of obesity may be a central nervous system-mediated disorder. Our findings establish that common variants in NRXN3 are associated with WC, BMI, and obesity.", - "journal_title": "PLoS genetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/19557197/" - } - ], - "ed422ead-ff75-46f2-9b00-3ccbbb5d3cd0": [ - { - "pub_id": "15116144", - "title": "Prevalence and correlates of orthostatic hypotension in middle-aged men and women in Korea: the Korean Health and Genome Study.", - "authors": "C Shin,R D Abbott,H Lee,J Kim,K Kimm", - "abstract": "To examine the prevalence and correlates of orthostatic hypotension (OH) in middle-aged adults enrolled in the Korean Health and Genome Study. Participants were 8908 individuals aged 40-69 years. Supine blood pressure (BP) was measured three times at 30-s intervals after at least 5 min of rest in the supine position and single standing BP was measured at 0 and 2 min after standing, respectively. OH was defined as a reduction in systolic BP or diastolic BP > or = 20 and 10 mmHg, respectively. The prevalence of OH at 0 and 2 min after standing was 12.3 and 2.9%, respectively. At 0 min of standing, OH frequency increased significantly with age from 6.4% in those aged 40-44 years to 23.1% in those aged 65-69 (P < 0.001). After adjustment for age and other characteristics, hypertension was associated with a 1.7-fold excess in the odds of OH in men and a 1.6-fold excess in women (P < 0.001). In contrast, an increase in body mass index (BMI) on the order of 5 kg/m2 was associated with a 20-30% reduction in the odds of OH (P < 0.001). Diabetes in women was also associated with a 1.4-fold excess in the odds of OH (P < 0.05). An increase in triglyceride by 136 mg/dl in men was associated with an increase in the odds of OH (P < 0.05). In conclusion, the prevalence and correlates of OH other than diabetes and triglycerides were notably similar in men and women. While the association between hypertension and OH has been observed elsewhere, low BMI in Korean adults with OH may be an important marker for subclinical morbidity or coexisting risk factors that need to be identified.", - "journal_title": "Journal of human hypertension", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/15116144/" - } - ], - "5830026d-dd78-4271-aa59-bfc997dace24": [ - { - "pub_id": "12697630", - "title": "Imaging genomics.", - "authors": "Ahmad R Hariri,Daniel R Weinberger", - "abstract": "The recent completion of a working draft of the human genome sequence promises to provide unprecedented opportunities to explore the genetic basis of individual differences in complex behaviours and vulnerability to neuropsychiatric illness. Functional neuroimaging, because of its unique ability to assay information processing at the level of brain within individuals, provides a powerful approach to such functional genomics. Recent fMRI studies have established important physiological links between functional genetic polymorphisms and robust differences in information processing within distinct brain regions and circuits that have been linked to the manifestation of various disease states such as Alzheimer's disease, schizophrenia and anxiety disorders. Importantly, all of these biological relationships have been revealed in relatively small samples of healthy volunteers and in the absence of observable differences at the level of behaviour, underscoring the power of a direct assay of brain physiology like fMRI in exploring the functional impact of genetic variation.", - "journal_title": "British medical bulletin", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/12697630/" - } - ], - "b2506939-4d34-4345-b11e-395b76e4c049": [ - { - "pub_id": "11750699", - "title": "Functional genomics: the coming of age for Tetrahymena thermophila.", - "authors": "Aaron P Turkewitz,Eduardo Orias,Geoffrey Kapler", - "abstract": "Over the past decade, researchers have manipulated the unique biology of Tetrahymena thermophila to generate a premier experimental organism for functional genomic analysis. A diverse array of DNA transformation methods have spearheaded in vivo strategies for discovering and dissecting universal eukaryotic processes, such as telomere addition and chromatin remodeling. Compartmentalization of this protist's genome into two functionally distinct nuclei - the silent 'germline' micronucleus and the transcriptionally active macronucleus - provides a powerful means for controlling the expression of transgenes. Heterokaryons that silently harbor homozygous recessive mutations (including lethal ones) in the germline have been exploited. The coupling of forward and reverse genetic approaches with genomics-based methods for gene discovery presents a bright future for research in this rising model eukaryote.", - "journal_title": "Trends in genetics : TIG", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/11750699/" - } - ], - "d2bbd79c-672b-4c18-8b37-717b9be32877": [ - { - "pub_id": "11604331", - "title": "Genomics: food and nutrition.", - "authors": "M A Roberts,D M Mutch,J B German", - "abstract": "Nutrition is traditionally a multidisciplinary field applying principles of molecular biochemistry and statistical epidemiology to integrative metabolism and population health. Genomics, with its global perspective, is now reinventing the future of human metabolic health. Creative experimental designs are addressing metabolic questions in nutrition ranging from energy regulation to aging, and from mechanisms of absorption to the interspecies molecular crosstalk of bacteria and human cells within the intestine.", - "journal_title": "Current opinion in biotechnology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/11604331/" - } - ], - "aa942230-9a43-4b5f-90d9-96d364861a57": [ - { - "pub_id": "16024186", - "title": "The mitochondrial genome in human adaptive radiation and disease: on the road to therapeutics and performance enhancement.", - "authors": "Douglas C Wallace", - "abstract": "The human mitochondrial genome consists of approximately 1500 genes, 37 encoded by the maternally inherited mitochondrial DNA (mtDNA) and the remainder encoded in the nuclear DNA (nDNA). The mtDNA is present in thousands of copies per cell and encodes proteins that are essential components of the mitochondrial energy generation pathway, oxidative phosphorylation (OXPHOS). OXPHOS generates heat to maintain our body temperature and ATP to do work. The mitochondria also produce much of the cellular reactive oxygen species (ROS) and can initiate apoptosis through activation of the mitochondrial permeability transition pore (mtPTP) in response to energy deficiency and oxidative damage. Mitochondrial ROS mutates the mtDNA and mtDNA mutations have been associated with a wide range of age-related diseases including neurodegenerative diseases, cardiomyopathy, diabetes and various cancers. The cellular accumulation of mtDNA mutations may also be the aging clock. Ancient mtDNA variants have also been adaptive and may influence individual health today. Mutations in nDNA-encoded mitochondrial genes can also disrupt OXPHOS, alter mtDNA replication, and affect mitochondrial division. In an effort to treat mitochondrial disease, both metabolic and genetic interventions have been attempted. Metabolic interventions have been directed at increasing energy output, reducing ROS production and stabilizing the mtPTP. Genetic therapies have attempted introduction of nucleic acids into the mitochondrion, nDNA-mitochondrial genes into the nucleus, and mtDNA-encoded genes into the nucleus. These therapeutic approaches might also be used to enhance performance, but we must be careful that catering to short term individual interests might undermine our capacity to adapt and survive.", - "journal_title": "Gene", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/16024186/" - } - ], - "b47e2055-8573-46ac-aec5-c2697df4d4b9": [ - { - "pub_id": "12882352", - "title": "Mitochondrial dysfunction leads to telomere attrition and genomic instability.", - "authors": "Lin Liu,James R Trimarchi,Peter J S Smith,David L Keefe", - "abstract": "Mitochondrial dysfunction and oxidative stress have been implicated in cellular senescence, apoptosis, aging and aging-associated pathologies. Telomere shortening and genomic instability have also been associated with replicative senescence, aging and cancer. Here we show that mitochondrial dysfunction leads to telomere attrition, telomere loss, and chromosome fusion and breakage, accompanied by apoptosis. An antioxidant prevented telomere loss and genomic instability in cells with dysfunctional mitochondria, suggesting that reactive oxygen species are mediators linking mitochondrial dysfunction and genomic instability. Further, nuclear transfer protected genomes from telomere dysfunction and promoted cell survival by reconstitution with functional mitochondria. This work links mitochondrial dysfunction and genomic instability and may provide new therapeutic strategies to combat certain mitochondrial and aging-associated pathologies.", - "journal_title": "Aging cell", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/12882352/" - } - ], - "54a4546b-117d-4950-b75f-5cfda3f7f453": [ - { - "pub_id": "16885361", - "title": "Mutation of succinate dehydrogenase subunit C results in increased O2.-, oxidative stress, and genomic instability.", - "authors": "Benjamin G Slane,N\u00f9khet Aykin-Burns,Brian J Smith,Amanda L Kalen,Prabhat C Goswami,Frederick E Domann,Douglas R Spitz", - "abstract": "Mutations in genes coding for succinate dehydrogenase (SDH) subunits are believed to contribute to cancer and aging, but the mechanism for this is unclear. Hamster fibroblasts expressing a mutation in SDH subunit C (SDHC; B9) showed 3-fold increases in dihydroethidine and dichlorodihydrofluorescein (CDCFH(2)) oxidation indicative of increased steady-state levels of O2(.-) and H2O2, increases in glutathione/glutathione disulfide (indicative of oxidative stress), as well as increases in superoxide dismutase activity, relative to parental B1 cells. B9 cells also showed characteristics associated with cancer cells, including aneuploidy, increases in glucose consumption, and sensitivity to glucose deprivation-induced cytotoxicity. Expression of wild-type (WT) human SDHC in B9 cells caused prooxidant production, glucose consumption, sensitivity to glucose deprivation-induced cytotoxicity, and aneuploidy to revert to the WT phenotype. These data show that SDHC mutations cause increased O2(.-) production, metabolic oxidative stress, and genomic instability and that mutations in genes coding for mitochondrial electron transport chain proteins can contribute to phenotypic changes associated with cancer cells. These results also allow for the speculation that DNA damage to genes coding for electron transport chain proteins could result in a \"mutator phenotype\" by increasing steady-state levels of O2(.-) and H2O2.", - "journal_title": "Cancer research", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/16885361/" - } - ], - "03718264-02e2-4e4b-a2ac-ef82029f6bc0": [ - { - "pub_id": "19521821", - "title": "A genomic approach to yeast chronological aging.", - "authors": "Christopher R Burtner,Christopher J Murakami,Matt Kaeberlein", - "abstract": "Yeast is a useful model organism to study the genetic and biochemical mechanisms of aging. Genomic studies of aging in yeast have been limited, however, by traditional methodologies that require a large investment of labor and resources. In this chapter, we describe a newly-developed method for quantitatively measuring the chronological life span of each strain contained in the yeast ORF deletion collection. Our approach involves determining population survival by monitoring outgrowth kinetics using a Bioscreen C MBR shaker/incubator/plate reader. This method has accuracy comparable to traditional assays, while allowing for higher throughput and decreased variability in measurement.", - "journal_title": "Methods in molecular biology (Clifton, N.J.)", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/19521821/" - } - ], - "ddd79d05-8140-48d7-a7fe-5685bb6b50f8": [ - { - "pub_id": "15039484", - "title": "Additive regulation of hepatic gene expression by dwarfism and caloric restriction.", - "authors": "Tomoshi Tsuchiya,Joseph M Dhahbi,Xinping Cui,Patricia L Mote,Andrzej Bartke,Stephen R Spindler", - "abstract": "Disrupted growth hormone/insulin-like growth factor-1 signaling (DF) and caloric restriction (CR) extend life span and delay the onset of age-related diseases in rodents. In combination, these interventions additively extend life span. To investigate the molecular basis for these effects, we performed genome-wide, microarray expression analysis of liver from homozygous and heterozygous Ames dwarf mice fed ad libitum or CR. CR and DF additively affected a group of 95 genes. Individually and together, DF and CR independently affected the expression of 212 and 77 genes, respectively. These results indicate that DF and CR affect overlapping sets of genes and additively affect a subset of genes. Together, the interventions produced changes in gene expression consistent with increased insulin, glucagon and catecholamine sensitivity, gluconeogenesis, protein turnover, lipid beta-oxidation, apoptosis, and xenobiotic and oxidant metabolism; and decreased cell proliferation, lipid and cholesterol synthesis, and chaperone expression. These data suggest that the additive effects of DF and CR on life span develop from their additive effects on the level of expression of some genes and from their independent effects on other genes. These results provide a novel and focused group of genes closely associated with the regulation of life span in mammals.", - "journal_title": "Physiological genomics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/15039484/" - } - ], - "415c3edb-c00f-44fb-a260-69bb996c76ff": [ - { - "pub_id": "15970797", - "title": "Characterization of the monomethylarsonate reductase and dehydroascorbate reductase activities of Omega class glutathione transferase variants: implications for arsenic metabolism and the age-at-onset of Alzheimer's and Parkinson's diseases.", - "authors": "Erica M Schmuck,Philip G Board,Astrid K Whitbread,Natasha Tetlow,Juleen A Cavanaugh,Anneke C Blackburn,Amir Masoumi", - "abstract": "There are two functional Omega class glutathione transferase (GST) genes in humans. GSTO1 is polymorphic with several coding region alleles, including an A140D substitution, a potential deletion of E155 and an E208K substitution. GSTO2 is also polymorphic with an N142D substitution in the coding region. We investigated the effect of these variations on the enzyme's thioltransferase, dehydroascorbate reductase, monomethylarsonate reductase and dimethylarsonate reductase activities. Variant proteins were expressed in Escherichia coli and purified by Ni-agarose affinity chromatography. GSTO2-2 was insoluble and had to be dissolved and refolded from 8 M urea. The A140D and E208K substitutions in GSTO1-1 did not alter specific activity. The deletion of E155 caused a two- to three-fold increase in the specific activity with each substrate. This deletion also caused a significant decrease in the enzyme's heat stability. The E155 deletion has been linked to abnormal arsenic excretion patterns; however, the available data do not clearly identify the cause of this abnormality. We found that GSTO2-2 has activity with the same substrates as GSTO1-1, and the dehydroascorbate reductase activity of GSTO2-2 is approximately 70-100-fold higher than that of GSTO1-1. The polymorphic N142D substitution had no effect on the specific activity of the enzyme with any substrate. The most notable feature of GSTO2-2 was its very high dehydroascorbate reductase activity, which suggests that GSTO2-2 may significantly protect against oxidative stress by recycling ascorbate. A defect in ascorbate metabolism may provide a common mechanism by which the Omega class GSTs influence the age-at-onset of Alzheimer's and Parkinson's diseases.", - "journal_title": "Pharmacogenetics and genomics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/15970797/" - } - ], - "99453f85-eaeb-41da-b97b-8729554dcbfc": [ - { - "pub_id": "17726092", - "title": "Global expression profiles from C57BL/6J and DBA/2J mouse lungs to determine aging-related genes.", - "authors": "Vikas Misra,Hannah Lee,Anju Singh,Kewu Huang,Rajesh K Thimmulappa,Wayne Mitzner,Shyam Biswal,Clarke G Tankersley", - "abstract": "This study identified gene expression profiles that provided evidence for genomic mechanisms underlying the pathophysiology of aging lung. Aging lungs from C57BL/6 (B6) and DBA/2 (D2) mouse strains differ in physiology and morphometry. Lungs were harvested from B6 mice at 2, 18, and 26 mo and from D2 mice at 2 and 18 mo of age. Purified RNA was subjected to oligonucleotide microarray analyses, and differential expression analyses were performed for comparison of various data sets. A significant majority of differentially expressed genes were upregulated with aging in both strains. Aging D2 lungs uniquely exhibited upregulation in stress-response genes including xenobiotic detoxification cascades. In contrast, aging B6 lungs showed downregulation of heat shock-response genes. Age-dependent downregulation of genes common to both B6 and D2 strains included several collagen genes (e.g., Col1a1 and Col3a1). There was a greater elastin gene (Eln) expression in D2 mice at 2 mo, and Eln was uniquely downregulated with age in this strain. The matrix metalloproteinase 14 gene (Mmp14), critical to alveolar structural integrity, was also downregulated with aging in D2 mice only. Several polymorphisms in the regulatory and untranslated regions of Mmp14 were identified between strains, suggesting that variation in Mmp14 gene regulation contributes to accelerated aging of lungs in D2 mice. In summary, lungs of B6 and D2 mice age with variable rates at the gene expression level, and these quantifiable genomic differences provide a template for understanding the variability in age-dependent changes in lung structure and function.", - "journal_title": "Physiological genomics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/17726092/" - } - ], - "e4609e13-7046-45a8-bf4f-242d84c8bac0": [ - { - "pub_id": "19716530", - "title": "The role of epigenetics in aging and age-related diseases.", - "authors": "Vincenzo Calvanese,Ester Lara,Arnold Kahn,Mario F Fraga", - "abstract": "The role of epigenetics in aging and age-related diseases is a key issue in molecular physiology and medicine because certain epigenetic factors are thought to mediate, at least in part, the relationship between the genome and the environment. An active role for epigenetics in aging must meet two prior conditions: there must be specific epigenetic changes during aging and they must be functionally associated with the aged phenotype. Assuming that specific epigenetic modifications can have a direct functional outcome in aging, it is also essential to establish whether they depend on genetic, environmental or stochastic factors, and if they can be transmitted from one generation to the next. Here we discuss current knowledge about these matters and future directions in the field.", - "journal_title": "Ageing research reviews", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/19716530/" - } - ], - "046184a9-f062-4da2-9900-641aab9468e1": [ - { - "pub_id": "12717633", - "title": "A whole-genome screen of a quantitative trait of age-related maculopathy in sibships from the Beaver Dam Eye Study.", - "authors": "James H Schick,Sudha K Iyengar,Barbara E Klein,Ronald Klein,Karlie Reading,Rachel Liptak,Christopher Millard,Kristine E Lee,Sandra C Tomany,Emily L Moore,Bonnie A Fijal,Robert C Elston", - "abstract": "Age-related maculopathy (ARM) is a leading cause of visual impairment among the elderly in Western populations. To identify ARM-susceptibility loci, we genotyped a subset of subjects from the Beaver Dam (WI) Eye Study and performed a model-free genomewide linkage analysis for markers linked to a quantitative measure of ARM. We initially genotyped 345 autosomal markers in 325 individuals (N=263 sib pairs) from 102 pedigrees. Ten regions suggestive of linkage with ARM were observed on chromosomes 3, 5, 6, 12, 15, and 16. Prior to fine mapping, the most significant regions were an 18-cM region on chromosome 12, near D12S1300 (P=.0159); a region on chromosome 3, near D3S1763, with a P value of.0062; and a 6-cM region on chromosome 16, near D16S769, with a P value of.0086. After expanding our analysis to include 25 additional fine-mapping markers, we found that a 14-cM region on chromosome 12, near D12S346 (located at 106.89 cM), showed the strongest indication of linkage, with a P value of.004. Three other regions, on chromosomes 5, 6, and 15, that were nominally significant at P< or =.01 are also appropriate for fine mapping.", - "journal_title": "American journal of human genetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/12717633/" - } - ], - "ae8ee9dc-aa7c-450c-87cf-06694d28471c": [ - { - "pub_id": "17456900", - "title": "Sex-specific regulation of gene expression in the aging monkey aorta.", - "authors": "Hongyu Qiu,Bin Tian,Ranilo G Resuello,Filipinas F Natividad,Athanasios Peppas,You-Tang Shen,Dorothy E Vatner,Stephen F Vatner,Christophe Depre", - "abstract": "Although increased vascular stiffness is more prominent in aging males than females, and males are more prone to vascular disease with aging, no study has investigated the genes potentially responsible for sex differences in vascular aging. We tested the hypothesis that the transcriptional adaptation to aging differs in males and females using a monkey model, which is not only physiologically and phylogenetically closer to humans than the more commonly studied rodent models but also is not afflicted with the most common forms of vascular disease that accompany the aging process in humans, e.g., atherosclerosis, hypertension, and diabetes. The transcriptional profile of the aorta was compared by high-density microarrays between young and old males or females (n = 6/group). About 600 genes were expressed differentially when comparing old versus young animals. Surprisingly, <5% of these genes were shared between males and females. Radical differences between sexes were especially apparent for genes regulating the extracellular matrix, which relates to stiffness. Aging males were also more prone than females to genes switching smooth muscle cells from the \"contractile\" to \"secretory\" phenotype. Other sex differences involved genes participating in DNA repair, stress response, and cell signaling. Therefore, major differences of gene regulation exist between males and females in vascular aging, which may underlie the physiological differences characterizing aging arteries in males and females. Furthermore, the analyses in young monkeys demonstrated differences in genes regulating vascular structure, implying that the sex differences in vascular stiffness that develop with aging are programmed at an early age.", - "journal_title": "Physiological genomics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/17456900/" - } - ], - "4eea3cf1-d67b-4ae8-b585-a002aff76f9c": [ - { - "pub_id": "19039255", - "title": "Canada: public health genomics.", - "authors": "J Little,B Potter,J Allanson,T Caulfield,J C Carroll,B Wilson", - "abstract": "Canada has a diverse population of 32 million people and a universal, publicly funded health care system provided through provincial and territorial health insurance plans. Public health activities are resourced at provincial/territorial level with strategic coordination from national bodies. Canada has one of the longest-standing genetics professional specialty organizations and is one of the few countries offering master's level training designed specifically for genetic counselors. Prenatal screening is offered as part of routine clinical prenatal services with variable uptake. Surveillance of the effect of prenatal screening and diagnosis on the birth prevalence of congenital anomalies is limited by gaps and variations in surveillance systems. Newborn screening programs vary between provinces and territories in terms of organization and conditions screened for. The last decade has witnessed a four-fold increase in requests for genetic testing, especially for late onset diseases. Tests are performed in provincial laboratories or outside Canada. There is wide variation in participation in laboratory quality assurance schemes, and there are few regulatory frameworks in Canada that are directly relevant to genetics testing services or population genetics. Health technology assessment in Canada is conducted by a diverse range of organizations, several of which have produced reports related to genetics. Several large-scale population cohort studies are underway or planned, with initiatives to harmonize their conduct and the management of ethical issues, both within Canada and with similar projects in other countries.", - "journal_title": "Public health genomics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/19039255/" - } - ], - "4a8820d5-7cb3-4883-9ae1-35c99b29cd4d": [ - { - "pub_id": "20157529", - "title": "Adaptation, aging, and genomic information.", - "authors": "Michael R Rose", - "abstract": "Aging is not simply an accumulation of damage or inappropriate higher-order signaling, though it does secondarily involve both of these subsidiary mechanisms. Rather, aging occurs because of the extensive absence of adaptive genomic information required for survival to, and function at, later adult ages, due to the declining forces of natural selection during adult life. This absence of information then secondarily leads to misallocations and damage at every level of biological organization. But the primary problem is a failure of adaptation at later ages. Contemporary proposals concerning means by which human aging can be ended or cured which are based on simple signaling or damage theories will thus reliably fail. Strategies based on reverse-engineering age-extended adaptation using experimental evolution and genomics offer the prospect of systematically greater success.", - "journal_title": "Aging", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/20157529/" - } - ], - "0b6d1fe0-e041-4764-8b87-40b141fd16c0": [ - { - "pub_id": "15711547", - "title": "Uncovering regulatory pathways that affect hematopoietic stem cell function using 'genetical genomics'.", - "authors": "Leonid Bystrykh,Ellen Weersing,Bert Dontje,Sue Sutton,Mathew T Pletcher,Tim Wiltshire,Andrew I Su,Edo Vellenga,Jintao Wang,Kenneth F Manly,Lu Lu,Elissa J Chesler,Rudi Alberts,Ritsert C Jansen,Robert W Williams,Michael P Cooke,Gerald de Haan", - "abstract": "We combined large-scale mRNA expression analysis and gene mapping to identify genes and loci that control hematopoietic stem cell (HSC) function. We measured mRNA expression levels in purified HSCs isolated from a panel of densely genotyped recombinant inbred mouse strains. We mapped quantitative trait loci (QTLs) associated with variation in expression of thousands of transcripts. By comparing the physical transcript position with the location of the controlling QTL, we identified polymorphic cis-acting stem cell genes. We also identified multiple trans-acting control loci that modify expression of large numbers of genes. These groups of coregulated transcripts identify pathways that specify variation in stem cells. We illustrate this concept with the identification of candidate genes involved with HSC turnover. We compared expression QTLs in HSCs and brain from the same mice and identified both shared and tissue-specific QTLs. Our data are accessible through WebQTL, a web-based interface that allows custom genetic linkage analysis and identification of coregulated transcripts.", - "journal_title": "Nature genetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/15711547/" - } - ], - "246942c7-3ea0-446e-a4f5-cb1e060c33b5": [ - { - "pub_id": "25719666", - "title": "Whole genomes redefine the mutational landscape of pancreatic cancer.", - "authors": "Nicola Waddell,Marina Pajic,Ann-Marie Patch,David K Chang,Karin S Kassahn,Peter Bailey,Amber L Johns,David Miller,Katia Nones,Kelly Quek,Michael C J Quinn,Alan J Robertson,Muhammad Z H Fadlullah,Tim J C Bruxner,Angelika N Christ,Ivon Harliwong,Senel Idrisoglu,Suzanne Manning,Craig Nourse,Ehsan Nourbakhsh,Shivangi Wani,Peter J Wilson,Emma Markham,Nicole Cloonan,Matthew J Anderson,J Lynn Fink,Oliver Holmes,Stephen H Kazakoff,Conrad Leonard,Felicity Newell,Barsha Poudel,Sarah Song,Darrin Taylor,Nick Waddell,Scott Wood,Qinying Xu,Jianmin Wu,Mark Pinese,Mark J Cowley,Hong C Lee,Marc D Jones,Adnan M Nagrial,Jeremy Humphris,Lorraine A Chantrill,Venessa Chin,Angela M Steinmann,Amanda Mawson,Emily S Humphrey,Emily K Colvin,Angela Chou,Christopher J Scarlett,Andreia V Pinho,Marc Giry-Laterriere,Ilse Rooman,Jaswinder S Samra,James G Kench,Jessica A Pettitt,Neil D Merrett,Christopher Toon,Krishna Epari,Nam Q Nguyen,Andrew Barbour,Nikolajs Zeps,Nigel B Jamieson,Janet S Graham,Simone P Niclou,Rolf Bjerkvig,Robert Gr\u00fctzmann,Daniela Aust,Ralph H Hruban,Anirban Maitra,Christine A Iacobuzio-Donahue,Christopher L Wolfgang,Richard A Morgan,Rita T Lawlor,Vincenzo Corbo,Claudio Bassi,Massimo Falconi,Giuseppe Zamboni,Giampaolo Tortora,Margaret A Tempero, ,Anthony J Gill,James R Eshleman,Christian Pilarsky,Aldo Scarpa,Elizabeth A Musgrove,John V Pearson,Andrew V Biankin,Sean M Grimmond", - "abstract": "Pancreatic cancer remains one of the most lethal of malignancies and a major health burden. We performed whole-genome sequencing and copy number variation (CNV) analysis of 100 pancreatic ductal adenocarcinomas (PDACs). Chromosomal rearrangements leading to gene disruption were prevalent, affecting genes known to be important in pancreatic cancer (TP53, SMAD4, CDKN2A, ARID1A and ROBO2) and new candidate drivers of pancreatic carcinogenesis (KDM6A and PREX2). Patterns of structural variation (variation in chromosomal structure) classified PDACs into 4 subtypes with potential clinical utility: the subtypes were termed stable, locally rearranged, scattered and unstable. A significant proportion harboured focal amplifications, many of which contained druggable oncogenes (ERBB2, MET, FGFR1, CDK6, PIK3R3 and PIK3CA), but at low individual patient prevalence. Genomic instability co-segregated with inactivation of DNA maintenance genes (BRCA1, BRCA2 or PALB2) and a mutational signature of DNA damage repair deficiency. Of 8 patients who received platinum therapy, 4 of 5 individuals with these measures of defective DNA maintenance responded.", - "journal_title": "Nature", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/25719666/" - } - ], - "f2a907a8-298a-433f-8d61-01731824b7de": [ - { - "pub_id": "12595580", - "title": "Age-related impairment of the transcriptional responses to oxidative stress in the mouse heart.", - "authors": "Michael G Edwards,Deepayan Sarkar,Roger Klopp,Jason D Morrow,Richard Weindruch,Tomas A Prolla", - "abstract": "To investigate the transcriptional response to oxidative stress in the heart and how it changes with age, we examined the cardiac gene expression profiles of young (5-mo-old), middle-aged (15-mo-old), and old (25-mo-old) C57BL/6 mice treated with a single intraperitoneal injection of paraquat (50 mg/kg). Mice were killed at 0, 1, 3, 5, and 7 h after paraquat treatment, and the gene expression profile was obtained with high-density oligonucleotide microarrays. Of 9,977 genes represented on the microarray, 249 transcripts in the young mice, 298 transcripts in the middle-aged mice, and 256 transcripts in the old mice displayed a significant change in mRNA levels (ANOVA, P < 0.01). Among these, a total of 55 transcripts were determined to be paraquat responsive for all age groups. Genes commonly induced in all age groups include those associated with stress, inflammatory, immune, and growth factor responses. Interestingly, only young mice displayed a significant increase in expression of all three isoforms of GADD45, a DNA damage-responsive gene. Additionally, the number of immediate early response genes (IEGs) found to be induced by paraquat was considerably higher in the younger animals. These results demonstrate that, at the transcriptional level, there is an age-related impairment of specific inducible pathways in the response to oxidative stress in the mouse heart.", - "journal_title": "Physiological genomics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/12595580/" - } - ], - "2c71b513-2040-4d28-82a5-1997913ffd5a": [ - { - "pub_id": "20942671", - "title": "Ancestry and disease in the age of genomic medicine.", - "authors": "Charles N Rotimi,Lynn B Jorde", - "abstract": "", - "journal_title": "The New England journal of medicine", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/20942671/" - } - ], - "8aa54f40-80f7-42f5-b7ff-1e91334db2c1": [ - { - "pub_id": "11237011", - "title": "Initial sequencing and analysis of the human genome.", - "authors": "E S Lander,L M Linton,B Birren,C Nusbaum,M C Zody,J Baldwin,K Devon,K Dewar,M Doyle,W FitzHugh,R Funke,D Gage,K Harris,A Heaford,J Howland,L Kann,J Lehoczky,R LeVine,P McEwan,K McKernan,J Meldrim,J P Mesirov,C Miranda,W Morris,J Naylor,C Raymond,M Rosetti,R Santos,A Sheridan,C Sougnez,Y Stange-Thomann,N Stojanovic,A Subramanian,D Wyman,J Rogers,J Sulston,R Ainscough,S Beck,D Bentley,J Burton,C Clee,N Carter,A Coulson,R Deadman,P Deloukas,A Dunham,I Dunham,R Durbin,L French,D Grafham,S Gregory,T Hubbard,S Humphray,A Hunt,M Jones,C Lloyd,A McMurray,L Matthews,S Mercer,S Milne,J C Mullikin,A Mungall,R Plumb,M Ross,R Shownkeen,S Sims,R H Waterston,R K Wilson,L W Hillier,J D McPherson,M A Marra,E R Mardis,L A Fulton,A T Chinwalla,K H Pepin,W R Gish,S L Chissoe,M C Wendl,K D Delehaunty,T L Miner,A Delehaunty,J B Kramer,L L Cook,R S Fulton,D L Johnson,P J Minx,S W Clifton,T Hawkins,E Branscomb,P Predki,P Richardson,S Wenning,T Slezak,N Doggett,J F Cheng,A Olsen,S Lucas,C Elkin,E Uberbacher,M Frazier,R A Gibbs,D M Muzny,S E Scherer,J B Bouck,E J Sodergren,K C Worley,C M Rives,J H Gorrell,M L Metzker,S L Naylor,R S Kucherlapati,D L Nelson,G M Weinstock,Y Sakaki,A Fujiyama,M Hattori,T Yada,A Toyoda,T Itoh,C Kawagoe,H Watanabe,Y Totoki,T Taylor,J Weissenbach,R Heilig,W Saurin,F Artiguenave,P Brottier,T Bruls,E Pelletier,C Robert,P Wincker,D R Smith,L Doucette-Stamm,M Rubenfield,K Weinstock,H M Lee,J Dubois,A Rosenthal,M Platzer,G Nyakatura,S Taudien,A Rump,H Yang,J Yu,J Wang,G Huang,J Gu,L Hood,L Rowen,A Madan,S Qin,R W Davis,N A Federspiel,A P Abola,M J Proctor,R M Myers,J Schmutz,M Dickson,J Grimwood,D R Cox,M V Olson,R Kaul,C Raymond,N Shimizu,K Kawasaki,S Minoshima,G A Evans,M Athanasiou,R Schultz,B A Roe,F Chen,H Pan,J Ramser,H Lehrach,R Reinhardt,W R McCombie,M de la Bastide,N Dedhia,H Bl\u00f6cker,K Hornischer,G Nordsiek,R Agarwala,L Aravind,J A Bailey,A Bateman,S Batzoglou,E Birney,P Bork,D G Brown,C B Burge,L Cerutti,H C Chen,D Church,M Clamp,R R Copley,T Doerks,S R Eddy,E E Eichler,T S Furey,J Galagan,J G Gilbert,C Harmon,Y Hayashizaki,D Haussler,H Hermjakob,K Hokamp,W Jang,L S Johnson,T A Jones,S Kasif,A Kaspryzk,S Kennedy,W J Kent,P Kitts,E V Koonin,I Korf,D Kulp,D Lancet,T M Lowe,A McLysaght,T Mikkelsen,J V Moran,N Mulder,V J Pollara,C P Ponting,G Schuler,J Schultz,G Slater,A F Smit,E Stupka,J Szustakowki,D Thierry-Mieg,J Thierry-Mieg,L Wagner,J Wallis,R Wheeler,A Williams,Y I Wolf,K H Wolfe,S P Yang,R F Yeh,F Collins,M S Guyer,J Peterson,A Felsenfeld,K A Wetterstrand,A Patrinos,M J Morgan,P de Jong,J J Catanese,K Osoegawa,H Shizuya,S Choi,Y J Chen,J Szustakowki, ", - "abstract": "The human genome holds an extraordinary trove of information about human development, physiology, medicine and evolution. Here we report the results of an international collaboration to produce and make freely available a draft sequence of the human genome. We also present an initial analysis of the data, describing some of the insights that can be gleaned from the sequence.", - "journal_title": "Nature", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/11237011/" - } - ], - "2f3f259f-716a-4b40-af69-e5df5a21b862": [ - { - "pub_id": "16166375", - "title": "Shelterin: the protein complex that shapes and safeguards human telomeres.", - "authors": "Titia de Lange", - "abstract": "Added by telomerase, arrays of TTAGGG repeats specify the ends of human chromosomes. A complex formed by six telomere-specific proteins associates with this sequence and protects chromosome ends. By analogy to other chromosomal protein complexes such as condensin and cohesin, I will refer to this complex as shelterin. Three shelterin subunits, TRF1, TRF2, and POT1 directly recognize TTAGGG repeats. They are interconnected by three additional shelterin proteins, TIN2, TPP1, and Rap1, forming a complex that allows cells to distinguish telomeres from sites of DNA damage. Without the protective activity of shelterin, telomeres are no longer hidden from the DNA damage surveillance and chromosome ends are inappropriately processed by DNA repair pathways. How does shelterin avert these events? The current data argue that shelterin is not a static structural component of the telomere. Instead, shelterin is emerging as a protein complex with DNA remodeling activity that acts together with several associated DNA repair factors to change the structure of the telomeric DNA, thereby protecting chromosome ends. Six shelterin subunits: TRF1, TRF2, TIN2, Rap1, TPP1, and POT1.", - "journal_title": "Genes & development", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/16166375/" - } - ], - "eea4020b-1e14-4af9-9d67-f75d1802fdcd": [ - { - "pub_id": "16484772", - "title": "Sex-specific telomere length profiles and age-dependent erosion dynamics of individual chromosome arms in humans.", - "authors": "S Mayer,S Br\u00fcderlein,S Perner,I Waibel,A Holdenried,N Ciloglu,C Hasel,T Mattfeldt,K V Nielsen,P M\u00f6ller", - "abstract": "During aging, telomeres are gradually shortened, eventually leading to cellular senescence. By T/C-FISH (telomere/centromere-FISH), we investigated human telomere length differences on single chromosome arms of 205 individuals in different age groups and sexes. For all chromosome arms, we found a linear correlation between telomere length and donor age. Generally, males had shorter telomeres and higher attrition rates. Every chromosome arm had its individual age-specific telomere length and erosion pattern, resulting in an unexpected heterogeneity in chromosome-specific regression lines. This differential erosion pattern, however, does not seem to be accidental, since we found a correlation between average telomere length of single chromosome arms in newborns and their annual attrition rate. Apart from the above-mentioned sex-specific discrepancies, chromosome arm-specific telomere lengths were strikingly similar in men and women. This implies a mechanism that arm specifically regulates the telomere length independent of gender, thus leading to interchromosomal telomere variations.", - "journal_title": "Cytogenetic and genome research", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/16484772/" - } - ], - "0381d0d4-717f-470b-a8d4-562475cf58bb": [ - { - "pub_id": "17640558", - "title": "Trends in oxidative aging theories.", - "authors": "Florian L Muller,Michael S Lustgarten,Youngmok Jang,Arlan Richardson,Holly Van Remmen", - "abstract": "The early observations on the rate-of-living theory by Max Rubner and the report by Gershman that oxygen free radicals exist in vivo culminated in the seminal proposal in the 1950s by Denham Harman that reactive oxygen species are a cause of aging (free radical theory of aging). The goal of this review is to analyze recent findings relevant in evaluating Harman's theory using experimental results as grouped by model organisms (i.e., invertebrate models and mice). In this regard, we have focused primarily on recent work involving genetic manipulations. Because the free radical theory of aging is not the only theorem proposed to explain the mechanism(s) involved in aging at the molecular level, we also discuss how this theory is related to other areas of research in biogerontology, specifically, telomere/cell senescence, genomic instability, and the mitochondrial hypothesis of aging. We also discuss where we think the free radical theory is headed. It is now possible to give at least a partial answer to the question whether oxidative stress determines life span as Harman posed so long ago. Based on studies to date, we argue that a tentative case for oxidative stress as a life-span determinant can be made in Drosophila melanogaster. Studies in mice argue for a role of oxidative stress in age-related disease, especially cancer; however, with regard to aging per se, the data either do not support or remain inconclusive on whether oxidative stress determines life span.", - "journal_title": "Free radical biology & medicine", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/17640558/" - } - ], - "a5154017-1607-499f-9d85-9fdbb47f4623": [ - { - "pub_id": "20936643", - "title": "Environmental biosafety in the age of synthetic biology: do we really need a radical new approach? Environmental fates of microorganisms bearing synthetic genomes could be predicted from previous data on traditionally engineered bacteria for in situ bioremediation.", - "authors": "Victor de Lorenzo", - "abstract": "", - "journal_title": "BioEssays : news and reviews in molecular, cellular and developmental biology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/20936643/" - } - ], - "74bfe52f-840b-4022-8122-b2d9c583ea5d": [ - { - "pub_id": "17339271", - "title": "Heritable rather than age-related environmental and stochastic factors dominate variation in DNA methylation of the human IGF2/H19 locus.", - "authors": "Bastiaan T Heijmans,Dennis Kremer,Elmar W Tobi,Dorret I Boomsma,P Eline Slagboom", - "abstract": "Epigenetic variation may significantly contribute to the risk of common disease. Currently, little is known about the extent and causes of epigenetic variation. Here, we investigated the contribution of heritable influences and the combined effect of environmental and stochastic factors to variation in DNA methylation of the IGF2/H19 locus. Moreover, we tested whether this locus was subject to age-related degeneration of epigenetic patterns as was previously suggested for global methylation. We measured methylation of the H19 and IGF2 differentially methylated regions (DMRs) in 196 adolescent and 176 middle-aged twins using a recently developed mass spectrometry-based method. We observed substantial variation in DNA methylation across individuals, underscoring that DNA methylation is a quantitative trait. Analysis of data in monozygotic and dizygotic twins revealed that a significant part of this variation could be attributed to heritable factors. The heritability of methylation of individual CpG sites varied between 20 and 74% for the H19 DMR and was even higher, between 57 and 97%, for the IGF2 DMR. Remarkably, the combined influence of environmental and stochastic factors on DNA methylation was not greater in middle-age than in adolescence, suggesting a limited role for age-related degeneration of methylation patterns at this locus. Single nucleotide polymorphisms in the IGF2/H19 locus were significantly associated with DNA methylation of the IGF2 DMR (P = 0.004). A preliminary analysis suggested an association between H19 DMR methylation and body size (P < 0.05). Our study shows that variation in DNA methylation of the IGF2/H19 locus is mainly determined by heritable factors and single nucleotide polymorphisms (SNPs) in cis, rather than the cumulative effect of environmental and stochastic factors occurring with age.", - "journal_title": "Human molecular genetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/17339271/" - } - ], - "3bf70612-23e6-41b8-9b88-ce9ba23c1edf": [ - { - "pub_id": "9988222", - "title": "Molecular biology of aging.", - "authors": "F B Johnson,D A Sinclair,L Guarente", - "abstract": "", - "journal_title": "Cell", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/9988222/" - } - ], - "c11ed7a9-f8b0-41e8-97e3-0756c3e721f4": [ - { - "pub_id": "11115379", - "title": "A genome scan for renal function among hypertensives: the HyperGEN study.", - "authors": "A T DeWan,D K Arnett,L D Atwood,M A Province,C E Lewis,S C Hunt,J Eckfeldt", - "abstract": "Decreased renal function is often a complication of hypertension. Although it has been suggested that the response of the kidney to hypertension has an underlying genetic component, there is limited information suggesting that specific genetic regions or candidate genes contribute to the variability in creatinine clearance, a commonly used measure of kidney function. As part of the Hypertension Genetic Epidemiology Network (HyperGEN) study, creatinine clearance measurements were assessed in a large biracial sample of hypertensive siblings (466 African American subjects and 634 white subjects in 215 and 265 sibships, respectively). All participants were hypertensive before the age of 60 years, and the mean age of the siblings was 52 years among the African American subjects and 61 years among the white subjects. Two residual models were created for creatinine clearance: a minimally adjusted model (which included age and age(2)) and a fully adjusted model (which included age, age(2), lean body mass, pulse rate, pulse pressure, hormone-replacement therapy, educational status, and physical activity). Standardized residuals were calculated separately for men and women in both racial groups. The heritability of the residual creatinine clearance was 17% and 18% among the African American and white subjects, respectively. We conducted multipoint variance components linkage analysis using GENEHUNTER2 and 387 anonymous markers (Cooperative Human Linkage Center screening set 8). The best evidence for linkage in African American subjects was found on chromosome 3 (LOD = 3.61 at 214.6 cM, 3q27) with the fully adjusted model, and the best evidence in white subjects was found on chromosome 3 (LOD = 3.36 at 115.1 cM) with the minimally adjusted model. Positional candidate genes that are contained in and around the region on chromosome 3 (214.6 cM) that may contribute to renal function include enoyl-CoA hydratase/3-hydroxyacyl-CoA dehydrogenase (EHHADH) and apolipoprotein D (ApoD). These findings suggest there may be genetic regions related to the variability of creatinine clearance among hypertensive individuals.", - "journal_title": "American journal of human genetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/11115379/" - } - ], - "e4473845-c00a-48b6-8a98-4062aba353f8": [ - { - "pub_id": "18760390", - "title": "Genome-wide SNP-based linkage scan identifies a locus on 8q24 for an age-related hearing impairment trait.", - "authors": "Jeroen R Huyghe,Lut Van Laer,Jan-Jaap Hendrickx,Erik Fransen,Kelly Demeester,Vedat Topsakal,Sylvia Kunst,Minna Manninen,Mona Jensen,Amanda Bonaconsa,Manuela Mazzoli,Manuela Baur,Samuli Hannula,Elina M\u00e4ki-Torkko,Angeles Espeso,Els Van Eyken,Antonia Flaquer,Christian Becker,Dafydd Stephens,Martti Sorri,Eva Orzan,Michael Bille,Agnete Parving,Ilmari Pyykk\u00f6,Cor W R J Cremers,Hannie Kremer,Paul H Van de Heyning,Thomas F Wienker,Peter N\u00fcrnberg,Markus Pfister,Guy Van Camp", - "abstract": "Age-related hearing impairment (ARHI), or presbycusis, is a very common multifactorial disorder. Despite the knowledge that genetics play an important role in the etiology of human ARHI as revealed by heritability studies, to date, its precise genetic determinants remain elusive. Here we report the results of a cross-sectional family-based genetic study employing audiometric data. By using principal component analysis, we were able to reduce the dimensionality of this multivariate phenotype while capturing most of the variation and retaining biologically important features of the audiograms. We conducted a genome-wide association as well as a linkage scan with high-density SNP microarrays. Because of the presence of genetic population substructure, association testing was stratified after which evidence was combined by meta-analysis. No association signals reaching genome-wide significance were detected. Linkage analysis identified a linkage peak on 8q24.13-q24.22 for a trait correlated to audiogram shape. The signal reached genome-wide significance, as assessed by simulations. This finding represents the first locus for an ARHI trait.", - "journal_title": "American journal of human genetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/18760390/" - } - ], - "2e2ca797-e122-4d79-a058-21fea5d823ab": [ - { - "pub_id": "20400778", - "title": "Genomic variation associated with mortality among adults of European and African ancestry with heart failure: the cohorts for heart and aging research in genomic epidemiology consortium.", - "authors": "Alanna C Morrison,Janine F Felix,L Adrienne Cupples,Nicole L Glazer,Laura R Loehr,Abbas Dehghan,Serkalem Demissie,Joshua C Bis,Wayne D Rosamond,Yurii S Aulchenko,Ying A Wang,Talin Haritunians,Aaron R Folsom,Fernando Rivadeneira,Emelia J Benjamin,Thomas Lumley,David Couper,Bruno H Stricker,Christopher J O'Donnell,Kenneth M Rice,Patricia P Chang,Albert Hofman,Daniel Levy,Jerome I Rotter,Ervin R Fox,Andre G Uitterlinden,Thomas J Wang,Bruce M Psaty,James T Willerson,Cornelia M van Duijn,Eric Boerwinkle,Jacqueline C M Witteman,Ramachandran S Vasan,Nicholas L Smith", - "abstract": "Prognosis and survival are significant concerns for individuals with heart failure (HF). To better understand the pathophysiology of HF prognosis, the association between 2,366,858 single-nucleotide polymorphisms (SNPs) and all-cause mortality was evaluated among individuals with incident HF from 4 community-based prospective cohorts: the Atherosclerosis Risk in Communities Study, the Cardiovascular Health Study, the Framingham Heart Study, and the Rotterdam Study. Participants were 2526 individuals of European ancestry and 466 individuals of African ancestry who experienced an incident HF event during follow-up in the respective cohorts. Within each study, the association between genetic variants and time to mortality among individuals with HF was assessed by Cox proportional hazards models that included adjustment for sex and age at the time of the HF event. Prospective fixed-effect meta-analyses were conducted for the 4 study populations of European ancestry (N=1645 deaths) and for the 2 populations of African ancestry (N=281 deaths). Genome-wide significance was set at P=5.0x10(-7). Meta-analytic findings among individuals of European ancestry revealed 1 genome-wide significant locus on chromosome 3p22 in an intron of CKLF-like MARVEL transmembrane domain containing 7 (CMTM7, P=3.2x10(-7)). Eight additional loci in individuals of European ancestry and 4 loci in individuals of African ancestry were identified by high-signal SNPs (P<1.0x10(-5)) but did not meet genome-wide significance. This study identified a novel locus associated with all-cause mortality among individuals of European ancestry with HF. This finding warrants additional investigation, including replication, in other studies of HF.", - "journal_title": "Circulation. Cardiovascular genetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/20400778/" - } - ], - "b67847d5-d5f7-4c4d-9713-4b42e6cefe14": [ - { - "pub_id": "14679299", - "title": "Life-long reduction in MnSOD activity results in increased DNA damage and higher incidence of cancer but does not accelerate aging.", - "authors": "Holly Van Remmen,Yuji Ikeno,Michelle Hamilton,Mohammad Pahlavani,Norman Wolf,Suzanne R Thorpe,Nathan L Alderson,John W Baynes,Charles J Epstein,Ting-Ting Huang,James Nelson,Randy Strong,Arlan Richardson", - "abstract": "Mice heterozygous for the Sod2 gene (Sod2+/- mice) have been used to study the phenotype of life-long reduced Mn-superoxide dismutase (MnSOD) activity. The Sod2+/- mice have reduced MnSOD activity (50%) in all tissues throughout life. The Sod2+/- mice have increased oxidative damage as demonstrated by significantly elevated levels of 8-oxo-2-deoxyguanosine (8oxodG) in nuclear DNA in all tissues of Sod2+/- mice studied. The levels of 8oxodG in nuclear DNA increased with age in all tissues of Sod2+/- and wild-type (WT) mice, and at 26 mo of age, the levels of 8oxodG in nuclear DNA were significantly higher (from 15% in heart to over 60% in liver) in the Sod2+/- mice compared with WT mice. The level of 8oxodG was also higher in mitochondrial DNA isolated from liver and brain in Sod2+/- mice compared with WT mice. The increased oxidative damage to DNA in the Sod2+/- mice is associated with a 100% increase in tumor incidence (the number of mice with tumors) in old Sod2+/- mice compared with the old WT mice. However, the life spans (mean and maximum survival) of the Sod2+/- and WT mice were identical. In addition, biomarkers of aging, such as cataract formation, immune response, and formation of glycoxidation products carboxymethyl lysine and pentosidine in skin collagen changed with age to the same extent in both WT and Sod2+/- mice. Thus life-long reduction of MnSOD activity leads to increased levels of oxidative damage to DNA and increased cancer incidence but does not appear to affect aging.", - "journal_title": "Physiological genomics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/14679299/" - } - ], - "22aa5462-abf8-4b1e-9391-ff8afb85a83e": [ - { - "pub_id": "14968411", - "title": "Age-related macular degeneration: a high-resolution genome scan for susceptibility loci in a population enriched for late-stage disease.", - "authors": "Gon\u00e7alo R Abecasis,Beverly M Yashar,Yu Zhao,Noor M Ghiasvand,Sepideh Zareparsi,Kari E H Branham,Adam C Reddick,Edward H Trager,Shigeo Yoshida,John Bahling,Elena Filippova,Susan Elner,Mark W Johnson,Andrew K Vine,Paul A Sieving,Samuel G Jacobson,Julia E Richards,Anand Swaroop", - "abstract": "Age-related macular degeneration (AMD) is a complex multifactorial disease that affects the central region of the retina. AMD is clinically heterogeneous, leading to geographic atrophy (GA) and/or choroidal neovascularization (CNV) at advanced stages. Considerable data exists in support of a genetic predisposition for AMD. Recent linkage studies have provided evidence in favor of several AMD susceptibility loci. We have performed a high-resolution (5-cM) genome scan of 412 affected relative pairs that were enriched for late-stage disease (GA and/or CNV). Nonparametric linkage analysis was performed using two different diagnostic criteria and also by dividing the affected individuals according to GA or CNV phenotype. Our results demonstrate evidence of linkage in regions that were suggested in at least one previous study at chromosomes 1q (236-240 cM in the Marshfield genetic map), 5p (40-50 cM), and 9q (111 cM). Multipoint analysis of affected relatives with CNV provided evidence of additional susceptibility loci on chromosomes 2p (10 cM) and 22q (25 cM). A recently identified Gln5345Arg change in HEMICENTIN-1 on chromosome 1q25 was not detected in 274 affected members in the restricted group with AMD, 346 additional patients with AMD, and 237 unaffected controls. Our results consolidate the chromosomal locations of several AMD susceptibility loci and, together with previous reports, should facilitate the search for disease-associated sequence variants.", - "journal_title": "American journal of human genetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/14968411/" - } - ], - "d54db58c-5e5f-4552-a0cb-4e27787aee00": [ - { - "pub_id": "15020720", - "title": "Proinflammatory phenotype of coronary arteries promotes endothelial apoptosis in aging.", - "authors": "Anna Csiszar,Zoltan Ungvari,Akos Koller,John G Edwards,Gabor Kaley", - "abstract": "Previously we demonstrated that aging in coronary arteries is associated with proinflammatory phenotypic changes and decreased NO bioavailability, which, we hypothesized, promotes vascular disease by enhancing endothelial apoptosis. To test this hypothesis we characterized proapoptotic alterations in the phenotype of coronary arteries of aged (26 mo old) and young (3 mo old) F344 rats. DNA fragmentation analysis and TUNEL assay showed that in aged vessels there was an approximately fivefold increase in the number of apoptotic endothelial cells. In aged coronary arteries there was an increased expression of TNFalpha, TNFbeta, and caspase 9 (microarray, real-time PCR), as well as increased caspase 9 and caspase 3 activity, whereas expression of TNFR1, TNFalpha-converting enzyme (TACE), Bcl-2, Bcl-X(L), Bid, Bax, caspase 8, and caspase 3 were unchanged. In vessel culture (18 h) incubation of aged coronary arteries with a TNF blocking antibody or the NO donor S-nitroso-penicillamine (SNAP) decreased apoptotic cell death. Incubation of young arteries with exogenous TNFalpha increased caspase 9 activity and elicited endothelial apoptosis, which was attenuated by SNAP. Inhibition of NO synthesis in cultured young coronary arteries also induced apoptotic cell death and potentiated the apoptotic effect of TNFalpha. Thus we propose that age-related upregulation of TNFalpha and caspase 9 and decreased bioavailability of NO promote endothelial apoptosis in coronary arteries that may lead to impaired endothelial function and ischemic heart disease in the elderly.", - "journal_title": "Physiological genomics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/15020720/" - } - ], - "0f6d520d-9874-4e28-bf0a-d562ea244565": [ - { - "pub_id": "17284601", - "title": "Telomere dysfunction as a cause of genomic instability in Werner syndrome.", - "authors": "Laure Crabbe,Anna Jauch,Colleen M Naeger,Heidi Holtgreve-Grez,Jan Karlseder", - "abstract": "Werner syndrome (WS) is a rare human premature aging disease caused by mutations in the gene encoding the RecQ helicase WRN. In addition to the aging features, this disorder is marked by genomic instability, associated with an elevated incidence of cancer. Several lines of evidence suggest that telomere dysfunction is associated with the aging phenotype of the syndrome; however, the origin of the genomic instability observed in WS cells and the reason for the high incidence of cancer in WS have not been established. We previously proposed that WRN helicase activity was necessary to prevent dramatic telomere loss during DNA replication. Here we demonstrate that replication-associated telomere loss is responsible for the chromosome fusions found in WS fibroblasts. Moreover, using metaphase analysis we show that telomere elongation by telomerase can significantly reduce the appearance of new chromosomal aberrations in cells lacking WRN, similar to complementation of WS cells with WRN. Our results suggest that the genome instability in WS cells depends directly on telomere dysfunction, linking chromosome end maintenance to chromosomal aberrations in this disease.", - "journal_title": "Proceedings of the National Academy of Sciences of the United States of America", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/17284601/" - } - ], - "35702811-a454-400a-ad4b-fa269af823e1": [ - { - "pub_id": "15084750", - "title": "Genome-wide RNA interference screen identifies previously undescribed regulators of polyglutamine aggregation.", - "authors": "Ellen A A Nollen,Susana M Garcia,Gijs van Haaften,Soojin Kim,Alejandro Chavez,Richard I Morimoto,Ronald H A Plasterk", - "abstract": "Protein misfolding and the formation of aggregates are increasingly recognized components of the pathology of human genetic disease and hallmarks of many neurodegenerative disorders. As exemplified by polyglutamine diseases, the propensity for protein misfolding is associated with the length of polyglutamine expansions and age-dependent changes in protein-folding homeostasis, suggesting a critical role for a protein homeostatic buffer. To identify the complement of protein factors that protects cells against the formation of protein aggregates, we tested transgenic Caenorhabditis elegans strains expressing polyglutamine expansion yellow fluorescent protein fusion proteins at the threshold length associated with the age-dependent appearance of protein aggregation. We used genome-wide RNA interference to identify genes that, when suppressed, resulted in the premature appearance of protein aggregates. Our screen identified 186 genes corresponding to five principal classes of polyglutamine regulators: genes involved in RNA metabolism, protein synthesis, protein folding, and protein degradation; and those involved in protein trafficking. We propose that each of these classes represents a molecular machine collectively comprising the protein homeostatic buffer that responds to the expression of damaged proteins to prevent their misfolding and aggregation.", - "journal_title": "Proceedings of the National Academy of Sciences of the United States of America", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/15084750/" - } - ], - "3ea25157-b80f-4ef1-ba04-f8238294dba7": [ - { - "pub_id": "20049741", - "title": "Neurodegenerative diseases: Lessons from genome-wide screens in small model organisms.", - "authors": "Tjakko J van Ham,Rainer Breitling,Morris A Swertz,Ellen A A Nollen", - "abstract": "Various age-related neurodegenerative diseases, including Parkinson's disease, polyglutamine expansion diseases and Alzheimer's disease, are associated with the accumulation of misfolded proteins in aggregates in the brain. How and why these proteins form aggregates and cause disease is still poorly understood. Small model organisms--the baker's yeast Saccharomyces cerevisiae, the nematode worm Caenorhabditis elegans and the fruit fly Drosophila melanogaster--have been used to model these diseases and high-throughput genetic screens using these models have led to the identification of a large number of genes that modify aggregation and toxicity of the disease proteins. In this review, we revisit these models and provide a comprehensive comparison of the genetic screens performed so far. Our integrative analysis highlights alterations of a wide variety of basic cellular processes. Not all disease proteins are influenced by alterations in the same cellular processes and despite the unifying theme of protein misfolding and aggregation, the pathology of each of the age-related misfolding disorders can be induced or influenced by a disease-protein-specific subset of molecular processes.", - "journal_title": "EMBO molecular medicine", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/20049741/" - } - ], - "7ce1d264-5ae0-49cc-945c-68945bd2f67a": [ - { - "pub_id": "19851476", - "title": "Genomic instability and DNA damage responses in progeria arising from defective maturation of prelamin A.", - "authors": "Phillip R Musich,Yue Zou", - "abstract": "Progeria syndromes have in common a premature aging phenotype and increased genome instability. The susceptibility to DNA damage arises from a compromised repair system, either in the repair proteins themselves or in the DNA damage response pathways. The most severe progerias stem from mutations affecting lamin A production, a filamentous protein of the nuclear lamina. Hutchinson-Gilford progeria syndrome (HGPS) patients are heterozygous for aLMNA gene mutation while Restrictive Dermopathy (RD) individuals have a homozygous deficiency in the processing protease Zmpste24. These mutations generate the mutant lamin A proteins progerin and FC-lamina A, respectively, which cause nuclear deformations and chromatin perturbations. Genome instability is observed even though genome maintenance and repair genes appear normal. The unresolved question is what features of the DNA damage response pathways are deficient in HGPS and RD cells. Here we review and discuss recent findings which resolve some mechanistic details of how the accumulation of progerin/FC-lamin A proteins may disrupt DNA damage response pathways in HGPS and RD cells. As the mutant lamin proteins accumulate they sequester replication and repair factors, leading to stalled replication forks which collapse into DNA double-strand beaks (DSBs). In a reaction unique to HGPS and RD cells these accessible DSB termini bind Xeroderma pigmentosum group A (XPA) protein which excludes normal binding by DNA DSB repair proteins. The bound XPA also signals activation of ATM and ATR, arresting cell cycle progression, leading to arrested growth. In addition, the effective sequestration of XPA at these DSB damage sites makes HGPS and RD cells more sensitive to ultraviolet light and other mutagens normally repaired by the nucleotide excision repair pathway of which XPA is a necessary and specific component.", - "journal_title": "Aging", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/19851476/" - } - ], - "8eeeac28-3955-416f-8185-14e6bebeca48": [ - { - "pub_id": "12750738", - "title": "The dawning era of polymer therapeutics.", - "authors": "Ruth Duncan", - "abstract": "As we enter the twenty-first century, research at the interface of polymer chemistry and the biomedical sciences has given rise to the first nano-sized (5-100 nm) polymer-based pharmaceuticals, the 'polymer therapeutics'. Polymer therapeutics include rationally designed macromolecular drugs, polymer-drug and polymer-protein conjugates, polymeric micelles containing covalently bound drug, and polyplexes for DNA delivery. The successful clinical application of polymer-protein conjugates, and promising clinical results arising from trials with polymer-anticancer-drug conjugates, bode well for the future design and development of the ever more sophisticated bio-nanotechnologies that are needed to realize the full potential of the post-genomic age.", - "journal_title": "Nature reviews. Drug discovery", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/12750738/" - } - ], - "1d5215ad-2882-4cb3-9424-09853bcdc543": [ - { - "pub_id": "11920285", - "title": "PARK3 influences age at onset in Parkinson disease: a genome scan in the GenePD study.", - "authors": "Anita L DeStefano,Mark F Lew,Lawrence I Golbe,Margery H Mark,Alice M Lazzarini,Mark Guttman,Erwin Montgomery,Cheryl H Waters,Carlos Singer,Ray L Watts,Lillian J Currie,G Frederick Wooten,Nancy E Maher,Jemma B Wilk,Kristin M Sullivan,Karen M Slater,Marie H Saint-Hilaire,Robert G Feldman,Oksana Suchowersky,Anne-Louise Lafontaine,Nancy Labelle,John H Growdon,Peter Vieregge,Peter P Pramstaller,Christine Klein,Jean P Hubble,Carson R Reider,Mark Stacy,Marcy E MacDonald,James F Gusella,Richard H Myers", - "abstract": "Parkinson disease (PD) is a late-onset neurodegenerative disorder. The mean age at onset is 61 years, but the disease can range from juvenile cases to cases in the 8th or 9th decade of life. The parkin gene on chromosome 6q and loci on chromosome 1p35-36 and 1p36 are responsible for some cases of autosomal recessive early-onset parkinsonism, but they do not appear to influence susceptibility or variability of age at onset for idiopathic PD. We have performed a genomewide linkage analysis using variance-component methodology to identify genes influencing age at onset of PD in a population of affected relatives (mainly affected sibling pairs) participating in the GenePD study. Four chromosomal loci showed suggestive evidence of linkage: chromosome 2p (maximum multipoint LOD [MaxLOD] = 2.08), chromosome 9q (MaxLOD = 2.00), chromosome 20 (MaxLOD = 1.82), and chromosome 21 (MaxLOD = 2.21). The 2p and 9q locations that we report here have previously been reported as loci influencing PD affection status. Association between PD age at onset and allele 174 of marker D2S1394, located on 2p13, was observed in the GenePD sample (P=.02). This 174 allele is common to the PD haplotype observed in two families that show linkage to PARK3 and have autosomal dominant PD, which suggests that this allele may be in linkage disequilibrium with a mutation influencing PD susceptibility or age at onset of PD.", - "journal_title": "American journal of human genetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/11920285/" - } - ], - "a92f3f91-728a-40f2-8810-e5df2ec972f4": [ - { - "pub_id": "19801982", - "title": "Twenty bone-mineral-density loci identified by large-scale meta-analysis of genome-wide association studies.", - "authors": "Fernando Rivadeneira,Unnur Styrk\u00e1rsdottir,Karol Estrada,Bjarni V Halld\u00f3rsson,Yi-Hsiang Hsu,J Brent Richards,M Carola Zillikens,Fotini K Kavvoura,Najaf Amin,Yurii S Aulchenko,L Adrienne Cupples,Panagiotis Deloukas,Serkalem Demissie,Elin Grundberg,Albert Hofman,Augustine Kong,David Karasik,Joyce B van Meurs,Ben Oostra,Tomi Pastinen,Huibert A P Pols,Gunnar Sigurdsson,Nicole Soranzo,Gudmar Thorleifsson,Unnur Thorsteinsdottir,Frances M K Williams,Scott G Wilson,Yanhua Zhou,Stuart H Ralston,Cornelia M van Duijn,Timothy Spector,Douglas P Kiel,Kari Stefansson,John P A Ioannidis,Andr\u00e9 G Uitterlinden, ", - "abstract": "Bone mineral density (BMD) is a heritable complex trait used in the clinical diagnosis of osteoporosis and the assessment of fracture risk. We performed meta-analysis of five genome-wide association studies of femoral neck and lumbar spine BMD in 19,195 subjects of Northern European descent. We identified 20 BMD loci that reached genome-wide significance (GWS; P < 5 x 10(-8)), of which 13 map to regions not previously associated with this trait: 1p31.3 (GPR177), 2p21 (SPTBN1), 3p22 (CTNNB1), 4q21.1 (MEPE), 5q14 (MEF2C), 7p14 (STARD3NL), 7q21.3 (FLJ42280), 11p11.2 (LRP4, ARHGAP1, F2), 11p14.1 (DCDC5), 11p15 (SOX6), 16q24 (FOXL1), 17q21 (HDAC5) and 17q12 (CRHR1). The meta-analysis also confirmed at GWS level seven known BMD loci on 1p36 (ZBTB40), 6q25 (ESR1), 8q24 (TNFRSF11B), 11q13.4 (LRP5), 12q13 (SP7), 13q14 (TNFSF11) and 18q21 (TNFRSF11A). The many SNPs associated with BMD map to genes in signaling pathways with relevance to bone metabolism and highlight the complex genetic architecture that underlies osteoporosis and variation in BMD.", - "journal_title": "Nature genetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/19801982/" - } - ], - "4f010a74-a9b4-4538-94f7-ae8f35c8b96e": [ - { - "pub_id": "9114820", - "title": "Genetic and functional changes in mitochondria associated with aging.", - "authors": "T Ozawa", - "abstract": "This review is devoted to the molecular genetics and bioenergetics of human mitochondria related to the mechanism of aging. Morphological and functional changes of mitochondria associated with age and age-related disease are overviewed with special reference to the changes in enzymes encoded by mitochondrial-inherent genome. The somatically acquired mutations and oxidative damage of the genome, which lead an individual to the fragmentation of mitochondrial DNA, cellular energy crisis, naturally occurring cell death (apoptosis), and tissue degeneration and atrophy, are reviewed with relation to the inherited point mutational genotypes and the deletion types of mitochondrial DNA. Theories of aging are discussed with disclosed evidence relevant to them. Some trials to prevent age-related damage in mitochondria are introduced for the development of what may be called mitochondrial medicine.", - "journal_title": "Physiological reviews", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/9114820/" - } - ], - "c15aadd7-adc7-4998-aae7-00f428e68340": [ - { - "pub_id": "17559308", - "title": "Combined genome scans for body stature in 6,602 European twins: evidence for common Caucasian loci.", - "authors": "Markus Perola,Sampo Sammalisto,Tero Hiekkalinna,Nick G Martin,Peter M Visscher,Grant W Montgomery,Beben Benyamin,Jennifer R Harris,Dorret Boomsma,Gonneke Willemsen,Jouke-Jan Hottenga,Kaare Christensen,Kirsten Ohm Kyvik,Thorkild I A S\u00f8rensen,Nancy L Pedersen,Patrik K E Magnusson,Tim D Spector,Elisabeth Widen,Karri Silventoinen,Jaakko Kaprio,Aarno Palotie,Leena Peltonen, ", - "abstract": "Twin cohorts provide a unique advantage for investigations of the role of genetics and environment in the etiology of variation in common complex traits by reducing the variance due to environment, age, and cohort differences. The GenomEUtwin (http://www.genomeutwin.org) consortium consists of eight twin cohorts (Australian, Danish, Dutch, Finnish, Italian, Norwegian, Swedish, and United Kingdom) with the total resource of hundreds of thousands of twin pairs. We performed quantitative trait locus (QTL) analysis of one of the most heritable human complex traits, adult stature (body height) using genome-wide scans performed for 3,817 families (8,450 individuals) derived from twin cohorts from Australia, Denmark, Finland, Netherlands, Sweden, and United Kingdom with an approximate ten-centimorgan microsatellite marker map. The marker maps for different studies differed and they were combined and related to the sequence positions using software developed by us, which is publicly available (https://apps.bioinfo.helsinki.fi/software/cartographer.aspx). Variance component linkage analysis was performed with age, sex, and country of origin as covariates. The covariate adjusted heritability was 81% for stature in the pooled dataset. We found evidence for a major QTL for human stature on 8q21.3 (multipoint logarithm of the odds 3.28), and suggestive evidence for loci on Chromosomes X, 7, and 20. Some evidence of sex heterogeneity was found, however, no obvious female-specific QTLs emerged. Several cohorts contributed to the identified loci, suggesting an evolutionarily old genetic variant having effects on stature in European-based populations. To facilitate the genetic studies of stature we have also set up a website that lists all stature genome scans published and their most significant loci (http://www.genomeutwin.org/stature_gene_map.htm).", - "journal_title": "PLoS genetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/17559308/" - } - ], - "e4541c0c-53fb-4c2c-b550-40728c356549": [ - { - "pub_id": "12421760", - "title": "Genome dynamics in aging mice.", - "authors": "Martijn E T Doll\u00e9,Jan Vijg", - "abstract": "Random spontaneous genome rearrangements are difficult to detect in vivo, especially in postmitotic tissues. Using a lacZ-plasmid reporter mouse model, we have previously presented evidence for the accumulation of large genome rearrangements in various tissues, including postmitotic tissues, during aging. These rearrangements, which were found to be organ-specific and to increase with age, have one breakpoint in the lacZ-reporter locus and the second elsewhere in the mouse genome. In this present work, we have used a mouse genome sequence database to physically characterize a total of 49 genome rearrangements in the brain, heart, and liver from young and old mice at two lacZ-plasmid reporter loci. Half of all breakpoints in the mouse genome occurred in chromosomes 3 and 4, each carrying a lacZ-reporter cluster, at distances varying from <100 kb to 66 Mb, indicating intrachromosomal deletions or inversions. The other half of the breakpoints in the mouse genome was found randomly on any of the other chromosomes, indicating translocations. Alternatively, part of the intra- and extrachromosomal events could involve transpositions. Regions of extended homology were not found at the breakpoints. These results lead us to postulate potential mechanisms for the origin of large genome rearrangements in mouse tissues and to predict their possible impact as a potential cause of aging.", - "journal_title": "Genome research", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/12421760/" - } - ], - "45765a4b-f153-48af-8041-03e623579925": [ - { - "pub_id": "19968875", - "title": "Genes and gene expression modules associated with caloric restriction and aging in the laboratory mouse.", - "authors": "William R Swindell", - "abstract": "Caloric restriction (CR) counters deleterious effects of aging and, for most mouse genotypes, increases mean and maximum lifespan. Previous analyses of microarray data have identified gene expression responses to CR that are shared among multiple mouse tissues, including the activation of anti-oxidant, tumor suppressor and anti-inflammatory pathways. These analyses have provided useful research directions, but have been restricted to a limited number of tissues, and have focused on individual genes, rather than whole-genome transcriptional networks. Furthermore, CR is thought to oppose age-associated gene expression patterns, but detailed statistical investigations of this hypothesis have not been carried out. Systemic effects of CR and aging were identified by examining transcriptional responses to CR in 17 mouse tissue types, as well as responses to aging in 22 tissues. CR broadly induced the expression of genes known to inhibit oxidative stress (e.g., Mt1, Mt2), inflammation (e.g., Nfkbia, Timp3) and tumorigenesis (e.g., Txnip, Zbtb16). Additionally, a network-based investigation revealed that CR regulates a large co-expression module containing genes associated with the metabolism and splicing of mRNA (e.g., Cpsf6, Sfpq, Sfrs18). The effects of aging were, to a considerable degree, similar among groups of co-expressed genes. Age-related gene expression patterns characteristic of most mouse tissues were identified, including up regulation of granulin (Grn) and secreted phosphoprotein 1 (Spp1). The transcriptional association between CR and aging varied at different levels of analysis. With respect to gene subsets associated with certain biological processes (e.g., immunity and inflammation), CR opposed age-associated expression patterns. However, among all genes, global transcriptional effects of CR were only weakly related to those of aging. The study of aging, and of interventions thought to combat aging, has much to gain from data-driven and unbiased genomic investigations. Expression patterns identified in this analysis characterize a generalized response of mammalian cells to CR and/or aging. These patterns may be of importance in determining effects of CR on overall lifespan, or as factors that underlie age-related disease. The association between CR and aging warrants further study, but most evidence indicates that CR does not induce a genome-wide \"reversal\" of age-associated gene expression patterns.", - "journal_title": "BMC genomics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/19968875/" - } - ], - "4a8a6975-b710-4db0-8061-104e25760239": [ - { - "pub_id": "19210790", - "title": "High tandem repeat content in the genome of the short-lived annual fish Nothobranchius furzeri: a new vertebrate model for aging research.", - "authors": "Kathrin Reichwald,Chris Lauber,Indrajit Nanda,Jeanette Kirschner,Nils Hartmann,Susanne Schories,Ulrike Gausmann,Stefan Taudien,Markus B Schilhabel,Karol Szafranski,Gernot Gl\u00f6ckner,Michael Schmid,Alessandro Cellerino,Manfred Schartl,Christoph Englert,Matthias Platzer", - "abstract": "The annual fish Nothobranchius furzeri is the vertebrate with the shortest known life span in captivity. Fish of the GRZ strain live only three to four months under optimal laboratory conditions, show explosive growth, early sexual maturation and age-dependent physiological and behavioral decline, and express aging related biomarkers. Treatment with resveratrol and low temperature significantly extends the maximum life span. These features make N. furzeri a promising new vertebrate model for age research. To contribute to establishing N. furzeri as a new model organism, we provide a first insight into its genome and a comparison to medaka, stickleback, tetraodon and zebrafish. The N. furzeri genome contains 19 chromosomes (2n = 38). Its genome of between 1.6 and 1.9 Gb is the largest among the analyzed fish species and has, at 45%, the highest repeat content. Remarkably, tandem repeats comprise 21%, which is 4-12 times more than in the other four fish species. In addition, G+C-rich tandem repeats preferentially localize to centromeric regions. Phylogenetic analysis based on coding sequences identifies medaka as the closest relative. Genotyping of an initial set of 27 markers and multi-locus fingerprinting of one microsatellite provides the first molecular evidence that the GRZ strain is highly inbred. Our work presents a first basis for systematic genomic and genetic analyses aimed at understanding the mechanisms of life span determination in N. furzeri.", - "journal_title": "Genome biology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/19210790/" - } - ], - "3f41e709-4cf1-472b-b12b-804c6ebb07c9": [ - { - "pub_id": "19405847", - "title": "Unraveling a multifactorial late-onset disease: from genetic susceptibility to disease mechanisms for age-related macular degeneration.", - "authors": "Anand Swaroop,Emily Y Chew,Catherine Bowes Rickman,Gon\u00e7alo R Abecasis", - "abstract": "Aging-associated neurodegenerative diseases significantly influence the quality of life of affected individuals. Genetic approaches, combined with genomic technology, have provided powerful insights into common late-onset diseases, such as age-related macular degeneration (AMD). Here, we discuss current findings on the genetics of AMD to highlight areas of rapid progress and new challenges. We also attempt to integrate available genetic and biochemical data with cellular pathways involved in aging to formulate an integrated model of AMD pathogenesis.", - "journal_title": "Annual review of genomics and human genetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/19405847/" - } - ], - "c59757a9-deea-491e-a93c-3dfdb3d217f8": [ - { - "pub_id": "33536631", - "title": "A genome-wide meta-analysis yields 46 new loci associating with biomarkers of iron homeostasis.", - "authors": "Steven Bell,Andreas S Rigas,Magnus K Magnusson,Egil Ferkingstad,Elias Allara,Gyda Bjornsdottir,Anna Ramond,Erik S\u00f8rensen,Gisli H Halldorsson,Dirk S Paul,Kristoffer S Burgdorf,Hannes P Eggertsson,Joanna M M Howson,Lise W Th\u00f8rner,Snaedis Kristmundsdottir,William J Astle,Christian Erikstrup,Jon K Sigurdsson,Dragana Vuckovic,Khoa M Dinh,Vinicius Tragante,Praveen Surendran,Ole B Pedersen,Brynjar Vidarsson,Tao Jiang,Helene M Paarup,Pall T Onundarson,Parsa Akbari,Kaspar R Nielsen,Sigrun H Lund,Kristinn Juliusson,Magnus I Magnusson,Michael L Frigge,Asmundur Oddsson,Isleifur Olafsson,Stephen Kaptoge,Henrik Hjalgrim,Gudmundur Runarsson,Angela M Wood,Ingileif Jonsdottir,Thomas F Hansen,Olof Sigurdardottir,Hreinn Stefansson,David Rye, ,James E Peters,David Westergaard,Hilma Holm,Nicole Soranzo,Karina Banasik,Gudmar Thorleifsson,Willem H Ouwehand,Unnur Thorsteinsdottir,David J Roberts,Patrick Sulem,Adam S Butterworth,Daniel F Gudbjartsson,John Danesh,S\u00f8ren Brunak,Emanuele Di Angelantonio,Henrik Ullum,Kari Stefansson", - "abstract": "Iron is essential for many biological functions and iron deficiency and overload have major health implications. We performed a meta-analysis of three genome-wide association studies from Iceland, the UK and Denmark of blood levels of ferritin (N\u2009=\u2009246,139), total iron binding capacity (N\u2009=\u2009135,430), iron (N\u2009=\u2009163,511) and transferrin saturation (N\u2009=\u2009131,471). We found 62 independent sequence variants associating with iron homeostasis parameters at 56 loci, including 46 novel loci. Variants at DUOX2, F5, SLC11A2 and TMPRSS6 associate with iron deficiency anemia, while variants at TF, HFE, TFR2 and TMPRSS6 associate with iron overload. A HBS1L-MYB intergenic region variant associates both with increased risk of iron overload and reduced risk of iron deficiency anemia. The DUOX2 missense variant is present in 14% of the population, associates with all iron homeostasis biomarkers, and increases the risk of iron deficiency anemia by 29%. The associations implicate proteins contributing to the main physiological processes involved in iron homeostasis: iron sensing and storage, inflammation, absorption of iron from the gut, iron recycling, erythropoiesis and bleeding/menstruation.", - "journal_title": "Communications biology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/33536631/" - } - ], - "9cb6af34-60b1-4f60-bd83-5a8fc2f22842": [ - { - "pub_id": "17304236", - "title": "Immunosenescence comes of age. Symposium on Aging Research in Immunology: The Impact of Genomics.", - "authors": "Graham Pawelec", - "abstract": "", - "journal_title": "EMBO reports", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/17304236/" - } - ], - "9387c2d5-61cf-4f22-869d-29f5ee760c3c": [ - { - "pub_id": "11281459", - "title": "Marked differences in unilateral isolated retinoblastomas from young and older children studied by comparative genomic hybridization.", - "authors": "S Herzog,D R Lohmann,K Buiting,A Sch\u00fcler,B Horsthemke,H Rehder,H Rieder", - "abstract": "Although it is established that the loss of function of both alleles of the RB1 gene is a prerequisite for the development of retinoblastoma, little is known about the genetic events that are required for tumor progression. We used comparative genomic hybridization (CGH) to search for DNA copy number changes in isolated unilateral retinoblastomas. From a series of 66 patients with retinoblastomas with somatic mutations in both RB1 alleles, tumor samples from 13 children with the youngest (2.0-9.8 months) and 13 with the oldest (36.2-84.1 months) age at operation were studied. Loss at 13q14, the location of RB1, was demonstrated in two tumors only. Recurring chromosome imbalances included gains at 6p (11/26), 1q (10/26), 2p (4/26), and 17q (4/26), gains of the entire chromosome 19 (3/26), and losses at 16q (9/26). A commonly gained region at 1q32 was identified. Increased dosage of GAC1, a candidate oncogene located in 1q32, was found in two of four tumors by Southern blot analysis. Comparison of the CGH findings revealed that retinoblastomas from children with an older age at operation showed significantly more frequent (13/13 cases vs 4/13 cases; P = 0.0005) and more complex genetic abnormalities (median, 5 changes/abnormal tumor vs median, 1.5 changes/abnormal tumor; P = 0.003) than retinoblastomas from children with a young age at operation. Gains at 1q, 2p, 17q, of the entire chromosome 19 and losses of 16q were restricted to the older age group. Our results suggest that the progression of retinoblastomas from older patients follows mutational pathways different from those of younger patients.", - "journal_title": "Human genetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/11281459/" - } - ], - "0917c1ee-0dcb-4b6b-a424-5db3d61f8a2c": [ - { - "pub_id": "15610761", - "title": "Diverse aging rates in metazoans: targets for functional genomics.", - "authors": "Steven N Austad", - "abstract": "Aging, or senescence, has typically been measured by demographic analysis, which has its merits but is blind to key aspects of functional development and deterioration. If one uses demographic analyses, however, the approach providing most insight is the analysis of age-specific mortality. The continuing increase in DNA sequencing power combined with emerging computational techniques will allow in the near future detailed investigation of mechanisms of aging in diverse species beyond the typical laboratory bestiary. A comparative approach of this sort needs to consider, in addition to simple longevity, the effects of phylogeny and body size on the species in question. Insight may be gained from the study of species exhibiting accelerated aging relative to more \"typical\" species. These naturally short-lived species, such as several small shrews and marsupials, avoid the worry inherent in \"accelerated aging\" genotypes of common models, which is that they are only short-lived because of some idiosyncratic pathology unrelated to general aging. A case of special interest that has yet to be seriously investigated is the domestic dog, in which selective breeding has produced phenotypes within the same species that age at two-fold different rates. Exceptionally long-lived species offer exceptional opportunities to discover whether there are few or many ways to create long-lived organisms. Slow-aging species with the most to offer include bats and naked mole-rats. Perhaps no fundamental question in biology is more intriguing that why and how nature has produced such a dazzling array of aging rates. The development of functional genetics over the next several decades promises to lead us toward an answer.", - "journal_title": "Mechanisms of ageing and development", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/15610761/" - } - ], - "31b4f021-4bb8-4489-8ced-b65539cbe285": [ - { - "pub_id": "17942417", - "title": "Two faces of p53: aging and tumor suppression.", - "authors": "Francis Rodier,Judith Campisi,Dipa Bhaumik", - "abstract": "The p53 tumor suppressor protein, often termed guardian of the genome, integrates diverse physiological signals in mammalian cells. In response to stress signals, perhaps the best studied of which is the response to DNA damage, p53 becomes functionally active and triggers either a transient cell cycle arrest, cell death (apoptosis) or permanent cell cycle arrest (cellular senescence). Both apoptosis and cellular senescence are potent tumor suppressor mechanisms that irreversibly prevent damaged cells from undergoing neoplastic transformation. However, both processes can also deplete renewable tissues of proliferation-competent progenitor or stem cells. Such depletion, in turn, can compromise the structure and function of tissues, which is a hallmark of aging. Moreover, whereas apoptotic cells are by definition eliminated from tissues, senescent cells can persist, acquire altered functions, and thus alter tissue microenvironments in ways that can promote both cancer and aging phenotypes. Recent evidence suggests that increased p53 activity can, at least under some circumstances, promote organismal aging. Here, we discuss the role of p53 as a key regulator of the DNA damage responses, and discuss how p53 integrates the outcome of the DNA damage response to optimally balance tumor suppression and longevity.", - "journal_title": "Nucleic acids research", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/17942417/" - } - ], - "ee850069-4957-4159-97b9-38253ef00b18": [ - { - "pub_id": "18234529", - "title": "Genome-wide analysis of aging and learning-related genes in the hippocampal dentate gyrus.", - "authors": "Corinna Burger,M Cecilia Lopez,Henry V Baker,Ronald J Mandel,Nick Muzyczka", - "abstract": "We have previously described the transcriptional changes that occur in the hippocampal CA1 field of aged rats following a Morris Water Maze (MWM) training paradigm. In this report we proceed with the analysis of the dentate region from the same animals. Animals were first identified as age learning-impaired or age-superior learners when compared to young rats based on their performance in the MWM. Messenger RNA was isolated from the dentate gyrus of each animal to interrogate Affymetrix RAE 230A rat genome microarrays. Microarray profiling identified 1129 genes that were differentially expressed between aged and young rats as a result of aging, and independent of their behavioral training (p<0.005). We applied Ingenuity Pathway Analysis (IPA) algorithms to identify the significant biological processes underlying age-related changes in the dentate gyrus. The most significant functions, as calculated by IPA, included cell movement, cell growth and proliferation, nervous system development and function, cellular assembly and organization, cell morphology and cell death. These significant processes are consistent with age-related changes in neurogenesis, and the neurogenic markers were generally found to be downregulated in senescent animals. In addition, statistical analysis of the different experimental groups of aged animals recognized 85 genes (p<0.005) that were different in the dentate gyrus of aged rats that had learned the MWM when compared to learning impaired and a number of controls for stress, exercise and non-spatial learning. The list of learning-related genes expressed in the dentate adds to the set of genes we previously described in the CA1 region. This long list of genes constitutes a starting tool to elucidating the molecular pathways involved in learning and memory formation.", - "journal_title": "Neurobiology of learning and memory", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/18234529/" - } - ], - "ed9ff7d5-f842-454a-b7f9-02a720459913": [ - { - "pub_id": "15317747", - "title": "Age-associated alteration of gene expression patterns in mouse oocytes.", - "authors": "Toshio Hamatani,Geppino Falco,Mark G Carter,Hidenori Akutsu,Carole A Stagg,Alexei A Sharov,Dawood B Dudekula,Vincent VanBuren,Minoru S H Ko", - "abstract": "Decreasing oocyte competence with maternal aging is a major factor in human infertility. To investigate the age-dependent molecular changes in a mouse model, we compared the expression profiles of metaphase II oocytes collected from 5- to 6-week-old mice with those collected from 42- to 45-week-old mice using the NIA 22K 60-mer oligo microarray. Among approximately 11,000 genes whose transcripts were detected in oocytes, about 5% (530) showed statistically significant expression changes, excluding the possibility of global decline in transcript abundance. Consistent with the generally accepted view of aging, the differentially expressed genes included ones involved in mitochondrial function and oxidative stress. However, the expression of other genes involved in chromatin structure, DNA methylation, genome stability and RNA helicases was also altered, suggesting the existence of additional mechanisms for aging. Among the transcripts decreased with aging, we identified and characterized a group of new oocyte-specific genes, members of the human NACHT, leucine-rich repeat and PYD-containing (NALP) gene family. These results have implications for aging research as well as for clinical ooplasmic donation to rejuvenate aging oocytes.", - "journal_title": "Human molecular genetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/15317747/" - } - ], - "0994b822-ee9e-4fbd-8438-e0d9b4ed1a39": [ - { - "pub_id": "18926708", - "title": "Rising from the RecQ-age: the role of human RecQ helicases in genome maintenance.", - "authors": "Vilhelm A Bohr", - "abstract": "The RecQ helicases are guardians of the genome. Members of this conserved family of proteins have a key role in protecting and stabilizing the genome against deleterious changes. Deficiencies in RecQ helicases can lead to high levels of genomic instability and, in humans, to premature aging and increased susceptibility to cancer. Their diverse roles in DNA metabolism, which include a role in telomere maintenance, reflect interactions with multiple cellular proteins, some of which are multifunctional and also have very diverse functions. The results of in vitro cellular and biochemical studies have been complimented by recent in vivo studies using genetically modified mouse strains. Together, these approaches are helping to unravel the mechanism(s) of action and biological functions of the RecQ helicases.", - "journal_title": "Trends in biochemical sciences", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/18926708/" - } - ], - "f0849937-dc25-42f4-a512-99783761674d": [ - { - "pub_id": "14757579", - "title": "Genomic DNA methylation of juvenile and mature Acacia mangium micropropagated in vitro with reference to leaf morphology as a phase change marker.", - "authors": "Franc-Christophe Baurens,Joris Nicolleau,Thierry Legavre,Jean-Luc Verdeil,Olivier Monteuuis", - "abstract": "Genomic DNA methylation was analyzed in Acacia mangium Willd. microshoots micropropagated in vitro from juvenile and mature explants, and in relation to leaf morphology of the microshoots, which is considered a phase change indicator. Based on high performance liquid chromatography (HPLC) analyses, we found more DNA methylation in microshoots exhibiting juvenile leaf morphology (22.4%) than in microshoots of the mature phyllode morphological type (20.7%), irrespective of the age of the source material. Overall, the degree of DNA methylation in A. mangium microshoots was consistent with values reported for other angiosperms. Complementary investigations based on methylation sensitive amplification polymorphism (MSAP) techniques established that, of 1204 fragments revealed by the different primer pairs used, 49 (i.e., 4.08%) were derived from C(5m)CGG methylated sites. Three of these C(5m)CGG sites were exclusive to the juvenile plant material, and three sites were exclusive to the mature source. No fragments were associated specifically with leaf morphology, rather than with plant age. Thus, although the two age classes could not be distinguished based on a quantitative HPLC measure of DNA methylation, qualitative differences existed, as demonstrated by the six age-specific markers identified by MSAP. The reliability of the MSAP data was confirmed on a larger sample of juvenile plant material, which suggested that the total of six methylation markers detected is probably an underestimation of the age-related differences in DNA methylation that may exist between juvenile and mature plant materials.", - "journal_title": "Tree physiology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/14757579/" - } - ], - "6a53805f-4f6f-49a8-8c28-935ce41e5560": [ - { - "pub_id": "15517022", - "title": "RNA-interference-based functional genomics in mammalian cells: reverse genetics coming of age.", - "authors": "Jose Silva,Kenneth Chang,Gregory J Hannon,Fabiola V Rivas", - "abstract": "Sequencing of complete genomes has provided researchers with a wealth of information to study genome organization, genetic instability, and polymorphisms, as well as a knowledge of all potentially expressed genes. The identification of all genes encoded in the human genome opens the door for large-scale systematic gene silencing using small interfering RNAs (siRNAs) and short hairpin RNAs (shRNAs). With the recent development of siRNA and shRNA expression libraries, the application of RNAi technology to assign function to cancer genes and to delineate molecular pathways in which these genes affect in normal and transformed cells, will contribute significantly to the knowledge necessary to develop new and also improve existing cancer therapy.", - "journal_title": "Oncogene", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/15517022/" - } - ], - "82d3ceec-9dcc-4d08-8121-bd48fcbee9e9": [ - { - "pub_id": "33692499", - "title": "Epidemiology and genomics of prostate cancer in Asian men.", - "authors": "Yao Zhu,Miao Mo,Yu Wei,Junlong Wu,Jian Pan,Stephen J Freedland,Ying Zheng,Dingwei Ye", - "abstract": "Prostate cancer is a global health problem, but incidence varies considerably across different continents. Asia is traditionally considered a low-incidence area, but the incidence and mortality of prostate cancer have rapidly increased across the continent. Substantial differences in epidemiological features have been observed among different Asian regions, and incidence, as well as mortality-to-incidence ratio, is associated with the human development index. Prostate cancer mortality decreased in Japan and Israel from 2007 to 2016, but mortality has increased in Thailand, Kyrgyzstan and Uzbekistan over the same period. Genomic analyses have shown a low prevalence of ERG oncoprotein in the East Asian population, alongside a low rate of PTEN loss, high CHD1 enrichments and high FOXA1 alterations. Contributions from single-nucleotide polymorphisms to prostate cancer risk vary with ethnicity, but germline mutation rates of DNA damage repair genes in metastatic prostate cancer are comparable in Chinese and white patients from the USA and UK. Pharmacogenomic features of testosterone metabolism might contribute to disparities seen in the response to androgen deprivation between East Asian men and white American and European men. Overall, considerable diversity in epidemiology and genomics of prostate cancer across Asia defines disease characteristics in these populations, but studies in this area are under-represented in the literature. Taking into account this intracontinental and intercontinental heterogeneity, translational studies are required in order to develop ethnicity-specific treatment strategies.", - "journal_title": "Nature reviews. Urology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/33692499/" - } - ], - "1ad95d2f-52ea-4f5a-b9ab-33ee217644a0": [ - { - "pub_id": "12007414", - "title": "Genome-wide transcript profiles in aging and calorically restricted Drosophila melanogaster.", - "authors": "Scott D Pletcher,Stuart J Macdonald,Richard Marguerie,Ulrich Certa,Stephen C Stearns,David B Goldstein,Linda Partridge", - "abstract": "We characterized RNA transcript levels for the whole Drosophila genome during normal aging. We compared age-dependent profiles from animals aged under full-nutrient conditions with profiles obtained from animals maintained on a low-calorie medium to determine if caloric restriction slows the aging process. Specific biological functions impacted by caloric restriction were identified using the Gene Ontology annotation. We used the global patterns of expression profiles to test if particular genomic regions contribute differentially to changes in transcript profiles with age and if global disregulation of gene expression occurs during aging. Whole-genome transcript profiles contained a statistically powerful genetic signature of normal aging. Nearly 23% of the genome changed in transcript representation with age. Caloric restriction was accompanied by a slowing of the progression of normal, age-related changes in transcript levels. Many genes, including those associated with stress response and oogenesis, showed age-dependent transcript representation. Caloric restriction resulted in the downregulation of genes primarily involved in cell growth, metabolism, and reproduction. We found no evidence that age-dependent changes in transcription level were confined to genes localized to specific regions of the genome and found no support for widespread disregulation of gene expression with age. Aging is characterized by highly dynamic changes in the expression of many genes, which provides a powerful molecular description of the normal aging process. Caloric restriction extends life span by slowing down the rate of normal aging. Transcription levels of genes from a wide variety of biological functions and processes are impacted by age and dietary conditions.", - "journal_title": "Current biology : CB", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/12007414/" - } - ], - "ae831b22-137e-443b-b722-f5d650ca05b7": [ - { - "pub_id": "17065327", - "title": "Genomic dissection of behavioral maturation in the honey bee.", - "authors": "Charles W Whitfield,Yehuda Ben-Shahar,Charles Brillet,Isabelle Leoncini,Didier Crauser,Yves Leconte,Sandra Rodriguez-Zas,Gene E Robinson", - "abstract": "Honey bees undergo an age-related, socially regulated transition from working in the hive to foraging that has been previously associated with changes in the expression of thousands of genes in the brain. To understand the meaning of these changes, we conducted microarray analyses to examine the following: (i) the ontogeny of gene expression preceding the onset of foraging, (ii) the effects of physiological and genetic factors that influence this behavioral transition, and (iii) the effects of foraging experience. Although >85% of approximately 5,500 genes showed brain differences, principal component analysis revealed discrete influences of age, behavior, genotype, environment, and experience. Young bees not yet competent to forage showed extensive, age-related expression changes, essentially complete by 8 days of age, coinciding with previously described structural brain changes. Subsequent changes were not age-related but were largely related to effects of juvenile hormone (JH), suggesting that the increase in JH that influences the hive bee-forager transition may cause many of these changes. Other treatments that also influence the onset age of foraging induced many changes but with little overlap, suggesting that multiple pathways affect behavioral maturation. Subspecies differences in onset age of foraging were correlated with differences in JH and JH-target gene expression, suggesting that this endocrine system mediates the genetic differences. We also used this multifactorial approach to identify candidate genes for behavioral maturation. This successful dissection of gene expression indicates that, for social behavior, gene expression in the brain can provide a robust indicator of the interaction between hereditary and environmental information.", - "journal_title": "Proceedings of the National Academy of Sciences of the United States of America", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/17065327/" - } - ], - "5a8540de-d034-4dc4-b08b-e96e22f47ff8": [ - { - "pub_id": "18391173", - "title": "Telomeres and aging.", - "authors": "Geraldine Aubert,Peter M Lansdorp", - "abstract": "Telomeres play a central role in cell fate and aging by adjusting the cellular response to stress and growth stimulation on the basis of previous cell divisions and DNA damage. At least a few hundred nucleotides of telomere repeats must \"cap\" each chromosome end to avoid activation of DNA repair pathways. Repair of critically short or \"uncapped\" telomeres by telomerase or recombination is limited in most somatic cells and apoptosis or cellular senescence is triggered when too many \"uncapped\" telomeres accumulate. The chance of the latter increases as the average telomere length decreases. The average telomere length is set and maintained in cells of the germline which typically express high levels of telomerase. In somatic cells, telomere length is very heterogeneous but typically declines with age, posing a barrier to tumor growth but also contributing to loss of cells with age. Loss of (stem) cells via telomere attrition provides strong selection for abnormal and malignant cells, a process facilitated by the genome instability and aneuploidy triggered by dysfunctional telomeres. The crucial role of telomeres in cell turnover and aging is highlighted by patients with 50% of normal telomerase levels resulting from a mutation in one of the telomerase genes. Short telomeres in such patients are implicated in a variety of disorders including dyskeratosis congenita, aplastic anemia, pulmonary fibrosis, and cancer. Here the role of telomeres and telomerase in human aging and aging-associated diseases is reviewed.", - "journal_title": "Physiological reviews", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/18391173/" - } - ], - "fabfccb1-4ba7-47b4-8415-941742ddea40": [ - { - "pub_id": "29857629", - "title": "Qualitative assessment of genotoxicity using random amplified polymorphic DNA: Comparison of genomic template stability with key fitness parameters in Daphnia magna exposed to benzo[a]pyrene.", - "authors": "Franck A Atienzar,Mercedes Conradi,Andrew J Evenden,Awadhesh N Jha,Michael H Depledge", - "abstract": "A method of DNA profiling using the random amplified polymorphic DNA (RAPD) was used to assess toxicant-induced DNA effects in laboratory populations of Daphnia magna exposed to varying concentrations of the genotoxic hydrocarbon benzo[a]pyrene. These effects, represented by changes in the RAPD profiles, were compared with a number of key ecological fitness parameters (age-specific survival, age-specific fecundity, net reproductive rate, and intrinsic rate of population increase). Not only was the RAPD profiling method shown to be a rapid and reproducible assay of toxicant-induced DNA effects, but the qualitative measure of genomic template stability compared favorably with the traditional indices of fitness. The RAPD profiles, however, exhibited higher sensitivity in detecting toxic effects. The significance of these findings for future ecotoxicological studies is discussed.", - "journal_title": "Environmental toxicology and chemistry", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/29857629/" - } - ], - "fd5edd5b-25d5-41ef-b9ad-7599905b844f": [ - { - "pub_id": "9023106", - "title": "Multi-organ characterization of mitochondrial genomic rearrangements in ad libitum and caloric restricted mice show striking somatic mitochondrial DNA rearrangements with age.", - "authors": "S Melov,D Hinerfeld,L Esposito,D C Wallace", - "abstract": "Mitochondrial DNA (mtDNA) rearrangements have been shown to accumulate with age in the post-mitotic tissues of a variety of animals and have been hypothesized to result in the age-related decline of mitochondrial bioenergetics leading to tissue and organ failure. Caloric restriction in rodents has been shown to extend life span supporting an association between bioenergetics and senescence. In the present study, we use full length mtDNA amplification by long-extension polymerase chain reaction (LX-PCR) to demonstrate that mice accumulate a wide variety of mtDNA rearrangements with age in post mitotic tissues. Similarly, using an alternative PCR strategy, we have found that 2-4 kb minicircles containing the origin of heavy-strand replication accumulate with age in heart but not brain. Analysis of mtDNA structure and conformation by Southern blots of unrestricted DNA resolved by field inversion gel electrophoresis have revealed that the brain mtDNAs of young animals contain the traditional linear, nicked, and supercoiled mtDNAs while old animals accumulate substantial levels of a slower migrating species we designate age-specific mtDNAs. In old caloric restricted animals, a wide variety of rearranged mtDNAs can be detected by LX-PCR in post mitotic tissues, but Southern blots of unrestricted DNA reveals a marked reduction in the levels of the age- specific mtDNA species. These observations confirm that mtDNA mutations accumulate with age in mice and suggest that caloric restriction impedes this progress.", - "journal_title": "Nucleic acids research", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/9023106/" - } - ], - "fe32b103-5dba-4cf0-b8af-762a71a5f5e6": [ - { - "pub_id": "16584578", - "title": "Specific age-related signatures in Drosophila body parts transcriptome.", - "authors": "Fabrice Girardot,Christelle Lasbleiz,V\u00e9ronique Monnier,Herv\u00e9 Tricoire", - "abstract": "During the last two decades progress in the genetics of aging in invertebrate models such as C. elegans and D. melanogaster has clearly demonstrated the existence of regulatory pathways that control the rate of aging in these organisms, such as the insulin-like pathway, the Jun kinase pathway and the Sir2 deacetylase pathway. Moreover, it was rapidly shown that some of these pathways are conserved from yeast to humans. In parallel to genetic studies, genomic expression approaches have given us significant information on the gene expression modifications that occur during aging either in wild type or long-lived mutant animals. But most of the genomic studies of invertebrate models have been performed so far on whole animals, while several recent studies in mammals have shown that the effects of aging are tissue specific. We used oligonucleotide microarrays to address the specificities of transcriptional responses in aging Drosophila in head, thorax or whole body. These fly parts are enriched in transcripts that represent different and complementary sets of genes. We present evidence for both specific and common transcriptional responses during the aging process in these tissues. About half of the genes described as downregulated with age are linked to reproduction and enriched in gonads. Greater downregulation of mitochondrial genes, activation of the JNK pathway and upregulation of proteasome subunits in the thorax of aged flies all suggest that muscle may be particularly sensitive to aging. Simultaneous age-related impairment of synaptic transmission gene expression is observed in fly heads. In addition, a detailed comparison with other microarray data indicates that in aged flies there are significant deviations from the canonical responses to oxidative stress and immune stress. Our data demonstrates the advantages and value of regionalized and comparative analysis of gene expression in aging animals. Adding to the age-regulated genes already identified in whole animal studies, it provides lists of new regionalized genes to be studied for their functional role in the aging process. This work also emphasizes the need for such experiments to reveal in greater detail the consequences of the transcriptional modifications induced by aging regulatory pathways.", - "journal_title": "BMC genomics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/16584578/" - } - ], - "c22a8591-7422-4bed-a75b-7ad1000e1ee8": [ - { - "pub_id": "11863377", - "title": "Parkinson's disease and apolipoprotein E: possible association with dementia but not age at onset.", - "authors": "Abbas Parsian,Brad Racette,L Jane Goldsmith,Joel S Perlmutter", - "abstract": "Idiopathic Parkinson's disease (PD) is an age-dependent, neurodegenerative condition frequently associated with dementia. Although it is predominantly a sporadic disease, 20-30% of cases are familial, suggesting a complex mode of inheritance. Apolipoprotein E (APOE) allele epsilon4 has been associated with familial and sporadic late-onset senile dementia of the Alzheimer's type. To investigate the role of this gene in the development of dementia associated with PD and age at onset of PD, we evaluated the frequency of APOE gene polymorphism in a sample of PD patients with (n=118) and without (n=167) a family history, as well as matched normal controls (n=96). The PD sample was categorized according to age at onset and presence or absence of dementia. Kaplan-Meier survival analysis was used to plot genotype-specific age at onset distribution curves. Allele frequencies of APOE in PD patients with and without a family history and normal controls were not significantly different. APOE genotypes were also similar between the groups. However, the frequencies of epsilon4 allele and epsilon4/- genotype in the PD group with dementia were more than twofold higher than in normal controls, and the differences were statistically significant. There were no differences in the allele and genotype frequencies of the APOE gene between PD groups with different age at onset. The familial PD had significantly earlier age at onset than sporadic PD (Log-rank test, P=0.027). The age at onset distribution curves for different genotype groups were similar, and their differences were not statistically significant (P=0.38). After the Bonferroni's correction for multiple tests, the positive results are not significant at the P<0.05 level. We conclude that APOE does not play an important role in susceptibility to PD or age at onset of PD, but may play a role in dementia associated with PD in our sample.", - "journal_title": "Genomics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/11863377/" - } - ], - "4a27da1c-b184-47e8-bef2-de6435d7c3f5": [ - { - "pub_id": "11526246", - "title": "A genome-wide scan for linkage to human exceptional longevity identifies a locus on chromosome 4.", - "authors": "A A Puca,M J Daly,S J Brewster,T C Matise,J Barrett,M Shea-Drinkwater,S Kang,E Joyce,J Nicoli,E Benson,L M Kunkel,T Perls", - "abstract": "Substantial evidence supports the familial aggregation of exceptional longevity. The existence of rare families demonstrating clustering for this phenotype suggests that a genetic etiology may be an important component. Previous attempts at localizing loci predisposing for exceptional longevity have been limited to association studies of candidate gene polymorphisms. In this study, a genome-wide scan for such predisposing loci was conducted by using 308 individuals belonging to 137 sibships demonstrating exceptional longevity. By using nonparametric analysis, significant evidence for linkage was noted for chromosome 4 at D4S1564 with a MLS of 3.65 (P = 0.044). The analysis was corroborated by a parametric analysis (P = 0.052). These linkage results indicate the likelihood that there exists a gene, or genes, that exerts a substantial influence on the ability to achieve exceptional old age. Identification of the genes in humans that allow certain individuals to live to extreme old age should lead to insights on cellular pathways that are important to the aging process.", - "journal_title": "Proceedings of the National Academy of Sciences of the United States of America", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/11526246/" - } - ], - "e2ae5136-6b5c-4d91-b6f4-522345085d06": [ - { - "pub_id": "14504236", - "title": "A method for detecting recent selection in the human genome from allele age estimates.", - "authors": "Christopher Toomajian,Richard S Ajioka,Lynn B Jorde,James P Kushner,Martin Kreitman", - "abstract": "Mutations that have recently increased in frequency by positive natural selection are an important component of naturally occurring variation that affects fitness. To identify such variants, we developed a method to test for recent selection by estimating the age of an allele from the extent of haplotype sharing at linked sites. Neutral coalescent simulations are then used to determine the likelihood of this age given the allele's observed frequency. We applied this method to a common disease allele, the hemochromatosis-associated HFE C282Y mutation. Our results allow us to reject neutral models incorporating plausible human demographic histories for HFE C282Y and one other young but common allele, indicating positive selection at HFE or a linked locus. This method will be useful for scanning the human genome for alleles under selection using the haplotype map now being constructed.", - "journal_title": "Genetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/14504236/" - } - ], - "c6cba282-84b5-4eb9-8d84-9aa5d8467c56": [ - { - "pub_id": "19728478", - "title": "Neuroplasticity, psychosocial genomics, and the biopsychosocial paradigm in the 21st century.", - "authors": "Eric L Garland,Matthew Owen Howard", - "abstract": "The biopsychosocial perspective is a foundation of social work theory and practice. Recent research on neuroplasticity and psychosocial genomics lends compelling support to this perspective by elucidating mechanisms through which psychosocial forces shape neurobiology. Investigations of neuroplasticity demonstrate that the adult brain can continue to form novel neural connections and grow new neurons in response to learning or training even into old age. These findings are complemented by the contributions of psychosocial genomics, a field of scientific inquiry that explores the modulating effects of experience on gene expression. Findings from these new sciences provide external validation for the biopsychosocial perspective and offer important insights into the manifold means by which socioenvironmental experiences influence neurobiological structure and function across the life course.", - "journal_title": "Health & social work", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/19728478/" - } - ], - "568742e6-18f8-4163-a31f-a23de9fd256e": [ - { - "pub_id": "12529476", - "title": "In for the long run: focus on \"Lifelong voluntary exercise in the mouse prevents age-related alterations in gene expression in the heart\".", - "authors": "Stephen Welle,Susan B Glueck", - "abstract": "", - "journal_title": "Physiological genomics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/12529476/" - } - ], - "a11e6040-b902-47d4-9a5b-dcb851b13fb8": [ - { - "pub_id": "15687482", - "title": "Identification of a molecular signature of sarcopenia.", - "authors": "Paul G Giresi,Eric J Stevenson,Joachim Theilhaber,Alan Koncarevic,Jascha Parkington,Roger A Fielding,Susan C Kandarian", - "abstract": "Investigating the molecular mechanisms underlying sarcopenia in humans with the use of microarrays has been complicated by low sample size and the variability inherent in human gene expression profiles. We have conducted a study using Affymetrix GeneChips to identify a molecular signature of aged skeletal muscle. The molecular signature was defined as the set of expressed genes that best distinguished the vastus lateralis muscle of young (n = 10) and older (n = 12) male subjects, when a k-nearest neighbor supervised classification method was used in conjunction with a signal-to-noise ratio gene selection method and a holdout cross-validation procedure. The age-specific expression signature was comprised of 45 genes; 27 were upregulated and 18 were downregulated. This signature also correctly classified 75% of the muscle samples from young and older subjects published by an independent laboratory, based on their expression profiles. The signature revealed increased expression of several genes involved in mediating cellular responses to inflammation and apoptosis, including complement component C1QA, Galectin-1, C/EBP-beta, and FOXO3A, among others. The increased expressions of genes that regulate pre-mRNA splicing, localization, and modification of RNA comprise markers of the aging signature. Downregulated genes in the signature were the glutamine transporter SLC38A1, a TRAF-6 inhibitory zinc finger protein, and membrane-bound transcription factor protease S2P, among others. The sarcopenia signature developed here will be useful as a molecular model to judge the effectiveness of exercise and other therapeutic treatments aimed at ameliorating the effects of muscle loss associated with aging.", - "journal_title": "Physiological genomics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/15687482/" - } - ], - "eb38cf4d-c8d9-4c4b-bcd7-8022211433d3": [ - { - "pub_id": "20032323", - "title": "Genetic variants associated with Lp(a) lipoprotein level and coronary disease.", - "authors": "Robert Clarke,John F Peden,Jemma C Hopewell,Theodosios Kyriakou,Anuj Goel,Simon C Heath,Sarah Parish,Simona Barlera,Maria Grazia Franzosi,Stephan Rust,Derrick Bennett,Angela Silveira,Anders Malarstig,Fiona R Green,Mark Lathrop,Bruna Gigante,Karin Leander,Ulf de Faire,Udo Seedorf,Anders Hamsten,Rory Collins,Hugh Watkins,Martin Farrall, ", - "abstract": "An increased level of Lp(a) lipoprotein has been identified as a risk factor for coronary artery disease that is highly heritable. The genetic determinants of the Lp(a) lipoprotein level and their relevance for the risk of coronary disease are incompletely understood. We used a novel gene chip containing 48,742 single-nucleotide polymorphisms (SNPs) in 2100 candidate genes to test for associations in 3145 case subjects with coronary disease and 3352 control subjects. Replication was tested in three independent populations involving 4846 additional case subjects with coronary disease and 4594 control subjects. Three chromosomal regions (6q26-27, 9p21, and 1p13) were strongly associated with the risk of coronary disease. The LPA locus on 6q26-27 encoding Lp(a) lipoprotein had the strongest association. We identified a common variant (rs10455872) at the LPA locus with an odds ratio for coronary disease of 1.70 (95% confidence interval [CI], 1.49 to 1.95) and another independent variant (rs3798220) with an odds ratio of 1.92 (95% CI, 1.48 to 2.49). Both variants were strongly associated with an increased level of Lp(a) lipoprotein, a reduced copy number in LPA (which determines the number of kringle IV-type 2 repeats), and a small Lp(a) lipoprotein size. Replication studies confirmed the effects of both variants on the Lp(a) lipoprotein level and the risk of coronary disease. A meta-analysis showed that with a genotype score involving both LPA SNPs, the odds ratios for coronary disease were 1.51 (95% CI, 1.38 to 1.66) for one variant and 2.57 (95% CI, 1.80 to 3.67) for two or more variants. After adjustment for the Lp(a) lipoprotein level, the association between the LPA genotype score and the risk of coronary disease was abolished. We identified two LPA variants that were strongly associated with both an increased level of Lp(a) lipoprotein and an increased risk of coronary disease. Our findings provide support for a causal role of Lp(a) lipoprotein in coronary disease.", - "journal_title": "The New England journal of medicine", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/20032323/" - } - ], - "4475c8be-18cb-434c-919d-58ac2590f2e4": [ - { - "pub_id": "20140198", - "title": "Exacerbated innate host response to SARS-CoV in aged non-human primates.", - "authors": "Saskia L Smits,Anna de Lang,Judith M A van den Brand,Lonneke M Leijten,Wilfred F van IJcken,Marinus J C Eijkemans,Geert van Amerongen,Thijs Kuiken,Arno C Andeweg,Albert D M E Osterhaus,Bart L Haagmans", - "abstract": "The emergence of viral respiratory pathogens with pandemic potential, such as severe acute respiratory syndrome coronavirus (SARS-CoV) and influenza A H5N1, urges the need for deciphering their pathogenesis to develop new intervention strategies. SARS-CoV infection causes acute lung injury (ALI) that may develop into life-threatening acute respiratory distress syndrome (ARDS) with advanced age correlating positively with adverse disease outcome. The molecular pathways, however, that cause virus-induced ALI/ARDS in aged individuals are ill-defined. Here, we show that SARS-CoV-infected aged macaques develop more severe pathology than young adult animals, even though viral replication levels are similar. Comprehensive genomic analyses indicate that aged macaques have a stronger host response to virus infection than young adult macaques, with an increase in differential expression of genes associated with inflammation, with NF-kappaB as central player, whereas expression of type I interferon (IFN)-beta is reduced. Therapeutic treatment of SARS-CoV-infected aged macaques with type I IFN reduces pathology and diminishes pro-inflammatory gene expression, including interleukin-8 (IL-8) levels, without affecting virus replication in the lungs. Thus, ALI in SARS-CoV-infected aged macaques developed as a result of an exacerbated innate host response. The anti-inflammatory action of type I IFN reveals a potential intervention strategy for virus-induced ALI.", - "journal_title": "PLoS pathogens", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/20140198/" - } - ], - "8555fab6-5674-4bfa-b5e5-335c564a9e02": [ - { - "pub_id": "19776035", - "title": "Age-associated cognitive decline.", - "authors": "Ian J Deary,Janie Corley,Alan J Gow,Sarah E Harris,Lorna M Houlihan,Riccardo E Marioni,Lars Penke,Snorri B Rafnsson,John M Starr", - "abstract": "Age-associated cognitive decline-or normal (non-pathological, normative, usual) cognitive ageing-is an important human experience which differs in extent between individuals. The determinants of the differences in age-related cognitive decline are not fully understood. Progress in the field is taking place across many areas of biomedical and psychosocial sciences. The phenotype of normal cognitive ageing is well described. Some mental capabilities are well maintained into old age. From early adulthood, there are declines in mental domains such as processing speed, reasoning, memory and executive functions, some of which is underpinned by a decline in a general cognitive factor. There are contributions to understanding individual differences in normal cognitive ageing from genetics, general health and medical disorders such as atherosclerotic disease, biological processes such as inflammation, neurobiological changes, diet and lifestyle. Many of these effect sizes are small; some are poorly replicated; and in some cases, there is the possibility of reverse causation, with prior cognitive ability causing the supposed 'cause' of cognitive ability in old age. Genome-wide scans are a likely source to establish genetic contributions. The role of vascular factors in cognitive ageing is increasingly studied and understood. The same applies to diet, biomarkers such as inflammation and lifestyle factors such as exercise. There are marked advances in brain imaging, affording better in vivo studies of brain correlates of cognitive changes. There is growing appreciation that factors affecting general bodily ageing also influence cognitive functions in old age.", - "journal_title": "British medical bulletin", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/19776035/" - } - ], - "6ec33801-5ba6-46c6-86db-687f4749916c": [ - { - "pub_id": "11137987", - "title": "Methylation meets genomics.", - "authors": "A P Feinberg", - "abstract": "", - "journal_title": "Nature genetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/11137987/" - } - ], - "0d6572db-a7d2-46c5-840b-ff88f791af4f": [ - { - "pub_id": "12184986", - "title": "Genomic DNA methylation-demethylation during aging and reinvigoration of Pinus radiata.", - "authors": "Mario F Fraga,Roberto Rodr\u00edguez,Maria Jes\u00fas Ca\u00f1al", - "abstract": "In animals, DNA methylation is related to gene silencing during ontogenic development. Little is known about DNA methylation in plants, although occasional changes in the DNA methylation state of specific gene promoters have been reported in angiosperms during some developmental processes. We found large differences in the extent of DNA methylation between meristematic areas of juvenile and mature Pinus radiata D. Don. trees, whereas differences in the extent of DNA methylation between differentiated tissues of juvenile and mature trees were small. In meristematic areas, there was a gradual decrease in extent of DNA methylation as the degree of reinvigoration increased. The observed changes in extent of DNA methylation during aging and reinvigoration indicate that reinvigoration could be a consequence of epigenetic modifications opposite in direction to those that occur during aging.", - "journal_title": "Tree physiology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/12184986/" - } - ], - "efd5747f-9e8b-45e8-9e04-bb31131d44fa": [ - { - "pub_id": "33634751", - "title": "Guidelines for the use and interpretation of assays for monitoring autophagy (4th edition)<sup>1</sup>.", - "authors": "Daniel J Klionsky,Amal Kamal Abdel-Aziz,Sara Abdelfatah,Mahmoud Abdellatif,Asghar Abdoli,Steffen Abel,Hagai Abeliovich,Marie H Abildgaard,Yakubu Princely Abudu,Abraham Acevedo-Arozena,Iannis E Adamopoulos,Khosrow Adeli,Timon E Adolph,Annagrazia Adornetto,Elma Aflaki,Galila Agam,Anupam Agarwal,Bharat B Aggarwal,Maria Agnello,Patrizia Agostinis,Javed N Agrewala,Alexander Agrotis,Patricia V Aguilar,S Tariq Ahmad,Zubair M Ahmed,Ulises Ahumada-Castro,Sonja Aits,Shu Aizawa,Yunus Akkoc,Tonia Akoumianaki,Hafize Aysin Akpinar,Ahmed M Al-Abd,Lina Al-Akra,Abeer Al-Gharaibeh,Moulay A Alaoui-Jamali,Simon Alberti,El\u00edsabet Alcocer-G\u00f3mez,Cristiano Alessandri,Muhammad Ali,M Abdul Alim Al-Bari,Saeb Aliwaini,Javad Alizadeh,Eug\u00e8nia Almacellas,Alexandru Almasan,Alicia Alonso,Guillermo D Alonso,Nihal Altan-Bonnet,Dario C Altieri,\u00c9lida M C \u00c1lvarez,Sara Alves,Cristine Alves da Costa,Mazen M Alzaharna,Marialaura Amadio,Consuelo Amantini,Cristina Amaral,Susanna Ambrosio,Amal O Amer,Veena Ammanathan,Zhenyi An,Stig U Andersen,Shaida A Andrabi,Magaiver Andrade-Silva,Allen M Andres,Sabrina Angelini,David Ann,Uche C Anozie,Mohammad Y Ansari,Pedro Antas,Adam Antebi,Zuri\u00f1e Ant\u00f3n,Tahira Anwar,Lionel Apetoh,Nadezda Apostolova,Toshiyuki Araki,Yasuhiro Araki,Kohei Arasaki,Wagner L Ara\u00fajo,Jun Araya,Catherine Arden,Maria-Angeles Ar\u00e9valo,Sandro Arguelles,Esperanza Arias,Jyothi Arikkath,Hirokazu Arimoto,Aileen R Ariosa,Darius Armstrong-James,Laetitia Arnaun\u00e9-Pelloquin,Angeles Aroca,Daniela S Arroyo,Ivica Arsov,Rub\u00e9n Artero,Dalia Maria Lucia Asaro,Michael Aschner,Milad Ashrafizadeh,Osnat Ashur-Fabian,Atanas G Atanasov,Alicia K Au,Patrick Auberger,Holger W Auner,Laure Aurelian,Riccardo Autelli,Laura Avagliano,Yenniffer \u00c1valos,Sanja Aveic,C\u00e9lia Alexandra Aveleira,Tamar Avin-Wittenberg,Yucel Aydin,Scott Ayton,Srinivas Ayyadevara,Maria Azzopardi,Misuzu Baba,Jonathan M Backer,Steven K Backues,Dong-Hun Bae,Ok-Nam Bae,Soo Han Bae,Eric H Baehrecke,Ahruem Baek,Seung-Hoon Baek,Sung Hee Baek,Giacinto Bagetta,Agnieszka Bagniewska-Zadworna,Hua Bai,Jie Bai,Xiyuan Bai,Yidong Bai,Nandadulal Bairagi,Shounak Baksi,Teresa Balbi,Cosima T Baldari,Walter Balduini,Andrea Ballabio,Maria Ballester,Salma Balazadeh,Rena Balzan,Rina Bandopadhyay,Sreeparna Banerjee,Sulagna Banerjee,\u00c1gnes B\u00e1nr\u00e9ti,Yan Bao,Mauricio S Baptista,Alessandra Baracca,Cristiana Barbati,Ariadna Bargiela,Daniela Baril\u00e0,Peter G Barlow,Sami J Barmada,Esther Barreiro,George E Barreto,Jiri Bartek,Bonnie Bartel,Alberto Bartolome,Gaurav R Barve,Suresh H Basagoudanavar,Diane C Bassham,Robert C Bast,Alakananda Basu,Henri Batoko,Isabella Batten,Etienne E Baulieu,Bradley L Baumgarner,Jagadeesh Bayry,Rupert Beale,Isabelle Beau,Florian Beaumatin,Luiz R G Bechara,George R Beck,Michael F Beers,Jakob Begun,Christian Behrends,Georg M N Behrens,Roberto Bei,Eloy Bejarano,Shai Bel,Christian Behl,Amine Belaid,Na\u00efma Belgareh-Touz\u00e9,Cristina Bellarosa,Francesca Belleudi,Melissa Bell\u00f3 P\u00e9rez,Raquel Bello-Morales,Jackeline Soares de Oliveira Beltran,Sebasti\u00e1n Beltran,Doris Mangiaracina Benbrook,Mykolas Bendorius,Bruno A Benitez,Irene Benito-Cuesta,Julien Bensalem,Martin W Berchtold,Sabina Berezowska,Daniele Bergamaschi,Matteo Bergami,Andreas Bergmann,Laura Berliocchi,Clarisse Berlioz-Torrent,Am\u00e9lie Bernard,Lionel Berthoux,Cagri G Besirli,Sebastien Besteiro,Virginie M Betin,Rudi Beyaert,Jelena S Bezbradica,Kiran Bhaskar,Ingrid Bhatia-Kissova,Resham Bhattacharya,Sujoy Bhattacharya,Shalmoli Bhattacharyya,Md Shenuarin Bhuiyan,Sujit Kumar Bhutia,Lanrong Bi,Xiaolin Bi,Trevor J Biden,Krikor Bijian,Viktor A Billes,Nadine Binart,Claudia Bincoletto,Asa B Birgisdottir,Geir Bjorkoy,Gonzalo Blanco,Ana Blas-Garcia,Janusz Blasiak,Robert Blomgran,Klas Blomgren,Janice S Blum,Emilio Boada-Romero,Mirta Boban,Kathleen Boesze-Battaglia,Philippe Boeuf,Barry Boland,Pascale Bomont,Paolo Bonaldo,Srinivasa Reddy Bonam,Laura Bonfili,Juan S Bonifacino,Brian A Boone,Martin D Bootman,Matteo Bordi,Christoph Borner,Beat C Bornhauser,Gautam Borthakur,J\u00fcrgen Bosch,Santanu Bose,Luis M Botana,Juan Botas,Chantal M Boulanger,Michael E Boulton,Mathieu Bourdenx,Benjamin Bourgeois,Nollaig M Bourke,Guilhem Bousquet,Patricia Boya,Peter V Bozhkov,Luiz H M Bozi,Tolga O Bozkurt,Doug E Brackney,Christian H Brandts,Ralf J Braun,Gerhard H Braus,Roberto Bravo-Sagua,Jos\u00e9 M Bravo-San Pedro,Patrick Brest,Marie-Agn\u00e8s Bringer,Alfredo Briones-Herrera,V Courtney Broaddus,Peter Brodersen,Jeffrey L Brodsky,Steven L Brody,Paola G Bronson,Jeff M Bronstein,Carolyn N Brown,Rhoderick E Brown,Patricia C Brum,John H Brumell,Nicola Brunetti-Pierri,Daniele Bruno,Robert J Bryson-Richardson,Cecilia Bucci,Carmen Buchrieser,Marta Bueno,Laura Elisa Buitrago-Molina,Simone Buraschi,Shilpa Buch,J Ross Buchan,Erin M Buckingham,Hikmet Budak,Mauricio Budini,Geert Bultynck,Florin Burada,Joseph R Burgoyne,M Isabel Bur\u00f3n,Victor Bustos,Sabrina B\u00fcttner,Elena Butturini,Aaron Byrd,Isabel Cabas,Sandra Cabrera-Benitez,Ken Cadwell,Jingjing Cai,Lu Cai,Qian Cai,Montserrat Cair\u00f3,Jose A Calbet,Guy A Caldwell,Kim A Caldwell,Jarrod A Call,Riccardo Calvani,Ana C Calvo,Miguel Calvo-Rubio Barrera,Niels Os Camara,Jacques H Camonis,Nadine Camougrand,Michelangelo Campanella,Edward M Campbell,Fran\u00e7ois-Xavier Campbell-Valois,Silvia Campello,Ilaria Campesi,Juliane C Campos,Olivier Camuzard,Jorge Cancino,Danilo Candido de Almeida,Laura Canesi,Isabella Caniggia,Barbara Canonico,Carles Cant\u00ed,Bin Cao,Michele Caraglia,Beatriz Caram\u00e9s,Evie H Carchman,Elena Cardenal-Mu\u00f1oz,Cesar Cardenas,Luis Cardenas,Sandra M Cardoso,Jennifer S Carew,Georges F Carle,Gillian Carleton,Silvia Carloni,Didac Carmona-Gutierrez,Leticia A Carneiro,Oliana Carnevali,Julian M Carosi,Serena Carra,Alice Carrier,Lucie Carrier,Bernadette Carroll,A Brent Carter,Andreia Neves Carvalho,Magali Casanova,Caty Casas,Josefina Casas,Chiara Cassioli,Eliseo F Castillo,Karen Castillo,Sonia Castillo-Lluva,Francesca Castoldi,Marco Castori,Ariel F Castro,Margarida Castro-Caldas,Javier Castro-Hernandez,Susana Castro-Obregon,Sergio D Catz,Claudia Cavadas,Federica Cavaliere,Gabriella Cavallini,Maria Cavinato,Maria L Cayuela,Paula Cebollada Rica,Valentina Cecarini,Francesco Cecconi,Marzanna Cechowska-Pasko,Simone Cenci,Vict\u00f2ria Ceperuelo-Mallafr\u00e9,Jo\u00e3o J Cerqueira,Janete M Cerutti,Davide Cervia,Vildan Bozok Cetintas,Silvia Cetrullo,Han-Jung Chae,Andrei S Chagin,Chee-Yin Chai,Gopal Chakrabarti,Oishee Chakrabarti,Tapas Chakraborty,Trinad Chakraborty,Mounia Chami,Georgios Chamilos,David W Chan,Edmond Y W Chan,Edward D Chan,H Y Edwin Chan,Helen H Chan,Hung Chan,Matthew T V Chan,Yau Sang Chan,Partha K Chandra,Chih-Peng Chang,Chunmei Chang,Hao-Chun Chang,Kai Chang,Jie Chao,Tracey Chapman,Nicolas Charlet-Berguerand,Samrat Chatterjee,Shail K Chaube,Anu Chaudhary,Santosh Chauhan,Edward Chaum,Fr\u00e9d\u00e9ric Checler,Michael E Cheetham,Chang-Shi Chen,Guang-Chao Chen,Jian-Fu Chen,Liam L Chen,Leilei Chen,Lin Chen,Mingliang Chen,Mu-Kuan Chen,Ning Chen,Quan Chen,Ruey-Hwa Chen,Shi Chen,Wei Chen,Weiqiang Chen,Xin-Ming Chen,Xiong-Wen Chen,Xu Chen,Yan Chen,Ye-Guang Chen,Yingyu Chen,Yongqiang Chen,Yu-Jen Chen,Yue-Qin Chen,Zhefan Stephen Chen,Zhi Chen,Zhi-Hua Chen,Zhijian J Chen,Zhixiang Chen,Hanhua Cheng,Jun Cheng,Shi-Yuan Cheng,Wei Cheng,Xiaodong Cheng,Xiu-Tang Cheng,Yiyun Cheng,Zhiyong Cheng,Zhong Chen,Heesun Cheong,Jit Kong Cheong,Boris V Chernyak,Sara Cherry,Chi Fai Randy Cheung,Chun Hei Antonio Cheung,King-Ho Cheung,Eric Chevet,Richard J Chi,Alan Kwok Shing Chiang,Ferdinando Chiaradonna,Roberto Chiarelli,Mario Chiariello,Nathalia Chica,Susanna Chiocca,Mario Chiong,Shih-Hwa Chiou,Abhilash I Chiramel,Valerio Chiurchi\u00f9,Dong-Hyung Cho,Seong-Kyu Choe,Augustine M K Choi,Mary E Choi,Kamalika Roy Choudhury,Norman S Chow,Charleen T Chu,Jason P Chua,John Jia En Chua,Hyewon Chung,Kin Pan Chung,Seockhoon Chung,So-Hyang Chung,Yuen-Li Chung,Valentina Cianfanelli,Iwona A Ciechomska,Mariana Cifuentes,Laura Cinque,Sebahattin Cirak,Mara Cirone,Michael J Clague,Robert Clarke,Emilio Clementi,Eliana M Coccia,Patrice Codogno,Ehud Cohen,Mickael M Cohen,Tania Colasanti,Fiorella Colasuonno,Robert A Colbert,Anna Colell,Miodrag \u010coli\u0107,Nuria S Coll,Mark O Collins,Mar\u00eda I Colombo,Daniel A Col\u00f3n-Ramos,Lydie Combaret,Sergio Comincini,M\u00e1rcia R Cominetti,Antonella Consiglio,Andrea Conte,Fabrizio Conti,Viorica Raluca Contu,Mark R Cookson,Kevin M Coombs,Isabelle Coppens,Maria Tiziana Corasaniti,Dale P Corkery,Nils Cordes,Katia Cortese,Maria do Carmo Costa,Sarah Costantino,Paola Costelli,Ana Coto-Montes,Peter J Crack,Jose L Crespo,Alfredo Criollo,Valeria Crippa,Riccardo Cristofani,Tamas Csizmadia,Antonio Cuadrado,Bing Cui,Jun Cui,Yixian Cui,Yong Cui,Emmanuel Culetto,Andrea C Cumino,Andrey V Cybulsky,Mark J Czaja,Stanislaw J Czuczwar,Stefania D'Adamo,Marcello D'Amelio,Daniela D'Arcangelo,Andrew C D'Lugos,Gabriella D'Orazi,James A da Silva,Hormos Salimi Dafsari,Ruben K Dagda,Yasin Dagdas,Maria Daglia,Xiaoxia Dai,Yun Dai,Yuyuan Dai,Jessica Dal Col,Paul Dalhaimer,Luisa Dalla Valle,Tobias Dallenga,Guillaume Dalmasso,Markus Damme,Ilaria Dando,Nico P Dantuma,April L Darling,Hiranmoy Das,Srinivasan Dasarathy,Santosh K Dasari,Srikanta Dash,Oliver Daumke,Adrian N Dauphinee,Jeffrey S Davies,Valeria A D\u00e1vila,Roger J Davis,Tanja Davis,Sharadha Dayalan Naidu,Francesca De Amicis,Karolien De Bosscher,Francesca De Felice,Lucia De Franceschi,Chiara De Leonibus,Mayara G de Mattos Barbosa,Guido R Y De Meyer,Angelo De Milito,Cosimo De Nunzio,Clara De Palma,Mauro De Santi,Claudio De Virgilio,Daniela De Zio,Jayanta Debnath,Brian J DeBosch,Jean-Paul Decuypere,Mark A Deehan,Gianluca Deflorian,James DeGregori,Benjamin Dehay,Gabriel Del Rio,Joe R Delaney,Lea M D Delbridge,Elizabeth Delorme-Axford,M Victoria Delpino,Francesca Demarchi,Vilma Dembitz,Nicholas D Demers,Hongbin Deng,Zhiqiang Deng,Joern Dengjel,Paul Dent,Donna Denton,Melvin L DePamphilis,Channing J Der,Vojo Deretic,Albert Descoteaux,Laura Devis,Sushil Devkota,Olivier Devuyst,Grant Dewson,Mahendiran Dharmasivam,Rohan Dhiman,Diego di Bernardo,Manlio Di Cristina,Fabio Di Domenico,Pietro Di Fazio,Alessio Di Fonzo,Giovanni Di Guardo,Gianni M Di Guglielmo,Luca Di Leo,Chiara Di Malta,Alessia Di Nardo,Martina Di Rienzo,Federica Di Sano,George Diallinas,Jiajie Diao,Guillermo Diaz-Araya,In\u00e9s D\u00edaz-Laviada,Jared M Dickinson,Marc Diederich,M\u00e9lanie Dieud\u00e9,Ivan Dikic,Shiping Ding,Wen-Xing Ding,Luciana Dini,Jelena Dini\u0107,Miroslav Dinic,Albena T Dinkova-Kostova,Marc S Dionne,J\u00f6rg H W Distler,Abhinav Diwan,Ian M C Dixon,Mojgan Djavaheri-Mergny,Ina Dobrinski,Oxana Dobrovinskaya,Radek Dobrowolski,Renwick C J Dobson,Jelena \u0110oki\u0107,Serap Dokmeci Emre,Massimo Donadelli,Bo Dong,Xiaonan Dong,Zhiwu Dong,Gerald W Dorn Ii,Volker Dotsch,Huan Dou,Juan Dou,Moataz Dowaidar,Sami Dridi,Liat Drucker,Ailian Du,Caigan Du,Guangwei Du,Hai-Ning Du,Li-Lin Du,Andr\u00e9 du Toit,Shao-Bin Duan,Xiaoqiong Duan,S\u00f3nia P Duarte,Anna Dubrovska,Elaine A Dunlop,Nicolas Dupont,Ra\u00fal V Dur\u00e1n,Bilikere S Dwarakanath,Sergey A Dyshlovoy,Darius Ebrahimi-Fakhari,Leopold Eckhart,Charles L Edelstein,Thomas Efferth,Eftekhar Eftekharpour,Ludwig Eichinger,Nabil Eid,Tobias Eisenberg,N Tony Eissa,Sanaa Eissa,Miriam Ejarque,Abdeljabar El Andaloussi,Nazira El-Hage,Shahenda El-Naggar,Anna Maria Eleuteri,Eman S El-Shafey,Mohamed Elgendy,Aristides G Eliopoulos,Mar\u00eda M Elizalde,Philip M Elks,Hans-Peter Elsasser,Eslam S Elsherbiny,Brooke M Emerling,N C Tolga Emre,Christina H Eng,Nikolai Engedal,Anna-Mart Engelbrecht,Agnete S T Engelsen,Jorrit M Enserink,Ricardo Escalante,Audrey Esclatine,Mafalda Escobar-Henriques,Eeva-Liisa Eskelinen,Lucile Espert,Makandjou-Ola Eusebio,Gemma Fabrias,Cinzia Fabrizi,Antonio Facchiano,Francesco Facchiano,Bengt Fadeel,Claudio Fader,Alex C Faesen,W Douglas Fairlie,Alberto Falc\u00f3,Bjorn H Falkenburger,Daping Fan,Jie Fan,Yanbo Fan,Evandro F Fang,Yanshan Fang,Yognqi Fang,Manolis Fanto,Tamar Farfel-Becker,Mathias Faure,Gholamreza Fazeli,Anthony O Fedele,Arthur M Feldman,Du Feng,Jiachun Feng,Lifeng Feng,Yibin Feng,Yuchen Feng,Wei Feng,Thais Fenz Araujo,Thomas A Ferguson,\u00c1lvaro F Fern\u00e1ndez,Jose C Fernandez-Checa,Sonia Fern\u00e1ndez-Veledo,Alisdair R Fernie,Anthony W Ferrante,Alessandra Ferraresi,Merari F Ferrari,Julio C B Ferreira,Susan Ferro-Novick,Antonio Figueras,Riccardo Filadi,Nicoletta Filigheddu,Eduardo Filippi-Chiela,Giuseppe Filomeni,Gian Maria Fimia,Vittorio Fineschi,Francesca Finetti,Steven Finkbeiner,Edward A Fisher,Paul B Fisher,Flavio Flamigni,Steven J Fliesler,Trude H Flo,Ida Florance,Oliver Florey,Tullio Florio,Erika Fodor,Carlo Follo,Edward A Fon,Antonella Forlino,Francesco Fornai,Paola Fortini,Anna Fracassi,Alessandro Fraldi,Brunella Franco,Rodrigo Franco,Flavia Franconi,Lisa B Frankel,Scott L Friedman,Leopold F Fr\u00f6hlich,Gema Fr\u00fchbeck,Jose M Fuentes,Yukio Fujiki,Naonobu Fujita,Yuuki Fujiwara,Mitsunori Fukuda,Simone Fulda,Luc Furic,Norihiko Furuya,Carmela Fusco,Michaela U Gack,Lidia Gaffke,Sehamuddin Galadari,Alessia Galasso,Maria F Galindo,Sachith Gallolu Kankanamalage,Lorenzo Galluzzi,Vincent Galy,Noor Gammoh,Boyi Gan,Ian G Ganley,Feng Gao,Hui Gao,Minghui Gao,Ping Gao,Shou-Jiang Gao,Wentao Gao,Xiaobo Gao,Ana Garcera,Maria No\u00e9 Garcia,Ver\u00f3nica E Garcia,Francisco Garc\u00eda-Del Portillo,Vega Garcia-Escudero,Aracely Garcia-Garcia,Marina Garcia-Macia,Diana Garc\u00eda-Moreno,Carmen Garcia-Ruiz,Patricia Garc\u00eda-Sanz,Abhishek D Garg,Ricardo Gargini,Tina Garofalo,Robert F Garry,Nils C Gassen,Damian Gatica,Liang Ge,Wanzhong Ge,Ruth Geiss-Friedlander,Cecilia Gelfi,Pascal Genschik,Ian E Gentle,Valeria Gerbino,Christoph Gerhardt,Kyla Germain,Marc Germain,David A Gewirtz,Elham Ghasemipour Afshar,Saeid Ghavami,Alessandra Ghigo,Manosij Ghosh,Georgios Giamas,Claudia Giampietri,Alexandra Giatromanolaki,Gary E Gibson,Spencer B Gibson,Vanessa Ginet,Edward Giniger,Carlotta Giorgi,Henrique Girao,Stephen E Girardin,Mridhula Giridharan,Sandy Giuliano,Cecilia Giulivi,Sylvie Giuriato,Julien Giustiniani,Alexander Gluschko,Veit Goder,Alexander Goginashvili,Jakub Golab,David C Goldstone,Anna Golebiewska,Luciana R Gomes,Rodrigo Gomez,Rub\u00e9n G\u00f3mez-S\u00e1nchez,Maria Catalina Gomez-Puerto,Raquel Gomez-Sintes,Qingqiu Gong,Felix M Goni,Javier Gonz\u00e1lez-Gallego,Tomas Gonzalez-Hernandez,Rosa A Gonzalez-Polo,Jose A Gonzalez-Reyes,Patricia Gonz\u00e1lez-Rodr\u00edguez,Ing Swie Goping,Marina S Gorbatyuk,Nikolai V Gorbunov,K\u0131van\u00e7 G\u00f6rg\u00fcl\u00fc,Roxana M Gorojod,Sharon M Gorski,Sandro Goruppi,Cecilia Gotor,Roberta A Gottlieb,Illana Gozes,Devrim Gozuacik,Martin Graef,Markus H Gr\u00e4ler,Veronica Granatiero,Daniel Grasso,Joshua P Gray,Douglas R Green,Alexander Greenhough,Stephen L Gregory,Edward F Griffin,Mark W Grinstaff,Frederic Gros,Charles Grose,Angelina S Gross,Florian Gruber,Paolo Grumati,Tilman Grune,Xueyan Gu,Jun-Lin Guan,Carlos M Guardia,Kishore Guda,Flora Guerra,Consuelo Guerri,Prasun Guha,Carlos Guill\u00e9n,Shashi Gujar,Anna Gukovskaya,Ilya Gukovsky,Jan Gunst,Andreas G\u00fcnther,Anyonya R Guntur,Chuanyong Guo,Chun Guo,Hongqing Guo,Lian-Wang Guo,Ming Guo,Pawan Gupta,Shashi Kumar Gupta,Swapnil Gupta,Veer Bala Gupta,Vivek Gupta,Asa B Gustafsson,David D Gutterman,Ranjitha H B,Annakaisa Haapasalo,James E Haber,Aleksandra Ha\u0107,Shinji Hadano,Anders J Hafr\u00e9n,Mansour Haidar,Belinda S Hall,Gunnel Halld\u00e9n,Anne Hamacher-Brady,Andrea Hamann,Maho Hamasaki,Weidong Han,Malene Hansen,Phyllis I Hanson,Zijian Hao,Masaru Harada,Ljubica Harhaji-Trajkovic,Nirmala Hariharan,Nigil Haroon,James Harris,Takafumi Hasegawa,Noor Hasima Nagoor,Jeffrey A Haspel,Volker Haucke,Wayne D Hawkins,Bruce A Hay,Cole M Haynes,Soren B Hayrabedyan,Thomas S Hays,Congcong He,Qin He,Rong-Rong He,You-Wen He,Yu-Ying He,Yasser Heakal,Alexander M Heberle,J Fielding Hejtmancik,Gudmundur Vignir Helgason,Vanessa Henkel,Marc Herb,Alexander Hergovich,Anna Herman-Antosiewicz,Agust\u00edn Hern\u00e1ndez,Carlos Hernandez,Sergio Hernandez-Diaz,Virginia Hernandez-Gea,Amaury Herpin,Judit Herreros,Javier H Herv\u00e1s,Daniel Hesselson,Claudio Hetz,Volker T Heussler,Yujiro Higuchi,Sabine Hilfiker,Joseph A Hill,William S Hlavacek,Emmanuel A Ho,Idy H T Ho,Philip Wing-Lok Ho,Shu-Leong Ho,Wan Yun Ho,G Aaron Hobbs,Mark Hochstrasser,Peter H M Hoet,Daniel Hofius,Paul Hofman,Annika H\u00f6hn,Carina I Holmberg,Jose R Hombrebueno,Chang-Won Hong Yi-Ren Hong,Lora V Hooper,Thorsten Hoppe,Rastislav Horos,Yujin Hoshida,I-Lun Hsin,Hsin-Yun Hsu,Bing Hu,Dong Hu,Li-Fang Hu,Ming Chang Hu,Ronggui Hu,Wei Hu,Yu-Chen Hu,Zhuo-Wei Hu,Fang Hua,Jinlian Hua,Yingqi Hua,Chongmin Huan,Canhua Huang,Chuanshu Huang,Chuanxin Huang,Chunling Huang,Haishan Huang,Kun Huang,Michael L H Huang,Rui Huang,Shan Huang,Tianzhi Huang,Xing Huang,Yuxiang Jack Huang,Tobias B Huber,Virginie Hubert,Christian A Hubner,Stephanie M Hughes,William E Hughes,Magali Humbert,Gerhard Hummer,James H Hurley,Sabah Hussain,Salik Hussain,Patrick J Hussey,Martina Hutabarat,Hui-Yun Hwang,Seungmin Hwang,Antonio Ieni,Fumiyo Ikeda,Yusuke Imagawa,Yuzuru Imai,Carol Imbriano,Masaya Imoto,Denise M Inman,Ken Inoki,Juan Iovanna,Renato V Iozzo,Giuseppe Ippolito,Javier E Irazoqui,Pablo Iribarren,Mohd Ishaq,Makoto Ishikawa,Nestor Ishimwe,Ciro Isidoro,Nahed Ismail,Shohreh Issazadeh-Navikas,Eisuke Itakura,Daisuke Ito,Davor Ivankovic,Sa\u0161ka Ivanova,Anand Krishnan V Iyer,Jos\u00e9 M Izquierdo,Masanori Izumi,Marja J\u00e4\u00e4ttel\u00e4,Majid Sakhi Jabir,William T Jackson,Nadia Jacobo-Herrera,Anne-Claire Jacomin,Elise Jacquin,Pooja Jadiya,Hartmut Jaeschke,Chinnaswamy Jagannath,Arjen J Jakobi,Johan Jakobsson,Bassam Janji,Pidder Jansen-D\u00fcrr,Patric J Jansson,Jonathan Jantsch,S\u0142awomir Januszewski,Alagie Jassey,Steve Jean,H\u00e9l\u00e8ne Jeltsch-David,Pavla Jendelova,Andreas Jenny,Thomas E Jensen,Niels Jessen,Jenna L Jewell,Jing Ji,Lijun Jia,Rui Jia,Liwen Jiang,Qing Jiang,Richeng Jiang,Teng Jiang,Xuejun Jiang,Yu Jiang,Maria Jimenez-Sanchez,Eun-Jung Jin,Fengyan Jin,Hongchuan Jin,Li Jin,Luqi Jin,Meiyan Jin,Si Jin,Eun-Kyeong Jo,Carine Joffre,Terje Johansen,Gail V W Johnson,Simon A Johnston,Eija Jokitalo,Mohit Kumar Jolly,Leo A B Joosten,Joaquin Jordan,Bertrand Joseph,Dianwen Ju,Jeong-Sun Ju,Jingfang Ju,Esmeralda Ju\u00e1rez,Delphine Judith,G\u00e1bor Juh\u00e1sz,Youngsoo Jun,Chang Hwa Jung,Sung-Chul Jung,Yong Keun Jung,Heinz Jungbluth,Johannes Jungverdorben,Steffen Just,Kai Kaarniranta,Allen Kaasik,Tomohiro Kabuta,Daniel Kaganovich,Alon Kahana,Renate Kain,Shinjo Kajimura,Maria Kalamvoki,Manjula Kalia,Danuta S Kalinowski,Nina Kaludercic,Ioanna Kalvari,Joanna Kaminska,Vitaliy O Kaminskyy,Hiromitsu Kanamori,Keizo Kanasaki,Chanhee Kang,Rui Kang,Sang Sun Kang,Senthilvelrajan Kaniyappan,Tomotake Kanki,Thirumala-Devi Kanneganti,Anumantha G Kanthasamy,Arthi Kanthasamy,Marc Kantorow,Orsolya Kapuy,Michalis V Karamouzis,Md Razaul Karim,Parimal Karmakar,Rajesh G Katare,Masaru Kato,Stefan H E Kaufmann,Anu Kauppinen,Gur P Kaushal,Susmita Kaushik,Kiyoshi Kawasaki,Kemal Kazan,Po-Yuan Ke,Damien J Keating,Ursula Keber,John H Kehrl,Kate E Keller,Christian W Keller,Jongsook Kim Kemper,Candia M Kenific,Oliver Kepp,Stephanie Kermorgant,Andreas Kern,Robin Ketteler,Tom G Keulers,Boris Khalfin,Hany Khalil,Bilon Khambu,Shahid Y Khan,Vinoth Kumar Megraj Khandelwal,Rekha Khandia,Widuri Kho,Noopur V Khobrekar,Sataree Khuansuwan,Mukhran Khundadze,Samuel A Killackey,Dasol Kim,Deok Ryong Kim,Do-Hyung Kim,Dong-Eun Kim,Eun Young Kim,Eun-Kyoung Kim,Hak-Rim Kim,Hee-Sik Kim, Hyung-Ryong Kim,Jeong Hun Kim,Jin Kyung Kim,Jin-Hoi Kim,Joungmok Kim,Ju Hwan Kim,Keun Il Kim,Peter K Kim,Seong-Jun Kim,Scot R Kimball,Adi Kimchi,Alec C Kimmelman,Tomonori Kimura,Matthew A King,Kerri J Kinghorn,Conan G Kinsey,Vladimir Kirkin,Lorrie A Kirshenbaum,Sergey L Kiselev,Shuji Kishi,Katsuhiko Kitamoto,Yasushi Kitaoka,Kaio Kitazato,Richard N Kitsis,Josef T Kittler,Ole Kjaerulff,Peter S Klein,Thomas Klopstock,Jochen Klucken,Helene Kn\u00e6velsrud,Roland L Knorr,Ben C B Ko,Fred Ko,Jiunn-Liang Ko,Hotaka Kobayashi,Satoru Kobayashi,Ina Koch,Jan C Koch,Ulrich Koenig,Donat K\u00f6gel,Young Ho Koh,Masato Koike,Sepp D Kohlwein,Nur M Kocaturk,Masaaki Komatsu,Jeannette K\u00f6nig,Toru Kono,Benjamin T Kopp,Tamas 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Li,Liwu Li,Mei Li,Min Li,Min Li,Ming Li,Mingchuan Li,Pin-Lan Li,Ming-Qing Li,Qing Li,Sheng Li,Tiangang Li,Wei Li,Wenming Li,Xue Li,Yi-Ping Li,Yuan Li,Zhiqiang Li,Zhiyong Li,Zhiyuan Li,Jiqin Lian,Chengyu Liang,Qiangrong Liang,Weicheng Liang,Yongheng Liang,YongTian Liang,Guanghong Liao,Lujian Liao,Mingzhi Liao,Yung-Feng Liao,Mariangela Librizzi,Pearl P Y Lie,Mary A Lilly,Hyunjung J Lim,Thania R R Lima,Federica Limana,Chao Lin,Chih-Wen Lin,Dar-Shong Lin,Fu-Cheng Lin,Jiandie D Lin,Kurt M Lin,Kwang-Huei Lin,Liang-Tzung Lin,Pei-Hui Lin,Qiong Lin,Shaofeng Lin,Su-Ju Lin,Wenyu Lin,Xueying Lin,Yao-Xin Lin,Yee-Shin Lin,Rafael Linden,Paula Lindner,Shuo-Chien Ling,Paul Lingor,Amelia K Linnemann,Yih-Cherng Liou,Marta M Lipinski,Sa\u0161ka Lipov\u0161ek,Vitor A Lira,Natalia Lisiak,Paloma B Liton,Chao Liu,Ching-Hsuan Liu,Chun-Feng Liu,Cui Hua Liu,Fang Liu,Hao Liu,Hsiao-Sheng Liu,Hua-Feng Liu,Huifang Liu,Jia Liu,Jing Liu,Julia Liu,Leyuan Liu,Longhua Liu,Meilian Liu,Qin Liu,Wei Liu,Wende Liu,Xiao-Hong Liu,Xiaodong Liu,Xingguo Liu,Xu Liu,Xuedong Liu,Yanfen Liu,Yang Liu,Yang Liu,Yueyang Liu,Yule Liu,J Andrew Livingston,Gerard Lizard,Jose M Lizcano,Senka Ljubojevic-Holzer,Matilde E LLeonart,David Llobet-Nav\u00e0s,Alicia Llorente,Chih Hung Lo,Dami\u00e1n Lobato-M\u00e1rquez,Qi Long,Yun Chau Long,Ben Loos,Julia A Loos,Manuela G L\u00f3pez,Guillermo L\u00f3pez-Dom\u00e9nech,Jos\u00e9 Antonio L\u00f3pez-Guerrero,Ana T L\u00f3pez-Jim\u00e9nez,\u00d3scar L\u00f3pez-P\u00e9rez,Israel L\u00f3pez-Valero,Magdalena J Lorenowicz,Mar Lorente,Peter Lorincz,Laura Lossi,Sophie Lotersztajn,Penny E Lovat,Jonathan F Lovell,Alenka Lovy,P\u00e9ter L\u0151w,Guang Lu,Haocheng Lu,Jia-Hong Lu,Jin-Jian Lu,Mengji Lu,Shuyan Lu,Alessandro Luciani,John M Lucocq,Paula Ludovico,Micah A Luftig,Morten Luhr,Diego Luis-Ravelo,Julian J Lum,Liany Luna-Dulcey,Anders H Lund,Viktor K Lund,Jan D L\u00fcnemann,Patrick L\u00fcningschr\u00f6r,Honglin Luo,Rongcan Luo,Shouqing Luo,Zhi Luo,Claudio Luparello,Bernhard 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Nieto-Diaz,Per Nilsson,Shunbin Ning,Rituraj Niranjan,Hiroshi Nishimune,Mireia Niso-Santano,Ralph A Nixon,Annalisa Nobili,Clevio Nobrega,Takeshi Noda,Ux\u00eda Nogueira-Recalde,Trevor M Nolan,Ivan Nombela,Ivana Novak,Beatriz Novoa,Takashi Nozawa,Nobuyuki Nukina,Carmen Nussbaum-Krammer,Jesper Nylandsted,Tracey R O'Donovan,Se\u00f3nadh M O'Leary,Eyleen J O'Rourke,Mary P O'Sullivan,Timothy E O'Sullivan,Salvatore Oddo,Ina Oehme,Michinaga Ogawa,Eric Ogier-Denis,Margret H Ogmundsdottir,Besim Ogretmen,Goo Taeg Oh,Seon-Hee Oh,Young J Oh,Takashi Ohama,Yohei Ohashi,Masaki Ohmuraya,Vasileios Oikonomou,Rani Ojha,Koji Okamoto,Hitoshi Okazawa,Masahide Oku,Sara Oliv\u00e1n,Jorge M A Oliveira,Michael Ollmann,James A Olzmann,Shakib Omari,M Bishr Omary,Gizem \u00d6nal,Martin Ondrej,Sang-Bing Ong,Sang-Ging Ong,Anna Onnis,Juan A Orellana,Sara Orellana-Mu\u00f1oz,Maria Del Mar Ortega-Villaizan,Xilma R Ortiz-Gonzalez,Elena Ortona,Heinz D Osiewacz,Abdel-Hamid K Osman,Rosario Osta,Marisa S Otegui,Kinya Otsu,Christiane Ott,Luisa Ottobrini,Jing-Hsiung James Ou,Tiago F Outeiro,Inger Oynebraten,Melek Ozturk,Gilles Pag\u00e8s,Susanta Pahari,Marta Pajares,Utpal B Pajvani,Rituraj Pal,Simona Paladino,Nicolas Pallet,Michela Palmieri,Giuseppe Palmisano,Camilla Palumbo,Francesco Pampaloni,Lifeng Pan,Qingjun Pan,Wenliang Pan,Xin Pan,Ganna Panasyuk,Rahul Pandey,Udai B Pandey,Vrajesh Pandya,Francesco Paneni,Shirley Y Pang,Elisa Panzarini,Daniela L Papademetrio,Elena Papaleo,Daniel Papinski,Diana Papp,Eun Chan Park,Hwan Tae Park,Ji-Man Park,Jong-In Park,Joon Tae Park,Junsoo Park,Sang Chul Park,Sang-Youel Park,Abraham H Parola,Jan B Parys,Adrien Pasquier,Benoit Pasquier,Jo\u00e3o F Passos,Nunzia Pastore,Hemal H Patel,Daniel Patschan,Sophie Pattingre,Gustavo Pedraza-Alva,Jose Pedraza-Chaverri,Zully Pedrozo,Gang Pei,Jianming Pei,Hadas Peled-Zehavi,Joaqu\u00edn M Pellegrini,Joffrey Pelletier,Miguel A Pe\u00f1alva,Di Peng,Ying Peng,Fabio Penna,Maria Pennuto,Francesca Pentimalli,Cl\u00e1udia Mf Pereira,Gustavo J S Pereira,Lilian C Pereira,Luis Pereira de Almeida,Nirma D Perera,\u00c1ngel P\u00e9rez-Lara,Ana B Perez-Oliva,Mar\u00eda Esther P\u00e9rez-P\u00e9rez,Palsamy Periyasamy,Andras Perl,Cristiana Perrotta,Ida Perrotta,Richard G Pestell,Morten Petersen,Irina Petrache,Goran Petrovski,Thorsten Pfirrmann,Astrid S Pfister,Jennifer A Philips,Huifeng Pi,Anna Picca,Alicia M Pickrell,Sandy Picot,Giovanna M Pierantoni,Marina Pierdominici,Philippe Pierre,Val\u00e9rie Pierrefite-Carle,Karolina Pierzynowska,Federico Pietrocola,Miroslawa Pietruczuk,Claudio Pignata,Felipe X Pimentel-Mui\u00f1os,Mario Pinar,Roberta O Pinheiro,Ronit Pinkas-Kramarski,Paolo Pinton,Karolina Pircs,Sujan Piya,Paola Pizzo,Theo S Plantinga,Harald W Platta,Ainhoa Plaza-Zabala,Markus Plomann,Egor Y Plotnikov,Helene Plun-Favreau,Ryszard Pluta,Roger Pocock,Stefanie P\u00f6ggeler,Christian Pohl,Marc Poirot,Angelo Poletti,Marisa Ponpuak,Hana Popelka,Blagovesta Popova,Helena Porta,Soledad Porte Alcon,Eliana Portilla-Fernandez,Martin Post,Malia B Potts,Joanna Poulton,Ted Powers,Veena Prahlad,Tomasz K Prajsnar,Domenico Pratic\u00f2,Rosaria Prencipe,Muriel Priault,Tassula Proikas-Cezanne,Vasilis J Promponas,Christopher G Proud,Rosa Puertollano,Luigi Puglielli,Thomas Pulinilkunnil,Deepika Puri,Rajat Puri,Julien Puyal,Xiaopeng Qi,Yongmei Qi,Wenbin Qian,Lei Qiang,Yu Qiu,Joe Quadrilatero,Jorge Quarleri,Nina Raben,Hannah Rabinowich,Debora Ragona,Michael J Ragusa,Nader Rahimi,Marveh Rahmati,Valeria Raia,Nuno Raimundo,Namakkal-Soorappan Rajasekaran,Sriganesh Ramachandra Rao,Abdelhaq Rami,Ignacio Ram\u00edrez-Pardo,David B Ramsden,Felix Randow,Pundi N Rangarajan,Danilo Ranieri,Hai Rao,Lang Rao,Rekha Rao,Sumit Rathore,J Arjuna Ratnayaka,Edward A Ratovitski,Palaniyandi Ravanan,Gloria Ravegnini,Swapan K Ray,Babak Razani,Vito Rebecca,Fulvio Reggiori,Anne R\u00e9gnier-Vigouroux,Andreas S Reichert,David Reigada,Jan H Reiling,Theo Rein,Siegfried Reipert,Rokeya Sultana Rekha,Hongmei Ren,Jun Ren,Weichao Ren,Tristan Renault,Giorgia Renga,Karen Reue,Kim Rewitz,Bruna Ribeiro de Andrade Ramos,S Amer Riazuddin,Teresa M Ribeiro-Rodrigues,Jean-Ehrland Ricci,Romeo Ricci,Victoria Riccio,Des R Richardson,Yasuko Rikihisa,Makarand V Risbud,Ruth M Risue\u00f1o,Konstantinos Ritis,Salvatore Rizza,Rosario Rizzuto,Helen C Roberts,Luke D Roberts,Katherine J Robinson,Maria Carmela Roccheri,Stephane Rocchi,George G Rodney,Tiago Rodrigues,Vagner Ramon Rodrigues Silva,Amaia Rodriguez,Ruth Rodriguez-Barrueco,Nieves Rodriguez-Henche,Humberto Rodriguez-Rocha,Jeroen Roelofs,Robert S Rogers,Vladimir V Rogov,Ana I Rojo,Krzysztof Rolka,Vanina Romanello,Luigina Romani,Alessandra Romano,Patricia S Romano,David Romeo-Guitart,Luis C Romero,Montserrat Romero,Joseph C Roney,Christopher Rongo,Sante Roperto,Mathias T Rosenfeldt,Philip Rosenstiel,Anne G Rosenwald,Kevin A Roth,Lynn Roth,Steven Roth,Kasper M A Rouschop,Benoit D Roussel,Sophie Roux,Patrizia Rovere-Querini,Ajit Roy,Aurore Rozieres,Diego Ruano,David C Rubinsztein,Maria P Rubtsova,Klaus Ruckdeschel,Christoph Ruckenstuhl,Emil Rudolf,R\u00fcdiger Rudolf,Alessandra Ruggieri,Avnika Ashok Ruparelia,Paola Rusmini,Ryan R Russell,Gian Luigi Russo,Maria Russo,Rossella Russo,Oxana O Ryabaya,Kevin M Ryan,Kwon-Yul Ryu,Maria Sabater-Arcis,Ulka Sachdev,Michael Sacher,Carsten Sachse,Abhishek Sadhu,Junichi Sadoshima,Nathaniel Safren,Paul Saftig,Antonia P Sagona,Gaurav Sahay,Amirhossein Sahebkar,Mustafa Sahin,Ozgur Sahin,Sumit Sahni,Nayuta Saito,Shigeru Saito,Tsunenori Saito,Ryohei Sakai,Yasuyoshi Sakai,Jun-Ichi Sakamaki,Kalle Saksela,Gloria Salazar,Anna Salazar-Degracia,Ghasem H Salekdeh,Ashok K Saluja,Bel\u00e9m Sampaio-Marques,Maria Cecilia Sanchez,Jose A Sanchez-Alcazar,Victoria Sanchez-Vera,Vanessa Sancho-Shimizu,J Thomas Sanderson,Marco Sandri,Stefano Santaguida,Laura Santambrogio,Magda M Santana,Giorgio Santoni,Alberto Sanz,Pascual Sanz,Shweta Saran,Marco Sardiello,Timothy J Sargeant,Apurva Sarin,Chinmoy Sarkar,Sovan Sarkar,Maria-Rosa Sarrias,Surajit Sarkar,Dipanka Tanu Sarmah,Jaakko Sarparanta,Aishwarya Sathyanarayan,Ranganayaki Sathyanarayanan,K Matthew Scaglione,Francesca Scatozza,Liliana Schaefer,Zachary T Schafer,Ulrich E Schaible,Anthony H V Schapira,Michael Scharl,Hermann M Schatzl,Catherine H Schein,Wiep Scheper,David Scheuring,Maria Vittoria Schiaffino,Monica Schiappacassi,Rainer Schindl,Uwe Schlattner,Oliver Schmidt,Roland Schmitt,Stephen D Schmidt,Ingo Schmitz,Eran Schmukler,Anja Schneider,Bianca E Schneider,Romana Schober,Alejandra C Schoijet,Micah B Schott,Michael Schramm,Bernd Schr\u00f6der,Kai Schuh,Christoph Sch\u00fcller,Ryan J Schulze,Lea Sch\u00fcrmanns,Jens C Schwamborn,Melanie Schwarten,Filippo Scialo,Sebastiano Sciarretta,Melanie J Scott,Kathleen W Scotto,A Ivana Scovassi,Andrea Scrima,Aurora Scrivo,David Sebastian,Salwa Sebti,Simon Sedej,Laura Segatori,Nava Segev,Per O Seglen,Iban Seiliez,Ekihiro Seki,Scott B Selleck,Frank W Sellke,Joshua T Selsby,Michael Sendtner,Serif Senturk,Elena Seranova,Consolato Sergi,Ruth Serra-Moreno,Hiromi Sesaki,Carmine Settembre,Subba Rao Gangi Setty,Gianluca Sgarbi,Ou Sha,John J Shacka,Javeed A Shah,Dantong Shang,Changshun Shao,Feng Shao,Soroush Sharbati,Lisa M Sharkey,Dipali Sharma,Gaurav Sharma,Kulbhushan Sharma,Pawan Sharma,Surendra Sharma,Han-Ming Shen,Hongtao Shen,Jiangang Shen,Ming Shen,Weili Shen,Zheni Shen,Rui Sheng,Zhi Sheng,Zu-Hang Sheng,Jianjian Shi,Xiaobing Shi,Ying-Hong Shi,Kahori Shiba-Fukushima,Jeng-Jer Shieh,Yohta Shimada,Shigeomi Shimizu,Makoto Shimozawa,Takahiro Shintani,Christopher J Shoemaker,Shahla Shojaei,Ikuo Shoji,Bhupendra V Shravage,Viji Shridhar,Chih-Wen Shu,Hong-Bing Shu,Ke Shui,Arvind K Shukla,Timothy E Shutt,Valentina Sica,Aleem Siddiqui,Amanda Sierra,Virginia Sierra-Torre,Santiago Signorelli,Payel Sil,Bruno J de Andrade Silva,Johnatas D Silva,Eduardo Silva-Pavez,Sandrine Silvente-Poirot,Rachel E Simmonds,Anna Katharina Simon,Hans-Uwe Simon,Matias Simons,Anurag Singh,Lalit P Singh,Rajat Singh,Shivendra V Singh,Shrawan K Singh,Sudha B Singh,Sunaina Singh,Surinder Pal Singh,Debasish Sinha,Rohit Anthony Sinha,Sangita Sinha,Agnieszka Sirko,Kapil Sirohi,Efthimios L Sivridis,Panagiotis Skendros,Aleksandra Skirycz,Iva Slaninov\u00e1,Soraya S Smaili,Andrei Smertenko,Matthew D Smith,Stefaan J Soenen,Eun Jung Sohn,Sophia P M Sok,Giancarlo Solaini,Thierry Soldati,Scott A Soleimanpour,Rosa M Soler,Alexei Solovchenko,Jason A Somarelli,Avinash Sonawane,Fuyong Song,Hyun Kyu Song,Ju-Xian Song,Kunhua Song,Zhiyin Song,Leandro R Soria,Maurizio Sorice,Alexander A Soukas,Sandra-Fausia Soukup,Diana Sousa,Nadia Sousa,Paul A Spagnuolo,Stephen A Spector,M M Srinivas Bharath,Daret St Clair,Venturina Stagni,Leopoldo Staiano,Clint A Stalnecker,Metodi V Stankov,Peter B Stathopulos,Katja Stefan,Sven Marcel Stefan,Leonidas Stefanis,Joan S Steffan,Alexander Steinkasserer,Harald Stenmark,Jared Sterneckert,Craig Stevens,Veronika Stoka,Stephan Storch,Bj\u00f6rn Stork,Flavie Strappazzon,Anne Marie Strohecker,Dwayne G Stupack,Huanxing Su,Ling-Yan Su,Longxiang Su,Ana M Suarez-Fontes,Carlos S Subauste,Selvakumar Subbian,Paula V Subirada,Ganapasam Sudhandiran,Carolyn M Sue,Xinbing Sui,Corey Summers,Guangchao Sun,Jun Sun,Kang Sun,Meng-Xiang Sun,Qiming Sun,Yi Sun,Zhongjie Sun,Karen K S Sunahara,Eva Sundberg,Katalin Susztak,Peter Sutovsky,Hidekazu Suzuki,Gary Sweeney,J David Symons,Stephen Cho Wing Sze,Nathaniel J Szewczyk,Anna Tab\u0119cka-\u0141onczynska,Claudio Tabolacci,Frank Tacke,Heinrich Taegtmeyer,Marco Tafani,Mitsuo Tagaya,Haoran Tai,Stephen W G Tait,Yoshinori Takahashi,Szabolcs Takats,Priti Talwar,Chit Tam,Shing Yau Tam,Davide Tampellini,Atsushi Tamura,Chong Teik Tan,Eng-King Tan,Ya-Qin Tan,Masaki Tanaka,Motomasa Tanaka,Daolin Tang,Jingfeng Tang,Tie-Shan Tang,Isei Tanida,Zhipeng Tao,Mohammed Taouis,Lars Tatenhorst,Nektarios Tavernarakis,Allen Taylor,Gregory A Taylor,Joan M Taylor,Elena Tchetina,Andrew R Tee,Irmgard Tegeder,David Teis,Natercia Teixeira,Fatima Teixeira-Clerc,Kumsal A Tekirdag,Tewin Tencomnao,Sandra Tenreiro,Alexei V Tepikin,Pilar S Testillano,Gianluca Tettamanti,Pierre-Louis Tharaux,Kathrin Thedieck,Arvind A Thekkinghat,Stefano Thellung,Josephine W Thinwa,V P Thirumalaikumar,Sufi Mary Thomas,Paul G Thomes,Andrew Thorburn,Lipi Thukral,Thomas Thum,Michael Thumm,Ling Tian,Ales Tichy,Andreas Till,Vincent Timmerman,Vladimir I Titorenko,Sokol V Todi,Krassimira Todorova,Janne M Toivonen,Luana Tomaipitinca,Dhanendra Tomar,Cristina Tomas-Zapico,Sergej Tomi\u0107,Benjamin Chun-Kit Tong,Chao Tong,Xin Tong,Sharon A Tooze,Maria L Torgersen,Satoru Torii,Liliana Torres-L\u00f3pez,Alicia Torriglia,Christina G Towers,Roberto Towns,Shinya Toyokuni,Vladimir Trajkovic,Donatella Tramontano,Quynh-Giao Tran,Leonardo H Travassos,Charles B Trelford,Shirley Tremel,Ioannis P Trougakos,Betty P Tsao,Mario P Tschan,Hung-Fat Tse,Tak Fu Tse,Hitoshi Tsugawa,Andrey S Tsvetkov,David A Tumbarello,Yasin Tumtas,Mar\u00eda J Tu\u00f1\u00f3n,Sandra Turcotte,Boris Turk,Vito Turk,Bradley J Turner,Richard I Tuxworth,Jessica K Tyler,Elena V Tyutereva,Yasuo Uchiyama,Aslihan Ugun-Klusek,Holm H Uhlig,Marzena U\u0142amek-Kozio\u0142,Ilya V Ulasov,Midori Umekawa,Christian Ungermann,Rei Unno,Sylvie Urbe,Elisabet Uribe-Carretero,Suayib \u00dcst\u00fcn,Vladimir N Uversky,Thomas Vaccari,Maria I Vaccaro,Bj\u00f6rn F Vahsen,Helin Vakifahmetoglu-Norberg,Rut Valdor,Maria J Valente,Ayel\u00e9n Valko,Richard B Vallee,Angela M Valverde,Greet Van den Berghe,Stijn van der Veen,Luc Van Kaer,Jorg van Loosdregt,Sjoerd J L van Wijk,Wim Vandenberghe,Ilse Vanhorebeek,Marcos A Vannier-Santos,Nicola Vannini,M Cristina Vanrell,Chiara Vantaggiato,Gabriele Varano,Isabel Varela-Nieto,M\u00e1t\u00e9 Varga,M Helena Vasconcelos,Somya Vats,Demetrios G Vavvas,Ignacio Vega-Naredo,Silvia Vega-Rubin-de-Celis,Guillermo Velasco,Ariadna P Vel\u00e1zquez,Tibor Vellai,Edo Vellenga,Francesca Velotti,Mireille Verdier,Panayotis Verginis,Isabelle Vergne,Paul Verkade,Manish Verma,Patrik Verstreken,Tim Vervliet,J\u00f6rg Vervoorts,Alexandre T Vessoni,Victor M Victor,Michel Vidal,Chiara Vidoni,Otilia V Vieira,Richard D Vierstra,Sonia Vigan\u00f3,Helena Vihinen,Vinoy Vijayan,Miquel Vila,Mar\u00e7al Vilar,Jos\u00e9 M Villalba,Antonio Villalobo,Beatriz Villarejo-Zori,Francesc Villarroya,Joan Villarroya,Olivier Vincent,Cecile Vindis,Christophe Viret,Maria Teresa Viscomi,Dora Visnjic,Ilio Vitale,David J Vocadlo,Olga V Voitsekhovskaja,Cinzia Volont\u00e9,Mattia Volta,Marta Vomero,Clarissa Von Haefen,Marc A Vooijs,Wolfgang Voos,Ljubica Vucicevic,Richard Wade-Martins,Satoshi Waguri,Kenrick A Waite,Shuji Wakatsuki,David W Walker,Mark J Walker,Simon A Walker,Jochen Walter,Francisco G Wandosell,Bo Wang,Chao-Yung Wang,Chen Wang,Chenran Wang,Chenwei Wang,Cun-Yu Wang,Dong Wang,Fangyang Wang,Feng Wang,Fengming Wang,Guansong Wang,Han Wang,Hao Wang,Hexiang Wang,Hong-Gang Wang,Jianrong Wang,Jigang Wang,Jiou Wang,Jundong Wang,Kui Wang,Lianrong Wang,Liming Wang,Maggie Haitian Wang,Meiqing Wang,Nanbu Wang,Pengwei Wang,Peipei Wang,Ping Wang,Ping Wang,Qing Jun Wang,Qing Wang,Qing Kenneth Wang,Qiong A Wang,Wen-Tao Wang,Wuyang Wang,Xinnan Wang,Xuejun Wang,Yan Wang,Yanchang Wang,Yanzhuang Wang,Yen-Yun Wang,Yihua Wang,Yipeng Wang,Yu Wang,Yuqi Wang,Zhe Wang,Zhenyu Wang,Zhouguang Wang,Gary Warnes,Verena Warnsmann,Hirotaka Watada,Eizo Watanabe,Maxinne Watchon,Anna Wawrzy\u0144ska,Timothy E Weaver,Grzegorz Wegrzyn,Ann M Wehman,Huafeng Wei,Lei Wei,Taotao Wei,Yongjie Wei,Oliver H Weiergr\u00e4ber,Conrad C Weihl,G\u00fcnther Weindl,Ralf Weiskirchen,Alan Wells,Runxia H Wen,Xin Wen,Antonia Werner,Beatrice Weykopf,Sally P Wheatley,J Lindsay Whitton,Alexander J Whitworth,Katarzyna Wiktorska,Manon E Wildenberg,Tom Wileman,Simon Wilkinson,Dieter Willbold,Brett Williams,Robin S B Williams,Roger L Williams,Peter R Williamson,Richard A Wilson,Beate Winner,Nathaniel J Winsor,Steven S Witkin,Harald Wodrich,Ute Woehlbier,Thomas Wollert,Esther Wong,Jack Ho Wong,Richard W Wong,Vincent Kam Wai Wong,W Wei-Lynn Wong,An-Guo Wu,Chengbiao Wu,Jian Wu,Junfang Wu,Kenneth K Wu,Min Wu,Shan-Ying Wu,Shengzhou Wu,Shu-Yan Wu,Shufang Wu,William K K Wu,Xiaohong Wu,Xiaoqing Wu,Yao-Wen Wu,Yihua Wu,Ramnik J Xavier,Hongguang Xia,Lixin Xia,Zhengyuan Xia,Ge Xiang,Jin Xiang,Mingliang Xiang,Wei Xiang,Bin Xiao,Guozhi Xiao,Hengyi Xiao,Hong-Tao Xiao,Jian Xiao,Lan Xiao,Shi Xiao,Yin Xiao,Baoming Xie,Chuan-Ming Xie,Min Xie,Yuxiang Xie,Zhiping Xie,Zhonglin Xie,Maria Xilouri,Congfeng Xu,En Xu,Haoxing Xu,Jing Xu,JinRong Xu,Liang Xu,Wen Wen Xu,Xiulong Xu,Yu Xue,Sokhna M S Yakhine-Diop,Masamitsu Yamaguchi,Osamu Yamaguchi,Ai Yamamoto,Shunhei Yamashina,Shengmin Yan,Shian-Jang Yan,Zhen Yan,Yasuo Yanagi,Chuanbin Yang,Dun-Sheng Yang,Huan Yang,Huang-Tian Yang,Hui Yang,Jin-Ming Yang,Jing Yang,Jingyu Yang,Ling Yang,Liu Yang,Ming Yang,Pei-Ming Yang,Qian Yang,Seungwon Yang,Shu Yang,Shun-Fa Yang,Wannian Yang,Wei Yuan Yang,Xiaoyong Yang,Xuesong Yang,Yi Yang,Ying Yang,Honghong Yao,Shenggen Yao,Xiaoqiang Yao,Yong-Gang Yao,Yong-Ming Yao,Takahiro Yasui,Meysam Yazdankhah,Paul M Yen,Cong Yi,Xiao-Ming Yin,Yanhai Yin,Zhangyuan Yin,Ziyi Yin,Meidan Ying,Zheng Ying,Calvin K Yip,Stephanie Pei Tung Yiu,Young H Yoo,Kiyotsugu Yoshida,Saori R Yoshii,Tamotsu Yoshimori,Bahman Yousefi,Boxuan Yu,Haiyang Yu,Jun Yu,Jun Yu,Li Yu,Ming-Lung Yu,Seong-Woon Yu,Victor C Yu,W Haung Yu,Zhengping Yu,Zhou Yu,Junying Yuan,Ling-Qing Yuan,Shilin Yuan,Shyng-Shiou F Yuan,Yanggang Yuan,Zengqiang Yuan,Jianbo Yue,Zhenyu Yue,Jeanho Yun,Raymond L Yung,David N Zacks,Gabriele Zaffagnini,Vanessa O Zambelli,Isabella Zanella,Qun S Zang,Sara Zanivan,Silvia Zappavigna,Pilar Zaragoza,Konstantinos S Zarbalis,Amir Zarebkohan,Amira Zarrouk,Scott O Zeitlin,Jialiu Zeng,Ju-Deng Zeng,Eva \u017derovnik,Lixuan Zhan,Bin Zhang,Donna D Zhang,Hanlin Zhang,Hong Zhang,Hong Zhang,Honghe Zhang,Huafeng Zhang,Huaye Zhang,Hui Zhang,Hui-Ling Zhang,Jianbin Zhang,Jianhua Zhang,Jing-Pu Zhang,Kalin Y B Zhang,Leshuai W Zhang,Lin Zhang,Lisheng Zhang,Lu Zhang,Luoying Zhang,Menghuan Zhang,Peng Zhang,Sheng Zhang,Wei Zhang,Xiangnan Zhang,Xiao-Wei Zhang,Xiaolei Zhang,Xiaoyan Zhang,Xin Zhang,Xinxin Zhang,Xu Dong Zhang,Yang Zhang,Yanjin Zhang,Yi Zhang,Ying-Dong Zhang,Yingmei Zhang,Yuan-Yuan Zhang,Yuchen Zhang,Zhe Zhang,Zhengguang Zhang,Zhibing Zhang,Zhihai Zhang,Zhiyong Zhang,Zili Zhang,Haobin Zhao,Lei Zhao,Shuang Zhao,Tongbiao Zhao,Xiao-Fan Zhao,Ying Zhao,Yongchao Zhao,Yongliang Zhao,Yuting Zhao,Guoping Zheng,Kai Zheng,Ling Zheng,Shizhong Zheng,Xi-Long Zheng,Yi Zheng,Zu-Guo Zheng,Boris Zhivotovsky,Qing Zhong,Ao Zhou,Ben Zhou,Cefan Zhou,Gang Zhou,Hao Zhou,Hong Zhou,Hongbo Zhou,Jie Zhou,Jing Zhou,Jing Zhou,Jiyong Zhou,Kailiang Zhou,Rongjia Zhou,Xu-Jie Zhou,Yanshuang Zhou,Yinghong Zhou,Yubin Zhou,Zheng-Yu Zhou,Zhou Zhou,Binglin Zhu,Changlian Zhu,Guo-Qing Zhu,Haining Zhu,Hongxin Zhu,Hua Zhu,Wei-Guo Zhu,Yanping Zhu,Yushan Zhu,Haixia Zhuang,Xiaohong Zhuang,Katarzyna Zientara-Rytter,Christine M Zimmermann,Elena Ziviani,Teresa Zoladek,Wei-Xing Zong,Dmitry B Zorov,Antonio Zorzano,Weiping Zou,Zhen Zou,Zhengzhi Zou,Steven Zuryn,Werner Zwerschke,Beate Brand-Saberi,X Charlie Dong,Chandra Shekar Kenchappa,Zuguo Li,Yong Lin,Shigeru Oshima,Yueguang Rong,Judith C Sluimer,Christina L Stallings,Chun-Kit Tong", - "abstract": "In 2008, we published the first set of guidelines for standardizing research in autophagy. Since then, this topic has received increasing attention, and many scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Thus, it is important to formulate on a regular basis updated guidelines for monitoring autophagy in different organisms. Despite numerous reviews, there continues to be confusion regarding acceptable methods to evaluate autophagy, especially in multicellular eukaryotes. Here, we present a set of guidelines for investigators to select and interpret methods to examine autophagy and related processes, and for reviewers to provide realistic and reasonable critiques of reports that are focused on these processes. These guidelines are not meant to be a dogmatic set of rules, because the appropriateness of any assay largely depends on the question being asked and the system being used. Moreover, no individual assay is perfect for every situation, calling for the use of multiple techniques to properly monitor autophagy in each experimental setting. Finally, several core components of the autophagy machinery have been implicated in distinct autophagic processes (canonical and noncanonical autophagy), implying that genetic approaches to block autophagy should rely on targeting two or more autophagy-related genes that ideally participate in distinct steps of the pathway. Along similar lines, because multiple proteins involved in autophagy also regulate other cellular pathways including apoptosis, not all of them can be used as a specific marker for <i>bona fide</i> autophagic responses. Here, we critically discuss current methods of assessing autophagy and the information they can, or cannot, provide. Our ultimate goal is to encourage intellectual and technical innovation in the field.", - "journal_title": "Autophagy", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/33634751/" - } - ], - "fcdb7fa8-6ac7-40bb-8272-0fc7dd599bf3": [ - { - "pub_id": "9241260", - "title": "Tumour-suppressor genes: evolving definitions in the genomic age.", - "authors": "D Haber,E Harlow", - "abstract": "", - "journal_title": "Nature genetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/9241260/" - } - ], - "8d9cfa59-b9e7-43d9-99ed-38df1827706f": [ - { - "pub_id": "19812404", - "title": "DNA damage, aging, and cancer.", - "authors": "Jan H J Hoeijmakers", - "abstract": "", - "journal_title": "The New England journal of medicine", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/19812404/" - } - ], - "d3b803ac-491d-4011-bad5-8dfba254d58b": [ - { - "pub_id": "18311139", - "title": "DNA deletions and clonal mutations drive premature aging in mitochondrial mutator mice.", - "authors": "Marc Vermulst,Jonathan Wanagat,Gregory C Kujoth,Jason H Bielas,Peter S Rabinovitch,Tomas A Prolla,Lawrence A Loeb", - "abstract": "Mitochondrial DNA (mtDNA) mutations are thought to have a causal role in many age-related pathologies. Here we identify mtDNA deletions as a driving force behind the premature aging phenotype of mitochondrial mutator mice, and provide evidence for a homology-directed DNA repair mechanism in mitochondria that is directly linked to the formation of mtDNA deletions. In addition, our results demonstrate that the rate at which mtDNA mutations reach phenotypic expression differs markedly among tissues, which may be an important factor in determining the tolerance of a tissue to random mitochondrial mutagenesis.", - "journal_title": "Nature genetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/18311139/" - } - ], - "f4e2fa75-559b-4fa9-b722-bdac03f7715a": [ - { - "pub_id": "20546537", - "title": "Genome-wide association studies of pigmentation and skin cancer: a review and meta-analysis.", - "authors": "Meg R Gerstenblith,Jianxin Shi,Maria Teresa Landi", - "abstract": "Recent genome-wide association studies (GWAS) identified genetic loci associated with pigmentation, nevi, and skin cancer. We performed a review and meta-analysis of GWAS results, grouping them into four categories: (i) loci associated with pigmentation (hair, eye, and/or skin color), cutaneous UV-response (sun sensitivity and/or freckling), and skin cancer; (ii) loci associated with nevi and melanoma; (iii) loci associated with pigmentation and/or cutaneous UV-response but not skin cancer; and (iv) loci associated distinctly with skin cancer, mostly basal cell carcinoma, but not pigmentation or cutaneous UV-response. These findings suggest at least two pathways for melanoma development (via pigmentation and via nevi), and two pathways for basal cell carcinoma development (via pigmentation and independent of pigmentation). However, further work is necessary to separate the association with skin cancer from the association with pigmentation. As with any GWAS, the identified loci may not include the causal variants and may need confirmation by direct genome sequencing.", - "journal_title": "Pigment cell & melanoma research", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/20546537/" - } - ], - "07bc540a-58b7-4907-8dbe-32d98618c5df": [ - { - "pub_id": "19668339", - "title": "Hippocampal atrophy as a quantitative trait in a genome-wide association study identifying novel susceptibility genes for Alzheimer's disease.", - "authors": "Steven G Potkin,Guia Guffanti,Anita Lakatos,Jessica A Turner,Frithjof Kruggel,James H Fallon,Andrew J Saykin,Alessandro Orro,Sara Lupoli,Erika Salvi,Michael Weiner,Fabio Macciardi, ", - "abstract": "With the exception of APOE epsilon4 allele, the common genetic risk factors for sporadic Alzheimer's Disease (AD) are unknown. We completed a genome-wide association study on 381 participants in the ADNI (Alzheimer's Disease Neuroimaging Initiative) study. Samples were genotyped using the Illumina Human610-Quad BeadChip. 516,645 unique Single Nucleotide Polymorphisms (SNPs) were included in the analysis following quality control measures. The genotype data and raw genetic data are freely available for download (LONI, http://www.loni.ucla.edu/ADNI/Data/). Two analyses were completed: a standard case-control analysis, and a novel approach using hippocampal atrophy measured on MRI as an objectively defined, quantitative phenotype. A General Linear Model was applied to identify SNPs for which there was an interaction between the genotype and diagnosis on the quantitative trait. The case-control analysis identified APOE and a new risk gene, TOMM40 (translocase of outer mitochondrial membrane 40), at a genome-wide significance level of < or =10(-6) (10(-11) for a haplotype). TOMM40 risk alleles were approximately twice as frequent in AD subjects as controls. The quantitative trait analysis identified 21 genes or chromosomal areas with at least one SNP with a p-value < or =10(-6), which can be considered potential \"new\" candidate loci to explore in the etiology of sporadic AD. These candidates included EFNA5, CAND1, MAGI2, ARSB, and PRUNE2, genes involved in the regulation of protein degradation, apoptosis, neuronal loss and neurodevelopment. Thus, we identified common genetic variants associated with the increased risk of developing AD in the ADNI cohort, and present publicly available genome-wide data. Supportive evidence based on case-control studies and biological plausibility by gene annotation is provided. Currently no available sample with both imaging and genetic data is available for replication. Using hippocampal atrophy as a quantitative phenotype in a genome-wide scan, we have identified candidate risk genes for sporadic Alzheimer's disease that merit further investigation.", - "journal_title": "PloS one", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/19668339/" - } - ], - "c2df1cd8-c962-4fac-88c9-cad52f7753b0": [ - { - "pub_id": "17326724", - "title": "Impaired genome maintenance suppresses the growth hormone--insulin-like growth factor 1 axis in mice with Cockayne syndrome.", - "authors": "Ingrid van der Pluijm,George A Garinis,Renata M C Brandt,Theo G M F Gorgels,Susan W Wijnhoven,Karin E M Diderich,Jan de Wit,James R Mitchell,Conny van Oostrom,Rudolf Beems,Laura J Niedernhofer,Susana Velasco,Errol C Friedberg,Kiyoji Tanaka,Harry van Steeg,Jan H J Hoeijmakers,Gijsbertus T J van der Horst", - "abstract": "Cockayne syndrome (CS) is a photosensitive, DNA repair disorder associated with progeria that is caused by a defect in the transcription-coupled repair subpathway of nucleotide excision repair (NER). Here, complete inactivation of NER in Csb(m/m)/Xpa(-/-) mutants causes a phenotype that reliably mimics the human progeroid CS syndrome. Newborn Csb(m/m)/Xpa(-/-) mice display attenuated growth, progressive neurological dysfunction, retinal degeneration, cachexia, kyphosis, and die before weaning. Mouse liver transcriptome analysis and several physiological endpoints revealed systemic suppression of the growth hormone/insulin-like growth factor 1 (GH/IGF1) somatotroph axis and oxidative metabolism, increased antioxidant responses, and hypoglycemia together with hepatic glycogen and fat accumulation. Broad genome-wide parallels between Csb(m/m)/Xpa(-/-) and naturally aged mouse liver transcriptomes suggested that these changes are intrinsic to natural ageing and the DNA repair-deficient mice. Importantly, wild-type mice exposed to a low dose of chronic genotoxic stress recapitulated this response, thereby pointing to a novel link between genome instability and the age-related decline of the somatotroph axis.", - "journal_title": "PLoS biology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/17326724/" - } - ], - "b639b9e7-02e5-4c54-81f6-42e80c40ea6c": [ - { - "pub_id": "16386658", - "title": "Genomics and cardiac arrhythmias.", - "authors": "Robert Roberts", - "abstract": "Sudden cardiac death in patients younger than 35 years of age is primarily due to genetic causes. Familial hypertrophic cardiomyopathy accounting for 30% to 40% is associated with structural heart disease while the Brugada syndrome and the long QT syndrome (LQTS) are associated with normal cardiac function. This is a review of the genetics of supraventricular and ventricular arrhythmias. Atrial fibrillation is mapped to nine chromosomal loci and four genes are identified. AMP-activated protein kinase is one gene responsible for Wolff-Parkinson-White syndrome. The LQTS and the Brugada syndromes are due to defects primarily in cardiac sodium and potassium ion channels. The role of single nucleotide polymorphisms in predisposing to arrhythmias in acquired disorders such as hypertrophy is discussed.", - "journal_title": "Journal of the American College of Cardiology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/16386658/" - } - ], - "aa902d92-468c-4007-ad31-45aaa77d5de0": [ - { - "pub_id": "12777046", - "title": "The age of the Arabidopsis thaliana genome duplication.", - "authors": "Maria D Ermolaeva,Martin Wu,Jonathan A Eisen,Steven L Salzberg", - "abstract": "We estimate the timing of the Arabidopsis thaliana whole-genome duplication by means of phylogenetic and statistical analysis, and propose two possible scenarios for the duplication. The first one, based on the assumption that the duplicated segments diverged from an autotetraploid form, places the duplication at about 38 million years ago, after the Arabidopsis lineage diverged from that of soybean (Glycine max) and before it diverged from its sister genus, Brassica. The second scenario assumes that the ancestor was allotetraploid, and suggests that the duplication is younger than 38 million years and may have contributed to the Arabidopsis-Brassica divergence. In each case, our estimate places the age of the genome duplication as significantly younger than previously reported.", - "journal_title": "Plant molecular biology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/12777046/" - } - ], - "c64e358e-f7a8-4b15-9852-bf3a644178c2": [ - { - "pub_id": "17933510", - "title": "Crop evolution: from genetics to genomics.", - "authors": "John M Burke,Jutta C Burger,Mark A Chapman", - "abstract": "The advent of the genomics age has greatly facilitated the study of crop evolution. While full-scale genome sequencing projects are underway for just a handful of crop plants, recent years have witnessed a tremendous increase in the availability of DNA sequence data for virtually all major crops. Such resources have bolstered 'traditional' genetic approaches such as QTL mapping and candidate gene-based association studies. They have also allowed us to undertake genome-wide analyses in which we simultaneously consider the importance of a large and essentially random collection of genes. These sorts of analyses promise a more or less unbiased view of the genetic basis of crop evolution and will probably result in the identification of agronomically important genes that would have otherwise been overlooked.", - "journal_title": "Current opinion in genetics & development", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/17933510/" - } - ], - "68a39578-ff44-4b37-9168-bf079c3808b0": [ - { - "pub_id": "15608272", - "title": "MITOMAP: a human mitochondrial genome database--2004 update.", - "authors": "Marty C Brandon,Marie T Lott,Kevin Cuong Nguyen,Syawal Spolim,Shamkant B Navathe,Pierre Baldi,Douglas C Wallace", - "abstract": "MITOMAP (http://www.MITOMAP.org), a database for the human mitochondrial genome, has grown rapidly in data content over the past several years as interest in the role of mitochondrial DNA (mtDNA) variation in human origins, forensics, degenerative diseases, cancer and aging has increased dramatically. To accommodate this information explosion, MITOMAP has implemented a new relational database and an improved search engine, and all programs have been rewritten. System administrative changes have been made to improve security and efficiency, and to make MITOMAP compatible with a new automatic mtDNA sequence analyzer known as Mitomaster.", - "journal_title": "Nucleic acids research", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/15608272/" - } - ], - "bd1e682b-b5c0-43ac-9e5a-d922560f9ace": [ - { - "pub_id": "15247023", - "title": "Genomic instability, aging, and cellular senescence.", - "authors": "Rita A Busuttil,Martijn Doll\u00e9,Judith Campisi,Jan Vijga", - "abstract": "Aging can be defined in practical terms as a series of time-related processes that ultimately bring life to a close. Genomic instability has been implicated as a major causal factor in aging. Here, we describe the use of a transgenic mouse model, harboring lacZ reporter genes as part of a plasmid construct integrated at one or more chromosomal locations, to study genomic instability during aging of different mouse organs and tissues as well as in mouse embryonic fibroblasts during primary culture.", - "journal_title": "Annals of the New York Academy of Sciences", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/15247023/" - } - ], - "9f2895a4-086c-4eed-8558-9e047bde41a9": [ - { - "pub_id": "32260373", - "title": "Inflammation and Premature Ageing in Chronic Kidney Disease.", - "authors": "Thomas Ebert,Sven-Christian Pawelzik,Anna Witasp,Samsul Arefin,Sam Hobson,Karolina Kublickiene,Paul G Shiels,Magnus B\u00e4ck,Peter Stenvinkel", - "abstract": "Persistent low-grade inflammation and premature ageing are hallmarks of the uremic phenotype and contribute to impaired health status, reduced quality of life, and premature mortality in chronic kidney disease (CKD). Because there is a huge global burden of disease due to CKD, treatment strategies targeting inflammation and premature ageing in CKD are of particular interest. Several distinct features of the uremic phenotype may represent potential treatment options to attenuate the risk of progression and poor outcome in CKD. The nuclear factor erythroid 2-related factor 2 (NRF2)-kelch-like erythroid cell-derived protein with CNC homology [ECH]-associated protein 1 (KEAP1) signaling pathway, the endocrine phosphate-fibroblast growth factor-23-klotho axis, increased cellular senescence, and impaired mitochondrial biogenesis are currently the most promising candidates, and different pharmaceutical compounds are already under evaluation. If studies in humans show beneficial effects, carefully phenotyped patients with CKD can benefit from them.", - "journal_title": "Toxins", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/32260373/" - } - ], - "113cb521-b79d-4b44-8250-dc1013ea2cb3": [ - { - "pub_id": "17988385", - "title": "Gene expression atlas of the mouse central nervous system: impact and interactions of age, energy intake and gender.", - "authors": "Xiangru Xu,Ming Zhan,Wenzhen Duan,Vinayakumar Prabhu,Randall Brenneman,William Wood,Jeff Firman,Huai Li,Peisu Zhang,Carol Ibe,Alan B Zonderman,Dan L Longo,Suresh Poosala,Kevin G Becker,Mark P Mattson", - "abstract": "The structural and functional complexity of the mammalian central nervous system (CNS) is organized and modified by complicated molecular signaling processes that are poorly understood. We measured transcripts of 16,896 genes in 5 CNS regions from cohorts of young, middle-aged and old male and female mice that had been maintained on either a control diet or a low energy diet known to retard aging. Each CNS region (cerebral cortex, hippocampus, striatum, cerebellum and spinal cord) possessed its own unique transcriptome fingerprint that was independent of age, gender and energy intake. Less than 10% of genes were significantly affected by age, diet or gender, with most of these changes occurring between middle and old age. The transcriptome of the spinal cord was the most responsive to age, diet and gender, while the striatal transcriptome was the least responsive. Gender and energy restriction had particularly robust influences on the hippocampal transcriptome of middle-aged mice. Prominent functional groups of age- and energy-sensitive genes were those encoding proteins involved in DNA damage responses (Werner and telomere-associated proteins), mitochondrial and proteasome functions, cell fate determination (Wnt and Notch signaling) and synaptic vesicle trafficking. Mouse CNS transcriptomes responded to age, energy intake and gender in a regionally distinctive manner. The systematic transcriptome dataset also provides a window into mechanisms of age-, diet- and sex-related CNS plasticity and vulnerability.", - "journal_title": "Genome biology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/17988385/" - } - ], - "7a0e513b-c41b-4e8c-8123-9e3e58b6200f": [ - { - "pub_id": "18084025", - "title": "Genome-wide tracking of unmethylated DNA Alu repeats in normal and cancer cells.", - "authors": "Jairo Rodriguez,Laura Vives,Mireia Jord\u00e0,Cristina Morales,Mar Mu\u00f1oz,Elisenda Vendrell,Miguel A Peinado", - "abstract": "Methylation of the cytosine is the most frequent epigenetic modification of DNA in mammalian cells. In humans, most of the methylated cytosines are found in CpG-rich sequences within tandem and interspersed repeats that make up to 45% of the human genome, being Alu repeats the most common family. Demethylation of Alu elements occurs in aging and cancer processes and has been associated with gene reactivation and genomic instability. By targeting the unmethylated SmaI site within the Alu sequence as a surrogate marker, we have quantified and identified unmethylated Alu elements on the genomic scale. Normal colon epithelial cells contain in average 25 486 +/- 10 157 unmethylated Alu's per haploid genome, while in tumor cells this figure is 41 995 +/- 17 187 (P = 0.004). There is an inverse relationship in Alu families with respect to their age and methylation status: the youngest elements exhibit the highest prevalence of the SmaI site (AluY: 42%; AluS: 18%, AluJ: 5%) but the lower rates of unmethylation (AluY: 1.65%; AluS: 3.1%, AluJ: 12%). Data are consistent with a stronger silencing pressure on the youngest repetitive elements, which are closer to genes. Further insights into the functional implications of atypical unmethylation states in Alu elements will surely contribute to decipher genomic organization and gene regulation in complex organisms.", - "journal_title": "Nucleic acids research", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/18084025/" - } - ], - "b7732bf6-6d94-42ba-b4a2-65ea1e438512": [ - { - "pub_id": "15450201", - "title": "The molecular epidemiology of mumps virus.", - "authors": "Kathrin M\u00fchlemann", - "abstract": "The molecular epidemiology of MuV is characterized by the co-existence of 10 (or more) distinct genotypes named A-J based on the nucleotide sequence of the SH gene. MuV show distinct geographic clustering. More than one genotype may circulate simultaneously in a geographic region. Limited data suggest redistribution of genotypes to occur over time. The selective forces remain speculative. Currently used vaccine strains belong to different genotypes. Some MuV genotypes (C, D, H, J) and vaccine strains (Urabe Am9) have been associated with enhanced neurovirulence. Also, reduced cross-neutralization capacity has been observed between genotype A and genotypes C and D. At present vaccine failure cannot be attributed to this phenomenon. Strain redistribution may lead to the emergence of new MuV strains with enhanced neurovirulence or reduced cross-neutralization capacity with current vaccine strains. Close monitoring of the genotype distribution of MuV and genotype-specific population immunity is needed in the vaccine era.", - "journal_title": "Infection, genetics and evolution : journal of molecular epidemiology and evolutionary genetics in infectious diseases", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/15450201/" - } - ], - "45e6e891-e190-42a4-878f-4a5ca3e06ef1": [ - { - "pub_id": "19041753", - "title": "SIRT1 redistribution on chromatin promotes genomic stability but alters gene expression during aging.", - "authors": "Philipp Oberdoerffer,Shaday Michan,Michael McVay,Raul Mostoslavsky,James Vann,Sang-Kyu Park,Andrea Hartlerode,Judith Stegmuller,Angela Hafner,Patrick Loerch,Sarah M Wright,Kevin D Mills,Azad Bonni,Bruce A Yankner,Ralph Scully,Tomas A Prolla,Frederick W Alt,David A Sinclair", - "abstract": "Genomic instability and alterations in gene expression are hallmarks of eukaryotic aging. The yeast histone deacetylase Sir2 silences transcription and stabilizes repetitive DNA, but during aging or in response to a DNA break, the Sir complex relocalizes to sites of genomic instability, resulting in the desilencing of genes that cause sterility, a characteristic of yeast aging. Using embryonic stem cells, we show that mammalian Sir2, SIRT1, represses repetitive DNA and a functionally diverse set of genes across the mouse genome. In response to DNA damage, SIRT1 dissociates from these loci and relocalizes to DNA breaks to promote repair, resulting in transcriptional changes that parallel those in the aging mouse brain. Increased SIRT1 expression promotes survival in a mouse model of genomic instability and suppresses age-dependent transcriptional changes. Thus, DNA damage-induced redistribution of SIRT1 and other chromatin-modifying proteins may be a conserved mechanism of aging in eukaryotes.", - "journal_title": "Cell", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/19041753/" - } - ], - "c27fcebe-d4ff-4a18-8bf8-ad1bfde28485": [ - { - "pub_id": "10552928", - "title": "Rothmund-thomson syndrome responsible gene, RECQL4: genomic structure and products.", - "authors": "S Kitao,N M Lindor,M Shiratori,Y Furuichi,A Shimamoto", - "abstract": "RECQL4 is the fourth gene identified as a member of the human DNA helicase RecQ gene family including the genes for Werner syndrome (WRN) and Bloom syndrome, both of which are characterized by genomic instability. Recently, RECQL4 was identified as the gene responsible for some cases of Rothmund-Thomson syndrome (RTS), a rare autosomal recessive genetic disorder that shows chromosomal instability, premature aging, and a high risk of mesenchymal tumors. In this study, we show the genomic organization of the RECQL4 gene, including the exon-intron boundaries, the transcription initiation sites, and the potential promoter sequences, which facilitates further mutation analysis of the RECQL4 gene and studies to elucidate the pathogenesis behind RTS. The RECQL4 gene is in a small genome of 6.5 kb and consists of 21 exons. In the 5' upstream region, one Sp1 site and several AP 2 sites exist near the capping site, suggesting that the expression of RECQL4 is regulated by a housekeeping-type promoter similar to WRN. By comparative Northern blot analysis, we show that the RECQL4 transcripts are severely down-regulated in the cells from RTS patients, similar to our previous observation for WRN transcripts in cells from Werner patients. Immunocytochemical analysis indicated that the RECQL4 protein expressed in HeLa cells is in the nucleus and appears to be localized mainly in the nucleoplasm similar to WRN helicase.", - "journal_title": "Genomics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/10552928/" - } - ], - "b95accd9-0ce8-464e-9de4-49aea32cf3b7": [ - { - "pub_id": "20466884", - "title": "Genetic evidence for high-altitude adaptation in Tibet.", - "authors": "Tatum S Simonson,Yingzhong Yang,Chad D Huff,Haixia Yun,Ga Qin,David J Witherspoon,Zhenzhong Bai,Felipe R Lorenzo,Jinchuan Xing,Lynn B Jorde,Josef T Prchal,RiLi Ge", - "abstract": "Tibetans have lived at very high altitudes for thousands of years, and they have a distinctive suite of physiological traits that enable them to tolerate environmental hypoxia. These phenotypes are clearly the result of adaptation to this environment, but their genetic basis remains unknown. We report genome-wide scans that reveal positive selection in several regions that contain genes whose products are likely involved in high-altitude adaptation. Positively selected haplotypes of EGLN1 and PPARA were significantly associated with the decreased hemoglobin phenotype that is unique to this highland population. Identification of these genes provides support for previously hypothesized mechanisms of high-altitude adaptation and illuminates the complexity of hypoxia-response pathways in humans.", - "journal_title": "Science (New York, N.Y.)", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/20466884/" - } - ], - "1ccb0d11-1c88-4b08-b40d-4039a954745f": [ - { - "pub_id": "16769434", - "title": "Beyond the evolutionary theory of ageing, from functional genomics to evo-gero.", - "authors": "Linda Partridge,David Gems", - "abstract": "By the mid 1970s, the mechanisms by which ageing can evolve had a secure theoretical basis in population genetics. Here, we discuss how subsequent evolutionary work has focussed on testing and extending this theory, and on attempting to integrate it with other emerging facets of the biology of ageing, such as genetic studies of long-lived mutants and of phenotypic plasticity in ageing, such as in response to nutritional status. We also describe how functional genomic studies are providing new insights into the evolutionary forces shaping genome evolution and lifespan control. Future challenges include understanding the biochemistry of longevity and how its failure generates ageing and associated diseases, and the determination of the genetic basis of lifespan evolution and the great plasticity that it displays.", - "journal_title": "Trends in ecology & evolution", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/16769434/" - } - ], - "bff81d81-874a-4b4f-aef3-40b1dd93a852": [ - { - "pub_id": "14708011", - "title": "Ageing, repetitive genomes and DNA damage.", - "authors": "Michael R Lieber,Zarir E Karanjawala", - "abstract": "The mitochondrial production of reactive oxygen species is inversely proportional to longevity in animals. A key question now is, which molecules, among those that are oxidized, affect the lifespan of the organism most significantly?", - "journal_title": "Nature reviews. Molecular cell biology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/14708011/" - } - ], - "c60bf03f-0735-4575-a02d-886b4e1889e4": [ - { - "pub_id": "29783316", - "title": "Biobank governance in the post-genomic age.", - "authors": "Herbert Gottweis,Georg Lauss", - "abstract": "Biobank governance is about the regulation of the relationship between individual citizens, society and biobanks. Its key agenda is to link society, citizens and biobanks with respect to issues of consent, privacy, ownership, access and benefit sharing. With the transformation of biobank research from local/national activities towards transnational projects and the emergence of post-genomic medical research, biobanks need to establish novel governance structures. We consider governance solutions that focus on 'bioethical-theoretical' arguments to be of only limited value in this context. By contrast, we think the key lies in developing participatory arrangements that are responsive to the views of patients and 'lay people', and also operate on a transnational level. The social-political and communicative competence of biobank infrastructures must be improved, thereby assuring the long-term legitimacy and commitment to these often highly expensive projects from a large variety of different stakeholders over the decades.", - "journal_title": "Personalized medicine", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/29783316/" - } - ], - "7a7d4607-f2a0-4c69-82bf-a016ba250603": [ - { - "pub_id": "11704029", - "title": "Age-related maculopathy: an expanded genome-wide scan with evidence of susceptibility loci within the 1q31 and 17q25 regions.", - "authors": "D E Weeks,Y P Conley,H J Tsai,T S Mah,P J Rosenfeld,T O Paul,A W Eller,L S Morse,J P Dailey,R E Ferrell,M B Gorin", - "abstract": "We seek to identify genetic loci that contribute to age-related maculopathy susceptibility. Families consisting of at least two siblings affected by age-related maculopathy were ascertained using eye care records and fundus photographs. Additional family members were used to increase the power to detect linkage. Microsatellite genotyping was conducted by the National Heart, Lung and Blood Institute Mammalian Genotyping Service and the National Institutes of Health Center for Inherited Disease Research. Linkage analyses were conducted with parametric (autosomal dominant; heterogeneity lod score) and nonparametric methods (S(all) statistic) using three diagnostic models. False-positive rates were determined from simulations using actual pedigrees and genotyping data. Under our least stringent diagnostic model, model C, 860 affected individuals from 391 families (452 sib pairs) were genotyped. Sixty-five percent of the affected individuals had evidence of exudative disease. Four regions, 1q31, 9p13, 10q26, and 17q25, showed multipoint heterogeneity lod scores or S(all) scores of 2.0 or greater (under at least one model). Under our most stringent diagnostic model, model A, the 1q31 heterogeneity lod score was 2.46 between D1S1660 and D1S1647. Under model C, the 17q25 heterogeneity lod score at D17S928 was 3.16. Using a threshold of 1.5, additional loci on chromosomes 2 and 12 were identified. The locus on chromosome 1q31 independently confirms a report by Klein and associates mapping an age-related maculopathy susceptibility gene to this region. Simulations indicate that the 1q31 and 17q25 loci are unlikely to be false positives. There was no evidence that other known macular or retinal dystrophy candidate gene regions are major contributors to the genetics of age-related maculopathy.", - "journal_title": "American journal of ophthalmology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/11704029/" - } - ], - "965d5bf3-c68f-4339-a643-870bb0b273dd": [ - { - "pub_id": "17914905", - "title": "Viral evolution in the genomic age.", - "authors": "Edward C Holmes", - "abstract": "The remarkable increase in the number of viral genome sequences represents both opportunities and challenges for understanding disease ecology and evolution, and must stimulate researchers to address questions that were previously considered out of reach.", - "journal_title": "PLoS biology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/17914905/" - } - ], - "8881b5b0-fd7a-400d-9dd2-d4c3f9b012b4": [ - { - "pub_id": "15729734", - "title": "Genome screen for loci influencing age at onset and rate of decline in late onset Alzheimer's disease.", - "authors": "Peter Holmans,Marian Hamshere,Paul Hollingworth,Frances Rice,Nigel Tunstall,Sue Jones,Pamela Moore,Fabienne Wavrant DeVrieze,Amanda Myers,Richard Crook,Danielle Compton,Helen Marshall,David Meyer,Shantia Shears,Jeremy Booth,Dzanan Ramic,Nigel Williams,Nadine Norton,Richard Abraham,Pat Kehoe,Hywel Williams,Varuni Rudrasingham,Mick O'Donovan,Lesley Jones,John Hardy,Alison Goate,Simon Lovestone,Michael Owen,Julie Williams", - "abstract": "We performed an affected sib-pair (ASP) linkage analysis to test for the effects of age at onset (AAO), rate of decline (ROD), and Apolipoprotein E (APOE) genotype on linkage to late-onset Alzheimer's disease (AD) in a sample comprising 428 sib-pairs. We observed linkage of mean AAO to chromosome 21 in the whole sample (max LOD = 2.57). This came entirely from the NIMH sample (max LOD = 3.62), and was strongest in pairs with high mean AAO (>80). A similar effect was observed on chromosome 2q in the NIMH sample (max LOD = 2.73); this region was not typed in the IADC/UK sample. Suggestive evidence was observed in the combined sample of linkage of AAO difference to chromosome 19q (max LOD = 2.33) in the vicinity of APOE and 12p (max LOD = 2.22), with linkage strongest in sib-pairs with similar AAO. Mean ROD showed suggestive evidence of linkage to chromosome 9q in the whole sample (max LOD = 2.29), with the effect strongest in the NIMH sample (max LOD = 3.58), and in pairs with high mean ROD. Additional suggestive evidence was also observed in the NIMH sample with AAO difference on chromosome 6p (max LOD = 2.44) and 15p (max LOD = 1.87), with linkage strongest in pairs with similar AAO, and in the UK sample with mean ROD on chromosome 1p (max LOD = 2.73, linkage strongest in pairs with high mean ROD). We also observed suggestive evidence of increased identical by descent (IBD) in APOE epsilon4 homozygotes on chromosome 1 (max LOD = 3.08) and chromosome 9 (max LOD = 3.34). The previously reported genome-wide linkage of AD to chromosome 10 was not influenced by any of the covariates studied.", - "journal_title": "American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/15729734/" - } - ], - "a68762fb-d3d0-4589-80a2-24ad1fca73a9": [ - { - "pub_id": "17274801", - "title": "Primary laminopathy fibroblasts display altered genome organization and apoptosis.", - "authors": "Karen J Meaburn,Erik Cabuy,Gisele Bonne,Nicolas Levy,Glenn E Morris,Giuseppe Novelli,Ian R Kill,Joanna M Bridger", - "abstract": "A number of diseases associated with specific tissue degeneration and premature aging have mutations in the nuclear envelope proteins A-type lamins or emerin. Those diseases with A-type lamin mutation are inclusively termed laminopathies. Due to various hypothetical roles of nuclear envelope proteins in genome function we investigated whether alterations to normal genomic behaviour are apparent in cells with mutations in A-type lamins and emerin. Even though the distributions of these proteins in proliferating laminopathy fibroblasts appear normal, there is abnormal nuclear positioning of both chromosome 18 and 13 territories, from the nuclear periphery to the interior. This genomic organization mimics that found in normal nonproliferating quiescent or senescent cells. This finding is supported by distributions of modified pRb in the laminopathy cells. All laminopathy cell lines tested and an X-linked Emery-Dreifuss muscular dystrophy cell line also demonstrate increased incidences of apoptosis. The most extreme cases of apoptosis occur in cells derived from diseases with mutations in the tail region of the LMNA gene, such as Dunningan-type familial partial lipodystrophy and mandibuloacral dysplasia, and this correlates with a significant level of micronucleation in these cells.", - "journal_title": "Aging cell", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/17274801/" - } - ], - "3dfe0ec3-b3a6-4a08-8929-e54cab3ec262": [ - { - "pub_id": "11432815", - "title": "Listeria pathogenesis and molecular virulence determinants.", - "authors": "J A V\u00e1zquez-Boland,M Kuhn,P Berche,T Chakraborty,G Dom\u00ednguez-Bernal,W Goebel,B Gonz\u00e1lez-Zorn,J Wehland,J Kreft", - "abstract": "The gram-positive bacterium Listeria monocytogenes is the causative agent of listeriosis, a highly fatal opportunistic foodborne infection. Pregnant women, neonates, the elderly, and debilitated or immunocompromised patients in general are predominantly affected, although the disease can also develop in normal individuals. Clinical manifestations of invasive listeriosis are usually severe and include abortion, sepsis, and meningoencephalitis. Listeriosis can also manifest as a febrile gastroenteritis syndrome. In addition to humans, L. monocytogenes affects many vertebrate species, including birds. Listeria ivanovii, a second pathogenic species of the genus, is specific for ruminants. Our current view of the pathophysiology of listeriosis derives largely from studies with the mouse infection model. Pathogenic listeriae enter the host primarily through the intestine. The liver is thought to be their first target organ after intestinal translocation. In the liver, listeriae actively multiply until the infection is controlled by a cell-mediated immune response. This initial, subclinical step of listeriosis is thought to be common due to the frequent presence of pathogenic L. monocytogenes in food. In normal individuals, the continual exposure to listerial antigens probably contributes to the maintenance of anti-Listeria memory T cells. However, in debilitated and immunocompromised patients, the unrestricted proliferation of listeriae in the liver may result in prolonged low-level bacteremia, leading to invasion of the preferred secondary target organs (the brain and the gravid uterus) and to overt clinical disease. L. monocytogenes and L. ivanovii are facultative intracellular parasites able to survive in macrophages and to invade a variety of normally nonphagocytic cells, such as epithelial cells, hepatocytes, and endothelial cells. In all these cell types, pathogenic listeriae go through an intracellular life cycle involving early escape from the phagocytic vacuole, rapid intracytoplasmic multiplication, bacterially induced actin-based motility, and direct spread to neighboring cells, in which they reinitiate the cycle. In this way, listeriae disseminate in host tissues sheltered from the humoral arm of the immune system. Over the last 15 years, a number of virulence factors involved in key steps of this intracellular life cycle have been identified. This review describes in detail the molecular determinants of Listeria virulence and their mechanism of action and summarizes the current knowledge on the pathophysiology of listeriosis and the cell biology and host cell responses to Listeria infection. This article provides an updated perspective of the development of our understanding of Listeria pathogenesis from the first molecular genetic analyses of virulence mechanisms reported in 1985 until the start of the genomic era of Listeria research.", - "journal_title": "Clinical microbiology reviews", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/11432815/" - } - ], - "f6823249-1934-4f36-87f0-27a06a42c041": [ - { - "pub_id": "18192065", - "title": "Age to survive: DNA damage and aging.", - "authors": "Bj\u00f6rn Schumacher,George A Garinis,Jan H J Hoeijmakers", - "abstract": "Aging represents the progressive functional decline and increased mortality risk common to nearly all metazoans. Recent findings experimentally link DNA damage and organismal aging: longevity-regulating genetic pathways respond to the accumulation of DNA damage and other stress conditions and conversely influence the rate of damage accumulation and its impact for cancer and aging. This novel insight has emerged from studies on human progeroid diseases and mouse models that have deficient DNA repair pathways. Here we discuss a unified concept of an evolutionarily conserved 'survival' response that shifts the organism's resources from growth to maintenance as an adaptation to stresses, such as starvation and DNA damage. This shift protects the organism from cancer and promotes healthy aging.", - "journal_title": "Trends in genetics : TIG", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/18192065/" - } - ], - "86f3ad99-5b3a-4d70-b1de-a42b97c072fc": [ - { - "pub_id": "20087186", - "title": "Genetics of bronchopulmonary dysplasia in the age of genomics.", - "authors": "Pascal M Lavoie,Marie-Pierre Dub\u00e9", - "abstract": "According to recent evidence, susceptibility to bronchopulmonary dysplasia (BPD) in preterm infants is predominantly inherited. The purpose of this review is to discuss current published genetic association studies in light of the accumulated knowledge in genomics. Major advances in the development of next-generation genotyping and sequencing platforms, statistical methodologies, inventories of functional outcome of some common genetic polymorphisms and large-scale cataloguing of genetic variability among many of the world's ethnic populations have greatly facilitated the study of polygenic conditions. For BPD, genetic-association studies have primarily focused on components of innate (e.g. first-line) immune and antioxidant defences, mechanisms of vascular and lung remodelling, and surfactant proteins. However, studies have been limited in sample size and therefore fraught with a high probability of false-positive and false-negative associations. Nonetheless, candidate gene associations have indicated some novel biological pathways and provide a conceptual framework for the design of larger, collaborative population-based studies. Although studies to date have not been able to identify reproducible genetic risk markers for BPD, they have directed us towards new, promising research avenues.", - "journal_title": "Current opinion in pediatrics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/20087186/" - } - ], - "5d133558-fc58-42c7-8407-b3e734e8db9c": [ - { - "pub_id": "10325435", - "title": "Cell-by-cell scanning of whole mitochondrial genomes in aged human heart reveals a significant fraction of myocytes with clonally expanded deletions.", - "authors": "K Khrapko,N Bodyak,W G Thilly,N J van Orsouw,X Zhang,H A Coller,T T Perls,M Upton,J Vijg,J Y Wei", - "abstract": "Quantitative information on the cell-to-cell distribution of all possible mitochondrial DNA (mtDNA) mutations in young and aged tissues is needed to assess the relevance of these mutations to the aging process. In the present study, we used PCR amplification of full-length mitochondrial genomes from single cells to scan human cardiomyocytes for all possible large deletions in mtDNA. Analysis of more than 350 individual cells that were derived from three middle-aged and four centenarian donors demonstrates that while most of the cells contain no deletions, in certain cardiomyocytes a significant portion of the mtDNA molecules carried one particular deletion. Different affected cells contained different deletions. Although similar numbers of cells were screened for each donor, these deletion-rich cells were found only in the hearts of old donors, where they occurred at a frequency of up to one in seven cells. These initial observations demonstrate the efficiency of the method and indicate that mitochondrial mutations have the potential to play an important role in human myocardial aging.", - "journal_title": "Nucleic acids research", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/10325435/" - } - ], - "dc322053-2672-4c26-b739-5b58c50476ed": [ - { - "pub_id": "15562319", - "title": "A transcriptional profile of aging in the human kidney.", - "authors": "Graham E J Rodwell,Rebecca Sonu,Jacob M Zahn,James Lund,Julie Wilhelmy,Lingli Wang,Wenzhong Xiao,Michael Mindrinos,Emily Crane,Eran Segal,Bryan D Myers,James D Brooks,Ronald W Davis,John Higgins,Art B Owen,Stuart K Kim", - "abstract": "In this study, we found 985 genes that change expression in the cortex and the medulla of the kidney with age. Some of the genes whose transcripts increase in abundance with age are known to be specifically expressed in immune cells, suggesting that immune surveillance or inflammation increases with age. The age-regulated genes show a similar aging profile in the cortex and the medulla, suggesting a common underlying mechanism for aging. Expression profiles of these age-regulated genes mark not only age, but also the relative health and physiology of the kidney in older individuals. Finally, the set of aging-regulated kidney genes suggests specific mechanisms and pathways that may play a role in kidney degeneration with age.", - "journal_title": "PLoS biology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/15562319/" - } - ], - "c115a753-78ae-49b9-aed4-0ef4cea7d47a": [ - { - "pub_id": "18330824", - "title": "Whole-genome microarray and targeted analysis of angiogenesis-regulating gene expression (ENG, FLT1, VEGF, PlGF) in placentas from pre-eclamptic and small-for-gestational-age pregnancies.", - "authors": "Johanne Holm Toft,Ingrid Alsos Lian,Adi Laurentiu Tarca,Offer Erez,Jimmy Espinoza,Irina Poliakova Eide,Line Bj\u00f8rge,Sorin Draghici,Roberto Romero,Rigmor Austgulen", - "abstract": "To compare the placental pathology associated with pre-eclampsia (PE) and/or fetal growth restriction, the transcriptomes of placental tissues from PE and small-for-gestational-age (SGA) pregnancies were explored. In addition, a targeted analysis of angiogenesis-regulating gene expression was performed. Whole-genome microarray analysis was performed on placental tissue from gestational age-matched PE (n = 10), SGA (n = 8) and PE + SGA (n = 10) pregnancies. The expression of genes regulating angiogenesis (endoglin (ENG), fms-related tyrosine kinase 1 (FLT1), vascular endothelial growth factor (VEGF) and placental growth factor (PlGF)) was analyzed by quantitative real time reverse transcriptase polymerase chain reaction (qRT-PCR). Microarray analysis did not reveal any significant differences between groups. However, an increased expression of ENG and FLT1 was detected by qRT-PCR in the PE + SGA group. The placental transcriptome did not differ between groups, although an increased anti-angiogenic gene expression in PE + SGA was observed with qRT-PCR analysis. Based on this, we conclude that although microarray technology may represent a powerful tool in generating new hypothesis in complex fields, it may not be sensitive enough to detect subtle changes in gene expression.", - "journal_title": "The journal of maternal-fetal & neonatal medicine : the official journal of the European Association of Perinatal Medicine, the Federation of Asia and Oceania Perinatal Societies, the International Society of Perinatal Obstetricians", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/18330824/" - } - ], - "070cac79-e1c1-450a-955b-bac2b730b3e5": [ - { - "pub_id": "18755320", - "title": "Genetic and epigenetic contributions to human nutrition and health: managing genome-diet interactions.", - "authors": "Patrick J Stover,Marie A Caudill", - "abstract": "The Institute of Medicine recently convened a workshop to review the state of the various domains of nutritional genomics research and policy and to provide guidance for further development and translation of this knowledge into nutrition practice and policy. Nutritional genomics holds the promise to revolutionize both clinical and public health nutrition practice and facilitate the establishment of (a) genome-informed nutrient and food-based dietary guidelines for disease prevention and healthful aging, (b) individualized medical nutrition therapy for disease management, and (c) better targeted public health nutrition interventions (including micronutrient fortification and supplementation) that maximize benefit and minimize adverse outcomes within genetically diverse human populations. As the field of nutritional genomics matures, which will include filling fundamental gaps in knowledge of nutrient-genome interactions in health and disease and demonstrating the potential benefits of customizing nutrition prescriptions based on genetics, registered dietitians will be faced with the opportunity of making genetically driven dietary recommendations aimed at improving human health.", - "journal_title": "Journal of the American Dietetic Association", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/18755320/" - } - ], - "be8d8300-2a5b-4121-9ff3-31bb52c5603a": [ - { - "pub_id": "17137723", - "title": "Genome dynamics and transcriptional deregulation in aging.", - "authors": "R Busuttil,R Bahar,J Vijg", - "abstract": "Genome instability has been implicated as a major cause of both cancer and aging. Using a lacZ-plasmid transgenic mouse model we have shown that mutations accumulate with age in a tissue-specific manner. Genome rearrangements, including translocations and large deletions, are a major component of the mutation spectrum in some tissues at old age such as heart. Such large mutations were also induced by hydrogen peroxide (H2O2) in lacZ-plasmid mouse embryonic fibroblasts (MEFs) and demonstrated to be replication-independent. This was in contrast to ultraviolet light-induced point mutations, which were much more abundant in proliferating than in quiescent MEFs. To test if large rearrangements could adversely affect patterns of gene expression we PCR-amplified global mRNA content of single MEFs treated with H2O2. Such treatment resulted in a significant increase in cell-to-cell variation in gene expression, which was found to parallel the induction and persistence of genome rearrangement mutations at the lacZ reporter locus. Increased transcriptional noise was also found among single cardiomyocytes from old mice as compared with similar cells from young mice. While these results do not directly indicate a cause and effect relationship between genome rearrangement mutations and transcriptional deregulation, they do underscore the stochastic nature of genotoxic effects on cells and tissues and could provide a mechanism for age-related cellular degeneration in postmitotic tissue, such as heart or brain.", - "journal_title": "Neuroscience", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/17137723/" - } - ], - "4ec6d6c4-9908-4619-91a6-c66d7f1f6a6a": [ - { - "pub_id": "19903761", - "title": "Differential genomic responses in old vs. young humans despite similar levels of modest muscle damage after resistance loading.", - "authors": "Anna E Thalacker-Mercer,Louis J Dell'Italia,Xiangqin Cui,James M Cross,Marcas M Bamman", - "abstract": "Across numerous model systems, aging skeletal muscle demonstrates an impaired regenerative response when exposed to the same stimulus as young muscle. To better understand the impact of aging in a human model, we compared changes to the skeletal muscle transcriptome induced by unaccustomed high-intensity resistance loading (RL) sufficient to cause moderate muscle damage in young (37 yr) vs. older (73 yr) adults. Serum creatine kinase was elevated 46% 24 h after RL in all subjects with no age differences, indicating similar degrees of myofiber membrane wounding by age. Despite this similarity, from genomic microarrays 318 unique transcripts were differentially expressed after RL in old vs. only 87 in young subjects. Follow-up pathways analysis and functional annotation revealed among old subjects upregulation of transcripts related to stress and cellular compromise, inflammation and immune responses, necrosis, and protein degradation and changes in expression (up- and downregulation) of transcripts related to skeletal and muscular development, cell growth and proliferation, protein synthesis, fibrosis and connective tissue function, myoblast-myotube fusion and cell-cell adhesion, and structural integrity. Overall the transcript-level changes indicative of undue inflammatory and stress responses in these older adults were not mirrored in young subjects. Follow-up immunoblotting revealed higher protein expression among old subjects for NF-kappaB, heat shock protein (HSP)70, and IL-6 signaling [total and phosphorylated signal transducer and activator of transcription (STAT)3 at Tyr705]. Together, these novel findings suggest that young and old adults are equally susceptible to RL-mediated damage, yet the muscles of older adults are much more sensitive to this modest degree of damage-launching a robust transcriptome-level response that may begin to reveal key differences in the regenerative capacity of skeletal muscle with advancing age.", - "journal_title": "Physiological genomics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/19903761/" - } - ], - "930832a7-4402-40e0-8df6-420a649e1f57": [ - { - "pub_id": "12783983", - "title": "Gene expression profile of aging in human muscle.", - "authors": "Stephen Welle,Andrew I Brooks,Joseph M Delehanty,Nancy Needler,Charles A Thornton", - "abstract": "Studies of gene expression related to aging of skeletal muscle have included few subjects or a limited number of genes. We conducted the present study to produce more comprehensive gene expression profiles. RNA was extracted from vastus lateralis biopsies obtained from healthy young (21-27 yr old, n = 8) and older men (67-75 yr old, n = 8) and was analyzed with high-density oligonucleotide arrays. Of the approximately 44,000 probe sets on the arrays, approximately 18,000 yielded adequate signals for statistical analysis. There were approximately 700 probe sets for which t-tests or rank sum tests indicated a difference (P <or= 0.01) in mean expression between young and old and for which the estimated false discovery rate was <10%. Most of these differences were less than 1.5-fold in magnitude. Genes that encode proteins involved in energy metabolism and mitochondrial protein synthesis were expressed at a lower level in older muscle. Genes encoding metallothioneins, high-mobility-group proteins, heterogeneous nuclear ribonucleoproteins and other RNA binding/processing proteins, and components of the ubiquitin-proteasome proteolytic pathway were expressed at higher levels in older muscle. Expression of numerous genes involved with stress responses, hormone/cytokine/growth factor signaling, control of the cell cycle and apoptosis, and transcriptional regulation appeared to be affected by aging. More transcripts were detected in older muscle, suggesting dedifferentiation, an increased number of splice variants, or increased cellular heterogeneity. We conclude that in human skeletal muscle the expression of many genes tends to increase or decrease between the third and seventh decades. The changes are modest when averaged over all of the cells in the tissue.", - "journal_title": "Physiological genomics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/12783983/" - } - ], - "1e9e819d-203b-4da7-ac20-c081acc73280": [ - { - "pub_id": "17559965", - "title": "Epigenetics and aging: the targets and the marks.", - "authors": "Mario F Fraga,Manel Esteller", - "abstract": "'Aging epigenetics' is an emerging field that promises exciting revelations in the near future. Here we focus on the functional and biological significance of the epigenetic alterations that accumulate during aging and are important in tumorigenesis. Paradigmatic examples are provided by the global loss of DNA methylation in aging and cancer and by the promoter hypermethylation of genes with a dual role in tumor suppression and progeria, such as the Werner syndrome (WRN) and lamin A/C genes. Another twist is provided by sirtuins, a family of NAD-dependent deacetylases that act on Lys16 of histone H4, which are emerging as a link between cellular transformation and lifespan.", - "journal_title": "Trends in genetics : TIG", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/17559965/" - } - ], - "dbfe8986-e861-496f-a534-7bb9ca061ad6": [ - { - "pub_id": "20804570", - "title": "Breast cancer prognostic classification in the molecular era: the role of histological grade.", - "authors": "Emad A Rakha,Jorge S Reis-Filho,Frederick Baehner,David J Dabbs,Thomas Decker,Vincenzo Eusebi,Stephen B Fox,Shu Ichihara,Jocelyne Jacquemier,Sunil R Lakhani,Jos\u00e9 Palacios,Andrea L Richardson,Stuart J Schnitt,Fernando C Schmitt,Puay-Hoon Tan,Gary M Tse,Sunil Badve,Ian O Ellis", - "abstract": "Breast cancer is a heterogeneous disease with varied morphological appearances, molecular features, behavior, and response to therapy. Current routine clinical management of breast cancer relies on the availability of robust clinical and pathological prognostic and predictive factors to support clinical and patient decision making in which potentially suitable treatment options are increasingly available. One of the best-established prognostic factors in breast cancer is histological grade, which represents the morphological assessment of tumor biological characteristics and has been shown to be able to generate important information related to the clinical behavior of breast cancers. Genome-wide microarray-based expression profiling studies have unraveled several characteristics of breast cancer biology and have provided further evidence that the biological features captured by histological grade are important in determining tumor behavior. Also, expression profiling studies have generated clinically useful data that have significantly improved our understanding of the biology of breast cancer, and these studies are undergoing evaluation as improved prognostic and predictive tools in clinical practice. Clinical acceptance of these molecular assays will require them to be more than expensive surrogates of established traditional factors such as histological grade. It is essential that they provide additional prognostic or predictive information above and beyond that offered by current parameters. Here, we present an analysis of the validity of histological grade as a prognostic factor and a consensus view on the significance of histological grade and its role in breast cancer classification and staging systems in this era of emerging clinical use of molecular classifiers.", - "journal_title": "Breast cancer research : BCR", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/20804570/" - } - ], - "07a65640-5673-4f13-8f8f-080c387cfc53": [ - { - "pub_id": "15126279", - "title": "Mitochondrial genome single nucleotide polymorphisms and their phenotypes in the Japanese.", - "authors": "Masashi Tanaka,Takeshi Takeyasu,Noriyuki Fuku,Guo Li-Jun,Miyuki Kurata", - "abstract": "Polymorphisms in the human mitochondrial genome have been used for the elucidation of phylogenetic relationships among various ethnic groups. Because analysis by mitochondrial genetics has detected pathogenic mutations causing mitochondrial encephalomyopathy or cardiomyopathy, most of the mitochondrial single nucleotide polymorphisms (mtSNPs) found in control subjects have been regarded as merely normal variants. However, we cannot exclude the possibility that the mitochondrial functional differences among individuals are ascribable at least in part to the mtSNPs of each individual. Human lifespan in ancient history was much shorter than that at the present time. Therefore, it is reasonable to speculate that certain mtSNPs that predispose one toward susceptibility to adult- or elderly-onset diseases, such as Parkinson's disease and Alzheimer's disease, have never been a target for natural selection in the past. Similarly, thrifty mtSNPs that had been advantageous for survival under severe famine or cold climate conditions might turn out to be related to satiation-related diseases, such as diabetes mellitus and obesity. To examine these hypotheses, we have constructed a mtSNP database by sequencing the entire mitochondrial genomes of 672 subjects: 96 in each of seven groups (i.e., centenarians, young obese or non-obese subjects, diabetic patients with or without major vascular involvement, patients with Parkinson's disease, and those with Alzheimer's disease).", - "journal_title": "Annals of the New York Academy of Sciences", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/15126279/" - } - ], - "12a8e7de-7d85-4a89-b90e-0f59b58f9114": [ - { - "pub_id": "20219944", - "title": "Age-dependent DNA methylation of genes that are suppressed in stem cells is a hallmark of cancer.", - "authors": "Andrew E Teschendorff,Usha Menon,Aleksandra Gentry-Maharaj,Susan J Ramus,Daniel J Weisenberger,Hui Shen,Mihaela Campan,Houtan Noushmehr,Christopher G Bell,A Peter Maxwell,David A Savage,Elisabeth Mueller-Holzner,Christian Marth,Gabrijela Kocjan,Simon A Gayther,Allison Jones,Stephan Beck,Wolfgang Wagner,Peter W Laird,Ian J Jacobs,Martin Widschwendter", - "abstract": "Polycomb group proteins (PCGs) are involved in repression of genes that are required for stem cell differentiation. Recently, it was shown that promoters of PCG target genes (PCGTs) are 12-fold more likely to be methylated in cancer than non-PCGTs. Age is the most important demographic risk factor for cancer, and we hypothesized that its carcinogenic potential may be referred by irreversibly stabilizing stem cell features. To test this, we analyzed the methylation status of over 27,000 CpGs mapping to promoters of approximately 14,000 genes in whole blood samples from 261 postmenopausal women. We demonstrate that stem cell PCGTs are far more likely to become methylated with age than non-targets (odds ratio = 5.3 [3.8-7.4], P < 10(-10)), independently of sex, tissue type, disease state, and methylation platform. We identified a specific subset of 69 PCGT CpGs that undergo hypermethylation with age and validated this methylation signature in seven independent data sets encompassing over 900 samples, including normal and cancer solid tissues and a population of bone marrow mesenchymal stem/stromal cells (P < 10(-5)). We find that the age-PCGT methylation signature is present in preneoplastic conditions and may drive gene expression changes associated with carcinogenesis. These findings shed substantial novel insights into the epigenetic effects of aging and support the view that age may predispose to malignant transformation by irreversibly stabilizing stem cell features.", - "journal_title": "Genome research", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/20219944/" - } - ], - "3641c4cb-cff0-4678-9c1d-70008be8e871": [ - { - "pub_id": "12490529", - "title": "Results of a high-resolution genome screen of 437 Alzheimer's disease families.", - "authors": "Deborah Blacker,Lars Bertram,Aleister J Saunders,Thomas J Moscarillo,Marilyn S Albert,Howard Wiener,Rodney T Perry,Julianne S Collins,Lindy E Harrell,Rodney C P Go,Amy Mahoney,Terri Beaty,M Danielle Fallin,Dimitrios Avramopoulos,Gary A Chase,Marshal F Folstein,Melvin G McInnis,Susan S Bassett,Kimberly J Doheny,Elizabeth W Pugh,Rudolph E Tanzi, ", - "abstract": "Alzheimer's disease (AD) is a devastating neurodegenerative disorder of late life with complex inheritance. Mutations in three known genes lead to the rare early-onset autosomal dominant form of AD, while a common polymorphism (epsilon 4) in the gene encoding apolipoprotein E (APOE ) is a risk factor for more typical late-onset (>60 years) AD. A recent study concluded that there are up to four additional genes with an equal or greater contribution to the disease. We performed a 9 cM genome screen of 437 families with AD, the full National Institute of Mental Health (NIMH) sample, which has been carefully ascertained, evaluated and followed by our group over the last decade. Performing standard parametric and non-parametric linkage analyses, we observed a 'highly significant' linkage peak by Lander and Kruglyak criteria on chromosome 19q13, which probably represents APOE. Twelve additional locations-on 1q23, 3p26, 4q32, 5p14, 6p21, 6q27, 9q22, 10q24, 11q25, 14q22, 15q26 and 21q22-met criteria for 'suggestive' linkage [i.e. two-point lod score (TLS) >/=1.9 and/or multipoint lod score (MLS) >/=2.2] in at least one of our analyses. Although some of these will surely prove to be false positives, these linkage signals should provide a valuable framework for future studies aimed at identifying additional susceptibility genes for late-onset AD.", - "journal_title": "Human molecular genetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/12490529/" - } - ], - "5028edee-f846-4819-aa94-28b36b5bb3f9": [ - { - "pub_id": "12544485", - "title": "Integration of genetics into clinical teaching in medical school education.", - "authors": "Bruce R Korf", - "abstract": "Medical genetics has moved from the study of rare conditions to the illumination of disorders that impact the entire spectrum of medical practice. While there have been a number of predictions and concerns about this impact, this article examines three areas where medical genetics is clearly an important tool in medical practice. First, a family history aids in risk assessment, even in common disorders that are multifactorial. Second, by elucidating molecular pathways, gene identification may lead to the development of more efficacious medications that have fewer side effects. Third, an awareness of population-based risk and the availability of genetic screening in these populations will help physicians assess an individual patient's risk. To fully benefit from genetically based medical approaches, physicians will need to master a new set of principles and clinical skills. However, genetics has traditionally been taught as a basic science, sometimes under the purview of cell biology or biochemistry. Often, then, genetics has little or no place in clinical teaching. This article describes an effort at Harvard Medical School to integrate genetics into both the preclinical and the clinical curricula. The author looks at the underlying pedagogy, how basic science teaching in genetics is provided, and an approach currently being used to include genetics in clinical teaching.", - "journal_title": "Genetics in medicine : official journal of the American College of Medical Genetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/12544485/" - } - ], - "3f4b83bb-072a-4040-8a96-7dd0580f1ccf": [ - { - "pub_id": "12204535", - "title": "Telomere dysfunction provokes regional amplification and deletion in cancer genomes.", - "authors": "R\u00f3n\u00e1n C O'Hagan,Sandy Chang,Richard S Maser,Ramya Mohan,Steven E Artandi,Lynda Chin,Ronald A DePinho", - "abstract": "Telomere dysfunction and associated fusion-breakage in the mouse encourages epithelial carcinogenesis and a more humanized genomic profile that includes nonreciprocal translocations (NRTs). Here, array comparative genomic hybridization was used to determine the pathogenic significance of NRTs and to determine whether telomere dysfunction also drives amplifications and deletions of cancer-relevant loci. Compared to tumors arising in mice with intact telomeres, tumors with telomere dysfunction possessed higher levels of genomic instability and showed numerous amplifications and deletions in regions syntenic to human cancer hotspots. These observations suggest that telomere-based crisis provides a mechanism of chromosomal instability, including regional amplifications and deletions, that drives carcinogenesis. This model provides a platform for discovery of genes responsible for the major cancers affecting aged humans.", - "journal_title": "Cancer cell", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/12204535/" - } - ], - "b2f8ed5d-05c9-4a1e-8bf6-9d273a646a11": [ - { - "pub_id": "15886309", - "title": "Genomic and proteomic profiling of lung cancers: lung cancer classification in the age of targeted therapy.", - "authors": "Matthew Meyerson,David Carbone", - "abstract": "Both proteomic and genomic methods offer promise for the classification of human lung carcinomas. This review summarizes the range of proteomic methods in development for lung cancer classification, and describes a number of recent analyses of messenger RNA expression in lung cancer. Multiple independent studies of mRNA expression profiles in lung adenocarcinoma have proven highly reproducible. Analyses of the relationship between expression profiles and tumor development and differentiation, the presence or absence of specific pathogenic mutations, patient prognosis and survival after surgical treatment, and specific histopathology all appear to be promising.", - "journal_title": "Journal of clinical oncology : official journal of the American Society of Clinical Oncology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/15886309/" - } - ], - "c93ceb60-ed9b-4e1a-ab3c-f82aa7d70fca": [ - { - "pub_id": "17942423", - "title": "Caloric restriction and genomic stability.", - "authors": "Ahmad R Heydari,Archana Unnikrishnan,Lisa Ventrella Lucente,Arlan Richardson", - "abstract": "Caloric restriction (CR) reduces the incidence and progression of spontaneous and induced tumors in laboratory rodents while increasing mean and maximum life spans. It has been suggested that CR extends longevity and reduces age-related pathologies by reducing the levels of DNA damage and mutations that accumulate with age. This hypothesis is attractive because the integrity of the genome is essential to a cell/organism and because it is supported by observations that both cancer and immunological defects, which increase significantly with age and are delayed by CR, are associated with changes in DNA damage and/or DNA repair. Over the last three decades, numerous laboratories have examined the effects of CR on the integrity of the genome and the ability of cells to repair DNA. The majority of studies performed indicate that the age-related increase in oxidative damage to DNA is significantly reduced by CR. Early studies suggest that CR reduces DNA damage by enhancing DNA repair. With the advent of genomic technology and our increased understanding of specific repair pathways, CR has been shown to have a significant effect on major DNA repair pathways, such as NER, BER and double-strand break repair.", - "journal_title": "Nucleic acids research", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/17942423/" - } - ], - "769c658b-76c2-4192-91d8-177b4d8c6ffa": [ - { - "pub_id": "16192704", - "title": "Biological aging and the etiology of aneuploidy.", - "authors": "D Warburton", - "abstract": "A prevalent hypothesis concerning the cause of the rise in aneuploid conceptions with maternal age is that the changes that accompany normal ovarian aging increase the rate of meiotic errors in the oocyte. Biological aging of the ovary is accompanied by a decline in both the total oocyte pool and the number of antral follicles maturing per cycle, as well as changes in the levels of circulating reproductive hormones. The biological aging hypothesis predicts that aneuploidy rates should be higher in women with a prematurely reduced oocyte pool, and that women with trisomic conceptions should show signs of earlier ovarian aging than women of the same chronological age without trisomic conceptions. Comprehensive studies of aneuploidy in groups of women with known causes of premature ovarian failure remain to be done, though anecdotal evidence does suggest increased rates of pregnancy loss and aneuploidy. Smoking, which is a well-documented cause of earlier ovarian aging, is not associated with an increase in aneuploid conceptions. Evidence from women with unilateral ovariectomies is inconsistent. Support for the biological aging hypothesis was provided by one study showing that menopause occurred about a year earlier in women with a trisomic spontaneous abortion compared to women with chromosomally normal conceptions. Associations between high FSH and pregnancies with Down syndrome and chromosomally abnormal spontaneous abortions have also been reported. However, the most direct test of the hypothesis, which compared antral follicle counts and hormonal levels in women with trisomic pregnancies and those with chromosomally normal pregnancies, failed to find a difference in the expected direction. A prospective study of FSH levels in women with subfertility also failed to find an association with the rate of pregnancy loss. The bulk of evidence thus suggests that, if the processes of biological aging are indeed related to aneuploidy, they probably involve factors other than those measured by oocyte or antral follicle pool size and reproductive hormone levels.", - "journal_title": "Cytogenetic and genome research", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/16192704/" - } - ], - "50756157-d596-4c90-8f3b-cec31507b97d": [ - { - "pub_id": "17049789", - "title": "The short-lived fish Nothobranchius furzeri as a new model system for aging studies.", - "authors": "Eva Terzibasi,Dario Riccardo Valenzano,Alessandro Cellerino", - "abstract": "Genetic and pharmacological research on aging is hampered by the lifespan of available vertebrate models. We recently initiated studies on Nothobranchius furzeri, a species with a maximum life expectancy in captivity of just three months which represents the shortest documented captive lifespan for a vertebrate. Further research on N. furzeri has demonstrated that 1. Short lifespan is tied with explosive growth and accelerated sexual maturation. 2. Short lifespan is correlated with expression of age-related behavioral and histological changes. 3. Lifespan and expression of age-related markers can be modulated by water temperature. 4. Resveratrol, a drug characterized for its life-extending action in Caenorhabditis elegans and Drosophila, increases lifespan and retards expression of age-related markers. 5. Aging-related genes can be easily isolated by homology cloning. Finally, different populations or species of Nothobranchius show large-scale differences in captive lifespan. In the last three years, N. furzeri has moved from biological curiosity to a promising model system for drug validation. Furthermore, this species occupies a favorable position in the Teleost's \"tree of life\". It is very close to the Japanese Medaka, and close to the pufferfishes and stickleback and might represent a very useful model for comparative genomics of aging.", - "journal_title": "Experimental gerontology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/17049789/" - } - ], - "3b4e2d29-59aa-4df8-8782-64219b918fd2": [ - { - "pub_id": "15927235", - "title": "Rapid and reversible induction of the longevity, anticancer and genomic effects of caloric restriction.", - "authors": "Stephen R Spindler", - "abstract": "It is widely held that caloric restriction (CR) extends lifespan by preventing or reducing the age-related accumulation of irreversible molecular damage. In contrast, our results suggest that CR can act rapidly to begin life and health span extension, and that its rapid genomic effects are closely linked to its health effects. We found that CR begins to extend lifespan and reduce cancer as a cause of death within 8 weeks in older mice, apparently by reducing the rate of tumor growth. Further, 8 weeks of CR progressively reproduces nearly three quarters of the genomic effects of long-term CR (LTCR) in liver. Fewer of the genomic effects of LTCR are rapidly reproduced by the initiation of CR in the heart, but the changes produced are keys to cardiovascular health. Thus, the genomic effects of CR may be established more rapidly in mitotic than in postmitotic tissues. Most of the genomic effects of LTCR dissipate 8 weeks after switching to a control diet. Consistent with these results, others have shown that acute CR rapidly and reversibly reduces the short-term risk of death in Drosophila to that of LTCR treated flies. Further, in late adulthood, acute CR partially or completely reverses age-related alterations of liver, brain and heart proteins. CR also rapidly and reversibly mitigates biomarkers of aging in adult rhesus macaques and humans. These data argue that highly conserved mechanisms for the rapid and reversible enhancement of life- and health-span exist for mitotic and postmitotic tissues.", - "journal_title": "Mechanisms of ageing and development", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/15927235/" - } - ], - "a7401384-f646-4d9d-b50d-658c9c556016": [ - { - "pub_id": "19430483", - "title": "Genome-wide association study identifies eight loci associated with blood pressure.", - "authors": "Christopher Newton-Cheh,Toby Johnson,Vesela Gateva,Martin D Tobin,Murielle Bochud,Lachlan Coin,Samer S Najjar,Jing Hua Zhao,Simon C Heath,Susana Eyheramendy,Konstantinos Papadakis,Benjamin F Voight,Laura J Scott,Feng Zhang,Martin Farrall,Toshiko Tanaka,Chris Wallace,John C Chambers,Kay-Tee Khaw,Peter Nilsson,Pim van der Harst,Silvia Polidoro,Diederick E Grobbee,N Charlotte Onland-Moret,Michiel L Bots,Louise V Wain,Katherine S Elliott,Alexander Teumer,Jian'an Luan,Gavin Lucas,Johanna Kuusisto,Paul R Burton,David Hadley,Wendy L McArdle, ,Morris Brown,Anna Dominiczak,Stephen J Newhouse,Nilesh J Samani,John Webster,Eleftheria Zeggini,Jacques S Beckmann,Sven Bergmann,Noha Lim,Kijoung Song,Peter Vollenweider,Gerard Waeber,Dawn M Waterworth,Xin Yuan,Leif Groop,Marju Orho-Melander,Alessandra Allione,Alessandra Di Gregorio,Simonetta Guarrera,Salvatore Panico,Fulvio Ricceri,Valeria Romanazzi,Carlotta Sacerdote,Paolo Vineis,In\u00eas Barroso,Manjinder S Sandhu,Robert N Luben,Gabriel J Crawford,Pekka Jousilahti,Markus Perola,Michael Boehnke,Lori L Bonnycastle,Francis S Collins,Anne U Jackson,Karen L Mohlke,Heather M Stringham,Timo T Valle,Cristen J Willer,Richard N Bergman,Mario A Morken,Angela D\u00f6ring,Christian Gieger,Thomas Illig,Thomas Meitinger,Elin Org,Arne Pfeufer,H Erich Wichmann,Sekar Kathiresan,Jaume Marrugat,Christopher J O'Donnell,Stephen M Schwartz,David S Siscovick,Isaac Subirana,Nelson B Freimer,Anna-Liisa Hartikainen,Mark I McCarthy,Paul F O'Reilly,Leena Peltonen,Anneli Pouta,Paul E de Jong,Harold Snieder,Wiek H van Gilst,Robert Clarke,Anuj Goel,Anders Hamsten,John F Peden,Udo Seedorf,Ann-Christine Syv\u00e4nen,Giovanni Tognoni,Edward G Lakatta,Serena Sanna,Paul Scheet,David Schlessinger,Angelo Scuteri,Marcus D\u00f6rr,Florian Ernst,Stephan B Felix,Georg Homuth,Roberto Lorbeer,Thorsten Reffelmann,Rainer Rettig,Uwe V\u00f6lker,Pilar Galan,Ivo G Gut,Serge Hercberg,G Mark Lathrop,Diana Zelenika,Panos Deloukas,Nicole Soranzo,Frances M Williams,Guangju Zhai,Veikko Salomaa,Markku Laakso,Roberto Elosua,Nita G Forouhi,Henry V\u00f6lzke,Cuno S Uiterwaal,Yvonne T van der Schouw,Mattijs E Numans,Giuseppe Matullo,Gerjan Navis,G\u00f6ran Berglund,Sheila A Bingham,Jaspal S Kooner,John M Connell,Stefania Bandinelli,Luigi Ferrucci,Hugh Watkins,Tim D Spector,Jaakko Tuomilehto,David Altshuler,David P Strachan,Maris Laan,Pierre Meneton,Nicholas J Wareham,Manuela Uda,Marjo-Riitta Jarvelin,Vincent Mooser,Olle Melander,Ruth J F Loos,Paul Elliott,Gon\u00e7alo R Abecasis,Mark Caulfield,Patricia B Munroe", - "abstract": "Elevated blood pressure is a common, heritable cause of cardiovascular disease worldwide. To date, identification of common genetic variants influencing blood pressure has proven challenging. We tested 2.5 million genotyped and imputed SNPs for association with systolic and diastolic blood pressure in 34,433 subjects of European ancestry from the Global BPgen consortium and followed up findings with direct genotyping (N \u2264 71,225 European ancestry, N \u2264 12,889 Indian Asian ancestry) and in silico comparison (CHARGE consortium, N = 29,136). We identified association between systolic or diastolic blood pressure and common variants in eight regions near the CYP17A1 (P = 7 \u00d7 10(-24)), CYP1A2 (P = 1 \u00d7 10(-23)), FGF5 (P = 1 \u00d7 10(-21)), SH2B3 (P = 3 \u00d7 10(-18)), MTHFR (P = 2 \u00d7 10(-13)), c10orf107 (P = 1 \u00d7 10(-9)), ZNF652 (P = 5 \u00d7 10(-9)) and PLCD3 (P = 1 \u00d7 10(-8)) genes. All variants associated with continuous blood pressure were associated with dichotomous hypertension. These associations between common variants and blood pressure and hypertension offer mechanistic insights into the regulation of blood pressure and may point to novel targets for interventions to prevent cardiovascular disease.", - "journal_title": "Nature genetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/19430483/" - } - ], - "43a28b54-22e0-4083-802e-b999df0b4a40": [ - { - "pub_id": "37074710", - "title": "Interplay of Metabolome and Gut Microbiome in Individuals With Major Depressive Disorder vs Control Individuals.", - "authors": "Najaf Amin,Jun Liu,Bruno Bonnechere,Siamak MahmoudianDehkordi,Matthias Arnold,Richa Batra,Yu-Jie Chiou,Marco Fernandes,M Arfan Ikram,Robert Kraaij,Jan Krumsiek,Danielle Newby,Kwangsik Nho,Djawad Radjabzadeh,Andrew J Saykin,Liu Shi,William Sproviero,Laura Winchester,Yang Yang,Alejo J Nevado-Holgado,Gabi Kastenm\u00fcller,Rima Kaddurah-Daouk,Cornelia M van Duijn", - "abstract": "Metabolomics reflect the net effect of genetic and environmental influences and thus provide a comprehensive approach to evaluating the pathogenesis of complex diseases, such as depression. To identify the metabolic signatures of major depressive disorder (MDD), elucidate the direction of associations using mendelian randomization, and evaluate the interplay of the human gut microbiome and metabolome in the development of MDD. This cohort study used data from participants in the UK Biobank cohort (n\u2009=\u2009500\u202f000; aged 37 to 73 years; recruited from 2006 to 2010) whose blood was profiled for metabolomics. Replication was sought in the PREDICT and BBMRI-NL studies. Publicly available summary statistics from a 2019 genome-wide association study of depression were used for the mendelian randomization (individuals with MDD\u2009=\u200959\u202f851; control individuals\u2009=\u2009113\u202f154). Summary statistics for the metabolites were obtained from OpenGWAS in MRbase (n\u2009=\u2009118\u202f000). To evaluate the interplay of the metabolome and the gut microbiome in the pathogenesis of depression, metabolic signatures of the gut microbiome were obtained from a 2019 study performed in Dutch cohorts. Data were analyzed from March to December 2021. Outcomes were lifetime and recurrent MDD, with 249 metabolites profiled with nuclear magnetic resonance spectroscopy with the Nightingale platform. The study included 6811 individuals with lifetime MDD compared with 51\u202f446 control individuals and 4370 individuals with recurrent MDD compared with 62\u202f508 control individuals. Individuals with lifetime MDD were younger (median [IQR] age, 56 [49-62] years vs 58 [51-64] years) and more often female (4447 [65%] vs 2364 [35%]) than control individuals. Metabolic signatures of MDD consisted of 124 metabolites spanning the energy and lipid metabolism pathways. Novel findings included 49 metabolites, including those involved in the tricarboxylic acid cycle (ie, citrate and pyruvate). Citrate was significantly decreased (\u03b2 [SE], -0.07 [0.02]; FDR\u2009=\u20094\u2009\u00d7\u200910-04) and pyruvate was significantly increased (\u03b2 [SE], 0.04 [0.02]; FDR\u2009=\u20090.02) in individuals with MDD. Changes observed in these metabolites, particularly lipoproteins, were consistent with the differential composition of gut microbiota belonging to the order Clostridiales and the phyla Proteobacteria/Pseudomonadota and Bacteroidetes/Bacteroidota. Mendelian randomization suggested that fatty acids and intermediate and very large density lipoproteins changed in association with the disease process but high-density lipoproteins and the metabolites in the tricarboxylic acid cycle did not. The study findings showed that energy metabolism was disturbed in individuals with MDD and that the interplay of the gut microbiome and blood metabolome may play a role in lipid metabolism in individuals with MDD.", - "journal_title": "JAMA psychiatry", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/37074710/" - } - ], - "ca184a2f-f84b-40a1-86c2-b7886bed4612": [ - { - "pub_id": "19958484", - "title": "MitoInteractome: mitochondrial protein interactome database, and its application in 'aging network' analysis.", - "authors": "Rohit Reja,A J Venkatakrishnan,Jungwoo Lee,Byoung-Chul Kim,Jea-Woon Ryu,Sungsam Gong,Jong Bhak,Daeui Park", - "abstract": "Mitochondria play a vital role in the energy production and apoptotic process of eukaryotic cells. Proteins in the mitochondria are encoded by nuclear and mitochondrial genes. Owing to a large increase in the number of identified mitochondrial protein sequences and completed mitochondrial genomes, it has become necessary to provide a web-based database of mitochondrial protein information. We present 'MitoInteractome', a consolidated web-based portal containing a wealth of information on predicted protein-protein interactions, physico-chemical properties, polymorphism, and diseases related to the mitochondrial proteome. MitoInteractome contains 6,549 protein sequences which were extracted from the following databases: SwissProt, MitoP, MitoProteome, HPRD and Gene Ontology database. The first general mitochondrial interactome has been constructed based on the concept of 'homologous interaction' using PSIMAP (Protein Structural Interactome MAP) and PEIMAP (Protein Experimental Interactome MAP). Using the above mentioned methods, protein-protein interactions were predicted for 74 species. The mitochondrial protein interaction data of humans was used to construct a network for the aging process. Analysis of the 'aging network' gave us vital insights into the interactions among proteins that influence the aging process. MitoInteractome is a comprehensive database that would (1) aid in increasing our understanding of the molecular functions and interaction networks of mitochondrial proteins, (2) help in identifying new target proteins for experimental research using predicted protein-protein interaction information, and (3) help in identifying biomarkers for diagnosis and new molecular targets for drug development related to mitochondria. MitoInteractome is available at http://mitointeractome.kobic.kr/.", - "journal_title": "BMC genomics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/19958484/" - } - ], - "e562a7f1-f43a-4ca4-bf18-4196276b6170": [ - { - "pub_id": "11095759", - "title": "Genome-wide study of aging and oxidative stress response in Drosophila melanogaster.", - "authors": "S Zou,S Meadows,L Sharp,L Y Jan,Y N Jan", - "abstract": "Aging is a universal but poorly understood biological process. Free radicals accumulate with age and have been proposed to be a major cause of aging. We measured genome-wide changes in transcript levels as a function of age in Drosophila melanogaster and compared these changes with those caused by paraquat, a free-radical generator. A number of genes exhibited changes in transcript levels with both age and paraquat treatment. We also found genes whose transcript levels changed with age but not with paraquat treatment. This study suggests that free radicals play an important role in regulating transcript levels in aging but that they are not the only factors. This genome-wide survey also identifies candidates for molecular markers of aging.", - "journal_title": "Proceedings of the National Academy of Sciences of the United States of America", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/11095759/" - } - ], - "4b86a8fb-344e-4726-a8d5-355c317a1c33": [ - { - "pub_id": "11295148", - "title": "Vitamins/minerals and genomic stability in humans.", - "authors": "M Fenech,L R Ferguson", - "abstract": "Recommended dietary allowances (RDAs) of micronutrients have been traditionally derived as those levels necessary to prevent symptoms of deficiency diseases. There is increasing evidence that higher levels of many such micronutrients may be necessary for various DNA maintenance reactions, and that the current RDAs for some micronutrients may be inadequate to protect against genomic instability. Supplementation of a normal diet, with either vitamins and/or minerals or with isolated plant polyphenols, is becoming increasingly common in most Western populations. However, there is no clear agreement as to how much supplementation should occur, if at all, and genotypic differences are not accounted for. The 14 mini-reviews in this special issue summarise the role of specific micronutrients in various aspects of DNA maintenance: DNA synthesis, DNA repair, DNA methylation, gene mutation, chromosome breakage, chromosome segregation, gene expression, oxidative stress, necrosis and apoptosis. Evidence has been collated from mammalian and human experiments, both using in vitro cultures and in vivo approaches. Authors were asked to critically assess the strength of evidence as to whether the micronutrient can affect genomic stability in humans at realistic intake levels, and to estimate optimal dietary ranges where possible. Information on further research necessary is also documented. These reviews are an essential step towards a definition of RDAs designed to maintain genomic stability.", - "journal_title": "Mutation research", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/11295148/" - } - ], - "c9acd489-6022-4cc4-a209-262c9cc996a8": [ - { - "pub_id": "18798689", - "title": "Informed consent in the genomics era.", - "authors": "Deborah Mascalzoni,Andrew Hicks,Peter Pramstaller,Matthias Wjst", - "abstract": "Matthias Wjst and colleagues argue that traditional informed consent may no longer be appropriate when dealing with long-term studies using biological material.", - "journal_title": "PLoS medicine", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/18798689/" - } - ], - "6c865bbb-b27e-4faa-b6ee-619e17cf6dcd": [ - { - "pub_id": "15851668", - "title": "Genomes, phylogeny, and evolutionary systems biology.", - "authors": "M\u00f3nica Medina", - "abstract": "With the completion of the human genome and the growing number of diverse genomes being sequenced, a new age of evolutionary research is currently taking shape. The myriad of technological breakthroughs in biology that are leading to the unification of broad scientific fields such as molecular biology, biochemistry, physics, mathematics, and computer science are now known as systems biology. Here, I present an overview, with an emphasis on eukaryotes, of how the postgenomics era is adopting comparative approaches that go beyond comparisons among model organisms to shape the nascent field of evolutionary systems biology.", - "journal_title": "Proceedings of the National Academy of Sciences of the United States of America", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/15851668/" - } - ], - "b5ae2bff-612d-496d-aa2d-09e6ee22d76c": [ - { - "pub_id": "30545857", - "title": "Comprehensive functional genomic resource and integrative model for the human brain.", - "authors": "Daifeng Wang,Shuang Liu,Jonathan Warrell,Hyejung Won,Xu Shi,Fabio C P Navarro,Declan Clarke,Mengting Gu,Prashant Emani,Yucheng T Yang,Min Xu,Michael J Gandal,Shaoke Lou,Jing Zhang,Jonathan J Park,Chengfei Yan,Suhn Kyong Rhie,Kasidet Manakongtreecheep,Holly Zhou,Aparna Nathan,Mette Peters,Eugenio Mattei,Dominic Fitzgerald,Tonya Brunetti,Jill Moore,Yan Jiang,Kiran Girdhar,Gabriel E Hoffman,Selim Kalayci,Zeynep H G\u00fcm\u00fc\u015f,Gregory E Crawford, ,Panos Roussos,Schahram Akbarian,Andrew E Jaffe,Kevin P White,Zhiping Weng,Nenad Sestan,Daniel H Geschwind,James A Knowles,Mark B Gerstein", - "abstract": "Despite progress in defining genetic risk for psychiatric disorders, their molecular mechanisms remain elusive. Addressing this, the PsychENCODE Consortium has generated a comprehensive online resource for the adult brain across 1866 individuals. The PsychENCODE resource contains ~79,000 brain-active enhancers, sets of Hi-C linkages, and topologically associating domains; single-cell expression profiles for many cell types; expression quantitative-trait loci (QTLs); and further QTLs associated with chromatin, splicing, and cell-type proportions. Integration shows that varying cell-type proportions largely account for the cross-population variation in expression (with >88% reconstruction accuracy). It also allows building of a gene regulatory network, linking genome-wide association study variants to genes (e.g., 321 for schizophrenia). We embed this network into an interpretable deep-learning model, which improves disease prediction by ~6-fold versus polygenic risk scores and identifies key genes and pathways in psychiatric disorders.", - "journal_title": "Science (New York, N.Y.)", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/30545857/" - } - ], - "c07bba46-9a4c-408c-8a8a-f7107e43e216": [ - { - "pub_id": "21909115", - "title": "Genetic variants in novel pathways influence blood pressure and cardiovascular disease risk.", - "authors": " ,Georg B Ehret,Patricia B Munroe,Kenneth M Rice,Murielle Bochud,Andrew D Johnson,Daniel I Chasman,Albert V Smith,Martin D Tobin,Germaine C Verwoert,Shih-Jen Hwang,Vasyl Pihur,Peter Vollenweider,Paul F O'Reilly,Najaf Amin,Jennifer L Bragg-Gresham,Alexander Teumer,Nicole L Glazer,Lenore Launer,Jing Hua Zhao,Yurii Aulchenko,Simon Heath,Siim S\u00f5ber,Afshin Parsa,Jian'an Luan,Pankaj Arora,Abbas Dehghan,Feng Zhang,Gavin Lucas,Andrew A Hicks,Anne U Jackson,John F Peden,Toshiko Tanaka,Sarah H Wild,Igor Rudan,Wilmar Igl,Yuri Milaneschi,Alex N Parker,Cristiano Fava,John C Chambers,Ervin R Fox,Meena Kumari,Min Jin Go,Pim van der Harst,Wen Hong Linda Kao,Marketa Sj\u00f6gren,D G Vinay,Myriam Alexander,Yasuharu Tabara,Sue Shaw-Hawkins,Peter H Whincup,Yongmei Liu,Gang Shi,Johanna Kuusisto,Bamidele Tayo,Mark Seielstad,Xueling Sim,Khanh-Dung Hoang Nguyen,Terho Lehtim\u00e4ki,Giuseppe Matullo,Ying Wu,Tom R Gaunt,N Charlotte Onland-Moret,Matthew N Cooper,Carl G P Platou,Elin Org,Rebecca Hardy,Santosh Dahgam,Jutta Palmen,Veronique Vitart,Peter S Braund,Tatiana Kuznetsova,Cuno S P M Uiterwaal,Adebowale Adeyemo,Walter Palmas,Harry Campbell,Barbara Ludwig,Maciej Tomaszewski,Ioanna Tzoulaki,Nicholette D Palmer, , , , , ,Thor Aspelund,Melissa Garcia,Yen-Pei C Chang,Jeffrey R O'Connell,Nanette I Steinle,Diederick E Grobbee,Dan E Arking,Sharon L Kardia,Alanna C Morrison,Dena Hernandez,Samer Najjar,Wendy L McArdle,David Hadley,Morris J Brown,John M Connell,Aroon D Hingorani,Ian N M Day,Debbie A Lawlor,John P Beilby,Robert W Lawrence,Robert Clarke,Jemma C Hopewell,Halit Ongen,Albert W Dreisbach,Yali Li,J Hunter Young,Joshua C Bis,Mika K\u00e4h\u00f6nen,Jorma Viikari,Linda S Adair,Nanette R Lee,Ming-Huei Chen,Matthias Olden,Cristian Pattaro,Judith A Hoffman Bolton,Anna K\u00f6ttgen,Sven Bergmann,Vincent Mooser,Nish Chaturvedi,Timothy M Frayling,Muhammad Islam,Tazeen H Jafar,Jeanette Erdmann,Smita R Kulkarni,Stefan R Bornstein,J\u00fcrgen Gr\u00e4ssler,Leif Groop,Benjamin F Voight,Johannes Kettunen,Philip Howard,Andrew Taylor,Simonetta Guarrera,Fulvio Ricceri,Valur Emilsson,Andrew Plump,In\u00eas Barroso,Kay-Tee Khaw,Alan B Weder,Steven C Hunt,Yan V Sun,Richard N Bergman,Francis S Collins,Lori L Bonnycastle,Laura J Scott,Heather M Stringham,Leena Peltonen,Markus Perola,Erkki Vartiainen,Stefan-Martin Brand,Jan A Staessen,Thomas J Wang,Paul R Burton,Maria Soler Artigas,Yanbin Dong,Harold Snieder,Xiaoling Wang,Haidong Zhu,Kurt K Lohman,Megan E Rudock,Susan R Heckbert,Nicholas L Smith,Kerri L Wiggins,Ayo Doumatey,Daniel Shriner,Gudrun Veldre,Margus Viigimaa,Sanjay Kinra,Dorairaj Prabhakaran,Vikal Tripathy,Carl D Langefeld,Annika Rosengren,Dag S Thelle,Anna Maria Corsi,Andrew Singleton,Terrence Forrester,Gina Hilton,Colin A McKenzie,Tunde Salako,Naoharu Iwai,Yoshikuni Kita,Toshio Ogihara,Takayoshi Ohkubo,Tomonori Okamura,Hirotsugu Ueshima,Satoshi Umemura,Susana Eyheramendy,Thomas Meitinger,H-Erich Wichmann,Yoon Shin Cho,Hyung-Lae Kim,Jong-Young Lee,James Scott,Joban S Sehmi,Weihua Zhang,Bo Hedblad,Peter Nilsson,George Davey Smith,Andrew Wong,Narisu Narisu,Alena Stan\u010d\u00e1kov\u00e1,Leslie J Raffel,Jie Yao,Sekar Kathiresan,Christopher J O'Donnell,Stephen M Schwartz,M Arfan Ikram,W T Longstreth,Thomas H Mosley,Sudha Seshadri,Nick R G Shrine,Louise V Wain,Mario A Morken,Amy J Swift,Jaana Laitinen,Inga Prokopenko,Paavo Zitting,Jackie A Cooper,Steve E Humphries,John Danesh,Asif Rasheed,Anuj Goel,Anders Hamsten,Hugh Watkins,Stephan J L Bakker,Wiek H van Gilst,Charles S Janipalli,K Radha Mani,Chittaranjan S Yajnik,Albert Hofman,Francesco U S Mattace-Raso,Ben A Oostra,Ayse Demirkan,Aaron Isaacs,Fernando Rivadeneira,Edward G Lakatta,Marco Orru,Angelo Scuteri,Mika Ala-Korpela,Antti J Kangas,Leo-Pekka Lyytik\u00e4inen,Pasi Soininen,Taru Tukiainen,Peter W\u00fcrtz,Rick Twee-Hee Ong,Marcus D\u00f6rr,Heyo K Kroemer,Uwe V\u00f6lker,Henry V\u00f6lzke,Pilar Galan,Serge Hercberg,Mark Lathrop,Diana Zelenika,Panos Deloukas,Massimo Mangino,Tim D Spector,Guangju Zhai,James F Meschia,Michael A Nalls,Pankaj Sharma,Janos Terzic,M V Kranthi Kumar,Matthew Denniff,Ewa Zukowska-Szczechowska,Lynne E Wagenknecht,F Gerald R Fowkes,Fadi J Charchar,Peter E H Schwarz,Caroline Hayward,Xiuqing Guo,Charles Rotimi,Michiel L Bots,Eva Brand,Nilesh J Samani,Ozren Polasek,Philippa J Talmud,Fredrik Nyberg,Diana Kuh,Maris Laan,Kristian Hveem,Lyle J Palmer,Yvonne T van der Schouw,Juan P Casas,Karen L Mohlke,Paolo Vineis,Olli Raitakari,Santhi K Ganesh,Tien Y Wong,E Shyong Tai,Richard S Cooper,Markku Laakso,Dabeeru C Rao,Tamara B Harris,Richard W Morris,Anna F Dominiczak,Mika Kivimaki,Michael G Marmot,Tetsuro Miki,Danish Saleheen,Giriraj R Chandak,Josef Coresh,Gerjan Navis,Veikko Salomaa,Bok-Ghee Han,Xiaofeng Zhu,Jaspal S Kooner,Olle Melander,Paul M Ridker,Stefania Bandinelli,Ulf B Gyllensten,Alan F Wright,James F Wilson,Luigi Ferrucci,Martin Farrall,Jaakko Tuomilehto,Peter P Pramstaller,Roberto Elosua,Nicole Soranzo,Eric J G Sijbrands,David Altshuler,Ruth J F Loos,Alan R Shuldiner,Christian Gieger,Pierre Meneton,Andre G Uitterlinden,Nicholas J Wareham,Vilmundur Gudnason,Jerome I Rotter,Rainer Rettig,Manuela Uda,David P Strachan,Jacqueline C M Witteman,Anna-Liisa Hartikainen,Jacques S Beckmann,Eric Boerwinkle,Ramachandran S Vasan,Michael Boehnke,Martin G Larson,Marjo-Riitta J\u00e4rvelin,Bruce M Psaty,Gon\u00e7alo R Abecasis,Aravinda Chakravarti,Paul Elliott,Cornelia M van Duijn,Christopher Newton-Cheh,Daniel Levy,Mark J Caulfield,Toby Johnson", - "abstract": "Blood pressure is a heritable trait influenced by several biological pathways and responsive to environmental stimuli. Over one billion people worldwide have hypertension (\u2265140\u2009mm\u2009Hg systolic blood pressure or\u2009 \u226590\u2009mm\u2009Hg diastolic blood pressure). Even small increments in blood pressure are associated with an increased risk of cardiovascular events. This genome-wide association study of systolic and diastolic blood pressure, which used a multi-stage design in 200,000 individuals of European descent, identified sixteen novel loci: six of these loci contain genes previously known or suspected to regulate blood pressure (GUCY1A3-GUCY1B3, NPR3-C5orf23, ADM, FURIN-FES, GOSR2, GNAS-EDN3); the other ten provide new clues to blood pressure physiology. A genetic risk score based on 29 genome-wide significant variants was associated with hypertension, left ventricular wall thickness, stroke and coronary artery disease, but not kidney disease or kidney function. We also observed associations with blood pressure in East Asian, South Asian and African ancestry individuals. Our findings provide new insights into the genetics and biology of blood pressure, and suggest potential novel therapeutic pathways for cardiovascular disease prevention.", - "journal_title": "Nature", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/21909115/" - } - ], - "ed7143b5-5071-4dd2-b427-601b83c8e7cd": [ - { - "pub_id": "18039866", - "title": "Drosophila biology in the genomic age.", - "authors": "Therese Ann Markow,Patrick M O'Grady", - "abstract": "Over the course of the past century, flies in the family Drosophilidae have been important models for understanding genetic, developmental, cellular, ecological, and evolutionary processes. Full genome sequences from a total of 12 species promise to extend this work by facilitating comparative studies of gene expression, of molecules such as proteins, of developmental mechanisms, and of ecological adaptation. Here we review basic biological and ecological information of the species whose genomes have recently been completely sequenced in the context of current research.", - "journal_title": "Genetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/18039866/" - } - ], - "10fb9a99-9ee1-435e-b909-de3e59ffb85c": [ - { - "pub_id": "28109988", - "title": "Epilepsy and restless legs syndrome.", - "authors": "James D Geyer,Emery E Geyer,Zachary Fetterman,Paul R Carney", - "abstract": "Restless legs syndrome (RLS) is a common neurological movement disorder occurring in approximately 10% of the general population. The prevalence of moderately severe RLS is 2.7% overall (3.7% for women and 1.7% for men). Epilepsy is also a common neurological disorder with significant associated morbidity and impact on quality of life. We evaluated the severity and frequency of primary RLS in patients with localization-related temporal lobe epilepsy (TLE) and investigated the role of prodromal RLS symptoms as a warning sign and lateralizing indicator. All epilepsy patients seen in the outpatient clinic were screened for movement disorders from 2005 to 2015. Ninety-eight consecutive patients with localization-related TLE (50 right TLE and 48 left TLE) who met inclusion criteria were seen in the outpatient clinic. The control group consisted of 50 individuals with no history or immediate family history of epilepsy. Each patient was evaluated with the International Restless Legs Study Group (IRLSSG) questionnaire, NIH RLS diagnostic criteria, ferritin level, and comprehensive sleep screening including polysomnography. Furthermore, patients with obstructive sleep apnea or a definite cause of secondary restless legs syndrome such as low serum ferritin or serum iron levels were also excluded from the study. There was a significant association between the type of epilepsy and whether or not patients had RLS \u03c7<sup>2</sup> (1)=10.17, p<.01, using the \u03c7<sup>2</sup> Goodness of Fit Test. Based on the odds ratio, the odds of patients having RLS were 4.60 times higher if they had right temporal epilepsy than if they had left temporal epilepsy, serving as a potential lateralizing indicator. A prodromal sensation of worsening RLS occurred in some patients providing the opportunity to intervene at an earlier stage in this subgroup. We identified frequent moderate to severe RLS in patients with epilepsy. The frequency of RLS was much more common than would typically be seen in patients of similar age. The restlessness was typically described as moderately severe. The RLS symptoms were more common and somewhat more severe in the right TLE group than the left TLE group.", - "journal_title": "Epilepsy & behavior : E&B", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/28109988/" - } - ], - "739fa29e-6012-4f81-bf31-7437340e7d8d": [ - { - "pub_id": "20717041", - "title": "Consumer perceptions of direct-to-consumer personalized genomic risk assessments.", - "authors": "Cinnamon S Bloss,Laura Ornowski,Elana Silver,Michele Cargill,Vance Vanier,Nicholas J Schork,Eric J Topol", - "abstract": "To evaluate consumer perceptions of direct-to-consumer personalized genomic risk assessments and assess the extent to which consumer characteristics may be associated with attitudes toward testing. Adult participants aged 18-85 years of age purchased a personalized genomic risk test at a subsidized rate and were administered a web-based health assessment that included questions regarding perceptions and attitudes toward undergoing testing. Assessments were obtained for 3640 individual study participants, and 49.7% expressed overall concerns about undergoing testing. Logistic regression analysis revealed that women were more likely to express concerns (odds ratio [OR] = 1.20, 95% confidence interval [CI]: 1.04 -1.39), as were individuals employed by a health care organization (OR = 1.23, 95% CI: 1.04 -1.46). Further, younger age (OR = 0.97, 95% CI: 0.96-0.98), higher education (OR = 1.09, 95% CI: 1.04 -1.14), and higher trait anxiety (OR = 1.28, 95% CI: 1.20-1.37) were also significantly associated with expressing concerns related to testing. Attitudes regarding disclosure of genetic risk for a nonpreventable disease were also assessed. None of the individuals in our sample indicated that they would definitely not want to know their risk, and a total of 82.4% indicated that they would want to know. Among individuals who undergo direct-to-consumer genetic testing, approximately half still express concerns about the process/experience. Further, given that concerns vary among different subgroups of consumers, if the clinical validity and utility of these tests are demonstrated, tailored genetic education and counseling services may be of benefit.", - "journal_title": "Genetics in medicine : official journal of the American College of Medical Genetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/20717041/" - } - ], - "f98d8320-363e-4bd0-b9db-ef63076dffd0": [ - { - "pub_id": "17481880", - "title": "Polycomb comes of age: genome-wide profiling of target sites.", - "authors": "Leonie Ringrose", - "abstract": "The Polycomb group proteins are best known for their role as epigenetic regulators of the fly homeotic (Hox) gene clusters, but it has long been clear that these well conserved proteins have many other targets. For example, they are vital for maintaining both the pluripotency of stem cells and the identity of differentiated cells. However, a comprehensive list of experimentally defined targets has been lacking. Six new studies use genome wide profiling techniques to map Polycomb targets in stem cells and differentiated cells in vertebrates and flies. The findings of these studies demand that we rethink some of our current assumptions about Polycomb function.", - "journal_title": "Current opinion in cell biology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/17481880/" - } - ], - "5c9aed30-dec7-49af-9401-3ec6fa0e1334": [ - { - "pub_id": "15492030", - "title": "An evaluation of the current state of genomic data privacy protection technology and a roadmap for the future.", - "authors": "Bradley A Malin", - "abstract": "The incorporation of genomic data into personal medical records poses many challenges to patient privacy. In response, various systems for preserving patient privacy in shared genomic data have been developed and deployed. Although these systems de-identify the data by removing explicit identifiers (e.g., name, address, or Social Security number) and incorporate sound security design principles, they suffer from a lack of formal modeling of inferences learnable from shared data. This report evaluates the extent to which current protection systems are capable of withstanding a range of re-identification methods, including genotype-phenotype inferences, location-visit patterns, family structures, and dictionary attacks. For a comparative re-identification analysis, the systems are mapped to a common formalism. Although there is variation in susceptibility, each system is deficient in its protection capacity. The author discovers patterns of protection failure and discusses several of the reasons why these systems are susceptible. The analyses and discussion within provide guideposts for the development of next-generation protection methods amenable to formal proofs.", - "journal_title": "Journal of the American Medical Informatics Association : JAMIA", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/15492030/" - } - ], - "2aff9645-9903-469c-b4c5-61a25d39d302": [ - { - "pub_id": "14735123", - "title": "Endosymbiotic gene transfer: organelle genomes forge eukaryotic chromosomes.", - "authors": "Jeremy N Timmis,Michael A Ayliffe,Chun Y Huang,William Martin", - "abstract": "", - "journal_title": "Nature reviews. Genetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/14735123/" - } - ], - "945d2a33-0919-4140-92f1-5fc48aff0fc8": [ - { - "pub_id": "14766537", - "title": "Microbial genomics and the periodic table.", - "authors": "Lawrence P Wackett,Anthony G Dodge,Lynda B M Ellis", - "abstract": "", - "journal_title": "Applied and environmental microbiology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/14766537/" - } - ], - "de28144e-045c-42b7-b969-3d27a125aab4": [ - { - "pub_id": "20547776", - "title": "The teleost anatomy ontology: anatomical representation for the genomics age.", - "authors": "Wasila M Dahdul,John G Lundberg,Peter E Midford,James P Balhoff,Hilmar Lapp,Todd J Vision,Melissa A Haendel,Monte Westerfield,Paula M Mabee", - "abstract": "The rich knowledge of morphological variation among organisms reported in the systematic literature has remained in free-text format, impractical for use in large-scale synthetic phylogenetic work. This noncomputable format has also precluded linkage to the large knowledgebase of genomic, genetic, developmental, and phenotype data in model organism databases. We have undertaken an effort to prototype a curated, ontology-based evolutionary morphology database that maps to these genetic databases (http://kb.phenoscape.org) to facilitate investigation into the mechanistic basis and evolution of phenotypic diversity. Among the first requirements in establishing this database was the development of a multispecies anatomy ontology with the goal of capturing anatomical data in a systematic and computable manner. An ontology is a formal representation of a set of concepts with defined relationships between those concepts. Multispecies anatomy ontologies in particular are an efficient way to represent the diversity of morphological structures in a clade of organisms, but they present challenges in their development relative to single-species anatomy ontologies. Here, we describe the Teleost Anatomy Ontology (TAO), a multispecies anatomy ontology for teleost fishes derived from the Zebrafish Anatomical Ontology (ZFA) for the purpose of annotating varying morphological features across species. To facilitate interoperability with other anatomy ontologies, TAO uses the Common Anatomy Reference Ontology as a template for its upper level nodes, and TAO and ZFA are synchronized, with zebrafish terms specified as subtypes of teleost terms. We found that the details of ontology architecture have ramifications for querying, and we present general challenges in developing a multispecies anatomy ontology, including refinement of definitions, taxon-specific relationships among terms, and representation of taxonomically variable developmental pathways.", - "journal_title": "Systematic biology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/20547776/" - } - ], - "d4ce3a65-6e25-4561-aee1-2715edc1c35d": [ - { - "pub_id": "18293366", - "title": "A new role of the rDNA and nucleolus in the nucleus--rDNA instability maintains genome integrity.", - "authors": "Takehiko Kobayashi", - "abstract": "The nucleolus is a region of the nucleus with high protein density and it acts as a ribosome factory. The nucleolus contains a distinct region of the genome, the ribosomal RNA gene repeats (rDNA) that supply ribosomal RNA (rRNA) molecules. The rDNA is the most-abundant gene and occupies a large part of the genome, for example, there are thousands of rDNA copies in the genomes of plant cells. Therefore, it is natural to suppose that the condition of the rDNA, such as its stability, might affect cellular functions. Here I would like to propose a new model regarding the roles of the rDNA and nucleolus. The key point of this model is that they act to preserve genome stability and trigger aging.", - "journal_title": "BioEssays : news and reviews in molecular, cellular and developmental biology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/18293366/" - } - ], - "6f38cfff-88f1-4333-bc97-293200855bbf": [ - { - "pub_id": "18266980", - "title": "The genomic response of the ipsilateral and contralateral cortex to stroke in aged rats.", - "authors": "A-M Buga,M Sascau,C Pisoschi,J G Herndon,C Kessler,A Popa-Wagner", - "abstract": "Aged rats recover poorly after unilateral stroke, whereas young rats recover readily possibly with the help from the contralateral, healthy hemisphere. In this study we asked whether anomalous, age-related changes in the transcriptional activity in the brains of aged rats could be one underlying factor contributing to reduced functional recovery. We analysed gene expression in the periinfarct and contralateral areas of 3-month- and 18-month-old Sprague Dawley rats. Our experimental end-points were cDNA arrays containing genes related to hypoxia signalling, DNA damage and apoptosis, cellular response to injury, axonal damage and re-growth, cell lineage differentiation, dendritogenesis and neurogenesis. The major transcriptional events observed were: (i) Early up-regulation of DNA damage and down-regulation of anti-apoptosis-related genes in the periinfarct region of aged rats after stroke; (ii) Impaired neurogenesis in the periinfarct area, especially in aged rats; (iii) Impaired neurogenesis in the contralateral (unlesioned) hemisphere of both young and aged rats at all times after stroke and (iv) Marked up-regulation, in aged rats, of genes associated with inflammation and scar formation. These results were confirmed with quantitative real-time PCR. We conclude that reduced transcriptional activity in the healthy, contralateral hemisphere of aged rats in conjunction with an early up-regulation of DNA damage-related genes and pro-apoptotic genes and down-regulation of axono- and neurogenesis in the periinfarct area are likely to account for poor neurorehabilitation after stroke in old rats.", - "journal_title": "Journal of cellular and molecular medicine", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/18266980/" - } - ], - "5864b124-77f0-4bb2-9c7e-7223b81037a0": [ - { - "pub_id": "20145230", - "title": "Age- and sex-specific genomic profiles in non-small cell lung cancer.", - "authors": "William Mostertz,Marvaretta Stevenson,Chaitanya Acharya,Isaac Chan,Kelli Walters,Wisut Lamlertthon,William Barry,Jeffrey Crawford,Joseph Nevins,Anil Potti", - "abstract": "Gene expression profiling may be useful in examining differences underlying age- and sex-specific outcomes in non-small cell lung cancer (NSCLC). To describe clinically relevant differences in the underlying biology of NSCLC based on patient age and sex. Retrospective analysis of 787 patients with predominantly early stage NSCLC performed at Duke University, Durham, North Carolina, from July 2008 to June 2009. Lung tumor samples with corresponding microarray and clinical data were used. All patients were divided into subgroups based on age (< 70 vs > or = 70 years old) or sex. Gene expression signatures representing oncogenic pathway activation and tumor biology/microenvironment status were applied to these samples to obtain patterns of activation/deregulation. Patterns of oncogenic and molecular signaling pathway activation that are reproducible and correlate with 5-year recurrence-free patient survival. Low- and high-risk patient clusters/cohorts were identified with the longest and shortest 5-year recurrence-free survival, respectively, within the age and sex NSCLC subgroups. These cohorts of NSCLC demonstrate similar patterns of pathway activation. In patients younger than 70 years, high-risk patients, with the shortest recurrence-free survival, demonstrated increased activation of the Src (25% vs 6%; P<.001) and tumor necrosis factor (76% vs 42%; P<.001) pathways compared with low-risk patients. High-risk patients aged 70 years or older demonstrated increased activation of the wound healing (40% vs 24%; P = .02) and invasiveness (64% vs 20%; P<.001) pathways compared with low-risk patients. In women, high-risk patients demonstrated increased activation of the invasiveness (99% vs 2%; P<.001) and STAT3 (72% vs 35%; P<.001) pathways while high-risk men demonstrated increased activation of the STAT3 (87% vs 18%; P<.001), tumor necrosis factor (90% vs 46%; P<.001), EGFR (13% vs 2%; P = .003), and wound healing (50% vs 22%; P<.001) pathways. Multivariate analyses confirmed the independent clinical relevance of the pathway-based subphenotypes in women (hazard ratio [HR], 2.02; 95% confidence interval [CI], 1.34-3.03; P<.001) and patients younger than 70 years (HR, 1.83; 95% CI, 1.24-2.71; P = .003). All observations were reproducible in split sample analyses. Among a cohort of patients with NSCLC, subgroups defined by oncogenic pathway activation profiles were associated with recurrence-free survival. These findings require validation in independent patient data sets.", - "journal_title": "JAMA", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/20145230/" - } - ], - "af3230f3-0b27-4767-a91c-e639a8ef1c9b": [ - { - "pub_id": "15020760", - "title": "A new resource for cereal genomics: 22K barley GeneChip comes of age.", - "authors": "Timothy J Close,Steve I Wanamaker,Rico A Caldo,Stacy M Turner,Daniel A Ashlock,Julie A Dickerson,Rod A Wing,Gary J Muehlbauer,Andris Kleinhofs,Roger P Wise", - "abstract": "In recent years, access to complete genomic sequences, coupled with rapidly accumulating data related to RNA and protein expression patterns, has made it possible to determine comprehensively how genes contribute to complex phenotypes. However, for major crop plants, publicly available, standard platforms for parallel expression analysis have been limited. We report the conception and design of the new publicly available, 22K Barley1 GeneChip probe array, a model for plants without a fully sequenced genome. Array content was derived from worldwide contribution of 350,000 high-quality ESTs from 84 cDNA libraries, in addition to 1,145 barley (Hordeum vulgare) gene sequences from the National Center for Biotechnology Information nonredundant database. Conserved sequences expressed in seedlings of wheat (Triticum aestivum), oat (Avena strigosa), rice (Oryza sativa), sorghum (Sorghum bicolor), and maize (Zea mays) were identified that will be valuable in the design of arrays across grasses. To enhance the usability of the data, BarleyBase, a MIAME-compliant, MySQL relational database, serves as a public repository for raw and normalized expression data from the Barley1 GeneChip probe array. Interconnecting links with PlantGDB and Gramene allow BarleyBase users to perform gene predictions using the 21,439 non-redundant Barley1 exemplar sequences or cross-species comparison at the genome level, respectively. We expect that this first generation array will accelerate hypothesis generation and gene discovery in disease defense pathways, responses to abiotic stresses, development, and evolutionary diversity in monocot plants.", - "journal_title": "Plant physiology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/15020760/" - } - ], - "e1589e7c-180f-48b5-adfb-4c5231b3eaf7": [ - { - "pub_id": "29304378", - "title": "Life-Course Genome-wide Association Study Meta-analysis of Total Body BMD and Assessment of Age-Specific Effects.", - "authors": "Carolina Medina-Gomez,John P Kemp,Katerina Trajanoska,Jian'an Luan,Alessandra Chesi,Tarunveer S Ahluwalia,Dennis O Mook-Kanamori,Annelies Ham,Fernando P Hartwig,Daniel S Evans,Raimo Joro,Ivana Nedeljkovic,Hou-Feng Zheng,Kun Zhu,Mustafa Atalay,Ching-Ti Liu,Maria Nethander,Linda Broer,Gudmar Porleifsson,Benjamin H Mullin,Samuel K Handelman,Mike A Nalls,Leon E Jessen,Denise H M Heppe,J Brent Richards,Carol Wang,Bo Chawes,Katharina E Schraut,Najaf Amin,Nick Wareham,David Karasik,Nathalie Van der Velde,M Arfan Ikram,Babette S Zemel,Yanhua Zhou,Christian J Carlsson,Yongmei Liu,Fiona E McGuigan,Cindy G Boer,Klaus B\u00f8nnelykke,Stuart H Ralston,John A Robbins,John P Walsh,M Carola Zillikens,Claudia Langenberg,Ruifang Li-Gao,Frances M K Williams,Tamara B Harris,Kristina Akesson,Rebecca D Jackson,Gunnar Sigurdsson,Martin den Heijer,Bram C J van der Eerden,Jeroen van de Peppel,Timothy D Spector,Craig Pennell,Bernardo L Horta,Janine F Felix,Jing Hua Zhao,Scott G Wilson,Ren\u00e9e de Mutsert,Hans Bisgaard,Unnur Styrk\u00e1rsd\u00f3ttir,Vincent W Jaddoe,Eric Orwoll,Timo A Lakka,Robert Scott,Struan F A Grant,Mattias Lorentzon,Cornelia M van Duijn,James F Wilson,Kari Stefansson,Bruce M Psaty,Douglas P Kiel,Claes Ohlsson,Evangelia Ntzani,Andre J van Wijnen,Vincenzo Forgetta,Mohsen Ghanbari,John G Logan,Graham R Williams,J H Duncan Bassett,Peter I Croucher,Evangelos Evangelou,Andre G Uitterlinden,Cheryl L Ackert-Bicknell,Jonathan H Tobias,David M Evans,Fernando Rivadeneira", - "abstract": "Bone mineral density (BMD) assessed by DXA is used to evaluate bone health. In children, total body (TB) measurements are commonly used; in older individuals, BMD at the lumbar spine (LS) and femoral neck (FN) is used to diagnose osteoporosis. To date, genetic variants in more than 60 loci have been identified as associated with BMD. To investigate the genetic determinants of TB-BMD variation along the life course and test for age-specific effects, we performed a meta-analysis of 30 genome-wide association studies (GWASs) of TB-BMD including 66,628 individuals overall and divided across five age strata, each spanning 15 years. We identified variants associated with TB-BMD at 80 loci, of which 36 have not been previously identified; overall, they explain approximately 10% of the TB-BMD variance when combining all age groups and influence the risk of fracture. Pathway and enrichment analysis of the association signals showed clustering within gene sets implicated in the regulation of cell growth and SMAD proteins, overexpressed in the musculoskeletal system, and enriched in enhancer and promoter regions. These findings reveal TB-BMD as a relevant trait for genetic studies of osteoporosis, enabling the identification of variants and pathways influencing different bone compartments. Only variants in ESR1 and close proximity to RANKL showed a clear effect dependency on age. This most likely indicates that the majority of genetic variants identified influence BMD early in life and that their effect can be captured throughout the life course.", - "journal_title": "American journal of human genetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/29304378/" - } - ], - "8ac5e1a9-093d-436c-bd4d-f070640c63de": [ - { - "pub_id": "18056786", - "title": "Gene expression changes of prostanoid synthases in endothelial cells and prostanoid receptors in vascular smooth muscle cells caused by aging and hypertension.", - "authors": "Eva H C Tang,Paul M Vanhoutte", - "abstract": "The present study was designed to assess whether or not changes in genomic expression of cyclooxygenases (COX-1, COX-2), endothelial nitric oxide synthase (eNOS), and prostanoid synthases in the endothelium and of prostanoid receptors in vascular smooth muscle contribute to the occurrence of endothelium-dependent contractions during aging and hypertension. Gene expression was quantified by real-time PCR using isolated endothelial cells and smooth muscle cells (SMC) from the aorta of Wistar-Kyoto and spontaneously hypertensive rats. Genes for all known prostanoid synthases and receptors were present in endothelial cells and SMC, respectively. Aging caused overexpression of eNOS, COX-1, COX-2, thromboxane synthase, hematopoietic-type prostaglandin D synthase, membrane prostaglandin E synthase-2, and prostaglandin F synthase in endothelial cells and COX-1 and prostaglandin E(2) (EP)(4) receptors in SMC. Hypertension augmented the expression of COX-1, prostacyclin synthase, thromboxane synthase, and hematopoietic-type prostaglandin D synthase in endothelial cells and prostaglandin D(2) (DP), EP(3), and EP(4) receptors in SMC. The increase in genomic expression of endothelial COX-1 explains why in aging and hypertension the endothelium has greater propensity to release cyclooxygenase-derived vasoconstrictive prostanoids. The expression of prostacyclin synthase was by far the most abundant, explaining why the majority of the COX-1-derived endoperoxides are transformed into prostacyclin, substantiating the role of prostacyclin as an endothelium-derived contracting factor. The expression of thromboxane synthase was increased in the cells of aging or hypertensive rats, explaining why the prostanoid can contribute to endothelium-dependent contractions. It is uncertain whether the gene modifications caused by aging and hypertension directly contribute to endothelium-dependent contractions or rather to vascular aging and the vascular complications of the hypertensive process.", - "journal_title": "Physiological genomics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/18056786/" - } - ], - "76cf7c7b-78ec-4502-8939-ca36fb104ec0": [ - { - "pub_id": "17700626", - "title": "The role of nuclear architecture in genomic instability and ageing.", - "authors": "Philipp Oberdoerffer,David A Sinclair", - "abstract": "Eukaryotes come in many shapes and sizes, yet one thing that they all seem to share is a decline in vitality and health over time--a process known as ageing. If there are conserved causes of ageing, they may be traced back to common biological structures that are inherently difficult to maintain throughout life. One such structure is chromatin, the DNA-protein complex that stabilizes the genome and dictates gene expression. Studies in the budding yeast Saccharomyces cerevisiae have pointed to chromatin reorganization as a main contributor to ageing in that species, which raises the possibility that similar processes underlie ageing in more complex organisms.", - "journal_title": "Nature reviews. Molecular cell biology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/17700626/" - } - ], - "ebf39506-7edf-4b27-8ab1-b1c30e76c17a": [ - { - "pub_id": "17091560", - "title": "Procedural misconceptions and informed consent: insights from empirical research on the clinical trials industry.", - "authors": "Jill A Fisher", - "abstract": "This paper provides a simultaneously reflexive and analytical framework to think about obstacles to truly informed consent in social science and biomedical research. To do so, it argues that informed consent often goes awry due to procedural misconceptions built into the research context. The concept of procedural misconception is introduced to describe how individuals respond to what is familiar in research settings and overlook what is different. In the context of biomedical research, procedural misconceptions can be seen to function as root causes of therapeutic misconceptions.", - "journal_title": "Kennedy Institute of Ethics journal", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/17091560/" - } - ], - "9c9ea233-2346-4471-acbf-c74691e99677": [ - { - "pub_id": "18513784", - "title": "HGPS and related premature aging disorders: from genomic identification to the first therapeutic approaches.", - "authors": "Sandrine Pereira,Patrice Bourgeois,Claire Navarro,Vera Esteves-Vieira,Pierre Cau,Annachiara De Sandre-Giovannoli,Nicolas L\u00e9vy", - "abstract": "Progeroid syndromes are heritable human disorders displaying features that recall premature ageing. In these syndromes, premature aging is defined as \"segmental\" since only some of its features are accelerated. A number of cellular biological pathways have been linked to aging, including regulation of the insulin/growth hormone axis, pathways involving ROS metabolism, caloric restriction, and DNA repair. The number of identified genes associated with progeroid syndromes has increased in recent years, possibly shedding light as well on mechanisms underlying ageing in general. Among these, premature aging syndromes related to alterations of the LMNA gene have recently been identified. This review focuses on Hutchinson-Gilford Progeria syndrome and Restrictive Dermopathy, two well-characterized Lamin-associated premature aging syndromes, pointing out the current knowledge concerning their pathophysiology and the development of possible therapeutic approaches.", - "journal_title": "Mechanisms of ageing and development", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/18513784/" - } - ], - "e91ce172-bee4-4874-a7f2-d6d5a6b262aa": [ - { - "pub_id": "19191644", - "title": "Severity of meningococcal disease associated with genomic bacterial load.", - "authors": "Tom Darton,Malcolm Guiver,Simone Naylor,Dominic L Jack,Edward B Kaczmarski,Raymond Borrow,Robert C Read", - "abstract": "Diagnostic polymerase chain reaction (PCR) detection of Neisseria meningitidis has enabled accurate quantification of the bacterial load in patients with meningococcal disease. Quantification of the N. meningitidis DNA level by real time-PCR was conducted on whole-blood samples obtained from patients presenting with meningococcal disease to hospitals throughout England and Wales over a 3-year period. Levels were correlated with clinical outcome, infecting serogroup, and host factors including, interleukin-1 genotype (IL-1). Bacterial loads were available for 1045 patients and were not associated with the age of the patient, delay in sample submission, or administration of antibiotics prior to admission. The median log bacterial load was higher in 95 patients who died (5.29 log(10)copies/mL; interquartile range, 4.41-6.30 log(10)copies/mL) than in 950 patients who survived (3.79 log(10)copies/mL; interquartile range, 2.87-4.71 log(10)copies/mL). Logistic regression revealed that age (odds ratio, 1.04 per 1-year increase in age) and bacterial load (odds ratio, 2.04 per log(10)-copies/mL increase) had a statistically significant effect on the risk of death. Infection with N. meningitidis serogroup C was associated with increased risk of death and an increased bacterial load. Also associated with a higher bacterial load were prolonged hospitalization (duration, >10 days); digit, limb, or soft-tissue loss; and requirement of hemodialysis. Carriage of IL-1RN(+2018) was associated with increased mortality (odds ratio, 2.14; P=.07) but not with a higher bacterial load. In meningococcal disease, bacterial load is associated with likelihood of death, development of permanent disease sequelae, and prolonged hospitalization. The bacterial load was relatively higher in patients infected with N. meningitidis serogroup C than in those infected with other serogroups. The effects of age and IL-1 genotype on mortality are independent of a high genomic bacterial load.", - "journal_title": "Clinical infectious diseases : an official publication of the Infectious Diseases Society of America", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/19191644/" - } - ], - "932ef21b-9235-4210-a99c-6153a901bb89": [ - { - "pub_id": "28864056", - "title": "Classification of patients with sepsis according to blood genomic endotype: a prospective cohort study.", - "authors": "Brendon P Scicluna,Lonneke A van Vught,Aeilko H Zwinderman,Maryse A Wiewel,Emma E Davenport,Katie L Burnham,Peter N\u00fcrnberg,Marcus J Schultz,Janneke Horn,Olaf L Cremer,Marc J Bonten,Charles J Hinds,Hector R Wong,Julian C Knight,Tom van der Poll, ", - "abstract": "Host responses during sepsis are highly heterogeneous, which hampers the identification of patients at high risk of mortality and their selection for targeted therapies. In this study, we aimed to identify biologically relevant molecular endotypes in patients with sepsis. This was a prospective observational cohort study that included consecutive patients admitted for sepsis to two intensive care units (ICUs) in the Netherlands between Jan 1, 2011, and July 20, 2012 (discovery and first validation cohorts) and patients admitted with sepsis due to community-acquired pneumonia to 29 ICUs in the UK (second validation cohort). We generated genome-wide blood gene expression profiles from admission samples and analysed them by unsupervised consensus clustering and machine learning. The primary objective of this study was to establish endotypes for patients with sepsis, and assess the association of these endotypes with clinical traits and survival outcomes. We also established candidate biomarkers for the endotypes to allow identification of patient endotypes in clinical practice. The discovery cohort had 306 patients, the first validation cohort had 216, and the second validation cohort had 265 patients. Four molecular endotypes for sepsis, designated Mars1-4, were identified in the discovery cohort, and were associated with 28-day mortality (log-rank p=0\u00b7022). In the discovery cohort, the worst outcome was found for patients classified as having a Mars1 endotype, and at 28 days, 35 (39%) of 90 people with a Mars1 endotype had died (hazard ratio [HR] vs all other endotypes 1\u00b786 [95% CI 1\u00b721-2\u00b786]; p=0\u00b70045), compared with 23 (22%) of 105 people with a Mars2 endotype (HR 0\u00b764 [0\u00b740-1\u00b704]; p=0\u00b7061), 16 (23%) of 71 people with a Mars3 endotype (HR 0\u00b771 [0\u00b741-1\u00b722]; p=0\u00b719), and 13 (33%) of 40 patients with a Mars4 endotype (HR 1\u00b713 [0\u00b763-2\u00b704]; p=0\u00b769). Analysis of the net reclassification improvement using a combined clinical and endotype model significantly improved risk prediction to 0\u00b733 (0\u00b709-0\u00b758; p=0\u00b7008). A 140-gene expression signature reliably stratified patients with sepsis to the four endotypes in both the first and second validation cohorts. Only Mars1 was consistently significantly associated with 28-day mortality across the cohorts. To facilitate possible clinical use, a biomarker was derived for each endotype; BPGM and TAP2 reliably identified patients with a Mars1 endotype. This study provides a method for the molecular classification of patients with sepsis to four different endotypes upon ICU admission. Detection of sepsis endotypes might assist in providing personalised patient management and in selection for trials. Center for Translational Molecular Medicine, Netherlands.", - "journal_title": "The Lancet. Respiratory medicine", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/28864056/" - } - ], - "5e157c2e-91b8-466d-a9fd-f91f8f432f0c": [ - { - "pub_id": "17460161", - "title": "Biological aging is no longer an unsolved problem.", - "authors": "Leonard Hayflick", - "abstract": "The belief that aging is still an unsolved problem in biology is no longer true. Of the two major classes of theories, the one class that is tenable is derivative of a single common denominator that results in only one fundamental theory of aging. In order to address this complex subject, it is necessary to first define the four phenomena that characterize the finitude of life. These phenomena are aging, the determinants of longevity, age-associated diseases, and death. There are only two fundamental ways in which age changes can occur. Aging occurs either as the result of a purposeful program driven by genes or by events that are not guided by a program but are stochastic or random, accidental events. The weight of evidence indicates that genes do not drive the aging process but the general loss of molecular fidelity does. Potential longevity is determined by the energetics of all molecules present at and after the time of reproductive maturation. Thus, every molecule, including those that compose the machinery involved in turnover, replacement, and repair, becomes the substrate that experiences the thermodynamic instability characteristic of the aging process. However, the determinants of the fidelity of all molecules produced before and after reproductive maturity are the determinants of longevity. This process is governed by the genome. Aging does not happen in a vacuum. Aging must be the result of changes that occur in molecules that have existed at one time with no age changes. It is the state of these pre-existing molecules that governs longevity determination. The distinction between the aging process and age-associated disease is not only based on the molecular definition of aging described above but it is also rooted in several practical observations. Unlike any disease, age changes (a) occur in every multicellular animal that reaches a fixed size at reproductive maturity, (b) cross virtually all species barriers, (c) occur in all members of a species only after the age of reproductive maturation, (d) occur in all animals removed from the wild and protected by humans even when that species probably has not experienced aging for thousands or even millions of years, (e) occur in virtually all animate and inanimate matter, and (f) have the same universal molecular etiology, that is, thermodynamic instability. Unlike aging, there is no disease or pathology that shares these six qualities. Because this critical distinction is poorly understood, there is a continuing belief that the resolution of age-associated diseases will advance our understanding of the fundamental aging process. It will not. The distinction between disease and aging is also critical for establishing science policy because although policy makers understand that the funding of research on age-associated diseases is an unquestioned good, they also must understand that the resolution of age-associated diseases will not provide insights into understanding the fundamental biology of age changes. They often believe that it will and base decisions on that misunderstanding. The impact has been to fund research on age-associated diseases at several orders of magnitude greater than what is available for research on the biology of aging. There is an almost universal belief by geriatricians and others that the greatest risk factor for all of the leading causes of death is old age. Why then are we not devoting significantly greater resources to understanding more about the greatest risk factor for every age-associated pathology by attempting to answer this fundamental question-\"What changes occur in biomolecules that lead to the manifestations of aging at higher orders of complexity and then increase vulnerability to all age-associated pathology?\"", - "journal_title": "Annals of the New York Academy of Sciences", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/17460161/" - } - ], - "b547b680-8602-4a15-8d91-6a6d3ffa19d2": [ - { - "pub_id": "12771225", - "title": "Precise determination of mitochondrial DNA copy number in human skeletal and cardiac muscle by a PCR-based assay: lack of change of copy number with age.", - "authors": "Francis J Miller,Franklin L Rosenfeldt,Chunfang Zhang,Anthony W Linnane,Phillip Nagley", - "abstract": "Deletions in mitochondrial DNA (mtDNA) accumulate with age in humans without overt mitochondriopathies, but relatively limited attention has been devoted to the measurement of the total number of mtDNA molecules per cell during ageing. We have developed a precise assay that determines mtDNA levels relative to nuclear DNA using a PCR-based procedure. Quantification was performed by reference to a single recombinant plasmid standard containing a copy of each target DNA sequence (mitochondrial and nuclear). Copy number of mtDNA was determined by amplifying a short region of the cytochrome b gene (although other regions of mtDNA were demonstrably useful). Nuclear DNA content was determined by amplification of a segment of the single copy beta-globin gene. The copy number of mtDNA per diploid nuclear genome in myocardium was 6970 +/- 920, significantly higher than that in skeletal muscle, 3650 +/- 620 (P = 0.006). In both human skeletal muscle and myocardium, there was no significant change in mtDNA copy number with age (from neonates to subjects older than 80 years). This PCR-based assay not only enables accurate determination of mtDNA relative to nuclear DNA but also has the potential to quantify accurately any DNA sequence in relation to any other.", - "journal_title": "Nucleic acids research", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/12771225/" - } - ], - "b82d6db0-c25a-45eb-ae8f-e9a83e461ddb": [ - { - "pub_id": "17611191", - "title": "The domestication of artichoke and cardoon: from Roman times to the genomic age.", - "authors": "Gabriella Sonnante,Domenico Pignone,Karl Hammer", - "abstract": "The history of domestication of artichoke and leafy cardoon is not yet fully understood and when and where it occurred remains unknown. Evidence supports the hypothesis that wild cardoon is the wild progenitor of both these crops. Selection for large, non-spiny heads resulted in artichoke and selection for non-spiny, large stalked tender leaves resulted in leafy cardoon. The two crops differ in their reproductive system: artichoke is mostly vegetatively propagated and perennial, while leafy cardoon is seed propagated and mostly grown as an annual plant. Here, new trends in artichoke cultivation are analysed, while the consequences of these tendencies on the conservation of artichoke genetic resources are highlighted. The historical and artistic records, together with recent literature on genetics and biosystematics, are examined with the aim of achieving a better understanding of the present-day knowledge on the domestication of these two crops. Historical, linguistic and artistic records are consistent with genetic and biosystematic data and indicate that the domestication of artichoke and cardoon diverged at different times and in different places. Apparently, artichoke was domesticated in Roman times, possibly in Sicily, and spread by the Arabs during early Middle Ages. The cardoon was probably domesticated in the western Mediterranean in a later period.", - "journal_title": "Annals of botany", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/17611191/" - } - ], - "c3ea569f-31e0-4061-8dd6-a9b02246511b": [ - { - "pub_id": "18094749", - "title": "A high quality draft consensus sequence of the genome of a heterozygous grapevine variety.", - "authors": "Riccardo Velasco,Andrey Zharkikh,Michela Troggio,Dustin A Cartwright,Alessandro Cestaro,Dmitry Pruss,Massimo Pindo,Lisa M Fitzgerald,Silvia Vezzulli,Julia Reid,Giulia Malacarne,Diana Iliev,Giuseppina Coppola,Bryan Wardell,Diego Micheletti,Teresita Macalma,Marco Facci,Jeff T Mitchell,Michele Perazzolli,Glenn Eldredge,Pamela Gatto,Rozan Oyzerski,Marco Moretto,Natalia Gutin,Marco Stefanini,Yang Chen,Cinzia Segala,Christine Davenport,Lorenzo Dematt\u00e8,Amy Mraz,Juri Battilana,Keith Stormo,Fabrizio Costa,Quanzhou Tao,Azeddine Si-Ammour,Tim Harkins,Angie Lackey,Clotilde Perbost,Bruce Taillon,Alessandra Stella,Victor Solovyev,Jeffrey A Fawcett,Lieven Sterck,Klaas Vandepoele,Stella M Grando,Stefano Toppo,Claudio Moser,Jerry Lanchbury,Robert Bogden,Mark Skolnick,Vittorio Sgaramella,Satish K Bhatnagar,Paolo Fontana,Alexander Gutin,Yves Van de Peer,Francesco Salamini,Roberto Viola", - "abstract": "Worldwide, grapes and their derived products have a large market. The cultivated grape species Vitis vinifera has potential to become a model for fruit trees genetics. Like many plant species, it is highly heterozygous, which is an additional challenge to modern whole genome shotgun sequencing. In this paper a high quality draft genome sequence of a cultivated clone of V. vinifera Pinot Noir is presented. We estimate the genome size of V. vinifera to be 504.6 Mb. Genomic sequences corresponding to 477.1 Mb were assembled in 2,093 metacontigs and 435.1 Mb were anchored to the 19 linkage groups (LGs). The number of predicted genes is 29,585, of which 96.1% were assigned to LGs. This assembly of the grape genome provides candidate genes implicated in traits relevant to grapevine cultivation, such as those influencing wine quality, via secondary metabolites, and those connected with the extreme susceptibility of grape to pathogens. Single nucleotide polymorphism (SNP) distribution was consistent with a diffuse haplotype structure across the genome. Of around 2,000,000 SNPs, 1,751,176 were mapped to chromosomes and one or more of them were identified in 86.7% of anchored genes. The relative age of grape duplicated genes was estimated and this made possible to reveal a relatively recent Vitis-specific large scale duplication event concerning at least 10 chromosomes (duplication not reported before). Sanger shotgun sequencing and highly efficient sequencing by synthesis (SBS), together with dedicated assembly programs, resolved a complex heterozygous genome. A consensus sequence of the genome and a set of mapped marker loci were generated. Homologous chromosomes of Pinot Noir differ by 11.2% of their DNA (hemizygous DNA plus chromosomal gaps). SNP markers are offered as a tool with the potential of introducing a new era in the molecular breeding of grape.", - "journal_title": "PloS one", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/18094749/" - } - ], - "5dedbd70-deac-4652-ac8e-6c768ad49a73": [ - { - "pub_id": "20591991", - "title": "Higher-order genome organization in human disease.", - "authors": "Tom Misteli", - "abstract": "Genomes are organized into complex higher-order structures by folding of the DNA into chromatin fibers, chromosome domains, and ultimately chromosomes. The higher-order organization of genomes is functionally important for gene regulation and control of gene expression programs. Defects in how chromatin is globally organized are relevant for physiological and pathological processes. Mutations and transcriptional misregulation of several global genome organizers are linked to human diseases and global alterations in chromatin structure are emerging as key players in maintenance of genome stability, aging, and the formation of cancer translocations.", - "journal_title": "Cold Spring Harbor perspectives in biology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/20591991/" - } - ], - "bf11c54e-7cc4-4fe2-97b0-70c464263846": [ - { - "pub_id": "16359963", - "title": "Genome-wide linkage analysis to age at natural menopause in a community-based sample: the Framingham Heart Study.", - "authors": "Joanne M Murabito,Qiong Yang,Caroline S Fox,L Adrienne Cupples", - "abstract": "To identify chromosomal regions linked to age at natural menopause. Two-generation families studied with a 10-centimorgan (cM) genome-wide scan. The Framingham Study, a community-based epidemiologic study. A total of 861 women in 291 families reporting a natural menopause (mean age at menopause, 49 years). None. Multipoint variance components linkage analysis was performed with Genehunter software (Whitehead Institute, Massachusetts Institute of Technology, Boston, MA) for age at natural menopause. In the crude variance components analysis, 11 chromosomes had a log odds ratio (LOD) score of > or =1.0. Two chromosomal regions revealed suggestive linkage: chromosome 8 at 26 cM (LOD 2.6; nearest marker GATA23D06) and chromosome 16 at 11 cM (LOD 2.4; nearest marker ATA41E04). In the analysis adjusted for generation, smoking, and body mass index, chromosome 11 revealed suggestive linkage at 113 cM (LOD 2.1; nearest marker GATA23E06). We have identified novel loci suggestive for linkage to age at natural menopause. Further research is needed to identify genes involved in the onset of menopause, which might provide insights into loss of fertility.", - "journal_title": "Fertility and sterility", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/16359963/" - } - ], - "c3c70600-e133-45a6-98cc-5aac2decd171": [ - { - "pub_id": "22021441", - "title": "Retrotransposition is associated with genome instability during chronological aging.", - "authors": "Patrick H Maxwell,William C Burhans,M Joan Curcio", - "abstract": "Genetic damage through mutations and genome rearrangements has been hypothesized to contribute to aging. The specific mechanisms responsible for age-induced increases in mutation and chromosome rearrangement frequencies and a potential causative role for DNA damage in aging are under active investigation. Retrotransposons are mobile genetic elements that cause insertion mutations and contribute to genome rearrangements through nonallelic recombination events in humans and other organisms. We have investigated the role of endogenous Ty1 retrotransposons in aging-associated increases in genome instability using the Saccharomyces cerevisiae chronological aging model. We show that age-induced increases in loss of heterozygosity and chromosome loss events are consistently diminished by mutations or treatments that reduce Ty1 retrotransposition. Ty1 mobility is elevated in very old yeast populations, and new retromobility events are often associated with chromosome rearrangements. These results reveal a correlation between retrotransposition and genome instability during yeast aging. Retrotransposition may contribute to genetic damage during aging in diverse organisms and provides a useful tool for studying whether genetic damage is a causative factor for aging.", - "journal_title": "Proceedings of the National Academy of Sciences of the United States of America", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/22021441/" - } - ], - "a1df6e72-7e5b-4bcf-bcb0-54b5bf5dc05e": [ - { - "pub_id": "19901537", - "title": "Loss of A-type lamins and genomic instability.", - "authors": "Ignacio Gonzalez-Suarez,Abena B Redwood,Susana Gonzalo", - "abstract": "Research performed in the last few years has revealed important roles for the spatial and temporal organization of the genome on genome function and integrity. A challenge in the field is to determine the molecular mechanisms involved in the organization of genome function. A-type lamins, key structural components of the nucleus, have been implicated in the maintenance of nuclear architecture and chromatin structure. Interestingly, alterations of A-type lamins lead to defects in DNA replication and repair as well as gene transcription and silencing. Elucidating the functions of these proteins is a topical subject since alterations of A-type lamins are associated with a variety of human diseases, ranging from muscular dystrophies and premature aging syndromes to cancer. Here, we discuss novels roles for A-type lamins in the maintenance of telomere structure, length and function as well as in the stabilization of a key DNA damage response factor. These studies support the notion that increased genomic instability due to defects in telomere biology and DNA repair contribute to the pathogenesis of lamin-related diseases.", - "journal_title": "Cell cycle (Georgetown, Tex.)", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/19901537/" - } - ], - "24ce8a0c-393a-4e27-b2e5-69b4675b2fa7": [ - { - "pub_id": "21292315", - "title": "Imputation of sequence variants for identification of genetic risks for Parkinson's disease: a meta-analysis of genome-wide association studies.", - "authors": " ,Michael A Nalls,Vincent Plagnol,Dena G Hernandez,Manu Sharma,Una-Marie Sheerin,Mohamad Saad,J Sim\u00f3n-S\u00e1nchez,Claudia Schulte,Suzanne Lesage,Sigurlaug Sveinbj\u00f6rnsd\u00f3ttir,K\u00e1ri Stef\u00e1nsson,Maria Martinez,John Hardy,Peter Heutink,Alexis Brice,Thomas Gasser,Andrew B Singleton,Nicholas W Wood", - "abstract": "Genome-wide association studies (GWAS) for Parkinson's disease have linked two loci (MAPT and SNCA) to risk of Parkinson's disease. We aimed to identify novel risk loci for Parkinson's disease. We did a meta-analysis of datasets from five Parkinson's disease GWAS from the USA and Europe to identify loci associated with Parkinson's disease (discovery phase). We then did replication analyses of significantly associated loci in an independent sample series. Estimates of population-attributable risk were calculated from estimates from the discovery and replication phases combined, and risk-profile estimates for loci identified in the discovery phase were calculated. The discovery phase consisted of 5333 case and 12\u2008019 control samples, with genotyped and imputed data at 7\u2008689\u2008524 SNPs. The replication phase consisted of 7053 case and 9007 control samples. We identified 11 loci that surpassed the threshold for genome-wide significance (p<5\u00d710(-8)). Six were previously identified loci (MAPT, SNCA, HLA-DRB5, BST1, GAK and LRRK2) and five were newly identified loci (ACMSD, STK39, MCCC1/LAMP3, SYT11, and CCDC62/HIP1R). The combined population-attributable risk was 60\u00b73% (95% CI 43\u00b77-69\u00b73). In the risk-profile analysis, the odds ratio in the highest quintile of disease risk was 2\u00b751 (95% CI 2\u00b723-2\u00b783) compared with 1\u00b700 in the lowest quintile of disease risk. These data provide an insight into the genetics of Parkinson's disease and the molecular cause of the disease and could provide future targets for therapies. Wellcome Trust, National Institute on Aging, and US Department of Defense.", - "journal_title": "Lancet (London, England)", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/21292315/" - } - ], - "2cbd68a5-90b6-4740-8f1b-5fa8e77f11e4": [ - { - "pub_id": "18591461", - "title": "Genomic association analysis suggests chromosome 12 locus influencing antihypertensive response to thiazide diuretic.", - "authors": "Stephen T Turner,Kent R Bailey,Brooke L Fridley,Arlene B Chapman,Gary L Schwartz,High Seng Chai,Hugues Sicotte,Jean-Pierre Kocher,Andr\u00e9i S Rodin,Eric Boerwinkle", - "abstract": "We conducted a genome-wide association study to identify novel genes influencing diastolic blood pressure (BP) response to hydrochlorothiazide, a commonly prescribed thiazide diuretic preferred for the treatment of high BP. Affymetrix GeneChip Human Mapping 100K Arrays were used to measure single nucleotide polymorphisms across the 22 autosomes in 194 non-Hispanic black subjects and 195 non-Hispanic white subjects with essential hypertension selected from opposite tertiles of the race- and sex-specific distributions of age-adjusted diastolic BP response to hydrochlorothiazide (25 mg daily, PO, for 4 weeks). The black sample consisted of 97 \"good\" responders (diastolic BP response [mean+/-SD]=-18.3+/-4.2 mm Hg; age=47.1+/-6.1 years; 51.5% women) and 97 \"poor\" responders (diastolic BP response=-0.18+/-4.3; age=47.4+/-6.5 years; 51.5% women). Haplotype trend regression identified a region of chromosome 12q15 in which haplotypes constructed from 3 successive single nucleotide polymorphisms (rs317689, rs315135, and rs7297610) in proximity to lysozyme (LYZ), YEATS domain containing 4 (YEATS4), and fibroblast growth receptor substrate 2 (FRS2) were significantly associated with diastolic BP response (nominal P=2.39 x 10(-7); Bonferroni corrected P=0.024; simulated experiment-wise P=0.040). Genotyping of 35 additional single nucleotide polymorphisms selected to \"tag\" linkage disequilibrium blocks in these genes provided corroboration that variation in LYZ and YEATS4 was associated with diastolic BP response in a statistically independent data set of 291 black subjects and in the sample of 294 white subjects. These results support the use of genome-wide association analyses to identify novel genes influencing antihypertensive drug responses.", - "journal_title": "Hypertension (Dallas, Tex. : 1979)", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/18591461/" - } - ], - "82437393-a1b1-4d2c-888c-43cc0b983f9d": [ - { - "pub_id": "37878311", - "title": "Personalized Initial Screening Age for Colorectal Cancer in Individuals at Average Risk.", - "authors": "Xuechen Chen,Thomas Heisser,Rafael Cardoso,Michael Hoffmeister,Hermann Brenner", - "abstract": "Colorectal cancer (CRC) risk varies widely in the population at average risk without a family history, but there are no established routines for translating this variation into personalized starting ages of screening. To illustrate derivation of risk-adapted starting ages of CRC screening based on the concept of risk advancement period (RAP) using sex and a polygenic risk score (PRS) as an example. This cohort study included participants in the UK Biobank study recruited in England, Wales, and Scotland between March 13, 2006, and October 1, 2010. Participants were aged 40 to 69 years, with no previous bowel cancer screening and no family history of CRC. Follow-up of cancer data was completed February 29, 2020, for England and Wales and January 31, 2021, for Scotland. The censoring date for death data was September 30, 2021, for England and Wales and October 31, 2021, for Scotland. Data on age, sex, and family history were collected at the baseline interview. A PRS was calculated based on 139 CRC-related risk loci. Hazard ratios (HRs) of sex and PRS with CRC risk and mortality were estimated using Cox proportional hazards regression models and were translated to RAPs to quantify how many years of age earlier or later men and individuals in higher or lower PRS deciles would reach risks comparable with those of the reference group (ie, women or those in the 5th and 6th PRS deciles). Among 242\u202f779 participants (median age, 55 [IQR, 48-61] years; 55.7% women), 2714 incident CRC cases were identified during a median follow-up of 11.2 (IQR, 10.5-11.8) years and 758 deaths during a median follow-up of 12.8 (IQR, 12.0-13.4) years. The HRs of CRC risk were 1.57 (95% CI, 1.46-1.70) for men vs women and ranged from 0.51 (95% CI, 0.41-0.62) to 2.29 (95% CI, 2.01-2.62) across PRS deciles compared with the reference. The RAPs were 5.6 (95% CI, 4.6-6.6) years for men vs women and ranged from -8.4 (95% CI, -11.0 to -5.9) to 10.3 (95% CI, 8.5-12.1) years across PRS deciles compared with the reference deciles. Risk-adapted starting ages of screening would vary by 24 years between men in the highest PRS decile and women in the lowest PRS decile. Similar results were obtained regarding CRC mortality. In this large cohort study including women and men at average risk of CRC, risk-adapted starting ages of screening strongly varied by sex and a PRS. The RAP concept could easily accommodate additional factors for defining personalized starting ages of screening.", - "journal_title": "JAMA network open", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/37878311/" - } - ], - "db69a0c9-d16f-40ff-b0ed-10ebeccf2857": [ - { - "pub_id": "22072915", - "title": "The role of microRNAs in the biology of rare diseases.", - "authors": "Marco Salvatore,Armando Magrelli,Domenica Taruscio", - "abstract": "Rare diseases (RD) are characterized by low prevalence and affect not more than five individuals per 10,000 in the European population; they are a large and heterogeneous group of disorders including more than 7,000 conditions and often involve all organs and tissues, with several clinical subtypes within the same disease. Very often information concerning either diagnosis and/or prognosis on many RD is insufficient. microRNAs are a class of small non-coding RNAs that regulate gene expression at the posttranscriptional level by either degrading or blocking translation of messenger RNA targets. Recently, microRNA expression patterns of body fluids underscored their potential as noninvasive biomarkers for various diseases. The role of microRNAs as potential biomarkers has become particularly attractive. The identification of disease-related microRNAs is essential for understanding the pathogenesis of diseases at the molecular level, and is critical for designing specific molecular tools for diagnosis, treatment and prevention. Computational analysis of microRNA-disease associations is an important complementary means for prioritizing microRNAs for further experimental examination. In this article, we explored the added value of miRs as biomarkers in a selected panel of RD hitting different tissues/systems at different life stages, but sharing the need of better biomarkers for diagnostic and prognostic purposes.", - "journal_title": "International journal of molecular sciences", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/22072915/" - } - ], - "b690d3d2-3e07-4b43-b4bd-dac859d8f1b2": [ - { - "pub_id": "20445092", - "title": "Colloquium paper: gene-culture coevolution in the age of genomics.", - "authors": "Peter J Richerson,Robert Boyd,Joseph Henrich", - "abstract": "The use of socially learned information (culture) is central to human adaptations. We investigate the hypothesis that the process of cultural evolution has played an active, leading role in the evolution of genes. Culture normally evolves more rapidly than genes, creating novel environments that expose genes to new selective pressures. Many human genes that have been shown to be under recent or current selection are changing as a result of new environments created by cultural innovations. Some changed in response to the development of agricultural subsistence systems in the Early and Middle Holocene. Alleles coding for adaptations to diets rich in plant starch (e.g., amylase copy number) and to epidemic diseases evolved as human populations expanded (e.g., sickle cell and G6PD deficiency alleles that provide protection against malaria). Large-scale scans using patterns of linkage disequilibrium to detect recent selection suggest that many more genes evolved in response to agriculture. Genetic change in response to the novel social environment of contemporary modern societies is also likely to be occurring. The functional effects of most of the alleles under selection during the last 10,000 years are currently unknown. Also unknown is the role of paleoenvironmental change in regulating the tempo of hominin evolution. Although the full extent of culture-driven gene-culture coevolution is thus far unknown for the deeper history of the human lineage, theory and some evidence suggest that such effects were profound. Genomic methods promise to have a major impact on our understanding of gene-culture coevolution over the span of hominin evolutionary history.", - "journal_title": "Proceedings of the National Academy of Sciences of the United States of America", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/20445092/" - } - ], - "cbd28940-51f7-4ca6-9ee9-75834117470d": [ - { - "pub_id": "15987700", - "title": "Meta-analysis of genome scans of age-related macular degeneration.", - "authors": "Sheila A Fisher,Goncalo R Abecasis,Beverly M Yashar,Sepideh Zareparsi,Anand Swaroop,Sudha K Iyengar,Barbara E K Klein,Ronald Klein,Kristine E Lee,Jacek Majewski,Dennis W Schultz,Michael L Klein,Johanna M Seddon,Susan L Santangelo,Daniel E Weeks,Yvette P Conley,Tammy S Mah,Silke Schmidt,Jonathan L Haines,Margaret A Pericak-Vance,Michael B Gorin,Heidi L Schulz,Fabio Pardi,Cathryn M Lewis,Bernhard H F Weber", - "abstract": "A genetic contribution to the development of age-related macular degeneration (AMD) is well established. Several genome-wide linkage studies have identified a number of putative susceptibility loci for AMD but only a few of these regions have been replicated in independent studies. Here, we perform a meta-analysis of six AMD genome screens using the genome-scan meta-analysis method, which allows linkage results from several studies to be combined, providing greater power to identify regions that show only weak evidence for linkage in individual studies. Results from non-parametric analysis for a broad AMD clinical phenotype (including two studies with quantitative traits) were extracted. For each study, 120 genomic bins of approximately 30 cM were defined and ranked according to maximum evidence for linkage within each bin. Bin ranks were weighted according to study size and summed across all studies; the summed rank (SR) for each bin was assessed empirically for significance using permutation methods. A high SR indicates a region with consistent evidence for linkage across studies. The strongest evidence for an AMD susceptibility locus was found on chromosome 10q26 where genome-wide significant linkage was observed (P=0.00025). Several other regions met the empirical significance criteria for bins likely to contain linked loci including adjacent pairs of bins on chromosomes 1q, 2p, 3p and 16. Several of the regions identified here showed only weak evidence for linkage in the individual studies. These results will help prioritize regions for future positional and functional candidate gene studies in AMD.", - "journal_title": "Human molecular genetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/15987700/" - } - ], - "4f0c4753-f320-417c-a9e7-8cb013763242": [ - { - "pub_id": "19223933", - "title": "Predicting human height by Victorian and genomic methods.", - "authors": "Yurii S Aulchenko,Maksim V Struchalin,Nadezhda M Belonogova,Tatiana I Axenovich,Michael N Weedon,Albert Hofman,Andre G Uitterlinden,Manfred Kayser,Ben A Oostra,Cornelia M van Duijn,A Cecile J W Janssens,Pavel M Borodin", - "abstract": "In the Victorian era, Sir Francis Galton showed that 'when dealing with the transmission of stature from parents to children, the average height of the two parents, ... is all we need care to know about them' (1886). One hundred and twenty-two years after Galton's work was published, 54 loci showing strong statistical evidence for association to human height were described, providing us with potential genomic means of human height prediction. In a population-based study of 5748 people, we find that a 54-loci genomic profile explained 4-6% of the sex- and age-adjusted height variance, and had limited ability to discriminate tall/short people, as characterized by the area under the receiver-operating characteristic curve (AUC). In a family-based study of 550 people, with both parents having height measurements, we find that the Galtonian mid-parental prediction method explained 40% of the sex- and age-adjusted height variance, and showed high discriminative accuracy. We have also explored how much variance a genomic profile should explain to reach certain AUC values. For highly heritable traits such as height, we conclude that in applications in which parental phenotypic information is available (eg, medicine), the Victorian Galton's method will long stay unsurpassed, in terms of both discriminative accuracy and costs. For less heritable traits, and in situations in which parental information is not available (eg, forensics), genomic methods may provide an alternative, given that the variants determining an essential proportion of the trait's variation can be identified.", - "journal_title": "European journal of human genetics : EJHG", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/19223933/" - } - ], - "a091f1b1-ee5a-4607-872d-db26a2d67f87": [ - { - "pub_id": "19439569", - "title": "Agrobacterium in the genomics age.", - "authors": "Stanton B Gelvin", - "abstract": "", - "journal_title": "Plant physiology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/19439569/" - } - ], - "64dc1669-193e-43ec-ad7b-6ad934f823e6": [ - { - "pub_id": "20961390", - "title": "Chromatin remodeling in the aging genome of Drosophila.", - "authors": "Jason G Wood,Sara Hillenmeyer,Charles Lawrence,Chengyi Chang,Suzanne Hosier,Will Lightfoot,Eric Mukherjee,Nan Jiang,Christoph Schorl,Alexander S Brodsky,Nicola Neretti,Stephen L Helfand", - "abstract": "Chromatin structure affects the accessibility of DNA to transcription, repair, and replication. Changes in chromatin structure occur during development, but less is known about changes during aging. We examined the state of chromatin structure and its effect on gene expression during aging in Drosophila at the whole genome and cellular level using whole-genome tiling microarrays of activation and repressive chromatin marks, whole-genome transcriptional microarrays and single-cell immunohistochemistry. We found dramatic reorganization of chromosomal regions with age. Mapping of H3K9me3 and HP1 signals to fly chromosomes reveals in young flies the expected high enrichment in the pericentric regions, the 4th chromosome, and islands of facultative heterochromatin dispersed throughout the genome. With age, there is a striking reduction in this enrichment resulting in a nearly equivalent level of H3K9me3 and HP1 in the pericentric regions, the 4th chromosome, facultative heterochromatin, and euchromatin. These extensive changes in repressive chromatin marks are associated with alterations in age-related gene expression. Large-scale changes in repressive marks with age are further substantiated by single-cell immunohistochemistry that shows changes in nuclear distribution of H3K9me3 and HP1 marks with age. Such epigenetic changes are expected to directly or indirectly impinge upon important cellular functions such as gene expression, DNA repair, and DNA replication. The combination of genome-wide approaches such as whole-genome chromatin immunoprecipitation and transcriptional studies in conjunction with single-cell immunohistochemistry as shown here provide a first step toward defining how changes in chromatin may contribute to the process of aging in metazoans.", - "journal_title": "Aging cell", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/20961390/" - } - ], - "c89f6c23-d5ac-4352-9b82-2ba559b20c0b": [ - { - "pub_id": "18055498", - "title": "DNA replication stress, genome instability and aging.", - "authors": "William C Burhans,Martin Weinberger", - "abstract": "Genome instability is a fundamentally important component of aging in all eukaryotes. How age-related genome instability occurs remains unclear. The free radical theory of aging posits oxidative damage to DNA and other cellular constituents as a primary determinant of aging. More recent versions of this theory predict that mitochondria are a major source of reactive oxygen species (ROS) that cause oxidative damage. Although substantial support for the free radical theory exists, the results of some tests of this theory have been contradictory or inconclusive. Enhanced growth signaling also has been implicated in aging. Many efforts to understand the effects of growth signaling on aging have focused on inhibition of oxidative stress responses that impact oxidative damage. However, recent experiments in the model organism Saccharomyces cerevisiae (budding yeast) and in higher eukaryotes suggest that growth signaling also impacts aging and/or age-related diseases--including cancer and neurodegeneration--by inducing DNA replication stress, which causes DNA damage. Replication stress, which has not been broadly considered as a factor in aging, may be enhanced by ROS that signal growth. In this article, we review evidence that points to DNA replication stress and replication stress-induced genome instability as important factors in aging.", - "journal_title": "Nucleic acids research", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/18055498/" - } - ], - "df272e44-8335-4287-84f5-3244134896c0": [ - { - "pub_id": "17077275", - "title": "Gene expression profiles in anatomically and functionally distinct regions of the normal aged human brain.", - "authors": "Winnie S Liang,Travis Dunckley,Thomas G Beach,Andrew Grover,Diego Mastroeni,Douglas G Walker,Richard J Caselli,Walter A Kukull,Daniel McKeel,John C Morris,Christine Hulette,Donald Schmechel,Gene E Alexander,Eric M Reiman,Joseph Rogers,Dietrich A Stephan", - "abstract": "In this article, we have characterized and compared gene expression profiles from laser capture microdissected neurons in six functionally and anatomically distinct regions from clinically and histopathologically normal aged human brains. These regions, which are also known to be differentially vulnerable to the histopathological and metabolic features of Alzheimer's disease (AD), include the entorhinal cortex and hippocampus (limbic and paralimbic areas vulnerable to early neurofibrillary tangle pathology in AD), posterior cingulate cortex (a paralimbic area vulnerable to early metabolic abnormalities in AD), temporal and prefrontal cortex (unimodal and heteromodal sensory association areas vulnerable to early neuritic plaque pathology in AD), and primary visual cortex (a primary sensory area relatively spared in early AD). These neuronal profiles will provide valuable reference information for future studies of the brain, in normal aging, AD and other neurological and psychiatric disorders.", - "journal_title": "Physiological genomics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/17077275/" - } - ], - "0df3c32c-ac79-45d0-a846-331bae5a7daf": [ - { - "pub_id": "20075015", - "title": "Roles of Werner syndrome protein in protection of genome integrity.", - "authors": "Marie L Rossi,Avik K Ghosh,Vilhelm A Bohr", - "abstract": "Werner syndrome protein (WRN) is one of a family of five human RecQ helicases implicated in the maintenance of genome stability. The conserved RecQ family also includes RecQ1, Bloom syndrome protein (BLM), RecQ4, and RecQ5 in humans, as well as Sgs1 in Saccharomyces cerevisiae, Rqh1 in Schizosaccharomyces pombe, and homologs in Caenorhabditis elegans, Xenopus laevis, and Drosophila melanogaster. Defects in three of the RecQ helicases, RecQ4, BLM, and WRN, cause human pathologies linked with cancer predisposition and premature aging. Mutations in the WRN gene are the causative factor of Werner syndrome (WS). WRN is one of the best characterized of the RecQ helicases and is known to have roles in DNA replication and repair, transcription, and telomere maintenance. Studies both in vitro and in vivo indicate that the roles of WRN in a variety of DNA processes are mediated by post-translational modifications, as well as several important protein-protein interactions. In this work, we will summarize some of the early studies on the cellular roles of WRN and highlight the recent findings that shed some light on the link between the protein with its cellular functions and the disease pathology.", - "journal_title": "DNA repair", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/20075015/" - } - ], - "7d57d11b-ffda-4206-bd55-382540c98a79": [ - { - "pub_id": "16530704", - "title": "Global DNA demethylation in gastrointestinal cancer is age dependent and precedes genomic damage.", - "authors": "Koichi Suzuki,Ikuko Suzuki,Andreas Leodolter,Sergio Alonso,Shina Horiuchi,Kentaro Yamashita,Manuel Perucho", - "abstract": "We studied the relationships between genetic and epigenetic alterations in gastrointestinal cancer by integrating DNA copy number changes determined by arbitrarily primed PCR (AP-PCR) with DNA methylation variations estimated by methylation-sensitive amplified fragment length polymorphism (MS-AFLP). We analyzed about 100 different chromosomal regions by AP-PCR and over 150 random CpG loci by MS-AFLP in human colon and gastric carcinomas. DNA hypomethylation and hypermethylation alterations distributed gradually and increased with cancer patient age, in contrast with the age-independent genomic alterations. Increased DNA hypomethylation and hypermethylation correlated with increased genomic damage, but only hypomethylation was highly significant in multivariate analyses. We conclude that age-dependent accumulation of DNA demethylation precedes diploidy loss in a significant subset of gastrointestinal cancers.", - "journal_title": "Cancer cell", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/16530704/" - } - ], - "58b305ff-7c05-4e31-aafe-7fb16a8a8049": [ - { - "pub_id": "17413015", - "title": "Linking brain imaging and genomics in the study of Alzheimer's disease and aging.", - "authors": "Eric M Reiman", - "abstract": "My colleagues and I have been using positron emission tomography (PET) and magnetic resonance imaging (MRI) to detect and track the brain changes associated with Alzheimer's disease (AD) and normal brain aging in cognitively normal persons with two copies, one copy, and no copies of the apolipoprotein E (APOE) epsilon4 allele, a common AD susceptibility gene. In this review article, I consider how brain imaging techniques could be used to evaluate putative AD prevention therapies in cognitively normal APOE epsilon4 carriers and putative age-modifying therapies in cognitively normal APOE epsilon4 noncarriers, how they could help investigate the individual and aggregate effects of putative AD risk modifiers, and how they could help guide the investigation of a molecular mechanism associated with AD vulnerability and normal neurological aging. I suggest how high-resolution genome-wide genetic and transcriptomic studies could further help in the scientific understanding of AD, aging, and other common and genetically complex phenotypes, such as variation in normal human memory performance, and in the discovery and evaluation of promising treatments for these phenotypes. Finally, I illustrate the push-pull relationship between brain imaging, genomics research, and other neuroscientific research in the study of AD and aging.", - "journal_title": "Annals of the New York Academy of Sciences", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/17413015/" - } - ], - "13e29c44-5cb1-4661-86bd-025e0b993f9a": [ - { - "pub_id": "15582155", - "title": "Human blood genomics: distinct profiles for gender, age and neurofibromatosis type 1.", - "authors": "Yang Tang,Aigang Lu,Ruiqiong Ran,Bruce J Aronow,Elizabeth K Schorry,Robert J Hopkin,Donald L Gilbert,Tracy A Glauser,Andrew D Hershey,Neil W Richtand,Michael Privitera,Arif Dalvi,Alok Sahay,Jerzy P Szaflarski,David M Ficker,Nancy Ratner,Frank R Sharp", - "abstract": "Application of gene expression profiling to human diseases will be limited by availability of tissue samples. It was postulated that germline genetic defects affect blood cells to produce unique expression patterns. This hypothesis was addressed by using a test neurological disease-neurofibromatosis type 1 (NF1), an autosomal dominant genetic disease caused by mutations of the NF1 gene at chromosome 17q11.2. Oligonucleotide arrays were used to survey the blood gene expression pattern of 12 NF1 patients compared to 96 controls. A group of genes related to tissue remodeling, bone development and tumor suppression were down-regulated in NF1 blood samples. In addition, there were blood genomic patterns for gender and age: Y chromosome genes showing higher expression in males, indicating a gene-dosage effect; and genes related to lymphocyte functions showing higher expression in children. The results suggest that genetic mutations can be manifested at the transcriptional level in peripheral blood cells and blood gene expression profiling may be useful for studying phenotypic differences of human genetic diseases and possibly providing diagnostic and prognostic markers.", - "journal_title": "Brain research. Molecular brain research", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/15582155/" - } - ], - "82f4e593-8f80-45d7-9de0-dbe9d6f234b8": [ - { - "pub_id": "21846794", - "title": "Analysis of alternative splicing associated with aging and neurodegeneration in the human brain.", - "authors": "James R Tollervey,Zhen Wang,Tibor Hortob\u00e1gyi,Joshua T Witten,Kathi Zarnack,Melis Kayikci,Tyson A Clark,Anthony C Schweitzer,Gregor Rot,Toma\u017e Curk,Bla\u017e Zupan,Boris Rogelj,Christopher E Shaw,Jernej Ule", - "abstract": "Age is the most important risk factor for neurodegeneration; however, the effects of aging and neurodegeneration on gene expression in the human brain have most often been studied separately. Here, we analyzed changes in transcript levels and alternative splicing in the temporal cortex of individuals of different ages who were cognitively normal, affected by frontotemporal lobar degeneration (FTLD), or affected by Alzheimer's disease (AD). We identified age-related splicing changes in cognitively normal individuals and found that these were present also in 95% of individuals with FTLD or AD, independent of their age. These changes were consistent with increased polypyrimidine tract binding protein (PTB)-dependent splicing activity. We also identified disease-specific splicing changes that were present in individuals with FTLD or AD, but not in cognitively normal individuals. These changes were consistent with the decreased neuro-oncological ventral antigen (NOVA)-dependent splicing regulation, and the decreased nuclear abundance of NOVA proteins. As expected, a dramatic down-regulation of neuronal genes was associated with disease, whereas a modest down-regulation of glial and neuronal genes was associated with aging. Whereas our data indicated that the age-related splicing changes are regulated independently of transcript-level changes, these two regulatory mechanisms affected expression of genes with similar functions, including metabolism and DNA repair. In conclusion, the alternative splicing changes identified in this study provide a new link between aging and neurodegeneration.", - "journal_title": "Genome research", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/21846794/" - } - ], - "da8e56fb-a05a-413a-aca0-89361bcc283b": [ - { - "pub_id": "21216877", - "title": "Distinct DNA methylation changes highly correlated with chronological age in the human brain.", - "authors": "Dena G Hernandez,Michael A Nalls,J Raphael Gibbs,Sampath Arepalli,Marcel van der Brug,Sean Chong,Matthew Moore,Dan L Longo,Mark R Cookson,Bryan J Traynor,Andrew B Singleton", - "abstract": "Methylation at CpG sites is a critical epigenetic modification in mammals. Altered DNA methylation has been suggested to be a central mechanism in development, some disease processes and cellular senescence. Quantifying the extent and identity of epigenetic changes in the aging process is therefore potentially important for understanding longevity and age-related diseases. In the current study, we have examined DNA methylation at >27,000 CpG sites throughout the human genome, in frontal cortex, temporal cortex, pons and cerebellum from 387 human donors between the ages of 1 and 102 years. We identify CpG loci that show a highly significant, consistent correlation between DNA methylation and chronological age. The majority of these loci are within CpG islands and there is a positive correlation between age and DNA methylation level. Lastly, we show that the CpG sites where the DNA methylation level is significantly associated with age are physically close to genes involved in DNA binding and regulation of transcription. This suggests that specific age-related DNA methylation changes may have quite a broad impact on gene expression in the human brain.", - "journal_title": "Human molecular genetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/21216877/" - } - ], - "2de167f7-5804-43f0-8fa7-25df2f0567ab": [ - { - "pub_id": "18798525", - "title": "Shaping segments: Hox gene function in the genomic age.", - "authors": "Stefanie D Hueber,Ingrid Lohmann", - "abstract": "Despite decades of research, morphogenesis along the various body axes remains one of the major mysteries in developmental biology. A milestone in the field was the realisation that a set of closely related regulators, called Hox genes, specifies the identity of body segments along the anterior-posterior (AP) axis in most animals. Hox genes have been highly conserved throughout metazoan evolution and code for homeodomain-containing transcription factors. Thus, they exert their function mainly through activation or repression of downstream genes. However, while much is known about Hox gene structure and molecular function, only a few target genes have been identified and studied in detail. Our knowledge of Hox downstream genes is therefore far from complete and consequently Hox-controlled morphogenesis is still poorly understood. Genome-wide approaches have facilitated the identification of large numbers of Hox downstream genes both in Drosophila and vertebrates, and represent a crucial step towards a comprehensive understanding of how Hox proteins drive morphological diversification. In this review, we focus on the role of Hox genes in shaping segmental morphologies along the AP axis in Drosophila, discuss some of the conclusions drawn from analyses of large target gene sets and highlight methods that could be used to gain a more thorough understanding of Hox molecular function. In addition, the mechanisms of Hox target gene regulation are considered with special emphasis on recent findings and their implications for Hox protein specificity in the context of the whole organism.", - "journal_title": "BioEssays : news and reviews in molecular, cellular and developmental biology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/18798525/" - } - ], - "f22e0d51-2f94-4786-b87d-41ed530a6f61": [ - { - "pub_id": "14665679", - "title": "RNA interference: biology, mechanism, and applications.", - "authors": "Neema Agrawal,P V N Dasaradhi,Asif Mohmmed,Pawan Malhotra,Raj K Bhatnagar,Sunil K Mukherjee", - "abstract": "Double-stranded RNA-mediated interference (RNAi) is a simple and rapid method of silencing gene expression in a range of organisms. The silencing of a gene is a consequence of degradation of RNA into short RNAs that activate ribonucleases to target homologous mRNA. The resulting phenotypes either are identical to those of genetic null mutants or resemble an allelic series of mutants. Specific gene silencing has been shown to be related to two ancient processes, cosuppression in plants and quelling in fungi, and has also been associated with regulatory processes such as transposon silencing, antiviral defense mechanisms, gene regulation, and chromosomal modification. Extensive genetic and biochemical analysis revealed a two-step mechanism of RNAi-induced gene silencing. The first step involves degradation of dsRNA into small interfering RNAs (siRNAs), 21 to 25 nucleotides long, by an RNase III-like activity. In the second step, the siRNAs join an RNase complex, RISC (RNA-induced silencing complex), which acts on the cognate mRNA and degrades it. Several key components such as Dicer, RNA-dependent RNA polymerase, helicases, and dsRNA endonucleases have been identified in different organisms for their roles in RNAi. Some of these components also control the development of many organisms by processing many noncoding RNAs, called micro-RNAs. The biogenesis and function of micro-RNAs resemble RNAi activities to a large extent. Recent studies indicate that in the context of RNAi, the genome also undergoes alterations in the form of DNA methylation, heterochromatin formation, and programmed DNA elimination. As a result of these changes, the silencing effect of gene functions is exercised as tightly as possible. Because of its exquisite specificity and efficiency, RNAi is being considered as an important tool not only for functional genomics, but also for gene-specific therapeutic activities that target the mRNAs of disease-related genes.", - "journal_title": "Microbiology and molecular biology reviews : MMBR", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/14665679/" - } - ], - "0eb74d71-2ff8-48ff-a7e4-c8b2dad370f9": [ - { - "pub_id": "15070816", - "title": "Whole genome scan for obstructive sleep apnea and obesity in African-American families.", - "authors": "Lyle J Palmer,Sarah G Buxbaum,Emma K Larkin,Sanjay R Patel,Robert C Elston,Peter V Tishler,Susan Redline", - "abstract": "Obstructive sleep apnea (OSA) is a common, chronic disease associated with obesity. OSA and obesity are both prevalent in African Americans, who are also at increased risk for secondary complications. To identify susceptibility loci for OSA, we undertook a 9-centimorgans genome scan in 59 African-American pedigrees ascertained on the basis of either an affected individual with laboratory-confirmed disease or a proband who was a neighborhood control subject. Variance component linkage analysis was performed for the quantitative phenotypes apnea-hypopnea index (AHI) and body mass index. A candidate region on chromosome 8q (logarithm of odds [LOD] = 1.29, p = 0.006) gave the only evidence for linkage to the AHI. Body mass index was linked to multiple regions, most significantly to markers on chromosome 4q (LOD = 2.63, p = 0.0006) and 8q (LOD = 2.56, p = 0.0007). Evidence of linkage to the AHI was only slightly reduced after adjustment for body mass index. After adjustment for the AHI, some of the primary linkages to body mass index were greatly reduced whereas others remained suggestive. Our results suggest that there are both shared and unshared genetic factors underlying susceptibility to OSA and obesity, and that the genetic determinants of obesity in this population may be modulated by apnea severity.", - "journal_title": "American journal of respiratory and critical care medicine", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/15070816/" - } - ], - "f0db8a37-76fc-4eaf-a667-4d2422ecc32f": [ - { - "pub_id": "14746985", - "title": "Comparative analysis of processed pseudogenes in the mouse and human genomes.", - "authors": "Zhaolei Zhang,Nick Carriero,Mark Gerstein", - "abstract": "Pseudogenes are important resources in evolutionary and comparative genomics because they provide molecular records of the ancient genes that existed in the genome millions of years ago. We have systematically identified approximately 5000 processed pseudogenes in the mouse genome, and estimated that approximately 60% are lineage specific, created after the mouse and human diverged. In both mouse and human genomes, similar types of genes give rise to many processed pseudogenes. These tend to be housekeeping genes, which are highly expressed in the germ line. Ribosomal-protein genes, in particular, form the largest sub-group. The processed pseudogenes in the mouse occur with a distinctly different chromosomal distribution than LINEs or SINEs - preferentially in GC-poor regions. Finally, the age distribution of mouse-processed pseudogenes closely resembles that of LINEs, in contrast to human, where the age distribution closely follows Alus (SINEs).", - "journal_title": "Trends in genetics : TIG", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/14746985/" - } - ], - "643a40b7-3f1c-4a11-a9cf-d70e678c14b8": [ - { - "pub_id": "17573962", - "title": "microRNA expression in the aging mouse lung.", - "authors": "Andrew E Williams,Mark M Perry,Sterghios A Moschos,Mark A Lindsay", - "abstract": "MicroRNAs (miRNAs) are a novel class of short double stranded RNA that mediate the post-transcriptional regulation of gene expression. Previous studies have implicated changes in miRNA expression in the regulation of development and the induction of diseases such as cancer. However, although miRNAs have been implicated in the process of aging in C. elegans, nothing is known of their role in mammalian tissues. To address this question, we have used a highly-sensitive, semi-quantitative RT-PCR based approach to measure the expression profile of 256 of the 493 currently identified miRNAs in the lungs from 6 month (adult) and 18 month (aged) old female BALB/c mice. We show that, despite the characteristic changes in anatomy and gene expression associated with lung aging, there were no significant changes in the expression of 256 miRNAs. Overall, these results show that miRNA transcription is unchanged during lung aging and suggests that stable expression of miRNAs might instead buffer age related changes in the expression of protein-encoding genes.", - "journal_title": "BMC genomics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/17573962/" - } - ], - "e21986c6-0d1a-4489-a20b-9ac1901b2a5d": [ - { - "pub_id": "31849324", - "title": "Evaluation of gene-environment interactions for colorectal cancer susceptibility loci using case-only and case-control designs.", - "authors": "Nan Song,Jeeyoo Lee,Sooyoung Cho,Jeongseon Kim,Jae Hwan Oh,Aesun Shin", - "abstract": "Genome-wide association studies (GWAS) have identified more than 40 colorectal cancer susceptibility loci, but only a small fraction of heritability was explained. To account for missing heritability, we investigated gene-environment interactions (G\u2009\u00d7\u2009Es) between GWAS-identified single-nucleotide polymorphisms (SNPs) and established risk or protective factors for colorectal cancer using both case-only and case-control study designs. Data on 703 colorectal cancer cases and 1406 healthy controls from the National Cancer Center in Korea were used. We tested interactions between 31 GWAS-identified SNPs and 13 established risk or protective factors for colorectal cancer (family history, body mass index, history of colorectal polyps, inflammatory bowel disease, and diabetes mellitus, alcohol drinking, smoking, regular exercise, regular aspirin use, postmenopausal hormone replace therapy, red meat and processed meat intake, and dairy consumption). Logistic regression models were used to assess G\u2009\u00d7\u2009Es for colorectal cancer risk. The SNP rs4444235 at 14q22.2 interacted with regular exercise in colorectal cancer (p<sub>case-only</sub>\u2009=\u20092.4\u2009\u00d7\u200910<sup>-\u20093</sup>, p<sub>case-control</sub>\u2009=\u20091.5\u2009\u00d7\u200910<sup>-\u20093</sup>). The risk allele (C) of rs4444235 increased the risk of colorectal cancer in regularly exercising individuals (OR\u2009=\u20091.47, 95% CI\u2009=\u20091.02-2.10) but decreased the risk in non-exercising individuals (OR\u2009=\u20090.76, 95% CI\u2009=\u20090.62-0.94). Furthermore, the G\u2009\u00d7\u2009E between the SNP rs2423279 at 20p12.3 and regular aspirin use was statistically significant (p<sub>case-only</sub>\u2009=\u20097.7\u2009\u00d7\u200910<sup>-\u20093</sup>, p<sub>case-control</sub>\u2009=\u20091.6\u2009\u00d7\u200910<sup>-\u20093</sup>). The additive effect of the risk allele (T) of rs2423279 on colorectal cancer risk was increased among regular aspirin users (OR\u2009=\u20094.62, 95% CI\u2009=\u20091.97-10.80). Our results suggest that SNP rs4444235 at 14q22.2 and SNP rs2423279 at 20p12.3 may interact with regular exercise and aspirin use in colorectal carcinogenesis.", - "journal_title": "BMC cancer", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/31849324/" - } - ], - "db90a971-e55a-4ab0-a3b1-05908d6771a4": [ - { - "pub_id": "21740922", - "title": "A genome-wide association study confirms APOE as the major gene influencing survival in long-lived individuals.", - "authors": "Almut Nebel,Rabea Kleindorp,Amke Caliebe,Michael Nothnagel,H\u00e9l\u00e8ne Blanch\u00e9,Olaf Junge,Michael Wittig,David Ellinghaus,Friederike Flachsbart,Heinz-Erich Wichmann,Thomas Meitinger,Susanna Nikolaus,Andre Franke,Michael Krawczak,Mark Lathrop,Stefan Schreiber", - "abstract": "We conducted a case-control genome-wide association study (GWAS) of human longevity, comparing 664,472 autosomal SNPs in 763 long-lived individuals (LLI; mean age: 99.7 years) and 1085 controls (mean age: 60.2 years) from Germany. Only one association, namely that of SNP rs4420638 near the APOC1 gene, achieved genome-wide significance (allele-based P=1.8\u00d710(-10)). However, logistic regression analysis revealed that this association, which was replicated in an independent German sample, is fully explicable by linkage disequilibrium with the APOE allele \u025b4, the only variant hitherto established as a major genetic determinant of survival into old age. Our GWAS failed to identify any additional autosomal susceptibility genes. One explanation for this lack of success in our study would be that GWAS provide only limited statistical power for a polygenic phenotype with loci of small effect such as human longevity. A recent GWAS in Dutch LLI independently confirmed the APOE-longevity association, thus strengthening the conclusion that this locus is a very, if not the most, important genetic factor influencing longevity.", - "journal_title": "Mechanisms of ageing and development", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/21740922/" - } - ], - "1681b372-e51f-4489-889b-37e74c284e0c": [ - { - "pub_id": "20031568", - "title": "Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium: Design of prospective meta-analyses of genome-wide association studies from 5 cohorts.", - "authors": "Bruce M Psaty,Christopher J O'Donnell,Vilmundur Gudnason,Kathryn L Lunetta,Aaron R Folsom,Jerome I Rotter,Andr\u00e9 G Uitterlinden,Tamara B Harris,Jacqueline C M Witteman,Eric Boerwinkle, ", - "abstract": "The primary aim of genome-wide association studies is to identify novel genetic loci associated with interindividual variation in the levels of risk factors, the degree of subclinical disease, or the risk of clinical disease. The requirement for large sample sizes and the importance of replication have served as powerful incentives for scientific collaboration. Methods- The Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium was formed to facilitate genome-wide association studies meta-analyses and replication opportunities among multiple large population-based cohort studies, which collect data in a standardized fashion and represent the preferred method for estimating disease incidence. The design of the Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium includes 5 prospective cohort studies from the United States and Europe: the Age, Gene/Environment Susceptibility-Reykjavik Study, the Atherosclerosis Risk in Communities Study, the Cardiovascular Health Study, the Framingham Heart Study, and the Rotterdam Study. With genome-wide data on a total of about 38 000 individuals, these cohort studies have a large number of health-related phenotypes measured in similar ways. For each harmonized trait, within-cohort genome-wide association study analyses are combined by meta-analysis. A prospective meta-analysis of data from all 5 cohorts, with a properly selected level of genome-wide statistical significance, is a powerful approach to finding genuine phenotypic associations with novel genetic loci. The Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium and collaborating non-member studies or consortia provide an excellent framework for the identification of the genetic determinants of risk factors, subclinical-disease measures, and clinical events.", - "journal_title": "Circulation. Cardiovascular genetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/20031568/" - } - ], - "f4762690-64e9-4f6d-9031-c249dc4a6d85": [ - { - "pub_id": "29642622", - "title": "Colibactin: More Than a New Bacterial Toxin.", - "authors": "Tiphanie Fa\u00efs,Julien Delmas,Nicolas Barnich,Richard Bonnet,Guillaume Dalmasso", - "abstract": "Cyclomodulins are bacterial toxins that interfere with the eukaryotic cell cycle. A new cyclomodulin called colibactin, which is synthetized by the <i>pks</i> genomic island, was discovered in 2006. Despite many efforts, colibactin has not yet been purified, and its structure remains elusive. Interestingly, the <i>pks</i> island is found in members of the family <i>Enterobacteriaceae</i> (mainly <i>Escherichia coli</i> and <i>Klebsiella pneumoniae</i>) isolated from different origins, including from intestinal microbiota, septicaemia, newborn meningitis, and urinary tract infections. Colibactin-producing bacteria induce chromosomal instability and DNA damage in eukaryotic cells, which leads to senescence of epithelial cells and apoptosis of immune cells. The <i>pks</i> island is mainly observed in B2 phylogroup <i>E. coli</i> strains, which include extra-intestinal pathogenic <i>E. coli</i> strains, and <i>pks</i><i>E. coli</i> are over-represented in biopsies isolated from colorectal cancer. In addition, <i>pks</i><i>E. coli</i> bacteria increase the number of tumours in diverse colorectal cancer mouse models. Thus, colibactin could have a major impact on human health. In the present review, we will focus on the biological effects of colibactin, the distribution of the <i>pks</i> island, and summarize what is currently known about its synthesis and its structure.", - "journal_title": "Toxins", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/29642622/" - } - ], - "f11c49bd-1a54-4ea4-bcc6-cd589806311f": [ - { - "pub_id": "14757817", - "title": "Major events in the genome evolution of vertebrates: paranome age and size differ considerably between ray-finned fishes and land vertebrates.", - "authors": "Klaas Vandepoele,Wouter De Vos,John S Taylor,Axel Meyer,Yves Van de Peer", - "abstract": "It has been suggested that fish have more genes than humans. Whether most of these additional genes originated through a complete (fish-specific) genome duplication or through many lineage-specific tandem gene or smaller block duplications and family expansions continues to be debated. We analyzed the complete genome of the pufferfish Takifugu rubripes (Fugu) and compared it with the paranome of humans. We show that most paralogous genes of Fugu are the result of three complete genome duplications. Both relative and absolute dating of the complete predicted set of protein-coding genes suggest that initial genome duplications, estimated to have occurred at least 600 million years ago, shaped the genome of all vertebrates. In addition, analysis of >150 block duplications in the Fugu genome clearly supports a fish-specific genome duplication (approximately equal to 320 million years ago) that coincided with the vast radiation of most modern ray-finned fishes. Unlike the human genome, Fugu contains very few recently duplicated genes; hence, many human genes are much younger than fish genes. This lack of recent gene duplication, or, alternatively, the accelerated rate of gene loss, is possibly one reason for the drastic reduction of the genome size of Fugu observed during the past 100 million years or so, subsequent to the additional genome duplication that ray-finned fishes but not land vertebrates experienced.", - "journal_title": "Proceedings of the National Academy of Sciences of the United States of America", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/14757817/" - } - ], - "1795d0e2-b0e9-4801-8537-c0e64f728ae5": [ - { - "pub_id": "21649900", - "title": "Cell cycle and aging, morphogenesis, and response to stimuli genes are individualized biomarkers of glioblastoma progression and survival.", - "authors": "Nicola V L Ser\u00e3o,Kristin R Delfino,Bruce R Southey,Jonathan E Beever,Sandra L Rodriguez-Zas", - "abstract": "Glioblastoma is a complex multifactorial disorder that has swift and devastating consequences. Few genes have been consistently identified as prognostic biomarkers of glioblastoma survival. The goal of this study was to identify general and clinical-dependent biomarker genes and biological processes of three complementary events: lifetime, overall and progression-free glioblastoma survival. A novel analytical strategy was developed to identify general associations between the biomarkers and glioblastoma, and associations that depend on cohort groups, such as race, gender, and therapy. Gene network inference, cross-validation and functional analyses further supported the identified biomarkers. A total of 61, 47 and 60 gene expression profiles were significantly associated with lifetime, overall, and progression-free survival, respectively. The vast majority of these genes have been previously reported to be associated with glioblastoma (35, 24, and 35 genes, respectively) or with other cancers (10, 19, and 15 genes, respectively) and the rest (16, 4, and 10 genes, respectively) are novel associations. Pik3r1, E2f3, Akr1c3, Csf1, Jag2, Plcg1, Rpl37a, Sod2, Topors, Hras, Mdm2, Camk2g, Fstl1, Il13ra1, Mtap and Tp53 were associated with multiple survival events.Most genes (from 90 to 96%) were associated with survival in a general or cohort-independent manner and thus the same trend is observed across all clinical levels studied. The most extreme associations between profiles and survival were observed for Syne1, Pdcd4, Ighg1, Tgfa, Pla2g7, and Paics. Several genes were found to have a cohort-dependent association with survival and these associations are the basis for individualized prognostic and gene-based therapies. C2, Egfr, Prkcb, Igf2bp3, and Gdf10 had gender-dependent associations; Sox10, Rps20, Rab31, and Vav3 had race-dependent associations; Chi3l1, Prkcb, Polr2d, and Apool had therapy-dependent associations. Biological processes associated glioblastoma survival included morphogenesis, cell cycle, aging, response to stimuli, and programmed cell death. Known biomarkers of glioblastoma survival were confirmed, and new general and clinical-dependent gene profiles were uncovered. The comparison of biomarkers across glioblastoma phases and functional analyses offered insights into the role of genes. These findings support the development of more accurate and personalized prognostic tools and gene-based therapies that improve the survival and quality of life of individuals afflicted by glioblastoma multiforme.", - "journal_title": "BMC medical genomics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/21649900/" - } - ], - "0bc591e0-bd1c-4c15-9e1e-3aa4499ad270": [ - { - "pub_id": "21118493", - "title": "Age and sex dependent changes in liver gene expression during the life cycle of the rat.", - "authors": "Joshua C Kwekel,Varsha G Desai,Carrie L Moland,William S Branham,James C Fuscoe", - "abstract": "Age- and sex-related susceptibility to adverse drug reactions and disease is a key concern in understanding drug safety and disease progression. We hypothesize that the underlying suite of hepatic genes expressed at various life cycle stages will impact susceptibility to adverse drug reactions. Understanding the basal liver gene expression patterns is a necessary first step in addressing this hypothesis and will inform our assessments of adverse drug reactions as the liver plays a central role in drug metabolism and biotransformation. Untreated male and female F344 rats were sacrificed at 2, 5, 6, 8, 15, 21, 52, 78, and 104 weeks of age. Liver tissues were collected for histology and gene expression analysis. Whole-genome rat microarrays were used to query global expression profiles. An initial list of differentially expressed genes was selected using criteria based upon p-value (p < 0.05) and fold-change (+/- 1.5). Three dimensional principal component analyses revealed differences between males and females beginning at 2 weeks with more divergent profiles beginning at 5 weeks. The greatest sex-differences were observed between 8 and 52 weeks before converging again at 104 weeks. K-means clustering identified groups of genes that displayed age-related patterns of expression. Various adult aging-related clusters represented gene pathways related to xenobiotic metabolism, DNA damage repair, and oxidative stress. These results suggest an underlying role for genes in specific clusters in potentiating age- and sex-related differences in susceptibility to adverse health effects. Furthermore, such a comprehensive picture of life cycle changes in gene expression deepens our understanding and informs the utility of liver gene expression biomarkers.", - "journal_title": "BMC genomics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/21118493/" - } - ], - "5b60f0ee-e224-4052-bc93-47b97532837b": [ - { - "pub_id": "19135889", - "title": "SIRT6 links histone H3 lysine 9 deacetylation to NF-kappaB-dependent gene expression and organismal life span.", - "authors": "Tiara L A Kawahara,Eriko Michishita,Adam S Adler,Mara Damian,Elisabeth Berber,Meihong Lin,Ron A McCord,Kristine C L Ongaigui,Lisa D Boxer,Howard Y Chang,Katrin F Chua", - "abstract": "Members of the sirtuin (SIRT) family of NAD-dependent deacetylases promote longevity in multiple organisms. Deficiency of mammalian SIRT6 leads to shortened life span and an aging-like phenotype in mice, but the underlying molecular mechanisms are unclear. Here we show that SIRT6 functions at chromatin to attenuate NF-kappaB signaling. SIRT6 interacts with the NF-kappaB RELA subunit and deacetylates histone H3 lysine 9 (H3K9) at NF-kappaB target gene promoters. In SIRT6-deficient cells, hyperacetylation of H3K9 at these target promoters is associated with increased RELA promoter occupancy and enhanced NF-kappaB-dependent modulation of gene expression, apoptosis, and cellular senescence. Computational genomics analyses revealed increased activity of NF-kappaB-driven gene expression programs in multiple Sirt6-deficient tissues in vivo. Moreover, haploinsufficiency of RelA rescues the early lethality and degenerative syndrome of Sirt6-deficient mice. We propose that SIRT6 attenuates NF-kappaB signaling via H3K9 deacetylation at chromatin, and hyperactive NF-kappaB signaling may contribute to premature and normal aging.", - "journal_title": "Cell", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/19135889/" - } - ], - "d95f3bff-219f-462a-876f-b46a8c8482ae": [ - { - "pub_id": "19881909", - "title": "MicroRNA: Implications for Alzheimer Disease and other Human CNS Disorders.", - "authors": "Olivier C Maes,Howard M Chertkow,Eugenia Wang,Hyman M Schipper", - "abstract": "Understanding complex diseases such as sporadic Alzheimer disease (AD) has been a major challenge. Unlike the familial forms of AD, the genetic and environmental risks factors identified for sporadic AD are extensive. MicroRNAs are one of the major noncoding RNAs that function as negative regulators to silence or suppress gene expression via translational inhibition or message degradation. Their discovery has evoked great excitement in biomedical research for their promise as potential disease biomarkers and therapeutic targets. Key microRNAs have been identified as essential for a variety of cellular events including cell lineage determination, proliferation, apoptosis, DNA repair, and cytoskeletal organization; most, if not all, acting to fine-tune gene expression at the post-transcriptional level in a host of cellular signaling networks. Dysfunctional microRNA-mediated regulation has been implicated in the pathogenesis of many disease states. Here, the current understanding of the role of miRNAs in the central nervous system is reviewed with emphasis on their impact on the etiopathogenesis of sporadic AD.", - "journal_title": "Current genomics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/19881909/" - } - ], - "55c80b9a-9289-4a39-a5c3-33c05c04d224": [ - { - "pub_id": "20690139", - "title": "Meta-analysis of genome-wide and replication association studies on prostate cancer.", - "authors": "Hong Liu,Bo Wang,Chunsheng Han", - "abstract": "Genome-wide and replication association studies (GWAs) have identified multiple loci at which common variants modestly influence the risk of developing prostate cancer (PCa). To enhance the power to identify loci associated with PCa, we constructed a meta-analysis of GWAs on PCa. Articles evaluating the effects of genome-wide SNPs on PCa were identified by searching the PubMed database. After extraction of relevant data, main and subgroup meta-analyses were performed to assess the effects of relevant SNPs on PCa. 21 eligible articles containing 71 subgroups were included in this meta-analysis. Significant associations were found between 31 SNPs and PCa. They were rs445114, rs620861, rs983085, rs1016343, rs1447295, rs1859962, rs2660753, rs2710646, rs2735839, rs3760511, rs4242382, rs4430796, rs4962416, rs5945572, rs5945619, rs6470494, rs6501455, rs6983267, rs6983561, rs7000448, rs7214479, rs7501939, rs7920517, rs7931342, rs9364554, rs9623117, rs10090154, rs10486567, rs10896449, rs10993994, and rs16901979. The weighted odds ratios for above SNPs ranged between 0.64 and 1.88 (all P\u2009<\u20090.05). Subgroup analysis further indicated that the significant associations of some SNPs existed only in specific ancestry population (P\u2009<\u200910\u207b\u2075). The current meta-analysis demonstrated the moderate effects of above 31 SNPs on PCa and 14 independent PCa risk loci were identified.", - "journal_title": "The Prostate", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/20690139/" - } - ], - "67f8bcbb-7d4b-47de-967f-d341b0b110cb": [ - { - "pub_id": "15720261", - "title": "Novel anticancer targets and drug discovery in post genomic age.", - "authors": "Qianbin Li,Wenfang Xu", - "abstract": "Cancer is a serious disease with a complex pathogenesis, which threats human life greatly. Currently, great efforts have been put to the identification of novel anticancer targets and the discovery of anticancer drugs following the progress of chemogenomics, which will be reviewed briefly in this article. Furthermore, during the past 5 years, the global effort of sequencing human genome has provided us with an enormous number of potential targets associated with cancer therapy. As a result, the New Drug Discovery (NDD) is undergoing a transition \"from gene to drug\". Accordingly, the targets for anticancer drugs studies now are focused on some biological macromolecular targets associated with cancer and several interactive mechanisms involved in the growth and metastasis of cancer cells as well as tumor angiogenesis, such as Matrix Metalloproteinases (MMPs), Aminopeptidase N (APN), Tyrosine Kinase (TK), Farnesyltransferase (FTase) and cell Signal Transduction Pathway and so forth. Among these targets the MMP-2, -9 and APN are the most extensively studied enzymes in our laboratory. The peptidomimetics Matrix Metalloproteinase Inhibitors (MMPIs) and APN inhibitors (APNIs) with the molecular scaffold of pyrrolidine, 3-amino-2-hydroxy-4-phenyl butyric acid (AHPA) and glutamylide, which have been designed and synthesized in our laboratory, will be described in the review, among which the pyrrolidine scaffold is patented with the IC(50) ranging from 1 nM to 300 nM against MMP-2, and MMP-9.", - "journal_title": "Current medicinal chemistry. Anti-cancer agents", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/15720261/" - } - ], - "3cbce5b1-fc62-4995-9902-c92c532dc11c": [ - { - "pub_id": "20385819", - "title": "Genetic variants near TIMP3 and high-density lipoprotein-associated loci influence susceptibility to age-related macular degeneration.", - "authors": "Wei Chen,Dwight Stambolian,Albert O Edwards,Kari E Branham,Mohammad Othman,Johanna Jakobsdottir,Nirubol Tosakulwong,Margaret A Pericak-Vance,Peter A Campochiaro,Michael L Klein,Perciliz L Tan,Yvette P Conley,Atsuhiro Kanda,Laura Kopplin,Yanming Li,Katherine J Augustaitis,Athanasios J Karoukis,William K Scott,Anita Agarwal,Jaclyn L Kovach,Stephen G Schwartz,Eric A Postel,Matthew Brooks,Keith H Baratz,William L Brown, ,Alexander J Brucker,Anton Orlin,Gary Brown,Allen Ho,Carl Regillo,Larry Donoso,Lifeng Tian,Brian Kaderli,Dexter Hadley,Stephanie A Hagstrom,Neal S Peachey,Ronald Klein,Barbara E K Klein,Norimoto Gotoh,Kenji Yamashiro,Frederick Ferris Iii,Jesen A Fagerness,Robyn Reynolds,Lindsay A Farrer,Ivana K Kim,Joan W Miller,Marta Cort\u00f3n,Angel Carracedo,Manuel Sanchez-Salorio,Elizabeth W Pugh,Kimberly F Doheny,Maria Brion,Margaret M Deangelis,Daniel E Weeks,Donald J Zack,Emily Y Chew,John R Heckenlively,Nagahisa Yoshimura,Sudha K Iyengar,Peter J Francis,Nicholas Katsanis,Johanna M Seddon,Jonathan L Haines,Michael B Gorin,Gon\u00e7alo R Abecasis,Anand Swaroop", - "abstract": "We executed a genome-wide association scan for age-related macular degeneration (AMD) in 2,157 cases and 1,150 controls. Our results validate AMD susceptibility loci near CFH (P < 10(-75)), ARMS2 (P < 10(-59)), C2/CFB (P < 10(-20)), C3 (P < 10(-9)), and CFI (P < 10(-6)). We compared our top findings with the Tufts/Massachusetts General Hospital genome-wide association study of advanced AMD (821 cases, 1,709 controls) and genotyped 30 promising markers in additional individuals (up to 7,749 cases and 4,625 controls). With these data, we identified a susceptibility locus near TIMP3 (overall P = 1.1 x 10(-11)), a metalloproteinase involved in degradation of the extracellular matrix and previously implicated in early-onset maculopathy. In addition, our data revealed strong association signals with alleles at two loci (LIPC, P = 1.3 x 10(-7); CETP, P = 7.4 x 10(-7)) that were previously associated with high-density lipoprotein cholesterol (HDL-c) levels in blood. Consistent with the hypothesis that HDL metabolism is associated with AMD pathogenesis, we also observed association with AMD of HDL-c-associated alleles near LPL (P = 3.0 x 10(-3)) and ABCA1 (P = 5.6 x 10(-4)). Multilocus analysis including all susceptibility loci showed that 329 of 331 individuals (99%) with the highest-risk genotypes were cases, and 85% of these had advanced AMD. Our studies extend the catalog of AMD associated loci, help identify individuals at high risk of disease, and provide clues about underlying cellular pathways that should eventually lead to new therapies.", - "journal_title": "Proceedings of the National Academy of Sciences of the United States of America", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/20385819/" - } - ], - "3f72832b-fad9-4d38-aed8-d22e5bd12a22": [ - { - "pub_id": "16701327", - "title": "Cytonuclear coevolution: the genomics of cooperation.", - "authors": "David M Rand,Robert A Haney,Adam J Fry", - "abstract": "Without mitochondria we would be in big trouble, and there would be a global biological energy crisis if it were not for chloroplasts. Fortunately, genomic evolution over the past two billion years has ensured that the functions of these key organelles are with us to stay. Whole-genome analyses have not only proven that mitochondria and chloroplasts are descended from formerly free-living bacteria, but have also shown that it is difficult to define eukaryotes without reference to the fusion and coevolution of host and endosymbiont genomes. Here, we review how the macro- and microevolutionary insights that follow from the genomics of cytonuclear interactions are uniting molecular evolution, structural proteomics, population genetics and problems in aging and disease. Our goals are to clarify the coevolutionary events that have governed nuclear and organelle evolution, and to encourage further critical analyses of these interactions as problems in the study of co-adapted gene complexes.", - "journal_title": "Trends in ecology & evolution", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/16701327/" - } - ], - "46cf6ed6-e4e2-471f-a397-05c69ced5fcd": [ - { - "pub_id": "18840782", - "title": "Genome-wide linkage and admixture mapping of type 2 diabetes in African American families from the American Diabetes Association GENNID (Genetics of NIDDM) Study Cohort.", - "authors": "Steven C Elbein,Swapan K Das,D Michael Hallman,Craig L Hanis,Sandra J Hasstedt", - "abstract": "We used a single nucleotide polymorphism (SNP) map in a large cohort of 580 African American families to identify regions linked to type 2 diabetes, age of type 2 diabetes diagnosis, and BMI. After removing outliers and problematic samples, we conducted linkage analysis using 5,914 SNPs in 1,344 individuals from 530 families. Linkage analysis was conducted using variance components for type 2 diabetes, age of type 2 diabetes diagnosis, and BMI and nonparametric linkage analyses. Ordered subset analyses were conducted ranking on age of type 2 diabetes diagnosis, BMI, waist circumference, waist-to-hip ratio, and amount of European admixture. Admixture mapping was conducted using 4,486 markers not in linkage disequilibrium. The strongest signal for type 2 diabetes (logarithm of odds [LOD] 4.53) was a broad peak on chromosome 2, with weaker linkage to age of type 2 diabetes diagnosis (LOD 1.82). Type 2 diabetes and age of type 2 diabetes diagnosis were linked to chromosome 13p (3-22 cM; LOD 2.42 and 2.46, respectively). Age of type 2 diabetes diagnosis was linked to 18p (66 cM; LOD 2.96). We replicated previous reports on chromosome 7p (79 cM; LOD 2.93). Ordered subset analysis did not overlap with linkage of unselected families. The best admixture score was on chromosome 12 (90 cM; P = 0.0003). The linkage regions on chromosomes 7 (27-78 cM) and 18p overlap prior reports, whereas regions on 2p and 13p linkage are novel. Among potential candidate genes implicated are TCF7L1, VAMP5, VAMP8, CDK8, INSIG2, IPF1, PAX8, IL18R1, members of the IL1 and IL1 receptor families, and MAP4K4. These studies provide a complementary approach to genome-wide association scans to identify causative genes for African American diabetes.", - "journal_title": "Diabetes", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/18840782/" - } - ], - "6fe20ab6-f924-4d4c-8183-1bd099d6a8b0": [ - { - "pub_id": "20838585", - "title": "Longitudinal genome-wide association of cardiovascular disease risk factors in the Bogalusa heart study.", - "authors": "Erin N Smith,Wei Chen,Mika K\u00e4h\u00f6nen,Johannes Kettunen,Terho Lehtim\u00e4ki,Leena Peltonen,Olli T Raitakari,Rany M Salem,Nicholas J Schork,Marian Shaw,Sathanur R Srinivasan,Eric J Topol,Jorma S Viikari,Gerald S Berenson,Sarah S Murray", - "abstract": "Cardiovascular disease (CVD) is the leading cause of death worldwide. Recent genome-wide association (GWA) studies have pinpointed many loci associated with CVD risk factors in adults. It is unclear, however, if these loci predict trait levels at all ages, if they are associated with how a trait develops over time, or if they could be used to screen individuals who are pre-symptomatic to provide the opportunity for preventive measures before disease onset. We completed a genome-wide association study on participants in the longitudinal Bogalusa Heart Study (BHS) and have characterized the association between genetic factors and the development of CVD risk factors from childhood to adulthood. We report 7 genome-wide significant associations involving CVD risk factors, two of which have been previously reported. Top regions were tested for replication in the Young Finns Study (YF) and two associations strongly replicated: rs247616 in CETP with HDL levels (combined P\u200a=\u200a9.7 x 10(-24)), and rs445925 at APOE with LDL levels (combined P\u200a=\u200a8.7 x 10(-19)). We show that SNPs previously identified in adult cross-sectional studies tend to show age-independent effects in the BHS with effect sizes consistent with previous reports. Previously identified variants were associated with adult trait levels above and beyond those seen in childhood; however, variants with time-dependent effects were also promising predictors. This is the first GWA study to evaluate the role of common genetic variants in the development of CVD risk factors in children as they advance through adulthood and highlights the utility of using longitudinal studies to identify genetic predictors of adult traits in children.", - "journal_title": "PLoS genetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/20838585/" - } - ], - "2186130e-2523-4fcc-a52f-fc2bdd986230": [ - { - "pub_id": "18039130", - "title": "The aging brain.", - "authors": "Bruce A Yankner,Tao Lu,Patrick Loerch", - "abstract": "Aging is accompanied by cognitive decline in a major segment of the population and is the primary risk factor for Alzheimer's disease and other prevalent neurodegenerative disorders. Despite this central role in disease pathogenesis and morbidity, the aging of the brain has not been well understood at a molecular level. This review seeks to integrate what is known about age-related cognitive and neuroanatomical changes with recent advances in understanding basic molecular mechanisms that underlie aging. An important issue is how normal brain aging transitions to pathological aging, giving rise to neurodegenerative disorders. Toxic protein aggregates have been identified as potential contributory factors, including amyloid beta-protein in Alzheimer's disease, tau in frontotemporal dementia, and alpha-synuclein in Parkinson's disease. However, current models of pathogenesis do not explain the origin of the common sporadic forms of these diseases or address the critical nexus between aging and disease. This review discusses potential approaches to unifying the systems biology of the aging brain with the pathogenesis of neurodegeneration.", - "journal_title": "Annual review of pathology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/18039130/" - } - ], - "3965fada-3e65-4db0-adc3-bf9931d62223": [ - { - "pub_id": "16387716", - "title": "Aging and genome maintenance.", - "authors": "Jan Vijg,Rita A Busuttil,Rumana Bahar,Martijn E T Doll\u00e9", - "abstract": "Genomic instability in somatic cells has been implicated as a major stochastic mechanism of aging. Using a transgenic mouse model with chromosomally integrated lacZ mutational target genes, we found mutations to accumulate with age at an organ- and tissue-specific rate. Also the spectrum of age-accumulated mutations was found to differ greatly from organ to organ; while initially similar, mutation spectra of different tissues diverged significantly over the lifetime. To explain how genomic instability, which is inherently stochastic, can be a causal factor in aging, it is proposed that randomly induced mutations may adversely affect normal patterns of gene regulation, resulting in a mosaic of cells at various stages on a trajectory of degeneration, eventually resulting in cell death or neoplastic transformation. To directly address this question we demonstrate that it is now possible to analyze single cells, isolated from old and young tissues, for specific alterations in gene expression.", - "journal_title": "Annals of the New York Academy of Sciences", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/16387716/" - } - ], - "996e02bf-91b2-4e81-89ba-1f661dfc662a": [ - { - "pub_id": "16024513", - "title": "Genomes optimize reproduction: aging as a consequence of the developmental program.", - "authors": "Jo\u00e3o Pedro de Magalh\u00e3es,George M Church", - "abstract": "Natural selection shapes genomes for reproduction, not for postreproductive survival. One hypothesis then is that the developmental program, optimized for reproduction, inadvertently regulates aging in mammals. Herein we review, revive, and refine the developmental theory of aging. Implications and experimental approaches for studying the progressive deterioration of physiological function that we call aging are also discussed.", - "journal_title": "Physiology (Bethesda, Md.)", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/16024513/" - } - ], - "29c57767-2e2c-4fbe-a8b2-629e1abd5628": [ - { - "pub_id": "17915019", - "title": "Gene expression profiling of long-lived dwarf mice: longevity-associated genes and relationships with diet, gender and aging.", - "authors": "William R Swindell", - "abstract": "Long-lived strains of dwarf mice carry mutations that suppress growth hormone (GH) and insulin-like growth factor I (IGF-I) signaling. The downstream effects of these endocrine abnormalities, however, are not well understood and it is unclear how these processes interact with aging mechanisms. This study presents a comparative analysis of microarray experiments that have measured hepatic gene expression levels in long-lived strains carrying one of four mutations (Prop1(df/df), Pit1(dw/dw), Ghrhr(lit/lit), GHR-KO) and describes how the effects of these mutations relate to one another at the transcriptional level. Points of overlap with the effects of calorie restriction (CR), CR mimetic compounds, low fat diets, gender dimorphism and aging were also examined. All dwarf mutations had larger and more consistent effects on IGF-I expression than dietary treatments. In comparison to dwarf mutations, however, the transcriptional effects of CR (and some CR mimetics) overlapped more strongly with those of aging. Surprisingly, the Ghrhr(lit/lit) mutation had much larger effects on gene expression than the GHR-KO mutation, even though both mutations affect the same endocrine pathway. Several genes potentially regulated or co-regulated with the IGF-I transcript in liver tissue were identified, including a DNA repair gene (Snm1) that is upregulated in proportion to IGF-I inhibition. A total of 13 genes exhibiting parallel differential expression patterns among all four strains of long-lived dwarf mice were identified, in addition to 30 genes with matching differential expression patterns in multiple long-lived dwarf strains and under CR. Comparative analysis of microarray datasets can identify patterns and consistencies not discernable from any one dataset individually. This study implements new analytical approaches to provide a detailed comparison among the effects of life-extending mutations, dietary treatments, gender and aging. This comparison provides insight into a broad range of issues relevant to the study of mammalian aging. In this context, 43 longevity-associated genes are identified and individual genes with the highest level of support among all microarray experiments are highlighted. These results provide promising targets for future experimental investigation as well as potential clues for understanding the functional basis of lifespan extension in mammalian systems.", - "journal_title": "BMC genomics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/17915019/" - } - ], - "4556f5ae-5b0b-4a30-87dc-fd8b28b6af92": [ - { - "pub_id": "23700391", - "title": "Gene expression classification of colon cancer into molecular subtypes: characterization, validation, and prognostic value.", - "authors": "Laetitia Marisa,Aur\u00e9lien de Reyni\u00e8s,Alex Duval,Janick Selves,Marie Pierre Gaub,Laure Vescovo,Marie-Christine Etienne-Grimaldi,Renaud Schiappa,Dominique Guenot,Mira Ayadi,Sylvain Kirzin,Maurice Chazal,Jean-Fran\u00e7ois Fl\u00e9jou,Daniel Benchimol,Anne Berger,Arnaud Lagarde,Erwan Pencreach,Fran\u00e7oise Piard,Dominique Elias,Yann Parc,Sylviane Olschwang,G\u00e9rard Milano,Pierre Laurent-Puig,Val\u00e9rie Boige", - "abstract": "Colon cancer (CC) pathological staging fails to accurately predict recurrence, and to date, no gene expression signature has proven reliable for prognosis stratification in clinical practice, perhaps because CC is a heterogeneous disease. The aim of this study was to establish a comprehensive molecular classification of CC based on mRNA expression profile analyses. Fresh-frozen primary tumor samples from a large multicenter cohort of 750 patients with stage I to IV CC who underwent surgery between 1987 and 2007 in seven centers were characterized for common DNA alterations, including BRAF, KRAS, and TP53 mutations, CpG island methylator phenotype, mismatch repair status, and chromosomal instability status, and were screened with whole genome and transcriptome arrays. 566 samples fulfilled RNA quality requirements. Unsupervised consensus hierarchical clustering applied to gene expression data from a discovery subset of 443 CC samples identified six molecular subtypes. These subtypes were associated with distinct clinicopathological characteristics, molecular alterations, specific enrichments of supervised gene expression signatures (stem cell phenotype-like, normal-like, serrated CC phenotype-like), and deregulated signaling pathways. Based on their main biological characteristics, we distinguished a deficient mismatch repair subtype, a KRAS mutant subtype, a cancer stem cell subtype, and three chromosomal instability subtypes, including one associated with down-regulated immune pathways, one with up-regulation of the Wnt pathway, and one displaying a normal-like gene expression profile. The classification was validated in the remaining 123 samples plus an independent set of 1,058 CC samples, including eight public datasets. Furthermore, prognosis was analyzed in the subset of stage II-III CC samples. The subtypes C4 and C6, but not the subtypes C1, C2, C3, and C5, were independently associated with shorter relapse-free survival, even after adjusting for age, sex, stage, and the emerging prognostic classifier Oncotype DX Colon Cancer Assay recurrence score (hazard ratio 1.5, 95% CI 1.1-2.1, p\u200a=\u200a0.0097). However, a limitation of this study is that information on tumor grade and number of nodes examined was not available. We describe the first, to our knowledge, robust transcriptome-based classification of CC that improves the current disease stratification based on clinicopathological variables and common DNA markers. The biological relevance of these subtypes is illustrated by significant differences in prognosis. This analysis provides possibilities for improving prognostic models and therapeutic strategies. In conclusion, we report a new classification of CC into six molecular subtypes that arise through distinct biological pathways.", - "journal_title": "PLoS medicine", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/23700391/" - } - ], - "73ff075a-f4fc-4d12-96ba-55135ac99fb0": [ - { - "pub_id": "20541252", - "title": "Common genetic determinants of vitamin D insufficiency: a genome-wide association study.", - "authors": "Thomas J Wang,Feng Zhang,J Brent Richards,Bryan Kestenbaum,Joyce B van Meurs,Diane Berry,Douglas P Kiel,Elizabeth A Streeten,Claes Ohlsson,Daniel L Koller,Leena Peltonen,Jason D Cooper,Paul F O'Reilly,Denise K Houston,Nicole L Glazer,Liesbeth Vandenput,Munro Peacock,Julia Shi,Fernando Rivadeneira,Mark I McCarthy,Pouta Anneli,Ian H de Boer,Massimo Mangino,Bernet Kato,Deborah J Smyth,Sarah L Booth,Paul F Jacques,Greg L Burke,Mark Goodarzi,Ching-Lung Cheung,Myles Wolf,Kenneth Rice,David Goltzman,Nick Hidiroglou,Martin Ladouceur,Nicholas J Wareham,Lynne J Hocking,Deborah Hart,Nigel K Arden,Cyrus Cooper,Suneil Malik,William D Fraser,Anna-Liisa Hartikainen,Guangju Zhai,Helen M Macdonald,Nita G Forouhi,Ruth J F Loos,David M Reid,Alan Hakim,Elaine Dennison,Yongmei Liu,Chris Power,Helen E Stevens,Laitinen Jaana,Ramachandran S Vasan,Nicole Soranzo,J\u00f6rg Bojunga,Bruce M Psaty,Mattias Lorentzon,Tatiana Foroud,Tamara B Harris,Albert Hofman,John-Olov Jansson,Jane A Cauley,Andre G Uitterlinden,Quince Gibson,Marjo-Riitta J\u00e4rvelin,David Karasik,David S Siscovick,Michael J Econs,Stephen B Kritchevsky,Jose C Florez,John A Todd,Josee Dupuis,Elina Hypp\u00f6nen,Timothy D Spector", - "abstract": "Vitamin D is crucial for maintenance of musculoskeletal health, and might also have a role in extraskeletal tissues. Determinants of circulating 25-hydroxyvitamin D concentrations include sun exposure and diet, but high heritability suggests that genetic factors could also play a part. We aimed to identify common genetic variants affecting vitamin D concentrations and risk of insufficiency. We undertook a genome-wide association study of 25-hydroxyvitamin D concentrations in 33 996 individuals of European descent from 15 cohorts. Five epidemiological cohorts were designated as discovery cohorts (n=16 125), five as in-silico replication cohorts (n=9367), and five as de-novo replication cohorts (n=8504). 25-hydroxyvitamin D concentrations were measured by radioimmunoassay, chemiluminescent assay, ELISA, or mass spectrometry. Vitamin D insufficiency was defined as concentrations lower than 75 nmol/L or 50 nmol/L. We combined results of genome-wide analyses across cohorts using Z-score-weighted meta-analysis. Genotype scores were constructed for confirmed variants. Variants at three loci reached genome-wide significance in discovery cohorts for association with 25-hydroxyvitamin D concentrations, and were confirmed in replication cohorts: 4p12 (overall p=1.9x10(-109) for rs2282679, in GC); 11q12 (p=2.1x10(-27) for rs12785878, near DHCR7); and 11p15 (p=3.3x10(-20) for rs10741657, near CYP2R1). Variants at an additional locus (20q13, CYP24A1) were genome-wide significant in the pooled sample (p=6.0x10(-10) for rs6013897). Participants with a genotype score (combining the three confirmed variants) in the highest quartile were at increased risk of having 25-hydroxyvitamin D concentrations lower than 75 nmol/L (OR 2.47, 95% CI 2.20-2.78, p=2.3x10(-48)) or lower than 50 nmol/L (1.92, 1.70-2.16, p=1.0x10(-26)) compared with those in the lowest quartile. Variants near genes involved in cholesterol synthesis, hydroxylation, and vitamin D transport affect vitamin D status. Genetic variation at these loci identifies individuals who have substantially raised risk of vitamin D insufficiency. Full funding sources listed at end of paper (see Acknowledgments).", - "journal_title": "Lancet (London, England)", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/20541252/" - } - ], - "4e3da469-3cb1-4779-8d92-fc9a55e2ca93": [ - { - "pub_id": "21829377", - "title": "Genetic loci associated with plasma phospholipid n-3 fatty acids: a meta-analysis of genome-wide association studies from the CHARGE Consortium.", - "authors": "Rozenn N Lemaitre,Toshiko Tanaka,Weihong Tang,Ani Manichaikul,Millennia Foy,Edmond K Kabagambe,Jennifer A Nettleton,Irena B King,Lu-Chen Weng,Sayanti Bhattacharya,Stefania Bandinelli,Joshua C Bis,Stephen S Rich,David R Jacobs,Antonio Cherubini,Barbara McKnight,Shuang Liang,Xiangjun Gu,Kenneth Rice,Cathy C Laurie,Thomas Lumley,Brian L Browning,Bruce M Psaty,Yii-Der I Chen,Yechiel Friedlander,Luc Djousse,Jason H Y Wu,David S Siscovick,Andr\u00e9 G Uitterlinden,Donna K Arnett,Luigi Ferrucci,Myriam Fornage,Michael Y Tsai,Dariush Mozaffarian,Lyn M Steffen", - "abstract": "Long-chain n-3 polyunsaturated fatty acids (PUFAs) can derive from diet or from \u03b1-linolenic acid (ALA) by elongation and desaturation. We investigated the association of common genetic variation with plasma phospholipid levels of the four major n-3 PUFAs by performing genome-wide association studies in five population-based cohorts comprising 8,866 subjects of European ancestry. Minor alleles of SNPs in FADS1 and FADS2 (desaturases) were associated with higher levels of ALA (p\u200a=\u200a3 x 10\u207b\u2076\u2074) and lower levels of eicosapentaenoic acid (EPA, p\u200a=\u200a5 x 10\u207b\u2075\u2078) and docosapentaenoic acid (DPA, p\u200a=\u200a4 x 10\u207b\u00b9\u2075\u2074). Minor alleles of SNPs in ELOVL2 (elongase) were associated with higher EPA (p\u200a=\u200a2 x 10\u207b\u00b9\u00b2) and DPA (p\u200a=\u200a1 x 10\u207b\u2074\u00b3) and lower docosahexaenoic acid (DHA, p\u200a=\u200a1 x 10\u207b\u00b9\u2075). In addition to genes in the n-3 pathway, we identified a novel association of DPA with several SNPs in GCKR (glucokinase regulator, p\u200a=\u200a1 x 10\u207b\u2078). We observed a weaker association between ALA and EPA among carriers of the minor allele of a representative SNP in FADS2 (rs1535), suggesting a lower rate of ALA-to-EPA conversion in these subjects. In samples of African, Chinese, and Hispanic ancestry, associations of n-3 PUFAs were similar with a representative SNP in FADS1 but less consistent with a representative SNP in ELOVL2. Our findings show that common variation in n-3 metabolic pathway genes and in GCKR influences plasma phospholipid levels of n-3 PUFAs in populations of European ancestry and, for FADS1, in other ancestries.", - "journal_title": "PLoS genetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/21829377/" - } - ], - "1f644643-0c87-4eaa-864a-4e7210ab6d1b": [ - { - "pub_id": "17460187", - "title": "Alterations to nuclear architecture and genome behavior in senescent cells.", - "authors": "Ishita S Mehta,Martin Figgitt,Craig S Clements,Ian R Kill,Joanna M Bridger", - "abstract": "The organization of the genome within interphase nuclei, and how it interacts with nuclear structures is important for the regulation of nuclear functions. Many of the studies researching the importance of genome organization and nuclear structure are performed in young, proliferating, and often transformed cells. These studies do not reveal anything about the nucleus or genome in nonproliferating cells, which may be relevant for the regulation of both proliferation and replicative senescence. Here, we provide an overview of what is known about the genome and nuclear structure in senescent cells. We review the evidence that nuclear structures, such as the nuclear lamina, nucleoli, the nuclear matrix, nuclear bodies (such as promyelocytic leukemia bodies), and nuclear morphology all become altered within growth-arrested or senescent cells. Specific alterations to the genome in senescent cells, as compared to young proliferating cells, are described, including aneuploidy, chromatin modifications, chromosome positioning, relocation of heterochromatin, and changes to telomeres.", - "journal_title": "Annals of the New York Academy of Sciences", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/17460187/" - } - ], - "4c059136-5a0c-4e60-8f22-89b3af002a99": [ - { - "pub_id": "16936732", - "title": "Common variation in three genes, including a noncoding variant in CFH, strongly influences risk of age-related macular degeneration.", - "authors": "Julian Maller,Sarah George,Shaun Purcell,Jes Fagerness,David Altshuler,Mark J Daly,Johanna M Seddon", - "abstract": "Age-related macular degeneration (AMD) is a common, late-onset disease with seemingly typical complexity: recurrence ratios for siblings of an affected individual are three- to sixfold higher than in the general population, and family-based analysis has resulted in only modestly significant evidence for linkage. In a case-control study drawn from a US-based population of European descent, we have identified a previously unrecognized common, noncoding variant in CFH, the gene encoding complement factor H, that substantially increases the influence of this locus on AMD, and we have strongly replicated the associations of four other previously reported common alleles in three genes (P values ranging from 10(-6) to 10(-70)). Despite excellent power to detect epistasis, we observed purely additive accumulation of risk from alleles at these genes. We found no differences in association of these loci with major phenotypic categories of advanced AMD. Genotypes at these five common SNPs define a broad spectrum of interindividual disease risk and explain about half of the classical sibling risk of AMD in our study population.", - "journal_title": "Nature genetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/16936732/" - } - ], - "ef8257bf-b7bd-4a0b-a6c8-3cbf35c522f9": [ - { - "pub_id": "17848974", - "title": "The quest for natural selection in the age of comparative genomics.", - "authors": "M Anisimova,D A Liberles", - "abstract": "Continued genome sequencing has fueled progress in statistical methods for understanding the action of natural selection at the molecular level. This article reviews various statistical techniques (and their applicability) for detecting adaptation events and the functional divergence of proteins. As large-scale automated studies become more frequent, they provide a useful resource for generating biological null hypotheses for further experimental and statistical testing. Furthermore, they shed light on typical patterns of lineage-specific evolution of organisms, on the functional and structural evolution of protein families and on the interplay between the two. More complex models are being developed to better reflect the underlying biological and chemical processes and to complement simpler statistical models. Linking molecular processes to their statistical signatures in genomes can be demanding, and the proper application of statistical models is discussed.", - "journal_title": "Heredity", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/17848974/" - } - ], - "5fefb0e4-e7f9-4df3-a984-ad4f61756cf7": [ - { - "pub_id": "21418511", - "title": "Genome-wide association study identifies a single major locus contributing to survival into old age; the APOE locus revisited.", - "authors": "Joris Deelen,Marian Beekman,Hae-Won Uh,Quinta Helmer,Maris Kuningas,Lene Christiansen,Dennis Kremer,Ruud van der Breggen,H Eka D Suchiman,Nico Lakenberg,Erik B van den Akker,Willemijn M Passtoors,Henning Tiemeier,Diana van Heemst,Anton J de Craen,Fernando Rivadeneira,Eco J de Geus,Markus Perola,Frans J van der Ouderaa,David A Gunn,Dorret I Boomsma,Andr\u00e9 G Uitterlinden,Kaare Christensen,Cornelia M van Duijn,Bastiaan T Heijmans,Jeanine J Houwing-Duistermaat,Rudi G J Westendorp,P Eline Slagboom", - "abstract": "By studying the loci that contribute to human longevity, we aim to identify mechanisms that contribute to healthy aging. To identify such loci, we performed a genome-wide association study (GWAS) comparing 403 unrelated nonagenarians from long-living families included in the Leiden Longevity Study (LLS) and 1670 younger population controls. The strongest candidate SNPs from this GWAS have been analyzed in a meta-analysis of nonagenarian cases from the Rotterdam Study, Leiden 85-plus study, and Danish 1905 cohort. Only one of the 62 prioritized SNPs from the GWAS analysis (P<1\u00d710(-4) ) showed genome-wide significance with survival into old age in the meta-analysis of 4149 nonagenarian cases and 7582 younger controls [OR=0.71 (95% CI 0.65-0.77), P=3.39 \u00d7 10(-17) ]. This SNP, rs2075650, is located in TOMM40 at chromosome 19q13.32 close to the apolipoprotein E (APOE) gene. Although there was only moderate linkage disequilibrium between rs2075650 and the ApoE \u03b54 defining SNP rs429358, we could not find an APOE-independent effect of rs2075650 on longevity, either in cross-sectional or in longitudinal analyses. As expected, rs429358 associated with metabolic phenotypes in the offspring of the nonagenarian cases from the LLS and their partners. In addition, we observed a novel association between this locus and serum levels of IGF-1 in women (P=0.005). In conclusion, the major locus determining familial longevity up to high age as detected by GWAS was marked by rs2075650, which tags the deleterious effects of the ApoE \u03b54 allele. No other major longevity locus was found.", - "journal_title": "Aging cell", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/21418511/" - } - ], - "01aa3979-60ed-4c76-bd6b-e2e9df1c4ce3": [ - { - "pub_id": "18166347", - "title": "Genomic methylation of leukocyte DNA in relation to colorectal adenoma among asymptomatic women.", - "authors": "Unhee Lim,Andrew Flood,Sang-Woon Choi,Demetrius Albanes,Amanda J Cross,Arthur Schatzkin,Rashmi Sinha,Hormuzd A Katki,Brooks Cash,Phillip Schoenfeld,Rachael Stolzenberg-Solomon", - "abstract": "Systemic inhibition of DNA methylation causes cancers in animals, in part by inducing genetic instability. Epidemiologic evidence linking low genomic methylation in systemic blood DNA to carcinogenesis is limited, however, specifically to the colorectum, in which genetic instability is a primary etiologic factor. We examined genomic methylation of leukocyte DNA in relation to colorectal adenoma (CRA) among asymptomatic women (40-79 years of age) participating in a multicenter colonoscopy screening study (CONCeRN Study, 2000-2002). Of all participants who completed self-administered risk factor and food frequency questionnaires, peripheral blood donation, and colonoscopy, 115 pairs of CRA cases and controls with matching age and month of blood draw were studied. Genomic methylation of leukocyte DNA was determined by liquid chromatography mass spectrometry. Conditional logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI). Compared with women in the lowest tertile of genomic methylation, women in the second (OR, 0.72; 95% CI: 0.34-1.52) and third tertiles (OR, 0.17; 95% CI: 0.06-0.49) had lower risk of CRA (P trend = .002). The inverse relationship was stronger for nonadvanced than for advanced adenoma and, less notably, for proximal than for distal adenoma. The association was also moderately more protective with low rather than high total folate intake but did not differ by other nutrients involved in 1-carbon metabolism or colorectal cancer risk factors. Our findings regarding asymptomatic CRA implicate systemic genomic methylation as a potential etiologic factor for an early stage of CRA.", - "journal_title": "Gastroenterology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/18166347/" - } - ], - "f2f55df4-7e90-4600-90a4-fa30a4c91c5f": [ - { - "pub_id": "14611660", - "title": "Whole-genome screening indicates a possible burst of formation of processed pseudogenes and Alu repeats by particular L1 subfamilies in ancestral primates.", - "authors": "Kazuhiko Ohshima,Masahira Hattori,Tetsusi Yada,Takashi Gojobori,Yoshiyuki Sakaki,Norihiro Okada", - "abstract": "Abundant pseudogenes are a feature of mammalian genomes. Processed pseudogenes (PPs) are reverse transcribed from mRNAs. Recent molecular biological studies show that mammalian long interspersed element 1 (L1)-encoded proteins may have been involved in PP reverse transcription. Here, we present the first comprehensive analysis of human PPs using all known human genes as queries. The human genome was queried and 3,664 candidate PPs were identified. The most abundant were copies of genes encoding keratin 18, glyceraldehyde-3-phosphate dehydrogenase and ribosomal protein L21. A simple method was developed to estimate the level of nucleotide substitutions (and therefore the age) of PPs. A Poisson-like age distribution was obtained with a mean age close to that of the Alu repeats, the predominant human short interspersed elements. These data suggest a nearly simultaneous burst of PP and Alu formation in the genomes of ancestral primates. The peak period of amplification of these two distinct retrotransposons was estimated to be 40-50 million years ago. Concordant amplification of certain L1 subfamilies with PPs and Alus was observed. We suggest that a burst of formation of PPs and Alus occurred in the genome of ancestral primates. One possible mechanism is that proteins encoded by members of particular L1 subfamilies acquired an enhanced ability to recognize cytosolic RNAs in trans.", - "journal_title": "Genome biology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/14611660/" - } - ], - "17de4c01-75e9-4e65-ae2e-603fb645905a": [ - { - "pub_id": "17291824", - "title": "Physcomitrella patens: mosses enter the genomic age.", - "authors": "Ralph S Quatrano,Stuart F McDaniel,Abha Khandelwal,Pierre-Fran\u00e7ois Perroud,David J Cove", - "abstract": "The sequenced genome of the moss Physcomitrella patens provides a powerful tool for comparative analyses of land plant genomes. In parallel, several tools for studying gene function have been developed in P. patens, including RNA interference, inducible promoters and gene targeting, a unique attribute of this plant system. The results of these initiatives are now being realized. For example, transcriptomic analyses illustrate commonalities among plant lineages in gene content, structure, and regulation. Transgenic studies show that the regulatory factors ABSCISIC ACID INSENSITIVE3 (ABI3) and LEAFY (LFY) have molecular functions that are conserved between moss and angiosperms, in spite of the fact that they function in non-homologous tissues. Future work in P. patens will contribute to our understanding of the molecular basis of plant development and evolution.", - "journal_title": "Current opinion in plant biology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/17291824/" - } - ], - "d1e53c55-903a-49ed-b550-47d52e10d1cc": [ - { - "pub_id": "16849531", - "title": "ChIP-chip comes of age for genome-wide functional analysis.", - "authors": "Jiejun Wu,Laura T Smith,Christoph Plass,Tim H-M Huang", - "abstract": "In the post-genome era, attention has focused on the functions of genome sequences and how they are regulated. The emerging epigenomic changes and the interactions between cis-acting elements and protein factors may play a central role in gene regulation. To understand the crosstalk between DNA and protein on a genome-wide scale, one emerging technique, called ChIP-chip, takes the strategy of combining chromatin immunoprecipitation with microarray. This new high-throughput strategy helps screen the targets of critical transcription factors and profile the genome-wide distribution of histone modifications, which will enable the feasibility of conducting a large-scale study, such as the Human Epigenome Project.", - "journal_title": "Cancer research", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/16849531/" - } - ], - "85500890-8c3c-4c43-9cc7-d702c6a44626": [ - { - "pub_id": "17381838", - "title": "Gene expression profiling of aging reveals activation of a p53-mediated transcriptional program.", - "authors": "Michael G Edwards,Rozalyn M Anderson,Ming Yuan,Christina M Kendziorski,Richard Weindruch,Tomas A Prolla", - "abstract": "Aging has been associated with widespread changes at the gene expression level in multiple mammalian tissues. We have used high density oligonucleotide arrays and novel statistical methods to identify specific transcriptional classes that may uncover biological processes that play a central role in mammalian aging. We identified 712 transcripts that are differentially expressed in young (5 month old) and old (25-month old) mouse skeletal muscle. Caloric restriction (CR) completely or partially reversed 87% of the changes in expression. Examination of individual genes revealed a transcriptional profile indicative of increased p53 activity in the older muscle. To determine whether the increase in p53 activity is associated with transcriptional activation of apoptotic targets, we performed RT-PCR on four well known mediators of p53-induced apoptosis: puma, noxa, tnfrsf10b and bok. Expression levels for these proapoptotic genes increased significantly with age (P < 0.05), while CR significantly lowered expression levels for these genes as compared to control fed old mice (P < 0.05). Age-related induction of p53-related genes was observed in multiple tissues, but was not observed in young SOD2+/- and GPX4+/- mice, suggesting that oxidative stress does not induce the expression of these genes. Western blot analysis confirmed that protein levels for both p21 and GADD45a, two established transcriptional targets of p53, were higher in the older muscle tissue. These observations support a role for p53-mediated transcriptional program in mammalian aging and suggest that mechanisms other than reactive oxygen species are involved in the age-related transcriptional activation of p53 targets.", - "journal_title": "BMC genomics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/17381838/" - } - ], - "e9258233-a175-4a28-a93e-713314fbd6c3": [ - { - "pub_id": "15318807", - "title": "Linking nutrition to genomics.", - "authors": "Matthias Bauer,Anne Hamm,Michael J Pankratz", - "abstract": "The new scientific field of nutrigenomics utilizes genomic tools, like microarrays, to analyze metabolic adaptations induced by variations in nutritional status. Here we describe how transcriptional regulation patterns caused by nutritional changes can be identified using gene expression profiling. This includes technical remarks on microarray analysis and data processing, as well as giving biological meaning to statistically solid data. We highlight our recent findings of transcriptional regulation of genes representing specific signaling and metabolic pathways in mouse liver under starvation. The results show strong correlations to previously identified responses to caloric restriction, which can be linked to lifespan extension.", - "journal_title": "Biological chemistry", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/15318807/" - } - ], - "48c2223a-b294-4c12-aee4-fae5d88c6b4d": [ - { - "pub_id": "35274129", - "title": "Genome-wide association study meta-analysis identifies three novel loci for circulating anti-M\u00fcllerian hormone levels in women.", - "authors": "Ren\u00e9e M G Verdiesen,Yvonne T van der Schouw,Carla H van Gils,W M Monique Verschuren,Frank J M Broekmans,Maria C Borges,Ana L Gon\u00e7alves Soares,Deborah A Lawlor,A Heather Eliassen,Peter Kraft,Dale P Sandler,Siob\u00e1n D Harlow,Jennifer A Smith,Nanette Santoro,Minouk J Schoemaker,Anthony J Swerdlow,Anna Murray,Katherine S Ruth,N Charlotte Onland-Moret", - "abstract": "Can additional genetic variants for circulating anti-M\u00fcllerian hormone (AMH) levels be identified through a genome-wide association study (GWAS) meta-analysis including a large sample of premenopausal women? We identified four loci associated with AMH levels at P < 5 \u00d7 10-8: the previously reported MCM8 locus and three novel signals in or near AMH, TEX41 and CDCA7. AMH is expressed by antral stage ovarian follicles in women, and variation in age-specific circulating AMH levels has been associated with disease outcomes. However, the physiological mechanisms underlying these AMH-disease associations are largely unknown. We performed a GWAS meta-analysis in which we combined summary statistics of a previous AMH GWAS with GWAS data from 3705 additional women from three different cohorts. In total, we included data from 7049 premenopausal female participants of European ancestry. The median age of study participants ranged from 15.3 to 48 years across cohorts. Circulating AMH levels were measured in either serum or plasma samples using different ELISA assays. Study-specific analyses were adjusted for age at blood collection and population stratification, and summary statistics were meta-analysed using a standard error-weighted approach. Subsequently, we functionally annotated GWAS variants that reached genome-wide significance (P < 5 \u00d7 10-8). We also performed a gene-based GWAS, pathway analysis and linkage disequilibrium score regression and Mendelian randomization (MR) analyses. We identified four loci associated with AMH levels at P < 5 \u00d7 10-8: the previously reported MCM8 locus and three novel signals in or near AMH, TEX41 and CDCA7. The strongest signal was a missense variant in the AMH gene (rs10417628). Most prioritized genes at the other three identified loci were involved in cell cycle regulation. Genetic correlation analyses indicated a strong positive correlation among single nucleotide polymorphisms for AMH levels and for age at menopause (rg = 0.82, FDR = 0.003). Exploratory two-sample MR analyses did not support causal effects of AMH on breast cancer or polycystic ovary syndrome risk, but should be interpreted with caution as they may be underpowered and the validity of genetic instruments could not be extensively explored. The full AMH GWAS summary statistics will made available after publication through the GWAS catalog (https://www.ebi.ac.uk/gwas/). Whilst this study doubled the sample size of the most recent GWAS, the statistical power is still relatively low. As a result, we may still lack power to identify more genetic variants for AMH and to determine causal effects of AMH on, for example, breast cancer. Also, follow-up studies are needed to investigate whether the signal for the AMH gene is caused by reduced AMH detection by certain assays instead of actual lower circulating AMH levels. Genes mapped to the MCM8, TEX41 and CDCA7 loci are involved in the cell cycle and processes such as DNA replication and apoptosis. The mechanism underlying their associations with AMH may affect the size of the ovarian follicle pool. Altogether, our results provide more insight into the biology of AMH and, accordingly, the biological processes involved in ovarian ageing. Nurses' Health Study and Nurses' Health Study II were supported by research grants from the National Institutes of Health (CA172726, CA186107, CA50385, CA87969, CA49449, CA67262, CA178949). The UK Medical Research Council and Wellcome (217065/Z/19/Z) and the University of Bristol provide core support for ALSPAC. This publication is the work of the listed authors, who will serve as guarantors for the contents of this article. A comprehensive list of grants funding is available on the ALSPAC website (http://www.bristol.ac.uk/alspac/external/documents/grant-acknowledgements.pdf). Funding for the collection of genotype and phenotype data used here was provided by the British Heart Foundation (SP/07/008/24066), Wellcome (WT092830M and WT08806) and UK Medical Research Council (G1001357). M.C.B., A.L.G.S. and D.A.L. work in a unit that is funded by the University of Bristol and UK Medical Research Council (MC_UU_00011/6). M.C.B.'s contribution to this work was funded by a UK Medical Research Council Skills Development Fellowship (MR/P014054/1) and D.A.L. is a National Institute of Health Research Senior Investigator (NF-0616-10102). A.L.G.S. was supported by the study of Dynamic longitudinal exposome trajectories in cardiovascular and metabolic non-communicable diseases (H2020-SC1-2019-Single-Stage-RTD, project ID 874739). The Doetinchem Cohort Study was financially supported by the Ministry of Health, Welfare and Sports of the Netherlands. The funder had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript. Ansh Labs performed the AMH measurements for the Doetinchem Cohort Study free of charge. Ansh Labs was not involved in the data analysis, interpretation or reporting, nor was it financially involved in any aspect of the study. R.M.G.V. was funded by the Honours Track of MSc Epidemiology, University Medical Center Utrecht with a grant from the Netherlands Organization for Scientific Research (NWO) (022.005.021). The Study of Women's Health Across the Nation (SWAN) has grant support from the National Institutes of Health (NIH), DHHS, through the National Institute on Aging (NIA), the National Institute of Nursing Research (NINR) and the NIH Office of Research on Women's Health (ORWH) (U01NR004061; U01AG012505, U01AG012535, U01AG012531, U01AG012539, U01AG012546, U01AG012553, U01AG012554, U01AG012495). The SWAN Genomic Analyses and SWAN Legacy have grant support from the NIA (U01AG017719). The Generations Study was funded by Breast Cancer Now and the Institute of Cancer Research (ICR). The ICR acknowledges NHS funding to the NIHR Biomedical Research Centre. The content of this manuscript is solely the responsibility of the authors and does not necessarily represent official views of the funders. The Sister Study was funded by the Intramural Research Program of the National Institutes of Health (NIH), National Institute of Environmental Health Sciences (Z01-ES044005 to D.P.S.); the AMH assays were supported by the Avon Foundation (02-2012-065 to H.B. Nichols and D.P.S.). The breast cancer genome-wide association analyses were supported by the Government of Canada through Genome Canada and the Canadian Institutes of Health Research, the 'Minist\u00e8re de l'\u00c9conomie, de la Science et de l'Innovation du Qu\u00e9bec' through Genome Qu\u00e9bec and grant PSR-SIIRI-701, The National Institutes of Health (U19 CA148065, X01HG007492), Cancer Research UK (C1287/A10118, C1287/A16563, C1287/A10710) and The European Union (HEALTH-F2-2009-223175 and H2020 633784 and 634935). All studies and funders are listed in Michailidou et al. (Nature, 2017). F.J.M.B. has received fees and grant support from Merck Serono and Ferring BV. D.A.L. has received financial support from several national and international government and charitable funders as well as from Medtronic Ltd and Roche Diagnostics for research that is unrelated to this study. N.S. is scientific consultant for Ansh Laboratories. The other authors declare no competing interests.", - "journal_title": "Human reproduction (Oxford, England)", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/35274129/" - } - ], - "625ffe89-d64b-4675-adc3-c333feddcd60": [ - { - "pub_id": "16253630", - "title": "Genome-wide search for genes affecting serum uric acid levels: the Framingham Heart Study.", - "authors": "Qiong Yang,Chao-Yu Guo,L Adrienne Cupples,Daniel Levy,Peter W F Wilson,Caroline S Fox", - "abstract": "Serum uric acid levels are associated with hypertension, cardiovascular disease, and renal disease. Uric acid has been shown to be heritable; however, genome-wide linkage analyses have not been reported. Genome-wide multipoint variance components linkage analyses with 401 markers spaced at approximately 10 centimorgan (cM) were conducted on 1258 subjects of the Framingham Heart Study, using the average of two serum uric acid measurements obtained in examinations 1 and 2 around 1971 and 1979. Covariates in fully adjusted model included sex, age, body mass index (BMI), serum creatinine, alcohol consumption, diabetes, diuretic treatment, and triglycerides. To investigate possible pleiotropic effects between uric acid and covariates that may have a genetic component, bivariate linkage analyses of uric acid with BMI, triglycerides, and glucose were conducted at the uric acid linkage regions. The heritability of uric acid was 0.63. The highest multipoint log-of-the-odds (LOD) score was 3.3 at 50 cM on chromosome 15 for age-sex-adjusted uric acid, but decreased to 1.5 after multivariable adjustment. Additional evidence of linkage was seen on chromosomes 2 (LOD score 1.1 at 4 cM) and 8 (LOD score 1.7 at 6 cM) for multivariable-adjusted uric acid. Pleiotropic effects were only found between uric acid and glucose and BMI at chromosomes 8 and 15 linkage locations, respectively. We have identified several novel loci linked to uric acid. We found possible pleiotropic effects between uric acid and BMI and glucose. Further research is necessary to identify the genes involved in uric acid metabolism and their roles in hypertension, cardiovascular disease, and renal disease.", - "journal_title": "Metabolism: clinical and experimental", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/16253630/" - } - ], - "4b11f852-d426-4b43-90da-e8e5549428ad": [ - { - "pub_id": "32857118", - "title": "Virtual Histology of Cortical Thickness and Shared Neurobiology in 6 Psychiatric Disorders.", - "authors": " , , , , , ,Yash Patel,Nadine Parker,Jean Shin,Derek Howard,Leon French,Sophia I Thomopoulos,Elena Pozzi,Yoshinari Abe,Christoph Ab\u00e9,Alan Anticevic,Martin Alda,Andre Aleman,Clara Alloza,Silvia Alonso-Lana,Stephanie H Ameis,Evdokia Anagnostou,Andrew A McIntosh,Celso Arango,Paul D Arnold,Philip Asherson,Francesca Assogna,Guillaume Auzias,Rosa Ayesa-Arriola,Geor Bakker,Nerisa Banaj,Tobias Banaschewski,Cibele E Bandeira,Alexandr Baranov,N\u00faria Bargall\u00f3,Claiton H D Bau,Sarah Baumeister,Bernhard T Baune,Mark A Bellgrove,Francesco Benedetti,Alessandro Bertolino,Premika S W Boedhoe,Marco Boks,Irene Bollettini,Caterina Del Mar Bonnin,Tiana Borgers,Stefan Borgwardt,Daniel Brandeis,Brian P Brennan,Jason M Bruggemann,Robin B\u00fclow,Geraldo F Busatto,Sara Calderoni,Vince D Calhoun,Rosa Calvo,Erick J Canales-Rodr\u00edguez,Dara M Cannon,Vaughan J Carr,Nicola Cascella,Mara Cercignani,Tiffany M Chaim-Avancini,Anastasia Christakou,David Coghill,Annette Conzelmann,Benedicto Crespo-Facorro,Ana I Cubillo,Kathryn R Cullen,Renata B Cupertino,Eileen Daly,Udo Dannlowski,Christopher G Davey,Damiaan Denys,Christine Deruelle,Annabella Di Giorgio,Erin W Dickie,Danai Dima,Katharina Dohm,Stefan Ehrlich,Benjamin A Ely,Tracy Erwin-Grabner,Thomas Ethofer,Damien A Fair,Andreas J Fallgatter,Stephen V Faraone,Mar Fatj\u00f3-Vilas,Jennifer M Fedor,Kate D Fitzgerald,Judith M Ford,Thomas Frodl,Cynthia H Y Fu,Janice M Fullerton,Matt C Gabel,David C Glahn,Gloria Roberts,Tinatin Gogberashvili,Jose M Goikolea,Ian H Gotlib,Roberto Goya-Maldonado,Hans J Grabe,Melissa J Green,Eugenio H Grevet,Nynke A Groenewold,Dominik Grotegerd,Oliver Gruber,Patricia Gruner,Amalia Guerrero-Pedraza,Raquel E Gur,Ruben C Gur,Shlomi Haar,Bartholomeus C M Haarman,Jan Haavik,Tim Hahn,Tomas Hajek,Benjamin J Harrison,Neil A Harrison,Catharina A Hartman,Heather C Whalley,Dirk J Heslenfeld,Derrek P Hibar,Eva Hilland,Yoshiyuki Hirano,Tiffany C Ho,Pieter J Hoekstra,Liesbeth Hoekstra,Sarah Hohmann,L E Hong,Cyril H\u00f6schl,Marie F H\u00f8vik,Fleur M Howells,Igor Nenadic,Maria Jalbrzikowski,Anthony C James,Joost Janssen,Fern Jaspers-Fayer,Jian Xu,Rune Jonassen,Georgii Karkashadze,Joseph A King,Tilo Kircher,Matthias Kirschner,Kathrin Koch,Peter Kochunov,Gregor Kohls,Kerstin Konrad,Bernd Kr\u00e4mer,Axel Krug,Jonna Kuntsi,Jun Soo Kwon,Mikael Land\u00e9n,Nils I Landr\u00f8,Luisa Lazaro,Irina S Lebedeva,Elisabeth J Leehr,Sara Lera-Miguel,Klaus-Peter Lesch,Christine Lochner,Mario R Louza,Beatriz Luna,Astri J Lundervold,Frank P MacMaster,Luigi A Maglanoc,Charles B Malpas,Maria J Portella,Rachel Marsh,Fiona M Martyn,David Mataix-Cols,Daniel H Mathalon,Hazel McCarthy,Colm McDonald,Genevieve McPhilemy,Susanne Meinert,Jos\u00e9 M Mench\u00f3n,Luciano Minuzzi,Philip B Mitchell,Carmen Moreno,Pedro Morgado,Filippo Muratori,Clodagh M Murphy,Declan Murphy,Benson Mwangi,Leila Nabulsi,Akiko Nakagawa,Takashi Nakamae,Leyla Namazova,Janardhanan Narayanaswamy,Neda Jahanshad,Danai D Nguyen,Rosa Nicolau,Ruth L O'Gorman Tuura,Kirsten O'Hearn,Jaap Oosterlaan,Nils Opel,Roel A Ophoff,Bob Oranje,Victor Ortiz Garc\u00eda de la Foz,Bronwyn J Overs,Yannis Paloyelis,Christos Pantelis,Mara Parellada,Paul Pauli,Maria Pic\u00f3-P\u00e9rez,Felipe A Picon,Fabrizio Piras,Federica Piras,Kerstin J Plessen,Edith Pomarol-Clotet,Adrian Preda,Olga Puig,Yann Quid\u00e9,Joaquim Radua,J Antoni Ramos-Quiroga,Paul E Rasser,Lisa Rauer,Janardhan Reddy,Ronny Redlich,Andreas Reif,Liesbeth Reneman,Jonathan Repple,Alessandra Retico,Vanesa Richarte,Anja Richter,Pedro G P Rosa,Katya K Rubia,Ryota Hashimoto,Matthew D Sacchet,Raymond Salvador,Javier Santonja,Kelvin Sarink,Salvador Sarr\u00f3,Theodore D Satterthwaite,Akira Sawa,Ulrich Schall,Peter R Schofield,Anouk Schrantee,Jochen Seitz,Mauricio H Serpa,Esther Seti\u00e9n-Suero,Philip Shaw,Devon Shook,Tim J Silk,Kang Sim,Schmitt Simon,Helen Blair Simpson,Aditya Singh,Antonin Skoch,Norbert Skokauskas,Jair C Soares,Noam Soreni,Carles Soriano-Mas,Gianfranco Spalletta,Filip Spaniel,Stephen M Lawrie,Emily R Stern,S Evelyn Stewart,Yoichiro Takayanagi,Henk S Temmingh,David F Tolin,David Tomecek,Diana Tordesillas-Guti\u00e9rrez,Michela Tosetti,Anne Uhlmann,Therese van Amelsvoort,Nic J A van der Wee,Steven J A van der Werff,Neeltje E M van Haren,Guido A van Wingen,Alasdair Vance,Javier V\u00e1zquez-Bourgon,Daniela Vecchio,Ganesan Venkatasubramanian,Eduard Vieta,Oscar Vilarroya,Yolanda Vives-Gilabert,Aristotle N Voineskos,Henry V\u00f6lzke,Georg G von Polier,Esther Walton,Thomas W Weickert,Cynthia Shannon Weickert,Andrea S Weideman,Katharina Wittfeld,Daniel H Wolf,Mon-Ju Wu,T T Yang,Kun Yang,Yuliya Yoncheva,Je-Yeon Yun,Yuqi Cheng,Marcus V Zanetti,Georg C Ziegler,Barbara Franke,Martine Hoogman,Jan K Buitelaar,Daan van Rooij,Ole A Andreassen,Christopher R K Ching,Dick J Veltman,Lianne Schmaal,Dan J Stein,Odile A van den Heuvel,Jessica A Turner,Theo G M van Erp,Zdenka Pausova,Paul M Thompson,Tom\u00e1\u0161 Paus", - "abstract": "Large-scale neuroimaging studies have revealed group differences in cortical thickness across many psychiatric disorders. The underlying neurobiology behind these differences is not well understood. To determine neurobiologic correlates of group differences in cortical thickness between cases and controls in 6 disorders: attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorder (ASD), bipolar disorder (BD), major depressive disorder (MDD), obsessive-compulsive disorder (OCD), and schizophrenia. Profiles of group differences in cortical thickness between cases and controls were generated using T1-weighted magnetic resonance images. Similarity between interregional profiles of cell-specific gene expression and those in the group differences in cortical thickness were investigated in each disorder. Next, principal component analysis was used to reveal a shared profile of group difference in thickness across the disorders. Analysis for gene coexpression, clustering, and enrichment for genes associated with these disorders were conducted. Data analysis was conducted between June and December 2019. The analysis included 145 cohorts across 6 psychiatric disorders drawn from the ENIGMA consortium. The numbers of cases and controls in each of the 6 disorders were as follows: ADHD: 1814 and 1602; ASD: 1748 and 1770; BD: 1547 and 3405; MDD: 2658 and 3572; OCD: 2266 and 2007; and schizophrenia: 2688 and 3244. Interregional profiles of group difference in cortical thickness between cases and controls. A total of 12 721 cases and 15 600 controls, ranging from ages 2 to 89 years, were included in this study. Interregional profiles of group differences in cortical thickness for each of the 6 psychiatric disorders were associated with profiles of gene expression specific to pyramidal (CA1) cells, astrocytes (except for BD), and microglia (except for OCD); collectively, gene-expression profiles of the 3 cell types explain between 25% and 54% of variance in interregional profiles of group differences in cortical thickness. Principal component analysis revealed a shared profile of difference in cortical thickness across the 6 disorders (48% variance explained); interregional profile of this principal component 1 was associated with that of the pyramidal-cell gene expression (explaining 56% of interregional variation). Coexpression analyses of these genes revealed 2 clusters: (1) a prenatal cluster enriched with genes involved in neurodevelopmental (axon guidance) processes and (2) a postnatal cluster enriched with genes involved in synaptic activity and plasticity-related processes. These clusters were enriched with genes associated with all 6 psychiatric disorders. In this study, shared neurobiologic processes were associated with differences in cortical thickness across multiple psychiatric disorders. These processes implicate a common role of prenatal development and postnatal functioning of the cerebral cortex in these disorders.", - "journal_title": "JAMA psychiatry", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/32857118/" - } - ], - "927f16f6-f2b3-47cc-a503-6aa9d254caac": [ - { - "pub_id": "19083132", - "title": "Roles of RECQ helicases in recombination based DNA repair, genomic stability and aging.", - "authors": "Dharmendra Kumar Singh,Byungchan Ahn,Vilhelm A Bohr", - "abstract": "The maintenance of the stability of genetic material is an essential feature of every living organism. Organisms across all kingdoms have evolved diverse and highly efficient repair mechanisms to protect the genome from deleterious consequences of various genotoxic factors that might tend to destabilize the integrity of the genome in each generation. One such group of proteins that is actively involved in genome surveillance is the RecQ helicase family. These proteins are highly conserved DNA helicases, which have diverse roles in multiple DNA metabolic processes such as DNA replication, recombination and DNA repair. In humans, five RecQ helicases have been identified and three of them namely, WRN, BLM and RecQL4 have been linked to genetic diseases characterized by genome instability, premature aging and cancer predisposition. This helicase family plays important roles in various DNA repair pathways including protecting the genome from illegitimate recombination during chromosome segregation in mitosis and assuring genome stability. This review mainly focuses on various roles of human RecQ helicases in the process of recombination-based DNA repair to maintain genome stability and physiological consequences of their defects in the development of cancer and premature aging.", - "journal_title": "Biogerontology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/19083132/" - } - ], - "81c3edc4-f625-45f2-bf78-e49faf118c88": [ - { - "pub_id": "20506564", - "title": "Genes, mutations, and human inherited disease at the dawn of the age of personalized genomics.", - "authors": "David N Cooper,Jian-Min Chen,Edward V Ball,Katy Howells,Matthew Mort,Andrew D Phillips,Nadia Chuzhanova,Michael Krawczak,Hildegard Kehrer-Sawatzki,Peter D Stenson", - "abstract": "The number of reported germline mutations in human nuclear genes, either underlying or associated with inherited disease, has now exceeded 100,000 in more than 3,700 different genes. The availability of these data has both revolutionized the study of the morbid anatomy of the human genome and facilitated \"personalized genomics.\" With approximately 300 new \"inherited disease genes\" (and approximately 10,000 new mutations) being identified annually, it is pertinent to ask how many \"inherited disease genes\" there are in the human genome, how many mutations reside within them, and where such lesions are likely to be located? To address these questions, it is necessary not only to reconsider how we define human genes but also to explore notions of gene \"essentiality\" and \"dispensability.\"Answers to these questions are now emerging from recent novel insights into genome structure and function and through complete genome sequence information derived from multiple individual human genomes. However, a change in focus toward screening functional genomic elements as opposed to genes sensu stricto will be required if we are to capitalize fully on recent technical and conceptual advances and identify new types of disease-associated mutation within noncoding regions remote from the genes whose function they disrupt.", - "journal_title": "Human mutation", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/20506564/" - } - ], - "520b36a2-4c9c-4894-a818-9917bd357982": [ - { - "pub_id": "18660849", - "title": "Longevity genomics across species.", - "authors": "Matt Kaeberlein", - "abstract": "Unbiased genome-wide studies of longevity in S. cerevisiae and C. elegans have led to the identification of more than one hundred genes that determine life span in one or both organisms. Key pathways have been uncovered linking nutrient and growth factor cues to longevity. Quantitative measures of the degree to which aging is evolutionary conserved are now possible. A major challenge for the future is determining which of these genes play a similar role in human aging and using that information to develop therapies toward age-associated diseases.", - "journal_title": "Current genomics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/18660849/" - } - ], - "a1a0b714-7c68-425a-bf73-68dab6fa806c": [ - { - "pub_id": "17076555", - "title": "Health is still social: contemporary examples in the age of the genome.", - "authors": "Timothy H Holtz,Seth M Holmes,Scott Stonington,Leon Eisenberg", - "abstract": "Holtz and colleagues argue that social medicine, including an understanding of the social roots of disease, is as important now as it has ever been.", - "journal_title": "PLoS medicine", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/17076555/" - } - ], - "d68e6278-f0d0-4cf3-9b0a-d29ec81f3267": [ - { - "pub_id": "19698799", - "title": "Aging, age-related macular degeneration, and the response-to-retention of apolipoprotein B-containing lipoproteins.", - "authors": "Christine A Curcio,Mark Johnson,Jiahn-Dar Huang,Martin Rudolf", - "abstract": "The largest risk factor for age-related macular degeneration (ARMD) is advanced age. A prominent age-related change in the human retina is the accumulation of histochemically detectable neutral lipid in normal Bruch's membrane (BrM) throughout adulthood. This change has the potential to have a major impact on physiology of the retinal pigment epithelium (RPE). It occurs in the same compartment as drusen and basal linear deposit, the pathognomonic extracellular, lipid-containing lesions of ARMD. Here we present evidence from light microscopic histochemistry, ultrastructure, lipid profiling of tissues and isolated lipoproteins, and gene expression analysis that this deposition can be accounted for by esterified cholesterol-rich, apolipoprotein B-containing lipoprotein particles constitutively produced by the RPE. This work collectively allows ARMD lesion formation and its aftermath to be conceptualized as a response to the retention of a sub-endothelial apolipoprotein B lipoprotein, similar to a widely accepted model of atherosclerotic coronary artery disease (CAD) (Tabas et al., 2007). This approach provides a wide knowledge base and sophisticated clinical armamentarium that can be readily exploited for the development of new model systems and the future benefit of ARMD patients.", - "journal_title": "Progress in retinal and eye research", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/19698799/" - } - ], - "6748ddcc-8878-48af-93fa-1d4adfc41638": [ - { - "pub_id": "17472752", - "title": "Decline of nucleotide excision repair capacity in aging Caenorhabditis elegans.", - "authors": "Joel N Meyer,Windy A Boyd,Gregory A Azzam,Astrid C Haugen,Jonathan H Freedman,Bennett Van Houten", - "abstract": "Caenorhabditis elegans is an important model for the study of DNA damage and repair related processes such as aging, neurodegeneration, and carcinogenesis. However, DNA repair is poorly characterized in this organism. We adapted a quantitative polymerase chain reaction assay to characterize repair of DNA damage induced by ultraviolet type C (UVC) radiation in C. elegans, and then tested whether DNA repair rates were affected by age in adults. UVC radiation induced lesions in young adult C. elegans, with a slope of 0.4 to 0.5 lesions per 10 kilobases of DNA per 100 J/m2, in both nuclear and mitochondrial targets. L1 and dauer larvae were more than fivefold more sensitive to lesion formation than were young adults. Nuclear repair kinetics in a well expressed nuclear gene were biphasic in nongravid adult nematodes: a faster, first order (half-life about 16 hours) phase lasting approximately 24 hours and resulting in removal of about 60% of the photoproducts was followed by a much slower phase. Repair in ten nuclear DNA regions was 15% and 50% higher in more actively transcribed regions in young and aging adults, respectively. Finally, repair was reduced by 30% to 50% in each of the ten nuclear regions in aging adults. However, this decrease in repair could not be explained by a reduction in expression of nucleotide excision repair genes, and we present a plausible mechanism, based on gene expression data, to account for this decrease. Repair of UVC-induced DNA damage in C. elegans is similar kinetically and genetically to repair in humans. Furthermore, this important repair process slows significantly in aging C. elegans, the first whole organism in which this question has been addressed.", - "journal_title": "Genome biology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/17472752/" - } - ], - "7bad9274-7ebe-4c6c-9dab-35565106efc2": [ - { - "pub_id": "18830410", - "title": "Evolution of the aging brain transcriptome and synaptic regulation.", - "authors": "Patrick M Loerch,Tao Lu,Kelly A Dakin,James M Vann,Adrian Isaacs,Chengiz Geula,Jianbin Wang,Ying Pan,Dana H Gabuzda,Cheng Li,Tomas A Prolla,Bruce A Yankner", - "abstract": "Alzheimer's disease and other neurodegenerative disorders of aging are characterized by clinical and pathological features that are relatively specific to humans. To obtain greater insight into how brain aging has evolved, we compared age-related gene expression changes in the cortex of humans, rhesus macaques, and mice on a genome-wide scale. A small subset of gene expression changes are conserved in all three species, including robust age-dependent upregulation of the neuroprotective gene apolipoprotein D (APOD) and downregulation of the synaptic cAMP signaling gene calcium/calmodulin-dependent protein kinase IV (CAMK4). However, analysis of gene ontology and cell type localization shows that humans and rhesus macaques have diverged from mice due to a dramatic increase in age-dependent repression of neuronal genes. Many of these age-regulated neuronal genes are associated with synaptic function. Notably, genes associated with GABA-ergic inhibitory function are robustly age-downregulated in humans but not in mice at the level of both mRNA and protein. Gene downregulation was not associated with overall neuronal or synaptic loss. Thus, repression of neuronal gene expression is a prominent and recently evolved feature of brain aging in humans and rhesus macaques that may alter neural networks and contribute to age-related cognitive changes.", - "journal_title": "PloS one", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/18830410/" - } - ], - "14268c6a-80b6-4406-936d-56036293a896": [ - { - "pub_id": "20068591", - "title": "A genome-wide association study for age-related hearing impairment in the Saami.", - "authors": "Lut Van Laer,Jeroen R Huyghe,Samuli Hannula,Els Van Eyken,Dietrich A Stephan,Elina M\u00e4ki-Torkko,Pekka Aikio,Erik Fransen,Alana Lysholm-Bernacchi,Martti Sorri,Matthew J Huentelman,Guy Van Camp", - "abstract": "This study aimed at contributing to the elucidation of the genetic basis of age-related hearing impairment (ARHI), a common multifactorial disease with an important genetic contribution as demonstrated by heritability studies. We conducted a genome-wide association study (GWAS) in the Finnish Saami, a small, ancient, genetically isolated population without evidence of demographic expansion. The choice of this study population was motivated by its anticipated higher extent of LD, potentially offering a substantial power advantage for association mapping. DNA samples and audiometric measurements were collected from 352 Finnish Saami individuals, aged between 50 and 75 years. To reduce the burden of multiple testing, we applied principal component (PC) analysis to the multivariate audiometric phenotype. The first three PCs captured 80% of the variation in hearing thresholds, while maintaining biologically important audiometric features. All subjects were genotyped with the Affymetrix 100 K chip. To account for multiple levels of relatedness among subjects, as well as for population stratification, association testing was performed using a mixed model. We summarised the top-ranking association signals for the three traits under study. The top-ranked SNP, rs457717 (P-value 3.55 x 10(-7)), was associated with PC3 and was localised in an intron of the IQ motif-containing GTPase-activating-like protein (IQGAP2). Intriguingly, the SNP rs161927 (P-value 0.000149), seventh-ranked for PC1, was positioned immediately downstream from the metabotropic glutamate receptor-7 gene (GRM7). As a previous GWAS of a European and Finnish sample set already suggested a role for GRM7 in ARHI, this study provides further evidence for the involvement of this gene.", - "journal_title": "European journal of human genetics : EJHG", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/20068591/" - } - ], - "71968c06-7fbb-4ebd-8b67-5b76268bdf4d": [ - { - "pub_id": "22064397", - "title": "Sequencing projects bring age-old wisdom to genomics.", - "authors": "Brendan Borrell", - "abstract": "", - "journal_title": "Nature medicine", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/22064397/" - } - ], - "2ebf48f0-d28d-46c3-a020-387cc3d4d1be": [ - { - "pub_id": "19189975", - "title": "Meta-analysis of age-related gene expression profiles identifies common signatures of aging.", - "authors": "Jo\u00e3o Pedro de Magalh\u00e3es,Jo\u00e3o Curado,George M Church", - "abstract": "Numerous microarray studies of aging have been conducted, yet given the noisy nature of gene expression changes with age, elucidating the transcriptional features of aging and how these relate to physiological, biochemical and pathological changes remains a critical problem. We performed a meta-analysis of age-related gene expression profiles using 27 datasets from mice, rats and humans. Our results reveal several common signatures of aging, including 56 genes consistently overexpressed with age, the most significant of which was APOD, and 17 genes underexpressed with age. We characterized the biological processes associated with these signatures and found that age-related gene expression changes most notably involve an overexpression of inflammation and immune response genes and of genes associated with the lysosome. An underexpression of collagen genes and of genes associated with energy metabolism, particularly mitochondrial genes, as well as alterations in the expression of genes related to apoptosis, cell cycle and cellular senescence biomarkers, were also observed. By employing a new method that emphasizes sensitivity, our work further reveals previously unknown transcriptional changes with age in many genes, processes and functions. We suggest these molecular signatures reflect a combination of degenerative processes but also transcriptional responses to the process of aging. Overall, our results help to understand how transcriptional changes relate to the process of aging and could serve as targets for future studies. http://genomics.senescence.info/uarrays/signatures.html. Supplementary data are available at Bioinformatics online.", - "journal_title": "Bioinformatics (Oxford, England)", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/19189975/" - } - ], - "bbbea92f-b985-40a6-8792-d84941177ed3": [ - { - "pub_id": "21677750", - "title": "A conditional knockout resource for the genome-wide study of mouse gene function.", - "authors": "William C Skarnes,Barry Rosen,Anthony P West,Manousos Koutsourakis,Wendy Bushell,Vivek Iyer,Alejandro O Mujica,Mark Thomas,Jennifer Harrow,Tony Cox,David Jackson,Jessica Severin,Patrick Biggs,Jun Fu,Michael Nefedov,Pieter J de Jong,A Francis Stewart,Allan Bradley", - "abstract": "Gene targeting in embryonic stem cells has become the principal technology for manipulation of the mouse genome, offering unrivalled accuracy in allele design and access to conditional mutagenesis. To bring these advantages to the wider research community, large-scale mouse knockout programmes are producing a permanent resource of targeted mutations in all protein-coding genes. Here we report the establishment of a high-throughput gene-targeting pipeline for the generation of reporter-tagged, conditional alleles. Computational allele design, 96-well modular vector construction and high-efficiency gene-targeting strategies have been combined to mutate genes on an unprecedented scale. So far, more than 12,000 vectors and 9,000 conditional targeted alleles have been produced in highly germline-competent C57BL/6N embryonic stem cells. High-throughput genome engineering highlighted by this study is broadly applicable to rat and human stem cells and provides a foundation for future genome-wide efforts aimed at deciphering the function of all genes encoded by the mammalian genome.", - "journal_title": "Nature", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/21677750/" - } - ], - "9292750d-3941-465c-8e2c-bb041f6bea0b": [ - { - "pub_id": "22032438", - "title": "Evidence for widespread changes in promoter methylation profile in human placenta in response to increasing gestational age and environmental/stochastic factors.", - "authors": "Boris Novakovic,Ryan K Yuen,Lavinia Gordon,Maria S Penaherrera,Andrew Sharkey,Ashley Moffett,Jeffrey M Craig,Wendy P Robinson,Richard Saffery", - "abstract": "The human placenta facilitates the exchange of nutrients, gas and waste between the fetal and maternal circulations. It also protects the fetus from the maternal immune response. Due to its role at the feto-maternal interface, the placenta is subject to many environmental exposures that can potentially alter its epigenetic profile. Previous studies have reported gene expression differences in placenta over gestation, as well as inter-individual variation in expression of some genes. However, the factors contributing to this variation in gene expression remain poorly understood. In this study, we performed a genome-wide DNA methylation analysis of gene promoters in placenta tissue from three pregnancy trimesters. We identified large-scale differences in DNA methylation levels between first, second and third trimesters, with an overall progressive increase in average methylation from first to third trimester. The most differentially methylated genes included many immune regulators, reflecting the change in placental immuno-modulation as pregnancy progresses. We also detected increased inter-individual variation in the third trimester relative to first and second, supporting an accumulation of environmentally induced (or stochastic) changes in DNA methylation pattern. These highly variable genes were enriched for those involved in amino acid and other metabolic pathways, potentially reflecting the adaptation of the human placenta to different environments. The identification of cellular pathways subject to drift in response to environmental influences provide a basis for future studies examining the role of specific environmental factors on DNA methylation pattern and placenta-associated adverse pregnancy outcomes.", - "journal_title": "BMC genomics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/22032438/" - } - ], - "ede27960-89ab-4018-a66f-f81a3cbcc3c1": [ - { - "pub_id": "19202148", - "title": "Assessing susceptibility to age-related macular degeneration with proteomic and genomic biomarkers.", - "authors": "Jiayin Gu,Gayle J T Pauer,Xiuzhen Yue,Umadevi Narendra,Gwen M Sturgill,James Bena,Xiaorong Gu,Neal S Peachey,Robert G Salomon,Stephanie A Hagstrom,John W Crabb, ", - "abstract": "Age-related macular degeneration (AMD) is a progressive disease and major cause of severe visual loss. Toward the discovery of tools for early identification of AMD susceptibility, we evaluated the combined predictive capability of proteomic and genomic AMD biomarkers. We quantified plasma carboxyethylpyrrole (CEP) oxidative protein modifications and CEP autoantibodies by ELISA in 916 AMD and 488 control donors. CEP adducts are uniquely generated from oxidation of docosahexaenoate-containing lipids that are abundant in the retina. Mean CEP adduct and autoantibody levels were found to be elevated in AMD plasma by approximately 60 and approximately 30%, respectively. The odds ratio for both CEP markers elevated was 3-fold greater or more in AMD than in control patients. Genotyping was performed for AMD risk polymorphisms associated with age-related maculopathy susceptibility 2 (ARMS2), high temperature requirement factor A1 (HTRA1), complement factor H, and complement C3, and the risk of AMD was predicted based on genotype alone or in combination with the CEP markers. The AMD risk predicted for those exhibiting elevated CEP markers and risk genotypes was 2-3-fold greater than the risk based on genotype alone. AMD donors carrying the ARMS2 and HTRA1 risk alleles were the most likely to exhibit elevated CEP markers. The results compellingly demonstrate higher mean CEP marker levels in AMD plasma over a broad age range. Receiver operating characteristic curves suggest that CEP markers alone can discriminate between AMD and control plasma donors with approximately 76% accuracy and in combination with genomic markers provide up to approximately 80% discrimination accuracy. Plasma CEP marker levels were altered slightly by several demographic and health factors that warrant further study. We conclude that CEP plasma biomarkers, particularly in combination with genomic markers, offer a potential early warning system for assessing susceptibility to this blinding, multifactorial disease.", - "journal_title": "Molecular & cellular proteomics : MCP", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/19202148/" - } - ], - "7355cae7-85c3-4a35-b413-b9db7906c374": [ - { - "pub_id": "18823527", - "title": "A genome-wide association study for late-onset Alzheimer's disease using DNA pooling.", - "authors": "Richard Abraham,Valentina Moskvina,Rebecca Sims,Paul Hollingworth,Angharad Morgan,Lyudmila Georgieva,Kimberley Dowzell,Sven Cichon,Axel M Hillmer,Michael C O'Donovan,Julie Williams,Michael J Owen,George Kirov", - "abstract": "Late-onset Alzheimer's disease (LOAD) is an age related neurodegenerative disease with a high prevalence that places major demands on healthcare resources in societies with increasingly aged populations. The only extensively replicable genetic risk factor for LOAD is the apolipoprotein E gene. In order to identify additional genetic risk loci we have conducted a genome-wide association (GWA) study in a large LOAD case - control sample, reducing costs through the use of DNA pooling. DNA samples were collected from 1,082 individuals with LOAD and 1,239 control subjects. Age at onset ranged from 60 to 95 and Controls were matched for age (mean = 76.53 years, SD = 33), gender and ethnicity. Equimolar amounts of each DNA sample were added to either a case or control pool. The pools were genotyped using Illumina HumanHap300 and Illumina Sentrix HumanHap240S arrays testing 561,494 SNPs. 114 of our best hit SNPs from the pooling data were identified and then individually genotyped in the case - control sample used to construct the pools. Highly significant association with LOAD was observed at the APOE locus confirming the validity of the pooled genotyping approach.For 109 SNPs outside the APOE locus, we obtained uncorrected p-values </= 0.05 for 74 after individual genotyping. To further test these associations, we added control data from 1400 subjects from the 1958 Birth Cohort with the evidence for association increasing to 3.4 x 10-6 for our strongest finding, rs727153.rs727153 lies 13 kb from the start of transcription of lecithin retinol acyltransferase (phosphatidylcholine - retinol O-acyltransferase, LRAT). Five of seven tag SNPs chosen to cover LRAT showed significant association with LOAD with a SNP in intron 2 of LRAT, showing greatest evidence of association (rs201825, p-value = 6.1 x 10-7). We have validated the pooling method for GWA studies by both identifying the APOE locus and by observing a strong enrichment for significantly associated SNPs. We provide evidence for LRAT as a novel candidate gene for LOAD. LRAT plays a prominent role in the Vitamin A cascade, a system that has been previously implicated in LOAD.", - "journal_title": "BMC medical genomics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/18823527/" - } - ], - "c41e0da8-d5b3-4ea0-bc0a-36de600b25ff": [ - { - "pub_id": "14730301", - "title": "Comparing genomic expression patterns across species identifies shared transcriptional profile in aging.", - "authors": "Steven A McCarroll,Coleen T Murphy,Sige Zou,Scott D Pletcher,Chen-Shan Chin,Yuh Nung Jan,Cynthia Kenyon,Cornelia I Bargmann,Hao Li", - "abstract": "We developed a method for systematically comparing gene expression patterns across organisms using genome-wide comparative analysis of DNA microarray experiments. We identified analogous gene expression programs comprising shared patterns of regulation across orthologous genes. Biological features of these patterns could be identified as highly conserved subpatterns that correspond to Gene Ontology categories. Here, we demonstrate these methods by analyzing a specific biological process, aging, and show that similar analysis can be applied to a range of biological processes. We found that two highly diverged animals, the nematode Caenorhabditis elegans and the fruit fly Drosophila melanogaster, implement a shared adult-onset expression program of genes involved in mitochondrial metabolism, DNA repair, catabolism, peptidolysis and cellular transport. Most of these changes were implemented early in adulthood. Using this approach to search databases of gene expression data, we found conserved transcriptional signatures in larval development, embryogenesis, gametogenesis and mRNA degradation.", - "journal_title": "Nature genetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/14730301/" - } - ], - "691c2efc-e01c-4d95-aea9-23adf84faa04": [ - { - "pub_id": "17903291", - "title": "The Framingham Heart Study 100K SNP genome-wide association study resource: overview of 17 phenotype working group reports.", - "authors": "L Adrienne Cupples,Heather T Arruda,Emelia J Benjamin,Ralph B D'Agostino,Serkalem Demissie,Anita L DeStefano,Jos\u00e9e Dupuis,Kathleen M Falls,Caroline S Fox,Daniel J Gottlieb,Diddahally R Govindaraju,Chao-Yu Guo,Nancy L Heard-Costa,Shih-Jen Hwang,Sekar Kathiresan,Douglas P Kiel,Jason M Laramie,Martin G Larson,Daniel Levy,Chun-Yu Liu,Kathryn L Lunetta,Matthew D Mailman,Alisa K Manning,James B Meigs,Joanne M Murabito,Christopher Newton-Cheh,George T O'Connor,Christopher J O'Donnell,Mona Pandey,Sudha Seshadri,Ramachandran S Vasan,Zhen Y Wang,Jemma B Wilk,Philip A Wolf,Qiong Yang,Larry D Atwood", - "abstract": "The Framingham Heart Study (FHS), founded in 1948 to examine the epidemiology of cardiovascular disease, is among the most comprehensively characterized multi-generational studies in the world. Many collected phenotypes have substantial genetic contributors; yet most genetic determinants remain to be identified. Using single nucleotide polymorphisms (SNPs) from a 100K genome-wide scan, we examine the associations of common polymorphisms with phenotypic variation in this community-based cohort and provide a full-disclosure, web-based resource of results for future replication studies. Adult participants (n = 1345) of the largest 310 pedigrees in the FHS, many biologically related, were genotyped with the 100K Affymetrix GeneChip. These genotypes were used to assess their contribution to 987 phenotypes collected in FHS over 56 years of follow up, including: cardiovascular risk factors and biomarkers; subclinical and clinical cardiovascular disease; cancer and longevity traits; and traits in pulmonary, sleep, neurology, renal, and bone domains. We conducted genome-wide variance components linkage and population-based and family-based association tests. The participants were white of European descent and from the FHS Original and Offspring Cohorts (examination 1 Offspring mean age 32 +/- 9 years, 54% women). This overview summarizes the methods, selected findings and limitations of the results presented in the accompanying series of 17 manuscripts. The presented association results are based on 70,897 autosomal SNPs meeting the following criteria: minor allele frequency > or + 10%, genotype call rate > or = 80%, Hardy-Weinberg equilibrium p-value > or = 0.001, and satisfying Mendelian consistency. Linkage analyses are based on 11,200 SNPs and short-tandem repeats. Results of phenotype-genotype linkages and associations for all autosomal SNPs are posted on the NCBI dbGaP website at http://www.ncbi.nlm.nih.gov/projects/gap/cgi-bin/study.cgi?id=phs000007 webcite. We have created a full-disclosure resource of results, posted on the dbGaP website, from a genome-wide association study in the FHS. Because we used three analytical approaches to examine the association and linkage of 987 phenotypes with thousands of SNPs, our results must be considered hypothesis-generating and need to be replicated. Results from the FHS 100K project with NCBI web posting provides a resource for investigators to identify high priority findings for replication.", - "journal_title": "BMC medical genetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/17903291/" - } - ], - "ac1729e4-095b-48f5-9074-410b67c8ff4d": [ - { - "pub_id": "21183061", - "title": "A comparison of dairy cattle breeding designs that use genomic selection.", - "authors": "M Lillehammer,T H E Meuwissen,A K Sonesson", - "abstract": "Different dairy cattle breeding schemes were compared using stochastic simulations, in which the accuracy of the genomic breeding values was dependent on the structure of the breeding scheme, through the availability of new genotyped animals with phenotypic information. Most studies that predict the gain by implementing genomic selection apply a deterministic approach that requires assumptions about the accuracy of the genomic breeding values. The achieved genetic gain, when genomic selection was the only selection method to directly identify elite sires for widespread use and progeny testing was omitted, was compared with using genomic selection for preselection of young bulls for progeny testing and to a conventional progeny test scheme. The rate of inbreeding could be reduced by selecting more sires every year. Selecting 20 sires directly on their genomic breeding values gave a higher genetic gain than any progeny testing scheme, with the same rate of inbreeding as the schemes that used genomic selection for preselection of bulls before progeny testing. The genomic selection breeding schemes could reduce the rate of inbreeding and still increase genetic gain, compared with the conventional breeding scheme. Since progeny testing is expensive, the breeding scheme omitting the progeny test will be the cheapest one. Keeping the progeny test and use of genomic selection for preselection still has some advantages. It gives higher accuracy of breeding values and does not require a complete restructuring of the breeding program. Comparing at the same rate of inbreeding, using genomic selection for elite sire selection only gives a 13% increase in genetic gain, compared with using genomic selection for preselection. One way to reduce the costs of the scheme where genomic selection was used for preselection is to reduce the number of progeny tested bulls. This was here achieved without getting lower genetic gain or a higher rate of inbreeding.", - "journal_title": "Journal of dairy science", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/21183061/" - } - ], - "4b22c8f7-e928-40fe-a55c-57f4272af594": [ - { - "pub_id": "20801718", - "title": "Chromosome 9p21 in amyotrophic lateral sclerosis in Finland: a genome-wide association study.", - "authors": "Hannu Laaksovirta,Terhi Peuralinna,Jennifer C Schymick,Sonja W Scholz,Shaoi-Lin Lai,Liisa Myllykangas,Raimo Sulkava,Lilja Jansson,Dena G Hernandez,J Raphael Gibbs,Michael A Nalls,David Heckerman,Pentti J Tienari,Bryan J Traynor", - "abstract": "The genetic cause of amyotrophic lateral sclerosis (ALS) is not well understood. Finland is a well suited location for a genome-wide association study of ALS because the incidence of the disease is one of the highest in the world, and because the genetic homogeneity of the Finnish population enhances the ability to detect risk loci. We aimed to identify genetic risk factors for ALS in the Finnish population. We did a genome-wide association study of Finnish patients with ALS and control individuals by use of Illumina genome-wide genotyping arrays. DNA was collected from patients who attended an ALS specialty clinic that receives referrals from neurologists throughout Finland. Control samples were from a population-based study of elderly Finnish individuals. Patients known to carry D90A alleles of the SOD1 gene (n=40) were included in the final analysis as positive controls to assess whether our genome-wide association study was able to detect an association signal at this locus. We obtained samples from 442 patients with ALS and 521 control individuals. After quality control filters were applied, 318\u2008167 single nucleotide polymorphisms (SNPs) from 405 people with ALS and 497 control individuals were available for analysis. We identified two association peaks that exceeded genome-wide significance. One was located on chromosome 21q22 (rs13048019, p=2\u00b758\u00d710(-8)), which corresponds to the autosomal recessive D90A allele of the SOD1 gene. The other was detected in a 232 kb block of linkage disequilibrium (rs3849942, p=9\u00b711\u00d710(-11)) in a region of chromosome 9p that was previously identified in linkage studies of families with ALS. Within this region, we defined a 42-SNP haplotype that was associated with significantly increased risk of ALS (p=7\u00b747\u00d710(-33) when people with familial ALS were compared with controls, odds ratio 21\u00b70, 95% CI 11\u00b72-39\u00b71) and which overlapped with an association locus recently reported for frontotemporal dementia. For the 93 patients with familial ALS, the population attributable risk for the chromosome 9p21 locus was 37\u00b79% (95% CI 27\u00b77-48\u00b71) and that for D90A homozygosity was 25\u00b75% (16\u00b79-34\u00b71). The chromosome 9p21 locus is a major cause of familial ALS in the Finnish population. Our data suggest the presence of a founder mutation for chromosome 9p21-linked ALS. Furthermore, the overlap with the risk haplotype recently reported for frontotemporal dementia provides further evidence of a shared genetic cause for these two neurodegenerative diseases. National Institutes of Health and National Institute on Aging, Microsoft Research, ALS Association, Helsinki University Central Hospital, Finnish Academy, Finnish Medical Society Duodecim, and Kuopio University.", - "journal_title": "The Lancet. Neurology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/20801718/" - } - ], - "bc738c00-2e7d-4296-8d03-6733395a70ac": [ - { - "pub_id": "21255418", - "title": "Breeding value prediction for production traits in layer chickens using pedigree or genomic relationships in a reduced animal model.", - "authors": "Anna Wolc,Chris Stricker,Jesus Arango,Petek Settar,Janet E Fulton,Neil P O'Sullivan,Rudolf Preisinger,David Habier,Rohan Fernando,Dorian J Garrick,Susan J Lamont,Jack C M Dekkers", - "abstract": "Genomic selection involves breeding value estimation of selection candidates based on high-density SNP genotypes. To quantify the potential benefit of genomic selection, accuracies of estimated breeding values (EBV) obtained with different methods using pedigree or high-density SNP genotypes were evaluated and compared in a commercial layer chicken breeding line. The following traits were analyzed: egg production, egg weight, egg color, shell strength, age at sexual maturity, body weight, albumen height, and yolk weight. Predictions appropriate for early or late selection were compared. A total of 2,708 birds were genotyped for 23,356 segregating SNP, including 1,563 females with records. Phenotypes on relatives without genotypes were incorporated in the analysis (in total 13,049 production records).The data were analyzed with a Reduced Animal Model using a relationship matrix based on pedigree data or on marker genotypes and with a Bayesian method using model averaging. Using a validation set that consisted of individuals from the generation following training, these methods were compared by correlating EBV with phenotypes corrected for fixed effects, selecting the top 30 individuals based on EBV and evaluating their mean phenotype, and by regressing phenotypes on EBV. Using high-density SNP genotypes increased accuracies of EBV up to two-fold for selection at an early age and by up to 88% for selection at a later age. Accuracy increases at an early age can be mostly attributed to improved estimates of parental EBV for shell quality and egg production, while for other egg quality traits it is mostly due to improved estimates of Mendelian sampling effects. A relatively small number of markers was sufficient to explain most of the genetic variation for egg weight and body weight.", - "journal_title": "Genetics, selection, evolution : GSE", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/21255418/" - } - ], - "35da53cd-498d-4d4a-b24b-6e8b9b8e8eac": [ - { - "pub_id": "15951485", - "title": "Mutational decay and age of chloroplast and mitochondrial genomes transferred recently to angiosperm nuclear chromosomes.", - "authors": "Chun Y Huang,Nicole Gr\u00fcnheit,Nahal Ahmadinejad,Jeremy N Timmis,William Martin", - "abstract": "Transfers of organelle DNA to the nucleus established several thousand functional genes in eukaryotic chromosomes over evolutionary time. Recent transfers have also contributed nonfunctional plastid (pt)- and mitochondrion (mt)-derived DNA (termed nupts and numts, respectively) to plant nuclear genomes. The two largest transferred organelle genome copies are 131-kb nuptDNA in rice (Oryza sativa) and 262-kb numtDNA in Arabidopsis (Arabidopsis thaliana). These transferred copies were compared in detail with their bona fide organelle counterparts, to which they are 99.77% and 99.91% identical, respectively. No evidence for purifying selection was found in either nuclear integrant, indicating that they are nonfunctional. Mutations attributable to 5-methylcytosine hypermutation have occurred at a 6- to 10-fold higher rate than other point mutations in Arabidopsis numtDNA and rice nuptDNA, respectively, revealing this as a major mechanism of mutational decay for these transferred organelle sequences. Short indels occurred preferentially within homopolymeric stretches but were less frequent than point mutations. The 131-kb nuptDNA is absent in the O. sativa subsp. indica or Oryza rufipogon nuclear genome, suggesting that it was transferred within the O. sativa subsp. japonica lineage and, as revealed by sequence comparisons, after its divergence from the indica chloroplast lineage. The time of the transfer for the rice nupt was estimated as 148,000 (74,000--296,000) years ago and that for the Arabidopsis numtDNA as 88,000 (44,000--176,000) years ago. The results reveal transfer and integration of entire organelle genomes into the nucleus as an ongoing evolutionary process and uncover mutational mechanisms affecting organelle genomes recently transferred into a new mutational environment.", - "journal_title": "Plant physiology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/15951485/" - } - ], - "d5979641-a7e8-4b37-a224-87bb0bf093b6": [ - { - "pub_id": "18768498", - "title": "Genomic DNA methylation among women in a multiethnic New York City birth cohort.", - "authors": "Mary Beth Terry,Jennifer S Ferris,Richard Pilsner,Julie D Flom,Parisa Tehranifar,Regina M Santella,Mary V Gamble,Ezra Susser", - "abstract": "One plausible mechanism for the environment to alter cancer susceptibility is through DNA methylation. Alterations in DNA methylation can lead to genomic instability and altered gene transcription. Genomic DNA methylation levels have been inversely associated with age, suggesting that factors throughout life may be associated with declines in DNA methylation. Using information from a multiethnic New York City birth cohort (born between 1959 and 1963), we examined whether genomic DNA methylation, measured in peripheral blood mononuclear cells, was associated with smoking exposure and other epidemiologic risk factors across the life course. Information on prenatal and childhood exposures was collected prospectively through 1971, and information on adult exposures and blood specimens were collected in adulthood from 2001 to 2007. Methylation levels of leukocyte DNA were determined using a [(3)H]-methyl acceptance assay where higher values of disintegrations per minute per microgram DNA indicate less DNA methylation. Genomic methylation of leukocyte DNA differed by ethnicity (66% of Blacks, 48% of Whites, and 29% of Hispanics were above the median level of disintegrations per minute per microgram DNA; P = 0.03). In multivariable modeling, DNA methylation was statistically significantly associated with maternal smoking during pregnancy, longer birth length, later age at menarche, nulliparity, and later age at first birth. These data, if replicated in larger samples, suggest that risk factors across the life course may be associated with DNA methylation in adulthood. Larger studies and studies that measure within-individual changes in DNA methylation over time are a necessary next step.", - "journal_title": "Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/18768498/" - } - ], - "616ddc34-12a0-4ca7-920f-f09a66ee7a4c": [ - { - "pub_id": "15676284", - "title": "A novel VNTR enhancer within the SIRT3 gene, a human homologue of SIR2, is associated with survival at oldest ages.", - "authors": "Dina Bellizzi,Giuseppina Rose,Paola Cavalcante,Giuseppina Covello,Serena Dato,Francesco De Rango,Valentina Greco,Marcello Maggiolini,Emidio Feraco,Vincenzo Mari,Claudio Franceschi,Giuseppe Passarino,Giovanna De Benedictis", - "abstract": "SIR2 genes control life span in model organisms, playing a central role in evolutionarily conserved pathways of aging and longevity. We wanted to verify whether similar effects may act in humans too. First, we searched for variability in the human sirtuin 3 gene (SIRT3) and discovered a VNTR polymorphism (72-bp repeat core) in intron 5. The alleles differed both for the number of repeats and for presence/absence of potential regulatory sites. Second, by transient transfection experiments, we demonstrated that the VNTR region has an allele-specific enhancer activity. Third, by analyzing allele frequencies as a function of age in a sample of 945 individuals (20-106 years), we found that the allele completely lacking enhancer activity is virtually absent in males older than 90 years. Thus the underexpression of a human sirtuin gene seems to be detrimental for longevity as it occurs in model organisms.", - "journal_title": "Genomics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/15676284/" - } - ], - "7fea81f0-193c-47c6-81b9-98ffb872fe1b": [ - { - "pub_id": "21358982", - "title": "Somatic genome variations in health and disease.", - "authors": "I Y Iourov,S G Vorsanova,Y B Yurov", - "abstract": "It is hard to imagine that all the cells of the human organism (about 10(14)) share identical genome. Moreover, the number of mitoses (about 10(16)) required for the organism's development and maturation during ontogeny suggests that at least a proportion of them could be abnormal leading, thereby, to large-scale genomic alterations in somatic cells. Experimental data do demonstrate such genomic variations to exist and to be involved in human development and interindividual genetic variability in health and disease. However, since current genomic technologies are mainly based on methods, which analyze genomes from a large pool of cells, intercellular or somatic genome variations are significantly less appreciated in modern bioscience. Here, a review of somatic genome variations occurring at all levels of genome organization (i.e. DNA sequence, subchromosomal and chromosomal) in health and disease is presented. Looking through the available literature, it was possible to show that the somatic cell genome is extremely variable. Additionally, being mainly associated with chromosome or genome instability (most commonly manifesting as aneuploidy), somatic genome variations are involved in pathogenesis of numerous human diseases. The latter mainly concerns diseases of the brain (i.e. autism, schizophrenia, Alzheimer's disease) and immune system (autoimmune diseases), chromosomal and some monogenic syndromes, cancers, infertility and prenatal mortality. Taking into account data on somatic genome variations and chromosome instability, it becomes possible to show that related processes can underlie non-malignant pathology such as (neuro)degeneration or other local tissue dysfunctions. Together, we suggest that detection and characterization of somatic genome behavior and variations can provide new opportunities for human genome research and genetics.", - "journal_title": "Current genomics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/21358982/" - } - ], - "24042f63-48c8-4ebd-8b91-92d6b34a0fcf": [ - { - "pub_id": "21062962", - "title": "One hundred years of pleiotropy: a retrospective.", - "authors": "Frank W Stearns", - "abstract": "Pleiotropy is defined as the phenomenon in which a single locus affects two or more distinct phenotypic traits. The term was formally introduced into the literature by the German geneticist Ludwig Plate in 1910, 100 years ago. Pleiotropy has had an important influence on the fields of physiological and medical genetics as well as on evolutionary biology. Different approaches to the study of pleiotropy have led to incongruence in the way that it is perceived and discussed among researchers in these fields. Furthermore, our understanding of the term has changed quite a bit since 1910, particularly in light of modern molecular data. This review traces the history of the term \"pleiotropy\" and reevaluates its current place in the field of genetics.", - "journal_title": "Genetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/21062962/" - } - ], - "646fe236-5194-47c0-a57c-2ef687cc402d": [ - { - "pub_id": "22987634", - "title": "Peroxiredoxins, gerontogenes linking aging to genome instability and cancer.", - "authors": "Thomas Nystr\u00f6m,Junsheng Yang,Mikael Molin", - "abstract": "Age is the highest risk factor known for a large number of maladies, including cancers. However, it is unclear how aging mechanistically predisposes the organism to such diseases and which gene products are the primary targets of the aging process. Recent studies suggest that peroxiredoxins, antioxidant enzymes preventing tumor development, are targets of age-related deterioration and that bolstering their activity (e.g., by caloric restriction) extends cellular life span. This review focuses on how the peroxiredoxin functions (i.e., as peroxidases, signal transducers, and molecular chaperones) fit with contemporary theories of aging and whether peroxiredoxins could be targeted therapeutically in the treatment of age-associated cancers.", - "journal_title": "Genes & development", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/22987634/" - } - ], - "ef3eb166-c397-4f39-a35c-ec7965934f30": [ - { - "pub_id": "23150934", - "title": "TREM2 variants in Alzheimer's disease.", - "authors": "Rita Guerreiro,Aleksandra Wojtas,Jose Bras,Minerva Carrasquillo,Ekaterina Rogaeva,Elisa Majounie,Carlos Cruchaga,Celeste Sassi,John S K Kauwe,Steven Younkin,Lilinaz Hazrati,John Collinge,Jennifer Pocock,Tammaryn Lashley,Julie Williams,Jean-Charles Lambert,Philippe Amouyel,Alison Goate,Rosa Rademakers,Kevin Morgan,John Powell,Peter St George-Hyslop,Andrew Singleton,John Hardy, ", - "abstract": "Homozygous loss-of-function mutations in TREM2, encoding the triggering receptor expressed on myeloid cells 2 protein, have previously been associated with an autosomal recessive form of early-onset dementia. We used genome, exome, and Sanger sequencing to analyze the genetic variability in TREM2 in a series of 1092 patients with Alzheimer's disease and 1107 controls (the discovery set). We then performed a meta-analysis on imputed data for the TREM2 variant rs75932628 (predicted to cause a R47H substitution) from three genomewide association studies of Alzheimer's disease and tested for the association of the variant with disease. We genotyped the R47H variant in an additional 1887 cases and 4061 controls. We then assayed the expression of TREM2 across different regions of the human brain and identified genes that are differentially expressed in a mouse model of Alzheimer's disease and in control mice. We found significantly more variants in exon 2 of TREM2 in patients with Alzheimer's disease than in controls in the discovery set (P=0.02). There were 22 variant alleles in 1092 patients with Alzheimer's disease and 5 variant alleles in 1107 controls (P<0.001). The most commonly associated variant, rs75932628 (encoding R47H), showed highly significant association with Alzheimer's disease (P<0.001). Meta-analysis of rs75932628 genotypes imputed from genomewide association studies confirmed this association (P=0.002), as did direct genotyping of an additional series of 1887 patients with Alzheimer's disease and 4061 controls (P<0.001). Trem2 expression differed between control mice and a mouse model of Alzheimer's disease. Heterozygous rare variants in TREM2 are associated with a significant increase in the risk of Alzheimer's disease. (Funded by Alzheimer's Research UK and others.).", - "journal_title": "The New England journal of medicine", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/23150934/" - } - ], - "b4134824-93ea-42a1-9d39-24cc4b6d775c": [ - { - "pub_id": "27184599", - "title": "Coming of age: ten years of next-generation sequencing technologies.", - "authors": "Sara Goodwin,John D McPherson,W Richard McCombie", - "abstract": "Since the completion of the human genome project in 2003, extraordinary progress has been made in genome sequencing technologies, which has led to a decreased cost per megabase and an increase in the number and diversity of sequenced genomes. An astonishing complexity of genome architecture has been revealed, bringing these sequencing technologies to even greater advancements. Some approaches maximize the number of bases sequenced in the least amount of time, generating a wealth of data that can be used to understand increasingly complex phenotypes. Alternatively, other approaches now aim to sequence longer contiguous pieces of DNA, which are essential for resolving structurally complex regions. These and other strategies are providing researchers and clinicians a variety of tools to probe genomes in greater depth, leading to an enhanced understanding of how genome sequence variants underlie phenotype and disease.", - "journal_title": "Nature reviews. Genetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/27184599/" - } - ], - "d5ff1163-b394-4374-81e7-21a53d4f8527": [ - { - "pub_id": "22982444", - "title": "Insights into phylogeny, sex function and age of Fragaria based on whole chloroplast genome sequencing.", - "authors": "Wambui Njuguna,Aaron Liston,Richard Cronn,Tia-Lynn Ashman,Nahla Bassil", - "abstract": "The cultivated strawberry is one of the youngest domesticated plants, developed in France in the 1700s from chance hybridization between two western hemisphere octoploid species. However, little is known about the evolution of the species that gave rise to this important fruit crop. Phylogenetic analysis of chloroplast genome sequences of 21 Fragaria species and subspecies resolves the western North American diploid F. vesca subsp. bracteata as sister to the clade of octoploid/decaploid species. No extant tetraploids or hexaploids are directly involved in the maternal ancestry of the octoploids. There is strong geographic segregation of chloroplast haplotypes in subsp. bracteata, and the gynodioecious Pacific Coast populations are implicated as both the maternal lineage and the source of male-sterility in the octoploid strawberries. Analysis of sexual system evolution in Fragaria provides evidence that the loss of male and female function can follow polyploidization, but does not seem to be associated with loss of self-incompatibility following genome doubling. Character-state mapping provided insight into sexual system evolution and its association with loss of self-incompatibility and genome doubling/merger. Fragaria attained its circumboreal and amphitropical distribution within the past one to four million years and the rise of the octoploid clade is dated at 0.372-2.05 million years ago.", - "journal_title": "Molecular phylogenetics and evolution", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/22982444/" - } - ], - "c8fbb24d-0a72-4a45-a552-6cd98a4a25a2": [ - { - "pub_id": "22454374", - "title": "Genomics and successful aging: grounds for renewed optimism?", - "authors": "L C Pilling,L W Harries,J Powell,D J Llewellyn,L Ferrucci,D Melzer", - "abstract": "Successful aging depends in part on delaying age-related disease onsets until later in life. Conditions including coronary artery disease, Alzheimer's disease, prostate cancer, and type 2 diabetes are moderately heritable. Genome-wide association studies have identified many risk associated single-nucleotide polymorphisms for these conditions, but much heritability remains unaccounted for. Nevertheless, a great deal is being learned. Here, we review age-related disease associated single-nucleotide polymorphisms and identify key underlying pathways including lipid handling, specific immune processes, early tissue development, and cell cycle control. Most age-related disease associated single-nucleotide polymorphisms do not affect coding regions of genes or protein makeup but instead influence regulation of gene expression. Recent evidence indicates that evolution of gene regulatory sites is fundamental to interspecies differences. Animal models relevant to human aging may therefore need to focus more on gene regulation rather than testing major disruptions to fundamental pathway genes. Recent larger scale human studies of in vivo genome-wide expression (notably from the InCHIANTI aging study) have identified changes in splicing, the \"fine tuning\" of protein sequences, as a potentially important factor in decline of cellular function with age. Studies of expression with muscle strength and cognition have shown striking concordance with certain mice models of muscle repair and beta-amyloid phagocytosis respectively. The emerging clearer picture of the genetic architecture of age-related diseases in humans is providing new insights into the underlying pathophysiological pathways involved. Translation of genomics into new approaches to prevention, tests and treatments to extend successful aging is therefore likely in the coming decades.", - "journal_title": "The journals of gerontology. Series A, Biological sciences and medical sciences", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/22454374/" - } - ], - "9ac30292-7d7f-4dbd-aa3e-bf6292977373": [ - { - "pub_id": "26515523", - "title": "Genomic epidemiology of age-associated meningococcal lineages in national surveillance: an observational cohort study.", - "authors": "Dorothea M C Hill,Jay Lucidarme,Stephen J Gray,Lynne S Newbold,Roisin Ure,Carina Brehony,Odile B Harrison,James E Bray,Keith A Jolley,Holly B Bratcher,Julian Parkhill,Christoph M Tang,Ray Borrow,Martin C J Maiden", - "abstract": "Invasive meningococcal disease (IMD) is a worldwide health issue that is potentially preventable with vaccination. In view of its sporadic nature and the high diversity of Neisseria meningitidis, epidemiological surveillance incorporating detailed isolate characterisation is crucial for effective control and understanding the evolving epidemiology of IMD. The Meningitis Research Foundation Meningococcus Genome Library (MRF-MGL) exploits whole-genome sequencing (WGS) for this purpose and presents data on a comprehensive and coherent IMD isolate collection from England and Wales via the internet. We assessed the contribution of these data to investigating IMD epidemiology. WGS data were obtained for all 899 IMD isolates available for England and Wales in epidemiological years 2010-11 and 2011-12. The data had been annotated at 1720 loci, analysed, and disseminated online. Information was also available on meningococcal population structure and vaccine (Bexsero, GlaxoSmithKline, Brentford, Middlesex, UK) antigen variants, which enabled the investigation of IMD-associated genotypes over time and by patients' age groups. Population genomic analyses were done with a hierarchical gene-by-gene approach. The methods used by MRF-MGL efficiently characterised IMD isolates and information was provided in plain language. At least 20 meningococcal lineages were identified, three of which (hyperinvasive clonal complexes 41/44 [lineage 3], 269 [lineage 2], and 23 [lineage 23]) were responsible for 528 (59%) of IMD isolates. Lineages were highly diverse and showed evidence of extensive recombination. Specific lineages were associated with IMD in particular age groups, with notable diversity in the youngest and oldest individuals. The increased incidence of IMD from 1984 to 2010 in England and Wales was due to successive and concurrent epidemics of different lineages. Genetically, 74% of isolates were characterised as encoding group B capsules: 16% group Y, 6% group W, and 3% group C. Exact peptide matches for individual Bexsero vaccine antigens were present in up to 26% of isolates. The MRF-MGL represents an effective, broadly applicable model for the storage, analysis, and dissemination of WGS data that can facilitate real-time genomic pathogen surveillance. The data revealed information crucial to effective deployment and assessment of vaccines against N meningitidis. Meningitis Research Foundation, Wellcome Trust, Public Health England, European Union.", - "journal_title": "The Lancet. Infectious diseases", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/26515523/" - } - ], - "c4a14c11-9cd3-4ae6-af0c-9002cf0b5a8a": [ - { - "pub_id": "23259602", - "title": "Genome-wide association scan of dental caries in the permanent dentition.", - "authors": "Xiaojing Wang,John R Shaffer,Zhen Zeng,Ferdouse Begum,Alexandre R Vieira,Jacqueline Noel,Ida Anjomshoaa,Karen T Cuenco,Myoung-Keun Lee,James Beck,Eric Boerwinkle,Marilyn C Cornelis,Frank B Hu,David R Crosslin,Cathy C Laurie,Sarah C Nelson,Kimberly F Doheny,Elizabeth W Pugh,Deborah E Polk,Robert J Weyant,Richard Crout,Daniel W McNeil,Daniel E Weeks,Eleanor Feingold,Mary L Marazita", - "abstract": "Over 90% of adults aged 20 years or older with permanent teeth have suffered from dental caries leading to pain, infection, or even tooth loss. Although caries prevalence has decreased over the past decade, there are still about 23% of dentate adults who have untreated carious lesions in the US. Dental caries is a complex disorder affected by both individual susceptibility and environmental factors. Approximately 35-55% of caries phenotypic variation in the permanent dentition is attributable to genes, though few specific caries genes have been identified. Therefore, we conducted the first genome-wide association study (GWAS) to identify genes affecting susceptibility to caries in adults. Five independent cohorts were included in this study, totaling more than 7000 participants. For each participant, dental caries was assessed and genetic markers (single nucleotide polymorphisms, SNPs) were genotyped or imputed across the entire genome. Due to the heterogeneity among the five cohorts regarding age, genotyping platform, quality of dental caries assessment, and study design, we first conducted genome-wide association (GWA) analyses on each of the five independent cohorts separately. We then performed three meta-analyses to combine results for: (i) the comparatively younger, Appalachian cohorts (N\u2009=\u20091483) with well-assessed caries phenotype, (ii) the comparatively older, non-Appalachian cohorts (N\u2009=\u20095960) with inferior caries phenotypes, and (iii) all five cohorts (N\u2009=\u20097443). Top ranking genetic loci within and across meta-analyses were scrutinized for biologically plausible roles on caries. Different sets of genes were nominated across the three meta-analyses, especially between the younger and older age cohorts. In general, we identified several suggestive loci (P-value\u2009\u2264\u200910E-05) within or near genes with plausible biological roles for dental caries, including RPS6KA2 and PTK2B, involved in p38-depenedent MAPK signaling, and RHOU and FZD1, involved in the Wnt signaling cascade. Both of these pathways have been implicated in dental caries. ADMTS3 and ISL1 are involved in tooth development, and TLR2 is involved in immune response to oral pathogens. As the first GWAS for dental caries in adults, this study nominated several novel caries genes for future study, which may lead to better understanding of cariogenesis, and ultimately, to improved disease predictions, prevention, and/or treatment.", - "journal_title": "BMC oral health", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/23259602/" - } - ], - "5030cbc8-e02c-4e3a-8cbc-0156ce123c99": [ - { - "pub_id": "22265401", - "title": "Aging, rejuvenation, and epigenetic reprogramming: resetting the aging clock.", - "authors": "Thomas A Rando,Howard Y Chang", - "abstract": "The underlying cause of aging remains one of the central mysteries of biology. Recent studies in several different systems suggest that not only may the rate of aging be modified by environmental and genetic factors, but also that the aging clock can be reversed, restoring characteristics of youthfulness to aged cells and tissues. This Review focuses on the emerging biology of rejuvenation through the lens of epigenetic reprogramming. By defining youthfulness and senescence as epigenetic states, a framework for asking new questions about the aging process emerges.", - "journal_title": "Cell", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/22265401/" - } - ], - "1f1c65bc-d563-4720-a801-8f44954044ea": [ - { - "pub_id": "34955377", - "title": "Colorectal Cancer Screening in the Elderly: Is Age Just a Number?", - "authors": "Waed Alswealmeen,Lili Sadri,Gabrielle Perrotti,Jaclyn Heilman,Kirran Bakshi,Soo Y Kim,David M Zebley,Steven A Fassler", - "abstract": "Colorectal cancer screening improved outcomes for patients diagnosed between the age of 45-75. Present life expectancy is beyond this limit, yet there are no guidelines for these ages. We aim to identify outcomes after screening and intervention in patients \u226575 years and correlate with frailty. Records between 2011 and 2019 were queried. Patients \u226575 screened and treated for colorectal cancer were included. Patient demographics, perioperative mortality, age at last colonoscopy and frailty score were calculated. A Modified Frailty Index from the Canadian Study of Health and Aging Frailty Index was used. A score of 1 to 11 was calculated based on patient comorbidities. The MFI was assigned from 0 to 11: 0 signified absence of frailty and 11 indicated maximum frailty. Of 179 patients were identified, 46.3% males. 171(95%) had elective and 8 (5%) had emergent surgery. The average age was 81.8 years. All colonoscopies were performed for symptoms. A modified frailty index was retrospectively calculated; 75% of patients scored between 0 and 2 and 1% scored >6. Older patients who underwent colonoscopy and surgery for symptomatic colon cancer had a low mortality, 2%. The average age was 6.8 years older than the recommended cutoff for colonoscopy screening. Most patients scored 0 to 2 on the modified frailty index, suggesting that not only are older patients more fit than previously thought, but also able to tolerate colorectal interventions more liberally. Utilizing frailty indices to identify screening patterns beyond 75 years of age might prove beneficial for this patient population. Further studies are recommended.", - "journal_title": "Clinical colorectal cancer", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/34955377/" - } - ], - "9dc88325-cbca-4697-acb4-0b10a1cd5cdd": [ - { - "pub_id": "31235808", - "title": "Genome-wide analysis of dental caries and periodontitis combining clinical and self-reported data.", - "authors": "Dmitry Shungin,Simon Haworth,Kimon Divaris,Cary S Agler,Yoichiro Kamatani,Myoung Keun Lee,Kelsey Grinde,George Hindy,Viivi Alaraudanjoki,Paula Pesonen,Alexander Teumer,Birte Holtfreter,Saori Sakaue,Jun Hirata,Yau-Hua Yu,Paul M Ridker,Franco Giulianini,Daniel I Chasman,Patrik K E Magnusson,Takeaki Sudo,Yukinori Okada,Uwe V\u00f6lker,Thomas Kocher,Vuokko Anttonen,Marja-Liisa Laitala,Marju Orho-Melander,Tamar Sofer,John R Shaffer,Alexandre Vieira,Mary L Marazita,Michiaki Kubo,Yasushi Furuichi,Kari E North,Steve Offenbacher,Erik Ingelsson,Paul W Franks,Nicholas J Timpson,Ingegerd Johansson", - "abstract": "Dental caries and periodontitis account for a vast burden of morbidity and healthcare spending, yet their genetic basis remains largely uncharacterized. Here, we identify self-reported dental disease proxies which have similar underlying genetic contributions to clinical disease measures and then combine these in a genome-wide association study meta-analysis, identifying 47 novel and conditionally-independent risk loci for dental caries. We show that the heritability of dental caries is enriched for conserved genomic regions and partially overlapping with a range of complex traits including smoking, education, personality traits and metabolic measures. Using cardio-metabolic traits as an example in Mendelian randomization analysis, we estimate causal relationships and provide evidence suggesting that the processes contributing to dental caries may have undesirable downstream effects on health.", - "journal_title": "Nature communications", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/31235808/" - } - ], - "daf409ff-a4e3-4fe8-8b13-dd191ed4bb01": [ - { - "pub_id": "22364233", - "title": "Systems-level analysis of age-related macular degeneration reveals global biomarkers and phenotype-specific functional networks.", - "authors": "Aaron M Newman,Natasha B Gallo,Lisa S Hancox,Norma J Miller,Carolyn M Radeke,Michelle A Maloney,James B Cooper,Gregory S Hageman,Don H Anderson,Lincoln V Johnson,Monte J Radeke", - "abstract": "Please see related commentary: http://www.biomedcentral.com/1741-7015/10/21/abstract Age-related macular degeneration (AMD) is a leading cause of blindness that affects the central region of the retinal pigmented epithelium (RPE), choroid, and neural retina. Initially characterized by an accumulation of sub-RPE deposits, AMD leads to progressive retinal degeneration, and in advanced cases, irreversible vision loss. Although genetic analysis, animal models, and cell culture systems have yielded important insights into AMD, the molecular pathways underlying AMD's onset and progression remain poorly delineated. We sought to better understand the molecular underpinnings of this devastating disease by performing the first comparative transcriptome analysis of AMD and normal human donor eyes. RPE-choroid and retina tissue samples were obtained from a common cohort of 31 normal, 26 AMD, and 11 potential pre-AMD human donor eyes. Transcriptome profiles were generated for macular and extramacular regions, and statistical and bioinformatic methods were employed to identify disease-associated gene signatures and functionally enriched protein association networks. Selected genes of high significance were validated using an independent donor cohort. We identified over 50 annotated genes enriched in cell-mediated immune responses that are globally over-expressed in RPE-choroid AMD phenotypes. Using a machine learning model and a second donor cohort, we show that the top 20 global genes are predictive of AMD clinical diagnosis. We also discovered functionally enriched gene sets in the RPE-choroid that delineate the advanced AMD phenotypes, neovascular AMD and geographic atrophy. Moreover, we identified a graded increase of transcript levels in the retina related to wound response, complement cascade, and neurogenesis that strongly correlates with decreased levels of phototransduction transcripts and increased AMD severity. Based on our findings, we assembled protein-protein interactomes that highlight functional networks likely to be involved in AMD pathogenesis. We discovered new global biomarkers and gene expression signatures of AMD. These results are consistent with a model whereby cell-based inflammatory responses represent a central feature of AMD etiology, and depending on genetics, environment, or stochastic factors, may give rise to the advanced AMD phenotypes characterized by angiogenesis and/or cell death. Genes regulating these immunological activities, along with numerous other genes identified here, represent promising new targets for AMD-directed therapeutics and diagnostics.", - "journal_title": "Genome medicine", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/22364233/" - } - ], - "988adc2c-d622-4b18-9a9c-1e413eaf4f82": [ - { - "pub_id": "21459472", - "title": "Adaptation in the age of ecological genomics: insights from parallelism and convergence.", - "authors": "Kathryn R Elmer,Axel Meyer", - "abstract": "Parallel phenotypic diversification in closely related species is a rigorous framework for testing the role of natural selection in evolution. Do parallel phenotypes always diversify by parallel genetic bases or does selection pave many alternative genomic routes to the same phenotypic ends? In this review, we show that the advent of next-generation sequencing technologies and the growing use of genomic approaches make it increasingly feasible to answer these fundamental questions using ecological and evolutionary 'non-model' populations of vertebrates in nature. While it is generally expected, and often observed, that closely related populations or species have parallel genetic bases to parallel phenotypes, exceptions are not rare and show that alternative genetic routes can result in similar phenotypes. Ultimately, this framework may illuminate the ecological conditions, evolutionary histories and genetic architectures that result in recurrent phenotypes and rapid adaptation.", - "journal_title": "Trends in ecology & evolution", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/21459472/" - } - ], - "282b000f-cc20-43c8-bd80-4eff37099ca7": [ - { - "pub_id": "21591945", - "title": "Genomics and the eye.", - "authors": "Val C Sheffield,Edwin M Stone", - "abstract": "", - "journal_title": "The New England journal of medicine", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/21591945/" - } - ], - "567f810a-930f-415b-928c-a7bc47e922c9": [ - { - "pub_id": "26673150", - "title": "Lifetime stress accelerates epigenetic aging in an urban, African American cohort: relevance of glucocorticoid signaling.", - "authors": "Anthony S Zannas,Janine Arloth,Tania Carrillo-Roa,Stella Iurato,Simone R\u00f6h,Kerry J Ressler,Charles B Nemeroff,Alicia K Smith,Bekh Bradley,Christine Heim,Andreas Menke,Jennifer F Lange,Tanja Br\u00fcckl,Marcus Ising,Naomi R Wray,Angelika Erhardt,Elisabeth B Binder,Divya Mehta", - "abstract": "Chronic psychological stress is associated with accelerated aging and increased risk for aging-related diseases, but the underlying molecular mechanisms are unclear. We examined the effect of lifetime stressors on a DNA methylation-based age predictor, epigenetic clock. After controlling for blood cell-type composition and lifestyle parameters, cumulative lifetime stress, but not childhood maltreatment or current stress alone, predicted accelerated epigenetic aging in an urban, African American cohort (n\u2009=\u2009392). This effect was primarily driven by personal life stressors, was more pronounced with advancing age, and was blunted in individuals with higher childhood abuse exposure. Hypothesizing that these epigenetic effects could be mediated by glucocorticoid signaling, we found that a high number (n\u2009=\u200985) of epigenetic clock CpG sites were located within glucocorticoid response elements. We further examined the functional effects of glucocorticoids on epigenetic clock CpGs in an independent sample with genome-wide DNA methylation (n\u2009=\u2009124) and gene expression data (n\u2009=\u2009297) before and after exposure to the glucocorticoid receptor agonist dexamethasone. Dexamethasone induced dynamic changes in methylation in 31.2\u00a0% (110/353) of these CpGs and transcription in 81.7\u00a0% (139/170) of genes neighboring epigenetic clock CpGs. Disease enrichment analysis of these dexamethasone-regulated genes showed enriched association for aging-related diseases, including coronary artery disease, arteriosclerosis, and leukemias. Cumulative lifetime stress may accelerate epigenetic aging, an effect that could be driven by glucocorticoid-induced epigenetic changes. These findings contribute to our understanding of mechanisms linking chronic stress with accelerated aging and heightened disease risk.", - "journal_title": "Genome biology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/26673150/" - } - ], - "64117a6f-8f79-4d73-8d60-449314d1f56c": [ - { - "pub_id": "22923132", - "title": "Role of epigenetics in human aging and longevity: genome-wide DNA methylation profile in centenarians and centenarians' offspring.", - "authors": "Davide Gentilini,Daniela Mari,Davide Castaldi,Daniel Remondini,Giulia Ogliari,Rita Ostan,Laura Bucci,Silvia M Sirchia,Silvia Tabano,Francesco Cavagnini,Daniela Monti,Claudio Franceschi,Anna Maria Di Blasio,Giovanni Vitale", - "abstract": "The role of epigenetics in the modulation of longevity has not been studied in humans. To this aim, (1) we evaluated the DNA methylation from peripheral leukocytes of 21 female centenarians, their 21 female offspring, 21 offspring of both non-long-lived parents, and 21 young women through ELISA assay, pyrosequencing analysis of Alu sequences, and quantification of methylation in CpG repeats outside CpG islands; (2) we compared the DNA methylation profiles of these populations through Infinium array for genome-wide CpG methylation analysis. We observed an age-related decrease in global DNA methylation and a delay of this process in centenarians' offspring. Interestingly, literature data suggest a link between the loss of DNA methylation observed during aging and the development of age-associated diseases. Genome-wide methylation analysis evidenced DNA methylation profiles specific for aging and longevity: (1) aging-associated DNA hypermethylation occurs predominantly in genes involved in the development of anatomical structures, organs, and multicellular organisms and in the regulation of transcription; (2) genes involved in nucleotide biosynthesis, metabolism, and control of signal transmission are differently methylated between centenarians' offspring and offspring of both non-long-lived parents, hypothesizing a role for these genes in human longevity. Our results suggest that a better preservation of DNA methylation status, a slower cell growing/metabolism, and a better control in signal transmission through epigenetic mechanisms may be involved in the process of human longevity. These data fit well with the observations related to the beneficial effects of mild hypothyroidism and insulin-like growth factor I system impairment on the modulation of human lifespan.", - "journal_title": "Age (Dordrecht, Netherlands)", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/22923132/" - } - ], - "732b2909-43e6-4565-b6c3-48d5313dfaa5": [ - { - "pub_id": "36153511", - "title": "Genomic prediction with whole-genome sequence data in intensely selected pig lines.", - "authors": "Roger Ros-Freixedes,Martin Johnsson,Andrew Whalen,Ching-Yi Chen,Bruno D Valente,William O Herring,Gregor Gorjanc,John M Hickey", - "abstract": "Early simulations indicated that whole-genome sequence data (WGS) could improve the accuracy of genomic predictions within and across breeds. However, empirical results have been ambiguous so far. Large datasets that capture most of the genomic diversity in a population must be assembled so that allele substitution effects are estimated with high accuracy. The objectives of this study were to use a large pig dataset from seven intensely selected lines to assess the benefits of using WGS for genomic prediction compared to using commercial marker arrays and to identify scenarios in which WGS provides the largest advantage. We sequenced 6931 individuals from seven commercial pig lines with different numerical sizes. Genotypes of 32.8 million variants were imputed for 396,100 individuals (17,224 to 104,661 per line). We used BayesR to perform genomic prediction for eight complex traits. Genomic predictions were performed using either data from a standard marker array or variants preselected from WGS based on association tests. The accuracies of genomic predictions based on preselected WGS variants were not robust across traits and lines and the improvements in prediction accuracy that we achieved so far with WGS compared to standard marker arrays were generally small. The most favourable results for WGS were obtained when the largest training sets were available and standard marker arrays were augmented with preselected variants with statistically significant associations to the trait. With this method and training sets of around 80k individuals, the accuracy of within-line genomic predictions was on average improved by 0.025. With multi-line training sets, improvements of 0.04 compared to marker arrays could be expected. Our results showed that WGS has limited potential to improve the accuracy of genomic predictions compared to marker arrays in intensely selected pig lines. Thus, although we expect that larger improvements in accuracy from the use of WGS are possible with a combination of larger training sets and optimised pipelines for generating and analysing such datasets, the use of WGS in the current implementations of genomic prediction should be carefully evaluated against the cost of large-scale WGS data on a case-by-case basis.", - "journal_title": "Genetics, selection, evolution : GSE", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/36153511/" - } - ], - "85cf192b-938e-4751-ab8f-36e41c6fb5ce": [ - { - "pub_id": "21493656", - "title": "Bismark: a flexible aligner and methylation caller for Bisulfite-Seq applications.", - "authors": "Felix Krueger,Simon R Andrews", - "abstract": "A combination of bisulfite treatment of DNA and high-throughput sequencing (BS-Seq) can capture a snapshot of a cell's epigenomic state by revealing its genome-wide cytosine methylation at single base resolution. Bismark is a flexible tool for the time-efficient analysis of BS-Seq data which performs both read mapping and methylation calling in a single convenient step. Its output discriminates between cytosines in CpG, CHG and CHH context and enables bench scientists to visualize and interpret their methylation data soon after the sequencing run is completed. Bismark is released under the GNU GPLv3+ licence. The source code is freely available from www.bioinformatics.bbsrc.ac.uk/projects/bismark/.", - "journal_title": "Bioinformatics (Oxford, England)", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/21493656/" - } - ], - "6df20592-9856-49a6-8bf3-f6a701ff3b56": [ - { - "pub_id": "21145717", - "title": "Trace elements and ageing, a genomic perspective using selenium as an example.", - "authors": "Catherine M\u00e9plan", - "abstract": "Trace elements are key regulators of metabolic and physiological pathways known to be altered during the ageing process and therefore have the capacity to modulate the rate of biological ageing. Optimal intake is required to maintain homeostasis and to increase cell protection. Deficiencies are associated with specific illnesses. However the contribution of commonly observed life-long sub-optimal intakes of trace elements to the development and severity of age-related chronic diseases is less appreciated. Additionally, reduce intake of several trace elements has been shown to be particularly challenging for elderly people. This review will use selenium as an example to illustrate how a trace element can influence ageing and how the Omics technologies could help to study the effect of trace elements on the ageing process. Although transcriptomics and proteomics approaches in animal models have so far enabled us to identify downstream targets of trace elements in pathways related to age-related diseases processes, future approaches of combining nutrigenomics with longevity studies in humans will help us to identify mechanisms whereby trace elements affect the ageing process.", - "journal_title": "Journal of trace elements in medicine and biology : organ of the Society for Minerals and Trace Elements (GMS)", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/21145717/" - } - ], - "9ee491f4-5f16-4cb2-b803-54f2fdee1dba": [ - { - "pub_id": "20602916", - "title": "Genomic duplication and overexpression of TJP2/ZO-2 leads to altered expression of apoptosis genes in progressive nonsyndromic hearing loss DFNA51.", - "authors": "Tom Walsh,Sarah B Pierce,Danielle R Lenz,Zippora Brownstein,Orit Dagan-Rosenfeld,Hashem Shahin,Wendy Roeb,Shane McCarthy,Alex S Nord,Carlos R Gordon,Ziva Ben-Neriah,Jonathan Sebat,Moien Kanaan,Ming K Lee,Moshe Frydman,Mary-Claire King,Karen B Avraham", - "abstract": "Age-related hearing loss is due to death over time, primarily by apoptosis, of hair cells in the inner ear. Studies of mutant genes responsible for inherited progressive hearing loss have suggested possible mechanisms for hair cell death, but critical connections between these mutations and the causes of progressive hearing loss have been elusive. In an Israeli kindred, dominant, adult-onset, progressive nonsyndromic hearing loss DFNA51 is due to a tandem inverted genomic duplication of 270 kb that includes the entire wild-type gene encoding the tight junction protein TJP2 (ZO-2). In the mammalian inner ear, TJP2 is expressed mainly in tight junctions, and also in the cytoplasm and nuclei. TJP2 expression normally decreases with age from embryonic development to adulthood. In cells of affected family members, TJP2 transcript and protein are overexpressed, leading to decreased phosphorylation of GSK-3beta and to altered expression of genes that regulate apoptosis. These results suggest that TJP2- and GSK-3beta-mediated increased susceptibility to apoptosis of cells of the inner ear is the mechanism for adult-onset hearing loss in this kindred and may serve as one model for age-related hearing loss in the general population.", - "journal_title": "American journal of human genetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/20602916/" - } - ], - "2c5d0c52-fe84-4d0d-8c79-33422aad3084": [ - { - "pub_id": "23826282", - "title": "Continuous Aging of the Human DNA Methylome Throughout the Human Lifespan.", - "authors": "Asa Johansson,Stefan Enroth,Ulf Gyllensten", - "abstract": "DNA methylation plays an important role in development of disease and the process of aging. In this study we examine DNA methylation at 476,366 sites throughout the genome of white blood cells from a population cohort (N\u200a=\u200a421) ranging in age from 14 to 94 years old. Age affects DNA methylation at almost one third (29%) of the sites (Bonferroni adjusted P-value <0.05), of which 60.5% becomes hypomethylated and 39.5% hypermethylated with increasing age. DNA methylation sites that are located within CpG islands (CGIs) more often become hypermethylated compared to sites outside an island. CpG sites in promoters are more unaffected by age, whereas sites in enhancers more often becomes hypo- or hypermethylated. Hypermethylated sites are overrepresented among genes that are involved in DNA binding, transcription regulation, processes of anatomical structure and developmental process and cortex neuron differentiation (P-value down to P\u200a=\u200a9.14*10(-67)). By contrast, hypomethylated sites are not strongly overrepresented among any biological function or process. Our results indicate that the 23% of the variation in DNA methylation is attributed chronological age, and that hypermethylation is more site-specific than hypomethylation. It appears that the change in DNA methylation partly overlap with regions that change histone modifications with age, indicating an interaction between the two major epigenetic mechanisms. Epigenetic modifications and change in gene expression over time most likely reflects the natural process of aging and variation between individuals might contribute to the development of age-related phenotypes and diseases such as type II diabetes, autoimmune and cardiovascular disease.", - "journal_title": "PloS one", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/23826282/" - } - ], - "0c80320f-bca2-4f46-858e-bd3fba2f67a2": [ - { - "pub_id": "20171287", - "title": "Voxelwise genome-wide association study (vGWAS).", - "authors": "Jason L Stein,Xue Hua,Suh Lee,April J Ho,Alex D Leow,Arthur W Toga,Andrew J Saykin,Li Shen,Tatiana Foroud,Nathan Pankratz,Matthew J Huentelman,David W Craig,Jill D Gerber,April N Allen,Jason J Corneveaux,Bryan M Dechairo,Steven G Potkin,Michael W Weiner,Paul Thompson, ", - "abstract": "The structure of the human brain is highly heritable, and is thought to be influenced by many common genetic variants, many of which are currently unknown. Recent advances in neuroimaging and genetics have allowed collection of both highly detailed structural brain scans and genome-wide genotype information. This wealth of information presents a new opportunity to find the genes influencing brain structure. Here we explore the relation between 448,293 single nucleotide polymorphisms in each of 31,622 voxels of the entire brain across 740 elderly subjects (mean age+/-s.d.: 75.52+/-6.82 years; 438 male) including subjects with Alzheimer's disease, Mild Cognitive Impairment, and healthy elderly controls from the Alzheimer's Disease Neuroimaging Initiative (ADNI). We used tensor-based morphometry to measure individual differences in brain structure at the voxel level relative to a study-specific template based on healthy elderly subjects. We then conducted a genome-wide association at each voxel to identify genetic variants of interest. By studying only the most associated variant at each voxel, we developed a novel method to address the multiple comparisons problem and computational burden associated with the unprecedented amount of data. No variant survived the strict significance criterion, but several genes worthy of further exploration were identified, including CSMD2 and CADPS2. These genes have high relevance to brain structure. This is the first voxelwise genome wide association study to our knowledge, and offers a novel method to discover genetic influences on brain structure.", - "journal_title": "NeuroImage", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/20171287/" - } - ], - "1c1f2541-c4ff-407a-b541-0e7859f5b49a": [ - { - "pub_id": "25888029", - "title": "Ageing-associated changes in the human DNA methylome: genomic locations and effects on gene expression.", - "authors": "Saara Marttila,Laura Kananen,Sergei H\u00e4yrynen,Juulia Jylh\u00e4v\u00e4,Tapio Nevalainen,Antti Hervonen,Marja Jylh\u00e4,Matti Nykter,Mikko Hurme", - "abstract": "Changes in DNA methylation are among the mechanisms contributing to the ageing process. We sought to identify ageing-associated DNA methylation changes at single-CpG-site resolution in blood leukocytes and to ensure that the observed changes were not due to differences in the proportions of leukocytes. The association between DNA methylation changes and gene expression levels was also investigated in the same individuals. We identified 8540 high-confidence ageing-associated CpG sites, 46% of which were hypermethylated in nonagenarians. The hypermethylation-associated genes belonged to a common category: they were predicted to be regulated by a common group of transcription factors and were enriched in a related set of GO terms and canonical pathways. Conversely, for the hypomethylation-associated genes only a limited set of GO terms and canonical pathways were identified. Among the 8540 CpG sites associated with ageing, methylation level of 377 sites was also associated with gene expression levels. These genes were enriched in GO terms and canonical pathways associated with immune system functions, particularly phagocytosis. We find that certain ageing-associated immune-system impairments may be mediated via changes in DNA methylation. The results also imply that ageing-associated hypo- and hypermethylation are distinct processes: hypermethylation could be caused by programmed changes, whereas hypomethylation could be the result of environmental and stochastic processes.", - "journal_title": "BMC genomics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/25888029/" - } - ], - "26900821-64cd-48dd-a5d0-dbb4a71d1cf0": [ - { - "pub_id": "20044523", - "title": "Genome-wide association studies of MRI-defined brain infarcts: meta-analysis from the CHARGE Consortium.", - "authors": "St\u00e9phanie Debette,Joshua C Bis,Myriam Fornage,Helena Schmidt,M Arfan Ikram,Sigurdur Sigurdsson,Gerardo Heiss,Maksim Struchalin,Albert V Smith,Aad van der Lugt,Charles DeCarli,Thomas Lumley,David S Knopman,Christian Enzinger,Gudny Eiriksdottir,Peter J Koudstaal,Anita L DeStefano,Bruce M Psaty,Carole Dufouil,Diane J Catellier,Franz Fazekas,Thor Aspelund,Yurii S Aulchenko,Alexa Beiser,Jerome I Rotter,Christophe Tzourio,Dean K Shibata,Maria Tscherner,Tamara B Harris,Fernando Rivadeneira,Larry D Atwood,Kenneth Rice,Rebecca F Gottesman,Mark A van Buchem,Andre G Uitterlinden,Margaret Kelly-Hayes,Mary Cushman,Yicheng Zhu,Eric Boerwinkle,Vilmundur Gudnason,Albert Hofman,Jose R Romero,Oscar Lopez,Cornelia M van Duijn,Rhoda Au,Susan R Heckbert,Philip A Wolf,Thomas H Mosley,Sudha Seshadri,Monique M B Breteler,Reinhold Schmidt,Lenore J Launer,W T Longstreth", - "abstract": "Previous studies examining genetic associations with MRI-defined brain infarct have yielded inconsistent findings. We investigated genetic variation underlying covert MRI infarct in persons without histories of transient ischemic attack or stroke. We performed meta-analysis of genome-wide association studies of white participants in 6 studies comprising the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium. Using 2.2 million genotyped and imputed single nucleotide polymorphisms, each study performed cross-sectional genome-wide association analysis of MRI infarct using age- and sex-adjusted logistic regression models. Study-specific findings were combined in an inverse-variance-weighted meta-analysis, including 9401 participants with mean age 69.7 (19.4% of whom had >or=1 MRI infarct). The most significant association was found with rs2208454 (minor allele frequency, 20%), located in intron 3 of MACRO domain containing 2 gene and in the downstream region of fibronectin leucine-rich transmembrane protein 3 gene. Each copy of the minor allele was associated with lower risk of MRI infarcts (odds ratio, 0.76; 95% confidence interval, 0.68-0.84; P=4.64x10(-7)). Highly suggestive associations (P<1.0x10(-5)) were also found for 22 other single nucleotide polymorphisms in linkage disequilibrium (r(2)>0.64) with rs2208454. The association with rs2208454 did not replicate in independent samples of 1822 white and 644 black participants, although 4 single nucleotide polymorphisms within 200 kb from rs2208454 were associated with MRI infarcts in the black population sample. This first community-based, genome-wide association study on covert MRI infarcts uncovered novel associations. Although replication of the association with top single nucleotide polymorphisms failed, possibly because of insufficient power, results in the black population sample are encouraging, and further efforts at replication are needed.", - "journal_title": "Stroke", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/20044523/" - } - ], - "8275b075-735b-44dc-b549-32ee94dec32e": [ - { - "pub_id": "25927677", - "title": "Rodent models for Alzheimer's disease drug discovery.", - "authors": "Daniela Puzzo,Walter Gulisano,Agostino Palmeri,Ottavio Arancio", - "abstract": "Alzheimer's disease (AD) is a neurodegenerative disorder characterized by memory loss and personality changes, leading to dementia. Histopathological hallmarks are represented by aggregates of beta-amyloid peptide (A\u03b2) in senile plaques and deposition of hyperphosphorylated tau protein in neurofibrillary tangles in the brain. Rare forms of early onset familial Alzheimer's disease are due to gene mutations. This has prompted researchers to develop genetically modified animals that could recapitulate the main features of the disease. The use of these models is complemented by non-genetically modified animals. This review summarizes the characteristics of the most used transgenic (Tg) and non-Tg models of AD. The authors have focused on models mainly used in their laboratories including amyloid precursor protein (APP) Tg2576, APP/presenilin 1, 3xAD, single h-Tau, non-Tg mice treated with acute injections of A\u03b2 or tau, and models of physiological aging. Animal models of disease might be very useful for studying the pathophysiology of the disease and for testing new therapeutics in preclinical studies but they do not reproduce the entire clinical features of human AD. When selecting a model, researchers should consider the various factors that might influence the phenotype. They should also consider the timing of testing/treating animals since the age at which each model develops certain aspects of the AD pathology varies.", - "journal_title": "Expert opinion on drug discovery", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/25927677/" - } - ], - "f2e7e775-6e18-4cd1-95fa-40cde42fbee7": [ - { - "pub_id": "27252396", - "title": "Genome Stability Requires p53.", - "authors": "Christine M Eischen", - "abstract": "It is now clear that functional p53 is critical to protect the genome from alterations that lead to tumorigenesis. However, with the myriad of cellular stresses and pathways linked to p53 activation, much remains unknown about how p53 maintains genome stability and the proteins involved. The current understanding of the multiple ways p53 contributes to genome stability and how two of its negative regulators, Mdm2 and Mdmx, induce genome instability will be described.", - "journal_title": "Cold Spring Harbor perspectives in medicine", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/27252396/" - } - ], - "9605f23b-0620-4c0c-8f38-d9e0171e7e64": [ - { - "pub_id": "22968929", - "title": "Extensive somatic L1 retrotransposition in colorectal tumors.", - "authors": "Szilvia Solyom,Adam D Ewing,Eric P Rahrmann,Tara Doucet,Heather H Nelson,Michael B Burns,Reuben S Harris,David F Sigmon,Alex Casella,Bracha Erlanger,Sarah Wheelan,Kyle R Upton,Ruchi Shukla,Geoffrey J Faulkner,David A Largaespada,Haig H Kazazian", - "abstract": "L1 retrotransposons comprise 17% of the human genome and are its only autonomous mobile elements. Although L1-induced insertional mutagenesis causes Mendelian disease, their mutagenic load in cancer has been elusive. Using L1-targeted resequencing of 16 colorectal tumor and matched normal DNAs, we found that certain cancers were excessively mutagenized by human-specific L1s, while no verifiable insertions were present in normal tissues. We confirmed de novo L1 insertions in malignancy by both validating and sequencing 69/107 tumor-specific insertions and retrieving both 5' and 3' junctions for 35. In contrast to germline polymorphic L1s, all insertions were severely 5' truncated. Validated insertion numbers varied from up to 17 in some tumors to none in three others, and correlated with the age of the patients. Numerous genes with a role in tumorigenesis were targeted, including ODZ3, ROBO2, PTPRM, PCM1, and CDH11. Thus, somatic retrotransposition may play an etiologic role in colorectal cancer.", - "journal_title": "Genome research", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/22968929/" - } - ], - "641e6306-3b0d-4b02-9dc4-0480325bfb9c": [ - { - "pub_id": "24747696", - "title": "Predictive genomics: a cancer hallmark network framework for predicting tumor clinical phenotypes using genome sequencing data.", - "authors": "Edwin Wang,Naif Zaman,Shauna Mcgee,Jean-S\u00e9bastien Milanese,Ali Masoudi-Nejad,Maureen O'Connor-McCourt", - "abstract": "Tumor genome sequencing leads to documenting thousands of DNA mutations and other genomic alterations. At present, these data cannot be analyzed adequately to aid in the understanding of tumorigenesis and its evolution. Moreover, we have little insight into how to use these data to predict clinical phenotypes and tumor progression to better design patient treatment. To meet these challenges, we discuss a cancer hallmark network framework for modeling genome sequencing data to predict cancer clonal evolution and associated clinical phenotypes. The framework includes: (1) cancer hallmarks that can be represented by a few molecular/signaling networks. 'Network operational signatures' which represent gene regulatory logics/strengths enable to quantify state transitions and measures of hallmark traits. Thus, sets of genomic alterations which are associated with network operational signatures could be linked to the state/measure of hallmark traits. The network operational signature transforms genotypic data (i.e., genomic alterations) to regulatory phenotypic profiles (i.e., regulatory logics/strengths), to cellular phenotypic profiles (i.e., hallmark traits) which lead to clinical phenotypic profiles (i.e., a collection of hallmark traits). Furthermore, the framework considers regulatory logics of the hallmark networks under tumor evolutionary dynamics and therefore also includes: (2) a self-promoting positive feedback loop that is dominated by a genomic instability network and a cell survival/proliferation network is the main driver of tumor clonal evolution. Surrounding tumor stroma and its host immune systems shape the evolutionary paths; (3) cell motility initiating metastasis is a byproduct of the above self-promoting loop activity during tumorigenesis; (4) an emerging hallmark network which triggers genome duplication dominates a feed-forward loop which in turn could act as a rate-limiting step for tumor formation; (5) mutations and other genomic alterations have specific patterns and tissue-specificity, which are driven by aging and other cancer-inducing agents. This framework represents the logics of complex cancer biology as a myriad of phenotypic complexities governed by a limited set of underlying organizing principles. It therefore adds to our understanding of tumor evolution and tumorigenesis, and moreover, potential usefulness of predicting tumors' evolutionary paths and clinical phenotypes. Strategies of using this framework in conjunction with genome sequencing data in an attempt to predict personalized drug targets, drug resistance, and metastasis for cancer patients, as well as cancer risks for healthy individuals are discussed. Accurate prediction of cancer clonal evolution and clinical phenotypes will have substantial impact on timely diagnosis, personalized treatment and personalized prevention of cancer.", - "journal_title": "Seminars in cancer biology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/24747696/" - } - ], - "b7d0ddf0-aec3-4510-a360-07365a83c2ca": [ - { - "pub_id": "21288483", - "title": "Dichloromethane-degrading bacteria in the genomic age.", - "authors": "Emilie E L Muller,Fran\u00e7oise Bringel,St\u00e9phane Vuilleumier", - "abstract": "Dichloromethane (DCM) is a volatile toxic halogenated solvent mainly produced and used industrially. DCM-degrading bacteria have long been models of choice for studying bacterial dehalogenation metabolism at the physiological, biochemical and genetic levels, and have also been used in bioremediation processes. DCM-degrading strains isolated in recent years will be discussed in the context of enzymes known to catalyze dehalogenation of DCM. Insights into the modes of adaptation of bacteria to DCM gained by comparative genomic analysis, highlight the importance of horizontal gene transfer in the dissemination of genes for DCM metabolism in the environment.", - "journal_title": "Research in microbiology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/21288483/" - } - ], - "d83ef54e-7cb6-4bc7-9d18-ea31022b676b": [ - { - "pub_id": "22670612", - "title": "Beyond the blot: cutting edge tools for genomics, proteomics and metabolomics analyses and previous successes.", - "authors": "A B Kimball,R A Grant,F Wang,R Osborne,J P Tiesman", - "abstract": "The skin has an amazing array of complex interacting biological processes. Recent advances in investigational techniques now allow evaluation of these processes at the level of the gene, protein and metabolite. Sometimes collectively known as the omics, these fields of inquiry, known as genomics, proteomics and metabolomics, respectively, are yielding new and important insights into skin structure and processes, its responses to injury and age, and the mechanisms by which new interventions and compounds may work to improve the health and integrity of this crucial organ.", - "journal_title": "The British journal of dermatology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/22670612/" - } - ], - "05346fc4-57eb-424f-8c9f-cc144e600cb6": [ - { - "pub_id": "27576376", - "title": "Genotype distribution-based inference of collective effects in genome-wide association studies: insights to age-related macular degeneration disease mechanism.", - "authors": "Hyung Jun Woo,Chenggang Yu,Kamal Kumar,Bert Gold,Jaques Reifman", - "abstract": "Genome-wide association studies provide important insights to the genetic component of disease risks. However, an existing challenge is how to incorporate collective effects of interactions beyond the level of independent single nucleotide polymorphism (SNP) tests. While methods considering each SNP pair separately have provided insights, a large portion of expected heritability may reside in higher-order interaction effects. We describe an inference approach (discrete discriminant analysis; DDA) designed to probe collective interactions while treating both genotypes and phenotypes as random variables. The genotype distributions in case and control groups are modeled separately based on empirical allele frequency and covariance data, whose differences yield disease risk parameters. We compared pairwise tests and collective inference methods, the latter based both on DDA and logistic regression. Analyses using simulated data demonstrated that significantly higher sensitivity and specificity can be achieved with collective inference in comparison to pairwise tests, and with DDA in comparison to logistic regression. Using age-related macular degeneration (AMD) data, we demonstrated two possible applications of DDA. In the first application, a genome-wide SNP set is reduced into a small number (\u223c100) of variants via filtering and SNP pairs with significant interactions are identified. We found that interactions between SNPs with highest AMD association were epigenetically active in the liver, adipocytes, and mesenchymal stem cells. In the other application, multiple groups of SNPs were formed from the genome-wide data and their relative strengths of association were compared using cross-validation. This analysis allowed us to discover novel collections of loci for which interactions between SNPs play significant roles in their disease association. In particular, we considered pathway-based groups of SNPs containing up to \u223c10, 000 variants in each group. In addition to pathways related to complement activation, our collective inference pointed to pathway groups involved in phospholipid synthesis, oxidative stress, and apoptosis, consistent with the AMD pathogenesis mechanism where the dysfunction of retinal pigment epithelium cells plays central roles. The simultaneous inference of collective interaction effects within a set of SNPs has the potential to reveal novel aspects of disease association.", - "journal_title": "BMC genomics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/27576376/" - } - ], - "8b95c7a6-0ca5-445e-8776-14d1e6550fa0": [ - { - "pub_id": "26072452", - "title": "Revisiting classic clines in Drosophila melanogaster in the age of genomics.", - "authors": "Jeffrey R Adrion,Matthew W Hahn,Brandon S Cooper", - "abstract": "Adaptation to spatially varying environments has been studied for decades, but advances in sequencing technology are now enabling researchers to investigate the landscape of genetic variation underlying this adaptation genome wide. In this review we highlight some of the decades-long research on local adaptation in Drosophila melanogaster from well-studied clines in North America and Australia. We explore the evidence for parallel adaptation and identify commonalities in the genes responding to clinal selection across continents as well as discussing instances where patterns differ among clines. We also investigate recent studies utilizing whole-genome data to identify clines in D. melanogaster and several other systems. Although connecting segregating genomic variation to variation in phenotypes and fitness remains challenging, clinal genomics is poised to increase our understanding of local adaptation and the selective pressures that drive the extensive phenotypic diversity observed in nature.", - "journal_title": "Trends in genetics : TIG", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/26072452/" - } - ], - "5cd6c6b4-ccfb-4771-9ea9-9b157f3b37ff": [ - { - "pub_id": "26731791", - "title": "Genome-Wide Analysis of DNA Methylation and Fine Particulate Matter Air Pollution in Three Study Populations: KORA F3, KORA F4, and the Normative Aging Study.", - "authors": "Tommaso Panni,Amar J Mehta,Joel D Schwartz,Andrea A Baccarelli,Allan C Just,Kathrin Wolf,Simone Wahl,Josef Cyrys,Sonja Kunze,Konstantin Strauch,Melanie Waldenberger,Annette Peters", - "abstract": "Epidemiological studies have reported associations between particulate matter (PM) concentrations and cancer and respiratory and cardiovascular diseases. DNA methylation has been identified as a possible link but so far it has only been analyzed in candidate sites. We studied the association between DNA methylation and short- and mid-term air pollution exposure using genome-wide data and identified potential biological pathways for additional investigation. We collected whole blood samples from three independent studies-KORA F3 (2004-2005) and F4 (2006-2008) in Germany, and the Normative Aging Study (1999-2007) in the United States-and measured genome-wide DNA methylation proportions with the Illumina 450k BeadChip. PM concentration was measured daily at fixed monitoring stations and three different trailing averages were considered and regressed against DNA methylation: 2-day, 7-day and 28-day. Meta-analysis was performed to pool the study-specific results. Random-effect meta-analysis revealed 12 CpG (cytosine-guanine dinucleotide) sites as associated with PM concentration (1 for 2-day average, 1 for 7-day, and 10 for 28-day) at a genome-wide Bonferroni significance level (p \u2264 7.5E-8); 9 out of these 12 sites expressed increased methylation. Through estimation of I2 for homogeneity assessment across the studies, 4 of these sites (annotated in NSMAF, C1orf212, MSGN1, NXN) showed p > 0.05 and I2 < 0.5: the site from the 7-day average results and 3 for the 28-day average. Applying false discovery rate, p-value < 0.05 was observed in 8 and 1,819 additional CpGs at 7- and 28-day average PM2.5 exposure respectively. The PM-related CpG sites found in our study suggest novel plausible systemic pathways linking ambient PM exposure to adverse health effect through variations in DNA methylation. Panni T, Mehta AJ, Schwartz JD, Baccarelli AA, Just AC, Wolf K, Wahl S, Cyrys J, Kunze S, Strauch K, Waldenberger M, Peters A. 2016. A genome-wide analysis of DNA methylation and fine particulate matter air pollution in three study populations: KORA F3, KORA F4, and the Normative Aging Study. Environ Health Perspect 124:983-990;\u2002http://dx.doi.org/10.1289/ehp.1509966.", - "journal_title": "Environmental health perspectives", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/26731791/" - } - ], - "486a8d03-9100-4f66-a0f7-8cbdaf30b804": [ - { - "pub_id": "25968125", - "title": "Erratum to: DNA methylation age of human tissues and cell types.", - "authors": "Steve Horvath", - "abstract": "", - "journal_title": "Genome biology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/25968125/" - } - ], - "01e0b7d9-78b2-4227-b79c-ae29e1444c5d": [ - { - "pub_id": "20100581", - "title": "Whole genome association study of brain-wide imaging phenotypes for identifying quantitative trait loci in MCI and AD: A study of the ADNI cohort.", - "authors": "Li Shen,Sungeun Kim,Shannon L Risacher,Kwangsik Nho,Shanker Swaminathan,John D West,Tatiana Foroud,Nathan Pankratz,Jason H Moore,Chantel D Sloan,Matthew J Huentelman,David W Craig,Bryan M Dechairo,Steven G Potkin,Clifford R Jack,Michael W Weiner,Andrew J Saykin, ", - "abstract": "A genome-wide, whole brain approach to investigate genetic effects on neuroimaging phenotypes for identifying quantitative trait loci is described. The Alzheimer's Disease Neuroimaging Initiative 1.5 T MRI and genetic dataset was investigated using voxel-based morphometry (VBM) and FreeSurfer parcellation followed by genome-wide association studies (GWAS). One hundred forty-two measures of grey matter (GM) density, volume, and cortical thickness were extracted from baseline scans. GWAS, using PLINK, were performed on each phenotype using quality-controlled genotype and scan data including 530,992 of 620,903 single nucleotide polymorphisms (SNPs) and 733 of 818 participants (175 AD, 354 amnestic mild cognitive impairment, MCI, and 204 healthy controls, HC). Hierarchical clustering and heat maps were used to analyze the GWAS results and associations are reported at two significance thresholds (p<10(-7) and p<10(-6)). As expected, SNPs in the APOE and TOMM40 genes were confirmed as markers strongly associated with multiple brain regions. Other top SNPs were proximal to the EPHA4, TP63 and NXPH1 genes. Detailed image analyses of rs6463843 (flanking NXPH1) revealed reduced global and regional GM density across diagnostic groups in TT relative to GG homozygotes. Interaction analysis indicated that AD patients homozygous for the T allele showed differential vulnerability to right hippocampal GM density loss. NXPH1 codes for a protein implicated in promotion of adhesion between dendrites and axons, a key factor in synaptic integrity, the loss of which is a hallmark of AD. A genome-wide, whole brain search strategy has the potential to reveal novel candidate genes and loci warranting further investigation and replication.", - "journal_title": "NeuroImage", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/20100581/" - } - ], - "ec4d1082-9077-4b81-a683-fb8ff4bf7939": [ - { - "pub_id": "35743088", - "title": "Zebrafish Larvae Behavior Models as a Tool for Drug Screenings and Pre-Clinical Trials: A Review.", - "authors": "Jo\u00e3o Gabriel Santos Rosa,Carla Lima,Monica Lopes-Ferreira", - "abstract": "To discover new molecules or review the biological activity and toxicity of therapeutic substances, drug development, and research relies on robust biological systems to obtain reliable results. Phenotype-based screenings can transpose the organism's compensatory pathways by adopting multi-target strategies for treating complex diseases, and zebrafish emerged as an important model for biomedical research and drug screenings. Zebrafish's clear correlation between neuro-anatomical and physiological features and behavior is very similar to that verified in mammals, enabling the construction of reliable and relevant experimental models for neurological disorders research. Zebrafish presents highly conserved physiological pathways that are found in higher vertebrates, including mammals, along with a robust behavioral repertoire. Moreover, it is very sensitive to pharmacological/environmental manipulations, and these behavioral phenotypes are detected in both larvae and adults. These advantages align with the 3Rs concept and qualify the zebrafish as a powerful tool for drug screenings and pre-clinical trials. This review highlights important behavioral domains studied in zebrafish larvae and their neurotransmitter systems and summarizes currently used techniques to evaluate and quantify zebrafish larvae behavior in laboratory studies.", - "journal_title": "International journal of molecular sciences", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/35743088/" - } - ], - "eb0d2e45-eeda-4022-a541-3b8015c9ee55": [ - { - "pub_id": "22325718", - "title": "Transcriptome remodeling associated with chronological aging in the dinoflagellate, Karenia brevis.", - "authors": "Jillian G Johnson,Jeanine S Morey,Marion G Neely,James C Ryan,Frances M Van Dolah", - "abstract": "The toxic dinoflagellate, Karenia brevis, forms dense blooms in the Gulf of Mexico that persist for many months in coastal waters, where they can cause extensive marine animal mortalities and human health impacts. The mechanisms that enable cell survival in high density, low growth blooms, and the mechanisms leading to often rapid bloom demise are not well understood. To gain an understanding of processes that underlie chronological aging in this dinoflagellate, a microarray study was carried out to identify changes in the global transcriptome that accompany the entry and maintenance of stationary phase up to the onset of cell death. The transcriptome of K. brevis was assayed using a custom 10,263 feature oligonucleotide microarray from mid-logarithmic growth to the onset of culture demise. A total of 2958 (29%) features were differentially expressed, with the mid-stationary phase timepoint demonstrating peak changes in expression. Gene ontology enrichment analyses identified a significant shift in transcripts involved in energy acquisition, ribosome biogenesis, gene expression, stress adaptation, calcium signaling, and putative brevetoxin biosynthesis. The extensive remodeling of the transcriptome observed in the transition into a quiescent non-dividing phase appears to be indicative of a global shift in the metabolic and signaling requirements and provides the basis from which to understand the process of chronological aging in a dinoflagellate.", - "journal_title": "Marine genomics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/22325718/" - } - ], - "81dbf2ac-29c3-4e7c-88af-be3e67c9feb1": [ - { - "pub_id": "27692902", - "title": "DNM3 and genetic modifiers of age of onset in LRRK2 Gly2019Ser parkinsonism: a genome-wide linkage and association study.", - "authors": "Joanne Trinh,Emil K Gustavsson,Carles Vilari\u00f1o-G\u00fcell,Stephanie Bortnick,Jeanne Latourelle,Marna B McKenzie,Chelsea Szu Tu,Ekaterina Nosova,Jaskaran Khinda,Austen Milnerwood,Suzanne Lesage,Alexis Brice,Meriem Tazir,Jan O Aasly,Laura Parkkinen,Hazal Haytural,Tatiana Foroud,Richard H Myers,Samia Ben Sassi,Emna Hentati,Fatma Nabli,Emna Farhat,Rim Amouri,Fay\u00e7al Hentati,Matthew J Farrer", - "abstract": "Leucine-rich repeat kinase 2 (LRRK2) mutation 6055G\u2192A (Gly2019Ser) accounts for roughly 1% of patients with Parkinson's disease in white populations, 13-30% in Ashkenazi Jewish populations, and 30-40% in North African Arab-Berber populations, although age of onset is variable. Some carriers have early-onset parkinsonism, whereas others remain asymptomatic despite advanced age. We aimed to use a genome-wide approach to identify genetic variability that directly affects LRRK2 Gly2019Ser penetrance. Between 2006 and 2012, we recruited Arab-Berber patients with Parkinson's disease and their family members (aged 18 years or older) at the Mongi Ben Hamida National Institute of Neurology (Tunis, Tunisia). Patients with Parkinson's disease were diagnosed by movement disorder specialists in accordance with the UK Parkinson's Disease Society Brain Bank criteria, without exclusion of familial parkinsonism. LRRK2 carrier status was confirmed by Sanger sequencing or TaqMan SNP assays-on-demand. We did genome-wide linkage analysis using data from multi-incident Arab-Berber families with Parkinson's disease and LRRK2 Gly2019Ser (with both affected and unaffected family members). We assessed Parkinson's disease age of onset both as a categorical variable (dichotomised by median onset) and as a quantitative trait. We used data from another cohort of unrelated Tunisian LRRK2 Gly2019Ser carriers for subsequent locus-specific genotyping and association analyses. Whole-genome sequencing in a subset of 14 unrelated Arab-Berber individuals who were LRRK2 Gly2019Ser carriers (seven with early-onset disease and seven elderly unaffected individuals) subsequently informed imputation and haplotype analyses. We replicated the findings in separate series of LRRK2 Gly2019Ser carriers originating from Algeria, France, Norway, and North America. We also investigated associations between genotype, gene, and protein expression in human striatal tissues and murine LRRK2 Gly2019Ser cortical neurons. Using data from 41 multi-incident Arab-Berber families with Parkinson's disease and LRRK2 Gly2019Ser (150 patients and 103 unaffected family members), we identified significant linkage on chromosome 1q23.3 to 1q24.3 (non-parametric logarithm of odds score 2\u00b79, model-based logarithm of odds score 4\u00b799, \u03b8=0 at D1S2768). In a cohort of unrelated Arab-Berber LRRK2 Gly2019Ser carriers, subsequent association mapping within the linkage region suggested genetic variability within DNM3 as an age-of-onset modifier of disease (n=232; rs2421947; haplotype p=1\u00b707\u2008\u00d7\u200810<sup>-7</sup>). We found that DNM3 rs2421947 was a haplotype tag for which the median onset of LRRK2 parkinsonism in GG carriers was 12\u00b75 years younger than that of CC carriers (Arab-Berber cohort, hazard ratio [HR] 1\u00b789, 95% CI 1\u00b720-2\u00b798). Replication analyses in separate series from Algeria, France, Norway, and North America (n=263) supported this finding (meta-analysis HR 1\u00b761, 95% CI 1\u00b715-2\u00b727, p=0\u00b702). In human striatum, DNM3 expression varied as a function of rs2421947 genotype, and dynamin-3 localisation was perturbed in murine LRRK2 Gly2019Ser cortical neurons. Genetic variability in DNM3 modifies age of onset for LRRK2 Gly2019Ser parkinsonism and informs disease-relevant translational neuroscience. Our results could be useful in genetic counselling for carriers of this mutation and in clinical trial design. The Canada Excellence Research Chairs (CERC), Leading Edge Endowment Fund (LEEF), Don Rix BC Leadership Chair in Genetic Medicine, National Institute on Aging, National Institute of Neurological Disorders and Stroke, the Michael J Fox Foundation, Mayo Foundation, the Roger de Spoelberch Foundation, and GlaxoSmithKline.", - "journal_title": "The Lancet. Neurology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/27692902/" - } - ], - "18e216d9-ea5c-4dfe-a30d-632163fcf39e": [ - { - "pub_id": "20596786", - "title": "How pleiotropic genetics of the musculoskeletal system can inform genomics and phenomics of aging.", - "authors": "David Karasik", - "abstract": "Genetic study can provide insight into the biologic mechanisms underlying inter-individual differences in susceptibility to (or resistance to) organisms' aging. Recent advances in molecular genetics and genetic epidemiology provide the necessary tools to perform a study of the genetic sources of biological aging. However, to be successful, the genetic study of a complex condition requires a heritable phenotype to be developed and validated. Genome-wide association studies offer an unbiased approach to identify new candidate genes for human diseases. It is hypothesized that convergent results from multiple aging-related traits will point out the genes responsible for the general aging of the organism. This perspective focuses on the musculoskeletal aging as an example of an approach to identify a downstream common pathway that summarizes aging processes. Since the musculoskeletal traits are linked to the state of many vital functions, disability, and ultimately survival rates, we postulate that there is significance in studying musculoskeletal aging. Construction of an integrated phenotype of aging can be achieved based on shared genetics among multiple musculoskeletal biomarkers. Valid biomarkers from other systems of the organism should be similarly explored. The new composite aging score needs to be validated by determining whether it predicts all-cause mortality, incidences of major chronic diseases, and disability late in life. Comprehensive databases on biomarkers of musculoskeletal aging in multiple large cohort studies, along with information on various health outcomes, are needed to validate the proposed measure of biological aging.", - "journal_title": "Age (Dordrecht, Netherlands)", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/20596786/" - } - ], - "26d254cc-5533-4adc-967a-caa754c715d8": [ - { - "pub_id": "27137838", - "title": "Reciprocal interactions between circadian clocks and aging.", - "authors": "Gareth Banks,Patrick M Nolan,Stuart N Peirson", - "abstract": "Virtually, all biological processes in the body are modulated by an internal circadian clock which optimizes physiological and behavioral performance according to the changing demands of the external 24-h world. This circadian clock undergoes a number of age-related changes, at both the physiological and molecular levels. While these changes have been considered to be part of the normal aging process, there is increasing evidence that disruptions to the circadian system can substantially impact upon aging and these impacts will have clear health implications. Here we review the current data of how both the physiological and core molecular clocks change with age and how feedback from external cues may modulate the aging of the circadian system.", - "journal_title": "Mammalian genome : official journal of the International Mammalian Genome Society", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/27137838/" - } - ], - "b72caae5-bb5a-4317-8d4d-21b41d60df21": [ - { - "pub_id": "21130836", - "title": "Whole genome association scan for genetic polymorphisms influencing information processing speed.", - "authors": "Michelle Luciano,Narelle K Hansell,Jari Lahti,Gail Davies,Sarah E Medland,Katri R\u00e4ikk\u00f6nen,Albert Tenesa,Elisabeth Widen,Kevin A McGhee,Aarno Palotie,David Liewald,David J Porteous,John M Starr,Grant W Montgomery,Nicholas G Martin,Johan G Eriksson,Margaret J Wright,Ian J Deary", - "abstract": "Processing speed is an important cognitive function that is compromised in psychiatric illness (e.g., schizophrenia, depression) and old age; it shares genetic background with complex cognition (e.g., working memory, reasoning). To find genes influencing speed we performed a genome-wide association scan in up to three cohorts: Brisbane (mean age 16 years; N = 1659); LBC1936 (mean age 70 years, N = 992); LBC1921 (mean age 82 years, N = 307), and; HBCS (mean age 64 years, N =1080). Meta-analysis of the common measures highlighted various suggestively significant (p < 1.21 \u00d7 10\u207b\u2075) SNPs and plausible candidate genes (e.g., TRIB3). A biological pathways analysis of the speed factor identified two common pathways from the KEGG database (cell junction, focal adhesion) in two cohorts, while a pathway analysis linked to the GO database revealed common pathways across pairs of speed measures (e.g., receptor binding, cellular metabolic process). These highlighted genes and pathways will be able to inform future research, including results for psychiatric disease.", - "journal_title": "Biological psychology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/21130836/" - } - ], - "0cadf172-639c-4943-b8ca-1add209cf039": [ - { - "pub_id": "25271306", - "title": "H3K4me1 marks DNA regions hypomethylated during aging in human stem and differentiated cells.", - "authors": "Agust\u00edn F Fern\u00e1ndez,Gustavo F Bay\u00f3n,Roc\u00edo G Urdinguio,Estela G Tora\u00f1o,Mar\u00eda G Garc\u00eda,Antonella Carella,Sandra Petrus-Reurer,Cecilia Ferrero,Pablo Martinez-Camblor,Isabel Cubillo,Javier Garc\u00eda-Castro,Jes\u00fas Delgado-Calle,Flor M P\u00e9rez-Campo,Jos\u00e9 A Riancho,Clara Bueno,Pablo Men\u00e9ndez,Anouk Mentink,Katia Mareschi,Fabian Claire,Corrado Fagnani,Emanuela Medda,Virgilia Toccaceli,Sonia Brescianini,Sebasti\u00e1n Moran,Manel Esteller,Alexandra Stolzing,Jan de Boer,Lorenza Nistic\u00f2,Maria A Stazi,Mario F Fraga", - "abstract": "In differentiated cells, aging is associated with hypermethylation of DNA regions enriched in repressive histone post-translational modifications. However, the chromatin marks associated with changes in DNA methylation in adult stem cells during lifetime are still largely unknown. Here, DNA methylation profiling of mesenchymal stem cells (MSCs) obtained from individuals aged 2 to 92 yr identified 18,735 hypermethylated and 45,407 hypomethylated CpG sites associated with aging. As in differentiated cells, hypermethylated sequences were enriched in chromatin repressive marks. Most importantly, hypomethylated CpG sites were strongly enriched in the active chromatin mark H3K4me1 in stem and differentiated cells, suggesting this is a cell type-independent chromatin signature of DNA hypomethylation during aging. Analysis of scedasticity showed that interindividual variability of DNA methylation increased during aging in MSCs and differentiated cells, providing a new avenue for the identification of DNA methylation changes over time. DNA methylation profiling of genetically identical individuals showed that both the tendency of DNA methylation changes and scedasticity depended on nongenetic as well as genetic factors. Our results indicate that the dynamics of DNA methylation during aging depend on a complex mixture of factors that include the DNA sequence, cell type, and chromatin context involved and that, depending on the locus, the changes can be modulated by genetic and/or external factors.", - "journal_title": "Genome research", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/25271306/" - } - ], - "5653ca57-53fc-41d8-868c-e65e207d21b4": [ - { - "pub_id": "27457926", - "title": "Menopause accelerates biological aging.", - "authors": "Morgan E Levine,Ake T Lu,Brian H Chen,Dena G Hernandez,Andrew B Singleton,Luigi Ferrucci,Stefania Bandinelli,Elias Salfati,JoAnn E Manson,Austin Quach,Cynthia D J Kusters,Diana Kuh,Andrew Wong,Andrew E Teschendorff,Martin Widschwendter,Beate R Ritz,Devin Absher,Themistocles L Assimes,Steve Horvath", - "abstract": "Although epigenetic processes have been linked to aging and disease in other systems, it is not yet known whether they relate to reproductive aging. Recently, we developed a highly accurate epigenetic biomarker of age (known as the \"epigenetic clock\"), which is based on DNA methylation levels. Here we carry out an epigenetic clock analysis of blood, saliva, and buccal epithelium using data from four large studies: the Women's Health Initiative (n = 1,864); Invecchiare nel Chianti (n = 200); Parkinson's disease, Environment, and Genes (n = 256); and the United Kingdom Medical Research Council National Survey of Health and Development (n = 790). We find that increased epigenetic age acceleration in blood is significantly associated with earlier menopause (P = 0.00091), bilateral oophorectomy (P = 0.0018), and a longer time since menopause (P = 0.017). Conversely, epigenetic age acceleration in buccal epithelium and saliva do not relate to age at menopause; however, a higher epigenetic age in saliva is exhibited in women who undergo bilateral oophorectomy (P = 0.0079), while a lower epigenetic age in buccal epithelium was found for women who underwent menopausal hormone therapy (P = 0.00078). Using genetic data, we find evidence of coheritability between age at menopause and epigenetic age acceleration in blood. Using Mendelian randomization analysis, we find that two SNPs that are highly associated with age at menopause exhibit a significant association with epigenetic age acceleration. Overall, our Mendelian randomization approach and other lines of evidence suggest that menopause accelerates epigenetic aging of blood, but mechanistic studies will be needed to dissect cause-and-effect relationships further.", - "journal_title": "Proceedings of the National Academy of Sciences of the United States of America", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/27457926/" - } - ], - "167857de-de5a-4d74-80a8-557f9a3bbe9e": [ - { - "pub_id": "26414676", - "title": "An atlas of genetic correlations across human diseases and traits.", - "authors": "Brendan Bulik-Sullivan,Hilary K Finucane,Verneri Anttila,Alexander Gusev,Felix R Day,Po-Ru Loh, , , ,Laramie Duncan,John R B Perry,Nick Patterson,Elise B Robinson,Mark J Daly,Alkes L Price,Benjamin M Neale", - "abstract": "Identifying genetic correlations between complex traits and diseases can provide useful etiological insights and help prioritize likely causal relationships. The major challenges preventing estimation of genetic correlation from genome-wide association study (GWAS) data with current methods are the lack of availability of individual-level genotype data and widespread sample overlap among meta-analyses. We circumvent these difficulties by introducing a technique-cross-trait LD Score regression-for estimating genetic correlation that requires only GWAS summary statistics and is not biased by sample overlap. We use this method to estimate 276 genetic correlations among 24 traits. The results include genetic correlations between anorexia nervosa and schizophrenia, anorexia and obesity, and educational attainment and several diseases. These results highlight the power of genome-wide analyses, as there currently are no significantly associated SNPs for anorexia nervosa and only three for educational attainment.", - "journal_title": "Nature genetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/26414676/" - } - ], - "300a4571-5e16-4245-a116-b45b7095e757": [ - { - "pub_id": "26255561", - "title": "Genetics of Inflammatory Bowel Diseases.", - "authors": "Dermot P B McGovern,Subra Kugathasan,Judy H Cho", - "abstract": "In this review, we provide an update on genome-wide association studies (GWAS) in inflammatory bowel disease (IBD). In addition, we summarize progress in defining the functional consequences of associated alleles for coding and noncoding genetic variation. In the small minority of loci where major association signals correspond to nonsynonymous variation, we summarize studies defining their functional effects and implications for therapeutic targeting. Importantly, the large majority of GWAS-associated loci involve noncoding variation, many of which modulate levels of gene expression. Recent expression quantitative trait loci (eQTL) studies have established that the expression of most human genes is regulated by noncoding genetic variations. Significant advances in defining the epigenetic landscape have demonstrated that IBD GWAS signals are highly enriched within cell-specific active enhancer marks. Studies in European ancestry populations have dominated the landscape of IBD genetics studies, but increasingly, studies in Asian and African-American populations are being reported. Common variation accounts for only a modest fraction of the predicted heritability and the role of rare genetic variation of higher effects (ie, odds ratios markedly deviating from 1) is increasingly being identified through sequencing efforts. These sequencing studies have been particularly productive in more severe very early onset cases. A major challenge in IBD genetics will be harnessing the vast array of genetic discovery for clinical utility through emerging precision medical initiatives. In this article, we discuss the rapidly evolving area of direct-to-consumer genetic testing and the current utility of clinical exome sequencing, especially in very early onset, severe IBD cases. We summarize recent progress in the pharmacogenetics of IBD with respect to partitioning patient responses to anti-TNF and thiopurine therapies. Highly collaborative studies across research centers and across subspecialties and disciplines will be required to fully realize the promise of genetic discovery in IBD.", - "journal_title": "Gastroenterology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/26255561/" - } - ], - "690a2ae6-962a-438c-91ca-60425a0c8d02": [ - { - "pub_id": "23925498", - "title": "Genetics of healthy aging and longevity.", - "authors": "Angela R Brooks-Wilson", - "abstract": "Longevity and healthy aging are among the most complex phenotypes studied to date. The heritability of age at death in adulthood is approximately 25 %. Studies of exceptionally long-lived individuals show that heritability is greatest at the oldest ages. Linkage studies of exceptionally long-lived families now support a longevity locus on chromosome 3; other putative longevity loci differ between studies. Candidate gene studies have identified variants at APOE and FOXO3A associated with longevity; other genes show inconsistent results. Genome-wide association scans (GWAS) of centenarians vs. younger controls reveal only APOE as achieving genome-wide significance (GWS); however, analyses of combinations of SNPs or genes represented among associations that do not reach GWS have identified pathways and signatures that converge upon genes and biological processes related to aging. The impact of these SNPs, which may exert joint effects, may be obscured by gene-environment interactions or inter-ethnic differences. GWAS and whole genome sequencing data both show that the risk alleles defined by GWAS of common complex diseases are, perhaps surprisingly, found in long-lived individuals, who may tolerate them by means of protective genetic factors. Such protective factors may 'buffer' the effects of specific risk alleles. Rare alleles are also likely to contribute to healthy aging and longevity. Epigenetics is quickly emerging as a critical aspect of aging and longevity. Centenarians delay age-related methylation changes, and they can pass this methylation preservation ability on to their offspring. Non-genetic factors, particularly lifestyle, clearly affect the development of age-related diseases and affect health and lifespan in the general population. To fully understand the desirable phenotypes of healthy aging and longevity, it will be necessary to examine whole genome data from large numbers of healthy long-lived individuals to look simultaneously at both common and rare alleles, with impeccable control for population stratification and consideration of non-genetic factors such as environment.", - "journal_title": "Human genetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/23925498/" - } - ], - "f9395d9c-814c-46dd-a857-780a33746cf2": [ - { - "pub_id": "26711261", - "title": "The Overlooked Fact: Fundamental Need for Spike-In Control for Virtually All Genome-Wide Analyses.", - "authors": "Kaifu Chen,Zheng Hu,Zheng Xia,Dongyu Zhao,Wei Li,Jessica K Tyler", - "abstract": "Genome-wide analyses of changes in gene expression, transcription factor occupancy on DNA, histone modification patterns on chromatin, genomic copy number variation, and nucleosome positioning have become popular in many modern laboratories, yielding a wealth of information during health and disease states. However, most of these studies have overlooked an inherent normalization problem that must be corrected with spike-in controls. Here we describe the reason why spike-in controls are so important and explain how to appropriately design and use spike-in controls for normalization. We also suggest ways to retrospectively renormalize data sets that were wrongly interpreted due to omission of spike-in controls.", - "journal_title": "Molecular and cellular biology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/26711261/" - } - ], - "b44331fe-e1b6-4685-9aa6-c8633ba3890e": [ - { - "pub_id": "22705444", - "title": "Animal models of age related macular degeneration.", - "authors": "Mark E Pennesi,Martha Neuringer,Robert J Courtney", - "abstract": "Age related macular degeneration (AMD) is the leading cause of vision loss of those over the age of 65 in the industrialized world. The prevalence and need to develop effective treatments for AMD has lead to the development of multiple animal models. AMD is a complex and heterogeneous disease that involves the interaction of both genetic and environmental factors with the unique anatomy of the human macula. Models in mice, rats, rabbits, pigs and non-human primates have recreated many of the histological features of AMD and provided much insight into the underlying pathological mechanisms of this disease. In spite of the large number of models developed, no one model yet recapitulates all of the features of human AMD. However, these models have helped reveal the roles of chronic oxidative damage, inflammation and immune dysregulation, and lipid metabolism in the development of AMD. Models for induced choroidal neovascularization have served as the backbone for testing new therapies. This article will review the diversity of animal models that exist for AMD as well as their strengths and limitations.", - "journal_title": "Molecular aspects of medicine", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/22705444/" - } - ], - "b9c40a53-ffe7-4965-a961-7e23e318c417": [ - { - "pub_id": "21207101", - "title": "Regulation of ribosomal RNA gene copy number and its role in modulating genome integrity and evolutionary adaptability in yeast.", - "authors": "Takehiko Kobayashi", - "abstract": "The genes encoding ribosomal RNA (rRNA) are the most abundant genes in the eukaryotic genome. They reside in tandem repetitive clusters, in some cases totaling hundreds of copies. Due to their repetitive structure and highly active transcription, the rRNA gene repeats are some of the most fragile sites in the chromosome. A unique gene amplification system compensates for loss of copies, thus maintaining copy number, albeit with some fluctuations. The unusual nature of rRNA gene repeats affects cellular functions such as senescence. In addition, we recently found that the repeat number determines sensitivity to DNA damage. In this review, I would like to introduce a new aspect of the rRNA gene repeat (called rDNA) as a center of maintenance of genome integrity and discuss its contribution to evolution.", - "journal_title": "Cellular and molecular life sciences : CMLS", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/21207101/" - } - ], - "8a5428b2-db20-41a4-890c-8dc8a4a2c17e": [ - { - "pub_id": "34027909", - "title": "Genome-Wide Association Study of Pelvic Organ Prolapse Using the Michigan Genomics Initiative.", - "authors": "Caroline K Cox,Anita Pandit,Matthew Zawistowski,Diptavo Dutta,Goutham Narla,Carolyn W Swenson", - "abstract": "The aim of this study was to (1) replicate previously identified genetic variants significantly associated with pelvic organ prolapse and (2) identify new genetic variants associated with pelvic organ prolapse using a genome-wide association study. Using our institution's database linking genetic and clinical data, we identified 1,329 women of European ancestry with an International Classification of Diseases, Ninth Revision (ICD-9)/ICD-10 code for prolapse, 767 of whom also had Current Procedural Terminology (CPT)/ICD-9/ICD-10 procedure codes for prolapse surgery, and 16,383 women of European ancestry older than 40 years without a prolapse diagnosis code as controls. Patients were genotyped using the Illumina HumanCoreExome chip and imputed to the Haplotype Reference Consortium. We tested 20 million single nucleotide polymorphisms (SNPs) for association with pelvic organ prolapse adjusting for relatedness, age, chip version, and 4 principal components. We compared our results with 18 previously identified genome-wide significant SNPs from the UK Biobank, Commun Biol (2020;3:129), and Obstet Gynecol (2011;118:1345-1353). No variants achieved genome-wide significance (P = 5 \u00d7 10-8). However, we replicated 4 SNPs with biologic plausibility at nominal significance (P \u2264 0.05): rs12325192 (P = 0.002), rs9306894 (P = 0.05), rs1920568 (P = 0.034), and rs1247943 (P = 0.041), which were all intergenic and nearest the genes SALL1, GDF7, TBX5, and TBX5, respectively. Our replication of 4 biologically plausible previously reported SNPs provides further evidence for a genetic contribution to prolapse, specifically that rs12325192, rs9306894, rs1920568, and rs1247943 may contribute to susceptibility for prolapse. These and previously reported associations that have not yet been replicated should be further explored in larger, more diverse cohorts, perhaps through meta-analysis.", - "journal_title": "Female pelvic medicine & reconstructive surgery", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/34027909/" - } - ], - "516fb027-d7ef-481b-95b2-89c25f4e4f8d": [ - { - "pub_id": "22156741", - "title": "Measuring genome instability in aging - a mini-review.", - "authors": "Wenge Li,Jan Vijg", - "abstract": "There is mounting evidence for an age-dependent accumulation of somatic mutations as a result of the inherent imperfection of DNA replication and repair. A possible age-related decline in genome maintenance systems may exacerbate this age-related loss of genome integrity. A review of the current methods of mutation detection is timely in view of the lack of insight as to the magnitude of somatic mutation accumulation, the types of mutations that accumulate, and their functional consequences. In this paper we review the current methods for measuring genome instability in organisms during aging or in relation to life span. The review is based on established and novel concepts from the existing literature, with some examples from our own laboratory. Studies using cytogenetic assays and endogenous or transgenic mutation reporter assays provide strong evidence for age-related increases of different types of mutations in animals and humans during aging. This increase in DNA mutations is tissue-specific and also differs between species. Today, our knowledge of somatic mutation profiles in aging is mainly derived from cytogenetics and the use of endogenous and transgenic mutation reporter assays. The emergence of new approaches, most notably massively parallel sequencing, will give us deeper insight into the nature of spontaneous genome instability and its possible causal relationship to aging and age-related disease.", - "journal_title": "Gerontology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/22156741/" - } - ], - "f9b13bea-b89c-4eb5-8f6b-00409a2f1c8d": [ - { - "pub_id": "23754948", - "title": "Sex-stratified genome-wide association studies including 270,000 individuals show sexual dimorphism in genetic loci for anthropometric traits.", - "authors": "Joshua C Randall,Thomas W Winkler,Zolt\u00e1n Kutalik,Sonja I Berndt,Anne U Jackson,Keri L Monda,Tuomas O Kilpel\u00e4inen,T\u00f5nu Esko,Reedik M\u00e4gi,Shengxu Li,Tsegaselassie Workalemahu,Mary F Feitosa,Damien C Croteau-Chonka,Felix R Day,Tove Fall,Teresa Ferreira,Stefan Gustafsson,Adam E Locke,Iain Mathieson,Andre Scherag,Sailaja Vedantam,Andrew R Wood,Liming Liang,Valgerdur Steinthorsdottir,Gudmar Thorleifsson,Emmanouil T Dermitzakis,Antigone S Dimas,Fredrik Karpe,Josine L Min,George Nicholson,Deborah J Clegg,Thomas Person,Jon P Krohn,Sabrina Bauer,Christa Buechler,Kristina Eisinger, ,Am\u00e9lie Bonnefond,Philippe Froguel, ,Jouke-Jan Hottenga,Inga Prokopenko,Lindsay L Waite,Tamara B Harris,Albert Vernon Smith,Alan R Shuldiner,Wendy L McArdle,Mark J Caulfield,Patricia B Munroe,Henrik Gr\u00f6nberg,Yii-Der Ida Chen,Guo Li,Jacques S Beckmann,Toby Johnson,Unnur Thorsteinsdottir,Maris Teder-Laving,Kay-Tee Khaw,Nicholas J Wareham,Jing Hua Zhao,Najaf Amin,Ben A Oostra,Aldi T Kraja,Michael A Province,L Adrienne Cupples,Nancy L Heard-Costa,Jaakko Kaprio,Samuli Ripatti,Ida Surakka,Francis S Collins,Jouko Saramies,Jaakko Tuomilehto,Antti Jula,Veikko Salomaa,Jeanette Erdmann,Christian Hengstenberg,Christina Loley,Heribert Schunkert,Claudia Lamina,H Erich Wichmann,Eva Albrecht,Christian Gieger,Andrew A Hicks,Asa Johansson,Peter P Pramstaller,Sekar Kathiresan,Elizabeth K Speliotes,Brenda Penninx,Anna-Liisa Hartikainen,Marjo-Riitta Jarvelin,Ulf Gyllensten,Dorret I Boomsma,Harry Campbell,James F Wilson,Stephen J Chanock,Martin Farrall,Anuj Goel,Carolina Medina-Gomez,Fernando Rivadeneira,Karol Estrada,Andr\u00e9 G Uitterlinden,Albert Hofman,M Carola Zillikens,Martin den Heijer,Lambertus A Kiemeney,Andrea Maschio,Per Hall,Jonathan Tyrer,Alexander Teumer,Henry V\u00f6lzke,Peter Kovacs,Anke T\u00f6njes,Massimo Mangino,Tim D Spector,Caroline Hayward,Igor Rudan,Alistair S Hall,Nilesh J Samani,Antony Paul Attwood,Jennifer G Sambrook,Joseph Hung,Lyle J Palmer,Marja-Liisa Lokki,Juha Sinisalo,Gabrielle Boucher,Heikki Huikuri,Mattias Lorentzon,Claes Ohlsson,Niina Eklund,Johan G Eriksson,Cristina Barlassina,Carlo Rivolta,Ilja M Nolte,Harold Snieder,Melanie M Van der Klauw,Jana V Van Vliet-Ostaptchouk,Pablo V Gejman,Jianxin Shi,Kevin B Jacobs,Zhaoming Wang,Stephan J L Bakker,Irene Mateo Leach,Gerjan Navis,Pim van der Harst,Nicholas G Martin,Sarah E Medland,Grant W Montgomery,Jian Yang,Daniel I Chasman,Paul M Ridker,Lynda M Rose,Terho Lehtim\u00e4ki,Olli Raitakari,Devin Absher,Carlos Iribarren,Hanneke Basart,Kees G Hovingh,Elina Hypp\u00f6nen,Chris Power,Denise Anderson,John P Beilby,Jennie Hui,Jennifer Jolley,Hendrik Sager,Stefan R Bornstein,Peter E H Schwarz,Kati Kristiansson,Markus Perola,Jaana Lindstr\u00f6m,Amy J Swift,Matti Uusitupa,Mustafa Atalay,Timo A Lakka,Rainer Rauramaa,Jennifer L Bolton,Gerry Fowkes,Ross M Fraser,Jackie F Price,Krista Fischer,Kaarel Krjut\u00e5 Kov,Andres Metspalu,Evelin Mihailov,Claudia Langenberg,Jian'an Luan,Ken K Ong,Peter S Chines,Sirkka M Keinanen-Kiukaanniemi,Timo E Saaristo,Sarah Edkins,Paul W Franks,G\u00f6ran Hallmans,Dmitry Shungin,Andrew David Morris,Colin N A Palmer,Raimund Erbel,Susanne Moebus,Markus M N\u00f6then,Sonali Pechlivanis,Kristian Hveem,Narisu Narisu,Anders Hamsten,Steve E Humphries,Rona J Strawbridge,Elena Tremoli,Harald Grallert,Barbara Thorand,Thomas Illig,Wolfgang Koenig,Martina M\u00fcller-Nurasyid,Annette Peters,Bernhard O Boehm,Marcus E Kleber,Winfried M\u00e4rz,Bernhard R Winkelmann,Johanna Kuusisto,Markku Laakso,Dominique Arveiler,Giancarlo Cesana,Kari Kuulasmaa,Jarmo Virtamo,John W G Yarnell,Diana Kuh,Andrew Wong,Lars Lind,Ulf de Faire,Bruna Gigante,Patrik K E Magnusson,Nancy L Pedersen,George Dedoussis,Maria Dimitriou,Genovefa Kolovou,Stavroula Kanoni,Kathleen Stirrups,Lori L Bonnycastle,Inger Nj\u00f8lstad,Tom Wilsgaard,Andrea Ganna,Emil Rehnberg,Aroon Hingorani,Mika Kivimaki,Meena Kumari,Themistocles L Assimes,In\u00eas Barroso,Michael Boehnke,Ingrid B Borecki,Panos Deloukas,Caroline S Fox,Timothy Frayling,Leif C Groop,Talin Haritunians,David Hunter,Erik Ingelsson,Robert Kaplan,Karen L Mohlke,Jeffrey R O'Connell,David Schlessinger,David P Strachan,Kari Stefansson,Cornelia M van Duijn,Gon\u00e7alo R Abecasis,Mark I McCarthy,Joel N Hirschhorn,Lu Qi,Ruth J F Loos,Cecilia M Lindgren,Kari E North,Iris M Heid", - "abstract": "Given the anthropometric differences between men and women and previous evidence of sex-difference in genetic effects, we conducted a genome-wide search for sexually dimorphic associations with height, weight, body mass index, waist circumference, hip circumference, and waist-to-hip-ratio (133,723 individuals) and took forward 348 SNPs into follow-up (additional 137,052 individuals) in a total of 94 studies. Seven loci displayed significant sex-difference (FDR<5%), including four previously established (near GRB14/COBLL1, LYPLAL1/SLC30A10, VEGFA, ADAMTS9) and three novel anthropometric trait loci (near MAP3K1, HSD17B4, PPARG), all of which were genome-wide significant in women (P<5\u00d710(-8)), but not in men. Sex-differences were apparent only for waist phenotypes, not for height, weight, BMI, or hip circumference. Moreover, we found no evidence for genetic effects with opposite directions in men versus women. The PPARG locus is of specific interest due to its role in diabetes genetics and therapy. Our results demonstrate the value of sex-specific GWAS to unravel the sexually dimorphic genetic underpinning of complex traits.", - "journal_title": "PLoS genetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/23754948/" - } - ], - "d7ce756e-ec30-48fa-94e9-c1bd62d6b5d9": [ - { - "pub_id": "20458013", - "title": "Prelamin A acts to accelerate smooth muscle cell senescence and is a novel biomarker of human vascular aging.", - "authors": "Cassandra D Ragnauth,Derek T Warren,Yiwen Liu,Rosamund McNair,Tamara Tajsic,Nichola Figg,Rukshana Shroff,Jeremy Skepper,Catherine M Shanahan", - "abstract": "Hutchinson-Gilford progeria syndrome is a rare inherited disorder of premature aging caused by mutations in LMNA or Zmpste24 that disrupt nuclear lamin A processing, leading to the accumulation of prelamin A. Patients develop severe premature arteriosclerosis characterized by vascular smooth muscle cell (VSMC) calcification and attrition. To determine whether defective lamin A processing is associated with vascular aging in the normal population, we examined the profile of lamin A expression in normal and aged VSMCs. In vitro, aged VSMCs rapidly accumulated prelamin A coincidently with nuclear morphology defects, and these defects were reversible by treatment with farnesylation inhibitors and statins. In human arteries, prelamin A accumulation was not observed in young healthy vessels but was prevalent in medial VSMCs from aged individuals and in atherosclerotic lesions, where it often colocalized with senescent and degenerate VSMCs. Prelamin A accumulation correlated with downregulation of the lamin A processing enzyme Zmpste24/FACE1, and FACE1 mRNA and protein levels were reduced in response to oxidative stress. Small interfering RNA knockdown of FACE1 reiterated the prelamin A-induced nuclear morphology defects characteristic of aged VSMCs, and overexpression of prelamin A accelerated VSMC senescence. We show that prelamin A acts to disrupt mitosis and induce DNA damage in VSMCs, leading to mitotic failure, genomic instability, and premature senescence. This study shows that prelamin A is a novel biomarker of VSMC aging and disease that acts to accelerate senescence. It therefore represents a novel target to ameliorate the effects of age-induced vascular dysfunction.", - "journal_title": "Circulation", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/20458013/" - } - ], - "cf5810e3-cbc8-4fe0-9411-87feba94f987": [ - { - "pub_id": "23267103", - "title": "Linkage analysis identifies a locus for plasma von Willebrand factor undetected by genome-wide association.", - "authors": "Karl C Desch,Ayse B Ozel,David Siemieniak,Yossi Kalish,Jordan A Shavit,Courtney D Thornburg,Anjali A Sharathkumar,Caitlin P McHugh,Cathy C Laurie,Andrew Crenshaw,Daniel B Mirel,Yoonhee Kim,Cheryl D Cropp,Anne M Molloy,Peadar N Kirke,Joan E Bailey-Wilson,Alexander F Wilson,James L Mills,John M Scott,Lawrence C Brody,Jun Z Li,David Ginsburg", - "abstract": "The plasma glycoprotein von Willebrand factor (VWF) exhibits fivefold antigen level variation across the normal human population determined by both genetic and environmental factors. Low levels of VWF are associated with bleeding and elevated levels with increased risk for thrombosis, myocardial infarction, and stroke. To identify additional genetic determinants of VWF antigen levels and to minimize the impact of age and illness-related environmental factors, we performed genome-wide association analysis in two young and healthy cohorts (n = 1,152 and n = 2,310) and identified signals at ABO (P < 7.9E-139) and VWF (P < 5.5E-16), consistent with previous reports. Additionally, linkage analysis based on sibling structure within the cohorts, identified significant signals at chromosome 2q12-2p13 (LOD score 5.3) and at the ABO locus on chromosome 9q34 (LOD score 2.9) that explained 19.2% and 24.5% of the variance in VWF levels, respectively. Given its strong effect, the linkage region on chromosome 2 could harbor a potentially important determinant of bleeding and thrombosis risk. The absence of a chromosome 2 association signal in this or previous association studies suggests a causative gene harboring many genetic variants that are individually rare, but in aggregate common. These results raise the possibility that similar loci could explain a significant portion of the \"missing heritability\" for other complex genetic traits.", - "journal_title": "Proceedings of the National Academy of Sciences of the United States of America", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/23267103/" - } - ], - "35e7b535-f3ed-4de4-a323-f1880a5873c2": [ - { - "pub_id": "22984365", - "title": "Population-based screening in the era of genomics.", - "authors": "Nora Pashayan,Paul Pharoah", - "abstract": "To date, risk profiles based on the known common susceptibility variants have limited value in predicting risk of disease but they could be used for risk stratification in prevention programmes at population level. We illustrate the potential utility of polygenic risk stratification using the case of population-based screening for prostate and breast cancer. We compared the number of individuals eligible for screening and the number of cases potentially detectable by screening in a population undergoing screening based on age alone with a population undergoing stratified screening based on age and polygenic risk profile. Stratified screening strategy based on age and genetic risk would potentially improve the efficiency of screening programmes and reduce their adverse consequences. Organisational, ethical, legal and social issues need to be addressed before stratified screening programmes could be implemented.", - "journal_title": "Personalized medicine", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/22984365/" - } - ], - "1bdbb53c-4d41-4006-a914-b1d7830feaae": [ - { - "pub_id": "24034465", - "title": "Differential DNA methylation with age displays both common and dynamic features across human tissues that are influenced by CpG landscape.", - "authors": "Kenneth Day,Lindsay L Waite,Anna Thalacker-Mercer,Andrew West,Marcas M Bamman,James D Brooks,Richard M Myers,Devin Absher", - "abstract": "DNA methylation is an epigenetic modification that changes with age in human tissues, although the mechanisms and specificity of this process are still poorly understood. We compared CpG methylation changes with age across 283 human blood, brain, kidney, and skeletal muscle samples using methylation arrays to identify tissue-specific age effects. We found age-associated CpGs (ageCGs) that are both tissue-specific and common across tissues. Tissue-specific age CGs are frequently located outside CpG islands with decreased methylation, and common ageCGs show the opposite trend. AgeCGs are significantly associated with poorly expressed genes, but those with decreasing methylation are linked with higher tissue-specific expression levels compared with increasing methylation. Therefore, tissue-specific gene expression may protect against common age-dependent methylation. Distinguished from other tissues, skeletal muscle age CGs are more associated with expression, enriched near genes related to myofiber contraction, and closer to muscle-specific CTCF binding sites. Kidney-specific ageCGs are more increasingly methylated compared to other tissues as measured by affiliation with kidney-specific expressed genes. Underlying chromatin features also mark common and tissue-specific age effects reflective of poised and active chromatin states, respectively. In contrast with decreasingly methylated ageCGs, increasingly methylated ageCGs are also generally further from CTCF binding sites and enriched within lamina associated domains. Our data identified common and tissue-specific DNA methylation changes with age that are reflective of CpG landscape and suggests both common and unique alterations within human tissues. Our findings also indicate that a simple epigenetic drift model is insufficient to explain all age-related changes in DNA methylation.", - "journal_title": "Genome biology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/24034465/" - } - ], - "5af250e7-afa6-4d32-80ee-7cd01d8a71b2": [ - { - "pub_id": "23128233", - "title": "Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease.", - "authors": "Luke Jostins,Stephan Ripke,Rinse K Weersma,Richard H Duerr,Dermot P McGovern,Ken Y Hui,James C Lee,L Philip Schumm,Yashoda Sharma,Carl A Anderson,Jonah Essers,Mitja Mitrovic,Kaida Ning,Isabelle Cleynen,Emilie Theatre,Sarah L Spain,Soumya Raychaudhuri,Philippe Goyette,Zhi Wei,Clara Abraham,Jean-Paul Achkar,Tariq Ahmad,Leila Amininejad,Ashwin N Ananthakrishnan,Vibeke Andersen,Jane M Andrews,Leonard Baidoo,Tobias Balschun,Peter A Bampton,Alain Bitton,Gabrielle Boucher,Stephan Brand,Carsten B\u00fcning,Ariella Cohain,Sven Cichon,Mauro D'Amato,Dirk De Jong,Kathy L Devaney,Marla Dubinsky,Cathryn Edwards,David Ellinghaus,Lynnette R Ferguson,Denis Franchimont,Karin Fransen,Richard Gearry,Michel Georges,Christian Gieger,J\u00fcrgen Glas,Talin Haritunians,Ailsa Hart,Chris Hawkey,Matija Hedl,Xinli Hu,Tom H Karlsen,Limas Kupcinskas,Subra Kugathasan,Anna Latiano,Debby Laukens,Ian C Lawrance,Charlie W Lees,Edouard Louis,Gillian Mahy,John Mansfield,Angharad R Morgan,Craig Mowat,William Newman,Orazio Palmieri,Cyriel Y Ponsioen,Uros Potocnik,Natalie J Prescott,Miguel Regueiro,Jerome I Rotter,Richard K Russell,Jeremy D Sanderson,Miquel Sans,Jack Satsangi,Stefan Schreiber,Lisa A Simms,Jurgita Sventoraityte,Stephan R Targan,Kent D Taylor,Mark Tremelling,Hein W Verspaget,Martine De Vos,Cisca Wijmenga,David C Wilson,Juliane Winkelmann,Ramnik J Xavier,Sebastian Zeissig,Bin Zhang,Clarence K Zhang,Hongyu Zhao, ,Mark S Silverberg,Vito Annese,Hakon Hakonarson,Steven R Brant,Graham Radford-Smith,Christopher G Mathew,John D Rioux,Eric E Schadt,Mark J Daly,Andre Franke,Miles Parkes,Severine Vermeire,Jeffrey C Barrett,Judy H Cho", - "abstract": "Crohn's disease and ulcerative colitis, the two common forms of inflammatory bowel disease (IBD), affect over 2.5 million people of European ancestry, with rising prevalence in other populations. Genome-wide association studies and subsequent meta-analyses of these two diseases as separate phenotypes have implicated previously unsuspected mechanisms, such as autophagy, in their pathogenesis and showed that some IBD loci are shared with other inflammatory diseases. Here we expand on the knowledge of relevant pathways by undertaking a meta-analysis of Crohn's disease and ulcerative colitis genome-wide association scans, followed by extensive validation of significant findings, with a combined total of more than 75,000 cases and controls. We identify 71 new associations, for a total of 163 IBD loci, that meet genome-wide significance thresholds. Most loci contribute to both phenotypes, and both directional (consistently favouring one allele over the course of human history) and balancing (favouring the retention of both alleles within populations) selection effects are evident. Many IBD loci are also implicated in other immune-mediated disorders, most notably with ankylosing spondylitis and psoriasis. We also observe considerable overlap between susceptibility loci for IBD and mycobacterial infection. Gene co-expression network analysis emphasizes this relationship, with pathways shared between host responses to mycobacteria and those predisposing to IBD.", - "journal_title": "Nature", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/23128233/" - } - ], - "f954b8d1-aa1a-4dd9-a7af-bbb4f4759c0f": [ - { - "pub_id": "26439355", - "title": "Morphological Phylogenetics in the Genomic Age.", - "authors": "Michael S Y Lee,Alessandro Palci", - "abstract": "Evolutionary trees underpin virtually all of biology, and the wealth of new genomic data has enabled us to reconstruct them with increasing detail and confidence. While phenotypic (typically morphological) traits are becoming less important in reconstructing evolutionary trees, they still serve vital and unique roles in phylogenetics, even for living taxa for which vast amounts of genetic information are available. Morphology remains a powerful independent source of evidence for testing molecular clades, and - through fossil phenotypes - the primary means for time-scaling phylogenies. Morphological phylogenetics is therefore vital for transforming undated molecular topologies into dated evolutionary trees. However, if morphology is to be employed to its full potential, biologists need to start scrutinising phenotypes in a more objective fashion, models of phenotypic evolution need to be improved, and approaches for analysing phenotypic traits and fossils together with genomic data need to be refined.", - "journal_title": "Current biology : CB", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/26439355/" - } - ], - "998c7a89-697c-4d3a-a430-a756218eebb3": [ - { - "pub_id": "26783965", - "title": "Iron Age and Anglo-Saxon genomes from East England reveal British migration history.", - "authors": "Stephan Schiffels,Wolfgang Haak,Pirita Paajanen,Bastien Llamas,Elizabeth Popescu,Louise Loe,Rachel Clarke,Alice Lyons,Richard Mortimer,Duncan Sayer,Chris Tyler-Smith,Alan Cooper,Richard Durbin", - "abstract": "British population history has been shaped by a series of immigrations, including the early Anglo-Saxon migrations after 400 CE. It remains an open question how these events affected the genetic composition of the current British population. Here, we present whole-genome sequences from 10 individuals excavated close to Cambridge in the East of England, ranging from the late Iron Age to the middle Anglo-Saxon period. By analysing shared rare variants with hundreds of modern samples from Britain and Europe, we estimate that on average the contemporary East English population derives 38% of its ancestry from Anglo-Saxon migrations. We gain further insight with a new method, rarecoal, which infers population history and identifies fine-scale genetic ancestry from rare variants. Using rarecoal we find that the Anglo-Saxon samples are closely related to modern Dutch and Danish populations, while the Iron Age samples share ancestors with multiple Northern European populations including Britain.", - "journal_title": "Nature communications", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/26783965/" - } - ], - "97290894-086d-438a-bbd2-907dd4cea2ab": [ - { - "pub_id": "20647238", - "title": "MicroRNA, mRNA, and protein expression link development and aging in human and macaque brain.", - "authors": "Mehmet Somel,Song Guo,Ning Fu,Zheng Yan,Hai Yang Hu,Ying Xu,Yuan Yuan,Zhibin Ning,Yuhui Hu,Corinna Menzel,Hao Hu,Michael Lachmann,Rong Zeng,Wei Chen,Philipp Khaitovich", - "abstract": "Changes in gene expression levels determine differentiation of tissues involved in development and are associated with functional decline in aging. Although development is tightly regulated, the transition between development and aging, as well as regulation of post-developmental changes, are not well understood. Here, we measured messenger RNA (mRNA), microRNA (miRNA), and protein expression in the prefrontal cortex of humans and rhesus macaques over the species' life spans. We find that few gene expression changes are unique to aging. Instead, the vast majority of miRNA and gene expression changes that occur in aging represent reversals or extensions of developmental patterns. Surprisingly, many gene expression changes previously attributed to aging, such as down-regulation of neural genes, initiate in early childhood. Our results indicate that miRNA and transcription factors regulate not only developmental but also post-developmental expression changes, with a number of regulatory processes continuing throughout the entire life span. Differential evolutionary conservation of the corresponding genomic regions implies that these regulatory processes, although beneficial in development, might be detrimental in aging. These results suggest a direct link between developmental regulation and expression changes taking place in aging.", - "journal_title": "Genome research", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/20647238/" - } - ], - "6a791749-060e-44db-b4c1-1a0182d0dedf": [ - { - "pub_id": "23443494", - "title": "Genome maintenance and transcription integrity in aging and disease.", - "authors": "Stefanie Wolters,Bj\u00f6rn Schumacher", - "abstract": "DNA damage contributes to cancer development and aging. Congenital syndromes that affect DNA repair processes are characterized by cancer susceptibility, developmental defects, and accelerated aging (Schumacher et al., 2008). DNA damage interferes with DNA metabolism by blocking replication and transcription. DNA polymerase blockage leads to replication arrest and can gives rise to genome instability. Transcription, on the other hand, is an essential process for utilizing the information encoded in the genome. DNA damage that interferes with transcription can lead to apoptosis and cellular senescence. Both processes are powerful tumor suppressors (Bartek and Lukas, 2007). Cellular response mechanisms to stalled RNA polymerase II complexes have only recently started to be uncovered. Transcription-coupled DNA damage responses might thus play important roles for the adjustments to DNA damage accumulation in the aging organism (Garinis et al., 2009). Here we review human disorders that are caused by defects in genome stability to explore the role of DNA damage in aging and disease. We discuss how the nucleotide excision repair system functions at the interface of transcription and repair and conclude with concepts how therapeutic targeting of transcription might be utilized in the treatment of cancer.", - "journal_title": "Frontiers in genetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/23443494/" - } - ], - "198bd45c-e3a3-4937-b83a-61914b64e43b": [ - { - "pub_id": "23106705", - "title": "Genomic basis of aging and life-history evolution in Drosophila melanogaster.", - "authors": "Silvia C Remolina,Peter L Chang,Jeff Leips,Sergey V Nuzhdin,Kimberly A Hughes", - "abstract": "Natural diversity in aging and other life-history patterns is a hallmark of organismal variation. Related species, populations, and individuals within populations show genetically based variation in life span and other aspects of age-related performance. Population differences are especially informative because these differences can be large relative to within-population variation and because they occur in organisms with otherwise similar genomes. We used experimental evolution to produce populations divergent for life span and late-age fertility and then used deep genome sequencing to detect sequence variants with nucleotide-level resolution. Several genes and genome regions showed strong signatures of selection, and the same regions were implicated in independent comparisons, suggesting that the same alleles were selected in replicate lines. Genes related to oogenesis, immunity, and protein degradation were implicated as important modifiers of late-life performance. Expression profiling and functional annotation narrowed the list of strong candidate genes to 38, most of which are novel candidates for regulating aging. Life span and early age fecundity were negatively correlated among populations; therefore, the alleles we identified also are candidate regulators of a major life-history trade-off. More generally, we argue that hitchhiking mapping can be a powerful tool for uncovering the molecular bases of quantitative genetic variation.", - "journal_title": "Evolution; international journal of organic evolution", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/23106705/" - } - ], - "6e353c51-355c-4cfd-82b4-77f800823a89": [ - { - "pub_id": "22234802", - "title": "Age-dependent accumulation of genomic aberrations and deregulation of cell cycle and telomerase genes in metastatic neuroblastoma.", - "authors": "Simona Coco,Jessica Theissen,Paola Scaruffi,Sara Stigliani,Stefano Moretti,Andr\u00e9 Oberthuer,Francesca Valdora,Matthias Fischer,Fabio Gallo,Barbara Hero,Stefano Bonassi,Frank Berthold,Gian Paolo Tonini", - "abstract": "About 50% of children with neuroblastoma (NB) show a metastatic disease and have a poor prognosis. However, disease progression is greatly variable and depends on patients' age and MYCN oncogene amplification. To investigate the role of patients' age in tumor aggressiveness, we performed array-CGH and gene expression profiles of three groups (G) of metastatic NBs: G1, stage 4S patients and MYCN single copy (MYCN-) tumors; G2, stage 4 patients, \u2264 18 months of age, MYCN- tumors and favorable outcome and G3, Stage 4 patients, \u2265 19 months with unfavorable outcome. G1 was characterized by numerical aberrations prevalently; on the contrary, all G3 tumors had structural rearrangements, whereas G2 showed an intermediate pattern. The average of numerical alterations decreased significantly from G1 to G2 to G3 (p < 0.01). Contrarily, the number of structural aberrations increased from G1 to G2 to G3 (p < 2.35 E-05). Noteworthy, G3/MYCN- NBs were characterized by several complex intrachromosome rearrangements. Expression analysis of the three groups showed significant differences in genes of Rho and Ras signaling pathways, development and adhesion, cell cycle regulation and telomerase activity. Accumulation of structural alterations increased with patients' age and was associated with a more aggressive disease. Abnormal expression of genes involved in cell cycle and telomerase in G3 may be responsible for the genomic instability in this cohort of patients. The higher DNA instability observed in G3/MYCN- NBs than in MYCN-amplified G3 may also explain why patients \u2265 19 months have a poor outcome independently by MYCN status.", - "journal_title": "International journal of cancer", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/22234802/" - } - ], - "efbf0489-7712-4774-9c85-554e33499b3f": [ - { - "pub_id": "27467180", - "title": "A Focus on the Epidemiology of Uveitis.", - "authors": "Theodora Tsirouki,Anna Dastiridou,Chrysanthos Symeonidis,Ourania Tounakaki,Irini Brazitikou,Christos Kalogeropoulos,Sofia Androudi", - "abstract": "Uveitis is a common, sight-threatening inflammatory ocular disease and includes multiple heterogeneous clinical entities. The prevalence of various types of uveitis depends upon multiple factors, such as age, sex, race, geographic distribution, environmental influence, genetics, and social habits. Epidemiologic research of uveitis is necessary to understand the etiology and immunopathogenesis of this group of diseases. The present study attempts to concentrate on the most recent information on the epidemiology of uveitis and compare it with previous knowledge. An extensive literature search was performed in the Medline database (PubMed) and included surveys completed until 2015. Articles that reported prevalence and incidence were studied. References cited in the articles were also studied. The incidence and prevalence of uveitis differs based on age, anatomic location of the inflammatory process (anterior, intermediate, posterior uveitis, panuveitis), gender, histopathology (granulomatous, non-granulomatous), type of inflammatory process (acute, chronic, recurrent), and etiology (infectious, non-infectious). Prevalence differs by geographic location. Idiopathic anterior uveitis is the most common form of uveitis in the community. Infectious causes are common (30-60%) in the developing countries. Herpes and toxoplasmosis are the leading infectious causes of uveitis. Non-infectious uveitic conditions are generally more common in the developed world. An increase in the prevalence of infectious etiologies, including tuberculosis and syphilis, has been seen in developed countries. Introduction of new treatment options has also changed patterns of disease. Introduction of new uveitis entities, changes in the incidence of already known disease and increased availability of diagnostic testing have all altered the epidemiology of uveitis in recent years. Knowledge of regional patterns of disease is essential. A more detailed classification of uveitis with the establishment of uniform diagnostic criteria and prospective population based studies would certainly benefit epidemiologic research and clinical practice.", - "journal_title": "Ocular immunology and inflammation", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/27467180/" - } - ], - "c23cce14-7b6d-44f2-9ccd-da4f1cd9f9fa": [ - { - "pub_id": "25864559", - "title": "Genome-wide sperm DNA methylation changes after 3 months of exercise training in humans.", - "authors": "Joshua Denham,Brendan J O'Brien,Jack T Harvey,Fadi J Charchar", - "abstract": "DNA methylation programs gene expression and is involved in numerous biological processes. Accumulating evidence supports transgenerational inheritance of DNA methylation changes in mammals via germ cells. Our aim was to determine the effect of exercise on sperm DNA methylation. Twenty-four men were recruited and assigned to an exercise intervention or control group. Clinical parameters were measured and sperm samples were donated by subjects before and after the 3-month time-period. Mature sperm global and genome-wide DNA methylation was assessed using an ELISA assay and the 450K BeadChip (Illumina). Global and genome-wide sperm DNA methylation was altered after 3 months of exercise training. DNA methylation changes occurred in genes related to numerous diseases such as schizophrenia and Parkinson's disease. Our study provides the first evidence showing exercise training reprograms the sperm methylome. Whether these DNA methylation changes are inherited to future generations warrants attention.", - "journal_title": "Epigenomics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/25864559/" - } - ], - "19d75e36-9f4a-4981-bbb7-994dd324f286": [ - { - "pub_id": "21282665", - "title": "The genome of the fire ant Solenopsis invicta.", - "authors": "Yannick Wurm,John Wang,Oksana Riba-Grognuz,Miguel Corona,Sanne Nygaard,Brendan G Hunt,Krista K Ingram,Laurent Falquet,Mingkwan Nipitwattanaphon,Dietrich Gotzek,Michiel B Dijkstra,Jan Oettler,Fabien Comtesse,Cheng-Jen Shih,Wen-Jer Wu,Chin-Cheng Yang,Jerome Thomas,Emmanuel Beaudoing,Sylvain Pradervand,Volker Flegel,Erin D Cook,Roberto Fabbretti,Heinz Stockinger,Li Long,William G Farmerie,Jane Oakey,Jacobus J Boomsma,Pekka Pamilo,Soojin V Yi,J\u00fcrgen Heinze,Michael A D Goodisman,Laurent Farinelli,Keith Harshman,Nicolas Hulo,Lorenzo Cerutti,Ioannis Xenarios,Dewayne Shoemaker,Laurent Keller", - "abstract": "Ants have evolved very complex societies and are key ecosystem members. Some ants, such as the fire ant Solenopsis invicta, are also major pests. Here, we present a draft genome of S. invicta, assembled from Roche 454 and Illumina sequencing reads obtained from a focal haploid male and his brothers. We used comparative genomic methods to obtain insight into the unique features of the S. invicta genome. For example, we found that this genome harbors four adjacent copies of vitellogenin. A phylogenetic analysis revealed that an ancestral vitellogenin gene first underwent a duplication that was followed by possibly independent duplications of each of the daughter vitellogenins. The vitellogenin genes have undergone subfunctionalization with queen- and worker-specific expression, possibly reflecting differential selection acting on the queen and worker castes. Additionally, we identified more than 400 putative olfactory receptors of which at least 297 are intact. This represents the largest repertoire reported so far in insects. S. invicta also harbors an expansion of a specific family of lipid-processing genes, two putative orthologs to the transformer/feminizer sex differentiation gene, a functional DNA methylation system, and a single putative telomerase ortholog. EST data indicate that this S. invicta telomerase ortholog has at least four spliceforms that differ in their use of two sets of mutually exclusive exons. Some of these and other unique aspects of the fire ant genome are likely linked to the complex social behavior of this species.", - "journal_title": "Proceedings of the National Academy of Sciences of the United States of America", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/21282665/" - } - ], - "d318e18d-dd1c-4660-a906-c242c87acaa4": [ - { - "pub_id": "23177740", - "title": "Genome-wide methylation profiles reveal quantitative views of human aging rates.", - "authors": "Gregory Hannum,Justin Guinney,Ling Zhao,Li Zhang,Guy Hughes,SriniVas Sadda,Brandy Klotzle,Marina Bibikova,Jian-Bing Fan,Yuan Gao,Rob Deconde,Menzies Chen,Indika Rajapakse,Stephen Friend,Trey Ideker,Kang Zhang", - "abstract": "The ability to measure human aging from molecular profiles has practical implications in many fields, including disease prevention and treatment, forensics, and extension of life. Although chronological age has been linked to changes in DNA methylation, the methylome has not yet been used to measure and compare human aging rates. Here, we build a quantitative model of aging using measurements at more than 450,000 CpG markers from the whole blood of 656 human individuals, aged 19 to 101. This model measures the rate at which an individual's methylome ages, which we show is impacted by gender and genetic variants. We also show that differences in aging rates help explain epigenetic drift and are reflected in the transcriptome. Moreover, we show how our aging model is upheld in other human tissues and reveals an advanced aging rate in tumor tissue. Our model highlights specific components of\u00a0the aging process and provides a quantitative readout for studying the role of methylation in age-related disease.", - "journal_title": "Molecular cell", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/23177740/" - } - ], - "db651cee-b5d0-4e41-a1d0-c9004678ee44": [ - { - "pub_id": "23756890", - "title": "Overview of Statistical Methods for Genome-Wide Association Studies (GWAS).", - "authors": "Ben Hayes", - "abstract": "This chapter provides an overview of statistical methods for genome-wide association studies (GWAS) in animals, plants, and humans. The simplest form of GWAS, a marker-by-marker analysis, is illustrated with a simple example. The problem of selecting a significance threshold that accounts for the large amount of multiple testing that occurs in GWAS is discussed. Population structure causes false positive associations in GWAS if not accounted for, and methods to deal with this are presented. Methodology for more complex models for GWAS, including haplotype-based approaches, accounting for identical by descent versus identical by state, and fitting all markers simultaneously are described and illustrated with examples.", - "journal_title": "Methods in molecular biology (Clifton, N.J.)", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/23756890/" - } - ], - "3adac8b3-be3a-4cf6-8791-c6e912beae9a": [ - { - "pub_id": "27558209", - "title": "Genome-wide methylation profile following prenatal and postnatal dietary omega-3 fatty acid supplementation in pigs.", - "authors": "R L Boddicker,J E Koltes,E R Fritz-Waters,L Koesterke,N Weeks,T Yin,V Mani,D Nettleton,J M Reecy,L H Baumgard,J D Spencer,N K Gabler,J W Ross", - "abstract": "The objective of this study was to determine how prenatal and postnatal dietary omega-3 fatty acids alter white blood cell (leukocyte) DNA methylation of offspring. Fifteen gilts (n\u00a0=\u00a05 per treatment) were selected from one of three treatments: (i) control diet throughout gestation, lactation and nursery phase (CON); (ii) algal omega-3 fatty acid supplementation enriched in EPA and DHA (Gromega<sup>\u2122</sup> ) fed throughout gestation, lactation and nursery phase (Cn3); or (iii) Gromega<sup>\u2122</sup> supplementation maternally, during gestation and lactation only, and control diet during the nursery phase (Mn3). At 11\u00a0weeks of age and after 8\u00a0weeks of post-weaning nursery feeding, buffy coat genomic DNA was subjected to methyl CpG binding protein sequencing. The methylation enriched profile mapped to 26% of the porcine genome. On chromosome 4, a 27.7-kb differentially methylated region downstream of RUNX1T1 was hypomethylated in the Mn3 and Cn3 groups by 91.6% and 85.0% respectively compared to CON pigs. Conversely, hypermethylation was detected in intergenic regions of chromosomes 4 and 12. Regulatory impact factor and differential hubbing methods were used to identify pathways that were coordinately regulated by methylation due to feeding EPA and DHA during pregnancy. Despite limited ability to detect differential methylation, we describe methods that allow the identification of coordinated epigenetic regulation that could not otherwise be detected from subtle single locus changes in methylation. These data provide evidence of novel epigenetic regulation by maternal and early life supplementation of omega-3 fatty acids that may have implications to growth and inflammatory processes.", - "journal_title": "Animal genetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/27558209/" - } - ], - "f6377ad6-4347-4044-9b73-71d282e20585": [ - { - "pub_id": "25955736", - "title": "Diagnosis and management of generalized anxiety disorder and panic disorder in adults.", - "authors": "Amy B Locke,Nell Kirst,Cameron G Shultz", - "abstract": "Generalized anxiety disorder (GAD) and panic disorder (PD) are among the most common mental disorders in the United States, and they can negatively impact a patient's quality of life and disrupt important activities of daily living. Evidence suggests that the rates of missed diagnoses and misdiagnosis of GAD and PD are high, with symptoms often ascribed to physical causes. Diagnosing GAD and PD requires a broad differential and caution to identify confounding variables and comorbid conditions. Screening and monitoring tools can be used to help make the diagnosis and monitor response to therapy. The GAD-7 and the Severity Measure for Panic Disorder are free diagnostic tools. Successful outcomes may require a combination of treatment modalities tailored to the individual patient. Treatment often includes medications such as selective serotonin reuptake inhibitors and/or psychotherapy, both of which are highly effective. Among psychotherapeutic treatments, cognitive behavior therapy has been studied widely and has an extensive evidence base. Benzodiazepines are effective in reducing anxiety symptoms, but their use is limited by risk of abuse and adverse effect profiles. Physical activity can reduce symptoms of GAD and PD. A number of complementary and alternative treatments are often used; however, evidence is limited for most. Several common botanicals and supplements can potentiate serotonin syndrome when used in combination with antidepressants. Medication should be continued for 12 months before tapering to prevent relapse.", - "journal_title": "American family physician", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/25955736/" - } - ], - "42cbc297-d57c-4c1f-8d3f-f9e52748b823": [ - { - "pub_id": "21146726", - "title": "Clinical aspects and molecular diagnostics of skin aging.", - "authors": "Christos C Zouboulis,Evgenia Makrantonaki", - "abstract": "This contribution will address the effect of aging on skin functions, with a particular focus on skin permeability, wound healing, angiogenesis, lipogenesis, sweat production, immune function, and vitamin D synthesis. With accelerating age, skin functions deteriorate due to structural and morphologic changes. Skin is prone to the development of several diseases, varying from benign to malignant. Because the number of persons aged 80 and older is expected to rise in the next decades, disease prevention will become an important issue. Screening examinations and prevention through public education starting at an early age regarding sun avoidance, the use of sunscreens and the importance of a balanced nutrition are the first steps for successful healthy aging. Although the fundamental mechanisms in the pathogenesis of aged skin are still poorly understood, a growing body of evidence points toward the involvement of multiple pathways. Recent data obtained by expression profiling studies and studies of progeroid syndromes illustrate that among the most important biologic processes involved in skin aging are alterations in DNA repair and stability, mitochondrial function, cell cycle and apoptosis, extracellular matrix, lipid synthesis, ubiquitin-induced proteolysis and cellular metabolism. Among others, a major factor that has been implicated in the initiation of aging is the physiologic decline of hormones occurring with age. However, hormones at age-specific levels may regulate not only age-associated mechanisms but also tumor suppressor pathways that influence carcinogenesis. Understanding the molecular mechanisms of aging may open new strategies to deal with the various diseases accompanying high age, including cancer.", - "journal_title": "Clinics in dermatology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/21146726/" - } - ], - "ab0a3234-c3b3-46be-8954-01eda9bc962e": [ - { - "pub_id": "27474438", - "title": "Nucleolar organizer regions: genomic 'dark matter' requiring illumination.", - "authors": "Brian McStay", - "abstract": "Nucleoli form around tandem arrays of a ribosomal gene repeat, termed nucleolar organizer regions (NORs). During metaphase, active NORs adopt a characteristic undercondensed morphology. Recent evidence indicates that the HMG-box-containing DNA-binding protein UBF (upstream binding factor) is directly responsible for this morphology and provides a mitotic bookmark to ensure rapid nucleolar formation beginning in telophase in human cells. This is likely to be a widely employed strategy, as UBF is present throughout metazoans. In higher eukaryotes, NORs are typically located within regions of chromosomes that form perinucleolar heterochromatin during interphase. Typically, the genomic architecture of NORs and the chromosomal regions within which they lie is very poorly described, yet recent evidence points to a role for context in their function. In Arabidopsis, NOR silencing appears to be controlled by sequences outside the rDNA (ribosomal DNA) array. Translocations reveal a role for context in the expression of the NOR on the X chromosome in Drosophila Recent work has begun on characterizing the genomic architecture of human NORs. A role for distal sequences located in perinucleolar heterochromatin has been inferred, as they exhibit a complex transcriptionally active chromatin structure. Links between rDNA genomic stability and aging in Saccharomyces cerevisiae are now well established, and indications are emerging that this is important in aging and replicative senescence in higher eukaryotes. This, combined with the fact that rDNA arrays are recombinational hot spots in cancer cells, has focused attention on DNA damage responses in NORs. The introduction of DNA double-strand breaks into rDNA arrays leads to a dramatic reorganization of nucleolar structure. Damaged rDNA repeats move from the nucleolar interior to form caps at the nucleolar periphery, presumably to facilitate repair, suggesting that the chromosomal context of human NORs contributes to their genomic stability. The inclusion of NORs and their surrounding chromosomal environments in future genome drafts now becomes a priority.", - "journal_title": "Genes & development", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/27474438/" - } - ], - "f4dfb05a-9c42-4290-b687-db31010e6449": [ - { - "pub_id": "27051996", - "title": "Genetic and environmental influences interact with age and sex in shaping the human methylome.", - "authors": "Jenny van Dongen,Michel G Nivard,Gonneke Willemsen,Jouke-Jan Hottenga,Quinta Helmer,Conor V Dolan,Erik A Ehli,Gareth E Davies,Maarten van Iterson,Charles E Breeze,Stephan Beck, ,H Eka Suchiman,Rick Jansen,Joyce B van Meurs,Bastiaan T Heijmans,P Eline Slagboom,Dorret I Boomsma", - "abstract": "The methylome is subject to genetic and environmental effects. Their impact may depend on sex and age, resulting in sex- and age-related physiological variation and disease susceptibility. Here we estimate the total heritability of DNA methylation levels in whole blood and estimate the variance explained by common single nucleotide polymorphisms at 411,169 sites in 2,603 individuals from twin families, to establish a catalogue of between-individual variation in DNA methylation. Heritability estimates vary across the genome (mean=19%) and interaction analyses reveal thousands of sites with sex-specific heritability as well as sites where the environmental variance increases with age. Integration with previously published data illustrates the impact of genome and environment across the lifespan at methylation sites associated with metabolic traits, smoking and ageing. These findings demonstrate that our catalogue holds valuable information on locations in the genome where methylation variation between people may reflect disease-relevant environmental exposures or genetic variation.", - "journal_title": "Nature communications", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/27051996/" - } - ], - "e9c5e256-7d7c-4669-8558-1d75a112b078": [ - { - "pub_id": "21269927", - "title": "Rotenone, paraquat, and Parkinson's disease.", - "authors": "Caroline M Tanner,Freya Kamel,G Webster Ross,Jane A Hoppin,Samuel M Goldman,Monica Korell,Connie Marras,Grace S Bhudhikanok,Meike Kasten,Anabel R Chade,Kathleen Comyns,Marie Barber Richards,Cheryl Meng,Benjamin Priestley,Hubert H Fernandez,Franca Cambi,David M Umbach,Aaron Blair,Dale P Sandler,J William Langston", - "abstract": "Mitochondrial dysfunction and oxidative stress are pathophysiologic mechanisms implicated in experimental models and genetic forms of Parkinson's disease (PD). Certain pesticides may affect these mechanisms, but no pesticide has been definitively associated with PD in humans. Our goal was to determine whether pesticides that cause mitochondrial dysfunction or oxidative stress are associated with PD or clinical features of parkinsonism in humans. We assessed lifetime use of pesticides selected by mechanism in a case-control study nested in the Agricultural Health Study (AHS). PD was diagnosed by movement disorders specialists. Controls were a stratified random sample of all AHS participants frequency-matched to cases by age, sex, and state at approximately three controls:one case. In 110 PD cases and 358 controls, PD was associated with use of a group of pesticides that inhibit mitochondrial complex I [odds ratio (OR)=1.7; 95% confidence interval (CI), 1.0-2.8] including rotenone (OR=2.5; 95% CI, 1.3-4.7) and with use of a group of pesticides that cause oxidative stress (OR = 2.0; 95% CI, 1.2-3.6), including paraquat (OR=2.5; 95% CI, 1.4-4.7). PD was positively associated with two groups of pesticides defined by mechanisms implicated experimentally-those that impair mitochondrial function and those that increase oxidative stress-supporting a role for these mechanisms in PD pathophysiology.", - "journal_title": "Environmental health perspectives", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/21269927/" - } - ], - "d741ee86-3a67-47fd-a0d8-918f77c6213d": [ - { - "pub_id": "20835748", - "title": "The renaissance of continuous culture in the post-genomics age.", - "authors": "Alan T Bull", - "abstract": "The development of continuous culture techniques 60\u00a0years ago and the subsequent formulation of theory and the diversification of experimental systems revolutionised microbiology and heralded a unique period of innovative research. Then, progressively, molecular biology and thence genomics and related high-information-density omics technologies took centre stage and microbial growth physiology in general faded from educational programmes and research funding priorities alike. However, there has been a gathering appreciation over the past decade that if the claims of systems biology are going to be realised, they will have to be based on rigorously controlled and reproducible microbial and cell growth platforms. This revival of continuous culture will be long lasting because its recognition as the growth system of choice is firmly established. The purpose of this review, therefore, is to remind microbiologists, particularly those new to continuous culture approaches, of the legacy of what I call the first age of continuous culture, and to explore a selection of researches that are using these techniques in this post-genomics age. The review looks at the impact of continuous culture across a comprehensive range of microbiological research and development. The ability to establish (quasi-) steady state conditions is a frequently stated advantage of continuous cultures thereby allowing environmental parameters to be manipulated without causing concomitant changes in the specific growth rate. However, the use of continuous cultures also enables the critical study of specified transition states and chemical, physical or biological perturbations. Such dynamic analyses enhance our understanding of microbial ecology and microbial pathology for example, and offer a wider scope for innovative drug discovery; they also can inform the optimization of batch and fed-batch operations that are characterized by sequential transitions states.", - "journal_title": "Journal of industrial microbiology & biotechnology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/20835748/" - } - ], - "18a8aa08-64fc-4903-8b57-b9b1a8b2f4e7": [ - { - "pub_id": "22689993", - "title": "Distinct DNA methylomes of newborns and centenarians.", - "authors": "Holger Heyn,Ning Li,Humberto J Ferreira,Sebastian Moran,David G Pisano,Antonio Gomez,Javier Diez,Jose V Sanchez-Mut,Fernando Setien,F Javier Carmona,Annibale A Puca,Sergi Sayols,Miguel A Pujana,Jordi Serra-Musach,Isabel Iglesias-Platas,Francesc Formiga,Agustin F Fernandez,Mario F Fraga,Simon C Heath,Alfonso Valencia,Ivo G Gut,Jun Wang,Manel Esteller", - "abstract": "Human aging cannot be fully understood in terms of the constrained genetic setting. Epigenetic drift is an alternative means of explaining age-associated alterations. To address this issue, we performed whole-genome bisulfite sequencing (WGBS) of newborn and centenarian genomes. The centenarian DNA had a lower DNA methylation content and a reduced correlation in the methylation status of neighboring cytosine--phosphate--guanine (CpGs) throughout the genome in comparison with the more homogeneously methylated newborn DNA. The more hypomethylated CpGs observed in the centenarian DNA compared with the neonate covered all genomic compartments, such as promoters, exonic, intronic, and intergenic regions. For regulatory regions, the most hypomethylated sequences in the centenarian DNA were present mainly at CpG-poor promoters and in tissue-specific genes, whereas a greater level of DNA methylation was observed in CpG island promoters. We extended the study to a larger cohort of newborn and nonagenarian samples using a 450,000 CpG-site DNA methylation microarray that reinforced the observation of more hypomethylated DNA sequences in the advanced age group. WGBS and 450,000 analyses of middle-age individuals demonstrated DNA methylomes in the crossroad between the newborn and the nonagenarian/centenarian groups. Our study constitutes a unique DNA methylation analysis of the extreme points of human life at a single-nucleotide resolution level.", - "journal_title": "Proceedings of the National Academy of Sciences of the United States of America", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/22689993/" - } - ], - "704b2d84-20df-49ba-a3be-43beac3070af": [ - { - "pub_id": "25565328", - "title": "Insights into the evolution of longevity from the bowhead whale genome.", - "authors": "Michael Keane,Jeremy Semeiks,Andrew E Webb,Yang I Li,V\u00edctor Quesada,Thomas Craig,Lone Bruhn Madsen,Sipko van Dam,David Brawand,Patr\u00edcia I Marques,Pawel Michalak,Lin Kang,Jong Bhak,Hyung-Soon Yim,Nick V Grishin,Nynne Hjort Nielsen,Mads Peter Heide-J\u00f8rgensen,Elias M Oziolor,Cole W Matson,George M Church,Gary W Stuart,John C Patton,J Craig George,Robert Suydam,Knud Larsen,Carlos L\u00f3pez-Ot\u00edn,Mary J O'Connell,John W Bickham,Bo Thomsen,Jo\u00e3o Pedro de Magalh\u00e3es", - "abstract": "The bowhead whale (Balaena mysticetus) is estimated to live over 200 years and is possibly the\u00a0longest-living mammal. These animals should possess protective molecular adaptations relevant to age-related diseases, particularly cancer. Here, we report the sequencing and comparative analysis of the bowhead whale genome and two transcriptomes from different populations. Our analysis identifies genes under positive selection and bowhead-specific mutations in genes linked to cancer and aging. In addition, we identify gene gain and loss involving genes associated with DNA repair, cell-cycle regulation, cancer, and aging. Our results expand our understanding of the evolution of mammalian longevity and suggest possible players involved in adaptive genetic changes conferring cancer resistance. We also found potentially relevant changes in genes related to additional processes, including thermoregulation, sensory perception, dietary adaptations, and immune response. Our data are made available online (http://www.bowhead-whale.org) to facilitate research in this long-lived species.", - "journal_title": "Cell reports", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/25565328/" - } - ], - "e165505a-b91d-44d1-8c5b-b187989711d3": [ - { - "pub_id": "29348681", - "title": "Impact of a five-dimensional framework on R&D productivity at AstraZeneca.", - "authors": "Paul Morgan,Dean G Brown,Simon Lennard,Mark J Anderton,J Carl Barrett,Ulf Eriksson,Mark Fidock,Bengt Hamr\u00e9n,Anthony Johnson,Ruth E March,James Matcham,Jerome Mettetal,David J Nicholls,Stefan Platz,Steve Rees,Michael A Snowden,Menelas N Pangalos", - "abstract": "In 2011, AstraZeneca embarked on a major revision of its research and development (R&D) strategy with the aim of improving R&D productivity, which was below industry averages in 2005-2010. A cornerstone of the revised strategy was to focus decision-making on five technical determinants (the right target, right tissue, right safety, right patient and right commercial potential). In this article, we describe the progress made using this '5R framework' in the hope that our experience could be useful to other companies tackling R&D productivity issues. We focus on the evolution of our approach to target validation, hit and lead optimization, pharmacokinetic/pharmacodynamic modelling and drug safety testing, which have helped improve the quality of candidate drug nomination, as well as the development of the right culture, where 'truth seeking' is encouraged by more rigorous and quantitative decision-making. We also discuss where the approach has failed and the lessons learned. Overall, the continued evolution and application of the 5R framework are beginning to have an impact, with success rates from candidate drug nomination to phase III completion improving from 4% in 2005-2010 to 19% in 2012-2016.", - "journal_title": "Nature reviews. Drug discovery", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/29348681/" - } - ], - "dbe60580-192b-414a-ade2-f816d8fc67e5": [ - { - "pub_id": "23496005", - "title": "Clinical, polysomnographic and genome-wide association analyses of narcolepsy with cataplexy: a European Narcolepsy Network study.", - "authors": "Gianina Luca,Jos\u00e9 Haba-Rubio,Yves Dauvilliers,Gert-Jan Lammers,Sebastiaan Overeem,Claire E Donjacour,Geert Mayer,Sirous Javidi,Alex Iranzo,Joan Santamaria,Rosa Peraita-Adrados,Hyun Hor,Zoltan Kutalik,Giuseppe Plazzi,Francesca Poli,Fabio Pizza,Isabelle Arnulf,Michel Lecendreux,Claudio Bassetti,Johannes Mathis,Raphael Heinzer,Poul Jennum,Stine Knudsen,Peter Geisler,Aleksandra Wierzbicka,Eva Feketeova,Corinne Pfister,Ramin Khatami,Christian Baumann,Mehdi Tafti, ", - "abstract": "The aim of this study was to describe the clinical and PSG characteristics of narcolepsy with cataplexy and their genetic predisposition by using the retrospective patient database of the European Narcolepsy Network (EU-NN). We have analysed retrospective data of 1099 patients with narcolepsy diagnosed according to International Classification of Sleep Disorders-2. Demographic and clinical characteristics, polysomnography and multiple sleep latency test data, hypocretin-1 levels, and genome-wide genotypes were available. We found a significantly lower age at sleepiness onset (men versus women: 23.74\u00a0\u00b1\u00a012.43 versus 21.49\u00a0\u00b1\u00a011.83, P\u00a0=\u00a00.003) and longer diagnostic delay in women (men versus women: 13.82\u00a0\u00b1\u00a013.79 versus 15.62\u00a0\u00b1\u00a014.94, P\u00a0=\u00a00.044). The mean diagnostic delay was 14.63\u00a0\u00b1\u00a014.31\u00a0years, and longer delay was associated with higher body mass index. The best predictors of short diagnostic delay were young age at diagnosis, cataplexy as the first symptom and higher frequency of cataplexy attacks. The mean multiple sleep latency negatively correlated with Epworth Sleepiness Scale (ESS) and with the number of sleep-onset rapid eye movement periods (SOREMPs), but none of the polysomnographic variables was associated with subjective or objective measures of sleepiness. Variant rs2859998 in UBXN2B gene showed a strong association (P\u00a0=\u00a01.28E-07) with the age at onset of excessive daytime sleepiness, and rs12425451 near the transcription factor TEAD4 (P\u00a0=\u00a01.97E-07) with the age at onset of cataplexy. Altogether, our results indicate that the diagnostic delay remains extremely long, age and gender substantially affect symptoms, and that a genetic predisposition affects the age at onset of symptoms.", - "journal_title": "Journal of sleep research", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/23496005/" - } - ], - "51448621-edf6-483d-8590-e7faab197b49": [ - { - "pub_id": "26758761", - "title": "Slowed aging during reproductive dormancy is reflected in genome-wide transcriptome changes in Drosophila melanogaster.", - "authors": "Lucie Ku\u010derov\u00e1,Olga I Kubrak,Jonas M Bengtsson,Hynek Strnad,S\u00f6ren Nylin,Ulrich Theopold,Dick R N\u00e4ssel", - "abstract": "In models extensively used in studies of aging and extended lifespan, such as C. elegans and Drosophila, adult senescence is regulated by gene networks that are likely to be similar to ones that underlie lifespan extension during dormancy. These include the evolutionarily conserved insulin/IGF, TOR and germ line-signaling pathways. Dormancy, also known as dauer stage in the larval worm or adult diapause in the fly, is triggered by adverse environmental conditions, and results in drastically extended lifespan with negligible senescence. It is furthermore characterized by increased stress resistance and somatic maintenance, developmental arrest and reallocated energy resources. In the fly Drosophila melanogaster adult reproductive diapause is additionally manifested in arrested ovary development, improved immune defense and altered metabolism. However, the molecular mechanisms behind this adaptive lifespan extension are not well understood. A genome wide analysis of transcript changes in diapausing D. melanogaster revealed a differential regulation of more than 4600 genes. Gene ontology (GO) and KEGG pathway analysis reveal that many of these genes are part of signaling pathways that regulate metabolism, stress responses, detoxification, immunity, protein synthesis and processes during aging. More specifically, gene readouts and detailed mapping of the pathways indicate downregulation of insulin-IGF (IIS), target of rapamycin (TOR) and MAP kinase signaling, whereas Toll-dependent immune signaling, Jun-N-terminal kinase (JNK) and Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathways are upregulated during diapause. Furthermore, we detected transcriptional regulation of a large number of genes specifically associated with aging and longevity. We find that many affected genes and signal pathways are shared between dormancy, aging and lifespan extension, including IIS, TOR, JAK/STAT and JNK. A substantial fraction of the genes affected by diapause have also been found to alter their expression in response to starvation and cold exposure in D. melanogaster, and the pathways overlap those reported in GO analysis of other invertebrates in dormancy or even hibernating mammals. Our study, thus, shows that D. melanogaster is a genetically tractable model for dormancy in other organisms and effects of dormancy on aging and lifespan.", - "journal_title": "BMC genomics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/26758761/" - } - ], - "d03b4942-3fe7-400a-a499-d3a1f1a979fc": [ - { - "pub_id": "27047754", - "title": "Attitudes towards personal genomics among older Swiss adults: An exploratory study.", - "authors": "Laura M\u00e4hlmann,Christina R\u00f6cke,Angela Brand,Ernst Hafen,Effy Vayena", - "abstract": "To explore attitudes of Swiss older adults towards personal genomics (PG). Using an anonymized voluntary paper-and-pencil survey, data were collected from 151 men and women aged 60-89\u00a0years attending the Seniorenuniversit\u00e4t Zurich, Switzerland (Seniors' University). Analyses were conducted using descriptive and inferential statistics. One third of the respondents were aware of PG, and more than half indicated interest in undergoing PG testing. The primary motivation provided was respondents' interest in finding out about their own disease risk, followed by willingness to contribute to scientific research. Forty-four percent were not interested in undergoing testing because results might be worrisome, or due to concerns about the validity of the results. Only a minority of respondents mentioned privacy-related concerns. Further, 66% were interested in undergoing clinic-based PG motivated by the opportunity to contribute to scientific research (78%) and 75% of all study participants indicated strong preferences to donate genomic data to public research institutions. This study indicates a relatively positive overall attitude towards personal genomic testing among older Swiss adults, a group not typically represented in surveys about personal genomics. Genomic data of older adults can be highly relevant to late life health and maintenance of quality of life. In addition they can be an invaluable source for better understanding of longevity, health and disease. Understanding the attitudes of this population towards genomic analyses, although important, remains under-examined.", - "journal_title": "Applied & translational genomics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/27047754/" - } - ], - "ab6a47ba-2131-4fc5-be5e-b81dd80d2a65": [ - { - "pub_id": "28834388", - "title": "Dry eye disease and oxidative stress.", - "authors": "Sophia Seen,Louis Tong", - "abstract": "Dry eye, an age-related condition, is a multifactorial disease of the tears and ocular surface that results in symptoms of discomfort, visual disturbance and tear film instability. Environmental factors are also often implicated in dry eye including exposure to pollutants, ultraviolet (UV) radiation and ozone as well as the chronic use of preserved eyedrops such as in the treatment of glaucoma. These factors increase oxidative stress and ocular surface inflammation. Here, we reviewed the cellular, animal and clinical studies that point to the role of oxidative stress in dry eye disease. The biomarkers used to indicate oxidative damage in ocular surface tissues include 8-hydroxy-2 deoxyguanosine (8-OHdG), 4-hydroxynonenal (HNE) and malondialdehyde (MDD). Antioxidative defences in the ocular surface occur in the form of tear proteins such as lactoferrin and S100A proteins, and enzymes such as superoxide dismutase (SOD), peroxidase, catalase and mitochondrial oxidative enzymes. An imbalance between the level of reactive oxygen species (ROS) and the action of protective enzymes will lead to oxidative damage, and possibly inflammation. A small number of interventional studies suggest that oxidative stress may be directly targeted in topical therapy of dry eye treatment. For example, in\u00a0vitro studies suggest that L-carnitine and pterostilbene, a blueberry component may reduce oxidative stress, and in animal studies, alpha-lipoic acid (ALP) and selenoprotein P may be helpful. Examples of treatments used in clinical trials include vitamin B12 eyedrops and iodide iontophoresis. With recent emphasis on ageing medicine and preventive holistic health, as well as the role of environmental science, research on oxidative stress in the ocular surface is likely to have increasing impact in the coming years.", - "journal_title": "Acta ophthalmologica", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/28834388/" - } - ], - "19578c9d-2f03-4ef0-86e8-2c79a5666815": [ - { - "pub_id": "21447998", - "title": "A genomic analysis of chronological longevity factors in budding yeast.", - "authors": "Christopher R Burtner,Christopher J Murakami,Brady Olsen,Brian K Kennedy,Matt Kaeberlein", - "abstract": "Chronological life span (CLS) has been studied as an aging paradigm in yeast. A few conserved aging genes have been identified that modulate both chronological and replicative longevity in yeast as well as longevity in the nematode Caenorhabditis elegans; however, a comprehensive analysis of the relationship between genetic control of chronological longevity and aging in other model systems has yet to be reported. To address this question, we performed a functional genomic analysis of chronological longevity for 550 single-gene deletion strains, which accounts for approximately 12% of the viable homozygous diploid deletion strains in the yeast ORF deletion collection. This study identified 33 previously unknown determinants of CLS. We found no significant enrichment for enhanced CLS among deletions corresponding to yeast orthologs of worm aging genes or among replicatively long-lived deletion strains, although a trend toward overlap was noted. In contrast, a subset of gene deletions identified from a screen for reduced acidification of culture media during growth to stationary phase was enriched for increased CLS. These results suggest that genetic control of CLS under the most commonly utilized assay conditions does not strongly overlap with longevity determinants in C. elegans, with the existing confined to a small number of genetic pathways. These data also further support the model that acidification of the culture medium plays an important role in survival during chronological aging in synthetic medium, and suggest that chronological aging studies using alternate medium conditions may be more informative with regard to aging of multicellular eukaryotes.", - "journal_title": "Cell cycle (Georgetown, Tex.)", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/21447998/" - } - ], - "37d7c321-8967-44f4-b7c0-e1f1f2a5ce9f": [ - { - "pub_id": "24362405", - "title": "Regulation of type I interferon responses.", - "authors": "Lionel B Ivashkiv,Laura T Donlin", - "abstract": "Type I interferons (IFNs) activate intracellular antimicrobial programmes and influence the development of innate and adaptive immune responses. Canonical type I IFN signalling activates the Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway, leading to transcription of IFN-stimulated genes (ISGs). Host, pathogen and environmental factors regulate the responses of cells to this signalling pathway and thus calibrate host defences while limiting tissue damage and preventing autoimmunity. Here, we summarize the signalling and epigenetic mechanisms that regulate type I IFN-induced STAT activation and ISG transcription and translation. These regulatory mechanisms determine the biological outcomes of type I IFN responses and whether pathogens are cleared effectively or chronic infection or autoimmune disease ensues.", - "journal_title": "Nature reviews. Immunology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/24362405/" - } - ], - "f3c57cf2-da42-4833-ab8d-99517f987aea": [ - { - "pub_id": "23796365", - "title": "Polar body biopsy.", - "authors": "Markus Montag,Maria K\u00f6ster,Thomas Strowitzki,Bettina Toth", - "abstract": "Polar body biopsy combined with array comparative genomic hybridization allows detection of maternal chromosomal aberrations. Although it has limitations, it can be seen as an alternative to blastomere and trophectoderm biopsy.", - "journal_title": "Fertility and sterility", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/23796365/" - } - ], - "853d242b-8c12-49f6-a89a-abc5a89f96d1": [ - { - "pub_id": "31891019", - "title": "Structural and Functional Analysis of human lung cancer risk associated hOGG1 variant Ser326Cys in DNA repair gene by molecular dynamics simulation.", - "authors": "Zainularifeen Abduljaleel", - "abstract": "Oxidative damaged DNA base lesions are repaired through human 8-oxoguanine DNA glycosylase gene (hOGG1) mediated pathways. A recent report based on the meta-analysis has suggested that the DNA Repair Gene hOGG1 variant Ser326Cys [3p26.2; allele S/C in nucleotide position \u03b1Helix2 Ser\u21d2Cys326] was associated with Lung Cancer risk in Caucasian population will alter the level Zhong et al., 2012. To the best of our knowledge, there has not been any such comprehensive in-silico investigation that validates the functional and structural impact of non-synonymous Lung Cancer Risk Associated Protein Domain (LCRAPD) mutation Ser326Cys (rs1052133) by molecular dynamics (MD) simulation approach following prediction of hOGG1 protein before and after the mutation. Further to the native and mutant protein structures, the amino acid residue and its secondary structure were observed through a solvent accessibility model for protein stability confirmation at the point of mutation. Taken together, this study suggests that the protein functional and structural studies could be a reasonable approach for investigating the impact of nsSNPs in future studies. In addition, 4295 patients samples incorporate with the analysis that genomic data types from cBioPortal. In the result, 4295 cases (91.5%) had alterations in all genes but the frequency of alterations in our targeted hOGG1 gene was shown with and without case alteration in the ratio (Logrank Test P-Value: 0.670) Kaplan-Meier by the number of patients at risk of the survival function.", - "journal_title": "Non-coding RNA research", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/31891019/" - } - ], - "1b0d41a8-0da5-415e-9a68-60356cb15d79": [ - { - "pub_id": "21233167", - "title": "AGE: defining breakpoints of genomic structural variants at single-nucleotide resolution, through optimal alignments with gap excision.", - "authors": "Alexej Abyzov,Mark Gerstein", - "abstract": "Defining the precise location of structural variations (SVs) at single-nucleotide breakpoint resolution is an important problem, as it is a prerequisite for classifying SVs, evaluating their functional impact and reconstructing personal genome sequences. Given approximate breakpoint locations and a bridging assembly or split read, the problem essentially reduces to finding a correct sequence alignment. Classical algorithms for alignment and their generalizations guarantee finding the optimal (in terms of scoring) global or local alignment of two sequences. However, they cannot generally be applied to finding the biologically correct alignment of genomic sequences containing SVs because of the need to simultaneously span the SV (e.g. make a large gap) and perform precise local alignments at the flanking ends. Here, we formulate the computations involved in this problem and describe a dynamic-programming algorithm for its solution. Specifically, our algorithm, called AGE for Alignment with Gap Excision, finds the optimal solution by simultaneously aligning the 5' and 3' ends of two given sequences and introducing a 'large-gap jump' between the local end alignments to maximize the total alignment score. We also describe extensions allowing the application of AGE to tandem duplications, inversions and complex events involving two large gaps. We develop a memory-efficient implementation of AGE (allowing application to long contigs) and make it available as a downloadable software package. Finally, we applied AGE for breakpoint determination and standardization in the 1000 Genomes Project by aligning locally assembled contigs to the human genome. AGE is freely available at http://sv.gersteinlab.org/age.", - "journal_title": "Bioinformatics (Oxford, England)", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/21233167/" - } - ], - "b3345afc-b81b-4eb6-8cea-cfa7e1ce8930": [ - { - "pub_id": "23738518", - "title": "A genome-wide association study for reading and language abilities in two population cohorts.", - "authors": "M Luciano,D M Evans,N K Hansell,S E Medland,G W Montgomery,N G Martin,M J Wright,T C Bates", - "abstract": "Candidate genes have been identified for both reading and language, but most of the heritable variance in these traits remains unexplained. Here, we report a genome-wide association meta-analysis of two large cohorts: population samples of Australian twins and siblings aged 12-25\u2009years (n\u2009=\u20091177 from 538 families), and a younger cohort of children of the UK Avon Longitudinal Study of Parents and their Children (aged 8 and 9\u2009years; maximum n\u2009=\u20095472). Suggestive association was indicated for reading measures and non-word repetition (NWR), with the greatest support found for single nucleotide polymorphisms (SNPs) in the pseudogene, ABCC13 (P\u2009=\u20097.34\u2009\u00d7\u200910(-8)), and the gene, DAZAP1 (P\u2009=\u20091.32\u2009\u00d7\u200910(-6)). Gene-based analyses showed significant association (P\u2009<\u20092.8\u2009\u00d7\u200910(-6)) for reading and spelling with genes CD2L1, CDC2L2 and RCAN3 in two loci on chromosome 1. Some support was found for the same SNPs having effects on both reading skill and NWR, which is compatible with behavior genetic evidence for influences of reading acquisition on phonological-task performance. The results implicate novel candidates for study in additional cohorts for reading and language abilities.", - "journal_title": "Genes, brain, and behavior", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/23738518/" - } - ], - "1d770027-0c56-4466-84dd-e22d9a5db1f4": [ - { - "pub_id": "25747401", - "title": "Lamins: nuclear intermediate filament proteins with fundamental functions in nuclear mechanics and genome regulation.", - "authors": "Yosef Gruenbaum,Roland Foisner", - "abstract": "Lamins are intermediate filament proteins that form a scaffold, termed nuclear lamina, at the nuclear periphery. A small fraction of lamins also localize throughout the nucleoplasm. Lamins bind to a growing number of nuclear protein complexes and are implicated in both nuclear and cytoskeletal organization, mechanical stability, chromatin organization, gene regulation, genome stability, differentiation, and tissue-specific functions. The lamin-based complexes and their specific functions also provide insights into possible disease mechanisms for human laminopathies, ranging from muscular dystrophy to accelerated aging, as observed in Hutchinson-Gilford progeria and atypical Werner syndromes.", - "journal_title": "Annual review of biochemistry", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/25747401/" - } - ], - "f251fa79-021a-43e2-bae0-c143da964657": [ - { - "pub_id": "26867640", - "title": "Effects of aging on the male reproductive system.", - "authors": "Sezgin Gunes,Gulgez Neslihan Taskurt Hekim,Mehmet Alper Arslan,Ramazan Asci", - "abstract": "The study aims to discuss the effects of aging on the male reproductive system. A systematic review was performed using PubMed from 1980 to 2014. Aging is a natural process comprising of irreversible changes due to a myriad of endogenous and environmental factors at the level of all organs and systems. In modern life, as more couples choose to postpone having a child due to various socioeconomic reasons, research for understanding the effects of aging on the reproductive system has gained an increased importance. Paternal aging also causes genetic and epigenetic changes in spermatozoa, which impair male reproductive functions through their adverse effects on sperm quality and count as, well as, on sexual organs and the hypothalamic-pituitary-gonadal axis. Hormone production, spermatogenesis, and testes undergo changes as a man ages. These small changes lead to decrease in both the quality and quantity of spermatozoa. The offspring of older fathers show high prevalence of genetic abnormalities, childhood cancers, and several neuropsychiatric disorders. In addition, the latest advances in assisted reproductive techniques give older men a chance to have a child even with poor semen parameters. Further studies should investigate the onset of gonadal senesce and its effects on aging men.", - "journal_title": "Journal of assisted reproduction and genetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/26867640/" - } - ], - "a9d0369f-c2bd-49f0-9053-3ece8d05d44c": [ - { - "pub_id": "27572652", - "title": "Bacterial genomics: Microbial GWAS coming of age.", - "authors": "Daniel Falush", - "abstract": "", - "journal_title": "Nature microbiology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/27572652/" - } - ], - "4ea59e0f-e254-4988-a69f-6c5d251fa174": [ - { - "pub_id": "23034122", - "title": "Aging effects on DNA methylation modules in human brain and blood tissue.", - "authors": "Steve Horvath,Yafeng Zhang,Peter Langfelder,Ren\u00e9 S Kahn,Marco P M Boks,Kristel van Eijk,Leonard H van den Berg,Roel A Ophoff", - "abstract": "Several recent studies reported aging effects on DNA methylation levels of individual CpG dinucleotides. But it is not yet known whether aging-related consensus modules, in the form of clusters of correlated CpG markers, can be found that are present in multiple human tissues. Such a module could facilitate the understanding of aging effects on multiple tissues. We therefore employed weighted correlation network analysis of 2,442 Illumina DNA methylation arrays from brain and blood tissues, which enabled the identification of an age-related co-methylation module. Module preservation analysis confirmed that this module can also be found in diverse independent data sets. Biological evaluation showed that module membership is associated with Polycomb group target occupancy counts, CpG island status and autosomal chromosome location. Functional enrichment analysis revealed that the aging-related consensus module comprises genes that are involved in nervous system development, neuron differentiation and neurogenesis, and that it contains promoter CpGs of genes known to be down-regulated in early Alzheimer's disease. A comparison with a standard, non-module based meta-analysis revealed that selecting CpGs based on module membership leads to significantly increased gene ontology enrichment, thus demonstrating that studying aging effects via consensus network analysis enhances the biological insights gained. Overall, our analysis revealed a robustly defined age-related co-methylation module that is present in multiple human tissues, including blood and brain. We conclude that blood is a promising surrogate for brain tissue when studying the effects of age on DNA methylation profiles.", - "journal_title": "Genome biology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/23034122/" - } - ], - "5bc7fbd4-c0b9-46d3-bb3b-aba3f61374fb": [ - { - "pub_id": "22313689", - "title": "Oxidative genome damage and its repair: implications in aging and neurodegenerative diseases.", - "authors": "Muralidhar L Hegde,Anil K Mantha,Tapas K Hazra,Kishor K Bhakat,Sankar Mitra,Bartosz Szczesny", - "abstract": "Reactive oxygen species (ROS), generated endogenously during respiration or exogenously by genotoxic agents, induce oxidized bases and single-strand breaks (SSBs) in DNA that are repaired via the base excision/SSB repair (BER/SSBR) pathway in both the nucleus and mitochondria. Tightly regulated BER/SSBR with multiple sub-pathways is highly complex, and is linked to the replication and transcription. The repair-initiating DNA glycosylases (DGs) or AP-endonuclease (APE1) control the sub-pathway by stably interacting with downstream proteins usually via their common interacting domain (CID). A nonconserved CID with disordered structure usually located at one of the termini includes the sequences for covalent modifications and/or organelle targeting. While the DGs are individually dispensable, the SSBR-initiating APE1 and polynucleotide kinase 3' phosphatase (PNKP) are essential. BER/SSBR of mammalian nuclear and mitochondrial genomes share the same early enzymes. Accumulation of oxidative damage in nuclear and mitochondrial genomes has been implicated in aging and various neurological disorders. While defects in BER/SSBR proteins have been linked to hereditary neurodegenerative diseases, our recent studies implicated transition metal-induced inhibition of NEIL family DGs in sporadic diseases. This review focuses on the recent advances in repair of oxidatively damages in mammalian genomes and their linkage to aging and neurological disorders.", - "journal_title": "Mechanisms of ageing and development", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/22313689/" - } - ], - "a50460cc-c759-4d59-880a-2f1238136b1b": [ - { - "pub_id": "25631445", - "title": "Comprehensive genomic characterization of head and neck squamous cell carcinomas.", - "authors": " ", - "abstract": "The Cancer Genome Atlas profiled 279 head and neck squamous cell carcinomas (HNSCCs) to provide a comprehensive landscape of somatic genomic alterations. Here we show that human-papillomavirus-associated tumours are dominated by helical domain mutations of the oncogene PIK3CA, novel alterations involving loss of TRAF3, and amplification of the cell cycle gene E2F1. Smoking-related HNSCCs demonstrate near universal loss-of-function TP53 mutations and CDKN2A inactivation with frequent copy number alterations including amplification of 3q26/28 and 11q13/22. A subgroup of oral cavity tumours with favourable clinical outcomes displayed infrequent copy number alterations in conjunction with activating mutations of HRAS or PIK3CA, coupled with inactivating mutations of CASP8, NOTCH1 and TP53. Other distinct subgroups contained loss-of-function alterations of the chromatin modifier NSD1, WNT pathway genes AJUBA and FAT1, and activation of oxidative stress factor NFE2L2, mainly in laryngeal tumours. Therapeutic candidate alterations were identified in most HNSCCs.", - "journal_title": "Nature", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/25631445/" - } - ], - "52c7f16a-71e5-4ae7-b932-87c1099b7571": [ - { - "pub_id": "21569623", - "title": "The nature, scope and impact of genomic prediction in beef cattle in the United States.", - "authors": "Dorian J Garrick", - "abstract": "Artificial selection has proven to be effective at altering the performance of animal production systems. Nevertheless, selection based on assessment of the genetic superiority of candidates is suboptimal as a result of errors in the prediction of genetic merit. Conventional breeding programs may extend phenotypic measurements on selection candidates to include correlated indicator traits, or delay selection decisions well beyond puberty so that phenotypic performance can be observed on progeny or other relatives. Extending the generation interval to increase the accuracy of selection reduces annual rates of gain compared to accurate selection and use of parents of the next generation at the immediate time they reach breeding age. Genomic prediction aims at reducing prediction errors at breeding age by exploiting information on the transmission of chromosome fragments from parents to selection candidates, in conjunction with knowledge on the value of every chromosome fragment. For genomic prediction to influence beef cattle breeding programs and the rate or cost of genetic gains, training analyses must be undertaken, and genomic prediction tools made available for breeders and other industry stakeholders. This paper reviews the nature or kind of studies currently underway, the scope or extent of some of those studies, and comments on the likely predictive value of genomic information for beef cattle improvement.", - "journal_title": "Genetics, selection, evolution : GSE", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/21569623/" - } - ], - "57e13f29-e003-4802-a8a3-93f75390b8b3": [ - { - "pub_id": "37056479", - "title": "Association of biological sex with clinical outcomes and biomarkers of Alzheimer's disease in adults with Down syndrome.", - "authors": "M Florencia Iulita,Alexandre Bejanin,Eduard Vilaplana,Maria Carmona-Iragui,Bessy Benejam,Laura Videla,Isabel Barroeta,Susana Fern\u00e1ndez,Miren Altuna,Jordi Pegueroles,Victor Montal,Silvia Valldeneu,Sandra Gim\u00e9nez,Sof\u00eda Gonz\u00e1lez-Ortiz,Soraya Torres,Shaimaa El Bounasri El Bennadi,Concepcion Padilla,Mateus Rozalem Aranha,Teresa Estell\u00e9s,Ignacio Ill\u00e1n-Gala,Olivia Belbin,Natalia Valle-Tamayo,Valle Camacho,Esther Blessing,Ricardo S Osorio,Sebastian Videla,Sylvain Lehmann,Anthony J Holland,Henrik Zetterberg,Kaj Blennow,Daniel Alcolea,Jordi Clarim\u00f3n,Shahid H Zaman,Rafael Blesa,Alberto Lle\u00f3,Juan Fortea", - "abstract": "The study of sex differences in Alzheimer's disease is increasingly recognized as a key priority in research and clinical development. People with Down syndrome represent the largest population with a genetic link to Alzheimer's disease (>90% in the 7th decade). Yet, sex differences in Alzheimer's disease manifestations have not been fully investigated in these individuals, who are key candidates for preventive clinical trials. In this double-centre, cross-sectional study of 628 adults with Down syndrome [46% female, 44.4 (34.6; 50.7) years], we compared Alzheimer's disease prevalence, as well as cognitive outcomes and AT(N) biomarkers across age and sex. Participants were recruited from a population-based health plan in Barcelona, Spain, and from a convenience sample recruited via services for people with intellectual disabilities in England and Scotland. They underwent assessment with the Cambridge Cognitive Examination for Older Adults with Down Syndrome, modified cued recall test and determinations of brain amyloidosis (CSF amyloid-\u03b2 42 / 40 and amyloid-PET), tau pathology (CSF and plasma phosphorylated-tau181) and neurodegeneration biomarkers (CSF and plasma neurofilament light, total-tau, fluorodeoxyglucose-PET and MRI). We used within-group locally estimated scatterplot smoothing models to compare the trajectory of biomarker changes with age in females versus males, as well as by apolipoprotein \u025b4 carriership. Our work revealed similar prevalence, age at diagnosis and Cambridge Cognitive Examination for Older Adults with Down Syndrome scores by sex, but males showed lower modified cued recall test scores from age 45 compared with females. AT(N) biomarkers were comparable in males and females. When considering apolipoprotein \u025b4, female \u025b4 carriers showed a 3-year earlier age at diagnosis compared with female non-carriers (50.5 versus 53.2 years, <i>P</i> = 0.01). This difference was not seen in males (52.2 versus 52.5 years, <i>P</i> = 0.76). Our exploratory analyses considering sex, apolipoprotein \u025b4 and biomarkers showed that female \u025b4 carriers tended to exhibit lower CSF amyloid-\u03b2 42/amyloid-\u03b2 40 ratios and lower hippocampal volume compared with females without this allele, in line with the clinical difference. This work showed that biological sex did not influence clinical and biomarker profiles of Alzheimer's disease in adults with Down syndrome. Consideration of apolipoprotein \u025b4 haplotype, particularly in females, may be important for clinical research and clinical trials that consider this population. Accounting for, reporting and publishing sex-stratified data, even when no sex differences are found, is central to helping advance precision medicine.", - "journal_title": "Brain communications", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/37056479/" - } - ], - "f0023238-b0f5-476f-a7dd-76f79f7b4719": [ - { - "pub_id": "21813020", - "title": "Mitochondrial genome deletions and minicircles are common in lice (Insecta: Phthiraptera).", - "authors": "Stephen L Cameron,Kazunori Yoshizawa,Atsushi Mizukoshi,Michael F Whiting,Kevin P Johnson", - "abstract": "The gene composition, gene order and structure of the mitochondrial genome are remarkably stable across bilaterian animals. Lice (Insecta: Phthiraptera) are a major exception to this genomic stability in that the canonical single chromosome with 37 genes found in almost all other bilaterians has been lost in multiple lineages in favour of multiple, minicircular chromosomes with less than 37 genes on each chromosome. Minicircular mt genomes are found in six of the ten louse species examined to date and three types of minicircles were identified: heteroplasmic minicircles which coexist with full sized mt genomes (type 1); multigene chromosomes with short, simple control regions, we infer that the genome consists of several such chromosomes (type 2); and multiple, single to three gene chromosomes with large, complex control regions (type 3). Mapping minicircle types onto a phylogenetic tree of lice fails to show a pattern of their occurrence consistent with an evolutionary series of minicircle types. Analysis of the nuclear-encoded, mitochondrially-targetted genes inferred from the body louse, Pediculus, suggests that the loss of mitochondrial single-stranded binding protein (mtSSB) may be responsible for the presence of minicircles in at least species with the most derived type 3 minicircles (Pediculus, Damalinia). Minicircular mt genomes are common in lice and appear to have arisen multiple times within the group. Life history adaptive explanations which attribute minicircular mt genomes in lice to the adoption of blood-feeding in the Anoplura are not supported by this expanded data set as minicircles are found in multiple non-blood feeding louse groups but are not found in the blood-feeding genus Heterodoxus. In contrast, a mechanist explanation based on the loss of mtSSB suggests that minicircles may be selectively favoured due to the incapacity of the mt replisome to synthesize long replicative products without mtSSB and thus the loss of this gene lead to the formation of minicircles in lice.", - "journal_title": "BMC genomics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/21813020/" - } - ], - "803004df-ea88-4a7d-b1db-3cef30cf1f62": [ - { - "pub_id": "27528664", - "title": "Genome-wide quantification of rare somatic mutations in normal human tissues using massively parallel sequencing.", - "authors": "Margaret L Hoang,Isaac Kinde,Cristian Tomasetti,K Wyatt McMahon,Thomas A Rosenquist,Arthur P Grollman,Kenneth W Kinzler,Bert Vogelstein,Nickolas Papadopoulos", - "abstract": "We present the bottleneck sequencing system (BotSeqS), a next-generation sequencing method that simultaneously quantifies rare somatic point mutations across the mitochondrial and nuclear genomes. BotSeqS combines molecular barcoding with a simple dilution step immediately before library amplification. We use BotSeqS to show age- and tissue-dependent accumulations of rare mutations and demonstrate that somatic mutational burden in normal human tissues can vary by several orders of magnitude, depending on biologic and environmental factors. We further show major differences between the mutational patterns of the mitochondrial and nuclear genomes in normal tissues. Lastly, the mutation spectra of normal tissues were different from each other, but similar to those of the cancers that arose in them. This technology can provide insights into the number and nature of genetic alterations in normal tissues and can be used to address a variety of fundamental questions about the genomes of diseased tissues.", - "journal_title": "Proceedings of the National Academy of Sciences of the United States of America", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/27528664/" - } - ], - "a6d53b68-dbe7-464f-91dc-2750d78cce93": [ - { - "pub_id": "27306145", - "title": "Population genomic structure and linkage disequilibrium analysis of South African goat breeds using genome-wide SNP data.", - "authors": "K Mdladla,E F Dzomba,H J Huson,F C Muchadeyi", - "abstract": "The sustainability of goat farming in marginal areas of southern Africa depends on local breeds that are adapted to specific agro-ecological conditions. Unimproved non-descript goats are the main genetic resources used for the development of commercial meat-type breeds of South Africa. Little is known about genetic diversity and the genetics of adaptation of these indigenous goat populations. This study investigated the genetic diversity, population structure and breed relations, linkage disequilibrium, effective population size and persistence of gametic phase in goat populations of South Africa. Three locally developed meat-type breeds of the Boer (n\u00a0=\u00a033), Savanna (n\u00a0=\u00a031), Kalahari Red (n\u00a0=\u00a040), a feral breed of Tankwa (n\u00a0=\u00a025) and unimproved non-descript village ecotypes (n\u00a0=\u00a0110) from four goat-producing provinces of the Eastern Cape, KwaZulu-Natal, Limpopo and North West were assessed using the Illumina Goat 50K SNP Bead Chip assay. The proportion of SNPs with minor allele frequencies >0.05 ranged from 84.22% in the Tankwa to 97.58% in the Xhosa ecotype, with a mean of 0.32\u00a0\u00b1\u00a00.13 across populations. Principal components analysis, admixture and pairwise FST identified Tankwa as a genetically distinct population and supported clustering of the populations according to their historical origins. Genome-wide FST identified 101 markers potentially under positive selection in the Tankwa. Average linkage disequilibrium was highest in the Tankwa (r(2) \u00a0=\u00a00.25\u00a0\u00b1\u00a00.26) and lowest in the village ecotypes (r(2) range\u00a0=\u00a00.09\u00a0\u00b1\u00a00.12 to 0.11\u00a0\u00b1\u00a00.14). We observed an effective population size of <150 for all populations 13 generations ago. The estimated correlations for all breed pairs were lower than 0.80 at marker distances >100\u00a0kb with the exception of those in Savanna and Tswana populations. This study highlights the high level of genetic diversity in South African indigenous goats as well as the utility of the genome-wide SNP marker panels in genetic studies of these populations.", - "journal_title": "Animal genetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/27306145/" - } - ], - "74f7aec5-e757-428b-8d8c-a72ec47a6164": [ - { - "pub_id": "23633909", - "title": "Genomics and genetics of aging.", - "authors": "Matt Kaeberlein", - "abstract": "", - "journal_title": "Current genomics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/23633909/" - } - ], - "26c9a758-1768-44bc-8fc2-2998a62bfe47": [ - { - "pub_id": "25648963", - "title": "Genome-wide studies of verbal declarative memory in nondemented older people: the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium.", - "authors": "St\u00e9phanie Debette,Carla A Ibrahim Verbaas,Jan Bressler,Maaike Schuur,Albert Smith,Joshua C Bis,Gail Davies,Christiane Wolf,Vilmundur Gudnason,Lori B Chibnik,Qiong Yang,Anita L deStefano,Dominique J F de Quervain,Velandai Srikanth,Jari Lahti,Hans J Grabe,Jennifer A Smith,Lutz Priebe,Lei Yu,Nazanin Karbalai,Caroline Hayward,James F Wilson,Harry Campbell,Katja Petrovic,Myriam Fornage,Ganesh Chauhan,Robin Yeo,Ruth Boxall,James Becker,Oliver Stegle,Karen A Mather,Vincent Chouraki,Qi Sun,Lynda M Rose,Susan Resnick,Christopher Oldmeadow,Mirna Kirin,Alan F Wright,Maria K Jonsdottir,Rhoda Au,Albert Becker,Najaf Amin,Mike A Nalls,Stephen T Turner,Sharon L R Kardia,Ben Oostra,Gwen Windham,Laura H Coker,Wei Zhao,David S Knopman,Gerardo Heiss,Michael E Griswold,Rebecca F Gottesman,Veronique Vitart,Nicholas D Hastie,Lina Zgaga,Igor Rudan,Ozren Polasek,Elizabeth G Holliday,Peter Schofield,Seung Hoan Choi,Toshiko Tanaka,Yang An,Rodney T Perry,Richard E Kennedy,Mich\u00e8le M Sale,Jing Wang,Virginia G Wadley,David C Liewald,Paul M Ridker,Alan J Gow,Alison Pattie,John M Starr,David Porteous,Xuan Liu,Russell Thomson,Nicola J Armstrong,Gudny Eiriksdottir,Arezoo A Assareh,Nicole A Kochan,Elisabeth Widen,Aarno Palotie,Yi-Chen Hsieh,Johan G Eriksson,Christian Vogler,John C van Swieten,Joshua M Shulman,Alexa Beiser,Jerome Rotter,Carsten O Schmidt,Wolfgang Hoffmann,Markus M N\u00f6then,Luigi Ferrucci,John Attia,Andre G Uitterlinden,Philippe Amouyel,Jean-Fran\u00e7ois Dartigues,H\u00e9l\u00e8ne Amieva,Katri R\u00e4ikk\u00f6nen,Melissa Garcia,Philip A Wolf,Albert Hofman,W T Longstreth,Bruce M Psaty,Eric Boerwinkle,Philip L DeJager,Perminder S Sachdev,Reinhold Schmidt,Monique M B Breteler,Alexander Teumer,Oscar L Lopez,Sven Cichon,Daniel I Chasman,Francine Grodstein,Bertram M\u00fcller-Myhsok,Christophe Tzourio,Andreas Papassotiropoulos,David A Bennett,M Arfan Ikram,Ian J Deary,Cornelia M van Duijn,Lenore Launer,Annette L Fitzpatrick,Sudha Seshadri,Thomas H Mosley, ", - "abstract": "Memory performance in older persons can reflect genetic influences on cognitive function and dementing processes. We aimed to identify genetic contributions to verbal declarative memory in a community setting. We conducted genome-wide association studies for paragraph or word list delayed recall in 19 cohorts from the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium, comprising 29,076 dementia- and stroke-free individuals of European descent, aged \u226545 years. Replication of suggestive associations (p < 5 \u00d7 10(-6)) was sought in 10,617 participants of European descent, 3811 African-Americans, and 1561 young adults. rs4420638, near APOE, was associated with poorer delayed recall performance in discovery (p = 5.57 \u00d7 10(-10)) and replication cohorts (p = 5.65 \u00d7 10(-8)). This association was stronger for paragraph than word list delayed recall and in the oldest persons. Two associations with specific tests, in subsets of the total sample, reached genome-wide significance in combined analyses of discovery and replication (rs11074779 [HS3ST4], p = 3.11 \u00d7 10(-8), and rs6813517 [SPOCK3], p = 2.58 \u00d7 10(-8)) near genes involved in immune response. A genetic score combining 58 independent suggestive memory risk variants was associated with increasing Alzheimer disease pathology in 725 autopsy samples. Association of memory risk loci with gene expression in 138 human hippocampus samples showed cis-associations with WDR48 and CLDN5, both related to ubiquitin metabolism. This largest study to date exploring the genetics of memory function in ~40,000 older individuals revealed genome-wide associations and suggested an involvement of immune and ubiquitin pathways.", - "journal_title": "Biological psychiatry", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/25648963/" - } - ], - "b69beead-2813-4ee2-a93c-f9e2210b1072": [ - { - "pub_id": "26132940", - "title": "Somatic Mutations and Clonal Hematopoiesis in Aplastic Anemia.", - "authors": "Tetsuichi Yoshizato,Bogdan Dumitriu,Kohei Hosokawa,Hideki Makishima,Kenichi Yoshida,Danielle Townsley,Aiko Sato-Otsubo,Yusuke Sato,Delong Liu,Hiromichi Suzuki,Colin O Wu,Yuichi Shiraishi,Michael J Clemente,Keisuke Kataoka,Yusuke Shiozawa,Yusuke Okuno,Kenichi Chiba,Hiroko Tanaka,Yasunobu Nagata,Takamasa Katagiri,Ayana Kon,Masashi Sanada,Phillip Scheinberg,Satoru Miyano,Jaroslaw P Maciejewski,Shinji Nakao,Neal S Young,Seishi Ogawa", - "abstract": "In patients with acquired aplastic anemia, destruction of hematopoietic cells by the immune system leads to pancytopenia. Patients have a response to immunosuppressive therapy, but myelodysplastic syndromes and acute myeloid leukemia develop in about 15% of the patients, usually many months to years after the diagnosis of aplastic anemia. We performed next-generation sequencing and array-based karyotyping using 668 blood samples obtained from 439 patients with aplastic anemia. We analyzed serial samples obtained from 82 patients. Somatic mutations in myeloid cancer candidate genes were present in one third of the patients, in a limited number of genes and at low initial variant allele frequency. Clonal hematopoiesis was detected in 47% of the patients, most frequently as acquired mutations. The prevalence of the mutations increased with age, and mutations had an age-related signature. DNMT3A-mutated and ASXL1-mutated clones tended to increase in size over time; the size of BCOR- and BCORL1-mutated and PIGA-mutated clones decreased or remained stable. Mutations in PIGA and BCOR and BCORL1 correlated with a better response to immunosuppressive therapy and longer and a higher rate of overall and progression-free survival; mutations in a subgroup of genes that included DNMT3A and ASXL1 were associated with worse outcomes. However, clonal dynamics were highly variable and might not necessarily have predicted the response to therapy and long-term survival among individual patients. Clonal hematopoiesis was prevalent in aplastic anemia. Some mutations were related to clinical outcomes. A highly biased set of mutations is evidence of Darwinian selection in the failed bone marrow environment. The pattern of somatic clones in individual patients over time was variable and frequently unpredictable. (Funded by Grant-in-Aid for Scientific Research and others.).", - "journal_title": "The New England journal of medicine", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/26132940/" - } - ], - "de13986a-50d9-4ba7-a12a-97bddf774ba9": [ - { - "pub_id": "26514200", - "title": "Genome Integrity in Aging: Human Syndromes, Mouse Models, and Therapeutic Options.", - "authors": "Wilbert P Vermeij,Jan H J Hoeijmakers,Joris Pothof", - "abstract": "Human syndromes and mouse mutants that exhibit accelerated but bona fide aging in multiple organs and tissues have been invaluable for the identification of nine denominators of aging: telomere attrition, genome instability, epigenetic alterations, mitochondrial dysfunction, deregulated nutrient sensing, altered intercellular communication, loss of proteostasis, cellular senescence and adult stem cell exhaustion. However, whether and how these instigators of aging interrelate or whether they have one root cause is currently largely unknown. Rare human progeroid syndromes and corresponding mouse mutants with resolved genetic defects highlight the dominant importance of genome maintenance for aging. A second class of aging-related disorders reveals a cross connection with metabolism. As genome maintenance and metabolism are closely interconnected, they may constitute the main underlying biology of aging. This review focuses on the role of genome stability in aging, its crosstalk with metabolism, and options for nutritional and/or pharmaceutical interventions that delay age-related pathology.", - "journal_title": "Annual review of pharmacology and toxicology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/26514200/" - } - ], - "c1df5fa6-1d3b-4085-9248-683c9666faa5": [ - { - "pub_id": "23633911", - "title": "Genome-Wide RNAi Longevity Screens in Caenorhabditis elegans.", - "authors": "Melana E Yanos,Christopher F Bennett,Matt Kaeberlein", - "abstract": "Progress in aging research has identified genetic and environmental factors that regulate longevity across species. The nematode worm Caenorhabditis elegans is a genetically tractable model system that has been widely used to investigate the molecular mechanisms of aging, and the development of RNA interference (RNAi) technology has provided a powerful tool for performing large-scale genetic screens in this organism. Genome-wide screens have identified hundreds of genes that influence lifespan, many of which fall into distinct functional classes and pathways. The purpose of this review is to summarize the results of large-scale RNAi longevity screens in C. elegans, and to provide an in-depth comparison and analysis of their methodology and most significant findings.", - "journal_title": "Current genomics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/23633911/" - } - ], - "d31cd645-82d6-4f06-b766-50d334ec6d5b": [ - { - "pub_id": "21427290", - "title": "Genome-wide promoter DNA methylation dynamics of human hematopoietic progenitor cells during differentiation and aging.", - "authors": "Michael T Bocker,Isabelle Hellwig,Achim Breiling,Volker Eckstein,Anthony D Ho,Frank Lyko", - "abstract": "DNA methylation plays an important role in the self-renewal of hematopoietic stem cells and in the commitment to the lymphoid or myeloid lineages. Using purified CD34\u207a hematopoietic progenitor cells and differentiated myeloid cell populations from the same human samples, we obtained detailed methylation profiles at distinct stages of hematopoiesis. We identified a defined set of differentiation-related genes that are methylated in CD34\u207a hematopoietic progenitor cells but show pronounced DNA hypomethylation in monocytes and in granulocytes. In addition, by comparing hematopoietic progenitor cells from umbilical cord blood to hematopoietic progenitor cells from peripheral blood of adult donors we were also able to analyze age-related methylation changes in CD34\u207a cells. Interestingly, the methylation changes observed in older progenitor cells showed a bimodal pattern with hypomethylation of differentiation-associated genes and de novo methylation events resembling epigenetic mutations. Our results thus provide detailed insight into the methylation dynamics during differentiation and suggest that epigenetic changes contribute to hematopoietic progenitor cell aging.", - "journal_title": "Blood", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/21427290/" - } - ], - "9ed8e340-25f2-49e2-9833-d2b035b4de4d": [ - { - "pub_id": "25261123", - "title": "Uncovering the defence responses of Eucalyptus to pests and pathogens in the genomics age.", - "authors": "Sanushka Naidoo,Carsten K\u00fclheim,Lizahn Zwart,Ronishree Mangwanda,Caryn N Oates,Erik A Visser,Feb\u00e9 E Wilken,Thandekile B Mamni,Alexander A Myburg", - "abstract": "Long-lived tree species are subject to attack by various pests and pathogens during their lifetime. This problem is exacerbated by climate change, which may increase the host range for pathogens and extend the period of infestation by pests. Plant defences may involve preformed barriers or induced resistance mechanisms based on recognition of the invader, complex signalling cascades, hormone signalling, activation of transcription factors and production of pathogenesis-related (PR) proteins with direct antimicrobial or anti-insect activity. Trees have evolved some unique defence mechanisms compared with well-studied model plants, which are mostly herbaceous annuals. The genome sequence of Eucalyptus grandis W. Hill ex Maiden has recently become available and provides a resource to extend our understanding of defence in large woody perennials. This review synthesizes existing knowledge of defence mechanisms in model plants and tree species and features mechanisms that may be important for defence in Eucalyptus, such as anatomical variants and the role of chemicals and proteins. Based on the E.\u2005grandis genome sequence, we have identified putative PR proteins based on sequence identity to the previously described plant PR proteins. Putative orthologues for PR-1, PR-2, PR-4, PR-5, PR-6, PR-7, PR-8, PR-9, PR-10, PR-12, PR-14, PR-15 and PR-17 have been identified and compared with their orthologues in Populus trichocarpa Torr. & A. Gray ex Hook and Arabidopsis thaliana (L.) Heynh. The survey of PR genes in Eucalyptus provides a first step in identifying defence gene targets that may be employed for protection of the species in future. Genomic resources available for Eucalyptus are discussed and approaches for improving resistance in these hardwood trees, earmarked as a bioenergy source in future, are considered.", - "journal_title": "Tree physiology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/25261123/" - } - ], - "3c5be623-22a8-41f7-9a44-2f6fc809ee94": [ - { - "pub_id": "26062507", - "title": "Population genomics of Bronze Age Eurasia.", - "authors": "Morten E Allentoft,Martin Sikora,Karl-G\u00f6ran Sj\u00f6gren,Simon Rasmussen,Morten Rasmussen,Jesper Stenderup,Peter B Damgaard,Hannes Schroeder,Torbj\u00f6rn Ahlstr\u00f6m,Lasse Vinner,Anna-Sapfo Malaspinas,Ashot Margaryan,Tom Higham,David Chivall,Niels Lynnerup,Lise Harvig,Justyna Baron,Philippe Della Casa,Pawe\u0142 D\u0105browski,Paul R Duffy,Alexander V Ebel,Andrey Epimakhov,Karin Frei,Miros\u0142aw Furmanek,Tomasz Gralak,Andrey Gromov,Stanis\u0142aw Gronkiewicz,Gisela Grupe,Tam\u00e1s Hajdu,Rados\u0142aw Jarysz,Valeri Khartanovich,Alexandr Khokhlov,Vikt\u00f3ria Kiss,Jan Kol\u00e1\u0159,Aivar Kriiska,Irena Lasak,Cristina Longhi,George McGlynn,Algimantas Merkevicius,Inga Merkyte,Mait Metspalu,Ruzan Mkrtchyan,Vyacheslav Moiseyev,L\u00e1szl\u00f3 Paja,Gy\u00f6rgy P\u00e1lfi,Dalia Pokutta,\u0141ukasz Pospieszny,T Douglas Price,Lehti Saag,Mikhail Sablin,Natalia Shishlina,V\u00e1clav Smr\u010dka,Vasilii I Soenov,Vajk Szever\u00e9nyi,Guszt\u00e1v T\u00f3th,Synaru V Trifanova,Liivi Varul,Magdolna Vicze,Levon Yepiskoposyan,Vladislav Zhitenev,Ludovic Orlando,Thomas Sicheritz-Pont\u00e9n,S\u00f8ren Brunak,Rasmus Nielsen,Kristian Kristiansen,Eske Willerslev", - "abstract": "The Bronze Age of Eurasia (around 3000-1000 BC) was a period of major cultural changes. However, there is debate about whether these changes resulted from the circulation of ideas or from human migrations, potentially also facilitating the spread of languages and certain phenotypic traits. We investigated this by using new, improved methods to sequence low-coverage genomes from 101 ancient humans from across Eurasia. We show that the Bronze Age was a highly dynamic period involving large-scale population migrations and replacements, responsible for shaping major parts of present-day demographic structure in both Europe and Asia. Our findings are consistent with the hypothesized spread of Indo-European languages during the Early Bronze Age. We also demonstrate that light skin pigmentation in Europeans was already present at high frequency in the Bronze Age, but not lactose tolerance, indicating a more recent onset of positive selection on lactose tolerance than previously thought.", - "journal_title": "Nature", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/26062507/" - } - ], - "ef2c9e1b-fce6-4649-aa06-8cad94740f79": [ - { - "pub_id": "23808484", - "title": "Post-genome-wide association study challenges for lipid traits: describing age as a modifier of gene-lipid associations in the Population Architecture using Genomics and Epidemiology (PAGE) study.", - "authors": "Logan Dumitrescu,Cara L Carty,Nora Franceschini,Lucia A Hindorff,Shelley A Cole,Petra B\u016f\u017ekov\u00e1,Fredrick R Schumacher,Charles B Eaton,Robert J Goodloe,David J Duggan,Jeff Haessler,Barbara Cochran,Brian E Henderson,Iona Cheng,Karen C Johnson,Chris S Carlson,Shelly-Ann Love,Kristin Brown-Gentry,Alejandro Q Nato,Miguel Quibrera,Garnet Anderson,Ralph V Shohet,Jos\u00e9 Luis Ambite,Lynne R Wilkens,Lo\u00efc Le Marchand,Christopher A Haiman,Steven Buyske,Charles Kooperberg,Kari E North,Myriam Fornage,Dana C Crawford", - "abstract": "Numerous common genetic variants that influence plasma high-density lipoprotein cholesterol, low-density lipoprotein cholesterol (LDL-C), and triglyceride distributions have been identified via genome-wide association studies (GWAS). However, whether or not these associations are age-dependent has largely been overlooked. We conducted an association study and meta-analysis in more than 22,000 European Americans between 49 previously identified GWAS variants and the three lipid traits, stratified by age (males: <50 or \u226550 years of age; females: pre- or postmenopausal). For each variant, a test of heterogeneity was performed between the two age strata and significant Phet values were used as evidence of age-specific genetic effects. We identified seven associations in females and eight in males that displayed suggestive heterogeneity by age (Phet < 0.05). The association between rs174547 (FADS1) and LDL-C in males displayed the most evidence for heterogeneity between age groups (Phet = 1.74E-03, I(2) = 89.8), with a significant association in older males (P = 1.39E-06) but not younger males (P = 0.99). However, none of the suggestive modifying effects survived adjustment for multiple testing, highlighting the challenges of identifying modifiers of modest SNP-trait associations despite large sample sizes.", - "journal_title": "Annals of human genetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/23808484/" - } - ], - "e287d50a-1e47-4721-a165-72f1e5a094df": [ - { - "pub_id": "22936721", - "title": "Inference of genome duplications from age distributions revisited.", - "authors": "Kevin Vanneste,Yves Van de Peer,Steven Maere", - "abstract": "Whole-genome duplications (WGDs), thought to facilitate evolutionary innovations and adaptations, have been uncovered in many phylogenetic lineages. WGDs are frequently inferred from duplicate age distributions, where they manifest themselves as peaks against a small-scale duplication background. However, the interpretation of duplicate age distributions is complicated by the use of K(S), the number of synonymous substitutions per synonymous site, as a proxy for the age of paralogs. Two particular concerns are the stochastic nature of synonymous substitutions leading to increasing uncertainty in K(S) with increasing age since duplication and K(S) saturation caused by the inability of evolutionary models to fully correct for the occurrence of multiple substitutions at the same site. K(S) stochasticity is expected to erode the signal of older WGDs, whereas K(S) saturation may lead to artificial peaks in the distribution. Here, we investigate the consequences of these effects on K(S)-based age distributions and WGD inference by simulating the evolution of duplicated sequences according to predefined real age distributions and re-estimating the corresponding K(S) distributions. We show that, although K(S) estimates can be used for WGD inference far beyond the commonly accepted K(S) threshold of 1, K(S) saturation effects can cause artificial peaks at higher ages. Moreover, K(S) stochasticity and saturation may lead to confounded peaks encompassing multiple WGD events and/or saturation artifacts. We argue that K(S) effects need to be properly accounted for when inferring WGDs from age distributions and that the failure to do so could lead to false inferences.", - "journal_title": "Molecular biology and evolution", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/22936721/" - } - ], - "64ab90a9-700a-4166-b7c3-ad57adafa4e2": [ - { - "pub_id": "26943586", - "title": "Loss of p53-mediated cell-cycle arrest, senescence and apoptosis promotes genomic instability and premature aging.", - "authors": "Tongyuan Li,Xiangyu Liu,Le Jiang,James Manfredi,Shan Zha,Wei Gu", - "abstract": "Although p53-mediated cell cycle arrest, senescence and apoptosis are well accepted as major tumor suppression mechanisms, the loss of these functions does not directly lead to tumorigenesis, suggesting that the precise roles of these canonical activities of p53 need to be redefined. Here, we report that the cells derived from the mutant mice expressing p533KR, an acetylation-defective mutant that fails to induce cell-cycle arrest, senescence and apoptosis, exhibit high levels of aneuploidy upon DNA damage. Moreover, the embryonic lethality caused by the deficiency of XRCC4, a key DNA double strand break repair factor, can be fully rescued in the p533KR/3KR background. Notably, despite high levels of genomic instability, p533KR/3KRXRCC4-/- mice, unlike p53-/- XRCC4-/- mice, are not succumbed to pro-B-cell lymphomas. Nevertheless, p533KR/3KR XRCC4-/- mice display aging-like phenotypes including testicular atrophy, kyphosis, and premature death. Further analyses demonstrate that SLC7A11 is downregulated and that p53-mediated ferroptosis is significantly induced in spleens and testis of p533KR/3KRXRCC4-/- mice. These results demonstrate that the direct role of p53-mediated cell cycle arrest, senescence and apoptosis is to control genomic stability in vivo. Our study not only validates the importance of ferroptosis in p53-mediated tumor suppression in vivo but also reveals that the combination of genomic instability and activation of ferroptosis may promote aging-associated phenotypes.", - "journal_title": "Oncotarget", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/26943586/" - } - ], - "60025cc7-4720-4a17-968d-22f2f67b688b": [ - { - "pub_id": "23704328", - "title": "Genome-wide association study of primary tooth eruption identifies pleiotropic loci associated with height and craniofacial distances.", - "authors": "Ghazaleh Fatemifar,Clive J Hoggart,Lavinia Paternoster,John P Kemp,Inga Prokopenko,Momoko Horikoshi,Victoria J Wright,Jon H Tobias,Stephen Richmond,Alexei I Zhurov,Arshed M Toma,Anneli Pouta,Anja Taanila,Kirsi Sipila,Raija L\u00e4hdesm\u00e4ki,Demetris Pillas,Frank Geller,Bjarke Feenstra,Mads Melbye,Ellen A Nohr,Susan M Ring,Beate St Pourcain,Nicholas J Timpson,George Davey Smith,Marjo-Riitta Jarvelin,David M Evans", - "abstract": "Twin and family studies indicate that the timing of primary tooth eruption is highly heritable, with estimates typically exceeding 80%. To identify variants involved in primary tooth eruption, we performed a population-based genome-wide association study of 'age at first tooth' and 'number of teeth' using 5998 and 6609 individuals, respectively, from the Avon Longitudinal Study of Parents and Children (ALSPAC) and 5403 individuals from the 1966 Northern Finland Birth Cohort (NFBC1966). We tested 2 446 724 SNPs imputed in both studies. Analyses were controlled for the effect of gestational age, sex and age of measurement. Results from the two studies were combined using fixed effects inverse variance meta-analysis. We identified a total of 15 independent loci, with 10 loci reaching genome-wide significance (P < 5 \u00d7 10(-8)) for 'age at first tooth' and 11 loci for 'number of teeth'. Together, these associations explain 6.06% of the variation in 'age of first tooth' and 4.76% of the variation in 'number of teeth'. The identified loci included eight previously unidentified loci, some containing genes known to play a role in tooth and other developmental pathways, including an SNP in the protein-coding region of BMP4 (rs17563, P = 9.080 \u00d7 10(-17)). Three of these loci, containing the genes HMGA2, AJUBA and ADK, also showed evidence of association with craniofacial distances, particularly those indexing facial width. Our results suggest that the genome-wide association approach is a powerful strategy for detecting variants involved in tooth eruption, and potentially craniofacial growth and more generally organ development.", - "journal_title": "Human molecular genetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/23704328/" - } - ], - "57aca40b-8cdf-43ef-b6e6-b9b477d46265": [ - { - "pub_id": "24138928", - "title": "DNA methylation age of human tissues and cell types.", - "authors": "Steve Horvath", - "abstract": "It is not yet known whether DNA methylation levels can be used to accurately predict age across a broad spectrum of human tissues and cell types, nor whether the resulting age prediction is a biologically meaningful measure. I developed a multi-tissue predictor of age that allows one to estimate the DNA methylation age of most tissues and cell types. The predictor, which is freely available, was developed using 8,000 samples from 82 Illumina DNA methylation array datasets, encompassing 51 healthy tissues and cell types. I found that DNA methylation age has the following properties: first, it is close to zero for embryonic and induced pluripotent stem cells; second, it correlates with cell passage number; third, it gives rise to a highly heritable measure of age acceleration; and, fourth, it is applicable to chimpanzee tissues. Analysis of 6,000 cancer samples from 32 datasets showed that all of the considered 20 cancer types exhibit significant age acceleration, with an average of 36 years. Low age-acceleration of cancer tissue is associated with a high number of somatic mutations and TP53 mutations, while mutations in steroid receptors greatly accelerate DNA methylation age in breast cancer. Finally, I characterize the 353 CpG sites that together form an aging clock in terms of chromatin states and tissue variance. I propose that DNA methylation age measures the cumulative effect of an epigenetic maintenance system. This novel epigenetic clock can be used to address a host of questions in developmental biology, cancer and aging research.", - "journal_title": "Genome biology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/24138928/" - } - ], - "59805231-0bd9-4cde-8043-f4a006dc244d": [ - { - "pub_id": "21508958", - "title": "Enterotypes of the human gut microbiome.", - "authors": "Manimozhiyan Arumugam,Jeroen Raes,Eric Pelletier,Denis Le Paslier,Takuji Yamada,Daniel R Mende,Gabriel R Fernandes,Julien Tap,Thomas Bruls,Jean-Michel Batto,Marcelo Bertalan,Natalia Borruel,Francesc Casellas,Leyden Fernandez,Laurent Gautier,Torben Hansen,Masahira Hattori,Tetsuya Hayashi,Michiel Kleerebezem,Ken Kurokawa,Marion Leclerc,Florence Levenez,Chaysavanh Manichanh,H Bj\u00f8rn Nielsen,Trine Nielsen,Nicolas Pons,Julie Poulain,Junjie Qin,Thomas Sicheritz-Ponten,Sebastian Tims,David Torrents,Edgardo Ugarte,Erwin G Zoetendal,Jun Wang,Francisco Guarner,Oluf Pedersen,Willem M de Vos,S\u00f8ren Brunak,Joel Dor\u00e9, ,Mar\u00eda Antol\u00edn,Fran\u00e7ois Artiguenave,Herv\u00e9 M Blottiere,Mathieu Almeida,Christian Brechot,Carlos Cara,Christian Chervaux,Antonella Cultrone,Christine Delorme,G\u00e9rard Denariaz,Rozenn Dervyn,Konrad U Foerstner,Carsten Friss,Maarten van de Guchte,Eric Guedon,Florence Haimet,Wolfgang Huber,Johan van Hylckama-Vlieg,Alexandre Jamet,Catherine Juste,Ghalia Kaci,Jan Knol,Omar Lakhdari,Severine Layec,Karine Le Roux,Emmanuelle Maguin,Alexandre M\u00e9rieux,Raquel Melo Minardi,Christine M'rini,Jean Muller,Raish Oozeer,Julian Parkhill,Pierre Renault,Maria Rescigno,Nicolas Sanchez,Shinichi Sunagawa,Antonio Torrejon,Keith Turner,Gaetana Vandemeulebrouck,Encarna Varela,Yohanan Winogradsky,Georg Zeller,Jean Weissenbach,S Dusko Ehrlich,Peer Bork", - "abstract": "Our knowledge of species and functional composition of the human gut microbiome is rapidly increasing, but it is still based on very few cohorts and little is known about variation across the world. By combining 22 newly sequenced faecal metagenomes of individuals from four countries with previously published data sets, here we identify three robust clusters (referred to as enterotypes hereafter) that are not nation or continent specific. We also confirmed the enterotypes in two published, larger cohorts, indicating that intestinal microbiota variation is generally stratified, not continuous. This indicates further the existence of a limited number of well-balanced host-microbial symbiotic states that might respond differently to diet and drug intake. The enterotypes are mostly driven by species composition, but abundant molecular functions are not necessarily provided by abundant species, highlighting the importance of a functional analysis to understand microbial communities. Although individual host properties such as body mass index, age, or gender cannot explain the observed enterotypes, data-driven marker genes or functional modules can be identified for each of these host properties. For example, twelve genes significantly correlate with age and three functional modules with the body mass index, hinting at a diagnostic potential of microbial markers.", - "journal_title": "Nature", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/21508958/" - } - ], - "8ebc0bfe-ca43-4bd1-8ddc-f6fad608c10a": [ - { - "pub_id": "23193293", - "title": "Human Ageing Genomic Resources: integrated databases and tools for the biology and genetics of ageing.", - "authors": "Robi Tacutu,Thomas Craig,Arie Budovsky,Daniel Wuttke,Gilad Lehmann,Dmitri Taranukha,Joana Costa,Vadim E Fraifeld,Jo\u00e3o Pedro de Magalh\u00e3es", - "abstract": "The Human Ageing Genomic Resources (HAGR, http://genomics.senescence.info) is a freely available online collection of research databases and tools for the biology and genetics of ageing. HAGR features now several databases with high-quality manually curated data: (i) GenAge, a database of genes associated with ageing in humans and model organisms; (ii) AnAge, an extensive collection of longevity records and complementary traits for >4000 vertebrate species; and (iii) GenDR, a newly incorporated database, containing both gene mutations that interfere with dietary restriction-mediated lifespan extension and consistent gene expression changes induced by dietary restriction. Since its creation about 10 years ago, major efforts have been undertaken to maintain the quality of data in HAGR, while further continuing to develop, improve and extend it. This article briefly describes the content of HAGR and details the major updates since its previous publications, in terms of both structure and content. The completely redesigned interface, more intuitive and more integrative of HAGR resources, is also presented. Altogether, we hope that through its improvements, the current version of HAGR will continue to provide users with the most comprehensive and accessible resources available today in the field of biogerontology.", - "journal_title": "Nucleic acids research", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/23193293/" - } - ], - "65c8287b-eb19-437a-b9ca-5aaa8664d429": [ - { - "pub_id": "31013638", - "title": "Oxidative Stress: A Key Modulator in Neurodegenerative Diseases.", - "authors": "Anju Singh,Ritushree Kukreti,Luciano Saso,Shrikant Kukreti", - "abstract": "Oxidative stress is proposed as a regulatory element in ageing and various neurological disorders. The excess of oxidants causes a reduction of antioxidants, which in turn produce an oxidation-reduction imbalance in organisms. Paucity of the antioxidant system generates oxidative-stress, characterized by elevated levels of reactive species (oxygen, hydroxyl free radical, and so on). Mitochondria play a key role in ATP supply to cells via oxidative phosphorylation, as well as synthesis of essential biological molecules. Various redox reactions catalyzed by enzymes take place in the oxidative phosphorylation process. An inefficient oxidative phosphorylation may generate reactive oxygen species (ROS), leading to mitochondrial dysfunction. Mitochondrial redox metabolism, phospholipid metabolism, and proteolytic pathways are found to be the major and potential source of free radicals. A lower concentration of ROS is essential for normal cellular signaling, whereas the higher concentration and long-time exposure of ROS cause damage to cellular macromolecules such as DNA, lipids and proteins, ultimately resulting in necrosis and apoptotic cell death. Normal and proper functioning of the central nervous system (CNS) is entirely dependent on the chemical integrity of brain. It is well established that the brain consumes a large amount of oxygen and is highly rich in lipid content, becoming prone to oxidative stress. A high consumption of oxygen leads to excessive production of ROS. Apart from this, the neuronal membranes are found to be rich in polyunsaturated fatty acids, which are highly susceptible to ROS. Various neurodegenerative diseases such as Parkinson's disease (PD), Alzheimer's disease (AD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS), among others, can be the result of biochemical alteration (due to oxidative stress) in bimolecular components. There is a need to understand the processes and role of oxidative stress in neurodegenerative diseases. This review is an effort towards improving our understanding of the pivotal role played by OS in neurodegenerative disorders.", - "journal_title": "Molecules (Basel, Switzerland)", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/31013638/" - } - ], - "a0a4c2f9-b64b-47a5-a8cd-095be90f6abe": [ - { - "pub_id": "23326517", - "title": "Insights into the genetic architecture of early stage age-related macular degeneration: a genome-wide association study meta-analysis.", - "authors": "Elizabeth G Holliday,Albert V Smith,Belinda K Cornes,Gabri\u00eblle H S Buitendijk,Richard A Jensen,Xueling Sim,Thor Aspelund,Tin Aung,Paul N Baird,Eric Boerwinkle,Ching Yu Cheng,Cornelia M van Duijn,Gudny Eiriksdottir,Vilmundur Gudnason,Tamara Harris,Alex W Hewitt,Michael Inouye,Fridbert Jonasson,Barbara E K Klein,Lenore Launer,Xiaohui Li,Gerald Liew,Thomas Lumley,Patrick McElduff,Barbara McKnight,Paul Mitchell,Bruce M Psaty,Elena Rochtchina,Jerome I Rotter,Rodney J Scott,Wanting Tay,Kent Taylor,Yik Ying Teo,Andr\u00e9 G Uitterlinden,Ananth Viswanathan,Sophia Xie, ,Johannes R Vingerling,Caroline C W Klaver,E Shyong Tai,David Siscovick,Ronald Klein,Mary Frances Cotch,Tien Y Wong,John Attia,Jie Jin Wang", - "abstract": "Genetic factors explain a majority of risk variance for age-related macular degeneration (AMD). While genome-wide association studies (GWAS) for late AMD implicate genes in complement, inflammatory and lipid pathways, the genetic architecture of early AMD has been relatively under studied. We conducted a GWAS meta-analysis of early AMD, including 4,089 individuals with prevalent signs of early AMD (soft drusen and/or retinal pigment epithelial changes) and 20,453 individuals without these signs. For various published late AMD risk loci, we also compared effect sizes between early and late AMD using an additional 484 individuals with prevalent late AMD. GWAS meta-analysis confirmed previously reported association of variants at the complement factor H (CFH) (peak P\u200a=\u200a1.5\u00d710(-31)) and age-related maculopathy susceptibility 2 (ARMS2) (P\u200a=\u200a4.3\u00d710(-24)) loci, and suggested Apolipoprotein E (ApoE) polymorphisms (rs2075650; P\u200a=\u200a1.1\u00d710(-6)) associated with early AMD. Other possible loci that did not reach GWAS significance included variants in the zinc finger protein gene GLI3 (rs2049622; P\u200a=\u200a8.9\u00d710(-6)) and upstream of GLI2 (rs6721654; P\u200a=\u200a6.5\u00d710(-6)), encoding retinal Sonic hedgehog signalling regulators, and in the tyrosinase (TYR) gene (rs621313; P\u200a=\u200a3.5\u00d710(-6)), involved in melanin biosynthesis. For a range of published, late AMD risk loci, estimated effect sizes were significantly lower for early than late AMD. This study confirms the involvement of multiple established AMD risk variants in early AMD, but suggests weaker genetic effects on the risk of early AMD relative to late AMD. Several biological processes were suggested to be potentially specific for early AMD, including pathways regulating RPE cell melanin content and signalling pathways potentially involved in retinal regeneration, generating hypotheses for further investigation.", - "journal_title": "PloS one", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/23326517/" - } - ], - "b9c2f906-2807-4e96-af2c-5625628a540f": [ - { - "pub_id": "22144573", - "title": "Genome-wide association study for coronary artery calcification with follow-up in myocardial infarction.", - "authors": "Christopher J O'Donnell,Maryam Kavousi,Albert V Smith,Sharon L R Kardia,Mary F Feitosa,Shih-Jen Hwang,Yan V Sun,Michael A Province,Thor Aspelund,Abbas Dehghan,Udo Hoffmann,Lawrence F Bielak,Qunyuan Zhang,Gudny Eiriksdottir,Cornelia M van Duijn,Caroline S Fox,Mariza de Andrade,Aldi T Kraja,Sigurdur Sigurdsson,Suzette E Elias-Smale,Joanne M Murabito,Lenore J Launer,Aad van der Lugt,Sekar Kathiresan, ,Gabriel P Krestin,David M Herrington,Timothy D Howard,Yongmei Liu,Wendy Post,Braxton D Mitchell,Jeffrey R O'Connell,Haiqing Shen,Alan R Shuldiner,David Altshuler,Roberto Elosua,Veikko Salomaa,Stephen M Schwartz,David S Siscovick,Benjamin F Voight,Joshua C Bis,Nicole L Glazer,Bruce M Psaty,Eric Boerwinkle,Gerardo Heiss,Stefan Blankenberg,Tanja Zeller,Philipp S Wild,Renate B Schnabel,Arne Schillert,Andreas Ziegler,Thomas F M\u00fcnzel,Charles C White,Jerome I Rotter,Michael Nalls,Matthijs Oudkerk,Andrew D Johnson,Anne B Newman,Andre G Uitterlinden,Joseph M Massaro,Julie Cunningham,Tamara B Harris,Albert Hofman,Patricia A Peyser,Ingrid B Borecki,L Adrienne Cupples,Vilmundur Gudnason,Jacqueline C M Witteman", - "abstract": "Coronary artery calcification (CAC) detected by computed tomography is a noninvasive measure of coronary atherosclerosis, which underlies most cases of myocardial infarction (MI). We sought to identify common genetic variants associated with CAC and further investigate their associations with MI. Computed tomography was used to assess quantity of CAC. A meta-analysis of genome-wide association studies for CAC was performed in 9961 men and women from 5 independent community-based cohorts, with replication in 3 additional independent cohorts (n=6032). We examined the top single-nucleotide polymorphisms (SNPs) associated with CAC quantity for association with MI in multiple large genome-wide association studies of MI. Genome-wide significant associations with CAC for SNPs on chromosome 9p21 near CDKN2A and CDKN2B (top SNP: rs1333049; P=7.58\u00d710(-19)) and 6p24 (top SNP: rs9349379, within the PHACTR1 gene; P=2.65\u00d710(-11)) replicated for CAC and for MI. Additionally, there is evidence for concordance of SNP associations with both CAC and MI at a number of other loci, including 3q22 (MRAS gene), 13q34 (COL4A1/COL4A2 genes), and 1p13 (SORT1 gene). SNPs in the 9p21 and PHACTR1 gene loci were strongly associated with CAC and MI, and there are suggestive associations with both CAC and MI of SNPs in additional loci. Multiple genetic loci are associated with development of both underlying coronary atherosclerosis and clinical events.", - "journal_title": "Circulation", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/22144573/" - } - ], - "8b03aabf-8965-42c9-a054-44592bd98e86": [ - { - "pub_id": "22005931", - "title": "Genome-wide association analysis of age-at-onset in Alzheimer's disease.", - "authors": "M I Kamboh,M M Barmada,F Y Demirci,R L Minster,M M Carrasquillo,V S Pankratz,S G Younkin,A J Saykin, ,R A Sweet,E Feingold,S T DeKosky,O L Lopez", - "abstract": "The risk of Alzheimer's disease (AD) is strongly determined by genetic factors and recent genome-wide association studies (GWAS) have identified several genes for the disease risk. In addition to the disease risk, age-at-onset (AAO) of AD has also strong genetic component with an estimated heritability of 42%. Identification of AAO genes may help to understand the biological mechanisms that regulate the onset of the disease. Here we report the first GWAS focused on identifying genes for the AAO of AD. We performed a genome-wide meta-analysis on three samples comprising a total of 2222 AD cases. A total of ~2.5 million directly genotyped or imputed single-nucleotide polymorphisms (SNPs) were analyzed in relation to AAO of AD. As expected, the most significant associations were observed in the apolipoprotein E (APOE) region on chromosome 19 where several SNPs surpassed the conservative genome-wide significant threshold (P<5E-08). The most significant SNP outside the APOE region was located in the DCHS2 gene on chromosome 4q31.3 (rs1466662; P=4.95E-07). There were 19 additional significant SNPs in this region at P<1E-04 and the DCHS2 gene is expressed in the cerebral cortex and thus is a potential candidate for affecting AAO in AD. These findings need to be confirmed in additional well-powered samples.", - "journal_title": "Molecular psychiatry", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/22005931/" - } - ], - "6a47ecdd-8613-4412-b905-92607e303946": [ - { - "pub_id": "22670614", - "title": "Application of genomics to breakthroughs in the cosmetic treatment of skin ageing and discoloration.", - "authors": "R Osborne,T Hakozaki,T Laughlin,D R Finlay", - "abstract": "The use of global gene expression profiling, also known as transcriptomics or genomics, provides a means to identify key pathways affected in ageing skin that can be improved with appropriate cosmetic compounds. Aspects of skin ageing that can be addressed include matrix production, barrier, lipid synthesis, antioxidant capacity and hyperpigmentation. Gene expression profiling together with in vitro human skin cell cultures for compound screening and verification have led to the identification of cosmetic compounds and an understanding of the biological effects of compounds such as niacinamide, Pal-KTTKS, hexamidine, retinyl propionate and sodium dehydroacetate. In addition, understanding of the decreased antioxidant capacity of aged skin has led to the identification of new antiageing ingredients, olive-derived fatty acid ethoxylates, which have been shown to restore antioxidant enzymes in skin keratinocytes and fibroblasts. Gene expression profiling of age spots has also provided an understanding of the role of undecylenoyl phenylalanine in reducing melanin production by an adrenergic receptor mechanism in melanocytes. The use of these compounds in cosmetic formulations for skin care can aid improvements in the appearance of aged skin, including the improved appearance of fine lines, wrinkles and age spots.", - "journal_title": "The British journal of dermatology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/22670614/" - } - ], - "448f8e9a-ae98-4553-bc96-130b14aa61b3": [ - { - "pub_id": "23050038", - "title": "Pleiotropic cellular functions of PARP1 in longevity and aging: genome maintenance meets inflammation.", - "authors": "Aswin Mangerich,Alexander B\u00fcrkle", - "abstract": "Aging is a multifactorial process that depends on diverse molecular and cellular mechanisms, such as genome maintenance and inflammation. The nuclear enzyme poly(ADP-ribose) polymerase 1 (PARP1), which catalyzes the synthesis of the biopolymer poly(ADP-ribose), exhibits an essential role in both processes. On the one hand, PARP1 serves as a genomic caretaker as it participates in chromatin remodelling, DNA repair, telomere maintenance, resolution of replicative stress, and cell cycle control. On the other hand, PARP1 acts as a mediator of inflammation due to its function as a regulator of NF-\u03baB and other transcription factors and its potential to induce cell death. Consequently, PARP1 represents an interesting player in several aging mechanisms and is discussed as a longevity assurance factor on the one hand and an aging-promoting factor on the other hand. Here, we review the molecular mechanisms underlying the various roles of PARP1 in longevity and aging with special emphasis on cellular studies and we briefly discuss the results in the context of in vivo studies in mice and humans.", - "journal_title": "Oxidative medicine and cellular longevity", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/23050038/" - } - ], - "57178200-243a-4962-af90-5e6b40e16237": [ - { - "pub_id": "27815632", - "title": "Genomics and CSF analyses implicate thyroid hormone in hippocampal sclerosis of aging.", - "authors": "Peter T Nelson,Yuriko Katsumata,Kwangsik Nho,Sergey C Artiushin,Gregory A Jicha,Wang-Xia Wang,Erin L Abner,Andrew J Saykin,Walter A Kukull, ,David W Fardo", - "abstract": "We report evidence of a novel pathogenetic mechanism in which thyroid hormone dysregulation contributes to dementia in elderly persons. Two single nucleotide polymorphisms (SNPs) on chromosome 12p12 were the initial foci of our study: rs704180 and rs73069071. These SNPs were identified by separate research groups as risk alleles for non-Alzheimer's neurodegeneration. We found that the rs73069071 risk genotype was associated with hippocampal sclerosis (HS) pathology among people with the rs704180 risk genotype (National Alzheimer's Coordinating Center/Alzheimer's Disease Genetic Consortium data; n\u00a0=\u00a02113, including 241 autopsy-confirmed HS cases). Furthermore, both rs704180 and rs73069071 risk genotypes were associated with widespread brain atrophy visualized by MRI (Alzheimer's Disease Neuroimaging Initiative data; n\u00a0=\u00a01239). In human brain samples from the Braineac database, both rs704180 and rs73069071 risk genotypes were associated with variation in expression of ABCC9, a gene which encodes a metabolic sensor protein in astrocytes. The rs73069071 risk genotype was also associated with altered expression of a nearby astrocyte-expressed gene, SLCO1C1. Analyses of human brain gene expression databases indicated that the chromosome 12p12 locus may regulate particular astrocyte-expressed genes induced by the active form of thyroid hormone, triiodothyronine (T3). This is informative biologically, because the SLCO1C1 protein transports thyroid hormone into astrocytes from blood. Guided by the genomic data, we tested the hypothesis that altered thyroid hormone levels could be detected in cerebrospinal fluid (CSF) obtained from persons with HS pathology. Total T3 levels in CSF were elevated in HS cases (p\u00a0<\u00a00.04 in two separately analyzed groups), but not in Alzheimer's disease cases, relative to controls. No change was detected in the serum levels of thyroid hormone (T3 or T4) in a subsample of HS cases prior to death. We conclude that brain thyroid hormone perturbation is a potential pathogenetic factor in HS that may also provide the basis for a novel CSF-based clinical biomarker.", - "journal_title": "Acta neuropathologica", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/27815632/" - } - ], - "a4cac151-7037-46e4-b810-0e40a1fe100d": [ - { - "pub_id": "21358986", - "title": "Ontogenetic variation of the human genome.", - "authors": "Y B Yurov,S G Vorsanova,I Y Iourov", - "abstract": "The human genome demonstrates variable levels of instability during ontogeny. Achieving the highest rate during early prenatal development, it decreases significantly throughout following ontogenetic stages. A failure to decrease or a spontaneous increase of genomic instability can promote infertility, pregnancy losses, chromosomal and genomic diseases, cancer, immunodeficiency, or brain diseases depending on developmental stage at which it occurs. Paradoxically, late ontogeny is associated with increase of genomic instability that is considered a probable mechanism for human aging. The latter is even more appreciable in human diseases associated with pathological or accelerated aging (i.e. Alzheimer's disease and ataxia-telangiectasia). These observations resulted in a hypothesis suggesting that somatic genomic variations throughout ontogeny are determinants of cellular vitality in health and disease including intrauterine development, postnatal life and aging. The most devastative effect of somatic genome variations is observed when it manifests as chromosome instability or aneuploidy, which has been repeatedly noted to produce pathologic conditions and to mediate developmental regulatory and aging processes. However, no commonly accepted concepts on the role of chromosome/genome instability in determination of human health span and life span are available. Here, a review of these ontogenetic variations is given to propose a new \"dynamic genome\" model for pathological and natural genomic changes throughout life that mimic those of phylogenetic diversity.", - "journal_title": "Current genomics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/21358986/" - } - ], - "955d01ac-1cd3-4b93-946e-cf49bee70689": [ - { - "pub_id": "21352535", - "title": "Dating the age of admixture via wavelet transform analysis of genome-wide data.", - "authors": "Irina Pugach,Rostislav Matveyev,Andreas Wollstein,Manfred Kayser,Mark Stoneking", - "abstract": "We describe a PCA-based genome scan approach to analyze genome-wide admixture structure, and introduce wavelet transform analysis as a method for estimating the time of admixture. We test the wavelet transform method with simulations and apply it to genome-wide SNP data from eight admixed human populations. The wavelet transform method offers better resolution than existing methods for dating admixture, and can be applied to either SNP or sequence data from humans or other species.", - "journal_title": "Genome biology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/21352535/" - } - ], - "5f96bea4-a48f-456c-87f0-8ef2bc715d79": [ - { - "pub_id": "20582226", - "title": "Water buffalo genome science comes of age.", - "authors": "Vanessa N Michelizzi,Michael V Dodson,Zengxiang Pan,M Elisabete J Amaral,Jennifer J Michal,Derek J McLean,James E Womack,Zhihua Jiang", - "abstract": "The water buffalo is vital to the lives of small farmers and to the economy of many countries worldwide. Not only are they draught animals, but they are also a source of meat, horns, skin and particularly the rich and precious milk that may be converted to creams, butter, yogurt and many cheeses. Genome analysis of water buffalo has advanced significantly in recent years. This review focuses on currently available genome resources in water buffalo in terms of cytogenetic characterization, whole genome mapping and next generation sequencing. No doubt, these resources indicate that genome science comes of age in the species and will provide knowledge and technologies to help optimize production potential, reproduction efficiency, product quality, nutritional value and resistance to diseases. As water buffalo and domestic cattle, both members of the Bovidae family, are closely related, the vast amount of cattle genetic/genomic resources might serve as shortcuts for the buffalo community to further advance genome science and biotechnologies in the species.", - "journal_title": "International journal of biological sciences", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/20582226/" - } - ], - "99b48cbb-bcd3-4c55-a4a6-a74bc8b54522": [ - { - "pub_id": "27621233", - "title": "Menopause: Genome stability as new paradigm.", - "authors": "Joop S E Laven,Jenny A Visser,Andre G Uitterlinden,Wilbert P Vermeij,Jan H J Hoeijmakers", - "abstract": "Menopause is defined as the age-dependent permanent cessation of menstruation and ovulation due to ovarian failure. Menopause occurs on average around the age of 51 years. Recent genome-wide association studies (GWAS) have identified over 44 genetic variants that are associated with age of onset of natural menopause. Genes linked with menopause can be classified into three major groups: genes implicated in genome stability (DNA repair), immune function and mitochondrial biogenesis. Biological and epidemiological data indicate that reproductive performance, age at menopause and longevity are interlinked through common genetic factors, which play a pivotal role in DNA repair and genome maintenance, which has been linked before with the process of ageing. Consequently, ageing of the soma as a result of inefficient DNA repair appears also to be responsible for failure to reproduce and the subsequent occurrence of menopause. In this way reproductive performance may be strongly linked to the physical condition of the soma and may be a very good predictor of general health in later life.", - "journal_title": "Maturitas", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/27621233/" - } - ], - "99445b90-1950-4299-815d-e912c5ae06ac": [ - { - "pub_id": "26579468", - "title": "Hydrogen sulfide prodrugs-a review.", - "authors": "Yueqin Zheng,Xingyue Ji,Kaili Ji,Binghe Wang", - "abstract": "Hydrogen sulfide (H2S) is recognized as one of three gasotransmitters together with nitric oxide (NO) and carbon monoxide (CO). As a signaling molecule, H2S plays an important role in physiology and shows great potential in pharmaceutical applications. Along this line, there is a need for the development of H2S prodrugs for various reasons. In this review, we summarize different H2S prodrugs, their chemical properties, and some of their potential therapeutic applications.", - "journal_title": "Acta pharmaceutica Sinica. B", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/26579468/" - } - ], - "41c9da42-4f25-4f43-90f2-90cab36b35f3": [ - { - "pub_id": "26691988", - "title": "A large genome-wide association study of age-related macular degeneration highlights contributions of rare and common variants.", - "authors": "Lars G Fritsche,Wilmar Igl,Jessica N Cooke Bailey,Felix Grassmann,Sebanti Sengupta,Jennifer L Bragg-Gresham,Kathryn P Burdon,Scott J Hebbring,Cindy Wen,Mathias Gorski,Ivana K Kim,David Cho,Donald Zack,Eric Souied,Hendrik P N Scholl,Elisa Bala,Kristine E Lee,David J Hunter,Rebecca J Sardell,Paul Mitchell,Joanna E Merriam,Valentina Cipriani,Joshua D Hoffman,Tina Schick,Yara T E Lechanteur,Robyn H Guymer,Matthew P Johnson,Yingda Jiang,Chloe M Stanton,Gabri\u00eblle H S Buitendijk,Xiaowei Zhan,Alan M Kwong,Alexis Boleda,Matthew Brooks,Linn Gieser,Rinki Ratnapriya,Kari E Branham,Johanna R Foerster,John R Heckenlively,Mohammad I Othman,Brendan J Vote,Helena Hai Liang,Emmanuelle Souzeau,Ian L McAllister,Timothy Isaacs,Janette Hall,Stewart Lake,David A Mackey,Ian J Constable,Jamie E Craig,Terrie E Kitchner,Zhenglin Yang,Zhiguang Su,Hongrong Luo,Daniel Chen,Hong Ouyang,Ken Flagg,Danni Lin,Guanping Mao,Henry Ferreyra,Klaus Stark,Claudia N von Strachwitz,Armin Wolf,Caroline Brandl,Guenther Rudolph,Matthias Olden,Margaux A Morrison,Denise J Morgan,Matthew Schu,Jeeyun Ahn,Giuliana Silvestri,Evangelia E Tsironi,Kyu Hyung Park,Lindsay A Farrer,Anton Orlin,Alexander Brucker,Mingyao Li,Christine A Curcio,Saddek Mohand-Sa\u00efd,Jos\u00e9-Alain Sahel,Isabelle Audo,Mustapha Benchaboune,Angela J Cree,Christina A Rennie,Srinivas V Goverdhan,Michelle Grunin,Shira Hagbi-Levi,Peter Campochiaro,Nicholas Katsanis,Frank G Holz,Fr\u00e9d\u00e9ric Blond,H\u00e9l\u00e8ne Blanch\u00e9,Jean-Fran\u00e7ois Deleuze,Robert P Igo,Barbara Truitt,Neal S Peachey,Stacy M Meuer,Chelsea E Myers,Emily L Moore,Ronald Klein,Michael A Hauser,Eric A Postel,Monique D Courtenay,Stephen G Schwartz,Jaclyn L Kovach,William K Scott,Gerald Liew,Ava G Tan,Bamini Gopinath,John C Merriam,R Theodore Smith,Jane C Khan,Humma Shahid,Anthony T Moore,J Allie McGrath,Rene\u00e9 Laux,Milam A Brantley,Anita Agarwal,Lebriz Ersoy,Albert Caramoy,Thomas Langmann,Nicole T M Saksens,Eiko K de Jong,Carel B Hoyng,Melinda S Cain,Andrea J Richardson,Tammy M Martin,John Blangero,Daniel E Weeks,Bal Dhillon,Cornelia M van Duijn,Kimberly F Doheny,Jane Romm,Caroline C W Klaver,Caroline Hayward,Michael B Gorin,Michael L Klein,Paul N Baird,Anneke I den Hollander,Sascha Fauser,John R W Yates,Rando Allikmets,Jie Jin Wang,Debra A Schaumberg,Barbara E K Klein,Stephanie A Hagstrom,Itay Chowers,Andrew J Lotery,Thierry L\u00e9veillard,Kang Zhang,Murray H Brilliant,Alex W Hewitt,Anand Swaroop,Emily Y Chew,Margaret A Pericak-Vance,Margaret DeAngelis,Dwight Stambolian,Jonathan L Haines,Sudha K Iyengar,Bernhard H F Weber,Gon\u00e7alo R Abecasis,Iris M Heid", - "abstract": "Advanced age-related macular degeneration (AMD) is the leading cause of blindness in the elderly, with limited therapeutic options. Here we report on a study of >12 million variants, including 163,714 directly genotyped, mostly rare, protein-altering variants. Analyzing 16,144 patients and 17,832 controls, we identify 52 independently associated common and rare variants (P < 5 \u00d7 10(-8)) distributed across 34 loci. Although wet and dry AMD subtypes exhibit predominantly shared genetics, we identify the first genetic association signal specific to wet AMD, near MMP9 (difference P value = 4.1 \u00d7 10(-10)). Very rare coding variants (frequency <0.1%) in CFH, CFI and TIMP3 suggest causal roles for these genes, as does a splice variant in SLC16A8. Our results support the hypothesis that rare coding variants can pinpoint causal genes within known genetic loci and illustrate that applying the approach systematically to detect new loci requires extremely large sample sizes.", - "journal_title": "Nature genetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/26691988/" - } - ], - "c7361625-831a-44a2-b04d-157a49d00c6a": [ - { - "pub_id": "25390934", - "title": "Whole-genome sequencing of the world's oldest people.", - "authors": "Hinco J Gierman,Kristen Fortney,Jared C Roach,Natalie S Coles,Hong Li,Gustavo Glusman,Glenn J Markov,Justin D Smith,Leroy Hood,L Stephen Coles,Stuart K Kim", - "abstract": "Supercentenarians (110 years or older) are the world's oldest people. Seventy four are alive worldwide, with twenty two in the United States. We performed whole-genome sequencing on 17 supercentenarians to explore the genetic basis underlying extreme human longevity. We found no significant evidence of enrichment for a single rare protein-altering variant or for a gene harboring different rare protein altering variants in supercentenarian compared to control genomes. We followed up on the gene most enriched for rare protein-altering variants in our cohort of supercentenarians, TSHZ3, by sequencing it in a second cohort of 99 long-lived individuals but did not find a significant enrichment. The genome of one supercentenarian had a pathogenic mutation in DSC2, known to predispose to arrhythmogenic right ventricular cardiomyopathy, which is recommended to be reported to this individual as an incidental finding according to a recent position statement by the American College of Medical Genetics and Genomics. Even with this pathogenic mutation, the proband lived to over 110 years. The entire list of rare protein-altering variants and DNA sequence of all 17 supercentenarian genomes is available as a resource to assist the discovery of the genetic basis of extreme longevity in future studies.", - "journal_title": "PloS one", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/25390934/" - } - ], - "1ccffff6-b4c3-4dc5-abb9-2cd5937382ae": [ - { - "pub_id": "26059970", - "title": "Measuring individual inbreeding in the age of genomics: marker-based measures are better than pedigrees.", - "authors": "M Kardos,G Luikart,F W Allendorf", - "abstract": "Inbreeding (mating between relatives) can dramatically reduce the fitness of offspring by causing parts of the genome to be identical by descent. Thus, measuring individual inbreeding is crucial for ecology, evolution and conservation biology. We used computer simulations to test whether the realized proportion of the genome that is identical by descent (IBDG) is predicted better by the pedigree inbreeding coefficient (FP) or by genomic (marker-based) measures of inbreeding. Genomic estimators of IBDG included the increase in individual homozygosity relative to mean Hardy-Weinberg expected homozygosity (FH), and two measures (FROH and FE) that use mapped genetic markers to estimate IBDG. IBDG was more strongly correlated with FH, FE and FROH than with FP across a broad range of simulated scenarios when thousands of SNPs were used. For example, IBDG was more strongly correlated with FROH, FH and FE (estimated with \u2a7e10\u2009000 SNPs) than with FP (estimated with 20 generations of complete pedigree) in populations with a recent reduction in the effective populations size (from Ne=500 to Ne=75). FROH, FH and FE generally explained >90% of the variance in IBDG (among individuals) when 35\u2009K or more SNPs were used. FP explained <80% of the variation in IBDG on average in all simulated scenarios, even when pedigrees included 20 generations. Our results demonstrate that IBDG can be more precisely estimated with large numbers of genetic markers than with pedigrees. We encourage researchers to adopt genomic marker-based measures of IBDG as thousands of loci can now be genotyped in any species.", - "journal_title": "Heredity", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/26059970/" - } - ], - "e9d26638-68c1-4223-b884-e35a6e94f8ac": [ - { - "pub_id": "23852118", - "title": "SIRT1 collaborates with ATM and HDAC1 to maintain genomic stability in neurons.", - "authors": "Matthew M Dobbin,Ram Madabhushi,Ling Pan,Yue Chen,Dohoon Kim,Jun Gao,Biafra Ahanonu,Ping-Chieh Pao,Yi Qiu,Yingming Zhao,Li-Huei Tsai", - "abstract": "Defects in DNA repair have been linked to cognitive decline with age and neurodegenerative disease, yet the mechanisms that protect neurons from genotoxic stress remain largely obscure. We sought to characterize the roles of the NAD(+)-dependent deacetylase SIRT1 in the neuronal response to DNA double-strand breaks (DSBs). We found that SIRT1 was rapidly recruited to DSBs in postmitotic neurons, where it showed a synergistic relationship with ataxia telangiectasia mutated (ATM). SIRT1 recruitment to breaks was ATM dependent; however, SIRT1 also stimulated ATM autophosphorylation and activity and stabilized ATM at DSB sites. After DSB induction, SIRT1 also bound the neuroprotective class I histone deacetylase HDAC1. We found that SIRT1 deacetylated HDAC1 and stimulated its enzymatic activity, which was necessary for DSB repair through the nonhomologous end-joining pathway. HDAC1 mutations that mimic a constitutively acetylated state rendered neurons more susceptible to DNA damage, whereas pharmacological SIRT1 activators that promoted HDAC1 deacetylation also reduced DNA damage in two mouse models of neurodegeneration. We propose that SIRT1 is an apical transducer of the DSB response and that SIRT1 activation offers an important therapeutic avenue in neurodegeneration.", - "journal_title": "Nature neuroscience", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/23852118/" - } - ], - "6f84efc7-4215-459d-a790-c653f831eb5f": [ - { - "pub_id": "28105925", - "title": "Computational genomics at BGRS\\SB-2016: introductory note.", - "authors": "Yuriy L Orlov,Ancha V Baranova,Ralf Hofest\u00e4dt,Nikolay A Kolchanov", - "abstract": "", - "journal_title": "BMC genomics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/28105925/" - } - ], - "d73bb52b-b382-4450-919c-c4abeeb01344": [ - { - "pub_id": "27654999", - "title": "Age-related accrual of methylomic variability is linked to fundamental ageing mechanisms.", - "authors": "Roderick C Slieker,Maarten van Iterson,Ren\u00e9 Luijk,Marian Beekman,Daria V Zhernakova,Matthijs H Moed,Hailiang Mei,Michiel van Galen,Patrick Deelen,Marc Jan Bonder,Alexandra Zhernakova,Andr\u00e9 G Uitterlinden,Ettje F Tigchelaar,Coen D A Stehouwer,Casper G Schalkwijk,Carla J H van der Kallen,Albert Hofman,Diana van Heemst,Eco J de Geus,Jenny van Dongen,Joris Deelen,Leonard H van den Berg,Joyce van Meurs,Rick Jansen,Peter A C 't Hoen,Lude Franke,Cisca Wijmenga,Jan H Veldink,Morris A Swertz,Marleen M J van Greevenbroek,Cornelia M van Duijn,Dorret I Boomsma, ,P Eline Slagboom,Bastiaan T Heijmans", - "abstract": "Epigenetic change is a hallmark of ageing but its link to ageing mechanisms in humans remains poorly understood. While DNA methylation at many CpG sites closely tracks chronological age, DNA methylation changes relevant to biological age are expected to gradually dissociate from chronological age, mirroring the increased heterogeneity in health status at older ages. Here, we report on the large-scale identification of 6366 age-related variably methylated positions (aVMPs) identified in 3295 whole blood DNA methylation profiles, 2044 of which have a matching RNA-seq gene expression profile. aVMPs are enriched at polycomb repressed regions and, accordingly, methylation at those positions is associated with the expression of genes encoding components of polycomb repressive complex 2 (PRC2) in trans. Further analysis revealed trans-associations for 1816 aVMPs with an additional 854 genes. These trans-associated aVMPs are characterized by either an age-related gain of methylation at CpG islands marked by PRC2 or a loss of methylation at enhancers. This distinct pattern extends to other tissues and multiple cancer types. Finally, genes associated with aVMPs in trans whose expression is variably upregulated with age (733 genes) play a key role in DNA repair and apoptosis, whereas downregulated aVMP-associated genes (121 genes) are mapped to defined pathways in cellular metabolism. Our results link age-related changes in DNA methylation to fundamental mechanisms that are thought to drive human ageing.", - "journal_title": "Genome biology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/27654999/" - } - ], - "aae7b412-75d9-4e03-8def-922049559a69": [ - { - "pub_id": "27032421", - "title": "Progress on the role of DNA methylation in aging and longevity.", - "authors": "Fu-Hui Xiao,Qing-Peng Kong,Benjamin Perry,Yong-Han He", - "abstract": "Aging is a major risk factor for individuals' health problems. Moreover, environmental signals have a widespread influence on the aging process. Epigenetic modification, e.g. DNA methylation, represents a link between genetic and environmental signals via the regulation of gene transcription. An abundance of literature indicates that aberrant epigenetic change occurs throughout the aging process at both the cellular and the organismal level. In particular, DNA methylation presents globally decreasing and site-specific increasing in aging. In this review, we focus on the crucial roles of DNA methylation in aging and age-related disease and highlight the great potential of DNA methylation as a therapeutic target in preventing age-related diseases and promoting healthy longevity.", - "journal_title": "Briefings in functional genomics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/27032421/" - } - ], - "97208bfc-8a54-409d-aa40-843a3cfde618": [ - { - "pub_id": "27496166", - "title": "The genome-wide role of HSF-1 in the regulation of gene expression in Caenorhabditis elegans.", - "authors": "Jessica Brunquell,Stephanie Morris,Yin Lu,Feng Cheng,Sandy D Westerheide", - "abstract": "The heat shock response, induced by cytoplasmic proteotoxic stress, is one of the most highly conserved transcriptional responses. This response, driven by the heat shock transcription factor HSF1, restores proteostasis through the induction of molecular chaperones and other genes. In addition to stress-dependent functions, HSF1 has also been implicated in various stress-independent functions. In C. elegans, the HSF1 homolog HSF-1 is an essential protein that is required to mount a stress-dependent response, as well as to coordinate various stress-independent processes including development, metabolism, and the regulation of lifespan. In this work, we have performed RNA-sequencing for C. elegans cultured in the presence and absence of hsf-1 RNAi followed by treatment with or without heat shock. This experimental design thus allows for the determination of both heat shock-dependent and -independent biological targets of HSF-1 on a genome-wide level. Our results confirm that C. elegans HSF-1 can regulate gene expression in both a stress-dependent and -independent fashion. Almost all genes regulated by HS require HSF-1, reinforcing the central role of this transcription factor in the response to heat stress. As expected, major categories of HSF-1-regulated genes include cytoprotection, development, metabolism, and aging. Within both the heat stress-dependent and -independent gene groups, significant numbers of genes are upregulated as well as downregulated, demonstrating that HSF-1 can both activate and repress gene expression either directly or indirectly. Surprisingly, the cellular process most highly regulated by HSF-1, both with and without heat stress, is cuticle structure. Via network analyses, we identify a nuclear hormone receptor as a common link between genes that are regulated by HSF-1 in a HS-dependent manner, and an epidermal growth factor receptor as a common link between genes that are regulated by HSF-1 in a HS-independent manner. HSF-1 therefore coordinates various physiological processes in C. elegans, and HSF-1 activity may be coordinated across tissues by nuclear hormone receptor and epidermal growth factor receptor signaling. This work provides genome-wide HSF-1 regulatory networks in C. elegans that are both heat stress-dependent and -independent. We show that HSF-1 is responsible for regulating many genes outside of classical heat stress-responsive genes, including genes involved in development, metabolism, and aging. The findings that a nuclear hormone receptor may coordinate the HS-induced HSF-1 transcriptional response, while an epidermal growth factor receptor may coordinate the HS-independent response, indicate that these factors could promote cell non-autonomous signaling that occurs through HSF-1. Finally, this work highlights the genes involved in cuticle structure as important HSF-1 targets that may play roles in promoting both cytoprotection as well as longevity.", - "journal_title": "BMC genomics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/27496166/" - } - ], - "51fa2d0a-262a-4e5b-9b48-bf0a4a8ee1f8": [ - { - "pub_id": "21873635", - "title": "Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium.", - "authors": "Pascale Gaudet,Michael S Livstone,Suzanna E Lewis,Paul D Thomas", - "abstract": "The goal of the Gene Ontology (GO) project is to provide a uniform way to describe the functions of gene products from organisms across all kingdoms of life and thereby enable analysis of genomic data. Protein annotations are either based on experiments or predicted from protein sequences. Since most sequences have not been experimentally characterized, most available annotations need to be based on predictions. To make as accurate inferences as possible, the GO Consortium's Reference Genome Project is using an explicit evolutionary framework to infer annotations of proteins from a broad set of genomes from experimental annotations in a semi-automated manner. Most components in the pipeline, such as selection of sequences, building multiple sequence alignments and phylogenetic trees, retrieving experimental annotations and depositing inferred annotations, are fully automated. However, the most crucial step in our pipeline relies on software-assisted curation by an expert biologist. This curation tool, Phylogenetic Annotation and INference Tool (PAINT) helps curators to infer annotations among members of a protein family. PAINT allows curators to make precise assertions as to when functions were gained and lost during evolution and record the evidence (e.g. experimentally supported GO annotations and phylogenetic information including orthology) for those assertions. In this article, we describe how we use PAINT to infer protein function in a phylogenetic context with emphasis on its strengths, limitations and guidelines. We also discuss specific examples showing how PAINT annotations compare with those generated by other highly used homology-based methods.", - "journal_title": "Briefings in bioinformatics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/21873635/" - } - ], - "1942712a-a39d-44f7-9b2d-609926374cbd": [ - { - "pub_id": "27490630", - "title": "Genome editing comes of age.", - "authors": "Jin-Soo Kim", - "abstract": "Genome editing harnesses programmable nucleases to cut and paste genetic information in a targeted manner in living cells and organisms. Here, I review the development of programmable nucleases, including zinc finger nucleases (ZFNs), TAL (transcription-activator-like) effector nucleases (TALENs) and CRISPR (cluster of regularly interspaced palindromic repeats)-Cas9 (CRISPR-associated protein 9) RNA-guided endonucleases (RGENs). I specifically highlight the key advances that set the foundation for the rapid and widespread implementation of CRISPR-Cas9 genome editing approaches that has revolutionized the field.", - "journal_title": "Nature protocols", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/27490630/" - } - ], - "f69bcfb9-d0e0-44c5-871d-2a6880950eed": [ - { - "pub_id": "25892967", - "title": "DNA methylation, its mediators and genome integrity.", - "authors": "Huan Meng,Ying Cao,Jinzhong Qin,Xiaoyu Song,Qing Zhang,Yun Shi,Liu Cao", - "abstract": "DNA methylation regulates many cellular processes, including embryonic development, transcription, chromatin structure, X-chromosome inactivation, genomic imprinting and chromosome stability. DNA methyltransferases establish and maintain the presence of 5-methylcytosine (5mC), and ten-eleven translocation cytosine dioxygenases (TETs) oxidise 5mC to 5-hydroxymethylcytosine (5hmC), 5-formylcytosine (5fC) and 5-carboxylcytosine (5caC), which can be removed by base excision repair (BER) proteins. Multiple forms of DNA methylation are recognised by methyl-CpG binding proteins (MeCPs), which play vital roles in chromatin-based transcriptional regulation, DNA repair and replication. Accordingly, defects in DNA methylation and its mediators may cause silencing of tumour suppressor genes and misregulation of multiple cell cycles, DNA repair and chromosome stability genes, and hence contribute to genome instability in various human diseases, including cancer. Thus, understanding functional genetic mutations and aberrant expression of these DNA methylation mediators is critical to deciphering the crosstalk between concurrent genetic and epigenetic alterations in specific cancer types and to the development of new therapeutic strategies.", - "journal_title": "International journal of biological sciences", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/25892967/" - } - ], - "936ddcae-95ca-496a-9ef0-182a6aa62a33": [ - { - "pub_id": "23788249", - "title": "ACMG recommendations for reporting of incidental findings in clinical exome and genome sequencing.", - "authors": "Robert C Green,Jonathan S Berg,Wayne W Grody,Sarah S Kalia,Bruce R Korf,Christa L Martin,Amy L McGuire,Robert L Nussbaum,Julianne M O'Daniel,Kelly E Ormond,Heidi L Rehm,Michael S Watson,Marc S Williams,Leslie G Biesecker, ", - "abstract": "In clinical exome and genome sequencing, there is a potential for the recognition and reporting of incidental or secondary findings unrelated to the indication for ordering the sequencing but of medical value for patient care. The American College of Medical Genetics and Genomics (ACMG) recently published a policy statement on clinical sequencing that emphasized the importance of alerting the patient to the possibility of such results in pretest patient discussions, clinical testing, and reporting of results. The ACMG appointed a Working Group on Incidental Findings in Clinical Exome and Genome Sequencing to make recommendations about responsible management of incidental findings when patients undergo exome or genome sequencing. This Working Group conducted a year-long consensus process, including an open forum at the 2012 Annual Meeting and review by outside experts, and produced recommendations that have been approved by the ACMG Board. Specific and detailed recommendations, and the background and rationale for these recommendations, are described herein. The ACMG recommends that laboratories performing clinical sequencing seek and report mutations of the specified classes or types in the genes listed here. This evaluation and reporting should be performed for all clinical germline (constitutional) exome and genome sequencing, including the \"normal\" of tumor-normal subtractive analyses in all subjects, irrespective of age but excluding fetal samples. We recognize that there are insufficient data on penetrance and clinical utility to fully support these recommendations, and we encourage the creation of an ongoing process for updating these recommendations at least annually as further data are collected.", - "journal_title": "Genetics in medicine : official journal of the American College of Medical Genetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/23788249/" - } - ], - "ae9d5a74-24c1-43f1-b514-5e3f10c91284": [ - { - "pub_id": "21115528", - "title": "Genomics of human longevity.", - "authors": "P E Slagboom,M Beekman,W M Passtoors,J Deelen,A A M Vaarhorst,J M Boer,E B van den Akker,D van Heemst,A J M de Craen,A B Maier,M Rozing,S P Mooijaart,B T Heijmans,R G J Westendorp", - "abstract": "In animal models, single-gene mutations in genes involved in insulin/IGF and target of rapamycin signalling pathways extend lifespan to a considerable extent. The genetic, genomic and epigenetic influences on human longevity are expected to be much more complex. Strikingly however, beneficial metabolic and cellular features of long-lived families resemble those in animals for whom the lifespan is extended by applying genetic manipulation and, especially, dietary restriction. Candidate gene studies in humans support the notion that human orthologues from longevity genes identified in lower species do contribute to longevity but that the influence of the genetic variants involved is small. Here we discuss how an integration of novel study designs, labour-intensive biobanking, deep phenotyping and genomic research may provide insights into the mechanisms that drive human longevity and healthy ageing, beyond the associations usually provided by molecular and genetic epidemiology. Although prospective studies of humans from the cradle to the grave have never been performed, it is feasible to extract life histories from different cohorts jointly covering the molecular changes that occur with age from early development all the way up to the age at death. By the integration of research in different study cohorts, and with research in animal models, biological research into human longevity is thus making considerable progress.", - "journal_title": "Philosophical transactions of the Royal Society of London. Series B, Biological sciences", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/21115528/" - } - ], - "44814475-77c2-4dc5-bdf0-499431f14479": [ - { - "pub_id": "36373988", - "title": "Skin care interventions in infants for preventing eczema and food allergy.", - "authors": "Maeve M Kelleher,Rachel Phillips,Sara J Brown,Suzie Cro,Victoria Cornelius,Karin C L\u00f8drup Carlsen,H\u00e5vard O Skjerven,Eva M Rehbinder,Adrian J Lowe,Eishika Dissanayake,Naoki Shimojo,Kaori Yonezawa,Yukihiro Ohya,Kiwako Yamamoto-Hanada,Kumiko Morita,Emma Axon,Michael Cork,Alison Cooke,Eleanor Van Vogt,Jochen Schmitt,Stephan Weidinger,Danielle McClanahan,Eric Simpson,Lelia Duley,Lisa M Askie,Hywel C Williams,Robert J Boyle", - "abstract": "Eczema and food allergy are common health conditions that usually begin in early childhood and often occur in the same people. They can be associated with an impaired skin barrier in early infancy. It is unclear whether trying to prevent or reverse an impaired skin barrier soon after birth is\u00a0effective for preventing eczema or food allergy. Primary objective To assess the effects of skin care interventions such as emollients for primary prevention of eczema and food allergy in infants. Secondary objective To identify features of study populations such as age, hereditary risk, and adherence to interventions\u00a0that are associated with the greatest treatment benefit or harm for both eczema and food allergy. We performed an updated search of the Cochrane Skin Specialised Register, CENTRAL, MEDLINE, and Embase in September 2021. We searched two trials registers in July 2021. We checked the reference lists of included studies and relevant systematic reviews, and scanned conference proceedings to identify further references to relevant randomised controlled trials (RCTs).\u00a0 SELECTION CRITERIA: We included RCTs\u00a0of skin care interventions that could potentially enhance skin barrier function, reduce dryness, or reduce subclinical inflammation in healthy\u00a0term (> 37 weeks)\u00a0infants (\u2264 12 months) without pre-existing\u00a0eczema,\u00a0food allergy, or other skin condition.\u00a0Eligible comparisons were\u00a0standard care in the locality\u00a0or no treatment.\u00a0Types of skin care interventions could include\u00a0moisturisers/emollients; bathing products; advice regarding reducing soap exposure and\u00a0bathing frequency; and use of water softeners. No minimum follow-up was required. This is a prospective individual participant data (IPD) meta-analysis. We used standard Cochrane methodological procedures, and primary analyses used the IPD dataset. Primary outcomes\u00a0were cumulative incidence of eczema and cumulative incidence of immunoglobulin (Ig)E-mediated\u00a0food allergy by one to three years, both measured at the closest available\u00a0time point to two years.\u00a0Secondary outcomes included\u00a0adverse events during the intervention period; eczema severity (clinician-assessed); parent report of eczema severity; time to onset of eczema; parent report of immediate food allergy; and allergic sensitisation to food or inhalant allergen. We identified 33\u00a0RCTs comprising 25,827\u00a0participants. Of these, 17 studies randomising 5823 participants reported information on one or more outcomes specified in this\u00a0review.\u00a0 We included 11 studies, randomising 5217 participants, in one or more meta-analyses (range 2 to 9\u00a0studies per individual meta-analysis), with 10 of these studies providing IPD; the remaining 6 studies were included in the narrative results only. \u00a0 Most studies were conducted at children's hospitals. Twenty-five studies, including all those contributing data to meta-analyses, randomised\u00a0newborns up to age three weeks to receive a skin care intervention\u00a0or\u00a0standard infant skin care. Eight of the 11 studies contributing to meta-analyses recruited infants at high risk of developing eczema or food allergy, although\u00a0the definition of high risk varied between studies.\u00a0Durations of intervention and follow-up ranged from 24 hours to three\u00a0years. All interventions were compared against\u00a0no skin care intervention or local standard care.\u00a0Of the 17 studies that reported information on our prespecified outcomes, 13 assessed emollients. We assessed most of the evidence in the review as low certainty and had some concerns about risk of bias. A rating of some concerns was most often due to lack of blinding of outcome assessors or significant missing data, which could have impacted outcome measurement but was judged unlikely to have done so.\u00a0We assessed the evidence for the primary food allergy outcome as high risk of bias due to the inclusion of only one trial,\u00a0where findings varied based on different assumptions about missing data. Skin care interventions during infancy probably do not change the risk of eczema by one to three years of age (risk ratio (RR) 1.03, 95% confidence interval (CI) 0.81 to 1.31; risk difference 5 more cases per 1000 infants, 95% CI 28 less to 47 more; moderate-certainty evidence; 3075 participants,\u00a07 trials) or time to onset of eczema (hazard ratio\u00a00.86, 95% CI 0.65 to 1.14; moderate-certainty evidence; 3349 participants, 9 trials). Skin care interventions during infancy may increase the risk of IgE-mediated food allergy by one to three years of age (RR 2.53, 95% CI 0.99 to 6.49; low-certainty evidence; 976 participants,\u00a01 trial) but may not change risk of allergic sensitisation to a food allergen by age one to three years (RR 1.05, 95% CI 0.64 to 1.71; low-certainty evidence; 1794 participants,\u00a03 trials). Skin care interventions during infancy may slightly increase risk of parent report of immediate reaction to a common food allergen at two years (RR 1.27, 95% CI 1.00 to 1.61; low-certainty evidence; 1171 participants,\u00a01 trial); however, this was only seen for cow's milk, and may be unreliable due to over-reporting of milk allergy in infants.\u00a0Skin care interventions during infancy probably increase risk of skin infection over the intervention period (RR 1.33, 95% CI 1.01 to 1.75; risk difference 17 more cases per 1000 infants, 95% CI one more to 38 more; moderate-certainty evidence; 2728 participants,\u00a06 trials) and may increase the risk of infant slippage\u00a0over the intervention period (RR 1.42, 95% CI 0.67 to 2.99; low-certainty evidence; 2538 participants, 4 trials) and stinging/allergic reactions to moisturisers (RR 2.24, 95% 0.67 to 7.43; low-certainty evidence; 343 participants,\u00a04 trials), although CIs for slippages and stinging/allergic reactions were wide and include the possibility of no effect or reduced risk. Preplanned subgroup analyses showed\u00a0that the effects of interventions were not influenced by age, duration of intervention, hereditary risk, filaggrin (FLG) mutation, chromosome 11 intergenic variant rs2212434,\u00a0or classification of intervention\u00a0type\u00a0for risk of developing eczema.\u00a0We could not evaluate these effects on risk of food allergy. Evidence was insufficient to show whether adherence to interventions influenced the relationship between skin care interventions and eczema or food allergy development. Based on low- to moderate-certainty evidence, skin care interventions such as emollients during the first year of life in healthy infants are probably not effective for preventing eczema; may increase risk of food allergy; and probably increase risk of skin infection. Further study is needed to understand whether different approaches to infant skin care might prevent eczema or food allergy.", - "journal_title": "The Cochrane database of systematic reviews", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/36373988/" - } - ], - "50b8428e-114f-47a4-b96f-edb19cf9d09f": [ - { - "pub_id": "25643325", - "title": "A genome-wide association study of myasthenia gravis.", - "authors": "Alan E Renton,Hannah A Pliner,Carlo Provenzano,Amelia Evoli,Roberta Ricciardi,Michael A Nalls,Giuseppe Marangi,Yevgeniya Abramzon,Sampath Arepalli,Sean Chong,Dena G Hernandez,Janel O Johnson,Emanuela Bartoccioni,Flavia Scuderi,Michelangelo Maestri,J Raphael Gibbs,Edoardo Errichiello,Adriano Chi\u00f2,Gabriella Restagno,Mario Sabatelli,Mark Macek,Sonja W Scholz,Andrea Corse,Vinay Chaudhry,Michael Benatar,Richard J Barohn,April McVey,Mamatha Pasnoor,Mazen M Dimachkie,Julie Rowin,John Kissel,Miriam Freimer,Henry J Kaminski,Donald B Sanders,Bernadette Lipscomb,Janice M Massey,Manisha Chopra,James F Howard,Wilma J Koopman,Michael W Nicolle,Robert M Pascuzzi,Alan Pestronk,Charlie Wulf,Julaine Florence,Derrick Blackmore,Aimee Soloway,Zaeem Siddiqi,Srikanth Muppidi,Gil Wolfe,David Richman,Michelle M Mezei,Theresa Jiwa,Joel Oger,Daniel B Drachman,Bryan J Traynor", - "abstract": "Myasthenia gravis is a chronic, autoimmune, neuromuscular disease characterized by fluctuating weakness of voluntary muscle groups. Although genetic factors are known to play a role in this neuroimmunological condition, the genetic etiology underlying myasthenia gravis is not well understood. To identify genetic variants that alter susceptibility to myasthenia gravis, we performed a genome-wide association study. DNA was obtained from 1032 white individuals from North America diagnosed as having acetylcholine receptor antibody-positive myasthenia gravis and 1998 race/ethnicity-matched control individuals from January 2010 to January 2011. These samples were genotyped on Illumina OmniExpress single-nucleotide polymorphism arrays. An independent cohort of 423 Italian cases and 467 Italian control individuals were used for replication. We calculated P values for association between 8,114,394 genotyped and imputed variants across the genome and risk for developing myasthenia gravis using logistic regression modeling. A threshold P value of 5.0\u00d710(-8) was set for genome-wide significance after Bonferroni correction for multiple testing. In the overall case-control cohort, we identified association signals at CTLA4 (rs231770; P=3.98\u00d710(-8); odds ratio, 1.37; 95% CI, 1.25-1.49), HLA-DQA1 (rs9271871; P=1.08\u00d710(-8); odds ratio, 2.31; 95% CI, 2.02-2.60), and TNFRSF11A (rs4263037; P=1.60\u00d710(-9); odds ratio, 1.41; 95% CI, 1.29-1.53). These findings replicated for CTLA4 and HLA-DQA1 in an independent cohort of Italian cases and control individuals. Further analysis revealed distinct, but overlapping, disease-associated loci for early- and late-onset forms of myasthenia gravis. In the late-onset cases, we identified 2 association peaks: one was located in TNFRSF11A (rs4263037; P=1.32\u00d710(-12); odds ratio, 1.56; 95% CI, 1.44-1.68) and the other was detected in the major histocompatibility complex on chromosome 6p21 (HLA-DQA1; rs9271871; P=7.02\u00d710(-18); odds ratio, 4.27; 95% CI, 3.92-4.62). Association within the major histocompatibility complex region was also observed in early-onset cases (HLA-DQA1; rs601006; P=2.52\u00d710(-11); odds ratio, 4.0; 95% CI, 3.57-4.43), although the set of single-nucleotide polymorphisms was different from that implicated among late-onset cases. Our genetic data provide insights into aberrant cellular mechanisms responsible for this prototypical autoimmune disorder. They also suggest that clinical trials of immunomodulatory drugs related to CTLA4 and that are already Food and Drug Administration approved as therapies for other autoimmune diseases could be considered for patients with refractory disease.", - "journal_title": "JAMA neurology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/25643325/" - } - ], - "1a5b8458-1372-4e98-ae82-b18537afc952": [ - { - "pub_id": "23041239", - "title": "Genetic risk factors for ischaemic stroke and its subtypes (the METASTROKE collaboration): a meta-analysis of genome-wide association studies.", - "authors": "Matthew Traylor,Martin Farrall,Elizabeth G Holliday,Cathie Sudlow,Jemma C Hopewell,Yu-Ching Cheng,Myriam Fornage,M Arfan Ikram,Rainer Malik,Steve Bevan,Unnur Thorsteinsdottir,Mike A Nalls,Wt Longstreth,Kerri L Wiggins,Sunaina Yadav,Eugenio A Parati,Anita L Destefano,Bradford B Worrall,Steven J Kittner,Muhammad Saleem Khan,Alex P Reiner,Anna Helgadottir,Sefanja Achterberg,Israel Fernandez-Cadenas,Sherine Abboud,Reinhold Schmidt,Matthew Walters,Wei-Min Chen,E Bernd Ringelstein,Martin O'Donnell,Weang Kee Ho,Joanna Pera,Robin Lemmens,Bo Norrving,Peter Higgins,Marianne Benn,Michele Sale,Gregor Kuhlenb\u00e4umer,Alexander S F Doney,Astrid M Vicente,Hossein Delavaran,Ale Algra,Gail Davies,Sofia A Oliveira,Colin N A Palmer,Ian Deary,Helena Schmidt,Massimo Pandolfo,Joan Montaner,Cara Carty,Paul I W de Bakker,Konstantinos Kostulas,Jose M Ferro,Natalie R van Zuydam,Einar Valdimarsson,B\u00f8rge G Nordestgaard,Arne Lindgren,Vincent Thijs,Agnieszka Slowik,Danish Saleheen,Guillaume Par\u00e9,Klaus Berger,Gudmar Thorleifsson, ,Albert Hofman,Thomas H Mosley,Braxton D Mitchell,Karen Furie,Robert Clarke,Christopher Levi,Sudha Seshadri,Andreas Gschwendtner,Giorgio B Boncoraglio,Pankaj Sharma,Joshua C Bis,Solveig Gretarsdottir,Bruce M Psaty,Peter M Rothwell,Jonathan Rosand,James F Meschia,Kari Stefansson,Martin Dichgans,Hugh S Markus, ", - "abstract": "Various genome-wide association studies (GWAS) have been done in ischaemic stroke, identifying a few loci associated with the disease, but sample sizes have been 3500 cases or less. We established the METASTROKE collaboration with the aim of validating associations from previous GWAS and identifying novel genetic associations through meta-analysis of GWAS datasets for ischaemic stroke and its subtypes. We meta-analysed data from 15 ischaemic stroke cohorts with a total of 12\u2008389 individuals with ischaemic stroke and 62\u2008004 controls, all of European ancestry. For the associations reaching genome-wide significance in METASTROKE, we did a further analysis, conditioning on the lead single nucleotide polymorphism in every associated region. Replication of novel suggestive signals was done in 13\u2008347 cases and 29\u2008083 controls. We verified previous associations for cardioembolic stroke near PITX2 (p=2\u00b78\u00d710(-16)) and ZFHX3 (p=2\u00b728\u00d710(-8)), and for large-vessel stroke at a 9p21 locus (p=3\u00b732\u00d710(-5)) and HDAC9 (p=2\u00b703\u00d710(-12)). Additionally, we verified that all associations were subtype specific. Conditional analysis in the three regions for which the associations reached genome-wide significance (PITX2, ZFHX3, and HDAC9) indicated that all the signal in each region could be attributed to one risk haplotype. We also identified 12 potentially novel loci at p<5\u00d710(-6). However, we were unable to replicate any of these novel associations in the replication cohort. Our results show that, although genetic variants can be detected in patients with ischaemic stroke when compared with controls, all associations we were able to confirm are specific to a stroke subtype. This finding has two implications. First, to maximise success of genetic studies in ischaemic stroke, detailed stroke subtyping is required. Second, different genetic pathophysiological mechanisms seem to be associated with different stroke subtypes. Wellcome Trust, UK Medical Research Council (MRC), Australian National and Medical Health Research Council, National Institutes of Health (NIH) including National Heart, Lung and Blood Institute (NHLBI), the National Institute on Aging (NIA), the National Human Genome Research Institute (NHGRI), and the National Institute of Neurological Disorders and Stroke (NINDS).", - "journal_title": "The Lancet. Neurology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/23041239/" - } - ], - "6636b1f6-bc4c-4952-b526-b7f8298ef8f1": [ - { - "pub_id": "23697701", - "title": "Longitudinal, genome-scale analysis of DNA methylation in twins from birth to 18 months of age reveals rapid epigenetic change in early life and pair-specific effects of discordance.", - "authors": "David Martino,Yuk Jin Loke,Lavinia Gordon,Miina Ollikainen,Mark N Cruickshank,Richard Saffery,Jeffrey M Craig", - "abstract": "The extent to which development- and age-associated epigenetic changes are influenced by genetic, environmental and stochastic factors remains to be discovered. Twins provide an ideal model with which to investigate these influences but previous cross-sectional twin studies provide contradictory evidence of within-pair epigenetic drift over time. Longitudinal twin studies can potentially address this discrepancy. In a pilot, genome-scale study of DNA from buccal epithelium, a relatively homogeneous tissue, we show that one-third of the CpGs assayed show dynamic methylation between birth and 18 months. Although all classes of annotated genomic regions assessed show an increase in DNA methylation over time, probes located in intragenic regions, enhancers and low-density CpG promoters are significantly over-represented, while CpG islands and high-CpG density promoters are depleted among the most dynamic probes. Comparison of co-twins demonstrated that within-pair drift in DNA methylation in our cohort is specific to a subset of pairs, who show more differences at 18 months. The rest of the pairs show either minimal change in methylation discordance, or more similar, converging methylation profiles at 18 months. As with age-associated regions, sites that change in their level of within-pair discordance between birth and 18 months are enriched in genes involved in development, but the average magnitude of change is smaller than for longitudinal change. Our findings suggest that DNA methylation in buccal epithelium is influenced by non-shared stochastic and environmental factors that could reflect a degree of epigenetic plasticity within an otherwise constrained developmental program.", - "journal_title": "Genome biology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/23697701/" - } - ], - "b96e07c6-2312-4c56-ab32-27acf984c7e5": [ - { - "pub_id": "22267201", - "title": "Meta-analyses identify 13 loci associated with age at menopause and highlight DNA repair and immune pathways.", - "authors": "Lisette Stolk,John R B Perry,Daniel I Chasman,Chunyan He,Massimo Mangino,Patrick Sulem,Maja Barbalic,Linda Broer,Enda M Byrne,Florian Ernst,T\u00f5nu Esko,Nora Franceschini,Daniel F Gudbjartsson,Jouke-Jan Hottenga,Peter Kraft,Patrick F McArdle,Eleonora Porcu,So-Youn Shin,Albert V Smith,Sophie van Wingerden,Guangju Zhai,Wei V Zhuang,Eva Albrecht,Behrooz Z Alizadeh,Thor Aspelund,Stefania Bandinelli,Lovorka Barac Lauc,Jacques S Beckmann,Mladen Boban,Eric Boerwinkle,Frank J Broekmans,Andrea Burri,Harry Campbell,Stephen J Chanock,Constance Chen,Marilyn C Cornelis,Tanguy Corre,Andrea D Coviello,Pio d'Adamo,Gail Davies,Ulf de Faire,Eco J C de Geus,Ian J Deary,George V Z Dedoussis,Panagiotis Deloukas,Shah Ebrahim,Gudny Eiriksdottir,Valur Emilsson,Johan G Eriksson,Bart C J M Fauser,Liana Ferreli,Luigi Ferrucci,Krista Fischer,Aaron R Folsom,Melissa E Garcia,Paolo Gasparini,Christian Gieger,Nicole Glazer,Diederick E Grobbee,Per Hall,Toomas Haller,Susan E Hankinson,Merli Hass,Caroline Hayward,Andrew C Heath,Albert Hofman,Erik Ingelsson,A Cecile J W Janssens,Andrew D Johnson,David Karasik,Sharon L R Kardia,Jules Keyzer,Douglas P Kiel,Ivana Kolcic,Zolt\u00e1n Kutalik,Jari Lahti,Sandra Lai,Triin Laisk,Joop S E Laven,Debbie A Lawlor,Jianjun Liu,Lorna M Lopez,Yvonne V Louwers,Patrik K E Magnusson,Mara Marongiu,Nicholas G Martin,Irena Martinovic Klaric,Corrado Masciullo,Barbara McKnight,Sarah E Medland,David Melzer,Vincent Mooser,Pau Navarro,Anne B Newman,Dale R Nyholt,N Charlotte Onland-Moret,Aarno Palotie,Guillaume Par\u00e9,Alex N Parker,Nancy L Pedersen,Petra H M Peeters,Giorgio Pistis,Andrew S Plump,Ozren Polasek,Victor J M Pop,Bruce M Psaty,Katri R\u00e4ikk\u00f6nen,Emil Rehnberg,Jerome I Rotter,Igor Rudan,Cinzia Sala,Andres Salumets,Angelo Scuteri,Andrew Singleton,Jennifer A Smith,Harold Snieder,Nicole Soranzo,Simon N Stacey,John M Starr,Maria G Stathopoulou,Kathleen Stirrups,Ronald P Stolk,Unnur Styrkarsdottir,Yan V Sun,Albert Tenesa,Barbara Thorand,Daniela Toniolo,Laufey Tryggvadottir,Kim Tsui,Sheila Ulivi,Rob M van Dam,Yvonne T van der Schouw,Carla H van Gils,Peter van Nierop,Jacqueline M Vink,Peter M Visscher,Marlies Voorhuis,G\u00e9rard Waeber,Henri Wallaschofski,H Erich Wichmann,Elisabeth Widen,Colette J M Wijnands-van Gent,Gonneke Willemsen,James F Wilson,Bruce H R Wolffenbuttel,Alan F Wright,Laura M Yerges-Armstrong,Tatijana Zemunik,Lina Zgaga,M Carola Zillikens,Marek Zygmunt, ,Alice M Arnold,Dorret I Boomsma,Julie E Buring,Laura Crisponi,Ellen W Demerath,Vilmundur Gudnason,Tamara B Harris,Frank B Hu,David J Hunter,Lenore J Launer,Andres Metspalu,Grant W Montgomery,Ben A Oostra,Paul M Ridker,Serena Sanna,David Schlessinger,Tim D Spector,Kari Stefansson,Elizabeth A Streeten,Unnur Thorsteinsdottir,Manuela Uda,Andr\u00e9 G Uitterlinden,Cornelia M van Duijn,Henry V\u00f6lzke,Anna Murray,Joanne M Murabito,Jenny A Visser,Kathryn L Lunetta", - "abstract": "To newly identify loci for age at natural menopause, we carried out a meta-analysis of 22 genome-wide association studies (GWAS) in 38,968 women of European descent, with replication in up to 14,435 women. In addition to four known loci, we identified 13 loci newly associated with age at natural menopause (at P < 5 \u00d7 10(-8)). Candidate genes located at these newly associated loci include genes implicated in DNA repair (EXO1, HELQ, UIMC1, FAM175A, FANCI, TLK1, POLG and PRIM1) and immune function (IL11, NLRP11 and PRRC2A (also known as BAT2)). Gene-set enrichment pathway analyses using the full GWAS data set identified exoDNase, NF-\u03baB signaling and mitochondrial dysfunction as biological processes related to timing of menopause.", - "journal_title": "Nature genetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/22267201/" - } - ], - "20f0a8d3-f2eb-4635-b2b3-76714a37f043": [ - { - "pub_id": "26087778", - "title": "How Well Do Customers of Direct-to-Consumer Personal Genomic Testing Services Comprehend Genetic Test Results? Findings from the Impact of Personal Genomics Study.", - "authors": "Jenny E Ostergren,Michele C Gornick,Deanna Alexis Carere,Sarah S Kalia,Wendy R Uhlmann,Mack T Ruffin,Joanna L Mountain,Robert C Green,J Scott Roberts, ", - "abstract": "To assess customer comprehension of health-related personal genomic testing (PGT) results. We presented sample reports of genetic results and examined responses to comprehension questions in 1,030 PGT customers (mean age: 46.7 years; 59.9% female; 79.0% college graduates; 14.9% non-White; 4.7% of Hispanic/Latino ethnicity). Sample reports presented a genetic risk for Alzheimer's disease and type 2 diabetes, carrier screening summary results for >30 conditions, results for phenylketonuria and cystic fibrosis, and drug response results for a statin drug. Logistic regression was used to identify correlates of participant comprehension. Participants exhibited high overall comprehension (mean score: 79.1% correct). The highest comprehension (range: 81.1-97.4% correct) was observed in the statin drug response and carrier screening summary results, and lower comprehension (range: 63.6-74.8% correct) on specific carrier screening results. Higher levels of numeracy, genetic knowledge, and education were significantly associated with greater comprehension. Older age (\u2265 60 years) was associated with lower comprehension scores. Most customers accurately interpreted the health implications of PGT results; however, comprehension varied by demographic characteristics, numeracy and genetic knowledge, and types and format of the genetic information presented. Results suggest a need to tailor the presentation of PGT results by test type and customer characteristics.", - "journal_title": "Public health genomics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/26087778/" - } - ], - "ad9d1f0d-9064-4b3d-a76b-b5591952c666": [ - { - "pub_id": "27005778", - "title": "Genome-wide study for circulating metabolites identifies 62 loci and reveals novel systemic effects of LPA.", - "authors": "Johannes Kettunen,Ay\u015fe Demirkan,Peter W\u00fcrtz,Harmen H M Draisma,Toomas Haller,Rajesh Rawal,Anika Vaarhorst,Antti J Kangas,Leo-Pekka Lyytik\u00e4inen,Matti Pirinen,Ren\u00e9 Pool,Antti-Pekka Sarin,Pasi Soininen,Taru Tukiainen,Qin Wang,Mika Tiainen,Tuulia Tynkkynen,Najaf Amin,Tanja Zeller,Marian Beekman,Joris Deelen,Ko Willems van Dijk,T\u00f5nu Esko,Jouke-Jan Hottenga,Elisabeth M van Leeuwen,Terho Lehtim\u00e4ki,Evelin Mihailov,Richard J Rose,Anton J M de Craen,Christian Gieger,Mika K\u00e4h\u00f6nen,Markus Perola,Stefan Blankenberg,Markku J Savolainen,Aswin Verhoeven,Jorma Viikari,Gonneke Willemsen,Dorret I Boomsma,Cornelia M van Duijn,Johan Eriksson,Antti Jula,Marjo-Riitta J\u00e4rvelin,Jaakko Kaprio,Andres Metspalu,Olli Raitakari,Veikko Salomaa,P Eline Slagboom,Melanie Waldenberger,Samuli Ripatti,Mika Ala-Korpela", - "abstract": "Genome-wide association studies have identified numerous loci linked with complex diseases, for which the molecular mechanisms remain largely unclear. Comprehensive molecular profiling of circulating metabolites captures highly heritable traits, which can help to uncover metabolic pathophysiology underlying established disease variants. We conduct an extended genome-wide association study of genetic influences on 123 circulating metabolic traits quantified by nuclear magnetic resonance metabolomics from up to 24,925 individuals and identify eight novel loci for amino acids, pyruvate and fatty acids. The LPA locus link with cardiovascular risk exemplifies how detailed metabolic profiling may inform underlying aetiology via extensive associations with very-low-density lipoprotein and triglyceride metabolism. Genetic fine mapping and Mendelian randomization uncover wide-spread causal effects of lipoprotein(a) on overall lipoprotein metabolism and we assess potential pleiotropic consequences of genetically elevated lipoprotein(a) on diverse morbidities via electronic health-care records. Our findings strengthen the argument for safe LPA-targeted intervention to reduce cardiovascular risk.", - "journal_title": "Nature communications", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/27005778/" - } - ], - "a4113d0f-5cb1-420d-97a4-463c488a2d56": [ - { - "pub_id": "22672568", - "title": "A genome-wide association study of venous thromboembolism identifies risk variants in chromosomes 1q24.2 and 9q.", - "authors": "J A Heit,S M Armasu,Y W Asmann,J M Cunningham,M E Matsumoto,T M Petterson,M De Andrade", - "abstract": "To identify venous thromboembolism (VTE) disease-susceptibility genes. We performed in silico genome wide association scan (GWAS) analyses using genotype data imputed to approximately 2.5 million single-nucleotide polymorphisms (SNPs) from adults with objectively-diagnosed VTE (n=1503), and controls frequency matched on age and gender (n=1459; discovery population). Single-nucleotide polymorphisms exceeding genome-wide significance were replicated in a separate population (VTE cases, n=1407; controls, n=1418). Genes associated with VTE were re-sequenced. Seven SNPs exceeded genome-wide significance (P<5\u00d710(-8)): four on chromosome 1q24.2 (F5 rs6025 [factor V Leiden], BLZF1 rs7538157, NME7 rs16861990 and SLC19A2 rs2038024) and three on chromosome 9q34.2 (ABO rs2519093 [ABO intron 1], rs495828, rs8176719 [ABO blood type O allele]). The replication study confirmed a significant association of F5, NME7 and ABO with VTE. However, F5 was the main signal on 1q24.2 as only ABO SNPs remained significantly associated with VTE after adjusting for F5 rs6025. This 1q24.2 region was shown to be inherited as a haplotype block. ABO re-sequencing identified 15 novel single nucleotide variations (SNV) in ABO intron 6 and the ABO 3' UTR that were strongly associated with VTE (P<10(-4)) and belonged to three distinct linkage disequilibrium (LD) blocks; none were in LD with ABO rs8176719 or rs2519093. Our sample size provided 80% power to detect odds ratios (ORs)=2.0 and 1.51 for minor allele frequencies=0.05 and 0.5, respectively (\u03b1=1\u00d710(-8); 1% VTE prevalence). Apart from F5 rs6025, ABO rs8176719, rs2519093 and F2 rs1799963, additional common and high VTE-risk SNPs among whites are unlikely.", - "journal_title": "Journal of thrombosis and haemostasis : JTH", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/22672568/" - } - ], - "f28aef80-335a-4631-a178-f9b0b588478e": [ - { - "pub_id": "26861258", - "title": "Aging-associated DNA methylation changes in middle-aged individuals: the Young Finns study.", - "authors": "L Kananen,S Marttila,T Nevalainen,J Jylh\u00e4v\u00e4,N Mononen,M K\u00e4h\u00f6nen,O T Raitakari,T Lehtim\u00e4ki,M Hurme", - "abstract": "Chronological aging-associated changes in the human DNA methylome have been studied by multiple epigenome-wide association studies (EWASs). Certain CpG sites have been identified as aging-associated in multiple studies, and the majority of the sites identified in various studies show common features regarding location and direction of the methylation change. However, as a whole, the sets of aging-associated CpGs identified in different studies, even with similar tissues and age ranges, show only limited overlap. In this study, we further explore and characterize CpG sites that show close relationship between their DNA methylation level and chronological age during adulthood and which bear the relationship regardless of blood cell type heterogeneity. In this study, with a multivariable regression model adjusted for cell type heterogeneity, we identified 1202 aging-associated CpG sites (a-CpGs, FDR < 5%), in whole blood in a population with an especially narrow age range (40 - 49 years). Repeatedly reported a-CpGs located in genes ELOVL2, FHL2, PENK and KLF14 were also identified. Regions with aging-associated hypermethylation were enriched regarding several gene ontology (GO) terms (especially in the cluster of developmental processes), whereas hypomethylated sites showed no enrichment. The genes with higher numbers of a-CpG hits were more often hypermethylated with advancing age. The comparison analysis revealed that of the 1202 a-CpGs identified in the present study, 987 were identified as differentially methylated also between nonagenarians and young adults in a previous study (The Vitality 90+ study), and importantly, the directions of changes were identical in the previous and in the present study. Here we report that aging-associated DNA methylation features can be identified in a middle-aged population with an age range of only 9 years. A great majority of these sites have been previously reported as aging-associated in a population aged 19 to 90 years. Aging is associated with different types of changes in DNA methylation, clock-like as well as random. We speculate that the a-CpGs identified here in a population with a narrow age-range represent clock-like changes, as they showed concordant methylation behavior in population spanning whole adulthood as well.", - "journal_title": "BMC genomics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/26861258/" - } - ], - "0e27d15f-e4a2-4902-b4a4-1e72c4202346": [ - { - "pub_id": "30099000", - "title": "Association between physical exercise and mental health in 1\u00b72 million individuals in the USA between 2011 and 2015: a cross-sectional study.", - "authors": "Sammi R Chekroud,Ralitza Gueorguieva,Amanda B Zheutlin,Martin Paulus,Harlan M Krumholz,John H Krystal,Adam M Chekroud", - "abstract": "Exercise is known to be associated with reduced risk of all-cause mortality, cardiovascular disease, stroke, and diabetes, but its association with mental health remains unclear. We aimed to examine the association between exercise and mental health burden in a large sample, and to better understand the influence of exercise type, frequency, duration, and intensity. In this cross-sectional study, we analysed data from 1\u2008237\u2008194 people aged 18 years or older in the USA from the 2011, 2013, and 2015 Centers for Disease Control and Prevention Behavioral Risk Factors Surveillance System survey. We compared the number of days of bad self-reported mental health between individuals who exercised and those who did not, using an exact non-parametric matching procedure to balance the two groups in terms of age, race, gender, marital status, income, education level, body-mass index category, self-reported physical health, and previous diagnosis of depression. We examined the effects of exercise type, duration, frequency, and intensity using regression methods adjusted for potential confounders, and did multiple sensitivity analyses. Individuals who exercised had 1\u00b749 (43\u00b72%) fewer days of poor mental health in the past month than individuals who did not exercise but were otherwise matched for several physical and sociodemographic characteristics (W=7\u00b742\u2008\u00d7\u200810<sup>10</sup>, p<2\u00b72\u2008\u00d7\u200810<sup>-16</sup>). All exercise types were associated with a lower mental health burden (minimum reduction of 11\u00b78% and maximum reduction of 22\u00b73%) than not exercising (p<2\u00b72\u2008\u00d7\u200810<sup>-16</sup> for all exercise types). The largest associations were seen for popular team sports (22\u00b73% lower), cycling (21\u00b76% lower), and aerobic and gym activities (20\u00b71% lower), as well as durations of 45 min and frequencies of three to five times per week. In a large US sample, physical exercise was significantly and meaningfully associated with self-reported mental health burden in the past month. More exercise was not always better. Differences as a function of exercise were large relative to other demographic variables such as education and income. Specific types, durations, and frequencies of exercise might be more effective clinical targets than others for reducing mental health burden, and merit interventional study. Cloud computing resources were provided by Microsoft.", - "journal_title": "The lancet. Psychiatry", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/30099000/" - } - ], - "6c2da9d6-ca7a-41a8-a8bc-072ba03d3e82": [ - { - "pub_id": "25332075", - "title": "The role of the retromer complex in aging-related neurodegeneration: a molecular and genomic review.", - "authors": "Christiane Reitz", - "abstract": "The retromer coat complex is a vital component of the intracellular trafficking mechanism sorting cargo from the endosomes to the trans-Golgi network or to the cell surface. In recent years, genes encoding components of the retromer coat complex and members of the vacuolar protein sorting 10 (Vps10) family of receptors, which play pleiotropic functions in protein trafficking and intracellular/intercellular signaling in neuronal and non-neuronal cells and are primary cargos of the retromer complex, have been implicated as genetic risk factors for sporadic and autosomal dominant forms of several neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease and frontotemporal lobar degeneration. In addition to their functions in protein trafficking, the members of the Vps10 receptor family (sortilin, SorL1, SorCS1, SorCS2, and SorCS3) modulate neurotrophic signaling pathways. Both sortilin and SorCS2 act as cell surface receptors to mediate acute responses to proneurotrophins. In addition, sortilin can modulate the intracellular response to brain-derived neurotrophic factor (BDNF) by direct control of BDNF levels and regulating anterograde trafficking of Trk receptors to the synapse. This review article summarizes the emerging data from this rapidly growing field of intracellular trafficking signaling in the pathogenesis of neurodegeneration.", - "journal_title": "Molecular genetics and genomics : MGG", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/25332075/" - } - ], - "87e2ac5a-bbdb-42a0-80d5-3438d54e32c9": [ - { - "pub_id": "26994357", - "title": "Enacting the molecular imperative: How gene-environment interaction research links bodies and environments in the post-genomic age.", - "authors": "Katherine Weatherford Darling,Sara L Ackerman,Robert H Hiatt,Sandra Soo-Jin Lee,Janet K Shim", - "abstract": "Despite a proclaimed shift from 'nature versus nurture' to 'genes and environment' paradigms within biomedical and genomic science, capturing the environment and identifying gene-environment interactions (GEIs) has remained a challenge. What does 'the environment' mean in the post-genomic age? In this paper, we present qualitative data from a study of 33 principal investigators funded by the U.S. National Institutes of Health to conduct etiological research on three complex diseases (cancer, cardiovascular disease and diabetes). We examine their research practices and perspectives on the environment through the concept of molecularization: the social processes and transformations through which phenomena (diseases, identities, pollution, food, racial/ethnic classifications) are re-defined in terms of their molecular components and described in the language of molecular biology. We show how GEI researchers' expansive conceptualizations of the environment ultimately yield to the imperative to molecularize and personalize the environment. They seek to 'go into the body' and re-work the boundaries between bodies and environments. In the process, they create epistemic hinges to facilitate a turn from efforts to understand social and environmental exposures outside the body, to quantifying their effects inside the body. GEI researchers respond to these emergent imperatives with a mixture of excitement, ambivalence and frustration. We reflect on how GEI researchers struggle to make meaning of molecules in their work, and how they grapple with molecularization as a methodological and rhetorical imperative as well as a process transforming biomedical research practices.", - "journal_title": "Social science & medicine (1982)", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/26994357/" - } - ], - "b684132e-10ca-40b3-b7de-2d97762f9d28": [ - { - "pub_id": "25670335", - "title": "Association of Alzheimer's disease GWAS loci with MRI markers of brain aging.", - "authors": "Ganesh Chauhan,Hieab H H Adams,Joshua C Bis,Galit Weinstein,Lei Yu,Anna Maria T\u00f6glhofer,Albert Vernon Smith,Sven J van der Lee,Rebecca F Gottesman,Russell Thomson,Jing Wang,Qiong Yang,Wiro J Niessen,Oscar L Lopez,James T Becker,Thanh G Phan,Richard J Beare,Konstantinos Arfanakis,Debra Fleischman,Meike W Vernooij,Bernard Mazoyer,Helena Schmidt,Velandai Srikanth,David S Knopman,Clifford R Jack,Philippe Amouyel,Albert Hofman,Charles DeCarli,Christophe Tzourio,Cornelia M van Duijn,David A Bennett,Reinhold Schmidt,William T Longstreth,Thomas H Mosley,Myriam Fornage,Lenore J Launer,Sudha Seshadri,M Arfan Ikram,Stephanie Debette", - "abstract": "Whether novel risk variants of Alzheimer's disease (AD) identified through genome-wide association studies also influence magnetic resonance imaging-based intermediate phenotypes of AD in the general population is unclear. We studied association of 24 AD risk loci with intracranial volume, total brain volume, hippocampal volume (HV), white matter hyperintensity burden, and brain infarcts in a meta-analysis of genetic association studies from large population-based samples (N = 8175-11,550). In single-SNP based tests, AD risk allele of APOE (rs2075650) was associated with smaller HV (p = 0.0054) and CD33 (rs3865444) with smaller intracranial volume (p = 0.0058). In gene-based tests, there was associations of HLA-DRB1 with total brain volume (p = 0.0006) and BIN1 with HV (p = 0.00089). A weighted AD genetic risk score was associated with smaller HV (beta \u00b1 SE = -0.047 \u00b1 0.013, p = 0.00041), even after excluding the APOE locus (p = 0.029). However, only association of AD genetic risk score with HV, including APOE, was significant after multiple testing correction (including number of independent phenotypes tested). These results suggest that novel AD genetic risk variants may contribute to structural brain aging in nondemented older community persons.", - "journal_title": "Neurobiology of aging", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/25670335/" - } - ], - "b4a3e096-ad2f-46e0-9482-101fc08c0b51": [ - { - "pub_id": "27687219", - "title": "Resistance training and redox homeostasis: Correlation with age-associated genomic changes.", - "authors": "Ivan Dimauro,Mattia Scalabrin,Cristina Fantini,Elisa Grazioli,Maria Reyes Beltran Valls,Neri Mercatelli,Attilio Parisi,Stefania Sabatini,Luigi Di Luigi,Daniela Caporossi", - "abstract": "Regular physical activity is effective as prevention and treatment for different chronic conditions related to the ageing processes. In fact, a sedentary lifestyle has been linked to a worsening of cellular ageing biomarkers such as telomere length (TL) and/or specific epigenetic changes (e.g. DNA methylation), with increase of the propensity to aging-related diseases and premature death. Extending our previous findings, we aimed to test the hypothesis that 12 weeks of low frequency, moderate intensity, explosive-type resistance training (EMRT) may attenuate age-associated genomic changes. To this aim, TL, global DNA methylation, TRF2, Ku80, SIRT1, SIRT2 and global protein acetylation, as well as other proteins involved in apoptotic pathway (Bcl-2, Bax and Caspase-3), antioxidant response (TrxR1 and MnSOD) and oxidative damage (myeloperoxidase) were evaluated before and after EMRT in whole blood or peripheral mononuclear cells (PBMCs) of elderly subjects. Our findings confirm the potential of EMRT to induce an adaptive change in the antioxidant protein systems at systemic level and suggest a putative role of resistance training in the reduction of global DNA methylation. Moreover, we observed that EMRT counteracts the telomeres' shortening in a manner that proved to be directly correlated with the amelioration of redox homeostasis and efficacy of training regime, evaluated as improvement of both muscle's power/strength and functional parameters.", - "journal_title": "Redox biology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/27687219/" - } - ], - "e8be2280-10e9-4b62-af14-0772947d2d7e": [ - { - "pub_id": "20843241", - "title": "Preparing for a consumer-driven genomic age.", - "authors": "James P Evans,David C Dale,Cathy Fomous", - "abstract": "", - "journal_title": "The New England journal of medicine", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/20843241/" - } - ], - "08f00cca-702a-4570-9d76-8aae947ce6f9": [ - { - "pub_id": "22037496", - "title": "5-hmC-mediated epigenetic dynamics during postnatal neurodevelopment and aging.", - "authors": "Keith E Szulwach,Xuekun Li,Yujing Li,Chun-Xiao Song,Hao Wu,Qing Dai,Hasan Irier,Anup K Upadhyay,Marla Gearing,Allan I Levey,Aparna Vasanthakumar,Lucy A Godley,Qiang Chang,Xiaodong Cheng,Chuan He,Peng Jin", - "abstract": "DNA methylation dynamics influence brain function and are altered in neurological disorders. 5-hydroxymethylcytosine (5-hmC), a DNA base that is derived from 5-methylcytosine, accounts for \u223c40% of modified cytosine in the brain and has been implicated in DNA methylation-related plasticity. We mapped 5-hmC genome-wide in mouse hippocampus and cerebellum at three different ages, which allowed us to assess its stability and dynamic regulation during postnatal neurodevelopment through adulthood. We found developmentally programmed acquisition of 5-hmC in neuronal cells. Epigenomic localization of 5-hmC-regulated regions revealed stable and dynamically modified loci during neurodevelopment and aging. By profiling 5-hmC in human cerebellum, we found conserved genomic features of 5-hmC. Finally, we found that 5-hmC levels were inversely correlated with methyl-CpG-binding protein 2 dosage, a protein encoded by a gene in which mutations cause Rett syndrome. These data suggest that 5-hmC-mediated epigenetic modification is critical in neurodevelopment and diseases.", - "journal_title": "Nature neuroscience", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/22037496/" - } - ], - "ee2d049c-3ef6-4507-aede-e7b503c24c86": [ - { - "pub_id": "26354523", - "title": "Endometrial cancer.", - "authors": "Philippe Morice,Alexandra Leary,Carien Creutzberg,Nadeem Abu-Rustum,Emile Darai", - "abstract": "Endometrial cancer is the most common gynaecological tumour in developed countries, and its incidence is increasing. The most frequently occurring histological subtype is endometrioid adenocarcinoma. Patients are often diagnosed when the disease is still confined to the uterus. Standard treatment consists of primary hysterectomy and bilateral salpingo-oophorectomy, often using minimally invasive approaches (laparoscopic or robotic). Lymph node surgical strategy is contingent on histological factors (subtype, tumour grade, involvement of lymphovascular space), disease stage (including myometrial invasion), patients' characteristics (age and comorbidities), and national and international guidelines. Adjuvant treatment is tailored according to histology and stage. Various classifications are used to assess the risks of recurrence and to determine optimum postoperative management. 5 year overall survival ranges from 74% to 91% in patients without metastatic disease. Trials are ongoing in patients at high risk of recurrence (including chemotherapy, chemoradiation therapy, and molecular targeted therapies) to assess the modalities that best balance optimisation of survival with the lowest adverse effects on quality of life.", - "journal_title": "Lancet (London, England)", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/26354523/" - } - ], - "adf0d2cf-95ab-4bbb-92b1-f8d6489b6b5f": [ - { - "pub_id": "32808580", - "title": "Sepsis-associated encephalopathy and septic encephalitis: an update.", - "authors": "Simone C Tauber,Marija Djukic,Johannes Gossner,Helmut Eiffert,Wolfgang Br\u00fcck,Roland Nau", - "abstract": "Sepsis-associated encephalopathy (SAE) and septic encephalitis (SE) are associated with increased mortality, long-term cognitive impairment, and focal neurological deficits. The PUBMED database was searched 2016-2020. The clinical manifestation of SAE is delirium, SE additionally is characterized by focal neurological symptoms. SAE is caused by inflammation with endothelial/microglial activation, increase of permeability of the blood-brain-barrier, hypoxia, imbalance of neurotransmitters, glial activation, axonal, and neuronal loss. Septic-embolic (SEE) and septic-metastatic encephalitis (SME) are characterized by focal ischemia (SEE) and small abscesses (SME). The continuum between SAE, SME, and SEE is documented by imaging techniques and autopsies. The backbone of treatment is rapid optimum antibiotic therapy. Experimental approaches focus on modulation of inflammation, stabilization of the blood-brain barrier, and restoration of membrane/mitochondrial function. The most promising diagnostic approaches are new imaging techniques. The most important measure to fight delirium remains establishment of daily structure and adequate sensory stimuli. Dexmedetomidine and melatonin appear to reduce the frequency of delirium, their efficacy in SAE and SE remains to be established. Drugs already licensed for other indications or available as food supplements which may be effective in SAE are statins, L-DOPA/benserazide, \u03b2-hydroxybutyrate, palmitoylethanolamide, and tetracyclines or other bactericidal non-lytic antibiotics.", - "journal_title": "Expert review of anti-infective therapy", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/32808580/" - } - ], - "e52068b3-bc21-48b4-9e22-6d720df79a73": [ - { - "pub_id": "21239051", - "title": "Identification of ADAMTS7 as a novel locus for coronary atherosclerosis and association of ABO with myocardial infarction in the presence of coronary atherosclerosis: two genome-wide association studies.", - "authors": "Muredach P Reilly,Mingyao Li,Jing He,Jane F Ferguson,Ioannis M Stylianou,Nehal N Mehta,Mary Susan Burnett,Joseph M Devaney,Christopher W Knouff,John R Thompson,Benjamin D Horne,Alexandre F R Stewart,Themistocles L Assimes,Philipp S Wild,Hooman Allayee,Patrick Linsel Nitschke,Riyaz S Patel, , ,Nicola Martinelli,Domenico Girelli,Arshed A Quyyumi,Jeffrey L Anderson,Jeanette Erdmann,Alistair S Hall,Heribert Schunkert,Thomas Quertermous,Stefan Blankenberg,Stanley L Hazen,Robert Roberts,Sekar Kathiresan,Nilesh J Samani,Stephen E Epstein,Daniel J Rader", - "abstract": "We tested whether genetic factors distinctly contribute to either development of coronary atherosclerosis or, specifically, to myocardial infarction in existing coronary atherosclerosis. We did two genome-wide association studies (GWAS) with coronary angiographic phenotyping in participants of European ancestry. To identify loci that predispose to angiographic coronary artery disease (CAD), we compared individuals who had this disorder (n=12,393) with those who did not (controls, n=7383). To identify loci that predispose to myocardial infarction, we compared patients who had angiographic CAD and myocardial infarction (n=5783) with those who had angiographic CAD but no myocardial infarction (n=3644). In the comparison of patients with angiographic CAD versus controls, we identified a novel locus, ADAMTS7 (p=4\u00b798\u00d710(-13)). In the comparison of patients with angiographic CAD who had myocardial infarction versus those with angiographic CAD but no myocardial infarction, we identified a novel association at the ABO locus (p=7\u00b762\u00d710(-9)). The ABO association was attributable to the glycotransferase-deficient enzyme that encodes the ABO blood group O phenotype previously proposed to protect against myocardial infarction. Our findings indicate that specific genetic predispositions promote the development of coronary atherosclerosis whereas others lead to myocardial infarction in the presence of coronary atherosclerosis. The relation to specific CAD phenotypes might modify how novel loci are applied in personalised risk assessment and used in the development of novel therapies for CAD. The PennCath and MedStar studies were supported by the Cardiovascular Institute of the University of Pennsylvania, by the MedStar Health Research Institute at Washington Hospital Center and by a research grant from GlaxoSmithKline. The funding and support for the other cohorts contributing to the paper are described in the webappendix.", - "journal_title": "Lancet (London, England)", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/21239051/" - } - ], - "1aa8d948-0416-4081-b822-933c817ef817": [ - { - "pub_id": "26685868", - "title": "Global genome splicing analysis reveals an increased number of alternatively spliced genes with aging.", - "authors": "Sof\u00eda A Rodr\u00edguez,Diana Grochov\u00e1,Tom\u00e1s McKenna,Bhavesh Borate,Niraj S Trivedi,Michael R Erdos,Maria Eriksson", - "abstract": "Alternative splicing (AS) is a key regulatory mechanism for the development of different tissues; however, not much is known about changes to alternative splicing during aging. Splicing events may become more frequent and widespread genome-wide as tissues age and the splicing machinery stringency decreases. Using skin, skeletal muscle, bone, thymus, and white adipose tissue from wild-type C57BL6/J male mice (4 and 18 months old), we examined the effect of age on splicing by AS analysis of the differential exon usage of the genome. The results identified a considerable number of AS genes in skeletal muscle, thymus, bone, and white adipose tissue between the different age groups (ranging from 27 to 246 AS genes corresponding to 0.3-3.2% of the total number of genes analyzed). For skin, skeletal muscle, and bone, we included a later age group (28 months old) that showed that the number of alternatively spliced genes increased with age in all three tissues (P < 0.01). Analysis of alternatively spliced genes across all tissues by gene ontology and pathway analysis identified 158 genes involved in RNA processing. Additional analysis of AS in a mouse model for the premature aging disease Hutchinson-Gilford progeria syndrome was performed. The results show that expression of the mutant protein, progerin, is associated with an impaired developmental splicing. As progerin accumulates, the number of genes with AS increases compared to in wild-type skin. Our results indicate the existence of a mechanism for increased AS during aging in several tissues, emphasizing that AS has a more important role in the aging process than previously known.", - "journal_title": "Aging cell", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/26685868/" - } - ], - "30284f3b-068c-49d1-b2e6-cbf7e10a20ea": [ - { - "pub_id": "23196856", - "title": "Early life socioeconomic factors and genomic DNA methylation in mid-life.", - "authors": "Parisa Tehranifar,Hui-Chen Wu,Xiaozhou Fan,Julie D Flom,Jennifer S Ferris,Yoon Hee Cho,Karina Gonzalez,Regina M Santella,Mary Beth Terry", - "abstract": "Epigenetic modifications may be one mechanism linking early life factors, including parental socioeconomic status (SES), to adult onset disease risk. However, SES influences on DNA methylation patterns remain largely unknown. In a US birth cohort of women, we examined whether indicators of early life and adult SES were associated with white blood cell methylation of repetitive elements (Sat2, Alu and LINE-1) in adulthood. Low family income at birth was associated with higher Sat2 methylation (\u03b2 = 19.7, 95% CI: 0.4, 39.0 for lowest vs. highest income quartile) and single parent family was associated with higher Alu methylation (\u03b2 = 23.5, 95% CI: 2.6, 44.4), after adjusting for other early life factors. Lower adult education was associated with lower Sat2 methylation (\u03b2 = -16.7, 95% CI: -29.0, -4.5). There were no associations between early life SES and LINE-1 methylation. Overall, our preliminary results suggest possible influences of SES across the life-course on genomic DNA methylation in adult women. However, these preliminary associations need to be replicated in larger prospective studies.", - "journal_title": "Epigenetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/23196856/" - } - ], - "1b1ff8af-26d0-46de-874e-a8b1da9485ac": [ - { - "pub_id": "23360310", - "title": "Genomes of replicatively senescent cells undergo global epigenetic changes leading to gene silencing and activation of transposable elements.", - "authors": "Marco De Cecco,Steven W Criscione,Edward J Peckham,Sara Hillenmeyer,Eliza A Hamm,Jayameenakshi Manivannan,Abigail L Peterson,Jill A Kreiling,Nicola Neretti,John M Sedivy", - "abstract": "Replicative cellular senescence is an important tumor suppression mechanism and also contributes to aging. Progression of both cancer and aging include significant epigenetic components, but the chromatin changes that take place during cellular senescence are not known. We used formaldehyde assisted isolation of regulatory elements (FAIRE) to map genome-wide chromatin conformations. In contrast to growing cells, whose genomes are rich with features of both open and closed chromatin, FAIRE profiles of senescent cells are significantly smoothened. This is due to FAIRE signal loss in promoters and enhancers of active genes, and FAIRE signal gain in heterochromatic gene-poor regions. Chromatin of major retrotransposon classes, Alu, SVA and L1, becomes relatively more open in senescent cells, affecting most strongly the evolutionarily recent elements, and leads to an increase in their transcription and ultimately transposition. Constitutive heterochromatin in centromeric and peri-centromeric regions also becomes relatively more open, and the transcription of satellite sequences increases. The peripheral heterochromatic compartment (PHC) becomes less prominent, and centromere structure becomes notably enlarged. These epigenetic changes progress slowly after the onset of senescence, with some, such as mobilization of retrotransposable elements becoming prominent only at late times. Many of these changes have also been noted in cancer cells.", - "journal_title": "Aging cell", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/23360310/" - } - ], - "68555763-71b0-4935-83ac-143f1d610e66": [ - { - "pub_id": "24330282", - "title": "Age-associated bidirectional modulation of gene expression in single identified R15 neuron of Aplysia.", - "authors": "Beena M Kadakkuzha,Komolitdin Akhmedov,Tom R Capo,Anthony C Carvalloza,Mohammad Fallahi,Sathyanarayanan V Puthanveettil", - "abstract": "Despite the advances in our understanding of aging-associated behavioral decline, relatively little is known about how aging affects neural circuits that regulate specific behaviors, particularly the expression of genes in specific neural circuits during aging. We have addressed this by exploring a peptidergic neuron R15, an identified neuron of the marine snail Aplysia californica. R15 is implicated in reproduction and osmoregulation and responds to neurotransmitters such as acetylcholine, serotonin and glutamate and is characterized by its action potential bursts. We examined changes in gene expression in R15 neurons during aging by microarray analyses of RNAs from two different age groups, mature and old animals. Specifically we find that 1083 ESTs are differentially regulated in mature and old R15 neurons. Bioinformatics analyses of these genes have identified specific biological pathways that are up or downregulated in mature and old neurons. Comparison with human signaling networks using pathway analyses have identified three major networks [(1) cell signaling, cell morphology, and skeletal muscular system development (2) cell death and survival, cellular function maintenance and embryonic development and (3) neurological diseases, developmental and hereditary disorders] altered in old R15 neurons. Furthermore, qPCR analysis of single R15 neurons to quantify expression levels of candidate regulators involved in transcription (CREB1) and translation (S6K) showed that aging is associated with a decrease in expression of these regulators, and similar analysis in three other neurons (L7, L11 and R2) showed that gene expression change during aging could be bidirectional. We find that aging is associated with bidirectional changes in gene expression. Detailed bioinformatics analyses and human homolog searches have identified specific biological processes and human-relevant signaling pathways in R15 that are affected during aging. Evaluation of gene expression changes in different neurons suggests specific transcriptomic signature of single neurons during aging.", - "journal_title": "BMC genomics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/24330282/" - } - ], - "28412831-a9d0-4399-a2cd-17e619843062": [ - { - "pub_id": "22056670", - "title": "Rejuvenating senescent and centenarian human cells by reprogramming through the pluripotent state.", - "authors": "Laure Lapasset,Ollivier Milhavet,Alexandre Prieur,Emilie Besnard,Amelie Babled,Nafissa A\u00eft-Hamou,Julia Leschik,Franck Pellestor,Jean-Marie Ramirez,John De Vos,Sylvain Lehmann,Jean-Marc Lemaitre", - "abstract": "Direct reprogramming of somatic cells into induced pluripotent stem cells (iPSCs) provides a unique opportunity to derive patient-specific stem cells with potential applications in tissue replacement therapies and without the ethical concerns of human embryonic stem cells (hESCs). However, cellular senescence, which contributes to aging and restricted longevity, has been described as a barrier to the derivation of iPSCs. Here we demonstrate, using an optimized protocol, that cellular senescence is not a limit to reprogramming and that age-related cellular physiology is reversible. Thus, we show that our iPSCs generated from senescent and centenarian cells have reset telomere size, gene expression profiles, oxidative stress, and mitochondrial metabolism, and are indistinguishable from hESCs. Finally, we show that senescent and centenarian-derived pluripotent stem cells are able to redifferentiate into fully rejuvenated cells. These results provide new insights into iPSC technology and pave the way for regenerative medicine for aged patients.", - "journal_title": "Genes & development", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/22056670/" - } - ], - "f3802c23-8f2b-49c4-81a5-22d1612d5157": [ - { - "pub_id": "21553638", - "title": "Different differences: the use of 'genetic ancestry' versus race in biomedical human genetic research.", - "authors": "Joan H Fujimura,Ramya Rajagopalan", - "abstract": "This article presents findings from our ethnographic research on biomedical scientists' studies of human genetic variation and common complex disease. We examine the socio-material work involved in genome-wide association studies (GWAS) and discuss whether, how, and when notions of race and ethnicity are or are not used. We analyze how researchers produce simultaneously different kinds of populations and population differences. Although many geneticists use race in their analyses, we find some who have invented a statistical genetics method and associated software that they use specifically to avoid using categories of race in their genetic analysis. Their method allows them to operationalize their concept of 'genetic ancestry' without resorting to notions of race and ethnicity. We focus on the construction and implementation of the software's algorithms, and discuss the consequences and implications of the software technology for debates and policies around the use of race in genetics research. We also demonstrate that the production and use of their method involves a dynamic and fluid assemblage of actors in various disciplines responding to disciplinary and sociopolitical contexts and concerns. This assemblage also includes particular discourses on human history and geography as they become entangled with research on genetic markers and disease.We introduce the concept of'genome geography' to analyze how some researchers studying human genetic variation'locate' stretches of DNA in different places and times. The concept of genetic ancestry and the practice of genome geography rely on old discourses, but they also incorporate new technologies, infrastructures, and political and scientific commitments. Some of these new technologies provide opportunities to change some of our institutional and cultural forms and frames around notions of difference and similarity. Nevertheless, we also highlight the slipperiness of genome geography and the tenacity of race and race concepts.", - "journal_title": "Social studies of science", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/21553638/" - } - ], - "5b5c0c2f-0b8b-43d0-b96a-3c7ddf68cead": [ - { - "pub_id": "23633913", - "title": "Chromatin remodeling, DNA damage repair and aging.", - "authors": "Baohua Liu,Raymond Kh Yip,Zhongjun Zhou", - "abstract": "Cells are constantly exposed to a variety of environmental and endogenous conditions causing DNA damage, which is detected and repaired by conserved DNA repair pathways to maintain genomic integrity. Chromatin remodeling is critical in this process, as the organization of eukaryotic DNA into compact chromatin presents a natural barrier to all DNA-related events. Studies on human premature aging syndromes together with normal aging have suggested that accumulated damages might lead to exhaustion of resources that are required for physiological functions and thus accelerate aging. In this manuscript, combining the present understandings and latest findings, we focus mainly on discussing the role of chromatin remodeling in the repair of DNA double-strand breaks (DSBs) and regulation of aging.", - "journal_title": "Current genomics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/23633913/" - } - ], - "940d5894-6bc8-49ed-920c-a6539bfdb0ac": [ - { - "pub_id": "20451302", - "title": "Genome-wide analysis of miRNA expression reveals a potential role for miR-144 in brain aging and spinocerebellar ataxia pathogenesis.", - "authors": "Stephan Persengiev,Ivanela Kondova,Nel Otting,Arnulf H Koeppen,Ronald E Bontrop", - "abstract": "Neurodegenerative pathologies associated with aging exhibit clinical and morphological features that are relatively specific to humans. To gain insights into the evolution of the regulatory mechanisms of the aged brain, we compared age-related differences in microRNA (miRNA) expression levels in the cortex and cerebellum of humans, chimpanzees and rhesus macaques on a genome-wide scale. In contrast to global miRNA downregulation, a small subset of miRNAs was found to be selectively upregulated in the aging brain of all 3 species. Notably, miR-144 that is highly conserved appeared to be associated with the aging progression. Moreover, miR-144 plays a central role in regulating the expression of ataxin 1 (ATXN1), the disease-causing gene for the development spinocerebellar ataxia type 1 (SCA1). miRNA activity, including miR-144, -101 and -130 processing, was increased in the cerebellum and cortex of SCA1 and Alzheimer patients relative to healthy aged brains. Importantly, miR-144 and -101 inhibition increased ATXN1 levels in human cells. Thus, the activation of miRNA expression in the aging brain may serve to reduce the cytotoxic effect of polyglutamine expanded ATXN1 and the deregulation of miRNA expression may be a risk factor for disease development.", - "journal_title": "Neurobiology of aging", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/20451302/" - } - ], - "f6f76837-b1cc-4fa0-bb1f-d82de2f2b950": [ - { - "pub_id": "23612305", - "title": "Neolithic mitochondrial haplogroup H genomes and the genetic origins of Europeans.", - "authors": "Paul Brotherton,Wolfgang Haak,Jennifer Templeton,Guido Brandt,Julien Soubrier,Christina Jane Adler,Stephen M Richards,Clio Der Sarkissian,Robert Ganslmeier,Susanne Friederich,Veit Dresely,Mannis van Oven,Rosalie Kenyon,Mark B Van der Hoek,Jonas Korlach,Khai Luong,Simon Y W Ho,Lluis Quintana-Murci,Doron M Behar,Harald Meller,Kurt W Alt,Alan Cooper, ", - "abstract": "Haplogroup H dominates present-day Western European mitochondrial DNA variability (>40%), yet was less common (~19%) among Early Neolithic farmers (~5450 BC) and virtually absent in Mesolithic hunter-gatherers. Here we investigate this major component of the maternal population history of modern Europeans and sequence 39 complete haplogroup H mitochondrial genomes from ancient human remains. We then compare this 'real-time' genetic data with cultural changes taking place between the Early Neolithic (~5450 BC) and Bronze Age (~2200 BC) in Central Europe. Our results reveal that the current diversity and distribution of haplogroup H were largely established by the Mid Neolithic (~4000 BC), but with substantial genetic contributions from subsequent pan-European cultures such as the Bell Beakers expanding out of Iberia in the Late Neolithic (~2800 BC). Dated haplogroup H genomes allow us to reconstruct the recent evolutionary history of haplogroup H and reveal a mutation rate 45% higher than current estimates for human mitochondria.", - "journal_title": "Nature communications", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/23612305/" - } - ], - "75618dec-c752-4ca4-a10a-54fc79f666f6": [ - { - "pub_id": "26969751", - "title": "International Genome-Wide Association Study Consortium Identifies Novel Loci Associated With Blood Pressure in Children and Adolescents.", - "authors": "Priyakumari Ganesh Parmar,H Rob Taal,Nicholas J Timpson,Elisabeth Thiering,Terho Lehtim\u00e4ki,Marcella Marinelli,Penelope A Lind,Laura D Howe,Germaine Verwoert,Ville Aalto,Andre G Uitterlinden,Laurent Briollais,Dave M Evans,Margie J Wright,John P Newnham,John B Whitfield,Leo-Pekka Lyytik\u00e4inen,Fernando Rivadeneira,Dorrett I Boomsma,Jorma Viikari,Matthew W Gillman,Beate St Pourcain,Jouke-Jan Hottenga,Grant W Montgomery,Albert Hofman,Mika K\u00e4h\u00f6nen,Nicholas G Martin,Martin D Tobin,Ollie Raitakari,Jesus Vioque,Vincent W V Jaddoe,Marjo-Riita Jarvelin,Lawrence J Beilin,Joachim Heinrich,Cornelia M van Duijn,Craig E Pennell,Debbie A Lawlor,Lyle J Palmer, ", - "abstract": "Our aim was to identify genetic variants associated with blood pressure (BP) in childhood and adolescence. Genome-wide association study data from participating European ancestry cohorts of the Early Genetics and Lifecourse Epidemiology (EAGLE) Consortium was meta-analyzed across 3 epochs; prepuberty (4-7 years), puberty (8-12 years), and postpuberty (13-20 years). Two novel loci were identified as having genome-wide associations with systolic BP across specific age epochs: rs1563894 (ITGA11, located in active H3K27Ac mark and transcription factor chromatin immunoprecipitation and 5'-C-phosphate-G-3' methylation site) during prepuberty (P=2.86\u00d710(-8)) and rs872256 during puberty (P=8.67\u00d710(-9)). Several single-nucleotide polymorphism clusters were also associated with childhood BP at P<5\u00d710(-3). Using a P value threshold of <5\u00d710(-3), we found some overlap in variants across the different age epochs within our study and between several single-nucleotide polymorphisms in any of the 3 epochs and adult BP-related single-nucleotide polymorphisms. Our results suggest that genetic determinants of BP act from childhood, develop over the lifecourse, and show some evidence of age-specific effects.", - "journal_title": "Circulation. Cardiovascular genetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/26969751/" - } - ], - "ce2dac58-c393-4892-9fd3-2d08fdb3e592": [ - { - "pub_id": "26638077", - "title": "Insights into Sex Chromosome Evolution and Aging from the Genome of a Short-Lived Fish.", - "authors": "Kathrin Reichwald,Andreas Petzold,Philipp Koch,Bryan R Downie,Nils Hartmann,Stefan Pietsch,Mario Baumgart,Domitille Chalopin,Marius Felder,Martin Bens,Arne Sahm,Karol Szafranski,Stefan Taudien,Marco Groth,Ivan Arisi,Anja Weise,Samarth S Bhatt,Virag Sharma,Johann M Kraus,Florian Schmid,Steffen Priebe,Thomas Liehr,Matthias G\u00f6rlach,Manuel E Than,Michael Hiller,Hans A Kestler,Jean-Nicolas Volff,Manfred Schartl,Alessandro Cellerino,Christoph Englert,Matthias Platzer", - "abstract": "The killifish Nothobranchius furzeri is the shortest-lived vertebrate that can be bred in the laboratory. Its rapid growth, early sexual maturation, fast aging, and arrested embryonic development (diapause) make it an attractive model organism in biomedical research. Here, we report a draft sequence of its genome that allowed us to uncover an intra-species Y chromosome polymorphism representing-in real time-different stages of sex chromosome formation that display features of early mammalian XY evolution \"in action.\" Our data suggest that gdf6Y, encoding a TGF-\u03b2 family growth factor, is the master sex-determining gene in N.\u00a0furzeri. Moreover, we observed genomic clustering of aging-related genes, identified genes under positive selection, and revealed significant similarities of gene expression profiles between diapause and aging, particularly for genes controlling cell cycle and translation. The annotated genome sequence is provided as an online resource (http://www.nothobranchius.info/NFINgb).", - "journal_title": "Cell", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/26638077/" - } - ], - "7f90614f-ea9d-496d-9ea2-da42a3a37d84": [ - { - "pub_id": "27140627", - "title": "A genetic method for dating ancient genomes provides a direct estimate of human generation interval in the last 45,000 years.", - "authors": "Priya Moorjani,Sriram Sankararaman,Qiaomei Fu,Molly Przeworski,Nick Patterson,David Reich", - "abstract": "The study of human evolution has been revolutionized by inferences from ancient DNA analyses. Key to these studies is the reliable estimation of the age of ancient specimens. High-resolution age estimates can often be obtained using radiocarbon dating, and, while precise and powerful, this method has some biases, making it of interest to directly use genetic data to infer a date for samples that have been sequenced. Here, we report a genetic method that uses the recombination clock. The idea is that an ancient genome has evolved less than the genomes of present-day individuals and thus has experienced fewer recombination events since the common ancestor. To implement this idea, we take advantage of the insight that all non-Africans have a common heritage of Neanderthal gene flow into their ancestors. Thus, we can estimate the date since Neanderthal admixture for present-day and ancient samples simultaneously and use the difference as a direct estimate of the ancient specimen's age. We apply our method to date five Upper Paleolithic Eurasian genomes with radiocarbon dates between 12,000 and 45,000 y ago and show an excellent correlation of the genetic and (14)C dates. By considering the slope of the correlation between the genetic dates, which are in units of generations, and the (14)C dates, which are in units of years, we infer that the mean generation interval in humans over this period has been 26-30 y. Extensions of this methodology that use older shared events may be applicable for dating beyond the radiocarbon frontier.", - "journal_title": "Proceedings of the National Academy of Sciences of the United States of America", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/27140627/" - } - ], - "8445153f-6286-49a3-b85f-791310383034": [ - { - "pub_id": "31701892", - "title": "Identification of novel risk loci, causal insights, and heritable risk for Parkinson's disease: a meta-analysis of genome-wide association studies.", - "authors": "Mike A Nalls,Cornelis Blauwendraat,Costanza L Vallerga,Karl Heilbron,Sara Bandres-Ciga,Diana Chang,Manuela Tan,Demis A Kia,Alastair J Noyce,Angli Xue,Jose Bras,Emily Young,Rainer von Coelln,Javier Sim\u00f3n-S\u00e1nchez,Claudia Schulte,Manu Sharma,Lynne Krohn,Lasse Pihlstr\u00f8m,Ari Siitonen,Hirotaka Iwaki,Hampton Leonard,Faraz Faghri,J Raphael Gibbs,Dena G Hernandez,Sonja W Scholz,Juan A Botia,Maria Martinez,Jean-Christophe Corvol,Suzanne Lesage,Joseph Jankovic,Lisa M Shulman,Margaret Sutherland,Pentti Tienari,Kari Majamaa,Mathias Toft,Ole A Andreassen,Tushar Bangale,Alexis Brice,Jian Yang,Ziv Gan-Or,Thomas Gasser,Peter Heutink,Joshua M Shulman,Nicholas W Wood,David A Hinds,John A Hardy,Huw R Morris,Jacob Gratten,Peter M Visscher,Robert R Graham,Andrew B Singleton, , , ", - "abstract": "Genome-wide association studies (GWAS) in Parkinson's disease have increased the scope of biological knowledge about the disease over the past decade. We aimed to use the largest aggregate of GWAS data to identify novel risk loci and gain further insight into the causes of Parkinson's disease. We did a meta-analysis of 17 datasets from Parkinson's disease GWAS available from European ancestry samples to nominate novel loci for disease risk. These datasets incorporated all available data. We then used these data to estimate heritable risk and develop predictive models of this heritability. We also used large gene expression and methylation resources to examine possible functional consequences as well as tissue, cell type, and biological pathway enrichments for the identified risk factors. Additionally, we examined shared genetic risk between Parkinson's disease and other phenotypes of interest via genetic correlations followed by Mendelian randomisation. Between Oct 1, 2017, and Aug 9, 2018, we analysed 7\u00b78 million single nucleotide polymorphisms in 37\u2008688 cases, 18\u2008618 UK Biobank proxy-cases (ie, individuals who do not have Parkinson's disease but have a first degree relative that does), and 1\u00b74 million controls. We identified 90 independent genome-wide significant risk signals across 78 genomic regions, including 38 novel independent risk signals in 37 loci. These 90 variants explained 16-36% of the heritable risk of Parkinson's disease depending on prevalence. Integrating methylation and expression data within a Mendelian randomisation framework identified putatively associated genes at 70 risk signals underlying GWAS loci for follow-up functional studies. Tissue-specific expression enrichment analyses suggested Parkinson's disease loci were heavily brain-enriched, with specific neuronal cell types being implicated from single cell data. We found significant genetic correlations with brain volumes (false discovery rate-adjusted p=0\u00b70035 for intracranial volume, p=0\u00b7024 for putamen volume), smoking status (p=0\u00b7024), and educational attainment (p=0\u00b7038). Mendelian randomisation between cognitive performance and Parkinson's disease risk showed a robust association (p=8\u00b700\u2008\u00d7\u200810<sup>-7</sup>). These data provide the most comprehensive survey of genetic risk within Parkinson's disease to date, to the best of our knowledge, by revealing many additional Parkinson's disease risk loci, providing a biological context for these risk factors, and showing that a considerable genetic component of this disease remains unidentified. These associations derived from European ancestry datasets will need to be followed-up with more diverse data. The National Institute on Aging at the National Institutes of Health (USA), The Michael J Fox Foundation, and The Parkinson's Foundation (see appendix for full list of funding sources).", - "journal_title": "The Lancet. Neurology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/31701892/" - } - ], - "8a08e602-d3ab-4bcf-b60c-c5b64a3a9e71": [ - { - "pub_id": "34804330", - "title": "Burden of non-communicable diseases in Tunisia, 1990-2017: results from the global burden of disease study.", - "authors": "Houyem Khiari,Rym Mallekh,Ines Cherif,Mohamed Hsairi", - "abstract": "non-communicable diseases (NCDs) are the leading cause of mortality and disability worldwide especially in developing countries such as Tunisia. We aimed to describe the national burden of non-communicable diseases in 2017 and to analyze disability-adjusted life year trends from 1990 to 2017 in Tunisia by cause and gender. we used Joinpoint regression analysis to assess trends of the age standardized disability-adjusted life year rate from 1990 to 2017 and to determine average annual percentage change. non-communicable diseases accounted for 87.7% of total disability-adjusted life year in Tunisia in 2017. The five leading causes of this rate in Tunisia in 2017 were cardiovascular diseases, musculoskeletal disorders, neoplasms, mental disorders and neurological disorders. The trend of disability-adjusted life year rate of non-communicable diseases decreased significantly from 23403.2 per 100.000 (95% CI: 20830.2-26285.8) in 1990 to 18454.6 (95% CI: 15611.3-21555.4) in 2017, with a change of -0.9%; p=0.00. The decrease of the age standardized disability-adjusted life year rate concerned mainly cardiovascular diseases and neoplasms secondly. This decrease was more important in female (change=-1.1, p=0.00) in comparison to males (change=-0.7, p=0.00). On the other hand, the increase of the standardized disability-adjusted life year rate was related to musculoskeletal disorders, diabetes, kidney disorders and substance use disorders with a significant annual percentage change of 0.1%, 0.2% and 1.3% (p=0.00) respectively. <b>Conclusion:</b> the implementation of the national strategy is the key solution to mitigate the impact of non-communicable diseases in Tunisia.", - "journal_title": "The Pan African medical journal", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/34804330/" - } - ], - "d174ea46-2c88-4047-a333-cb66e483a51f": [ - { - "pub_id": "22533606", - "title": "Genome-wide miRNA signatures of human longevity.", - "authors": "Abdou ElSharawy,Andreas Keller,Friederike Flachsbart,Anke Wendschlag,Gunnar Jacobs,Nathalie Kefer,Thomas Brefort,Petra Leidinger,Christina Backes,Eckart Meese,Stefan Schreiber,Philip Rosenstiel,Andre Franke,Almut Nebel", - "abstract": "Little is known about the functions of miRNAs in human longevity. Here, we present the first genome-wide miRNA study in long-lived individuals (LLI) who are considered a model for healthy aging. Using a microarray with 863 miRNAs, we compared the expression profiles obtained from blood samples of 15 centenarians and nonagenarians (mean age 96.4 years) with those of 55 younger individuals (mean age 45.9 years). Eighty miRNAs showed aging-associated expression changes, with 16 miRNAs being up-regulated and 64 down-regulated in the LLI relative to the younger probands. Seven of the eight selected aging-related biomarkers were technically validated using quantitative RT-PCR, confirming the microarray data. Three of the eight miRNAs were further investigated in independent samples of 15 LLI and 17 younger participants (mean age 101.5 and 36.9 years, respectively). Our screening confirmed previously published miRNAs of human aging, thus reflecting the utility of the applied approach. The hierarchical clustering analysis of the miRNA microarray expression data revealed a distinct separation between the LLI and the younger controls (P-value < 10(-5) ). The down-regulated miRNAs appeared as a cluster and were more often reported in the context of diseases than the up-regulated miRNAs. Moreover, many of the differentially regulated miRNAs are known to exhibit contrasting expression patterns in major age-related diseases. Further in silico analyses showed enrichment of potential targets of the down-regulated miRNAs in p53 and other cancer pathways. Altogether, synchronized miRNA-p53 activities could be involved in the prevention of tumorigenesis and the maintenance of genomic integrity during aging.", - "journal_title": "Aging cell", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/22533606/" - } - ], - "682fd742-1e20-4069-afd8-ab01e81c7603": [ - { - "pub_id": "25312911", - "title": "Phylostratigraphic bias creates spurious patterns of genome evolution.", - "authors": "Bryan A Moyers,Jianzhi Zhang", - "abstract": "Phylostratigraphy is a method for dating the evolutionary emergence of a gene or gene family by identifying its homologs across the tree of life, typically by using BLAST searches. Applying this method to all genes in a species, or genomic phylostratigraphy, allows investigation of genome-wide patterns in new gene origination at different evolutionary times and thus has been extensively used. However, gene age estimation depends on the challenging task of detecting distant homologs via sequence similarity, which is expected to have differential accuracies for different genes. Here, we evaluate the accuracy of phylostratigraphy by realistic computer simulation with parameters estimated from genomic data, and investigate the impact of its error on findings of genome evolution. We show that 1) phylostratigraphy substantially underestimates gene age for a considerable fraction of genes, 2) the error is especially serious when the protein evolves rapidly, is short, and/or its most conserved block of sites is small, and 3) these errors create spurious nonuniform distributions of various gene properties among age groups, many of which cannot be predicted a priori. Given the high likelihood that conclusions about gene age are faulty, we advocate the use of realistic simulation to determine if observations from phylostratigraphy are explainable, at least qualitatively, by a null model of biased measurement, and in all cases, critical evaluation of results.", - "journal_title": "Molecular biology and evolution", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/25312911/" - } - ], - "c03fc930-5c7b-4efd-9e5a-bb6f41748081": [ - { - "pub_id": "21798944", - "title": "Evidence for network evolution in an Arabidopsis interactome map.", - "authors": " ", - "abstract": "Plants have unique features that evolved in response to their environments and ecosystems. A full account of the complex cellular networks that underlie plant-specific functions is still missing. We describe a proteome-wide binary protein-protein interaction map for the interactome network of the plant Arabidopsis thaliana containing about 6200 highly reliable interactions between about 2700 proteins. A global organization of plant biological processes emerges from community analyses of the resulting network, together with large numbers of novel hypothetical functional links between proteins and pathways. We observe a dynamic rewiring of interactions following gene duplication events, providing evidence for a model of evolution acting upon interactome networks. This and future plant interactome maps should facilitate systems approaches to better understand plant biology and improve crops.", - "journal_title": "Science (New York, N.Y.)", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/21798944/" - } - ], - "f1f44b89-1d22-42b3-87e3-ed5eb93fca31": [ - { - "pub_id": "24518929", - "title": "Cohort Profile: Estonian Biobank of the Estonian Genome Center, University of Tartu.", - "authors": "Liis Leitsalu,Toomas Haller,T\u00f5nu Esko,Mari-Liis Tammesoo,Helene Alavere,Harold Snieder,Markus Perola,Pauline C Ng,Reedik M\u00e4gi,Lili Milani,Krista Fischer,Andres Metspalu", - "abstract": "The Estonian Biobank cohort is a volunteer-based sample of the Estonian resident adult population (aged \u226518 years). The current number of participants-close to 52000--represents a large proportion, 5%, of the Estonian adult population, making it ideally suited to population-based studies. General practitioners (GPs) and medical personnel in the special recruitment offices have recruited participants throughout the country. At baseline, the GPs performed a standardized health examination of the participants, who also donated blood samples for DNA, white blood cells and plasma tests and filled out a 16-module questionnaire on health-related topics such as lifestyle, diet and clinical diagnoses described in WHO ICD-10. A significant part of the cohort has whole genome sequencing (100), genome-wide single nucleotide polymorphism (SNP) array data (20 000) and/or NMR metabolome data (11 000) available (http://www.geenivaramu.ee/for-scientists/data-release/). The data are continuously updated through periodical linking to national electronic databases and registries. A part of the cohort has been re-contacted for follow-up purposes and resampling, and targeted invitations are possible for specific purposes, for example people with a specific diagnosis. The Estonian Genome Center of the University of Tartu is actively collaborating with many universities, research institutes and consortia and encourages fellow scientists worldwide to co-initiate new academic or industrial joint projects with us.", - "journal_title": "International journal of epidemiology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/24518929/" - } - ], - "271236e4-60b1-4fe9-a3cc-11748e3cc718": [ - { - "pub_id": "29162050", - "title": "Transcriptome profiling of aging Drosophila photoreceptors reveals gene expression trends that correlate with visual senescence.", - "authors": "Hana Hall,Patrick Medina,Daphne A Cooper,Spencer E Escobedo,Jeremiah Rounds,Kaelan J Brennan,Christopher Vincent,Pedro Miura,Rebecca Doerge,Vikki M Weake", - "abstract": "Aging is associated with functional decline of neurons and increased incidence of both neurodegenerative and ocular disease. Photoreceptor neurons in Drosophila melanogaster provide a powerful model for studying the molecular changes involved in functional senescence of neurons since decreased visual behavior precedes retinal degeneration. Here, we sought to identify gene expression changes and the genomic features of differentially regulated genes in photoreceptors that contribute to visual senescence. To identify gene expression changes that could lead to visual senescence, we characterized the aging transcriptome of Drosophila sensory neurons highly enriched for photoreceptors. We profiled the nuclear transcriptome of genetically-labeled photoreceptors over a 40\u00a0day time course and identified increased expression of genes involved in stress and DNA damage response, and decreased expression of genes required for neuronal function. We further show that combinations of promoter motifs robustly identify age-regulated genes, suggesting that transcription factors are important in driving expression changes in aging photoreceptors. However, long, highly expressed and heavily spliced genes are also more likely to be downregulated with age, indicating that other mechanisms could contribute to expression changes at these genes. Lastly, we identify that circular RNAs (circRNAs) strongly increase during aging in photoreceptors. Overall, we identified changes in gene expression in aging Drosophila photoreceptors that could account for visual senescence. Further, we show that genomic features predict these age-related changes, suggesting potential mechanisms that could be targeted to slow the rate of age-associated visual decline.", - "journal_title": "BMC genomics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/29162050/" - } - ], - "5c7e6804-3675-40f7-9683-fe9d57573638": [ - { - "pub_id": "22300631", - "title": "Age-associated DNA methylation in pediatric populations.", - "authors": "Reid S Alisch,Benjamin G Barwick,Pankaj Chopra,Leila K Myrick,Glen A Satten,Karen N Conneely,Stephen T Warren", - "abstract": "DNA methylation (DNAm) plays diverse roles in human biology, but this dynamic epigenetic mark remains far from fully characterized. Although earlier studies uncovered loci that undergo age-associated DNAm changes in adults, little is known about such changes during childhood. Despite profound DNAm plasticity during embryogenesis, monozygotic twins show indistinguishable childhood methylation, suggesting that DNAm is highly coordinated throughout early development. Here we examine the methylation of 27,578 CpG dinucleotides in peripheral blood DNA from a cross-sectional study of 398 boys, aged 3-17 yr, and find significant age-associated changes in DNAm at 2078 loci. These findings correspond well with pyrosequencing data and replicate in a second pediatric population (N = 78). Moreover, we report a deficit of age-related loci on the X chromosome, a preference for specific nucleotides immediately surrounding the interrogated CpG dinucleotide, and a primary association with developmental and immune ontological functions. Meta-analysis (N = 1158) with two adult populations reveals that despite a significant overlap of age-associated loci, most methylation changes do not follow a lifelong linear pattern due to a threefold to fourfold higher rate of change in children compared with adults; consequently, the vast majority of changes are more accurately modeled as a function of logarithmic age. We therefore conclude that age-related DNAm changes in peripheral blood occur more rapidly during childhood and are imperfectly accounted for by statistical corrections that are linear in age, further suggesting that future DNAm studies should be matched closely for age.", - "journal_title": "Genome research", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/22300631/" - } - ], - "3c78c2be-0bd2-4954-bb47-8b48f6125ed7": [ - { - "pub_id": "22094426", - "title": "Genome-wide analysis of yeast aging.", - "authors": "George L Sutphin,Brady A Olsen,Brian K Kennedy,Matt Kaeberlein", - "abstract": "In the past several decades the budding yeast Saccharomyces cerevisiae has emerged as a prominent model for aging research. The creation of a single-gene deletion collection covering the majority of open reading frames in the yeast genome and advances in genomic technologies have opened yeast research to genome-scale screens for a variety of phenotypes. A number of screens have been performed looking for genes that modify secondary age-associated phenotypes such as stress resistance or growth rate. More recently, moderate-throughput methods for measuring replicative life span and high-throughput methods for measuring chronological life span have allowed for the first unbiased screens aimed at directly identifying genes involved in determining yeast longevity. In this chapter we discuss large-scale life span studies performed in yeast and their implications for research related to the basic biology of aging.", - "journal_title": "Sub-cellular biochemistry", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/22094426/" - } - ], - "57aaccd2-a35a-4adc-8964-78be89c77275": [ - { - "pub_id": "23696674", - "title": "Clinical genomic database.", - "authors": "Benjamin D Solomon,Anh-Dao Nguyen,Kelly A Bear,Tyra G Wolfsberg", - "abstract": "Technological advances have greatly increased the availability of human genomic sequencing. However, the capacity to analyze genomic data in a clinically meaningful way lags behind the ability to generate such data. To help address this obstacle, we reviewed all conditions with genetic causes and constructed the Clinical Genomic Database (CGD) (http://research.nhgri.nih.gov/CGD/), a searchable, freely Web-accessible database of conditions based on the clinical utility of genetic diagnosis and the availability of specific medical interventions. The CGD currently includes a total of 2,616 genes organized clinically by affected organ systems and interventions (including preventive measures, disease surveillance, and medical or surgical interventions) that could be reasonably warranted by the identification of pathogenic mutations. To aid independent analysis and optimize new data incorporation, the CGD also includes all genetic conditions for which genetic knowledge may affect the selection of supportive care, informed medical decision-making, prognostic considerations, reproductive decisions, and allow avoidance of unnecessary testing, but for which specific interventions are not otherwise currently available. For each entry, the CGD includes the gene symbol, conditions, allelic conditions, clinical categorization (for both manifestations and interventions), mode of inheritance, affected age group, description of interventions/rationale, links to other complementary databases, including databases of variants and presumed pathogenic mutations, and links to PubMed references (>20,000). The CGD will be regularly maintained and updated to keep pace with scientific discovery. Further content-based expert opinions are actively solicited. Eventually, the CGD may assist the rapid curation of individual genomes as part of active medical care.", - "journal_title": "Proceedings of the National Academy of Sciences of the United States of America", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/23696674/" - } - ], - "64416b51-ed3d-40ab-b76c-06bc5f371d9e": [ - { - "pub_id": "27160975", - "title": "Single-cell genomics: coming of age.", - "authors": "Sten Linnarsson,Sarah A Teichmann", - "abstract": "", - "journal_title": "Genome biology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/27160975/" - } - ], - "80391b85-fdde-44ab-9116-c9301df544c8": [ - { - "pub_id": "22314054", - "title": "O-GlcNAcase is essential for embryonic development and maintenance of genomic stability.", - "authors": "Yong Ryoul Yang,Minseok Song,Ho Lee,Yoon Jeon,Eun-Jeong Choi,Hyun-Jun Jang,Hyo Youl Moon,Ha-Young Byun,Eung-Kyun Kim,Dae Hyun Kim,Mi Nam Lee,Ara Koh,Jaewang Ghim,Jang Hyun Choi,Whaseon Lee-Kwon,Kyong Tai Kim,Sung Ho Ryu,Pann-Ghill Suh", - "abstract": "Dysregulation of O-GlcNAc modification catalyzed by O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA) contributes to the etiology of chronic diseases of aging, including cancer, cardiovascular disease, type 2 diabetes, and Alzheimer's disease. Here we found that natural aging in wild-type mice was marked by a decrease in OGA and OGT protein levels and an increase in O-GlcNAcylation in various tissues. Genetic disruption of OGA resulted in constitutively elevated O-GlcNAcylation in embryos and led to neonatal lethality with developmental delay. Importantly, we observed that serum-stimulated cell cycle entry induced increased O-GlcNAcylation and decreased its level after release from G2/M arrest, indicating that O-GlcNAc cycling by OGT and OGA is required for precise cell cycle control. Constitutively, elevated O-GlcNAcylation by OGA disruption impaired cell proliferation and resulted in mitotic defects with downregulation of mitotic regulators. OGA loss led to mitotic defects including cytokinesis failure and binucleation, increased lagging chromosomes, and micronuclei formation. These findings suggest an important role for O-GlcNAc cycling by OGA in embryonic development and the regulation of the maintenance of genomic stability linked to the aging process.", - "journal_title": "Aging cell", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/22314054/" - } - ], - "98851dd4-ceae-4ee6-918e-6da8dee2a8d5": [ - { - "pub_id": "27990019", - "title": "Transcriptional architecture of the mammalian circadian clock.", - "authors": "Joseph S Takahashi", - "abstract": "Circadian clocks are endogenous oscillators that control 24-hour physiological and behavioural processes in organisms. These cell-autonomous clocks are composed of a transcription-translation-based autoregulatory feedback loop. With the development of next-generation sequencing approaches, biochemical and genomic insights into circadian function have recently come into focus. Genome-wide analyses of the clock transcriptional feedback loop have revealed a global circadian regulation of processes such as transcription factor occupancy, RNA polymerase II recruitment and initiation, nascent transcription, and chromatin remodelling. The genomic targets of circadian clocks are pervasive and are intimately linked to the regulation of metabolism, cell growth and physiology.", - "journal_title": "Nature reviews. Genetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/27990019/" - } - ], - "555a1533-2905-4d91-a3b6-2fca3679ab02": [ - { - "pub_id": "23746838", - "title": "The hallmarks of aging.", - "authors": "Carlos L\u00f3pez-Ot\u00edn,Maria A Blasco,Linda Partridge,Manuel Serrano,Guido Kroemer", - "abstract": "Aging is characterized by a progressive loss of physiological integrity, leading to impaired function and increased vulnerability to death. This deterioration is the primary risk factor for major human pathologies, including cancer, diabetes, cardiovascular disorders, and neurodegenerative diseases. Aging research has experienced an unprecedented advance over recent years, particularly with the discovery that the rate of aging is controlled, at least to some extent, by genetic pathways and biochemical processes conserved in evolution. This Review enumerates nine tentative hallmarks that represent common denominators of aging in different organisms, with special emphasis on mammalian aging. These hallmarks are: genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, deregulated nutrient sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, and altered intercellular communication. A major challenge is to dissect the interconnectedness between the candidate hallmarks and their relative contributions to aging, with the final goal of identifying pharmaceutical targets to improve human health during aging, with minimal side effects.", - "journal_title": "Cell", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/23746838/" - } - ], - "dc4b7f28-1419-4ff6-89f9-a5414844d2e5": [ - { - "pub_id": "23650146", - "title": "A genome-wide association study for venous thromboembolism: the extended cohorts for heart and aging research in genomic epidemiology (CHARGE) consortium.", - "authors": "Weihong Tang,Martina Teichert,Daniel I Chasman,John A Heit,Pierre-Emmanuel Morange,Guo Li,Nathan Pankratz,Frank W Leebeek,Guillaume Par\u00e9,Mariza de Andrade,Christophe Tzourio,Bruce M Psaty,Saonli Basu,Rikje Ruiter,Lynda Rose,Sebastian M Armasu,Thomas Lumley,Susan R Heckbert,Andr\u00e9 G Uitterlinden,Mark Lathrop,Kenneth M Rice,Mary Cushman,Albert Hofman,Jean-Charles Lambert,Nicole L Glazer,James S Pankow,Jacqueline C Witteman,Philippe Amouyel,Joshua C Bis,Edwin G Bovill,Xiaoxiao Kong,Russell P Tracy,Eric Boerwinkle,Jerome I Rotter,David-Alexandre Tr\u00e9gou\u00ebt,Daan W Loth,Bruno H Ch Stricker,Paul M Ridker,Aaron R Folsom,Nicholas L Smith", - "abstract": "Venous thromboembolism (VTE) is a common, heritable disease resulting in high rates of hospitalization and mortality. Yet few associations between VTE and genetic variants, all in the coagulation pathway, have been established. To identify additional genetic determinants of VTE, we conducted a two-stage genome-wide association study (GWAS) among individuals of European ancestry in the extended cohorts for heart and aging research in genomic epidemiology (CHARGE) VTE consortium. The discovery GWAS comprised 1,618 incident VTE cases out of 44,499 participants from six community-based studies. Genotypes for genome-wide single-nucleotide polymorphisms (SNPs) were imputed to approximately 2.5 million SNPs in HapMap and association with VTE assessed using study-design appropriate regression methods. Meta-analysis of these results identified two known loci, in F5 and ABO. Top 1,047 tag SNPs (P \u2264 0.0016) from the discovery GWAS were tested for association in an additional 3,231 cases and 3,536 controls from three case-control studies. In the combined data from these two stages, additional genome-wide significant associations were observed on 4q35 at F11 (top SNP rs4253399, intronic to F11) and on 4q28 at FGG (rs6536024, 9.7 kb from FGG; P < 5.0 \u00d7 10(-13) for both). The associations at the FGG locus were not completely explained by previously reported variants. Loci at or near SUSD1 and OTUD7A showed borderline yet novel associations (P < 5.0 \u00d7 10(-6) ) and constitute new candidate genes. In conclusion, this large GWAS replicated key genetic associations in F5 and ABO, and confirmed the importance of F11 and FGG loci for VTE. Future studies are warranted to better characterize the associations with F11 and FGG and to replicate the new candidate associations.", - "journal_title": "Genetic epidemiology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/23650146/" - } - ], - "a3e4a848-0617-4b01-a3db-428b393cf786": [ - { - "pub_id": "28161621", - "title": "Evolution of cancer suppression as revealed by mammalian comparative genomics.", - "authors": "Marc Tollis,Joshua D Schiffman,Amy M Boddy", - "abstract": "Cancer suppression is an important feature in the evolution of large and long-lived animals. While some tumor suppression pathways are conserved among all multicellular organisms, others mechanisms of cancer resistance are uniquely lineage specific. Comparative genomics has become a powerful tool to discover these unique and shared molecular adaptations in respect to cancer suppression. These findings may one day be translated to human patients through evolutionary medicine. Here, we will review theory and methods of comparative cancer genomics and highlight major findings of cancer suppression across mammals. Our current knowledge of cancer genomics suggests that more efficient DNA repair and higher sensitivity to DNA damage may be the key to tumor suppression in large or long-lived mammals.", - "journal_title": "Current opinion in genetics & development", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/28161621/" - } - ], - "54f64f33-f040-4b06-b48d-a68c7aa02d41": [ - { - "pub_id": "22869754", - "title": "Resolution of ray-finned fish phylogeny and timing of diversification.", - "authors": "Thomas J Near,Ron I Eytan,Alex Dornburg,Kristen L Kuhn,Jon A Moore,Matthew P Davis,Peter C Wainwright,Matt Friedman,W Leo Smith", - "abstract": "Ray-finned fishes make up half of all living vertebrate species. Nearly all ray-finned fishes are teleosts, which include most commercially important fish species, several model organisms for genomics and developmental biology, and the dominant component of marine and freshwater vertebrate faunas. Despite the economic and scientific importance of ray-finned fishes, the lack of a single comprehensive phylogeny with corresponding divergence-time estimates has limited our understanding of the evolution and diversification of this radiation. Our analyses, which use multiple nuclear gene sequences in conjunction with 36 fossil age constraints, result in a well-supported phylogeny of all major ray-finned fish lineages and molecular age estimates that are generally consistent with the fossil record. This phylogeny informs three long-standing problems: specifically identifying elopomorphs (eels and tarpons) as the sister lineage of all other teleosts, providing a unique hypothesis on the radiation of early euteleosts, and offering a promising strategy for resolution of the \"bush at the top of the tree\" that includes percomorphs and other spiny-finned teleosts. Contrasting our divergence time estimates with studies using a single nuclear gene or whole mitochondrial genomes, we find that the former underestimates ages of the oldest ray-finned fish divergences, but the latter dramatically overestimates ages for derived teleost lineages. Our time-calibrated phylogeny reveals that much of the diversification leading to extant groups of teleosts occurred between the late Mesozoic and early Cenozoic, identifying this period as the \"Second Age of Fishes.\"", - "journal_title": "Proceedings of the National Academy of Sciences of the United States of America", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/22869754/" - } - ], - "d14d0d85-f955-4ea4-b6f0-eefedc38e054": [ - { - "pub_id": "28217133", - "title": "A Perspective on CRN Proteins in the Genomics Age: Evolution, Classification, Delivery and Function Revisited.", - "authors": "Tiago M M M Amaro,Ga\u00ebtan J A Thilliez,Graham B Motion,Edgar Huitema", - "abstract": "Plant associated microbes rely on secreted virulence factors (effectors) to modulate host immunity and ensure progressive infection. Amongst the secreted protein repertoires defined and studied in pathogens to date, the CRNs (for CRinkling and Necrosis) have emerged as one of only a few highly conserved protein families, spread across several kingdoms. CRN proteins were first identified in plant pathogenic oomycetes where they were found to be modular factors that are secreted and translocated inside host cells by means of a conserved N-terminal domain. Subsequent localization and functional studies have led to the view that CRN C-termini execute their presumed effector function in the host nucleus, targeting processes required for immunity. These findings have led to great interest in this large protein family and driven the identification of additional CRN-like proteins in other organisms. The identification of CRN proteins and subsequent functional studies have markedly increased the number of candidate CRN protein sequences, expanded the range of phenotypes tentatively associated with function and revealed some of their molecular functions toward virulence. The increased number of characterized CRNs also has presented a set of challenges that may impede significant progress in the future. Here, we summarize our current understanding of the CRNs and re-assess some basic assumptions regarding this protein family. We will discuss the latest findings on CRN biology and highlight exciting new hypotheses that have emanated from the field. Finally, we will discuss new approaches to study CRN functions that would lead to a better understanding of CRN effector biology as well as the processes that lead to host susceptibility and immunity.", - "journal_title": "Frontiers in plant science", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/28217133/" - } - ], - "3c70a01a-7f94-48a8-ab46-2553cb3797ef": [ - { - "pub_id": "27513020", - "title": "An Introduction to Genome-Wide Association Studies: GWAS for Dummies.", - "authors": "A G Uitterlinden", - "abstract": "Although the genetic origin of many human diseases and phenotypes has been long and widely recognized, identification of the causative gene alleles has been limited, slow, and cumbersome. This has changed substantially with the introduction of genome-wide association studies (GWASs) a decade ago, fueled by studies and reference projects of human genetic diversity and the development of novel DNA analysis technology applicable to high-throughput and large-scale data generation. Although GWASs essentially combine epidemiological study designs with molecular genetic analysis techniques, it has also fundamentally changed the way in which research was done in human genetics by the introduction of large consortia of collaborating investigators. GWASs have over flooded many clinical and basic research areas with gene discoveries, including those in reproductive medicine. This review describes aspects of GWAS methodology and how this field of human genetics is developing.", - "journal_title": "Seminars in reproductive medicine", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/27513020/" - } - ], - "f6bde053-64e5-42d9-966d-9d5d5d82a068": [ - { - "pub_id": "23423909", - "title": "Identifying the genomic determinants of aging and longevity in human population studies: progress and challenges.", - "authors": "Joris Deelen,Marian Beekman,Miriam Capri,Claudio Franceschi,P Eline Slagboom", - "abstract": "Human lifespan variation is mainly determined by environmental factors, whereas the genetic contribution is 25-30% and expected to be polygenic. Two complementary fields go hand in hand in order to unravel the mechanisms of biological aging: genomic and biomarker research. Explorative and candidate gene studies of the human genome by genetic, transcriptomic, and epigenomic approaches have resulted in the identification of a limited number of interesting positive linkage regions, genes, and pathways that contribute to lifespan variation. The possibilities to further exploit these findings are rapidly increasing through the use of novel technologies, such as next-generation sequencing. Genomic research is progressively being integrated with biomarker studies on aging, including the application of (noninvasive) deep phenotyping and omics data - generated using novel technologies - in a wealth of studies in human populations. Hence, these studies may assist in obtaining a more holistic perspective on the role of the genome in aging and lifespan regulation.", - "journal_title": "BioEssays : news and reviews in molecular, cellular and developmental biology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/23423909/" - } - ], - "f84b9349-49e3-4428-8fb3-a286ddac62ac": [ - { - "pub_id": "26471037", - "title": "Age and prior blood feeding of Anopheles gambiae influences their susceptibility and gene expression patterns to ivermectin-containing blood meals.", - "authors": "Jonathan A Seaman,Haoues Alout,Jacob I Meyers,Mark D Stenglein,Roch K Dabir\u00e9,Saul Lozano-Fuentes,Timothy A Burton,Wojtek S Kuklinski,William C Black,Brian D Foy", - "abstract": "Ivermectin has been proposed as a novel malaria transmission control tool based on its insecticidal properties and unique route of acquisition through human blood. To maximize ivermectin's effect and identify potential resistance/tolerance mechanisms, it is important to understand its effect on mosquito physiology and potential to shift mosquito population age-structure. We therefore investigated ivermectin susceptibility and gene expression changes in several age groups of female Anopheles gambiae mosquitoes. The effect of aging on ivermectin susceptibility was analyzed in three age groups (2, 6, and 14-days) of colonized female Anopheles gambiaemosquitoes using standard survivorship assays. Gene expression patterns were then analyzed by transcriptome sequencing on an Illumina HiSeq 2500 platform. RT-qPCR was used to validate transcriptional changes and also to examine expression in a different, colonized strain and in wild mosquitoes, both of which blood fed naturally on an ivermectin-treated person. Mosquitoes of different ages and blood meal history died at different frequencies after ingesting ivermectin. Mortality was lowest in 2-day old mosquitoes exposed on their first blood meal and highest in 6-day old mosquitoes exposed on their second blood meal. Twenty-four hours following ivermectin ingestion, 101 and 187 genes were differentially-expressed relative to control blood-fed, in 2 and 6-day groups, respectively. Transcription patterns of select genes were similar in membrane-fed, colonized, and naturally-fed wild vectors. Transcripts from several unexpected functional classes were highly up-regulated, including Niemann-Pick Type C (NPC) genes, peritrophic matrix-associated genes, and immune-response genes, and these exhibited different transcription patterns between age groups, which may explain the observed susceptibility differences. Niemann-Pick Type 2 genes were the most highly up-regulated transcripts after ivermectin ingestion (up to 160 fold) and comparing phylogeny to transcriptional patterns revealed that NPCs have rapidly evolved and separate members respond to either blood meals or to ivermectin. We present evidence of increased ivermectin susceptibility in older An. gambiae mosquitoes that had previously bloodfed. Differential expression analysis suggests complex midgut interactions resulting from ivermectin ingestion that likely involve blood meal digestion physiological responses, midgut microflora, and innate immune responses. Thus, the transcription of certain gene families is consistently affected by ivermectin ingestion, and may provide important clues to ivermectin's broad effects on malaria vectors. These findings contribute to the growing understanding of ivermectin's potential as a transmission control tool.", - "journal_title": "BMC genomics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/26471037/" - } - ], - "0b642c38-c37b-48fb-bbff-9d943316691c": [ - { - "pub_id": "25967138", - "title": "Latest approaches for the treatment of obesity.", - "authors": "V Margaret Jackson,Danna M Breen,Jean-Philippe Fortin,Alice Liou,J Brent Kuzmiski,A Katrina Loomis,Marie-Laure Rives,Bhavik Shah,Philip A Carpino", - "abstract": "Obesity is a body weight disorder characterized by excess adiposity that increases the risk for developing co-morbidities such as type 2 diabetes. A large medical need exists for new anti-obesity treatments capable of promoting 10% or greater weight loss, with minimal side effects. The authors describe the application of monogenic forms of rare obesity and genome-wide association studies in selecting critical pathways for drug discovery. Furthermore, they review in detail several pathways and pharmacological targets in the central nervous system (e.g., the leptin-melanocortin axis, the opioid system, GLP-1/GLP-1 system, and FGF21/FGFR1c/\u03b2-Klotho axis) that play an important role in the regulation of feeding behavior and energy homeostasis. Special focus is given to new strategies that engage well-known targets via novel mechanisms in order to circumvent issues seen with previous drug candidates that failed in the clinic. Finally, the authors discuss the recent developments around fixed-dose combinations, targeted polypharmacology, and non-traditional combinations of drugs and devices. The future for new weight-loss approaches to treat obesity looks promising. Current therapies have shown modest effects on weight loss in the general obese population but will have greater impact in smaller homogeneous sub-populations of obese subjects using personalized medicine. Drug combinations that target multiple, complementary pathways have the potential to promote double-digit weight loss in a broader, heterogeneous patient population. Furthermore, the development of advanced subcutaneous delivery technologies has opened up opportunities to develop breakthrough peptide and biologic agents for the treatment of obesity.", - "journal_title": "Expert opinion on drug discovery", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/25967138/" - } - ], - "056c64d1-4d77-4e79-bd91-28c328bba156": [ - { - "pub_id": "21559242", - "title": "Metabolism, genomics, and DNA repair in the mouse aging liver.", - "authors": "Michel Lebel,Nadja C de Souza-Pinto,Vilhelm A Bohr", - "abstract": "The liver plays a pivotal role in the metabolism of nutrients, drugs, hormones, and metabolic waste products, thereby maintaining body homeostasis. The liver undergoes substantial changes in structure and function within old age. Such changes are associated with significant impairment of many hepatic metabolic and detoxification activities, with implications for systemic aging and age-related disease. It has become clear, using rodent models as biological tools, that genetic instability in the form of gross DNA rearrangements or point mutations accumulate in the liver with age. DNA lesions, such as oxidized bases or persistent breaks, increase with age and correlate well with the presence of senescent hepatocytes. The level of DNA damage and/or mutation can be affected by changes in carcinogen activation, decreased ability to repair DNA, or a combination of these factors. This paper covers some of the DNA repair pathways affecting liver homeostasis with age using rodents as model systems.", - "journal_title": "Current gerontology and geriatrics research", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/21559242/" - } - ], - "cb6fce33-33fe-4cf2-83fd-ed2d56bfaa6b": [ - { - "pub_id": "22561519", - "title": "Detectable clonal mosaicism and its relationship to aging and cancer.", - "authors": "Kevin B Jacobs,Meredith Yeager,Weiyin Zhou,Sholom Wacholder,Zhaoming Wang,Benjamin Rodriguez-Santiago,Amy Hutchinson,Xiang Deng,Chenwei Liu,Marie-Josephe Horner,Michael Cullen,Caroline G Epstein,Laurie Burdett,Michael C Dean,Nilanjan Chatterjee,Joshua Sampson,Charles C Chung,Joseph Kovaks,Susan M Gapstur,Victoria L Stevens,Lauren T Teras,Mia M Gaudet,Demetrius Albanes,Stephanie J Weinstein,Jarmo Virtamo,Philip R Taylor,Neal D Freedman,Christian C Abnet,Alisa M Goldstein,Nan Hu,Kai Yu,Jian-Min Yuan,Linda Liao,Ti Ding,You-Lin Qiao,Yu-Tang Gao,Woon-Puay Koh,Yong-Bing Xiang,Ze-Zhong Tang,Jin-Hu Fan,Melinda C Aldrich,Christopher Amos,William J Blot,Cathryn H Bock,Elizabeth M Gillanders,Curtis C Harris,Christopher A Haiman,Brian E Henderson,Laurence N Kolonel,Loic Le Marchand,Lorna H McNeill,Benjamin A Rybicki,Ann G Schwartz,Lisa B Signorello,Margaret R Spitz,John K Wiencke,Margaret Wrensch,Xifeng Wu,Krista A Zanetti,Regina G Ziegler,Jonine D Figueroa,Montserrat Garcia-Closas,Nuria Malats,Gaelle Marenne,Ludmila Prokunina-Olsson,Dalsu Baris,Molly Schwenn,Alison Johnson,Maria Teresa Landi,Lynn Goldin,Dario Consonni,Pier Alberto Bertazzi,Melissa Rotunno,Preetha Rajaraman,Ulrika Andersson,Laura E Beane Freeman,Christine D Berg,Julie E Buring,Mary A Butler,Tania Carreon,Maria Feychting,Anders Ahlbom,J Michael Gaziano,Graham G Giles,Goran Hallmans,Susan E Hankinson,Patricia Hartge,Roger Henriksson,Peter D Inskip,Christoffer Johansen,Annelie Landgren,Roberta McKean-Cowdin,Dominique S Michaud,Beatrice S Melin,Ulrike Peters,Avima M Ruder,Howard D Sesso,Gianluca Severi,Xiao-Ou Shu,Kala Visvanathan,Emily White,Alicja Wolk,Anne Zeleniuch-Jacquotte,Wei Zheng,Debra T Silverman,Manolis Kogevinas,Juan R Gonzalez,Olaya Villa,Donghui Li,Eric J Duell,Harvey A Risch,Sara H Olson,Charles Kooperberg,Brian M Wolpin,Li Jiao,Manal Hassan,William Wheeler,Alan A Arslan,H Bas Bueno-de-Mesquita,Charles S Fuchs,Steven Gallinger,Myron D Gross,Elizabeth A Holly,Alison P Klein,Andrea LaCroix,Margaret T Mandelson,Gloria Petersen,Marie-Christine Boutron-Ruault,Paige M Bracci,Federico Canzian,Kenneth Chang,Michelle Cotterchio,Edward L Giovannucci,Michael Goggins,Judith A Hoffman Bolton,Mazda Jenab,Kay-Tee Khaw,Vittorio Krogh,Robert C Kurtz,Robert R McWilliams,Julie B Mendelsohn,Kari G Rabe,Elio Riboli,Anne Tj\u00f8nneland,Geoffrey S Tobias,Dimitrios Trichopoulos,Joanne W Elena,Herbert Yu,Laufey Amundadottir,Rachael Z Stolzenberg-Solomon,Peter Kraft,Fredrick Schumacher,Daniel Stram,Sharon A Savage,Lisa Mirabello,Irene L Andrulis,Jay S Wunder,Ana Pati\u00f1o Garc\u00eda,Luis Sierrases\u00famaga,Donald A Barkauskas,Richard G Gorlick,Mark Purdue,Wong-Ho Chow,Lee E Moore,Kendra L Schwartz,Faith G Davis,Ann W Hsing,Sonja I Berndt,Amanda Black,Nicolas Wentzensen,Louise A Brinton,Jolanta Lissowska,Beata Peplonska,Katherine A McGlynn,Michael B Cook,Barry I Graubard,Christian P Kratz,Mark H Greene,Ralph L Erickson,David J Hunter,Gilles Thomas,Robert N Hoover,Francisco X Real,Joseph F Fraumeni,Neil E Caporaso,Margaret Tucker,Nathaniel Rothman,Luis A P\u00e9rez-Jurado,Stephen J Chanock", - "abstract": "In an analysis of 31,717 cancer cases and 26,136 cancer-free controls from 13 genome-wide association studies, we observed large chromosomal abnormalities in a subset of clones in DNA obtained from blood or buccal samples. We observed mosaic abnormalities, either aneuploidy or copy-neutral loss of heterozygosity, of >2 Mb in size in autosomes of 517 individuals (0.89%), with abnormal cell proportions of between 7% and 95%. In cancer-free individuals, frequency increased with age, from 0.23% under 50 years to 1.91% between 75 and 79 years (P = 4.8 \u00d7 10(-8)). Mosaic abnormalities were more frequent in individuals with solid tumors (0.97% versus 0.74% in cancer-free individuals; odds ratio (OR) = 1.25; P = 0.016), with stronger association with cases who had DNA collected before diagnosis or treatment (OR = 1.45; P = 0.0005). Detectable mosaicism was also more common in individuals for whom DNA was collected at least 1 year before diagnosis with leukemia compared to cancer-free individuals (OR = 35.4; P = 3.8 \u00d7 10(-11)). These findings underscore the time-dependent nature of somatic events in the etiology of cancer and potentially other late-onset diseases.", - "journal_title": "Nature genetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/22561519/" - } - ], - "a33f1707-3056-4885-b2d9-4084b71a96e8": [ - { - "pub_id": "28159067", - "title": "Infection control in the new age of genomic epidemiology.", - "authors": "Patrick Tang,Matthew A Croxen,Mohammad R Hasan,William W L Hsiao,Linda M Hoang", - "abstract": "With the growing importance of infectious diseases in health care and communicable disease outbreaks garnering increasing attention, new technologies are playing a greater role in helping us prevent health care-associated infections and provide optimal public health. The microbiology laboratory has always played a large role in infection control by providing tools to identify, characterize, and track pathogens. Recently, advances in DNA sequencing technology have ushered in a new era of genomic epidemiology, where traditional molecular diagnostics and genotyping methods are being enhanced and even replaced by genomics-based methods to aid epidemiologic investigations of communicable diseases. The ability to analyze and compare entire pathogen genomes has allowed for unprecedented resolution into how and why infectious diseases spread. As these genomics-based methods continue to improve in speed, cost, and accuracy, they will be increasingly used to inform and guide infection control and public health practices.", - "journal_title": "American journal of infection control", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/28159067/" - } - ], - "d14e93b5-01de-4208-8255-baae7898a7bb": [ - { - "pub_id": "26442115", - "title": "A new age in functional genomics using CRISPR/Cas9 in arrayed library screening.", - "authors": "Alexander Agrotis,Robin Ketteler", - "abstract": "CRISPR technology has rapidly changed the face of biological research, such that precise genome editing has now become routine for many labs within several years of its initial development. What makes CRISPR/Cas9 so revolutionary is the ability to target a protein (Cas9) to an exact genomic locus, through designing a specific short complementary nucleotide sequence, that together with a common scaffold sequence, constitute the guide RNA bridging the protein and the DNA. Wild-type Cas9 cleaves both DNA strands at its target sequence, but this protein can also be modified to exert many other functions. For instance, by attaching an activation domain to catalytically inactive Cas9 and targeting a promoter region, it is possible to stimulate the expression of a specific endogenous gene. In principle, any genomic region can be targeted, and recent efforts have successfully generated pooled guide RNA libraries for coding and regulatory regions of human, mouse and Drosophila genomes with high coverage, thus facilitating functional phenotypic screening. In this review, we will highlight recent developments in the area of CRISPR-based functional genomics and discuss potential future directions, with a special focus on mammalian cell systems and arrayed library screening.", - "journal_title": "Frontiers in genetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/26442115/" - } - ], - "3b5eb994-bede-47bd-a02d-f0da02cc0190": [ - { - "pub_id": "27482540", - "title": "Epigenetics and aging.", - "authors": "Sangita Pal,Jessica K Tyler", - "abstract": "Over the past decade, a growing number of studies have revealed that progressive changes to epigenetic information accompany aging in both dividing and nondividing cells. Functional studies in model organisms and humans indicate that epigenetic changes have a huge influence on the aging process. These epigenetic changes occur at various levels, including reduced bulk levels of the core histones, altered patterns of histone posttranslational modifications and DNA methylation, replacement of canonical histones with histone variants, and altered noncoding RNA expression, during both organismal aging and replicative senescence. The end result of epigenetic changes during aging is altered local accessibility to the genetic material, leading to aberrant gene expression, reactivation of transposable elements, and genomic instability. Strikingly, certain types of epigenetic information can function in a transgenerational manner to influence the life span of the offspring. Several important conclusions emerge from these studies: rather than being genetically predetermined, our life span is largely epigenetically determined; diet and other environmental influences can influence our life span by changing the epigenetic information; and inhibitors of epigenetic enzymes can influence life span of model organisms. These new findings provide better understanding of the mechanisms involved in aging. Given the reversible nature of epigenetic information, these studies highlight exciting avenues for therapeutic intervention in aging and age-associated diseases, including cancer.", - "journal_title": "Science advances", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/27482540/" - } - ], - "35088b89-641f-4905-9e1c-76177f7178ab": [ - { - "pub_id": "22617619", - "title": "Cultural and religious considerations in pediatric palliative care.", - "authors": "Lori Wiener,Denice Grady McConnell,Lauren Latella,Erica Ludi", - "abstract": "A growing multicultural society presents healthcare providers with a difficult task of providing appropriate care for individuals who have different life experiences, beliefs, value systems, religions, languages, and notions of healthcare. This is especially vital when end-of-life care is needed during childhood. There is a dearth of literature addressing cultural considerations in the pediatric palliative care field. As members of a specific culture often do not ascribe to the same religious traditions, the purpose of this article was to explore and review how culture and religion informs and shapes pediatric palliative care. Comprehensive literature searches were completed through an online search of nine databases for articles published between 1980 and 2011: PsychINFO, MEDLINE\u00ae, Journal of Citation Reports-Science Edition, Embase, Scopus, CINAHL\u00ae, Social Sciences Citation Index (SSCI), EBSCO, and Ovid. Key terms included: culture, transcultural, spiritual, international, ethnic, customs or religion AND end-of-life, palliative care, death, dying, cancer, or hospice, and children, pediatrics, or pediatric oncology. Reference lists in the retrieved articles were examined for additional studies that fit the inclusion criteria, and relevant articles were included for review. In addition, web-based searches of specific journals were conducted. These included, but were not limited to: Qualitative Health Research, Psycho-Oncology, Journal of Psychosocial Oncology, Journal of Pediatric Psychology, Journal of Pediatric Health Care, Journal of Pediatric Oncology Nursing, Omega, Social Work in Health Care, and Journal of Palliative Medicine. Thirty-seven articles met eligibility criteria. From these, seven distinct themes emerged that have implications for pediatric palliative care. These include the role of culture in decision-making, faith and the involvement of clergy, communication (spoken and unspoken language), communicating to children about death (truth telling), the meaning of pain and suffering, the meaning of death and dying, and location of end-of-life care. The review of the literature provides insight into the influence of religion and how culture informs lifestyle and shapes the experiences of illness, pain, and end-of-life care. Recommendations for providing culturally sensitive end-of-life care are offered through the framework outlined in the Initiative for Pediatric Palliative Care Quality Improvement Project of 2002. Cultural traditions are dynamic, never static, and cannot be generalized to all families. Guidelines to aid in approaches to palliative care are provided, and providers are encouraged to define these important differences for each family under their care.", - "journal_title": "Palliative & supportive care", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/22617619/" - } - ], - "6041a1eb-5376-4e06-a4df-0563f1b8a724": [ - { - "pub_id": "23329047", - "title": "Identifying personal genomes by surname inference.", - "authors": "Melissa Gymrek,Amy L McGuire,David Golan,Eran Halperin,Yaniv Erlich", - "abstract": "Sharing sequencing data sets without identifiers has become a common practice in genomics. Here, we report that surnames can be recovered from personal genomes by profiling short tandem repeats on the Y chromosome (Y-STRs) and querying recreational genetic genealogy databases. We show that a combination of a surname with other types of metadata, such as age and state, can be used to triangulate the identity of the target. A key feature of this technique is that it entirely relies on free, publicly accessible Internet resources. We quantitatively analyze the probability of identification for U.S. males. We further demonstrate the feasibility of this technique by tracing back with high probability the identities of multiple participants in public sequencing projects.", - "journal_title": "Science (New York, N.Y.)", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/23329047/" - } - ], - "8ce5a291-7ced-4160-a3dd-6d44ad2a922b": [ - { - "pub_id": "29217584", - "title": "Aging and neurodegeneration are associated with increased mutations in single human neurons.", - "authors": "Michael A Lodato,Rachel E Rodin,Craig L Bohrson,Michael E Coulter,Alison R Barton,Minseok Kwon,Maxwell A Sherman,Carl M Vitzthum,Lovelace J Luquette,Chandri N Yandava,Pengwei Yang,Thomas W Chittenden,Nicole E Hatem,Steven C Ryu,Mollie B Woodworth,Peter J Park,Christopher A Walsh", - "abstract": "It has long been hypothesized that aging and neurodegeneration are associated with somatic mutation in neurons; however, methodological hurdles have prevented testing this hypothesis directly. We used single-cell whole-genome sequencing to perform genome-wide somatic single-nucleotide variant (sSNV) identification on DNA from 161 single neurons from the prefrontal cortex and hippocampus of 15 normal individuals (aged 4 months to 82 years), as well as 9 individuals affected by early-onset neurodegeneration due to genetic disorders of DNA repair (Cockayne syndrome and xeroderma pigmentosum). sSNVs increased approximately linearly with age in both areas (with a higher rate in hippocampus) and were more abundant in neurodegenerative disease. The accumulation of somatic mutations with age-which we term genosenium-shows age-related, region-related, and disease-related molecular signatures and may be important in other human age-associated conditions.", - "journal_title": "Science (New York, N.Y.)", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/29217584/" - } - ], - "0d1d3a3a-bf49-49a1-9989-eaa2ff3064b9": [ - { - "pub_id": "23001564", - "title": "Genome-wide meta-analysis points to CTC1 and ZNF676 as genes regulating telomere homeostasis in humans.", - "authors": "Massimo Mangino,Shih-Jen Hwang,Timothy D Spector,Steven C Hunt,Masayuki Kimura,Annette L Fitzpatrick,Lene Christiansen,Inge Petersen,Clara C Elbers,Tamara Harris,Wei Chen,Sathanur R Srinivasan,Jeremy D Kark,Athanase Benetos,Said El Shamieh,Sophie Visvikis-Siest,Kaare Christensen,Gerald S Berenson,Ana M Valdes,Ana Vi\u00f1uela,Melissa Garcia,Donna K Arnett,Ulrich Broeckel,Michael A Province,James S Pankow,Candace Kammerer,Yongmei Liu,Michael Nalls,Sarah Tishkoff,Fridtjof Thomas,Elad Ziv,Bruce M Psaty,Joshua C Bis,Jerome I Rotter,Kent D Taylor,Erin Smith,Nicholas J Schork,Daniel Levy,Abraham Aviv", - "abstract": "Leukocyte telomere length (LTL) is associated with a number of common age-related diseases and is a heritable trait. Previous genome-wide association studies (GWASs) identified two loci on chromosomes 3q26.2 (TERC) and 10q24.33 (OBFC1) that are associated with the inter-individual LTL variation. We performed a meta-analysis of 9190 individuals from six independent GWAS and validated our findings in 2226 individuals from four additional studies. We confirmed previously reported associations with OBFC1 (rs9419958 P = 9.1 \u00d7 10(-11)) and with the telomerase RNA component TERC (rs1317082, P = 1.1 \u00d7 10(-8)). We also identified two novel genomic regions associated with LTL variation that map near a conserved telomere maintenance complex component 1 (CTC1; rs3027234, P = 3.6 \u00d7 10(-8)) on chromosome17p13.1 and zinc finger protein 676 (ZNF676; rs412658, P = 3.3 \u00d7 10(-8)) on 19p12. The minor allele of rs3027234 was associated with both shorter LTL and lower expression of CTC1. Our findings are consistent with the recent observations that point mutations in CTC1 cause short telomeres in both Arabidopsis and humans affected by a rare Mendelian syndrome. Overall, our results provide novel insights into the genetic architecture of inter-individual LTL variation in the general population.", - "journal_title": "Human molecular genetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/23001564/" - } - ], - "87288e58-c644-4a83-a246-138b44e1982a": [ - { - "pub_id": "35642214", - "title": "Microglia-Mediated Neuroinflammation: A Potential Target for the Treatment of Cardiovascular Diseases.", - "authors": "Menglong Wang,Wei Pan,Yao Xu,Jishou Zhang,Jun Wan,Hong Jiang", - "abstract": "Microglia are tissue-resident macrophages of the central nervous system (CNS). In the CNS, microglia play an important role in the monitoring and intervention of synaptic and neuron-level activities. Interventions targeting microglia have been shown to improve the prognosis of various neurological diseases. Recently, studies have observed the activation of microglia in different cardiovascular diseases. In addition, different approaches that regulate the activity of microglia have been shown to modulate the incidence and progression of cardiovascular diseases. The change in autonomic nervous system activity after neuroinflammation may be a potential intermediate link between microglia and cardiovascular diseases. Here, in this review, we will discuss recent updates on the regulatory role of microglia in hypertension, myocardial infarction and ischemia/reperfusion injury. We propose that microglia serve as neuroimmune modulators and potential targets for cardiovascular diseases.", - "journal_title": "Journal of inflammation research", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/35642214/" - } - ], - "856cc013-7bdf-4331-9448-2ce94ef2b6f5": [ - { - "pub_id": "24951455", - "title": "Alzheimer's disease risk genes and mechanisms of disease pathogenesis.", - "authors": "Celeste M Karch,Alison M Goate", - "abstract": "We review the genetic risk factors for late-onset Alzheimer's disease (AD) and their role in AD pathogenesis. More recent advances in understanding of the human genome-technologic advances in methods to analyze millions of polymorphisms in thousands of subjects-have revealed new genes associated with AD risk, including ABCA7, BIN1, CASS4, CD33, CD2AP, CELF1, CLU, CR1, DSG2, EPHA1, FERMT2, HLA-DRB5-DBR1, INPP5D, MS4A, MEF2C, NME8, PICALM, PTK2B, SLC24H4-RIN3, SORL1, and ZCWPW1. Emerging technologies to analyze the entire genome in large data sets have also revealed coding variants that increase AD risk: PLD3 and TREM2. We review the relationship between these AD risk genes and the cellular and neuropathologic features of AD. Understanding the mechanisms underlying the association of these genes with risk for disease will provide the most meaningful targets for therapeutic development to date.", - "journal_title": "Biological psychiatry", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/24951455/" - } - ], - "dd7d0036-dbbf-4b21-97d6-55d8ad6a791a": [ - { - "pub_id": "28983042", - "title": "A Fantastic Voyage in Genomics.", - "authors": "Laura M Zahn", - "abstract": "", - "journal_title": "Science (New York, N.Y.)", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/28983042/" - } - ], - "44d310dd-620f-4c6d-a79a-e3fcc6237998": [ - { - "pub_id": "25861810", - "title": "Impact of age, BMI and HbA1c levels on the genome-wide DNA methylation and mRNA expression patterns in human adipose tissue and identification of epigenetic biomarkers in blood.", - "authors": "Tina R\u00f6nn,Petr Volkov,Linn Gillberg,Milana Kokosar,Alexander Perfilyev,Anna Louisa Jacobsen,Sine W J\u00f8rgensen,Charlotte Br\u00f8ns,Per-Anders Jansson,Karl-Fredrik Eriksson,Oluf Pedersen,Torben Hansen,Leif Groop,Elisabet Stener-Victorin,Allan Vaag,Emma Nilsson,Charlotte Ling", - "abstract": "Increased age, BMI and HbA1c levels are risk factors for several non-communicable diseases. However, the impact of these factors on the genome-wide DNA methylation pattern in human adipose tissue remains unknown. We analyzed the DNA methylation of \u223c480 000 sites in human adipose tissue from 96 males and 94 females and related methylation to age, BMI and HbA1c. We also compared epigenetic signatures in adipose tissue and blood. Age was significantly associated with both altered DNA methylation and expression of 1050 genes (e.g. FHL2, NOX4 and PLG). Interestingly, many reported epigenetic biomarkers of aging in blood, including ELOVL2, FHL2, KLF14 and GLRA1, also showed significant correlations between adipose tissue DNA methylation and age in our study. The most significant association between age and adipose tissue DNA methylation was found upstream of ELOVL2. We identified 2825 genes (e.g. FTO, ITIH5, CCL18, MTCH2, IRS1 and SPP1) where both DNA methylation and expression correlated with BMI. Methylation at previously reported HIF3A sites correlated significantly with BMI in females only. HbA1c (range 28-46 mmol/mol) correlated significantly with the methylation of 711 sites, annotated to, for example, RAB37, TICAM1 and HLA-DPB1. Pathway analyses demonstrated that methylation levels associated with age and BMI are overrepresented among genes involved in cancer, type 2 diabetes and cardiovascular disease. Our results highlight the impact of age, BMI and HbA1c on epigenetic variation of candidate genes for obesity, type 2 diabetes and cancer in human adipose tissue. Importantly, we demonstrate that epigenetic biomarkers in blood can mirror age-related epigenetic signatures in target tissues for metabolic diseases such as adipose tissue.", - "journal_title": "Human molecular genetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/25861810/" - } - ], - "c6b165b1-a39e-4278-9615-8285c1999e7e": [ - { - "pub_id": "27380908", - "title": "Single-cell genome-wide bisulfite sequencing uncovers extensive heterogeneity in the mouse liver methylome.", - "authors": "Silvia Gravina,Xiao Dong,Bo Yu,Jan Vijg", - "abstract": "Transmission fidelity of CpG DNA methylation patterns is not foolproof, with error rates from less than 1 to well over 10\u00a0% per CpG site, dependent on preservation of the methylated or unmethylated state and the type of sequence. This suggests a fairly high chance of errors. However, the consequences of such errors in terms of cell-to-cell variation have never been demonstrated by experimentally measuring intra-tissue heterogeneity in an adult organism. We employ single-cell DNA methylomics to analyze heterogeneity of genome-wide 5-methylcytosine (5mC) patterns within mouse liver. Our results indicate a surprisingly high level of heterogeneity, corresponding to an average epivariation frequency of approximately 3.3\u00a0%, with regions containing H3K4me1 being the most variable and promoters and CpG islands the most stable. Our data also indicate that the level of 5mC heterogeneity is dependent on genomic features. We find that non-functional sites such as repeat elements and introns are mostly unstable and potentially functional sites such as gene promoters are mostly stable. By employing a protocol for whole-genome bisulfite sequencing of single cells, we show that the liver epigenome is highly unstable with an epivariation frequency in DNA methylation patterns of at least two orders of magnitude higher than somatic mutation frequencies.", - "journal_title": "Genome biology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/27380908/" - } - ], - "39304a1d-c6fd-4188-b6e9-6ef473466f18": [ - { - "pub_id": "23287722", - "title": "RNA-guided human genome engineering via Cas9.", - "authors": "Prashant Mali,Luhan Yang,Kevin M Esvelt,John Aach,Marc Guell,James E DiCarlo,Julie E Norville,George M Church", - "abstract": "Bacteria and archaea have evolved adaptive immune defenses, termed clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated (Cas) systems, that use short RNA to direct degradation of foreign nucleic acids. Here, we engineer the type II bacterial CRISPR system to function with custom guide RNA (gRNA) in human cells. For the endogenous AAVS1 locus, we obtained targeting rates of 10 to 25% in 293T cells, 13 to 8% in K562 cells, and 2 to 4% in induced pluripotent stem cells. We show that this process relies on CRISPR components; is sequence-specific; and, upon simultaneous introduction of multiple gRNAs, can effect multiplex editing of target loci. We also compute a genome-wide resource of ~190 K unique gRNAs targeting ~40.5% of human exons. Our results establish an RNA-guided editing tool for facile, robust, and multiplexable human genome engineering.", - "journal_title": "Science (New York, N.Y.)", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/23287722/" - } - ], - "144b7844-af9b-4873-a4de-b84f228258af": [ - { - "pub_id": "28749934", - "title": "The population genomics of archaeological transition in west Iberia: Investigation of ancient substructure using imputation and haplotype-based methods.", - "authors": "Rui Martiniano,Lara M Cassidy,Ros \u00d3'Maold\u00fain,Russell McLaughlin,Nuno M Silva,Licinio Manco,Daniel Fidalgo,Tania Pereira,Maria J Coelho,Miguel Serra,Joachim Burger,Rui Parreira,Elena Moran,Antonio C Valera,Eduardo Porfirio,Rui Boaventura,Ana M Silva,Daniel G Bradley", - "abstract": "We analyse new genomic data (0.05-2.95x) from 14 ancient individuals from Portugal distributed from the Middle Neolithic (4200-3500 BC) to the Middle Bronze Age (1740-1430 BC) and impute genomewide diploid genotypes in these together with published ancient Eurasians. While discontinuity is evident in the transition to agriculture across the region, sensitive haplotype-based analyses suggest a significant degree of local hunter-gatherer contribution to later Iberian Neolithic populations. A more subtle genetic influx is also apparent in the Bronze Age, detectable from analyses including haplotype sharing with both ancient and modern genomes, D-statistics and Y-chromosome lineages. However, the limited nature of this introgression contrasts with the major Steppe migration turnovers within third Millennium northern Europe and echoes the survival of non-Indo-European language in Iberia. Changes in genomic estimates of individual height across Europe are also associated with these major cultural transitions, and ancestral components continue to correlate with modern differences in stature.", - "journal_title": "PLoS genetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/28749934/" - } - ], - "b3304b0d-bebb-487f-beae-f5fb9026d9de": [ - { - "pub_id": "22305530", - "title": "Age-related somatic structural changes in the nuclear genome of human blood cells.", - "authors": "Lars A Forsberg,Chiara Rasi,Hamid R Razzaghian,Geeta Pakalapati,Lindsay Waite,Krista Stanton Thilbeault,Anna Ronowicz,Nathan E Wineinger,Hemant K Tiwari,Dorret Boomsma,Maxwell P Westerman,Jennifer R Harris,Robert Lyle,Magnus Essand,Fredrik Eriksson,Themistocles L Assimes,Carlos Iribarren,Eric Strachan,Terrance P O'Hanlon,Lisa G Rider,Frederick W Miller,Vilmantas Giedraitis,Lars Lannfelt,Martin Ingelsson,Arkadiusz Piotrowski,Nancy L Pedersen,Devin Absher,Jan P Dumanski", - "abstract": "Structural variations are among the most frequent interindividual genetic differences in the human genome. The frequency and distribution of de novo somatic structural variants in normal cells is, however, poorly explored. Using age-stratified cohorts of 318 monozygotic (MZ) twins and 296 single-born subjects, we describe age-related accumulation of copy-number variation in the nuclear genomes in vivo and frequency changes for both megabase- and kilobase-range variants. Megabase-range aberrations were found in 3.4% (9 of 264) of subjects \u226560 years old; these subjects included 78 MZ twin pairs and 108 single-born individuals. No such findings were observed in 81 MZ pairs or 180 single-born subjects who were \u226455 years old. Recurrent region- and gene-specific mutations, mostly deletions, were observed. Longitudinal analyses of 43 subjects whose data were collected 7-19 years apart suggest considerable variation in the rate of accumulation of clones carrying structural changes. Furthermore, the longitudinal analysis of individuals with structural aberrations suggests that there is a natural self-removal of aberrant cell clones from peripheral blood. In three healthy subjects, we detected somatic aberrations characteristic of patients with myelodysplastic syndrome. The recurrent rearrangements uncovered here are candidates for common age-related defects in human blood cells. We anticipate that extension of these results will allow determination of the genetic age of different somatic-cell lineages and estimation of possible individual differences between genetic and chronological age. Our work might also help to explain the cause of an age-related reduction in the number of cell clones in the blood; such a reduction is one of the hallmarks of immunosenescence.", - "journal_title": "American journal of human genetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/22305530/" - } - ], - "0d6942b4-e75f-4f44-98ac-b8378ef1d3c7": [ - { - "pub_id": "23633910", - "title": "Genome-scale studies of aging: challenges and opportunities.", - "authors": "Mark A McCormick,Brian K Kennedy", - "abstract": "Whole-genome studies involving a phenotype of interest are increasingly prevalent, in part due to a dramatic increase in speed at which many high throughput technologies can be performed coupled to simultaneous decreases in cost. This type of genome-scale methodology has been applied to the phenotype of lifespan, as well as to whole-transcriptome changes during the aging process or in mutants affecting aging. The value of high throughput discovery-based science in this field is clearly evident, but will it yield a true systems-level understanding of the aging process? Here we review some of this work to date, focusing on recent findings and the unanswered puzzles to which they point. In this context, we also discuss recent technological advances and some of the likely future directions that they portend.", - "journal_title": "Current genomics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/23633910/" - } - ], - "4851405f-bb2b-4406-a218-ffe408d257f8": [ - { - "pub_id": "28351423", - "title": "Epigenetic aging signatures in mice livers are slowed by dwarfism, calorie restriction and rapamycin treatment.", - "authors": "Tina Wang,Brian Tsui,Jason F Kreisberg,Neil A Robertson,Andrew M Gross,Michael Ku Yu,Hannah Carter,Holly M Brown-Borg,Peter D Adams,Trey Ideker", - "abstract": "Global but predictable changes impact the DNA methylome as we age, acting as a type of molecular clock. This clock can be hastened by conditions that decrease lifespan, raising the question of whether it can also be slowed, for example, by conditions that increase lifespan. Mice are particularly appealing organisms for studies of mammalian aging; however, epigenetic clocks have thus far been formulated only in humans. We first examined whether mice and humans experience similar patterns of change in the methylome with age. We found moderate conservation of CpG sites for which methylation is altered with age, with both species showing an increase in methylome disorder during aging. Based on this analysis, we formulated an epigenetic-aging model in mice using the liver methylomes of 107 mice from 0.2 to 26.0\u00a0months old. To examine whether epigenetic aging signatures are slowed by longevity-promoting interventions, we analyzed 28 additional methylomes from mice subjected to lifespan-extending conditions, including Prop1<sup>df/df</sup> dwarfism, calorie restriction or dietary rapamycin. We found that mice treated with these lifespan-extending interventions were significantly younger in epigenetic age than their untreated, wild-type age-matched controls. This study shows that lifespan-extending conditions can slow molecular changes associated with an epigenetic clock in mice livers.", - "journal_title": "Genome biology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/28351423/" - } - ], - "1c8416b0-bcd2-44ef-88aa-1182f5155336": [ - { - "pub_id": "22155603", - "title": "Systems biology-based analysis implicates a novel role for vitamin D metabolism in the pathogenesis of age-related macular degeneration.", - "authors": "Margaux A Morrison,Alexandra C Silveira,Nancy Huynh,Gyungah Jun,Silvia E Smith,Fani Zacharaki,Hajime Sato,Stephanie Loomis,Michael T Andreoli,Scott M Adams,Monte J Radeke,Austin S Jelcick,Yang Yuan,Aristoteles N Tsiloulis,Dimitrios Z Chatzoulis,Giuliana Silvestri,Maria G Kotoula,Evangelia E Tsironi,Bruce W Hollis,Rui Chen,Neena B Haider,Joan W Miller,Lindsay A Farrer,Gregory S Hageman,Ivana K Kim,Debra A Schaumberg,Margaret M DeAngelis", - "abstract": "Vitamin D has been shown to have anti-angiogenic properties and to play a protective role in several types of cancer, including breast, prostate and cutaneous melanoma. Similarly, vitamin D levels have been shown to be protective for risk of a number of conditions, including cardiovascular disease and chronic kidney disease, as well as numerous autoimmune disorders such as multiple sclerosis, inflammatory bowel diseases and type 1 diabetes mellitus. A study performed by Parekh et al. was the first to suggest a role for vitamin D in age-related macular degeneration (AMD) and showed a correlation between reduced serum vitamin D levels and risk for early AMD. Based on this study and the protective role of vitamin D in diseases with similar pathophysiology to AMD, we examined the role of vitamin D in a family-based cohort of 481 sibling pairs. Using extremely phenotypically discordant sibling pairs, initially we evaluated the association of neovascular AMD and vitamin D/sunlight-related epidemiological factors. After controlling for established AMD risk factors, including polymorphisms of the genes encoding complement factor H (CFH) and age-related maculopathy susceptibility 2/HtrA serine peptidase (ARMS2/HTRA1), and smoking history, we found that ultraviolet irradiance was protective for the development of neovascular AMD (p = 0.001). Although evaluation of serum vitamin D levels (25-hydroxyvitamin D [25(OH)D]) was higher in unaffected individuals than in their affected siblings, this finding did not reach statistical significance. Based on the relationship between ultraviolet irradiance and vitamin D production, we employed a candidate gene approach for evaluating common variation in key vitamin D pathway genes (the genes encoding the vitamin D receptor [VDR]; cytochrome P450, family 27, subfamily B, polypeptide 1 [CYP27B1]; cytochrome P450, family 24, subfamily A, polypeptide 1 [CYP24A1]; and CYP27A1) in this same family-based cohort. Initial findings were then validated and replicated in the extended family cohort, an unrelated case-control cohort from central Greece and a prospective nested case-control population from the Nurse's Health Study and Health Professionals Follow-Up Studies, which included patients with all subtypes of AMD for a total of 2,528 individuals. Single point variants in CYP24A1 (the gene encoding the catabolising enzyme of the vitamin D pathway) were demonstrated to influence AMD risk after controlling for smoking history, sex and age in all populations, both separately and, more importantly, in a meta-analysis. This is the first report demonstrating a genetic association between vitamin D metabolism and AMD risk. These findings were also supplemented with expression data from human donor eyes and human retinal cell lines. These data not only extend previous biological studies in the AMD field, but further emphasise common antecedents between several disorders with an inflammatory/immunogenic component such as cardiovascular disease, cancer and AMD.", - "journal_title": "Human genomics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/22155603/" - } - ], - "85680aef-3057-4498-be29-7eead0750234": [ - { - "pub_id": "26712024", - "title": "Neolithic and Bronze Age migration to Ireland and establishment of the insular Atlantic genome.", - "authors": "Lara M Cassidy,Rui Martiniano,Eileen M Murphy,Matthew D Teasdale,James Mallory,Barrie Hartwell,Daniel G Bradley", - "abstract": "The Neolithic and Bronze Age transitions were profound cultural shifts catalyzed in parts of Europe by migrations, first of early farmers from the Near East and then Bronze Age herders from the Pontic Steppe. However, a decades-long, unresolved controversy is whether population change or cultural adoption occurred at the Atlantic edge, within the British Isles. We address this issue by using the first whole genome data from prehistoric Irish individuals. A Neolithic woman (3343-3020 cal BC) from a megalithic burial (10.3\u00d7 coverage) possessed a genome of predominantly Near Eastern origin. She had some hunter-gatherer ancestry but belonged to a population of large effective size, suggesting a substantial influx of early farmers to the island. Three Bronze Age individuals from Rathlin Island (2026-1534 cal BC), including one high coverage (10.5\u00d7) genome, showed substantial Steppe genetic heritage indicating that the European population upheavals of the third millennium manifested all of the way from southern Siberia to the western ocean. This turnover invites the possibility of accompanying introduction of Indo-European, perhaps early Celtic, language. Irish Bronze Age haplotypic similarity is strongest within modern Irish, Scottish, and Welsh populations, and several important genetic variants that today show maximal or very high frequencies in Ireland appear at this horizon. These include those coding for lactase persistence, blue eye color, Y chromosome R1b haplotypes, and the hemochromatosis C282Y allele; to our knowledge, the first detection of a known Mendelian disease variant in prehistory. These findings together suggest the establishment of central attributes of the Irish genome 4,000 y ago.", - "journal_title": "Proceedings of the National Academy of Sciences of the United States of America", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/26712024/" - } - ], - "f9002547-db31-4f9e-abc1-7aace5c8ea18": [ - { - "pub_id": "29410709", - "title": "Genomic 5-mC contents in peripheral blood leukocytes were independent protective factors for coronary artery disease with a specific profile in different leukocyte subtypes.", - "authors": "Qianyun Deng,Wei Huang,Chunyan Peng,Jiajia Gao,Zuhua Li,Xueping Qiu,Na Yang,Bifeng Yuan,Fang Zheng", - "abstract": "Alterations in DNA methylation are demonstrated in atherosclerosis pathogenesis. However, changing rules of global DNA methylation and hydroxymethylation in peripheral blood leukocytes (PBLs) and different blood cell subtypes of coronary artery disease (CAD) patients are still inconclusive, and much less is known about mechanisms underlying. We recruited 265 CAD patients and 270 healthy controls with genomic DNA from PBLs, of which 50 patients and 50 controls were randomly chosen with DNA from isolated neutrophils, lymphocytes and monocytes, and RNA from PBLs. Genomic 5-methylcytosine (5-mC) and 5-hydroxymethylcytosine (5-hmC) contents were quantified by liquid chromatography-electrospray ionization-tandem mass spectrometry (LC-ESI-MS/MS) assay. Genomic 5-mC contents were negatively associated with the serum total cholesterol (TC) level (<i>P</i>\u2009=\u20090.010), age (<i>P</i>\u2009=\u20090.016), and PBL classifications (<i>P</i>\u2009=\u20090.023), explaining 6.8% individual variation in controls. Furthermore, genomic 5-mC contents were inversely associated with an increased risk of CAD (odds ratio (OR)\u2009=\u20090.325, 95% confidence interval (CI)\u2009=\u20090.237~0.445, <i>P</i>\u2009=\u20092.62\u2009\u00d7\u200910<sup>-\u200912</sup>), independent of PBL counts and classifications, age, sex, histories of hyperlipidemia, hypertension, and diabetes. Within-individual analysis showed a general 5-mC decrease in PBL subtypes, but significant difference was found in monocytes only (<i>P</i>\u2009=\u20090.001), accompanied by increased 5-hmC (<i>P</i>\u2009=\u20093.212\u2009\u00d7\u200910<sup>-\u20094</sup>). In addition, coincident to the reduced <i>DNMT1</i> expression in patients' PBLs, the expression level of DNMT1 was significantly lower (<i>P</i>\u2009=\u20090.022) in oxidized low-density lipoprotein (ox-LDL) stimulated THP-1-derived foam cells compared to THP-1 monocytes, with decreased genomic 5-mdC content (<i>P</i>\u2009=\u20090.038). Global hypomethylation of blood cells defined dominantly by the monocyte DNA hypomethylation is independently associated with the risk of CAD in Chinese Han population. The importance of monocytes in atherosclerosis pathophysiology may demonstrate via an epigenetic pathway, but prospective studies are still needed to test the causality.", - "journal_title": "Clinical epigenetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/29410709/" - } - ], - "a2468a32-95fb-4e3e-af0d-37d243d09d86": [ - { - "pub_id": "27515585", - "title": "Analysis of cancer genomes reveals basic features of human aging and its role in cancer development.", - "authors": "Dmitriy I Podolskiy,Alexei V Lobanov,Gregory V Kryukov,Vadim N Gladyshev", - "abstract": "Somatic mutations have long been implicated in aging and disease, but their impact on fitness and function is difficult to assess. Here by analysing human cancer genomes we identify mutational patterns associated with aging. Our analyses suggest that age-associated mutation load and burden double approximately every 8 years, similar to the all-cause mortality doubling time. This analysis further reveals variance in the rate of aging among different human tissues, for example, slightly accelerated aging of the reproductive system. Age-adjusted mutation load and burden correlate with the corresponding cancer incidence and precede it on average by 15 years, pointing to pre-clinical cancer development times. Behaviour of mutation load also exhibits gender differences and late-life reversals, explaining some gender-specific and late-life patterns in cancer incidence rates. Overall, this study characterizes some features of human aging and offers a mechanism for age being a risk factor for the onset of cancer.", - "journal_title": "Nature communications", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/27515585/" - } - ], - "e397ac93-f115-4cee-8b87-59137a017985": [ - { - "pub_id": "22768836", - "title": "Replicative and chronological aging in Saccharomyces cerevisiae.", - "authors": "Valter D Longo,Gerald S Shadel,Matt Kaeberlein,Brian Kennedy", - "abstract": "Saccharomyces cerevisiae has directly or indirectly contributed to the identification of arguably more mammalian genes that affect aging than any other model organism. Aging in yeast is assayed primarily by measurement of replicative or chronological life span. Here, we review the genes and mechanisms implicated in these two aging model systems and key remaining issues that need to be addressed for their optimization. Because of its well-characterized genome that is remarkably amenable to genetic manipulation and high-throughput screening procedures, S. cerevisiae will continue to serve as a leading model organism for studying pathways relevant to human aging and disease.", - "journal_title": "Cell metabolism", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/22768836/" - } - ], - "797d7ed3-c7fe-4c8d-a3a3-be34726c9567": [ - { - "pub_id": "24438712", - "title": "Budget impact analysis-principles of good practice: report of the ISPOR 2012 Budget Impact Analysis Good Practice II Task Force.", - "authors": "Sean D Sullivan,Josephine A Mauskopf,Federico Augustovski,J Jaime Caro,Karen M Lee,Mark Minchin,Ewa Orlewska,Pete Penna,Jose-Manuel Rodriguez Barrios,Wen-Yi Shau", - "abstract": "Budget impact analyses (BIAs) are an essential part of a comprehensive economic assessment of a health care intervention and are increasingly required by reimbursement authorities as part of a listing or reimbursement submission. The objective of this report was to present updated guidance on methods for those undertaking such analyses or for those reviewing the results of such analyses. This update was needed, in part, because of developments in BIA methods as well as a growing interest, particularly in emerging markets, in matters related to affordability and population health impacts of health care interventions. The Task Force was approved by the International Society for Pharmacoeconomics and Outcomes Research Health Sciences Policy Council and appointed by its Board of Directors. Members were experienced developers or users of BIAs; worked in academia and industry and as advisors to governments; and came from several countries in North America and South America, Oceania, Asia, and Europe. The Task Force solicited comments on the drafts from a core group of external reviewers and, more broadly, from the membership of the International Society for Pharmacoeconomics and Outcomes Research. The Task Force recommends that the design of a BIA for a new health care intervention should take into account relevant features of the health care system, possible access restrictions, the anticipated uptake of the new intervention, and the use and effects of the current and new interventions. The key elements of a BIA include estimating the size of the eligible population, the current mix of treatments and the expected mix after the introduction of the new intervention, the cost of the treatment mixes, and any changes expected in condition-related costs. Where possible, the BIA calculations should be performed by using a simple cost calculator approach because of its ease of use for budget holders. In instances, however, in which the changes in eligible population size, disease severity mix, or treatment patterns cannot be credibly captured by using the cost calculator approach, a cohort or patient-level condition-specific model may be used to estimate the budget impact of the new intervention, accounting appropriately for those entering and leaving the eligible population over time. In either case, the BIA should use data that reflect values specific to a particular decision maker's population. Sensitivity analysis should be of alternative scenarios chosen from the perspective of the decision maker. The validation of the model should include at least face validity with decision makers and verification of the calculations. Data sources for the BIA should include published clinical trial estimates and comparator studies for the efficacy and safety of the current and new interventions as well as the decision maker's own population for the other parameter estimates, where possible. Other data sources include the use of published data, well-recognized local or national statistical information, and, in special circumstances, expert opinion. Reporting of the BIA should provide detailed information about the input parameter values and calculations at a level of detail that would allow another modeler to replicate the analysis. The outcomes of the BIA should be presented in the format of interest to health care decision makers. In a computer program, options should be provided for different categories of costs to be included or excluded from the analysis. We recommend a framework for the BIA, provide guidance on the acquisition and use of data, and offer a common reporting format that will promote standardization and transparency. Adherence to these good research practice principles would not necessarily supersede jurisdiction-specific BIA guidelines but may support and enhance local recommendations or serve as a starting point for payers wishing to promulgate methodology guidelines.", - "journal_title": "Value in health : the journal of the International Society for Pharmacoeconomics and Outcomes Research", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/24438712/" - } - ], - "eebe82fc-8030-48d5-b4b6-dc27d4c324f1": [ - { - "pub_id": "25655936", - "title": "Cellular and molecular biology of aging endothelial cells.", - "authors": "Anthony J Donato,R Garrett Morgan,Ashley E Walker,Lisa A Lesniewski", - "abstract": "Cardiovascular disease (CVD) is the leading cause of death in the United States and aging is a major risk factor for CVD development. One of the major age-related arterial phenotypes thought to be responsible for the development of CVD in older adults is endothelial dysfunction. Endothelial function is modulated by traditional CVD risk factors in young adults, but advancing age is independently associated with the development of vascular endothelial dysfunction. This endothelial dysfunction results from a reduction in nitric oxide bioavailability downstream of endothelial oxidative stress and inflammation that can be further modulated by traditional CVD risk factors in older adults. Greater endothelial oxidative stress with aging is a result of augmented production from the intracellular enzymes NADPH oxidase and uncoupled eNOS, as well as from mitochondrial respiration in the absence of appropriate increases in antioxidant defenses as regulated by relevant transcription factors, such as FOXO. Interestingly, it appears that NFkB, a critical inflammatory transcription factor, is sensitive to this age-related endothelial redox change and its activation induces transcription of pro-inflammatory cytokines that can further suppress endothelial function, thus creating a vicious feed-forward cycle. This review will discuss the two macro-mechanistic processes, oxidative stress and inflammation, that contribute to endothelial dysfunction with advancing age as well as the cellular and molecular events that lead to the vicious cycle of inflammation and oxidative stress in the aged endothelium. Other potential mediators of this pro-inflammatory endothelial phenotype are increases in immune or senescent cells in the vasculature. Of note, genomic instability, telomere dysfunction or DNA damage has been shown to trigger cell senescence via the p53/p21 pathway and result in increased inflammatory signaling in arteries from older adults. This review will discuss the current state of knowledge regarding the emerging concepts of senescence and genomic instability as mechanisms underlying oxidative stress and inflammation in the aged endothelium. Lastly, energy sensitive/stress resistance pathways (SIRT-1, AMPK, mTOR) are altered in endothelial cells and/or arteries with aging and these pathways may modulate endothelial function via key oxidative stress and inflammation-related transcription factors. This review will also discuss what is known about the role of \"energy sensing\" longevity pathways in modulating endothelial function with advancing age. With the growing population of older adults, elucidating the cellular and molecular mechanisms of endothelial dysfunction with age is critical to establishing appropriate and measured strategies to utilize pharmacological and lifestyle interventions aimed at alleviating CVD risk. This article is part of a Special Issue entitled \"SI: CV Aging\".", - "journal_title": "Journal of molecular and cellular cardiology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/25655936/" - } - ], - "19187e76-fefd-46bc-8138-ee08f91aa293": [ - { - "pub_id": "25889241", - "title": "miR-10b-5p expression in Huntington's disease brain relates to age of onset and the extent of striatal involvement.", - "authors": "Andrew G Hoss,Adam Labadorf,Jeanne C Latourelle,Vinay K Kartha,Tiffany C Hadzi,James F Gusella,Marcy E MacDonald,Jiang-Fan Chen,Schahram Akbarian,Zhiping Weng,Jean Paul Vonsattel,Richard H Myers", - "abstract": "MicroRNAs (miRNAs) are small non-coding RNAs that recognize sites of complementarity of target messenger RNAs, resulting in transcriptional regulation and translational repression of target genes. In Huntington's disease (HD), a neurodegenerative disease caused by a trinucleotide repeat expansion, miRNA dyregulation has been reported, which may impact gene expression and modify the progression and severity of HD. We performed next-generation miRNA sequence analysis in prefrontal cortex (Brodmann Area 9) from 26 HD, 2 HD gene positive, and 36 control brains. Neuropathological information was available for all HD brains, including age at disease onset, CAG-repeat size, Vonsattel grade, and Hadzi-Vonsattel striatal and cortical scores, a continuous measure of the extent of neurodegeneration. Linear models were performed to examine the relationship of miRNA expression to these clinical features, and messenger RNA targets of associated miRNAs were tested for gene ontology term enrichment. We identified 75 miRNAs differentially expressed in HD brain (FDR q-value <0.05). Among the HD brains, nine miRNAs were significantly associated with Vonsattel grade of neuropathological involvement and three of these, miR-10b-5p, miR-10b-3p, and miR-302a-3p, significantly related to the Hadzi-Vonsattel striatal score (a continuous measure of striatal involvement) after adjustment for CAG length. Five miRNAs (miR-10b-5p, miR-196a-5p, miR-196b-5p, miR-10b-3p, and miR-106a-5p) were identified as having a significant relationship to CAG length-adjusted age of onset including miR-10b-5p, the mostly strongly over-expressed miRNA in HD cases. Although prefrontal cortex was the source of tissue profiled in these studies, the relationship of miR-10b-5p expression to striatal involvement in the disease was independent of cortical involvement. Correlation of miRNAs to the clinical features clustered by direction of effect and the gene targets of the observed miRNAs showed association to processes relating to nervous system development and transcriptional regulation. These results demonstrate that miRNA expression in cortical BA9 provides insight into striatal involvement and support a role for these miRNAs, particularly miR-10b-5p, in HD pathogenicity. The miRNAs identified in our studies of postmortem brain tissue may be detectable in peripheral fluids and thus warrant consideration as accessible biomarkers for disease stage, rate of progression, and other important clinical characteristics of HD.", - "journal_title": "BMC medical genomics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/25889241/" - } - ], - "d6d7d5ad-dba8-4f78-beed-6437c3e72059": [ - { - "pub_id": "26414678", - "title": "Partitioning heritability by functional annotation using genome-wide association summary statistics.", - "authors": "Hilary K Finucane,Brendan Bulik-Sullivan,Alexander Gusev,Gosia Trynka,Yakir Reshef,Po-Ru Loh,Verneri Anttila,Han Xu,Chongzhi Zang,Kyle Farh,Stephan Ripke,Felix R Day, , , ,Shaun Purcell,Eli Stahl,Sara Lindstrom,John R B Perry,Yukinori Okada,Soumya Raychaudhuri,Mark J Daly,Nick Patterson,Benjamin M Neale,Alkes L Price", - "abstract": "Recent work has demonstrated that some functional categories of the genome contribute disproportionately to the heritability of complex diseases. Here we analyze a broad set of functional elements, including cell type-specific elements, to estimate their polygenic contributions to heritability in genome-wide association studies (GWAS) of 17 complex diseases and traits with an average sample size of 73,599. To enable this analysis, we introduce a new method, stratified LD score regression, for partitioning heritability from GWAS summary statistics while accounting for linked markers. This new method is computationally tractable at very large sample sizes and leverages genome-wide information. Our findings include a large enrichment of heritability in conserved regions across many traits, a very large immunological disease-specific enrichment of heritability in FANTOM5 enhancers and many cell type-specific enrichments, including significant enrichment of central nervous system cell types in the heritability of body mass index, age at menarche, educational attainment and smoking behavior.", - "journal_title": "Nature genetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/26414678/" - } - ], - "1e4d8679-eb56-44fa-90b1-85dec34b7c36": [ - { - "pub_id": "26900923", - "title": "Integrated genomics and proteomics define huntingtin CAG length-dependent networks in mice.", - "authors": "Peter Langfelder,Jeffrey P Cantle,Doxa Chatzopoulou,Nan Wang,Fuying Gao,Ismael Al-Ramahi,Xiao-Hong Lu,Eliana Marisa Ramos,Karla El-Zein,Yining Zhao,Sandeep Deverasetty,Andreas Tebbe,Christoph Schaab,Daniel J Lavery,David Howland,Seung Kwak,Juan Botas,Jeffrey S Aaronson,Jim Rosinski,Giovanni Coppola,Steve Horvath,X William Yang", - "abstract": "To gain insight into how mutant huntingtin (mHtt) CAG repeat length modifies Huntington's disease (HD) pathogenesis, we profiled mRNA in over 600 brain and peripheral tissue samples from HD knock-in mice with increasing CAG repeat lengths. We found repeat length-dependent transcriptional signatures to be prominent in the striatum, less so in cortex, and minimal in the liver. Coexpression network analyses revealed 13 striatal and 5 cortical modules that correlated highly with CAG length and age, and that were preserved in HD models and sometimes in patients. Top striatal modules implicated mHtt CAG length and age in graded impairment in the expression of identity genes for striatal medium spiny neurons and in dysregulation of cyclic AMP signaling, cell death and protocadherin genes. We used proteomics to confirm 790 genes and 5 striatal modules with CAG length-dependent dysregulation at the protein level, and validated 22 striatal module genes as modifiers of mHtt toxicities in vivo.", - "journal_title": "Nature neuroscience", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/26900923/" - } - ], - "182674fa-8553-428d-9dcc-3113cb15f492": [ - { - "pub_id": "35173148", - "title": "Proteomic analysis of archival breast cancer clinical specimens identifies biological subtypes with distinct survival outcomes.", - "authors": "Karama Asleh,Gian Luca Negri,Sandra E Spencer Miko,Shane Colborne,Christopher S Hughes,Xiu Q Wang,Dongxia Gao,C Blake Gilks,Stephen K L Chia,Torsten O Nielsen,Gregg B Morin", - "abstract": "Despite advances in genomic classification of breast cancer, current clinical tests and treatment decisions are commonly based on protein level information. Formalin-fixed paraffin-embedded (FFPE) tissue specimens with extended clinical outcomes are widely available. Here, we perform comprehensive proteomic profiling of 300 FFPE breast cancer surgical specimens, 75 of each PAM50 subtype, from patients diagnosed in 2008-2013 (n\u2009=\u2009178) and 1986-1992 (n\u2009=\u2009122) with linked clinical outcomes. These two cohorts are analyzed separately, and we quantify 4214 proteins across all 300 samples. Within the aggressive PAM50-classified basal-like cases, proteomic profiling reveals two groups with one having characteristic immune hot expression features and highly favorable survival. Her2-Enriched cases separate into heterogeneous groups differing by extracellular matrix, lipid metabolism, and immune-response features. Within 88 triple-negative breast cancers, four proteomic clusters display features of basal-immune hot, basal-immune cold, mesenchymal, and luminal with disparate survival outcomes. Our proteomic analysis characterizes the heterogeneity of breast cancer in a clinically-applicable manner, identifies potential biomarkers and therapeutic targets, and provides a resource for clinical breast cancer classification.", - "journal_title": "Nature communications", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/35173148/" - } - ], - "22468c04-e85e-4d8f-9e2b-4d2d0c50f0d2": [ - { - "pub_id": "27189021", - "title": "Multi-ethnic genome-wide association study identifies novel locus for type 2 diabetes susceptibility.", - "authors": "James P Cook,Andrew P Morris", - "abstract": "Genome-wide association studies (GWAS) have traditionally been undertaken in homogeneous populations from the same ancestry group. However, with the increasing availability of GWAS in large-scale multi-ethnic cohorts, we have evaluated a framework for detecting association of genetic variants with complex traits, allowing for population structure, and developed a powerful test of heterogeneity in allelic effects between ancestry groups. We have applied the methodology to identify and characterise loci associated with susceptibility to type 2 diabetes (T2D) using GWAS data from the Resource for Genetic Epidemiology on Adult Health and Aging, a large multi-ethnic population-based cohort, created for investigating the genetic and environmental basis of age-related diseases. We identified a novel locus for T2D susceptibility at genome-wide significance (P<5 \u00d7 10(-8)) that maps to TOMM40-APOE, a region previously implicated in lipid metabolism and Alzheimer's disease. We have also confirmed previous reports that single-nucleotide polymorphisms at the TCF7L2 locus demonstrate the greatest extent of heterogeneity in allelic effects between ethnic groups, with the lowest risk observed in populations of East Asian ancestry.", - "journal_title": "European journal of human genetics : EJHG", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/27189021/" - } - ], - "5897be80-8424-4b15-94b3-892b9811c6bc": [ - { - "pub_id": "26462558", - "title": "Associations of circulating plasma microRNAs with age, body mass index and sex in a population-based study.", - "authors": "Sabine Ameling,Tim Kacprowski,Ravi Kumar Chilukoti,Carolin Malsch,Volkmar Liebscher,Karsten Suhre,Maik Pietzner,Nele Friedrich,Georg Homuth,Elke Hammer,Uwe V\u00f6lker", - "abstract": "Non-cellular blood circulating microRNAs (plasma miRNAs) represent a promising source for the development of prognostic and diagnostic tools owing to their minimally invasive sampling, high stability, and simple quantification by standard techniques such as RT-qPCR. So far, the majority of association studies involving plasma miRNAs were disease-specific case-control analyses. In contrast, in the present study, plasma miRNAs were analysed in a sample of 372 individuals from a population-based cohort study, the Study of Health in Pomerania (SHIP). Quantification of miRNA levels was performed by RT-qPCR using the Exiqon Serum/Plasma Focus microRNA PCR Panel V3.M covering 179 different miRNAs. Of these, 155 were included in our analyses after quality-control. Associations between plasma miRNAs and the phenotypes age, body mass index (BMI), and sex were assessed via a two-step linear regression approach per miRNA. The first step regressed out the technical parameters and the second step determined the remaining associations between the respective plasma miRNA and the phenotypes of interest. After regressing out technical parameters and adjusting for the respective other two phenotypes, 7, 15, and 35 plasma miRNAs were significantly (q < 0.05) associated with age, BMI, and sex, respectively. Additional adjustment for the blood cell parameters identified 12 and 19 miRNAs to be significantly associated with age and BMI, respectively. Most of the BMI-associated miRNAs likely originate from liver. Sex-associated differences in miRNA levels were largely determined by differences in blood cell parameters. Thus, only 7 as compared to originally 35 sex-associated miRNAs displayed sex-specific differences after adjustment for blood cell parameters. These findings emphasize that circulating miRNAs are strongly impacted by age, BMI, and sex. Hence, these parameters should be considered as covariates in association studies based on plasma miRNA levels. The established experimental and computational workflow can now be used in future screening studies to determine associations of plasma miRNAs with defined disease phenotypes.", - "journal_title": "BMC medical genomics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/26462558/" - } - ], - "69298301-70d0-402d-8db2-baa7e2fbc7e8": [ - { - "pub_id": "28874526", - "title": "Identification of individuals by trait prediction using whole-genome sequencing data.", - "authors": "Christoph Lippert,Riccardo Sabatini,M Cyrus Maher,Eun Yong Kang,Seunghak Lee,Okan Arikan,Alena Harley,Axel Bernal,Peter Garst,Victor Lavrenko,Ken Yocum,Theodore Wong,Mingfu Zhu,Wen-Yun Yang,Chris Chang,Tim Lu,Charlie W H Lee,Barry Hicks,Smriti Ramakrishnan,Haibao Tang,Chao Xie,Jason Piper,Suzanne Brewerton,Yaron Turpaz,Amalio Telenti,Rhonda K Roby,Franz J Och,J Craig Venter", - "abstract": "Prediction of human physical traits and demographic information from genomic data challenges privacy and data deidentification in personalized medicine. To explore the current capabilities of phenotype-based genomic identification, we applied whole-genome sequencing, detailed phenotyping, and statistical modeling to predict biometric traits in a cohort of 1,061 participants of diverse ancestry. Individually, for a large fraction of the traits, their predictive accuracy beyond ancestry and demographic information is limited. However, we have developed a maximum entropy algorithm that integrates multiple predictions to determine which genomic samples and phenotype measurements originate from the same person. Using this algorithm, we have reidentified an average of >8 of 10 held-out individuals in an ethnically mixed cohort and an average of 5 of either 10 African Americans or 10 Europeans. This work challenges current conceptions of personal privacy and may have far-reaching ethical and legal implications.", - "journal_title": "Proceedings of the National Academy of Sciences of the United States of America", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/28874526/" - } - ], - "c2096285-f52d-4cf9-a42c-00b5bd2306b8": [ - { - "pub_id": "28408026", - "title": "The Aging Cardiovascular System: Understanding It at the Cellular and Clinical Levels.", - "authors": "Francesco Paneni,Candela Diaz Ca\u00f1estro,Peter Libby,Thomas F L\u00fcscher,Giovanni G Camici", - "abstract": "Cardiovascular disease (CVD) presents a great burden for elderly patients, their caregivers, and health systems. Structural and functional alterations of vessels accumulate throughout life, culminating in increased risk of developing CVD. The growing elderly population worldwide highlights the need to understand how aging promotes CVD in order to develop new strategies to confront this challenge. This review provides examples of some major unresolved clinical problems encountered in daily cardiovascular practice as we care for elderly patients. Next, the authors summarize the current understanding of the mechanisms implicated in cardiovascular aging, and the potential for targeting novel pathways implicated in endothelial dysfunction, mitochondrial oxidative stress, chromatin remodeling, and genomic instability. Lastly, the authors consider critical aspects of vascular repair, including autologous transplantation of bone marrow-derived stem cells in elderly patients.", - "journal_title": "Journal of the American College of Cardiology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/28408026/" - } - ], - "844ab36b-9239-4d73-a61c-68f68acc4fd1": [ - { - "pub_id": "29224780", - "title": "A Living Biobank of Breast Cancer Organoids Captures Disease Heterogeneity.", - "authors": "Norman Sachs,Joep de Ligt,Oded Kopper,Ewa Gogola,Gergana Bounova,Fleur Weeber,Anjali Vanita Balgobind,Karin Wind,Ana Gracanin,Harry Begthel,Jeroen Korving,Ruben van Boxtel,Alexandra Alves Duarte,Daphne Lelieveld,Arne van Hoeck,Robert Frans Ernst,Francis Blokzijl,Isaac Johannes Nijman,Marlous Hoogstraat,Marieke van de Ven,David Anthony Egan,Vittoria Zinzalla,Jurgen Moll,Sylvia Fernandez Boj,Emile Eugene Voest,Lodewyk Wessels,Paul Joannes van Diest,Sven Rottenberg,Robert Gerhardus Jacob Vries,Edwin Cuppen,Hans Clevers", - "abstract": "Breast cancer (BC) comprises multiple distinct subtypes that differ genetically, pathologically, and clinically. Here, we describe a robust protocol for long-term culturing of human mammary epithelial organoids. Using this protocol, >100 primary and metastatic BC organoid lines were generated, broadly recapitulating the diversity of the disease. BC organoid morphologies typically matched the histopathology, hormone receptor status, and HER2 status of the original tumor. DNA copy number variations as well as sequence changes were consistent within tumor-organoid pairs and largely retained even after extended passaging. BC organoids furthermore populated all major gene-expression-based classification groups and allowed in\u00a0vitro drug screens that were consistent with in\u00a0vivo xeno-transplantations and patient response. This study describes a representative collection of well-characterized BC organoids available for cancer research and drug development, as well as a strategy to assess in\u00a0vitro drug response in a personalized fashion.", - "journal_title": "Cell", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/29224780/" - } - ], - "80fc751c-9dfc-4364-a5f7-c857c5ff718d": [ - { - "pub_id": "27559010", - "title": "Werner syndrome through the lens of tissue and tumour genomics.", - "authors": "Mari Tokita,Scott R Kennedy,Rosa Ana Risques,Stephen G Chun,Colin Pritchard,Junko Oshima,Yan Liu,Peter K Bryant-Greenwood,Piri Welcsh,Raymond J Monnat", - "abstract": "Werner syndrome (WS) is the canonical adult human progeroid ('premature aging') syndrome. Patients with this autosomal recessive Mendelian disorder display constitutional genomic instability and an elevated risk of important age-associated diseases including cancer. Remarkably few analyses of WS patient tissue and tumors have been performed to provide insight into WS disease pathogenesis or the high risk of neoplasia. We used autopsy tissue from four mutation-typed WS patients to characterize pathologic and genomic features of WS, and to determine genomic features of three neoplasms arising in two of these patients. The results of these analyses provide new information on WS pathology and genomics; provide a first genomic characterization of neoplasms arising in WS; and provide new histopathologic and genomic data to test several popular models of WS disease pathogenesis.", - "journal_title": "Scientific reports", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/27559010/" - } - ], - "b3044cc4-22d5-451c-81cf-8a3650afe16d": [ - { - "pub_id": "27846804", - "title": "Clinical utility of array comparative genomic hybridisation in prenatal setting.", - "authors": "Luca Lovrecic,Ziga Iztok Remec,Marija Volk,Gorazd Rudolf,Karin Writzl,Borut Peterlin", - "abstract": "The objective of reported study was to evaluate the clinical utility of prenatal microarray testing for submicroscopic genomic imbalances in routine prenatal settings and to stratify the findings according to the type of fetal ultrasound anomaly. From July 2012 to October 2015 chromosomal microarray testing was performed in 218 fetuses with varying indications for invasive prenatal diagnosis: abnormal karyotype, ultrasound anomalies, pathogenic variant in previous pregnancy or carriership in a parent. The detection rate in the group of fetuses with ultrasound anomalies was 10,0% for pathogenic copy number variants (CNVs), five of them being larger than 8\u00a0Mb and expected to be seen on prenatal karyotype. If only those pathogenic CNVs below the classical karyotype resolution are considered, chromosomal microarray testing provided an additional 7,7% diagnostic yield in here reported series. When stratified according to the ultrasound anomalies, the highest percentage of pathogenic CNVs were detected in the group of fetuses with multiple congenital anomalies (16,7%) and lowest in the group of isolated in utero growth restriction (6,3%). In the group of cases with isolated increased nuchal translucency we identified a small interstitial deletion of 16p24.1 involving FOXF1 gene. Prenatal aCGH also provided important insights into cases with seemingly balanced chromosomal rearrangements found on prenatal karyotype, where additional pathogenic CNV were discovered. Prenatal chromosomal microarray testing significantly increases the diagnostic yield when compared with conventional karyotyping. The highest added value is shown in prenatal diagnostics in fetuses with abnormal ultrasound results. Variants of unknown significance and risk factor CNVs present important challenges and should be discussed with parents in advance, therefore pretest counseling prior to prenatal testing is very important.", - "journal_title": "BMC medical genetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/27846804/" - } - ], - "136c7bb8-2970-474a-8855-6db7e2b47591": [ - { - "pub_id": "22054870", - "title": "A genome-wide scan for common variants affecting the rate of age-related cognitive decline.", - "authors": "Philip L De Jager,Joshua M Shulman,Lori B Chibnik,Brendan T Keenan,Towfique Raj,Robert S Wilson,Lei Yu,Sue E Leurgans,Dong Tran,Cristin Aubin,Christopher D Anderson,Alessandro Biffi,Jason J Corneveaux,Matthew J Huentelman, ,Jonathan Rosand,Mark J Daly,Amanda J Myers,Eric M Reiman,David A Bennett,Denis A Evans", - "abstract": "Age-related cognitive decline is likely promoted by accumulated brain injury due to chronic conditions of aging, including neurodegenerative and vascular disease. Because common neuronal mechanisms may mediate the adaptation to diverse cerebral insults, we hypothesized that susceptibility for age-related cognitive decline may be due in part to a shared genetic network. We have therefore performed a genome-wide association study using a quantitative measure of global cognitive decline slope, based on repeated measures of 17 cognitive tests in 749 subjects from the Religious Orders Study. Top results were evaluated in 3 independent replication cohorts, consisting of 2279 additional subjects with repeated cognitive testing. As expected, we find that the Alzheimer's disease (AD) susceptibility locus, APOE, is strongly associated with rate of cognitive decline (P(DISC) = 5.6 \u00d7 10(-9); P(JOINT)= 3.7 \u00d7 10(-27)). We additionally discover a variant, rs10808746, which shows consistent effects in the replication cohorts and modestly improved evidence of association in the joint analysis (P(DISC) = 6.7 \u00d7 10(-5); P(REP) = 9.4 \u00d7 10(-3); P(JOINT) = 2.3 \u00d7 10(-5)). This variant influences the expression of 2 adjacent genes, PDE7A and MTFR1, which are potential regulators of inflammation and oxidative injury, respectively. Using aggregate measures of genetic risk, we find that known susceptibility loci for cardiovascular disease, type 2 diabetes, and inflammatory diseases are not significantly associated with cognitive decline in our cohort. Our results suggest that intermediate phenotypes, when coupled with larger sample sizes, may be a useful tool to dissect susceptibility loci for age-related cognitive decline and uncover shared molecular pathways with a role in neuronal injury.", - "journal_title": "Neurobiology of aging", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/22054870/" - } - ], - "9c664a26-4eea-46bb-b58b-618f4faa0da6": [ - { - "pub_id": "25802367", - "title": "A Genome-Wide Chronological Study of Gene Expression and Two Histone Modifications, H3K4me3 and H3K9ac, during Developmental Leaf Senescence.", - "authors": "Judy A Brusslan,Giancarlo Bonora,Ana M Rus-Canterbury,Fayha Tariq,Artur Jaroszewicz,Matteo Pellegrini", - "abstract": "The genome-wide abundance of two histone modifications, H3K4me3 and H3K9ac (both associated with actively expressed genes), was monitored in Arabidopsis (Arabidopsis thaliana) leaves at different time points during developmental senescence along with expression in the form of RNA sequencing data. H3K9ac and H3K4me3 marks were highly convergent at all stages of leaf aging, but H3K4me3 marks covered nearly 2 times the gene area as H3K9ac marks. Genes with the greatest fold change in expression displayed the largest positively correlated percentage change in coverage for both marks. Most senescence up-regulated genes were premarked by H3K4me3 and H3K9ac but at levels below the whole-genome average, and for these genes, gene expression increased without a significant increase in either histone mark. However, for a subset of genes showing increased or decreased expression, the respective gain or loss of H3K4me3 marks was found to closely match the temporal changes in mRNA abundance; 22% of genes that increased expression during senescence showed accompanying changes in H3K4me3 modification, and they include numerous regulatory genes, which may act as primary response genes.", - "journal_title": "Plant physiology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/25802367/" - } - ], - "da4a9500-831f-48ab-acea-5ec7097276ed": [ - { - "pub_id": "27518561", - "title": "Epigenetic Mechanisms of Longevity and Aging.", - "authors": "Payel Sen,Parisha P Shah,Raffaella Nativio,Shelley L Berger", - "abstract": "Aging is an inevitable outcome of life, characterized by progressive decline in tissue and organ function and increased risk of mortality. Accumulating evidence links aging to genetic and epigenetic alterations. Given the reversible nature of epigenetic mechanisms, these pathways provide promising avenues for therapeutics against age-related decline and disease. In this review, we provide a comprehensive overview of epigenetic studies from invertebrate organisms, vertebrate models, tissues, and in\u00a0vitro systems. We establish links between common operative aging pathways and hallmark chromatin signatures that can be used to identify \"druggable\" targets to counter human aging and age-related disease.", - "journal_title": "Cell", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/27518561/" - } - ], - "e2ed975e-78b6-45c9-b8e1-bb17b976722d": [ - { - "pub_id": "26855260", - "title": "How retrotransposons shape genome regulation.", - "authors": "Paolo Mita,Jef D Boeke", - "abstract": "Retrotransposons are mutagenic units able to move within the genome. Despite many defenses deployed by the host to suppress potentially harmful activities of retrotransposons, these genetic units have found ways to meld with normal cellular functions through processes of exaptation and domestication. The same host mechanisms targeting transposon mobility allow for expansion and rewiring of gene regulatory networks on an evolutionary time scale. Recent works demonstrating retrotransposon activity during development, cell differentiation and neurogenesis shed new light on unexpected activities of transposable elements. Moreover, new technological advances illuminated subtler nuances of the complex relationship between retrotransposons and the host genome, clarifying the role of retroelements in evolution, development and impact on human disease.", - "journal_title": "Current opinion in genetics & development", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/26855260/" - } - ], - "c0e97d6a-8945-46e9-af6e-04e80d945c58": [ - { - "pub_id": "28706435", - "title": "Genome-Wide Polygenic Scores Predict Reading Performance Throughout the School Years.", - "authors": "Saskia Selzam,Philip S Dale,Richard K Wagner,John C DeFries,Martin Cederl\u00f6f,Paul F O'Reilly,Eva Krapohl,Robert Plomin", - "abstract": "It is now possible to create individual-specific genetic scores, called genome-wide polygenic scores (GPS). We used a GPS for years of education (<i>EduYears</i>) to predict reading performance assessed at UK National Curriculum Key Stages 1 (age 7), 2 (age 12) and 3 (age 14) and on reading tests administered at ages 7 and 12 in a UK sample of 5,825 unrelated individuals. <i>EduYears</i> GPS accounts for up to 5% of the variance in reading performance at age 14. GPS predictions remained significant after accounting for general cognitive ability and family socioeconomic status. Reading performance of children in the lowest and highest 12.5% of the <i>EduYears</i> GPS distribution differed by a mean growth in reading ability of approximately two school years. It seems certain that polygenic scores will be used to predict strengths and weaknesses in education.", - "journal_title": "Scientific studies of reading : the official journal of the Society for the Scientific Study of Reading", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/28706435/" - } - ], - "6421312e-6e85-4ff2-977c-a2f0b91d3c6a": [ - { - "pub_id": "27511193", - "title": "An epigenetic clock analysis of race/ethnicity, sex, and coronary heart disease.", - "authors": "Steve Horvath,Michael Gurven,Morgan E Levine,Benjamin C Trumble,Hillard Kaplan,Hooman Allayee,Beate R Ritz,Brian Chen,Ake T Lu,Tammy M Rickabaugh,Beth D Jamieson,Dianjianyi Sun,Shengxu Li,Wei Chen,Lluis Quintana-Murci,Maud Fagny,Michael S Kobor,Philip S Tsao,Alexander P Reiner,Kerstin L Edlefsen,Devin Absher,Themistocles L Assimes", - "abstract": "Epigenetic biomarkers of aging (the \"epigenetic clock\") have the potential to address puzzling findings surrounding mortality rates and incidence of cardio-metabolic disease such as: (1) women consistently exhibiting lower mortality than men despite having higher levels of morbidity; (2) racial/ethnic groups having different mortality rates even after adjusting for socioeconomic differences; (3) the black/white mortality cross-over effect in late adulthood; and (4) Hispanics in the United States having a longer life expectancy than Caucasians despite having a higher burden of traditional cardio-metabolic risk factors. We analyzed blood, saliva, and brain samples from seven different racial/ethnic groups. We assessed the intrinsic epigenetic age acceleration of blood (independent of blood cell counts) and the extrinsic epigenetic aging rates of blood (dependent on blood cell counts and tracks the age of the immune system). In blood, Hispanics and Tsimane Amerindians have lower intrinsic but higher extrinsic epigenetic aging rates than Caucasians. African-Americans have lower extrinsic epigenetic aging rates than Caucasians and Hispanics but no differences were found for the intrinsic measure. Men have higher epigenetic aging rates than women in blood, saliva, and brain tissue. Epigenetic aging rates are significantly associated with sex, race/ethnicity, and to a lesser extent with CHD risk factors, but not with incident CHD outcomes. These results may help elucidate lower than expected mortality rates observed in Hispanics, older African-Americans, and women.", - "journal_title": "Genome biology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/27511193/" - } - ], - "147b69a0-1397-4b1a-aa01-fa310677edb9": [ - { - "pub_id": "27726798", - "title": "The Evolutionary History, Demography, and Spread of the Mycobacterium tuberculosis Complex.", - "authors": "Maxime Barbier,Thierry Wirth", - "abstract": "With the advent of next-generation sequencing technology, the genotyping of clinical Mycobacterium tuberculosis strains went through a major breakup that dramatically improved the field of molecular epidemiology but also revolutionized our deep understanding of the M. tuberculosis complex evolutionary history. The intricate paths of the pathogen and its human host are reflected by a common geographical origin in Africa and strong biogeographical associations that largely reflect the past migration waves out of Africa. This long coevolutionary history is cardinal for our understanding of the host-pathogen dynamic, including past and ongoing demographic components, strains' genetic background, as well as the immune system genetic architecture of the host. Coalescent- and Bayesian-based analyses allowed us to reconstruct population size changes of M. tuberculosis through time, to date the most recent common ancestor and the several phylogenetic lineages. This information will ultimately help us to understand the spread of the Beijing lineage, the rise of multidrug-resistant sublineages, or the fall of others in the light of socioeconomic events, antibiotic programs, or host population densities. If we leave the present and go through the looking glass, thanks to our ability to handle small degraded molecules combined with targeted capture, paleomicrobiology covering the Pleistocene era will possibly unravel lineage replacements, dig out extinct ones, and eventually ask for major revisions of the current model.", - "journal_title": "Microbiology spectrum", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/27726798/" - } - ], - "ac27125c-9d08-40e3-a16f-099ee397bb3f": [ - { - "pub_id": "25444595", - "title": "NeuroX, a fast and efficient genotyping platform for investigation of neurodegenerative diseases.", - "authors": "Mike A Nalls,Jose Bras,Dena G Hernandez,Margaux F Keller,Elisa Majounie,Alan E Renton,Mohamad Saad,Iris Jansen,Rita Guerreiro,Steven Lubbe,Vincent Plagnol,J Raphael Gibbs,Claudia Schulte,Nathan Pankratz,Margaret Sutherland,Lars Bertram,Christina M Lill,Anita L DeStefano,Tatiana Faroud,Nicholas Eriksson,Joyce Y Tung,Connor Edsall,Noah Nichols,Janet Brooks,Sampath Arepalli,Hannah Pliner,Chris Letson,Peter Heutink,Maria Martinez,Thomas Gasser,Bryan J Traynor,Nick Wood,John Hardy,Andrew B Singleton, , ", - "abstract": "Our objective was to design a genotyping platform that would allow rapid genetic characterization of samples in the context of genetic mutations and risk factors associated with common neurodegenerative diseases. The platform needed to be relatively affordable, rapid to deploy, and use a common and accessible technology. Central to this project, we wanted to make the content of the platform open to any investigator without restriction. In designing this array we prioritized a number of types of genetic variability for inclusion, such as known risk alleles, disease-causing mutations, putative risk alleles, and other functionally important variants. The array was primarily designed to allow rapid screening of samples for disease-causing mutations and large population studies of risk factors. Notably, an explicit aim was to make this array widely available to facilitate data sharing across and within diseases. The resulting array, NeuroX, is a remarkably cost and time effective solution for high-quality genotyping. NeuroX comprises a backbone of standard Illumina exome content of approximately 240,000 variants, and over 24,000 custom content variants focusing on neurologic diseases. Data are generated at approximately $50-$60 per sample using a 12-sample format chip and regular Infinium infrastructure; thus, genotyping is rapid and accessible to many investigators. Here, we describe the design of NeuroX, discuss the utility of NeuroX in the analyses of rare and common risk variants, and present quality control metrics and a brief primer for the analysis of NeuroX derived data.", - "journal_title": "Neurobiology of aging", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/25444595/" - } - ], - "e934de49-36e3-4a85-a822-28c3532be918": [ - { - "pub_id": "23633914", - "title": "MicroRNA in Aging: From Discovery to Biology.", - "authors": "Hwa Jin Jung,Yousin Suh", - "abstract": "MicroRNAs (miRNAs) are small non-coding RNA molecules that negatively regulate gene expression of their targets at the post-transcriptional levels. A single miRNA can target up to several hundred mRNAs, thus capable of significantly altering gene expression regulatory networks. In-depth study and characterization of miRNAs has elucidated their critical functions in development, homeostasis, and disease. A link between miRNAs and longevity has been demonstrated in C. elegans, implicating their role in regulation of lifespan and in the aging process. Recent years have witnessed unprecedented technological advances in studies of miRNAs, including ultra-high throughput sequencing technologies that allow comprehensive discovery of miRNAs and their targets. Here we review the latest experimental approaches from the perspective of understanding miRNA gene expression regulatory networks in aging. We provide a methodological work flow that can be employed to discover aging-related miRNAs and their targets, and to functionally validate their roles in aging. Finally, we review the links between miRNAs known to act in the conserved pathways of aging and major aging-related diseases. Taken together, we hope to provide a focused review to facilitate future endeavor of uncovering the functional role of miRNA in aging.", - "journal_title": "Current genomics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/23633914/" - } - ], - "13d03658-3d79-4ae8-92d3-cd6d9f479b41": [ - { - "pub_id": "22072275", - "title": "Genetics of migraine in the age of genome-wide association studies.", - "authors": "Markus Sch\u00fcrks", - "abstract": "Genetic factors importantly contribute to migraine. However, unlike for rare monogenic forms of migraine, approaches to identify genes for common forms of migraine have been of limited success. Candidate gene association studies were often negative and positive results were often not replicated or replication failed. Further, the significance of positive results from linkage studies remains unclear owing to the inability to pinpoint the genes under the peaks that may be involved in migraine. Problems hampering these studies include limited sample sizes, methods of migraine ascertainment, and the heterogeneous clinical phenotype. Three genome-wide association studies are available now and have successfully identified four new genetic variants associated with migraine. One new variant (rs1835740) modulates glutamate homeostasis, thus integrates well with current concepts of neurotransmitter disturbances. This variant may be more specific for severe forms of migraine such as migraine with aura than migraine without aura. Another variant (rs11172113) implicates the lipoprotein receptor LRP1, which may interact with neuronal glutamate receptors, thus also providing a link to the glutamate pathway. In contrast, rs10166942 is in close proximity to TRPM8, which codes for a cold and pain sensor. For the first time this links a gene explicitly implicated in pain related pathways to migraine. The potential function of the fourth variant rs2651899 (PRDM16) in migraine is unclear. All these variants only confer a small to moderate change in risk for migraine, which concurs with migraine being a heterogeneous disorder. Ongoing large international collaborations will likely identify additional gene variants for migraine.", - "journal_title": "The journal of headache and pain", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/22072275/" - } - ], - "bf942243-0dab-4e4d-8362-3bd4c5f29746": [ - { - "pub_id": "23280227", - "title": "Association of all-cause mortality with overweight and obesity using standard body mass index categories: a systematic review and meta-analysis.", - "authors": "Katherine M Flegal,Brian K Kit,Heather Orpana,Barry I Graubard", - "abstract": "Estimates of the relative mortality risks associated with normal weight, overweight, and obesity may help to inform decision making in the clinical setting. To perform a systematic review of reported hazard ratios (HRs) of all-cause mortality for overweight and obesity relative to normal weight in the general population. PubMed and EMBASE electronic databases were searched through September 30, 2012, without language restrictions. Articles that reported HRs for all-cause mortality using standard body mass index (BMI) categories from prospective studies of general populations of adults were selected by consensus among multiple reviewers. Studies were excluded that used nonstandard categories or that were limited to adolescents or to those with specific medical conditions or to those undergoing specific procedures. PubMed searches yielded 7034 articles, of which 141 (2.0%) were eligible. An EMBASE search yielded 2 additional articles. After eliminating overlap, 97 studies were retained for analysis, providing a combined sample size of more than 2.88 million individuals and more than 270,000 deaths. Data were extracted by 1 reviewer and then reviewed by 3 independent reviewers. We selected the most complex model available for the full sample and used a variety of sensitivity analyses to address issues of possible overadjustment (adjusted for factors in causal pathway) or underadjustment (not adjusted for at least age, sex, and smoking). Random-effects summary all-cause mortality HRs for overweight (BMI of 25-<30), obesity (BMI of \u226530), grade 1 obesity (BMI of 30-<35), and grades 2 and 3 obesity (BMI of \u226535) were calculated relative to normal weight (BMI of 18.5-<25). The summary HRs were 0.94 (95% CI, 0.91-0.96) for overweight, 1.18 (95% CI, 1.12-1.25) for obesity (all grades combined), 0.95 (95% CI, 0.88-1.01) for grade 1 obesity, and 1.29 (95% CI, 1.18-1.41) for grades 2 and 3 obesity. These findings persisted when limited to studies with measured weight and height that were considered to be adequately adjusted. The HRs tended to be higher when weight and height were self-reported rather than measured. Relative to normal weight, both obesity (all grades) and grades 2 and 3 obesity were associated with significantly higher all-cause mortality. Grade 1 obesity overall was not associated with higher mortality, and overweight was associated with significantly lower all-cause mortality. The use of predefined standard BMI groupings can facilitate between-study comparisons.", - "journal_title": "JAMA", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/23280227/" - } - ], - "e913e8b9-7a8a-4a5e-9794-a947d94654a5": [ - { - "pub_id": "23834319", - "title": "Marsupials in the age of genomics.", - "authors": "Jennifer A Marshall Graves,Marilyn B Renfree", - "abstract": "Marsupials are \"alternative mammals\" that differ from eutherians most spectacularly in their mode of reproduction and sexual differentiation. They represent a 160-million-year-old isolate from the more numerous eutherians, making them particularly valuable for comparative genome studies that enlarge and enhance our understanding of the function and evolution of the mammalian genome. The genomes of three sequenced marsupial species are similar in size to those of mice and humans but show informative differences in base composition and repetitive elements. Small differences in gene sets and gene families between marsupials and eutherians may relate to physiological and environmental differences. Marsupial karyotypes are highly conserved in chromosome numbers, sizes, and G-banding patterns, and an ancestor with a 2n = 14 karyotype can be deduced. Marsupial sex chromosomes, partly homologous to those of eutherians, represent the ancestral therian XY pair. Epigenetic regulation of X inactivation in marsupials differs markedly from that of eutherians and has apparently retained an ancient silencing mechanism. Genomic imprinting of a smaller set of genes occurs in the marsupial placenta and, uniquely, in the mammary gland.", - "journal_title": "Annual review of genomics and human genetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/23834319/" - } - ], - "ab6b54c8-364d-427a-b892-016adfd85dcc": [ - { - "pub_id": "29310578", - "title": "A-to-I RNA editing in the rat brain is age-dependent, region-specific and sensitive to environmental stress across generations.", - "authors": "Hiba Zaidan,Gokul Ramaswami,Yaela N Golumbic,Noa Sher,Assaf Malik,Michal Barak,Dalia Galiani,Nava Dekel,Jin B Li,Inna Gaisler-Salomon", - "abstract": "Adenosine-to-inosine (A-to-I) RNA editing is an epigenetic modification catalyzed by adenosine deaminases acting on RNA (ADARs), and is especially prevalent in the brain. We used the highly accurate microfluidics-based multiplex PCR sequencing (mmPCR-seq) technique to assess the effects of development and environmental stress on A-to-I editing at 146 pre-selected, conserved sites in the rat prefrontal cortex and amygdala. Furthermore, we asked whether changes in editing can be observed in offspring of stress-exposed rats. In parallel, we assessed changes in ADARs expression levels. In agreement with previous studies, we found editing to be generally higher in adult compared to neonatal rat brain. At birth, editing was generally lower in prefrontal cortex than in amygdala. Stress affected editing at the serotonin receptor 2c (Htr2c), and editing at this site was significantly altered in offspring of rats exposed to prereproductive stress across two generations. Stress-induced changes in Htr2c editing measured with mmPCR-seq were comparable to changes measured with Sanger and Illumina sequencing. Developmental and stress-induced changes in Adar and Adarb1 mRNA expression were observed but did not correlate with editing changes. Our findings indicate that mmPCR-seq can accurately detect A-to-I RNA editing in rat brain samples, and confirm previous accounts of a developmental increase in RNA editing rates. Our findings also point to stress in adolescence as an environmental factor that alters RNA editing patterns several generations forward, joining a growing body of literature describing the transgenerational effects of stress.", - "journal_title": "BMC genomics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/29310578/" - } - ], - "cfa366b2-1f94-472a-9096-db9338e27735": [ - { - "pub_id": "25898983", - "title": "Transcriptomic profiles of aging in purified human immune cells.", - "authors": "Lindsay M Reynolds,Jingzhong Ding,Jackson R Taylor,Kurt Lohman,Nicola Soranzo,Alberto de la Fuente,Tie Fu Liu,Craig Johnson,R Graham Barr,Thomas C Register,Kathleen M Donohue,Monica V Talor,Daniela Cihakova,Charles Gu,Jasmin Divers,David Siscovick,Gregory Burke,Wendy Post,Steven Shea,David R Jacobs,Ina Hoeschele,Charles E McCall,Stephen B Kritchevsky,David Herrington,Russell P Tracy,Yongmei Liu", - "abstract": "Transcriptomic studies hold great potential towards understanding the human aging process. Previous transcriptomic studies have identified many genes with age-associated expression levels; however, small samples sizes and mixed cell types often make these results difficult to interpret. Using transcriptomic profiles in CD14+ monocytes from 1,264 participants of the Multi-Ethnic Study of Atherosclerosis (aged 55-94 years), we identified 2,704 genes differentially expressed with chronological age (false discovery rate, FDR\u2009\u2264\u20090.001). We further identified six networks of co-expressed genes that included prominent genes from three pathways: protein synthesis (particularly mitochondrial ribosomal genes), oxidative phosphorylation, and autophagy, with expression patterns suggesting these pathways decline with age. Expression of several chromatin remodeler and transcriptional modifier genes strongly correlated with expression of oxidative phosphorylation and ribosomal protein synthesis genes. 17% of genes with age-associated expression harbored CpG sites whose degree of methylation significantly mediated the relationship between age and gene expression (p\u2009<\u20090.05). Lastly, 15 genes with age-associated expression were also associated (FDR\u2009\u2264\u20090.01) with pulse pressure independent of chronological age. Comparing transcriptomic profiles of CD14+ monocytes to CD4+ T cells from a subset (n\u2009=\u2009423) of the population, we identified 30 age-associated (FDR\u2009<\u20090.01) genes in common, while larger sets of differentially expressed genes were unique to either T cells (188 genes) or monocytes (383 genes). At the pathway level, a decline in ribosomal protein synthesis machinery gene expression with age was detectable in both cell types. An overall decline in expression of ribosomal protein synthesis genes with age was detected in CD14+ monocytes and CD4+ T cells, demonstrating that some patterns of aging are likely shared between different cell types. Our findings also support cell-specific effects of age on gene expression, illustrating the importance of using purified cell samples for future transcriptomic studies. Longitudinal work is required to establish the relationship between identified age-associated genes/pathways and aging-related diseases.", - "journal_title": "BMC genomics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/25898983/" - } - ], - "1ca8585c-da20-470e-958a-4ffda9603834": [ - { - "pub_id": "29740155", - "title": "An update on the genetics of hyperuricaemia and gout.", - "authors": "Tanya J Major,Nicola Dalbeth,Eli A Stahl,Tony R Merriman", - "abstract": "A central aspect of the pathogenesis of gout is elevated urate concentrations, which lead to the formation of monosodium urate crystals. The clinical features of gout result from an individual's immune response to these deposited crystals. Genome-wide association studies (GWAS) have confirmed the importance of urate excretion in the control of serum urate levels and the risk of gout and have identified the kidneys, the gut and the liver as sites of urate regulation. The genetic contribution to the progression from hyperuricaemia to gout remains relatively poorly understood, although genes encoding proteins that are involved in the NLRP3 (NOD-, LRR- and pyrin domain-containing 3) inflammasome pathway play a part. Genome-wide and targeted sequencing is beginning to identify uncommon population-specific variants that are associated with urate levels and gout. Mendelian randomization studies using urate-associated genetic variants as unconfounded surrogates for lifelong urate exposure have not supported claims that urate is causal for metabolic conditions that are comorbidities of hyperuricaemia and gout. Genetic studies have also identified genetic variants that predict responsiveness to therapies (for example, urate-lowering drugs) for treatment of hyperuricaemia. Future research should focus on large GWAS (that include asymptomatic hyperuricaemic individuals) and on increasing the use of whole-genome sequencing data to identify uncommon genetic variants with increased penetrance that might provide opportunities for clinical translation.", - "journal_title": "Nature reviews. Rheumatology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/29740155/" - } - ], - "7fee50dc-7172-4574-a3e7-4961060a655b": [ - { - "pub_id": "27358654", - "title": "Profiling genome-wide DNA methylation.", - "authors": "Wai-Shin Yong,Fei-Man Hsu,Pao-Yang Chen", - "abstract": "DNA methylation is an epigenetic modification that plays an important role in regulating gene expression and therefore a broad range of biological processes and diseases. DNA methylation is tissue-specific, dynamic, sequence-context-dependent and trans-generationally heritable, and these complex patterns of methylation highlight the significance of profiling DNA methylation to answer biological questions. In this review, we surveyed major methylation assays, along with comparisons and biological examples, to provide an overview of DNA methylation profiling techniques. The advances in microarray and sequencing technologies make genome-wide profiling possible at a single-nucleotide or even a single-cell resolution. These profiling approaches vary in many aspects, such as DNA input, resolution, genomic region coverage, and bioinformatics analysis, and selecting a feasible method requires knowledge of these methods. We first introduce the biological background of DNA methylation and its pattern in plants, animals and fungi. We present an overview of major experimental approaches to profiling genome-wide DNA methylation and hydroxymethylation and then extend to the single-cell methylome. To evaluate these methods, we outline their strengths and weaknesses and perform comparisons across the different platforms. Due to the increasing need to compute high-throughput epigenomic data, we interrogate the computational pipeline for bisulfite sequencing data and also discuss the concept of identifying differentially methylated regions (DMRs). This review summarizes the experimental and computational concepts for profiling genome-wide DNA methylation, followed by biological examples. Overall, this review provides researchers useful guidance for the selection of a profiling method suited to specific research questions.", - "journal_title": "Epigenetics & chromatin", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/27358654/" - } - ], - "2251b0b8-3cc8-46ac-94f9-5296e53c2abc": [ - { - "pub_id": "23918660", - "title": "Age-associated epigenetic drift: implications, and a case of epigenetic thrift?", - "authors": "Andrew E Teschendorff,James West,Stephan Beck", - "abstract": "It is now well established that the genomic landscape of DNA methylation (DNAm) gets altered as a function of age, a process we here call 'epigenetic drift'. The biological, functional, clinical and evolutionary significance of this epigenetic drift, however, remains unclear. We here provide a brief review of epigenetic drift, focusing on the potential implications for ageing, stem cell biology and disease risk prediction. It has been demonstrated that epigenetic drift affects most of the genome, suggesting a global deregulation of DNAm patterns with age. A component of this drift is tissue-specific, allowing remarkably accurate age-predictive models to be constructed. Another component is tissue-independent, targeting stem cell differentiation pathways and affecting stem cells, which may explain the observed decline of stem cell function with age. Age-associated increases in DNAm target developmental genes, overlapping those associated with environmental disease risk factors and with disease itself, notably cancer. In particular, cancers and precursor cancer lesions exhibit aggravated age DNAm signatures. Epigenetic drift is also influenced by genetic factors. Thus, drift emerges as a promising biomarker for premature or biological ageing, and could potentially be used in geriatrics for disease risk prediction. Finally, we propose, in the context of human evolution, that epigenetic drift may represent a case of epigenetic thrift, or bet-hedging. In summary, this review demonstrates the growing importance of the 'ageing epigenome', with potentially far-reaching implications for understanding the effect of age on stem cell function and differentiation, as well as for disease prevention.", - "journal_title": "Human molecular genetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/23918660/" - } - ], - "c378bf6f-1896-4100-940e-4618a993730d": [ - { - "pub_id": "28360329", - "title": "Aging increases cell-to-cell transcriptional variability upon immune stimulation.", - "authors": "Celia Pilar Martinez-Jimenez,Nils Eling,Hung-Chang Chen,Catalina A Vallejos,Aleksandra A Kolodziejczyk,Frances Connor,Lovorka Stojic,Timothy F Rayner,Michael J T Stubbington,Sarah A Teichmann,Maike de la Roche,John C Marioni,Duncan T Odom", - "abstract": "Aging is characterized by progressive loss of physiological and cellular functions, but the molecular basis of this decline remains unclear. We explored how aging affects transcriptional dynamics using single-cell RNA sequencing of unstimulated and stimulated na\u00efve and effector memory CD4<sup>+</sup> T cells from young and old mice from two divergent species. In young animals, immunological activation drives a conserved transcriptomic switch, resulting in tightly controlled gene expression characterized by a strong up-regulation of a core activation program, coupled with a decrease in cell-to-cell variability. Aging perturbed the activation of this core program and increased expression heterogeneity across populations of cells in both species. These discoveries suggest that increased cell-to-cell transcriptional variability will be a hallmark feature of aging across most, if not all, mammalian tissues.", - "journal_title": "Science (New York, N.Y.)", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/28360329/" - } - ], - "a573908f-008a-46f1-a88a-c6cd32557ed7": [ - { - "pub_id": "22940096", - "title": "RECQL4 in genomic instability and aging.", - "authors": "Deborah L Croteau,Dharmendra Kumar Singh,Leslie Hoh Ferrarelli,Huiming Lu,Vilhelm A Bohr", - "abstract": "Helicases are ubiquitous proteins that unwind DNA and participate in DNA metabolism including replication, repair, transcription, and chromatin organization. The highly conserved RecQ helicase family proteins are important in these transactions and have been termed the guardians of the genome. Humans have five members of this family: WRN, BLM, RECQL4, RECQL1, and RECQL5. The first three of are associated with premature aging and cancer prone syndromes, but the latter two proteins have not yet been implicated in any human disease. Although WRN and BLM have been fairly well characterized, RECQL4 has only recently been intensively investigated. The sum of this work to date has shown that RECQL4 has helicase activity and localizes to telomeres and mitochondria. In addition, new protein partners are emerging, implicating RECQL4 in novel processes. Here, we describe these recent findings which place RECQL4 at the crossroads of genomic instability and aging processes.", - "journal_title": "Trends in genetics : TIG", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/22940096/" - } - ], - "d1550acb-9504-4d2b-a2b9-e3ab2df92efb": [ - { - "pub_id": "24323947", - "title": "Transposable elements become active and mobile in the genomes of aging mammalian somatic tissues.", - "authors": "Marco De Cecco,Steven W Criscione,Abigail L Peterson,Nicola Neretti,John M Sedivy,Jill A Kreiling", - "abstract": "Transposable elements (TEs) were discovered by Barbara McClintock in maize and have since been found to be ubiquitous in all living organisms. Transposition is mutagenic and organisms have evolved mechanisms to repress the activity of their endogenous TEs. Transposition in somatic cells is very low, but recent evidence suggests that it may be derepressed in some cases, such as cancer development. We have found that during normal aging several families of retrotransposable elements (RTEs) start being transcribed in mouse tissues. In advanced age the expression culminates in active transposition. These processes are counteracted by calorie restriction (CR), an intervention that slows down aging. Retrotransposition is also activated in age-associated, naturally occurring cancers in the mouse. We suggest that somatic retrotransposition is a hitherto unappreciated aging process. Mobilization of RTEs is likely to be an important contributor to the progressive dysfunction of aging cells.", - "journal_title": "Aging", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/24323947/" - } - ], - "45b992a8-b973-4316-82da-376b9addf7d7": [ - { - "pub_id": "26053498", - "title": "Whole-genome fingerprint of the DNA methylome during human B cell differentiation.", - "authors": "Marta Kulis,Angelika Merkel,Simon Heath,Ana C Queir\u00f3s,Ronald P Schuyler,Giancarlo Castellano,Ren\u00e9e Beekman,Emanuele Raineri,Anna Esteve,Guillem Clot,N\u00e9ria Verdaguer-Dot,Mart\u00ed Duran-Ferrer,Nuria Russi\u00f1ol,Roser Vilarrasa-Blasi,Simone Ecker,Vera Pancaldi,Daniel Rico,Lidia Agueda,Julie Blanc,David Richardson,Laura Clarke,Avik Datta,Marien Pascual,Xabier Agirre,Felipe Prosper,Diego Alignani,Bruno Paiva,Gersende Caron,Thierry Fest,Marcus O Muench,Marina E Fomin,Seung-Tae Lee,Joseph L Wiemels,Alfonso Valencia,Marta Gut,Paul Flicek,Hendrik G Stunnenberg,Reiner Siebert,Ralf K\u00fcppers,Ivo G Gut,El\u00edas Campo,Jos\u00e9 I Mart\u00edn-Subero", - "abstract": "We analyzed the DNA methylome of ten subpopulations spanning the entire B cell differentiation program by whole-genome bisulfite sequencing and high-density microarrays. We observed that non-CpG methylation disappeared upon B cell commitment, whereas CpG methylation changed extensively during B cell maturation, showing an accumulative pattern and affecting around 30% of all measured CpG sites. Early differentiation stages mainly displayed enhancer demethylation, which was associated with upregulation of key B cell transcription factors and affected multiple genes involved in B cell biology. Late differentiation stages, in contrast, showed extensive demethylation of heterochromatin and methylation gain at Polycomb-repressed areas, and genes with apparent functional impact in B cells were not affected. This signature, which has previously been linked to aging and cancer, was particularly widespread in mature cells with an extended lifespan. Comparing B cell neoplasms with their normal counterparts, we determined that they frequently acquire methylation changes in regions already undergoing dynamic methylation during normal B cell differentiation.", - "journal_title": "Nature genetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/26053498/" - } - ], - "38f806a9-f265-4854-b86b-38cf56b57dd8": [ - { - "pub_id": "23028804", - "title": "Mitochondrial genomic analysis of late onset Alzheimer's disease reveals protective haplogroups H6A1A/H6A1B: the Cache County Study on Memory in Aging.", - "authors": "Perry G Ridge,Taylor J Maxwell,Christopher D Corcoran,Maria C Norton,Joann T Tschanz,Elizabeth O'Brien,Richard A Kerber,Richard M Cawthon,Ronald G Munger,John S K Kauwe", - "abstract": "Alzheimer's disease (AD) is the most common cause of dementia and AD risk clusters within families. Part of the familial aggregation of AD is accounted for by excess maternal vs. paternal inheritance, a pattern consistent with mitochondrial inheritance. The role of specific mitochondrial DNA (mtDNA) variants and haplogroups in AD risk is uncertain. We determined the complete mitochondrial genome sequence of 1007 participants in the Cache County Study on Memory in Aging, a population-based prospective cohort study of dementia in northern Utah. AD diagnoses were made with a multi-stage protocol that included clinical examination and review by a panel of clinical experts. We used TreeScanning, a statistically robust approach based on haplotype networks, to analyze the mtDNA sequence data. Participants with major mitochondrial haplotypes H6A1A and H6A1B showed a reduced risk of AD (p=0.017, corrected for multiple comparisons). The protective haplotypes were defined by three variants: m.3915G>A, m.4727A>G, and m.9380G>A. These three variants characterize two different major haplogroups. Together m.4727A>G and m.9380G>A define H6A1, and it has been suggested m.3915G>A defines H6A. Additional variants differentiate H6A1A and H6A1B; however, none of these variants had a significant relationship with AD case-control status. Our findings provide evidence of a reduced risk of AD for individuals with mtDNA haplotypes H6A1A and H6A1B. These findings are the results of the largest study to date with complete mtDNA genome sequence data, yet the functional significance of the associated haplotypes remains unknown and replication in others studies is necessary.", - "journal_title": "PloS one", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/23028804/" - } - ], - "9cd585e3-7b20-4f3c-8bf8-36689039aa8a": [ - { - "pub_id": "25795171", - "title": "Breeding-assisted genomics.", - "authors": "Jesse Poland", - "abstract": "The revolution of inexpensive sequencing has ushered in an unprecedented age of genomics. The promise of using this technology to accelerate plant breeding is being realized with a vision of genomics-assisted breeding that will lead to rapid genetic gain for expensive and difficult traits. The reality is now that robust phenotypic data is an increasing limiting resource to complement the current wealth of genomic information. While genomics has been hailed as the discipline to fundamentally change the scope of plant breeding, a more symbiotic relationship is likely to emerge. In the context of developing and evaluating large populations needed for functional genomics, none excel in this area more than plant breeders. While genetic studies have long relied on dedicated, well-structured populations, the resources dedicated to these populations in the context of readily available, inexpensive genotyping is making this philosophy less tractable relative to directly focusing functional genomics on material in breeding programs. Through shifting effort for basic genomic studies from dedicated structured populations, to capturing the entire scope of genetic determinants in breeding lines, we can move towards not only furthering our understanding of functional genomics in plants, but also rapidly improving crops for increased food security, availability and nutrition.", - "journal_title": "Current opinion in plant biology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/25795171/" - } - ], - "0a4c8041-059f-46a9-8212-d859dfeadd2a": [ - { - "pub_id": "22589246", - "title": "A greatly extended PPARGC1A genomic locus encodes several new brain-specific isoforms and influences Huntington disease age of onset.", - "authors": "Selma M Soyal,Thomas K Felder,Simon Auer,Penelope Hahne,Hannes Oberkofler,Anke Witting,Markus Paulmichl,G Bernhard Landwehrmeyer,Patrick Weydt,Wolfgang Patsch, ", - "abstract": "PGC-1\u03b1 has been implicated in the pathogenesis of neurodegenerative disorders. Several single-nucleotide polymorphisms (SNPs) located in two separate haplotype blocks of PPARGC1A have shown associations with Huntington's disease (HD) and Parkinson's disease, but causative SNPs have not been identified. One SNP (rs7665116) was located in a highly conserved 233 bp region of intron 2. To determine whether rs7665116 is located in an alternative exon, we performed 5'-RLM-RACE from exon 3 and discovered multiple new transcripts that initiated from a common novel promoter located 587 kb upstream of exon 2, but did not contain the conserved region harboring rs7665116. Using real-time polymerase chain reaction, RNase protection assays and northern blotting, we show that the majority of these transcripts are brain specific and are at least equally or perhaps more abundant than the reference sequence PPARGC1A transcripts in whole brain. Two main transcripts containing independent methionine start codons encode full-length brain-specific PGC-1\u03b1 proteins that differ only at their N-termini (NTs) from PGC-1\u03b1, encoded by the reference sequence. Additional truncated isoforms containing these NTs that are similar to NT-PGC-1\u03b1 exist. Other transcripts may encode potential dominant negative forms, as they are predicted to lack the second LXXLL motif that serves as an interaction site for several nuclear receptors. Furthermore, we show that the new promoter is active in neuronal cell lines and describe haplotypes encompassing this region that are associated with HD age of onset. The discovery of such a large PPARGC1A genomic locus and multiple isoforms in brain warrants further functional studies and may provide new tissue-specific targets for treating neurodegenerative diseases.", - "journal_title": "Human molecular genetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/22589246/" - } - ], - "6ac32a33-e2af-40bb-aad6-9971c46023d4": [ - { - "pub_id": "23889843", - "title": "Gene expression changes with age in skin, adipose tissue, blood and brain.", - "authors": "Daniel Glass,Ana Vi\u00f1uela,Matthew N Davies,Adaikalavan Ramasamy,Leopold Parts,David Knowles,Andrew A Brown,Asa K Hedman,Kerrin S Small,Alfonso Buil,Elin Grundberg,Alexandra C Nica,Paola Di Meglio,Frank O Nestle,Mina Ryten, , ,Richard Durbin,Mark I McCarthy,Panagiotis Deloukas,Emmanouil T Dermitzakis,Michael E Weale,Veronique Bataille,Tim D Spector", - "abstract": "Previous studies have demonstrated that gene expression levels change with age. These changes are hypothesized to influence the aging rate of an individual. We analyzed gene expression changes with age in abdominal skin, subcutaneous adipose tissue and lymphoblastoid cell lines in 856 female twins in the age range of 39-85 years. Additionally, we investigated genotypic variants involved in genotype-by-age interactions to understand how the genomic regulation of gene expression alters with age. Using a linear mixed model, differential expression with age was identified in 1,672 genes in skin and 188 genes in adipose tissue. Only two genes expressed in lymphoblastoid cell lines showed significant changes with age. Genes significantly regulated by age were compared with expression profiles in 10 brain regions from 100 postmortem brains aged 16 to 83 years. We identified only one age-related gene common to the three tissues. There were 12 genes that showed differential expression with age in both skin and brain tissue and three common to adipose and brain tissues. Skin showed the most age-related gene expression changes of all the tissues investigated, with many of the genes being previously implicated in fatty acid metabolism, mitochondrial activity, cancer and splicing. A significant proportion of age-related changes in gene expression appear to be tissue-specific with only a few genes sharing an age effect in expression across tissues. More research is needed to improve our understanding of the genetic influences on aging and the relationship with age-related diseases.", - "journal_title": "Genome biology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/23889843/" - } - ], - "61ddd7e2-8b42-46a5-9f50-f64d4ffe5f04": [ - { - "pub_id": "25642630", - "title": "LD Score regression distinguishes confounding from polygenicity in genome-wide association studies.", - "authors": "Brendan K Bulik-Sullivan,Po-Ru Loh,Hilary K Finucane,Stephan Ripke,Jian Yang, ,Nick Patterson,Mark J Daly,Alkes L Price,Benjamin M Neale", - "abstract": "Both polygenicity (many small genetic effects) and confounding biases, such as cryptic relatedness and population stratification, can yield an inflated distribution of test statistics in genome-wide association studies (GWAS). However, current methods cannot distinguish between inflation from a true polygenic signal and bias. We have developed an approach, LD Score regression, that quantifies the contribution of each by examining the relationship between test statistics and linkage disequilibrium (LD). The LD Score regression intercept can be used to estimate a more powerful and accurate correction factor than genomic control. We find strong evidence that polygenicity accounts for the majority of the inflation in test statistics in many GWAS of large sample size.", - "journal_title": "Nature genetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/25642630/" - } - ], - "ec30a36c-fae2-48f3-971f-868fc837ebeb": [ - { - "pub_id": "29152902", - "title": "The genetics of human personality.", - "authors": "S Sanchez-Roige,J C Gray,J MacKillop,C-H Chen,A A Palmer", - "abstract": "Personality traits are the relatively enduring patterns of thoughts, feelings and behaviors that reflect the tendency to respond in certain ways under certain circumstances. Twin and family studies have showed that personality traits are moderately heritable, and can predict various lifetime outcomes, including psychopathology. The Research Domain Criteria characterizes psychiatric diseases as extremes of normal tendencies, including specific personality traits. This implies that heritable variation in personality traits, such as neuroticism, would share a common genetic basis with psychiatric diseases, such as major depressive disorder. Despite considerable efforts over the past several decades, the genetic variants that influence personality are only beginning to be identified. We review these recent and increasingly rapid developments, which focus on the assessment of personality via several commonly used personality questionnaires in healthy human subjects. Study designs covered include twin, linkage, candidate gene association studies, genome-wide association studies and polygenic analyses. Findings from genetic studies of personality have furthered our understanding about the genetic etiology of personality, which, like neuropsychiatric diseases themselves, is highly polygenic. Polygenic analyses have showed genetic correlations between personality and psychopathology, confirming that genetic studies of personality can help to elucidate the etiology of several neuropsychiatric diseases.", - "journal_title": "Genes, brain, and behavior", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/29152902/" - } - ], - "d9e4044a-7d17-4b49-9f00-5408fc312ed9": [ - { - "pub_id": "28507541", - "title": "The Importance of Bacterial Culture to Food Microbiology in the Age of Genomics.", - "authors": "Alexander Gill", - "abstract": "Culture-based and genomics methods provide different insights into the nature and behavior of bacteria. Maximizing the usefulness of both approaches requires recognizing their limitations and employing them appropriately. Genomic analysis excels at identifying bacteria and establishing the relatedness of isolates. Culture-based methods remain necessary for detection and enumeration, to determine viability, and to validate phenotype predictions made on the bias of genomic analysis. The purpose of this short paper is to discuss the application of culture-based analysis and genomics to the questions food microbiologists routinely need to ask regarding bacteria to ensure the safety of food and its economic production and distribution. To address these issues appropriate tools are required for the detection and enumeration of specific bacterial populations and the characterization of isolates for, identification, phylogenetics, and phenotype prediction.", - "journal_title": "Frontiers in microbiology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/28507541/" - } - ], - "6197ffbe-0114-430e-9be6-5f3d4d09f9a4": [ - { - "pub_id": "26913989", - "title": "Shared genetic contribution to Ischaemic Stroke and Alzheimer's Disease.", - "authors": "Matthew Traylor,Poneh Adib-Samii,Denise Harold, , ,Martin Dichgans,Julie Williams,Cathryn M Lewis,Hugh S Markus, , ", - "abstract": "Increasing evidence suggests epidemiological and pathological links between Alzheimer's disease (AD) and Ischaemic Stroke (IS). We investigated the evidence that shared genetic factors underpin the two diseases. Using genome wide association study (GWAS) data from METASTROKE+ (15,916 IS cases and 68,826 controls) and IGAP (17,008 AD cases and 37,154 controls), we evaluated known associations with AD and IS. On the subset of data for which we could obtain compatible genotype-level data (4,610 IS cases, 1,281 AD cases and 14,320 controls), we estimated the genome-wide genetic correlation (rG) between AD and IS, and the three subtypes (cardioembolic, small vessel, large vessel), using genome-wide SNP data. We then performed a meta-analysis and pathway analysis in the combined AD and small vessel stroke datasets to identify the SNPs and molecular pathways through which disease risk may be conferred. We found evidence of a shared genetic contribution between AD and small vessel stroke (rG(SE)=0.37(0.17); p=0.011). Conversely, there was no evidence to support shared genetic factors in AD and IS overall, or with the other stroke subtypes. Of the known GWAS associations with IS or AD, none reached significance for association with the other trait (or stroke subtypes). A meta-analysis of AD IGAP and METASTROKE+ small vessel stroke GWAS data highlighted a region (ATP5H/KCTD2/ICT1), associated with both diseases (p=1.8x10<sup>-8</sup> ). A pathway analysis identified four associated pathways, involving cholesterol transport and immune response. Our findings indicate shared genetic susceptibility to AD and small vessel stroke and highlight potential causal pathways and loci. This article is protected by copyright. All rights reserved.", - "journal_title": "Annals of neurology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/26913989/" - } - ], - "e2a18728-4c25-4c11-bb19-0b0cf2462a24": [ - { - "pub_id": "22504420", - "title": "Genome-wide meta-analysis identifies 56 bone mineral density loci and reveals 14 loci associated with risk of fracture.", - "authors": "Karol Estrada,Unnur Styrkarsdottir,Evangelos Evangelou,Yi-Hsiang Hsu,Emma L Duncan,Evangelia E Ntzani,Ling Oei,Omar M E Albagha,Najaf Amin,John P Kemp,Daniel L Koller,Guo Li,Ching-Ti Liu,Ryan L Minster,Alireza Moayyeri,Liesbeth Vandenput,Dana Willner,Su-Mei Xiao,Laura M Yerges-Armstrong,Hou-Feng Zheng,Nerea Alonso,Joel Eriksson,Candace M Kammerer,Stephen K Kaptoge,Paul J Leo,Gudmar Thorleifsson,Scott G Wilson,James F Wilson,Ville Aalto,Markku Alen,Aaron K Aragaki,Thor Aspelund,Jacqueline R Center,Zoe Dailiana,David J Duggan,Melissa Garcia,Nat\u00e0lia Garcia-Giralt,Sylvie Giroux,G\u00f6ran Hallmans,Lynne J Hocking,Lise Bjerre Husted,Karen A Jameson,Rita Khusainova,Ghi Su Kim,Charles Kooperberg,Theodora Koromila,Marcin Kruk,Marika Laaksonen,Andrea Z Lacroix,Seung Hun Lee,Ping C Leung,Joshua R Lewis,Laura Masi,Simona Mencej-Bedrac,Tuan V Nguyen,Xavier Nogues,Millan S Patel,Janez Prezelj,Lynda M Rose,Serena Scollen,Kristin Siggeirsdottir,Albert V Smith,Olle Svensson,Stella Trompet,Olivia Trummer,Natasja M van Schoor,Jean Woo,Kun Zhu,Susana Balcells,Maria Luisa Brandi,Brendan M Buckley,Sulin Cheng,Claus Christiansen,Cyrus Cooper,George Dedoussis,Ian Ford,Morten Frost,David Goltzman,Jes\u00fas Gonz\u00e1lez-Mac\u00edas,Mika K\u00e4h\u00f6nen,Magnus Karlsson,Elza Khusnutdinova,Jung-Min Koh,Panagoula Kollia,Bente Lomholt Langdahl,William D Leslie,Paul Lips,\u00d6sten Ljunggren,Roman S Lorenc,Janja Marc,Dan Mellstr\u00f6m,Barbara Obermayer-Pietsch,Jos\u00e9 M Olmos,Ulrika Pettersson-Kymmer,David M Reid,Jos\u00e9 A Riancho,Paul M Ridker,Fran\u00e7ois Rousseau,P Eline Slagboom,Nelson L S Tang,Roser Urreizti,Wim Van Hul,Jorma Viikari,Mar\u00eda T Zarrabeitia,Yurii S Aulchenko,Martha Castano-Betancourt,Elin Grundberg,Lizbeth Herrera,Thorvaldur Ingvarsson,Hrefna Johannsdottir,Tony Kwan,Rui Li,Robert Luben,Carolina Medina-G\u00f3mez,Stefan Th Palsson,Sjur Reppe,Jerome I Rotter,Gunnar Sigurdsson,Joyce B J van Meurs,Dominique Verlaan,Frances M K Williams,Andrew R Wood,Yanhua Zhou,Kaare M Gautvik,Tomi Pastinen,Soumya Raychaudhuri,Jane A Cauley,Daniel I Chasman,Graeme R Clark,Steven R Cummings,Patrick Danoy,Elaine M Dennison,Richard Eastell,John A Eisman,Vilmundur Gudnason,Albert Hofman,Rebecca D Jackson,Graeme Jones,J Wouter Jukema,Kay-Tee Khaw,Terho Lehtim\u00e4ki,Yongmei Liu,Mattias Lorentzon,Eugene McCloskey,Braxton D Mitchell,Kannabiran Nandakumar,Geoffrey C Nicholson,Ben A Oostra,Munro Peacock,Huibert A P Pols,Richard L Prince,Olli Raitakari,Ian R Reid,John Robbins,Philip N Sambrook,Pak Chung Sham,Alan R Shuldiner,Frances A Tylavsky,Cornelia M van Duijn,Nick J Wareham,L Adrienne Cupples,Michael J Econs,David M Evans,Tamara B Harris,Annie Wai Chee Kung,Bruce M Psaty,Jonathan Reeve,Timothy D Spector,Elizabeth A Streeten,M Carola Zillikens,Unnur Thorsteinsdottir,Claes Ohlsson,David Karasik,J Brent Richards,Matthew A Brown,Kari Stefansson,Andr\u00e9 G Uitterlinden,Stuart H Ralston,John P A Ioannidis,Douglas P Kiel,Fernando Rivadeneira", - "abstract": "Bone mineral density (BMD) is the most widely used predictor of fracture risk. We performed the largest meta-analysis to date on lumbar spine and femoral neck BMD, including 17 genome-wide association studies and 32,961 individuals of European and east Asian ancestry. We tested the top BMD-associated markers for replication in 50,933 independent subjects and for association with risk of low-trauma fracture in 31,016 individuals with a history of fracture (cases) and 102,444 controls. We identified 56 loci (32 new) associated with BMD at genome-wide significance (P < 5 \u00d7 10(-8)). Several of these factors cluster within the RANK-RANKL-OPG, mesenchymal stem cell differentiation, endochondral ossification and Wnt signaling pathways. However, we also discovered loci that were localized to genes not known to have a role in bone biology. Fourteen BMD-associated loci were also associated with fracture risk (P < 5 \u00d7 10(-4), Bonferroni corrected), of which six reached P < 5 \u00d7 10(-8), including at 18p11.21 (FAM210A), 7q21.3 (SLC25A13), 11q13.2 (LRP5), 4q22.1 (MEPE), 2p16.2 (SPTBN1) and 10q21.1 (DKK1). These findings shed light on the genetic architecture and pathophysiological mechanisms underlying BMD variation and fracture susceptibility.", - "journal_title": "Nature genetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/22504420/" - } - ], - "593b752f-f448-47be-8b83-13bc5e9eb0d4": [ - { - "pub_id": "27114037", - "title": "Whole-Genome Sequencing of a Healthy Aging Cohort.", - "authors": "Galina A Erikson,Dale L Bodian,Manuel Rueda,Bhuvan Molparia,Erick R Scott,Ashley A Scott-Van Zeeland,Sarah E Topol,Nathan E Wineinger,John E Niederhuber,Eric J Topol,Ali Torkamani", - "abstract": "Studies of long-lived individuals have revealed few genetic mechanisms for protection against age-associated disease. Therefore, we pursued genome sequencing of a related phenotype-healthy aging-to understand the genetics of disease-free aging without medical intervention. In contrast with studies of exceptional longevity, usually focused on\u00a0centenarians, healthy aging is not associated with known longevity variants, but is associated with reduced genetic susceptibility to Alzheimer and coronary artery disease. Additionally, healthy aging is not associated with a decreased rate of rare pathogenic variants, potentially indicating the presence of disease-resistance factors. In keeping with this possibility, we identify suggestive common and rare variant genetic associations implying that protection against cognitive decline is a genetic component of healthy aging. These findings, based on a relatively small cohort, require independent replication. Overall, our results suggest healthy aging is an overlapping but distinct phenotype from exceptional longevity that may be enriched with disease-protective genetic factors. VIDEO ABSTRACT.", - "journal_title": "Cell", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/27114037/" - } - ], - "52317cf1-f1e8-4692-904d-4bcd6f86ee61": [ - { - "pub_id": "23638709", - "title": "5' tRNA halves are present as abundant complexes in serum, concentrated in blood cells, and modulated by aging and calorie restriction.", - "authors": "Joseph M Dhahbi,Stephen R Spindler,Hani Atamna,Amy Yamakawa,Dario Boffelli,Patricia Mote,David I K Martin", - "abstract": "Small RNAs complex with proteins to mediate a variety of functions in animals and plants. Some small RNAs, particularly miRNAs, circulate in mammalian blood and may carry out a signaling function by entering target cells and modulating gene expression. The subject of this study is a set of circulating 30-33 nt RNAs that are processed derivatives of the 5' ends of a small subset of tRNA genes, and closely resemble cellular tRNA derivatives (tRFs, tiRNAs, half-tRNAs, 5' tRNA halves) previously shown to inhibit translation initiation in response to stress in cultured cells. In sequencing small RNAs extracted from mouse serum, we identified abundant 5' tRNA halves derived from a small subset of tRNAs, implying that they are produced by tRNA type-specific biogenesis and/or release. The 5' tRNA halves are not in exosomes or microvesicles, but circulate as particles of 100-300 kDa. The size of these particles suggest that the 5' tRNA halves are a component of a macromolecular complex; this is supported by the loss of 5' tRNA halves from serum or plasma treated with EDTA, a chelating agent, but their retention in plasma anticoagulated with heparin or citrate. A survey of somatic tissues reveals that 5' tRNA halves are concentrated within blood cells and hematopoietic tissues, but scant in other tissues, suggesting that they may be produced by blood cells. Serum levels of specific subtypes of 5' tRNA halves change markedly with age, either up or down, and these changes can be prevented by calorie restriction. We demonstrate that 5' tRNA halves circulate in the blood in a stable form, most likely as part of a nucleoprotein complex, and their serum levels are subject to regulation by age and calorie restriction. They may be produced by blood cells, but their cellular targets are not yet known. The characteristics of these circulating molecules, and their known function in suppression of translation initiation, suggest that they are a novel form of signaling molecule.", - "journal_title": "BMC genomics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/23638709/" - } - ], - "cc48e751-9e81-4869-897e-dc26bf4c96fa": [ - { - "pub_id": "24162737", - "title": "Meta-analysis of 74,046 individuals identifies 11 new susceptibility loci for Alzheimer's disease.", - "authors": "J C Lambert,C A Ibrahim-Verbaas,D Harold,A C Naj,R Sims,C Bellenguez,A L DeStafano,J C Bis,G W Beecham,B Grenier-Boley,G Russo,T A Thorton-Wells,N Jones,A V Smith,V Chouraki,C Thomas,M A Ikram,D Zelenika,B N Vardarajan,Y Kamatani,C F Lin,A Gerrish,H Schmidt,B Kunkle,M L Dunstan,A Ruiz,M T Bihoreau,S H Choi,C Reitz,F Pasquier,C Cruchaga,D Craig,N Amin,C Berr,O L Lopez,P L De Jager,V Deramecourt,J A Johnston,D Evans,S Lovestone,L Letenneur,F J Mor\u00f3n,D C Rubinsztein,G Eiriksdottir,K Sleegers,A M Goate,N Fi\u00e9vet,M W Huentelman,M Gill,K Brown,M I Kamboh,L Keller,P Barberger-Gateau,B McGuiness,E B Larson,R Green,A J Myers,C Dufouil,S Todd,D Wallon,S Love,E Rogaeva,J Gallacher,P St George-Hyslop,J Clarimon,A Lleo,A Bayer,D W Tsuang,L Yu,M Tsolaki,P Boss\u00f9,G Spalletta,P Proitsi,J Collinge,S Sorbi,F Sanchez-Garcia,N C Fox,J Hardy,M C Deniz Naranjo,P Bosco,R Clarke,C Brayne,D Galimberti,M Mancuso,F Matthews, , , , ,S Moebus,P Mecocci,M Del Zompo,W Maier,H Hampel,A Pilotto,M Bullido,F Panza,P Caffarra,B Nacmias,J R Gilbert,M Mayhaus,L Lannefelt,H Hakonarson,S Pichler,M M Carrasquillo,M Ingelsson,D Beekly,V Alvarez,F Zou,O Valladares,S G Younkin,E Coto,K L Hamilton-Nelson,W Gu,C Razquin,P Pastor,I Mateo,M J Owen,K M Faber,P V Jonsson,O Combarros,M C O'Donovan,L B Cantwell,H Soininen,D Blacker,S Mead,T H Mosley,D A Bennett,T B Harris,L Fratiglioni,C Holmes,R F de Bruijn,P Passmore,T J Montine,K Bettens,J I Rotter,A Brice,K Morgan,T M Foroud,W A Kukull,D Hannequin,J F Powell,M A Nalls,K Ritchie,K L Lunetta,J S Kauwe,E Boerwinkle,M Riemenschneider,M Boada,M Hiltuenen,E R Martin,R Schmidt,D Rujescu,L S Wang,J F Dartigues,R Mayeux,C Tzourio,A Hofman,M M N\u00f6then,C Graff,B M Psaty,L Jones,J L Haines,P A Holmans,M Lathrop,M A Pericak-Vance,L J Launer,L A Farrer,C M van Duijn,C Van Broeckhoven,V Moskvina,S Seshadri,J Williams,G D Schellenberg,P Amouyel", - "abstract": "Eleven susceptibility loci for late-onset Alzheimer's disease (LOAD) were identified by previous studies; however, a large portion of the genetic risk for this disease remains unexplained. We conducted a large, two-stage meta-analysis of genome-wide association studies (GWAS) in individuals of European ancestry. In stage 1, we used genotyped and imputed data (7,055,881 SNPs) to perform meta-analysis on 4 previously published GWAS data sets consisting of 17,008 Alzheimer's disease cases and 37,154 controls. In stage 2, 11,632 SNPs were genotyped and tested for association in an independent set of 8,572 Alzheimer's disease cases and 11,312 controls. In addition to the APOE locus (encoding apolipoprotein E), 19 loci reached genome-wide significance (P < 5 \u00d7 10(-8)) in the combined stage 1 and stage 2 analysis, of which 11 are newly associated with Alzheimer's disease.", - "journal_title": "Nature genetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/24162737/" - } - ], - "e2a02184-d59a-4884-b67e-67209b9b9ae2": [ - { - "pub_id": "22504421", - "title": "Common variants at 12q14 and 12q24 are associated with hippocampal volume.", - "authors": "Joshua C Bis,Charles DeCarli,Albert Vernon Smith,Fedde van der Lijn,Fabrice Crivello,Myriam Fornage,Stephanie Debette,Joshua M Shulman,Helena Schmidt,Velandai Srikanth,Maaike Schuur,Lei Yu,Seung-Hoan Choi,Sigurdur Sigurdsson,Benjamin F J Verhaaren,Anita L DeStefano,Jean-Charles Lambert,Clifford R Jack,Maksim Struchalin,Jim Stankovich,Carla A Ibrahim-Verbaas,Debra Fleischman,Alex Zijdenbos,Tom den Heijer,Bernard Mazoyer,Laura H Coker,Christian Enzinger,Patrick Danoy,Najaf Amin,Konstantinos Arfanakis,Mark A van Buchem,Ren\u00e9e F A G de Bruijn,Alexa Beiser,Carole Dufouil,Juebin Huang,Margherita Cavalieri,Russell Thomson,Wiro J Niessen,Lori B Chibnik,Gauti K Gislason,Albert Hofman,Aleksandra Pikula,Philippe Amouyel,Kevin B Freeman,Thanh G Phan,Ben A Oostra,Jason L Stein,Sarah E Medland,Alejandro Arias Vasquez,Derrek P Hibar,Margaret J Wright,Barbara Franke,Nicholas G Martin,Paul M Thompson, ,Michael A Nalls,Andre G Uitterlinden,Rhoda Au,Alexis Elbaz,Richard J Beare,John C van Swieten,Oscar L Lopez,Tamara B Harris,Vincent Chouraki,Monique M B Breteler,Philip L De Jager,James T Becker,Meike W Vernooij,David Knopman,Franz Fazekas,Philip A Wolf,Aad van der Lugt,Vilmundur Gudnason,W T Longstreth,Matthew A Brown,David A Bennett,Cornelia M van Duijn,Thomas H Mosley,Reinhold Schmidt,Christophe Tzourio,Lenore J Launer,M Arfan Ikram,Sudha Seshadri, ", - "abstract": "Aging is associated with reductions in hippocampal volume that are accelerated by Alzheimer's disease and vascular risk factors. Our genome-wide association study (GWAS) of dementia-free persons (n = 9,232) identified 46 SNPs at four loci with P values of <4.0 \u00d7 10(-7). In two additional samples (n = 2,318), associations were replicated at 12q14 within MSRB3-WIF1 (discovery and replication; rs17178006; P = 5.3 \u00d7 10(-11)) and at 12q24 near HRK-FBXW8 (rs7294919; P = 2.9 \u00d7 10(-11)). Remaining associations included one SNP at 2q24 within DPP4 (rs6741949; P = 2.9 \u00d7 10(-7)) and nine SNPs at 9p33 within ASTN2 (rs7852872; P = 1.0 \u00d7 10(-7)); along with the chromosome 12 associations, these loci were also associated with hippocampal volume (P < 0.05) in a third younger, more heterogeneous sample (n = 7,794). The SNP in ASTN2 also showed suggestive association with decline in cognition in a largely independent sample (n = 1,563). These associations implicate genes related to apoptosis (HRK), development (WIF1), oxidative stress (MSR3B), ubiquitination (FBXW8) and neuronal migration (ASTN2), as well as enzymes targeted by new diabetes medications (DPP4), indicating new genetic influences on hippocampal size and possibly the risk of cognitive decline and dementia.", - "journal_title": "Nature genetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/22504421/" - } - ], - "cd6e1167-80f7-43c2-94ba-079bf767cf90": [ - { - "pub_id": "27692817", - "title": "An overview of renal metabolomics.", - "authors": "Sahir Kalim,Eugene P Rhee", - "abstract": "The high-throughput, high-resolution phenotyping enabled by metabolomics has been applied increasingly to a variety of questions in nephrology research. This article provides an overview of current metabolomics methodologies and nomenclature, citing specific considerations in sample preparation, metabolite measurement, and data analysis that investigators should understand when examining the literature or designing a study. Furthermore, we review several notable findings that have emerged in the literature that both highlight some of the limitations of current profiling approaches, as well as outline specific strengths unique to metabolomics. More specifically, we review data on the following: (i) tryptophan metabolites and chronic kidney disease onset, illustrating the interpretation of metabolite data in the context of established biochemical pathways; (ii) trimethylamine-N-oxide and cardiovascular disease in chronic kidney disease, illustrating the integration of exogenous and endogenous inputs to the blood metabolome; and (iii) renal mitochondrial function in diabetic kidney disease and acute kidney injury, illustrating the potential for rapid translation of metabolite data for diagnostic or therapeutic aims. Finally, we review future directions, including the need to better characterize interperson and intraperson variation in the metabolome, pool existing data sets to identify the most robust signals, and capitalize on the discovery potential of emerging nontargeted methods.", - "journal_title": "Kidney international", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/27692817/" - } - ], - "3c56b3cd-bb3c-4174-888f-e7d48a6fdca7": [ - { - "pub_id": "28000382", - "title": "Aging impairs double-strand break repair by homologous recombination in Drosophila germ cells.", - "authors": "Laetitia Delabaere,Henry A Ertl,Dashiell J Massey,Carolyn M Hofley,Faraz Sohail,Elisa J Bienenstock,Hans Sebastian,Irene Chiolo,Jeannine R LaRocque", - "abstract": "Aging is characterized by genome instability, which contributes to cancer formation and cell lethality leading to organismal decline. The high levels of DNA double-strand breaks (DSBs) observed in old cells and premature aging syndromes are likely a primary source of genome instability, but the underlying cause of their formation is still unclear. DSBs might result from higher levels of damage or repair defects emerging with advancing age, but repair pathways in old organisms are still poorly understood. Here, we show that premeiotic germline cells of young and old flies have distinct differences in their ability to repair DSBs by the error-free pathway homologous recombination (HR). Repair of DSBs induced by either ionizing radiation (IR) or the endonuclease I-SceI is markedly defective in older flies. This correlates with a remarkable reduction in HR repair measured with the DR-white DSB repair reporter assay. Strikingly, most of this repair defect is already present at 8\u00a0days of age. Finally, HR defects correlate with increased expression of early HR components and increased recruitment of Rad51 to damage in older organisms. Thus, we propose that the defect in the HR pathway for germ cells in older flies occurs following Rad51 recruitment. These data reveal that DSB repair defects arise early in the aging process and suggest that HR deficiencies are a leading cause of genome instability in germ cells of older animals.", - "journal_title": "Aging cell", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/28000382/" - } - ], - "e267bad6-2123-48b3-924b-f97ebd998adc": [ - { - "pub_id": "24134860", - "title": "Analysis of epigenetic changes in survivors of preterm birth reveals the effect of gestational age and evidence for a long term legacy.", - "authors": "Mark N Cruickshank,Alicia Oshlack,Christiane Theda,Peter G Davis,David Martino,Penelope Sheehan,Yun Dai,Richard Saffery,Lex W Doyle,Jeffrey M Craig", - "abstract": "Preterm birth confers a high risk of adverse long term health outcomes for survivors, yet the underlying molecular mechanisms are unclear. We hypothesized that effects of preterm birth can be mediated through measurable epigenomic changes throughout development. We therefore used a longitudinal birth cohort to measure the epigenetic mark of DNA methylation at birth and 18\u00a0years comparing survivors of extremely preterm birth with infants born at term. Using 12 extreme preterm birth cases and 12 matched, term controls, we extracted DNA from archived neonatal blood spots and blood collected in a similar way at 18\u00a0years of age. DNA methylation was measured at 347,789 autosomal locations throughout the genome using Infinium HM450 arrays. Representative methylation differences were confirmed by Sequenom MassArray EpiTYPER. At birth we found 1,555 sites with significant differences in methylation between term and preterm babies. At 18\u00a0years of age, these differences had largely resolved, suggesting that DNA methylation differences at birth are mainly driven by factors relating to gestational age, such as cell composition and/or maturity. Using matched longitudinal samples, we found evidence for an epigenetic legacy associated with preterm birth, identifying persistent methylation differences at ten genomic loci. Longitudinal comparisons of DNA methylation at birth and 18\u00a0years uncovered a significant overlap between sites that were differentially-methylated at birth and those that changed with age. However, we note that overlapping sites may either differ in the same (300/1,555) or opposite (431/1,555) direction during gestation and aging respectively. We present evidence for widespread methylation differences between extreme preterm and term infants at birth that are largely resolved by 18\u00a0years of age. These results are consistent with methylation changes associated with blood cell development, cellular composition, immune induction and age at these time points. Finally, we identified ten probes significantly associated with preterm individuals and with greater than 5% methylation discordance at birth and 18\u00a0years that may reflect a long term epigenetic legacy of preterm birth.", - "journal_title": "Genome medicine", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/24134860/" - } - ], - "fb31688e-c581-4b96-8246-cdae69b9c898": [ - { - "pub_id": "26589500", - "title": "Immunoinformatics and epitope prediction in the age of genomic medicine.", - "authors": "Linus Backert,Oliver Kohlbacher", - "abstract": "Immunoinformatics involves the application of computational methods to immunological problems. Prediction of B- and T-cell epitopes has long been the focus of immunoinformatics, given the potential translational implications, and many tools have been developed. With the advent of next-generation sequencing (NGS) methods, an unprecedented wealth of information has become available that requires more-advanced immunoinformatics tools. Based on information from whole-genome sequencing, exome sequencing and RNA sequencing, it is possible to characterize with high accuracy an individual's human leukocyte antigen (HLA) allotype (i.e., the individual set of HLA alleles of the patient), as well as changes arising in the HLA ligandome (the collection of peptides presented by the HLA) owing to genomic variation. This has allowed new opportunities for translational applications of epitope prediction, such as epitope-based design of prophylactic and therapeutic vaccines, and personalized cancer immunotherapies. Here, we review a wide range of immunoinformatics tools, with a focus on B- and T-cell epitope prediction. We also highlight fundamental differences in the underlying algorithms and discuss the various metrics employed to assess prediction quality, comparing their strengths and weaknesses. Finally, we discuss the new challenges and opportunities presented by high-throughput data-sets for the field of epitope prediction.", - "journal_title": "Genome medicine", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/26589500/" - } - ], - "2bc3e5cf-1eaf-4bc3-917a-72b38a19fbeb": [ - { - "pub_id": "27717399", - "title": "An epigenetic clock for gestational age at birth based on blood methylation data.", - "authors": "Anna K Knight,Jeffrey M Craig,Christiane Theda,Marie B\u00e6kvad-Hansen,Jonas Bybjerg-Grauholm,Christine S Hansen,Mads V Hollegaard,David M Hougaard,Preben B Mortensen,Shantel M Weinsheimer,Thomas M Werge,Patricia A Brennan,Joseph F Cubells,D Jeffrey Newport,Zachary N Stowe,Jeanie L Y Cheong,Philippa Dalach,Lex W Doyle,Yuk J Loke,Andrea A Baccarelli,Allan C Just,Robert O Wright,Mara M T\u00e9llez-Rojo,Katherine Svensson,Letizia Trevisi,Elizabeth M Kennedy,Elisabeth B Binder,Stella Iurato,Darina Czamara,Katri R\u00e4ikk\u00f6nen,Jari M T Lahti,Anu-Katriina Pesonen,Eero Kajantie,Pia M Villa,Hannele Laivuori,Esa H\u00e4m\u00e4l\u00e4inen,Hea Jin Park,Lynn B Bailey,Sasha E Parets,Varun Kilaru,Ramkumar Menon,Steve Horvath,Nicole R Bush,Kaja Z LeWinn,Frances A Tylavsky,Karen N Conneely,Alicia K Smith", - "abstract": "Gestational age is often used as a proxy for developmental maturity by clinicians and researchers alike. DNA methylation has previously been shown to be associated with age and has been used to accurately estimate chronological age in children and adults. In the current study, we examine whether DNA methylation in cord blood can be used to estimate gestational age at birth. We find that gestational age can be accurately estimated from DNA methylation of neonatal cord blood and blood spot samples. We calculate a DNA methylation gestational age using 148 CpG sites selected through elastic net regression in six training datasets. We evaluate predictive accuracy in nine testing datasets and find that the accuracy of the DNA methylation gestational age is consistent with that of gestational age estimates based on established methods, such as ultrasound. We also find that an increased DNA methylation gestational age relative to clinical gestational age is associated with birthweight independent of gestational age, sex, and ancestry. DNA methylation can be used to accurately estimate gestational age at or near birth and may provide additional information relevant to developmental stage. Further studies of this predictor are warranted to determine its utility in clinical settings and for research purposes. When clinical estimates are available this measure may increase accuracy in the testing of hypotheses related to developmental age and other early life circumstances.", - "journal_title": "Genome biology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/27717399/" - } - ], - "bd3604a5-eb48-4c23-bb69-4b2c99e90499": [ - { - "pub_id": "26126540", - "title": "A comparison of genomic selection models across time in interior spruce (Picea engelmannii \u00d7 glauca) using unordered SNP imputation methods.", - "authors": "B Ratcliffe,O G El-Dien,J Kl\u00e1p\u0161t\u011b,I Porth,C Chen,B Jaquish,Y A El-Kassaby", - "abstract": "Genomic selection (GS) potentially offers an unparalleled advantage over traditional pedigree-based selection (TS) methods by reducing the time commitment required to carry out a single cycle of tree improvement. This quality is particularly appealing to tree breeders, where lengthy improvement cycles are the norm. We explored the prospect of implementing GS for interior spruce (Picea engelmannii \u00d7 glauca) utilizing a genotyped population of 769 trees belonging to 25 open-pollinated families. A series of repeated tree height measurements through ages 3-40 years permitted the testing of GS methods temporally. The genotyping-by-sequencing (GBS) platform was used for single nucleotide polymorphism (SNP) discovery in conjunction with three unordered imputation methods applied to a data set with 60% missing information. Further, three diverse GS models were evaluated based on predictive accuracy (PA), and their marker effects. Moderate levels of PA (0.31-0.55) were observed and were of sufficient capacity to deliver improved selection response over TS. Additionally, PA varied substantially through time accordingly with spatial competition among trees. As expected, temporal PA was well correlated with age-age genetic correlation (r=0.99), and decreased substantially with increasing difference in age between the training and validation populations (0.04-0.47). Moreover, our imputation comparisons indicate that k-nearest neighbor and singular value decomposition yielded a greater number of SNPs and gave higher predictive accuracies than imputing with the mean. Furthermore, the ridge regression (rrBLUP) and BayesC\u03c0 (BC\u03c0) models both yielded equal, and better PA than the generalized ridge regression heteroscedastic effect model for the traits evaluated.", - "journal_title": "Heredity", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/26126540/" - } - ], - "4d58cc2a-6a33-4bec-890d-4c817b7412f2": [ - { - "pub_id": "23153929", - "title": "Supportive evidence for 11 loci from genome-wide association studies in Parkinson's disease.", - "authors": "Lasse Pihlstr\u00f8m,Gunnar Axelsson,Kari Anne Bj\u00f8rnar\u00e5,Nil Dizdar,Camilla Fardell,Lars Forsgren,Bj\u00f6rn Holmberg,Jan Petter Larsen,Jan Linder,Hans Nissbrandt,Ole-Bj\u00f8rn Tysnes,Eilert Ohman,Espen Dietrichs,Mathias Toft", - "abstract": "Genome-wide association studies have identified a number of susceptibility loci in sporadic Parkinson's disease (PD). Recent larger studies and meta-analyses have greatly expanded the list of proposed association signals. We performed a case-control replication study in a Scandinavian population, analyzing samples from 1345 unrelated PD patients and 1225 control subjects collected by collaborating centers in Norway and Sweden. Single-nucleotide polymorphisms representing 18 loci previously reported at genome-wide significance levels were genotyped, as well as 4 near-significant, suggestive, loci. We replicated 11 association signals at p < 0.05 (SNCA, STK39, MAPT, GPNMB, CCDC62/HIP1R, SYT11, GAK, STX1B, MCCC1/LAMP3, ACMSD, and FGF20). The more recently nominated susceptibility loci were well represented among our positive findings, including 3 which have not previously been validated in independent studies. Conversely, some of the more well-established loci failed to replicate. While future meta-analyses should corroborate disease associations further on the level of common markers, efforts to pinpoint functional variants and understand the biological implications of each risk locus in PD are also warranted.", - "journal_title": "Neurobiology of aging", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/23153929/" - } - ], - "a95e6806-06d3-4775-8287-fda4cf6ac42f": [ - { - "pub_id": "22090473", - "title": "Genome-environment interactions that modulate aging: powerful targets for drug discovery.", - "authors": "Jo\u00e3o Pedro de Magalh\u00e3es,Daniel Wuttke,Shona H Wood,Michael Plank,Chintan Vora", - "abstract": "Aging is the major biomedical challenge of this century. The percentage of elderly people, and consequently the incidence of age-related diseases such as heart disease, cancer, and neurodegenerative diseases, is projected to increase considerably in the coming decades. Findings from model organisms have revealed that aging is a surprisingly plastic process that can be manipulated by both genetic and environmental factors. Here we review a broad range of findings in model organisms, from environmental to genetic manipulations of aging, with a focus on those with underlying gene-environment interactions with potential for drug discovery and development. One well-studied dietary manipulation of aging is caloric restriction, which consists of restricting the food intake of organisms without triggering malnutrition and has been shown to retard aging in model organisms. Caloric restriction is already being used as a paradigm for developing compounds that mimic its life-extension effects and might therefore have therapeutic value. The potential for further advances in this field is immense; hundreds of genes in several pathways have recently emerged as regulators of aging and caloric restriction in model organisms. Some of these genes, such as IGF1R and FOXO3, have also been associated with human longevity in genetic association studies. The parallel emergence of network approaches offers prospects to develop multitarget drugs and combinatorial therapies. Understanding how the environment modulates aging-related genes may lead to human applications and disease therapies through diet, lifestyle, or pharmacological interventions. Unlocking the capacity to manipulate human aging would result in unprecedented health benefits.", - "journal_title": "Pharmacological reviews", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/22090473/" - } - ], - "387a02e4-9c08-4b45-a857-4e0a13274f97": [ - { - "pub_id": "29393215", - "title": "Age Estimation with DNA: From Forensic DNA Fingerprinting to Forensic (Epi)Genomics: A Mini-Review.", - "authors": "Walther Parson", - "abstract": "Forensic genetics developed from protein-based techniques a quarter of a century ago and became famous as \"DNA fingerprinting,\" this being based on restriction fragment length polymorphisms (RFLPs) of high-molecular-weight DNA. The amplification of much smaller short tandem repeat (STR) sequences using the polymerase chain reaction soon replaced RFLP analysis and advanced to become the gold standard in genetic identification. Meanwhile, STR multiplexes have been developed and made commercially available which simultaneously amplify up to 30 STR loci from as little as 15 cells or fewer. The enormous information content that comes with the large variety of observed STR genotypes allows for genetic individualisation (with the exception of identical twins). Carefully selected core STR loci form the basis of intelligence-led DNA databases that provide investigative leads by linking unsolved crime scenes and criminals through their matched STR profiles. Nevertheless, the success of modern DNA fingerprinting depends on the availability of reference material from suspects. In order to provide new investigative leads in cases where such reference samples are absent, forensic scientists started to explore the prediction of phenotypic traits from the DNA of the evidentiary sample. This paradigm change now uses DNA and epigenetic markers to forecast characteristics that are useful to triage further investigative work. So far, the best investigated externally visible characteristics are eye, hair and skin colour, as well as geographic ancestry and age. Information on the chronological age of a stain donor (or any sample donor) is elemental for forensic investigations in a number of aspects and has, therefore, been explored by researchers in some detail. Among different methodological approaches tested to date, the methylation-sensitive analysis of carefully selected DNA markers (CpG sites) has brought the most promising results by providing prediction accuracies of \u00b13-4 years, which can be comparable to, or even surpass those from, eyewitness reports. This mini-review puts recent developments in age estimation via (epi)genetic methods in the context of the requirements and goals of forensic genetics and highlights paths to follow in the future of forensic genomics.", - "journal_title": "Gerontology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/29393215/" - } - ], - "6e7196b0-003a-4f4e-baea-3c4d2f56029a": [ - { - "pub_id": "25622253", - "title": "Oxidative stress, bone marrow failure, and genome instability in hematopoietic stem cells.", - "authors": "Christine Richardson,Shan Yan,C Greer Vestal", - "abstract": "Reactive oxygen species (ROS) can be generated by defective endogenous reduction of oxygen by cellular enzymes or in the mitochondrial respiratory pathway, as well as by exogenous exposure to UV or environmental damaging agents. Regulation of intracellular ROS levels is critical since increases above normal concentrations lead to oxidative stress and DNA damage. A growing body of evidence indicates that the inability to regulate high levels of ROS leading to alteration of cellular homeostasis or defective repair of ROS-induced damage lies at the root of diseases characterized by both neurodegeneration and bone marrow failure as well as cancer. That these diseases may be reflective of the dynamic ability of cells to respond to ROS through developmental stages and aging lies in the similarities between phenotypes at the cellular level. This review summarizes work linking the ability to regulate intracellular ROS to the hematopoietic stem cell phenotype, aging, and disease.", - "journal_title": "International journal of molecular sciences", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/25622253/" - } - ], - "7598244a-83a8-40b1-808b-bb2fef5afd47": [ - { - "pub_id": "25326637", - "title": "Clinical exome sequencing for genetic identification of rare Mendelian disorders.", - "authors": "Hane Lee,Joshua L Deignan,Naghmeh Dorrani,Samuel P Strom,Sibel Kantarci,Fabiola Quintero-Rivera,Kingshuk Das,Traci Toy,Bret Harry,Michael Yourshaw,Michelle Fox,Brent L Fogel,Julian A Martinez-Agosto,Derek A Wong,Vivian Y Chang,Perry B Shieh,Christina G S Palmer,Katrina M Dipple,Wayne W Grody,Eric Vilain,Stanley F Nelson", - "abstract": "Clinical exome sequencing (CES) is rapidly becoming a common molecular diagnostic test for individuals with rare genetic disorders. To report on initial clinical indications for CES referrals and molecular diagnostic rates for different indications and for different test types. Clinical exome sequencing was performed on 814 consecutive patients with undiagnosed, suspected genetic conditions at the University of California, Los Angeles, Clinical Genomics Center between January 2012 and August 2014. Clinical exome sequencing was conducted as trio-CES (both parents and their affected child sequenced simultaneously) to effectively detect de novo and compound heterozygous variants or as proband-CES (only the affected individual sequenced) when parental samples were not available. Clinical indications for CES requests, molecular diagnostic rates of CES overall and for phenotypic subgroups, and differences in molecular diagnostic rates between trio-CES and proband-CES. Of the 814 cases, the overall molecular diagnosis rate was 26% (213 of 814; 95% CI, 23%-29%). The molecular diagnosis rate for trio-CES was 31% (127 of 410 cases; 95% CI, 27%-36%) and 22% (74 of 338 cases; 95% CI, 18%-27%) for proband-CES. In cases of developmental delay in children (<5 years, n = 138), the molecular diagnosis rate was 41% (45 of 109; 95% CI, 32%-51%) for trio-CES cases and 9% (2 of 23, 95% CI, 1%-28%) for proband-CES cases. The significantly higher diagnostic yield (P value =\u2009.002; odds ratio, 7.4 [95% CI, 1.6-33.1]) of trio-CES was due to the identification of de novo and compound heterozygous variants. In this sample of patients with undiagnosed, suspected genetic conditions, trio-CES was associated with higher molecular diagnostic yield than proband-CES or traditional molecular diagnostic methods. Additional studies designed to validate these findings and to explore the effect of this approach on clinical and economic outcomes are warranted.", - "journal_title": "JAMA", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/25326637/" - } - ], - "321d2f0d-1650-4230-89df-cbda022d37bc": [ - { - "pub_id": "28187286", - "title": "Endogenous DNA Damage as a Source of Genomic Instability in Cancer.", - "authors": "Anthony Tubbs,Andr\u00e9 Nussenzweig", - "abstract": "Genome instability, defined as higher than normal rates of mutation, is a double-edged sword. As a source of genetic diversity and natural selection, mutations are beneficial for evolution. On the other hand, genomic instability can have catastrophic consequences for age-related diseases such as cancer. Mutations arise either from inactivation of DNA repair pathways or in a repair-competent background due to genotoxic stress from celluar processes such as transcription and replication that overwhelm high-fidelity DNA repair. Here, we review recent studies that shed light on endogenous sources of mutation and epigenomic features that promote genomic instability during cancer evolution.", - "journal_title": "Cell", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/28187286/" - } - ], - "f198eb32-5753-4013-bca3-c9b26e5cce9c": [ - { - "pub_id": "26404825", - "title": "Somatic mutation in cancer and normal cells.", - "authors": "I\u00f1igo Martincorena,Peter J Campbell", - "abstract": "Spontaneously occurring mutations accumulate in somatic cells throughout a person's lifetime. The majority of these mutations do not have a noticeable effect, but some can alter key cellular functions. Early somatic mutations can cause developmental disorders, whereas the progressive accumulation of mutations throughout life can lead to cancer and contribute to aging. Genome sequencing has revolutionized our understanding of somatic mutation in cancer, providing a detailed view of the mutational processes and genes that drive cancer. Yet, fundamental gaps remain in our knowledge of how normal cells evolve into cancer cells. We briefly summarize a number of the lessons learned over 5 years of cancer genome sequencing and discuss their implications for our understanding of cancer progression and aging.", - "journal_title": "Science (New York, N.Y.)", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/26404825/" - } - ], - "e455e87b-952e-4cce-a2e6-b2dda71b2ba0": [ - { - "pub_id": "28089213", - "title": "A genome-wide profiling of brain DNA hydroxymethylation in Alzheimer's disease.", - "authors": "Jinying Zhao,Yun Zhu,Jingyun Yang,Lin Li,Hao Wu,Philip L De Jager,Peng Jin,David A Bennett", - "abstract": "DNA methylation is a key epigenetic mechanism in brain aging and Alzheimer's disease (AD). The newly discovered 5-hydroxymethylcytosine mediates DNA demethylation, is highly abundant in the brain, and is dynamically regulated by life experiences. However, little is known about its genome-wide patterns and potential role in AD. Using a genome-wide capture followed by high-throughput sequencing, we studied the genome-wide distribution of 5-hydroxymethylcytosine at specific genomic loci in human AD brain and identified differentially hydroxymethylated regions (DhMRs) associated with AD pathology. We identified 517 DhMRs significantly associated with neuritic plaques and 60 DhMRs associated with neurofibrillary tangles. DNA hydroxymethylation in gene bodies was predominantly positively correlated with cis-acting gene expression. Moreover, genes showing differential hydroxymethylation were significantly enriched in neurobiological processes and clustered in functional gene ontology categories. Our results reveal a critical role of DNA hydroxymethylation in AD pathology and provide mechanistic insight into the molecular mechanisms underlying AD.", - "journal_title": "Alzheimer's & dementia : the journal of the Alzheimer's Association", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/28089213/" - } - ], - "66821b8c-9b35-411e-bde4-aba9acfe3e93": [ - { - "pub_id": "29507425", - "title": "Germline de novo mutation clusters arise during oocyte aging in genomic regions with high double-strand-break incidence.", - "authors": "Jakob M Goldmann,Vladimir B Seplyarskiy,Wendy S W Wong,Thierry Vilboux,Pieter B Neerincx,Dale L Bodian,Benjamin D Solomon,Joris A Veltman,John F Deeken,Christian Gilissen,John E Niederhuber", - "abstract": "Clustering of mutations has been observed in cancer genomes as well as for germline de novo mutations (DNMs). We identified 1,796 clustered DNMs (cDNMs) within whole-genome-sequencing data from 1,291 parent-offspring trios to investigate their patterns and infer a mutational mechanism. We found that the number of clusters on the maternal allele was positively correlated with maternal age and that these clusters consisted of more individual mutations with larger intermutational distances than those of paternal clusters. More than 50% of maternal clusters were located on chromosomes 8, 9 and 16, in previously identified regions with accelerated maternal mutation rates. Maternal clusters in these regions showed a distinct mutation signature characterized by C>G transversions. Finally, we found that maternal clusters were associated with processes involving double-strand-breaks (DSBs), such as meiotic gene conversions and de novo deletion events. This result suggested accumulation of DSB-induced mutations throughout oocyte aging as the mechanism underlying the formation of maternal mutation clusters.", - "journal_title": "Nature genetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/29507425/" - } - ], - "114f7a93-a26e-488d-bbef-2cc21c7488f8": [ - { - "pub_id": "28399939", - "title": "Multi-tissue DNA methylation age predictor in mouse.", - "authors": "Thomas M Stubbs,Marc Jan Bonder,Anne-Katrien Stark,Felix Krueger, ,Ferdinand von Meyenn,Oliver Stegle,Wolf Reik", - "abstract": "DNA\u00a0methylation changes at a discrete set of sites in the human genome are predictive of chronological and biological age. However, it is not known whether these changes are causative or a consequence of an underlying ageing process. It has also not been shown whether this epigenetic clock is unique to humans or conserved in the more experimentally tractable mouse. We have generated a comprehensive set of genome-scale base-resolution methylation maps from multiple mouse tissues spanning a wide range of ages. Many CpG sites show significant tissue-independent correlations with age which allowed us to develop a multi-tissue predictor of age in the mouse. Our model, which estimates age based on DNA methylation at 329 unique CpG sites, has a median absolute error of 3.33 weeks and has similar properties to the recently described human epigenetic clock. Using publicly available datasets, we find that the mouse clock is accurate enough to measure effects on biological age, including in the context of interventions. While females and males show no significant differences in predicted DNA methylation age, ovariectomy results in significant age acceleration in females. Furthermore, we identify significant differences in age-acceleration dependent on the lipid content of the diet. Here we identify and characterise an epigenetic predictor of age in mice, the mouse epigenetic clock. This clock will be instrumental for understanding the biology of ageing and will allow modulation of its ticking rate and resetting the clock in vivo to study the impact on biological age.", - "journal_title": "Genome biology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/28399939/" - } - ], - "0a5af96d-1409-46ae-bd52-31fbbcca0549": [ - { - "pub_id": "28652652", - "title": "Gallbladder cancer epidemiology, pathogenesis and molecular genetics: Recent update.", - "authors": "Aarti Sharma,Kiran Lata Sharma,Annapurna Gupta,Alka Yadav,Ashok Kumar", - "abstract": "Gallbladder cancer is a malignancy of biliary tract which is infrequent in developed countries but common in some specific geographical regions of developing countries. Late diagnosis and deprived prognosis are major problems for treatment of gallbladder carcinoma. The dramatic associations of this orphan cancer with various genetic and environmental factors are responsible for its poorly defined pathogenesis. An understanding to the relationship between epidemiology, molecular genetics and pathogenesis of gallbladder cancer can add new insights to its undetermined pathophysiology. Present review article provides a recent update regarding epidemiology, pathogenesis, and molecular genetics of gallbladder cancer. We systematically reviewed published literature on gallbladder cancer from online search engine PubMed (http://www.ncbi.nlm.nih.gov/pubmed). Various keywords used for retrieval of articles were Gallbladder, cancer Epidemiology, molecular genetics and bullion operators like AND, OR, NOT. Cross references were manually searched from various online search engines (http://www.ncbi.nlm.nih.gov/pubmed,https://scholar.google.co.in/, http://www.medline.com/home.jsp). Most of the articles published from 1982 to 2015 in peer reviewed journals have been included in this review.", - "journal_title": "World journal of gastroenterology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/28652652/" - } - ], - "08d5bc93-bc25-432e-9079-7d0cb35ed983": [ - { - "pub_id": "32310270", - "title": "Identification of Risk Loci for Parkinson Disease in Asians and Comparison of Risk Between Asians and Europeans: A Genome-Wide Association Study.", - "authors": "Jia Nee Foo,Elaine Guo Yan Chew,Sun Ju Chung,Rong Peng,Cornelis Blauwendraat,Mike A Nalls,Kin Y Mok,Wataru Satake,Tatsushi Toda,Yinxia Chao,Louis C S Tan,Moses Tandiono,Michelle M Lian,Ebonne Y Ng,Kumar-M Prakash,Wing-Lok Au,Wee-Yang Meah,Shi Qi Mok,Azlina Ahmad Annuar,Anne Y Y Chan,Ling Chen,Yongping Chen,Beom S Jeon,Lulu Jiang,Jia Lun Lim,Juei-Jueng Lin,Chunfeng Liu,Chengjie Mao,Vincent Mok,Zhong Pei,Hui-Fang Shang,Chang-He Shi,Kyuyoung Song,Ai Huey Tan,Yih-Ru Wu,Yu-Ming Xu,Renshi Xu,Yaping Yan,Jing Yang,BaoRong Zhang,Woon-Puay Koh,Shen-Yang Lim,Chiea Chuen Khor,Jianjun Liu,Eng-King Tan", - "abstract": "Large-scale genome-wide association studies in the European population have identified 90 risk variants associated with Parkinson disease (PD); however, there are limited studies in the largest population worldwide (ie, Asian). To identify novel genome-wide significant loci for PD in Asian individuals and to compare genetic risk between Asian and European cohorts. Genome-wide association data generated from PD cases and controls in an Asian population (ie, Singapore/Malaysia, Hong Kong, Taiwan, mainland China, and South Korea) were collected from January 1, 2016, to December 31, 2018, as part of an ongoing study. Results were combined with inverse variance meta-analysis, and replication of top loci in European and Japanese samples was performed. Discovery samples of 31\u202f575 individuals passing quality control of 35\u202f994 recruited were used, with a greater than 90% participation rate. A replication cohort of 1\u202f926\u202f361 European-ancestry and 3509 Japanese samples was analyzed. Parkinson disease was diagnosed using UK Parkinson's Disease Society Brain Bank Criteria. Genotypes of common variants, association with disease status, and polygenic risk scores. Of 31\u202f575 samples identified, 6724 PD cases (mean [SD] age, 64.3\u2009[10] years; age at onset, 58.8 [10.6] years; 3472 [53.2%] men) and 24\u202f851 controls (age, 59.4 [11.4] years; 11\u202f030 [45.0%] men) were analyzed in the discovery study. Eleven genome-wide significant loci were identified; 2 of these loci were novel (SV2C and WBSCR17) and 9 were previously found in Europeans. Replication in European-ancestry and Japanese samples showed robust association for SV2C (rs246814; odds ratio, 1.16; 95% CI, 1.11-1.21; P\u2009=\u20091.17\u2009\u00d7\u200910-10 in meta-analysis of discovery and replication samples) but showed potential genetic heterogeneity at WBSCR17 (rs9638616; I2=67.1%; P\u2009=\u20093.40\u2009\u00d7\u200910-3 for hetereogeneity). Polygenic risk score models including variants at these 11 loci were associated with a significant improvement in area under the curve over the model based on 78 European loci alone (63.1% vs 60.2%; P\u2009=\u20096.81\u2009\u00d7\u200910-12). This study identified 2 apparently novel gene loci and found 9 previously identified European loci to be associated with PD in this large, meta-genome-wide association study in a worldwide population of Asian individuals and reports similarities and differences in genetic risk factors between Asian and European individuals in the risk for PD. These findings may lead to improved stratification of Asian patients and controls based on polygenic risk scores. Our findings have potential academic and clinical importance for risk stratification and precision medicine in Asia.", - "journal_title": "JAMA neurology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/32310270/" - } - ], - "3043efd1-4b13-4300-b2a7-d1992c8d4e47": [ - { - "pub_id": "27143112", - "title": "The dog aging project: translational geroscience in companion animals.", - "authors": "Matt Kaeberlein,Kate E Creevy,Daniel E L Promislow", - "abstract": "Studies of the basic biology of aging have identified several genetic and pharmacological interventions that appear to modulate the rate of aging in laboratory model organisms, but a barrier to further progress has been the challenge of moving beyond these laboratory discoveries to impact health and quality of life for people. The domestic dog, Canis familiaris, offers a unique opportunity for surmounting this barrier in the near future. In particular, companion dogs share our environment and play an important role in improving the quality of life for millions of people. Here, we present a rationale for increasing the role of companion dogs as an animal model for both basic and clinical geroscience and describe complementary approaches and ongoing projects aimed at achieving this goal.", - "journal_title": "Mammalian genome : official journal of the International Mammalian Genome Society", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/27143112/" - } - ], - "bde7dc93-b9c5-4695-a867-092a1d178f78": [ - { - "pub_id": "33087284", - "title": "NTHL1 in genomic integrity, aging and cancer.", - "authors": "Lipsa Das,Victoria G Quintana,Joann B Sweasy", - "abstract": "Efficient DNA repair is essential to maintain genomic integrity. An average of 30,000 base lesions per cell are removed daily by the DNA glycosylases of the base excision repair machinery. With the advent of whole genome sequencing, many germline mutations in these DNA glycosylases have been identified and associated with various diseases, including cancer. In this graphical review, we discuss the function of the NTHL1 DNA glycosylase and how genomic mutations and altered function of this protein contributes to cancer and aging. We highlight its role in a rare tumor syndrome, NTHL1-associated polyposis (NAP), and summarize various other polymorphisms in NTHL1 that can induce early hallmarks of cancer, including genomic instability and cellular transformation.", - "journal_title": "DNA repair", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/33087284/" - } - ], - "535c4b3c-75f4-4ec4-a758-92f82b227176": [ - { - "pub_id": "30355080", - "title": "Mechanisms of Vascular Aging.", - "authors": "Zoltan Ungvari,Stefano Tarantini,Anthony J Donato,Veronica Galvan,Anna Csiszar", - "abstract": "Aging of the vasculature plays a central role in morbidity and mortality of older people. To develop novel treatments for amelioration of unsuccessful vascular aging and prevention of age-related vascular pathologies, it is essential to understand the cellular and functional changes that occur in the vasculature during aging. In this review, the pathophysiological roles of fundamental cellular and molecular mechanisms of aging, including oxidative stress, mitochondrial dysfunction, impaired resistance to molecular stressors, chronic low-grade inflammation, genomic instability, cellular senescence, epigenetic alterations, loss of protein homeostasis, deregulated nutrient sensing, and stem cell dysfunction in the vascular system are considered in terms of their contribution to the pathogenesis of both microvascular and macrovascular diseases associated with old age. The importance of progeronic and antigeronic circulating factors in relation to development of vascular aging phenotypes are discussed. Finally, future directions and opportunities to develop novel interventions to prevent/delay age-related vascular pathologies by targeting fundamental cellular and molecular aging processes are presented.", - "journal_title": "Circulation research", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/30355080/" - } - ], - "96ed23a8-7d89-4bb2-8433-f34dc6923a76": [ - { - "pub_id": "33020666", - "title": "A unified framework for joint-tissue transcriptome-wide association and Mendelian randomization analysis.", - "authors": "Dan Zhou,Yi Jiang,Xue Zhong,Nancy J Cox,Chunyu Liu,Eric R Gamazon", - "abstract": "Here, we present a joint-tissue imputation (JTI) approach and a Mendelian randomization framework for causal inference, MR-JTI. JTI borrows information across transcriptomes of different tissues, leveraging shared genetic regulation, to improve prediction performance in a tissue-dependent manner. Notably, JTI includes the single-tissue imputation method PrediXcan as a special case and outperforms other single-tissue approaches (the Bayesian sparse linear mixed model and Dirichlet process regression). MR-JTI models variant-level heterogeneity (primarily due to horizontal pleiotropy, addressing a major challenge of transcriptome-wide association study interpretation) and performs causal inference with type I error control. We make explicit the connection between the genetic architecture of gene expression and of complex traits and the suitability of Mendelian randomization as a causal inference strategy for transcriptome-wide association studies. We provide a resource of imputation models generated from GTEx and PsychENCODE panels. Analysis of biobanks and meta-analysis data, and extensive simulations show substantially improved statistical power, replication and causal mapping rate for JTI relative to existing approaches.", - "journal_title": "Nature genetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/33020666/" - } - ], - "846ae0a9-165f-4b25-8bcb-310c7da5eb44": [ - { - "pub_id": "28249563", - "title": "Genome-wide transcriptomics of aging in the rotifer Brachionus manjavacas, an emerging model system.", - "authors": "Kristin E Gribble,David B Mark Welch", - "abstract": "Understanding gene expression changes over lifespan in diverse animal species will lead to insights to conserved processes in the biology of aging and allow development of interventions to improve health. Rotifers are small aquatic invertebrates that have been used in aging studies for nearly 100\u00a0years and are now re-emerging as a modern model system. To provide a baseline to evaluate genetic responses to interventions that change health throughout lifespan and a framework for new hypotheses about the molecular genetic mechanisms of aging, we examined the transcriptome of an asexual female lineage of the rotifer Brachionus manjavacas at five life stages: eggs, neonates, and early-, late-, and post-reproductive adults. There are widespread shifts in gene expression over the lifespan of B. manjavacas; the largest change occurs between neonates and early reproductive adults and is characterized by down-regulation of developmental genes and up-regulation of genes involved in reproduction. The expression profile of post-reproductive adults was distinct from that of other life stages. While few genes were significantly differentially expressed in the late- to post-reproductive transition, gene set enrichment analysis revealed multiple down-regulated pathways in metabolism, maintenance and repair, and proteostasis, united by genes involved in mitochondrial function and oxidative phosphorylation. This study provides the first examination of changes in gene expression over lifespan in rotifers. We detected differential expression of many genes with human orthologs that are absent in Drosophila and C. elegans, highlighting the potential of the rotifer model in aging studies. Our findings suggest that small but coordinated changes in expression of many genes in pathways that integrate diverse functions drive the aging process. The observation of simultaneous declines in expression of genes in multiple pathways may have consequences for health and longevity not detected by single- or multi-gene knockdown in otherwise healthy animals. Investigation of subtle but genome-wide change in these pathways during aging is an important area for future study.", - "journal_title": "BMC genomics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/28249563/" - } - ], - "3077bd52-8450-4a43-be53-cb5d45a30d72": [ - { - "pub_id": "27354457", - "title": "Gross Motor Milestones and Subsequent Development.", - "authors": "Akhgar Ghassabian,Rajeshwari Sundaram,Erin Bell,Scott C Bello,Christopher Kus,Edwina Yeung", - "abstract": "We examined the longitudinal associations of age at achieving gross motor milestones and children's development in a US cohort of singletons and twins. In the Upstate KIDS study, a population-based study of children born between 2008 and 2010, information on age at achievement of motor milestones and developmental skills was available in 599 children (314 singletons, 259 twins, and 26 triplets). Mothers reported their children's major motor milestones at \u223c4, 8, 12, 18, and 24 months. At age 4 years, children's development was clinically assessed by using the Battelle Developmental Inventory, Second Edition (BDI-2). Primary analyses by using multivariate linear regressions were conducted in singletons. We also examined the associations in twins. Later achievement of standing with assistance predicted lower BDI-2 scores in singletons in adjusted models (B per SD of age at achievement, -21.9 [95% confidence interval (CI), -41.5 to -2.2]). Post hoc analysis on age of standing with assistance showed that associations were driven by differences in adaptive skills (B = -5.3 [95% CI, -9.0 to -1.6]) and cognitive skills (B = -5.9 [95% CI, -11.5 to -0.4]). Analyses restricted to twins suggested no association between the age at achievement of milestones and total BDI-2 score after adjustment for gestational age and birth weight. This study provides evidence that the age of achieving motor milestones may be an important basis for various aspects of later child development. In twins, key predictors of later development (eg, perinatal factors) overshadow the predictive role of milestones in infancy.", - "journal_title": "Pediatrics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/27354457/" - } - ], - "4cb0c33b-e92a-4ef0-a630-6d153f4372b8": [ - { - "pub_id": "30957308", - "title": "Parkinson's disease age at onset genome-wide association study: Defining heritability, genetic loci, and \u03b1-synuclein mechanisms.", - "authors": "Cornelis Blauwendraat,Karl Heilbron,Costanza L Vallerga,Sara Bandres-Ciga,Rainer von Coelln,Lasse Pihlstr\u00f8m,Javier Sim\u00f3n-S\u00e1nchez,Claudia Schulte,Manu Sharma,Lynne Krohn,Ari Siitonen,Hirotaka Iwaki,Hampton Leonard,Alastair J Noyce,Manuela Tan,J Raphael Gibbs,Dena G Hernandez,Sonja W Scholz,Joseph Jankovic,Lisa M Shulman,Suzanne Lesage,Jean-Christophe Corvol,Alexis Brice,Jacobus J van Hilten,Johan Marinus, ,Johanna Eerola-Rautio,Pentti Tienari,Kari Majamaa,Mathias Toft,Donald G Grosset,Thomas Gasser,Peter Heutink,Joshua M Shulman,Nicolas Wood,John Hardy,Huw R Morris,David A Hinds,Jacob Gratten,Peter M Visscher,Ziv Gan-Or,Mike A Nalls,Andrew B Singleton, ", - "abstract": "Increasing evidence supports an extensive and complex genetic contribution to PD. Previous genome-wide association studies (GWAS) have shed light on the genetic basis of risk for this disease. However, the genetic determinants of PD age at onset are largely unknown. To identify the genetic determinants of PD age at onset. Using genetic data of 28,568 PD cases, we performed a genome-wide association study based on PD age at onset. We estimated that the heritability of PD age at onset attributed to common genetic variation was \u223c0.11, lower than the overall heritability of risk for PD (\u223c0.27), likely, in part, because of the subjective nature of this measure. We found two genome-wide significant association signals, one at SNCA and the other a protein-coding variant in TMEM175, both of which are known PD risk loci and a Bonferroni-corrected significant effect at other known PD risk loci, GBA, INPP5F/BAG3, FAM47E/SCARB2, and MCCC1. Notably, SNCA, TMEM175, SCARB2, BAG3, and GBA have all been shown to be implicated in \u03b1-synuclein aggregation pathways. Remarkably, other well-established PD risk loci, such as GCH1 and MAPT, did not show a significant effect on age at onset of PD. Overall, we have performed the largest age at onset of PD genome-wide association studies to date, and our results show that not all PD risk loci influence age at onset with significant differences between risk alleles for age at onset. This provides a compelling picture, both within the context of functional characterization of disease-linked genetic variability and in defining differences between risk alleles for age at onset, or frank risk for disease. \u00a9 2019 International Parkinson and Movement Disorder Society.", - "journal_title": "Movement disorders : official journal of the Movement Disorder Society", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/30957308/" - } - ], - "481af5fa-c34b-4d72-8bee-439aedb74136": [ - { - "pub_id": "34240178", - "title": "Has translational genomics come of age in Africa?", - "authors": "Michelle Kamp,Amanda Krause,Michele Ramsay", - "abstract": "The rapid increase in genomics research in Africa and the growing promise of precision public health (PPH) begs the question of whether African genomics has come of age and is being translated into improved healthcare for Africans. An assessment of the continent's readiness suggests that genetic service delivery remains limited and extremely fragile. The paucity of data on mutation profiles for monogenic disorders and lack of large genome-wide association cohorts for complex traits in African populations is a significant barrier, coupled with extreme genetic variation across different regions and ethnic groups. Data from many different populations are essential to developing appropriate genetic services. Of the proposed genetic service delivery models currently used in Africa-Uncharacterized, Limited, Disease-focused, Emerging and Established-the first three best describe the situation in most African countries. Implementation is fraught with difficulties related to the scarcity of an appropriately skilled medical genetic workforce, limited infrastructure and processes, insufficient health funding and lack of political support, and overstretched health systems. There is a strong nucleus of determined and optimistic clinicians and scientists with a clear vision, and there is a hope for innovative solutions and technological leapfrogging. However, a multi-dimensional approach with active interventions to stimulate genomic research, clinical genetics and overarching healthcare systems is needed to reduce genetic service inequalities and accelerate PPH on the continent. Human and infrastructure capacity development, dedicated funding, political will and supporting legislation, and public education and awareness, are critical elements for success. Africa-relevant genomic and related health economics research remains imperative with an overarching need to translate knowledge into improved healthcare. Given the limited data and genetic services across most of Africa, the continent has not yet come of 'genomics' age.", - "journal_title": "Human molecular genetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/34240178/" - } - ], - "3776e53f-5f7d-4cf4-ab7c-5fe06a1c0570": [ - { - "pub_id": "31416575", - "title": "Functional genomics applications and therapeutic implications in sarcopenia.", - "authors": "Aicha Melouane,Abdelaziz Ghanemi,Mayumi Yoshioka,Jonny St-Amand", - "abstract": "The human genome contains around 20,000-25,000 genes coding for 30,000 proteins. Some proteins and genes represent therapeutic targets for human diseases. RNA and protein expression profiling tools allow the study of the molecular basis of aging and drug discovery validation. Throughout the life, there is an age-related and disease-related muscle decline. Sarcopenia is defined as a loss of muscle mass and a decrease in functional properties such as muscle strength and physical performance. Yet, there is still no consensus on the evaluation methods of sarcopenia prognosis. The main challenge of this complex biological phenomena is its multifactorial etiology. Thus, functional genomics methods attempt to shape the related scientific approaches via an innovative in-depth view on sarcopenia. Gene and drug high throughput screening combined with functional genomics allow the generation and the interpretation of a large amount of data related to sarcopenia and therapeutic progress. This review focuses on the application of selected functional genomics techniques such as RNA interference, RNA silencing, proteomics, transgenic mice, metabolomics, genomics, and epigenomics to better understand sarcopenia mechanisms.", - "journal_title": "Mutation research. Reviews in mutation research", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/31416575/" - } - ], - "8148a0fe-aec5-4326-ae36-5b2de0f8c8c9": [ - { - "pub_id": "29363785", - "title": "Revisiting the genomic hypomethylation hypothesis of aging.", - "authors": "Archana Unnikrishnan,Niran Hadad,Dustin R Masser,Jordan Jackson,Willard M Freeman,Arlan Richardson", - "abstract": "The genomic hypomethylation hypothesis of aging proposes that an overall decrease in global DNA methylation occurs with age, and it has been argued that the decrease in global DNA methylation could be an important factor in aging, resulting in the relaxation of gene expression regulation and abnormal gene expression. Since it was initially observed that DNA methylation decreased with age in 1974, 16 articles have been published describing the effect of age on global DNA methylation in various tissues from rodents and humans. We critically reviewed the publications on the effect of age on DNA methylation and the expression of the enzymes involved in DNA methylation to evaluate the validity of the hypomethylation hypothesis of aging. On the basis of the current scientific literature, we conclude that a decrease in the global methylation of the genome occurs in most if not all tissues/cells as an animal ages. However, age-related changes in DNA methylation in specific regions or at specific sites in the genome occur even though the global DNA methylation does not change.", - "journal_title": "Annals of the New York Academy of Sciences", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/29363785/" - } - ], - "0fc75a0d-3aa3-481a-8c0f-689bd7ae6104": [ - { - "pub_id": "29788292", - "title": "Biological Processes Modulating Longevity across Primates: A Phylogenetic Genome-Phenome Analysis.", - "authors": "Gerard Muntan\u00e9,Xavier Farr\u00e9,Juan Antonio Rodr\u00edguez,Cinta Pegueroles,David A Hughes,Jo\u00e3o Pedro de Magalh\u00e3es,Toni Gabald\u00f3n,Arcadi Navarro", - "abstract": "Aging is a complex process affecting different species and individuals in different ways. Comparing genetic variation across species with their aging phenotypes will help understanding the molecular basis of aging and longevity. Although most studies on aging have so far focused on short-lived model organisms, recent comparisons of genomic, transcriptomic, and metabolomic data across lineages with different lifespans are unveiling molecular signatures associated with longevity. Here, we examine the relationship between genomic variation and maximum lifespan across primate species. We used two different approaches. First, we searched for parallel amino-acid mutations that co-occur with increases in longevity across the primate linage. Twenty-five such amino-acid variants were identified, several of which have been previously reported by studies with different experimental setups and in different model organisms. The genes harboring these mutations are mainly enriched in functional categories such as wound healing, blood coagulation, and cardiovascular disorders. We demonstrate that these pathways are highly enriched for pleiotropic effects, as predicted by the antagonistic pleiotropy theory of aging. A second approach was focused on changes in rates of protein evolution across the primate phylogeny. Using the phylogenetic generalized least squares, we show that some genes exhibit strong correlations between their evolutionary rates and longevity-associated traits. These include genes in the Sphingosine 1-phosphate pathway, PI3K signaling, and the Thrombin/protease-activated receptor pathway, among other cardiovascular processes. Together, these results shed light into human senescence patterns and underscore the power of comparative genomics to identify pathways related to aging and longevity.", - "journal_title": "Molecular biology and evolution", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/29788292/" - } - ], - "d42e38fe-0cb2-4128-8e1a-de481be026e4": [ - { - "pub_id": "33859374", - "title": "Correlational selection in the age of genomics.", - "authors": "Erik I Svensson,Stevan J Arnold,Reinhard B\u00fcrger,Katalin Csill\u00e9ry,Jeremy Draghi,Jonathan M Henshaw,Adam G Jones,Stephen De Lisle,David A Marques,Katrina McGuigan,Monique N Simon,Anna Runemark", - "abstract": "Ecologists and evolutionary biologists are well aware that natural and sexual selection do not operate on traits in isolation, but instead act on combinations of traits. This long-recognized and pervasive phenomenon is known as multivariate selection, or-in the particular case where it favours correlations between interacting traits-correlational selection. Despite broad acknowledgement of correlational selection, the relevant theory has often been overlooked in genomic research. Here, we discuss theory and empirical findings from ecological, quantitative genetic and genomic research, linking key insights from different fields. Correlational selection can operate on both discrete trait combinations and quantitative characters, with profound implications for genomic architecture, linkage, pleiotropy, evolvability, modularity, phenotypic integration and phenotypic plasticity. We synthesize current knowledge and discuss promising research approaches that will enable us to understand how correlational selection shapes genomic architecture, thereby linking quantitative genetic approaches with emerging genomic methods. We suggest that research on correlational selection has great potential to integrate multiple fields in evolutionary biology, including developmental and functional biology, ecology, quantitative genetics, phenotypic polymorphisms, hybrid zones and speciation processes.", - "journal_title": "Nature ecology & evolution", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/33859374/" - } - ], - "f61d9614-5caf-4fc5-ad83-6de6cf19cdcd": [ - { - "pub_id": "31925603", - "title": "The genomics of acute myeloid leukemia in children.", - "authors": "Shannon E Conneely,Rachel E Rau", - "abstract": "Acute myeloid leukemia (AML) is a clinically, morphologically, and genetically heterogeneous disorder. Like many malignancies, the genomic landscape of pediatric AML has been mapped recently through sequencing of large cohorts of patients. Much has been learned about the biology of AML through studies of specific recurrent genetic lesions. Further, genetic lesions have been linked to specific clinical features, response to therapy, and outcome, leading to improvements in risk stratification. Lastly, targeted therapeutic approaches have been developed for the treatment of specific genetic lesions, some of which are already having a positive impact on outcomes. While the advances made based on the discoveries of sequencing studies are significant, much work is left. The biologic, clinical, and prognostic impact of a number of genetic lesions, including several seemingly unique to pediatric patients, remains undefined. While targeted approaches are being explored, for most, the efficacy and tolerability when incorporated into standard therapy is yet to be determined. Furthermore, the challenge of how to study small subpopulations with rare genetic lesions in an already rare disease will have to be considered. In all, while questions and challenges remain, precisely defining the genomic landscape of\u00a0AML, holds great promise for ultimately leading to improved outcomes for affected patients.", - "journal_title": "Cancer metastasis reviews", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/31925603/" - } - ], - "8b352d30-87c2-4f4b-8cac-2f3f90c3a0a7": [ - { - "pub_id": "37524436", - "title": "A transcriptome-based single-cell biological age model and resource for tissue-specific aging measures.", - "authors": "Shulin Mao,Jiayu Su,Longteng Wang,Xiaochen Bo,Cheng Li,Hebing Chen", - "abstract": "Accurately measuring biological age is crucial for improving healthcare for the elderly population. However, the complexity of aging biology poses challenges in how to robustly estimate aging and interpret the biological significance of the traits used for estimation. Here we present SCALE, a statistical pipeline that quantifies biological aging in different tissues using explainable features learned from literature and single-cell transcriptomic data. Applying SCALE to the \"Mouse Aging Cell Atlas\" (<i>Tabula Muris Senis</i>) data, we identified tissue-level transcriptomic aging programs for more than 20 murine tissues and created a multitissue resource of mouse quantitative aging-associated genes. We observe that SCALE correlates well with other age indicators, such as the accumulation of somatic mutations, and can distinguish subtle differences in aging even in cells of the same chronological age. We further compared SCALE with other transcriptomic and methylation \"clocks\" in data from aging muscle stem cells, Alzheimer's disease, and heterochronic parabiosis. Our results confirm that SCALE is more generalizable and reliable in assessing biological aging in aging-related diseases and rejuvenating interventions. Overall, SCALE represents a valuable advancement in our ability to measure aging accurately, robustly, and interpretably in single cells.", - "journal_title": "Genome research", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/37524436/" - } - ], - "e363bc90-3aa6-44af-ba2e-bb2ad19438d5": [ - { - "pub_id": "30510174", - "title": "Giant tortoise genomes provide insights into longevity and age-related disease.", - "authors": "V\u00edctor Quesada,Sandra Freitas-Rodr\u00edguez,Joshua Miller,Jos\u00e9 G P\u00e9rez-Silva,Zi-Feng Jiang,Washington Tapia,Olaya Santiago-Fern\u00e1ndez,Diana Campos-Iglesias,Lukas F K Kuderna,Maud Quinzin,Miguel G \u00c1lvarez,Dido Carrero,Luciano B Beheregaray,James P Gibbs,Ylenia Chiari,Scott Glaberman,Claudio Ciofi,Miguel Araujo-Voces,Pablo Mayoral,Javier R Arango,Isaac Tamargo-G\u00f3mez,David Roiz-Valle,Mar\u00eda Pascual-Torner,Benjamin R Evans,Danielle L Edwards,Ryan C Garrick,Michael A Russello,Nikos Poulakakis,Stephen J Gaughran,Danny O Rueda,Gabriel Bretones,Tom\u00e0s Marqu\u00e8s-Bonet,Kevin P White,Adalgisa Caccone,Carlos L\u00f3pez-Ot\u00edn", - "abstract": "Giant tortoises are among the longest-lived vertebrate animals and, as such, provide an excellent model to study traits like longevity and age-related diseases. However, genomic and molecular evolutionary information on giant tortoises is scarce. Here, we describe a global analysis of the genomes of Lonesome George-the iconic last member of Chelonoidis abingdonii-and the Aldabra giant tortoise (Aldabrachelys gigantea). Comparison of these genomes with those of related species, using both unsupervised and supervised analyses, led us to detect lineage-specific variants affecting DNA repair genes, inflammatory mediators and genes related to cancer development. Our study also hints at specific evolutionary strategies linked to increased lifespan, and expands our understanding of the genomic determinants of ageing. These new genome sequences also provide important resources to help the efforts for restoration of giant tortoise populations.", - "journal_title": "Nature ecology & evolution", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/30510174/" - } - ], - "16de415c-edd5-4bf7-9e6d-e8fcae3985f5": [ - { - "pub_id": "32004793", - "title": "The management of desmoid tumours: A joint global consensus-based guideline approach for adult and paediatric patients.", - "authors": " ", - "abstract": "Desmoid tumor (DT; other synonymously used terms: Desmoid-type fibromatosis, aggressive fibromatosis) is a rare and locally aggressive monoclonal, fibroblastic proliferation characterised by a variable and often unpredictable clinical course. Previously surgery was the standard primary treatment modality; however, in recent years a paradigm shift towards a more conservative management has been introduced and an effort to harmonise the strategy amongst clinicians has been made. We present herein an evidence-based, joint global consensus guideline approach to the management of this disease focussing on: molecular genetics, indications for an active treatment, and available systemic therapeutic options. This paper follows a one-day consensus meeting held in Milan, Italy, in June 2018 under the auspices of the European Reference Network for rare solid adult cancers, EURACAN, the European Organisation for Research and Treatment of Cancer (EORTC) Soft Tissue and Bone Sarcoma Group (STBSG) as well as Sarcoma Patients EuroNet (SPAEN) and The Desmoid tumour Research Foundation (DTRF). The meeting brought together over 50 adult and pediatric sarcoma experts from different disciplines, patients and patient advocates from Europe, North America and Japan.", - "journal_title": "European journal of cancer (Oxford, England : 1990)", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/32004793/" - } - ], - "dc38aee3-49b9-47a7-ae86-74e389bb0b91": [ - { - "pub_id": "26729443", - "title": "MET Exon 14 Mutations in Non-Small-Cell Lung Cancer Are Associated With Advanced Age and Stage-Dependent MET Genomic Amplification and c-Met Overexpression.", - "authors": "Mark M Awad,Geoffrey R Oxnard,David M Jackman,Daniel O Savukoski,Dimity Hall,Priyanka Shivdasani,Jennifer C Heng,Suzanne E Dahlberg,Pasi A J\u00e4nne,Suman Verma,James Christensen,Peter S Hammerman,Lynette M Sholl", - "abstract": "Non-small-cell lung cancers (NSCLCs) harboring mutations in MET exon 14 and its flanking introns may respond to c-Met inhibitors. We sought to describe the clinical, pathologic, and genomic characteristics of patients with cancer with MET exon 14 mutations. We interrogated next-generation sequencing results from 6,376 cancers to identify those harboring MET exon 14 mutations. Clinical characteristics of MET exon 14\u2002mutated NSCLCs were compared with those of NSCLCs with activating mutations in KRAS and EGFR. Co-occurring genomic mutations and copy number alterations were identified. c-Met immunohistochemistry and real-time polymerase chain reaction to detect exon 14 skipping were performed where sufficient tissue was available. MET exon 14 mutations were identified in 28 of 933 nonsquamous NSCLCs (3.0%) and were not seen in other cancer types in this study. Patients with MET exon 14-mutated NSCLC were significantly older (median age, 72.5 years) than patients with EGFR-mutant (median age, 61 years; P < .001) or KRAS-mutant NSCLC (median age, 65 years; P < .001). Among patients with MET exon 14 mutations, 68% were women, and 36% were never-smokers. Stage IV MET exon 14-mutated NSCLCs were significantly more likely to have concurrent MET genomic amplification (mean ratio of MET to chromosome 7, 4.3) and strong c-Met immunohistochemical expression (mean H score, 253) than stage IA to IIIB MET exon 14-mutated NSCLCs (mean ratio of MET to chromosome 7, 1.4; P = .007; mean H score, 155; P = .002) and stage IV MET exon 14-wild-type NSCLCs (mean ratio of MET to chromosome 7, 1.2; P < .001; mean H score, 142; P < .001). A patient whose lung cancer harbored a MET exon 14 mutation with concurrent genomic amplification of the mutated MET allele experienced a major partial response to the c-Met inhibitor crizotinib. MET exon 14 mutations represent a clinically unique molecular subtype of NSCLC. Prospective clinical trials with c-Met inhibitors will be necessary to validate MET exon 14 mutations as an important therapeutic target in NSCLC.", - "journal_title": "Journal of clinical oncology : official journal of the American Society of Clinical Oncology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/26729443/" - } - ], - "bf3255cf-b2c7-40ad-8cfc-ec9ac21346bf": [ - { - "pub_id": "29531354", - "title": "Multiancestry genome-wide association study of 520,000 subjects identifies 32 loci associated with stroke and stroke subtypes.", - "authors": "Rainer Malik,Ganesh Chauhan,Matthew Traylor,Muralidharan Sargurupremraj,Yukinori Okada,Aniket Mishra,Loes Rutten-Jacobs,Anne-Katrin Giese,Sander W van der Laan,Solveig Gretarsdottir,Christopher D Anderson,Michael Chong,Hieab H H Adams,Tetsuro Ago,Peter Almgren,Philippe Amouyel,Hakan Ay,Traci M Bartz,Oscar R Benavente,Steve Bevan,Giorgio B Boncoraglio,Robert D Brown,Adam S Butterworth,Caty Carrera,Cara L Carty,Daniel I Chasman,Wei-Min Chen,John W Cole,Adolfo Correa,Ioana Cotlarciuc,Carlos Cruchaga,John Danesh,Paul I W de Bakker,Anita L DeStefano,Marcel den Hoed,Qing Duan,Stefan T Engelter,Guido J Falcone,Rebecca F Gottesman,Raji P Grewal,Vilmundur Gudnason,Stefan Gustafsson,Jeffrey Haessler,Tamara B Harris,Ahamad Hassan,Aki S Havulinna,Susan R Heckbert,Elizabeth G Holliday,George Howard,Fang-Chi Hsu,Hyacinth I Hyacinth,M Arfan Ikram,Erik Ingelsson,Marguerite R Irvin,Xueqiu Jian,Jordi Jim\u00e9nez-Conde,Julie A Johnson,J Wouter Jukema,Masahiro Kanai,Keith L Keene,Brett M Kissela,Dawn O Kleindorfer,Charles Kooperberg,Michiaki Kubo,Leslie A Lange,Carl D Langefeld,Claudia Langenberg,Lenore J Launer,Jin-Moo Lee,Robin Lemmens,Didier Leys,Cathryn M Lewis,Wei-Yu Lin,Arne G Lindgren,Erik Lorentzen,Patrik K Magnusson,Jane Maguire,Ani Manichaikul,Patrick F McArdle,James F Meschia,Braxton D Mitchell,Thomas H Mosley,Michael A Nalls,Toshiharu Ninomiya,Martin J O'Donnell,Bruce M Psaty,Sara L Pulit,Kristiina Rannikm\u00e4e,Alexander P Reiner,Kathryn M Rexrode,Kenneth Rice,Stephen S Rich,Paul M Ridker,Natalia S Rost,Peter M Rothwell,Jerome I Rotter,Tatjana Rundek,Ralph L Sacco,Saori Sakaue,Michele M Sale,Veikko Salomaa,Bishwa R Sapkota,Reinhold Schmidt,Carsten O Schmidt,Ulf Schminke,Pankaj Sharma,Agnieszka Slowik,Cathie L M Sudlow,Christian Tanislav,Turgut Tatlisumak,Kent D Taylor,Vincent N S Thijs,Gudmar Thorleifsson,Unnur Thorsteinsdottir,Steffen Tiedt,Stella Trompet,Christophe Tzourio,Cornelia M van Duijn,Matthew Walters,Nicholas J Wareham,Sylvia Wassertheil-Smoller,James G Wilson,Kerri L Wiggins,Qiong Yang,Salim Yusuf, , , , , ,Joshua C Bis,Tomi Pastinen,Arno Ruusalepp,Eric E Schadt,Simon Koplev,Johan L M Bj\u00f6rkegren,Veronica Codoni,Mete Civelek,Nicholas L Smith,David A Tr\u00e9gou\u00ebt,Ingrid E Christophersen,Carolina Roselli,Steven A Lubitz,Patrick T Ellinor,E Shyong Tai,Jaspal S Kooner,Norihiro Kato,Jiang He,Pim van der Harst,Paul Elliott,John C Chambers,Fumihiko Takeuchi,Andrew D Johnson, , , , , , , , , , ,Dharambir K Sanghera,Olle Melander,Christina Jern,Daniel Strbian,Israel Fernandez-Cadenas,W T Longstreth,Arndt Rolfs,Jun Hata,Daniel Woo,Jonathan Rosand,Guillaume Pare,Jemma C Hopewell,Danish Saleheen,Kari Stefansson,Bradford B Worrall,Steven J Kittner,Sudha Seshadri,Myriam Fornage,Hugh S Markus,Joanna M M Howson,Yoichiro Kamatani,Stephanie Debette,Martin Dichgans", - "abstract": "Stroke has multiple etiologies, but the underlying genes and pathways are largely unknown. We conducted a multiancestry genome-wide-association meta-analysis in 521,612 individuals (67,162 cases and 454,450 controls) and discovered 22 new stroke risk loci, bringing the total to 32. We further found shared genetic variation with related vascular traits, including blood pressure, cardiac traits, and venous thromboembolism, at individual loci (n\u2009=\u200918), and\u00a0using genetic risk scores and linkage-disequilibrium-score regression. Several loci exhibited distinct association and pleiotropy patterns for etiological stroke subtypes. Eleven new susceptibility loci indicate mechanisms not previously implicated in stroke pathophysiology, with prioritization of risk variants and genes accomplished through bioinformatics analyses using extensive functional datasets. Stroke risk loci were significantly enriched in drug targets for antithrombotic therapy.", - "journal_title": "Nature genetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/29531354/" - } - ], - "0d85f688-0b8c-4dbe-af56-ffbd3be73ab4": [ - { - "pub_id": "27763635", - "title": "Genetics/genomics education for nongenetic health professionals: a systematic literature review.", - "authors": "Divya Talwar,Tung-Sung Tseng,Margaret Foster,Lei Xu,Lei-Shih Chen", - "abstract": "The completion of the Human Genome Project has enhanced avenues for disease prevention, diagnosis, and management. Owing to the shortage of genetic professionals, genetics/genomics training has been provided to nongenetic health professionals for years to establish their genomic competencies. We conducted a systematic literature review to summarize and evaluate the existing genetics/genomics education programs for nongenetic health professionals. Five electronic databases were searched from January 1990 to June 2016. Forty-four studies met our inclusion criteria. There was a growing publication trend. Program participants were mainly physicians and nurses. The curricula, which were most commonly provided face to face, included basic genetics; applied genetics/genomics; ethical, legal, and social implications of genetics/genomics; and/or genomic competencies/recommendations in particular professional fields. Only one-third of the curricula were theory-based. The majority of studies adopted a pre-/post-test design and lacked follow-up data collection. Nearly all studies reported participants' improvements in one or more of the following areas: knowledge, attitudes, skills, intention, self-efficacy, comfort level, and practice. However, most studies did not report participants' age, ethnicity, years of clinical practice, data validity, and data reliability. Many genetics/genomics education programs for nongenetic health professionals exist. Nevertheless, enhancement in methodological quality is needed to strengthen education initiatives.Genet Med advance online publication 20 October 2016.", - "journal_title": "Genetics in medicine : official journal of the American College of Medical Genetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/27763635/" - } - ], - "5d98d831-62f5-4763-8576-5333367b4fe2": [ - { - "pub_id": "35469708", - "title": "Immunity and lifespan: answering long-standing questions with comparative genomics.", - "authors": "Emily A O'Connor,Charlie K Cornwallis", - "abstract": "Long life requires individuals to defend themselves against pathogens over prolonged periods of time whilst minimising damage to themselves. In vertebrates, pathogen defence is provided by two integrated systems, innate and adaptive immunity. Innate immunity is relatively nonspecific, resulting in collateral damage to hosts, and does not involve canonical immunological memory. In contrast, adaptive immunity is highly specific and confers long-lasting memory, which are features that are predicted to facilitate long life. However, there is long-standing debate over the general importance of adaptive immunity for the evolution of extended lifespans, partly because this is difficult to test. We highlight how recent improvements in whole genome assemblies open the door to immunogenomic comparative analyses that enable the coevolution of longevity and specific immune traits to be disentangled.", - "journal_title": "Trends in genetics : TIG", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/35469708/" - } - ], - "a6bc2efd-61a7-4e07-ad5c-49234aa89431": [ - { - "pub_id": "36348440", - "title": "A review on the application of the exposome paradigm to unveil the environmental determinants of age-related diseases.", - "authors": "Enmin Ding,Yu Wang,Juan Liu,Song Tang,Xiaoming Shi", - "abstract": "Age-related diseases account for almost half of all diseases among adults worldwide, and their incidence is substantially affected by the exposome, which is the sum of all exogenous and endogenous environmental exposures and the human body's response to these exposures throughout the entire lifespan. Herein, we perform a comprehensive review of the epidemiological literature to determine the key elements of the exposome that affect the development of age-related diseases and the roles of aging hallmarks in this process. We find that most exposure assessments in previous aging studies have used a reductionist approach, whereby the effect of only a single environmental factor or a specific class of environmental factors on the development of age-related diseases has been examined. As such, there is a lack of a holistic and unbiased understanding of the effect of multiple environmental factors on the development of age-related diseases. To address this, we propose several research strategies based on an exposomic framework that could advance our understanding-in particular, from a mechanistic perspective-of how environmental factors affect the development of age-related diseases. We discuss the statistical methods and other methods that have been used in exposome-wide association studies, with a particular focus on multiomics technologies. We also address future challenges and opportunities in the realm of multidisciplinary approaches and genome-exposome epidemiology. Furthermore, we provide perspectives on precise public health services for vulnerable populations, public communications, the integration of risk exposure information, and the bench-to-bedside translation of research on age-related diseases.", - "journal_title": "Human genomics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/36348440/" - } - ], - "575ac4f2-a56f-46bf-9b00-ec7f723b129b": [ - { - "pub_id": "31012959", - "title": "The Burden of Breast Cancer Predisposition Variants Across The Age Spectrum Among 10 000 Patients.", - "authors": "Yanin Chavarri-Guerra,Carolyn B Hendricks,Sandra Brown,Catherine Marcum,Mary Hander,Zdenka E Segota,Chris Hake,Sharon Sand,Thomas P Slavin,Arti Hurria,Enrique Soto-Perez-de-Celis,Bita Nehoray,Kenneth B Blankstein,Kathleen R Blazer,Jeffrey N Weitzel, ", - "abstract": "Women diagnosed with breast cancer (BC) at an older age are less likely to undergo genetic cancer risk assessment and genetic testing since the guidelines and referrals are biased toward earlier age at diagnosis. Thus, we determined the prevalence and type of pathogenic cancer predisposition variants among women with a history of BC diagnosed at the age\u2009of 65 years or older vs younger than 65\u2009years. Prospective registration cohort. The Clinical Cancer Genomics Community Research Network, including 40 community-based clinics in the United States and 5 in Latin America. Women with BC and genetic testing results. Sociodemographic characteristics, clinical variables, and genetic profiles were compared between women aged 65 years and older and\u2009those younger than 65\u2009years at BC diagnosis. Among 588 women diagnosed with BC and aged 65\u2009years and older and 9412 diagnosed at younger than 65\u2009years, BC-associated pathogenic variants (PVs) were detected in 5.6% of those aged 65 years and older (n\u2009=\u200933) and 14.2% of those younger than 65\u2009years (n\u2009=\u20091340) (P\u2009<\u2009.01). PVs in high-risk genes (eg, BRCA1 and BRCA2) represented 81.1% of carriers among women aged 65\u2009years and older (n\u2009=\u200927) and 93.1% of those younger than 65\u2009years (n\u2009=\u20091248) (P\u2009=\u2009.01). BRCA2 PVs represented 42.4% of high-risk gene findings for those aged 65\u2009years and older, whereas BRCA1 PVs were most common among carriers younger than 65\u2009years (49.7%). PVs (n\u2009=\u20097) in moderate-risk genes represented 21.2% for carriers aged 65 years and older and 7.3% of those younger than 65 years (n\u2009=\u200998; P\u2009<\u2009.01). CHEK2 PVs were the most common moderate-risk gene finding in both groups. Clinically actionable BC susceptibility PVs, particularly in BRCA2 and CHEK2, were relatively prevalent among older women undergoing genetic testing. The significant burden of PVs for older women with BC provides a critical reminder to recognize the full spectrum of eligibility and provide genetic testing for older women, rather than exclusion based on chronological age alone. J Am Geriatr Soc 67:884-888, 2019.", - "journal_title": "Journal of the American Geriatrics Society", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/31012959/" - } - ], - "e4773b3b-814d-4306-8250-59dc03f09bc2": [ - { - "pub_id": "27364349", - "title": "Unraveling the message: insights into comparative genomics of the naked mole-rat.", - "authors": "Kaitlyn N Lewis,Ilya Soifer,Eugene Melamud,Margaret Roy,R Scott McIsaac,Matthew Hibbs,Rochelle Buffenstein", - "abstract": "Animals have evolved to survive, and even thrive, in different environments. Genetic adaptations may have indirectly created phenotypes that also resulted in a longer lifespan. One example of this phenomenon is the preternaturally long-lived naked mole-rat. This strictly subterranean rodent tolerates hypoxia, hypercapnia, and soil-based toxins. Naked mole-rats also exhibit pronounced resistance to cancer and an attenuated decline of many physiological characteristics that often decline as mammals age. Elucidating mechanisms that give rise to their unique phenotypes will lead to better understanding of subterranean ecophysiology and biology of aging. Comparative genomics could be a useful tool in this regard. Since the publication of a naked mole-rat genome assembly in 2011, analyses of genomic and transcriptomic data have enabled a clearer understanding of mole-rat evolutionary history and suggested molecular pathways (e.g., NRF2-signaling activation and DNA damage repair mechanisms) that may explain the extraordinarily longevity and unique health traits of this species. However, careful scrutiny and re-analysis suggest that some identified features result from incorrect or imprecise annotation and assembly of the naked mole-rat genome: in addition, some of these conclusions (e.g., genes involved in cancer resistance and hairlessness) are rejected when the analysis includes additional, more closely related species. We describe how the combination of better study design, improved genomic sequencing techniques, and new bioinformatic and data analytical tools will improve comparative genomics and ultimately bridge the gap between traditional model and nonmodel organisms.", - "journal_title": "Mammalian genome : official journal of the International Mammalian Genome Society", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/27364349/" - } - ], - "adf2d31e-e83d-47df-97af-3764e42aa80e": [ - { - "pub_id": "29121237", - "title": "Human Ageing Genomic Resources: new and updated databases.", - "authors": "Robi Tacutu,Daniel Thornton,Emily Johnson,Arie Budovsky,Diogo Barardo,Thomas Craig,Eugene Diana,Gilad Lehmann,Dmitri Toren,Jingwei Wang,Vadim E Fraifeld,Jo\u00e3o P de Magalh\u00e3es", - "abstract": "In spite of a growing body of research and data, human ageing remains a poorly understood process. Over 10 years ago we developed the Human Ageing Genomic Resources (HAGR), a collection of databases and tools for studying the biology and genetics of ageing. Here, we present HAGR's main functionalities, highlighting new additions and improvements. HAGR consists of six core databases: (i) the GenAge database of ageing-related genes, in turn composed of a dataset of >300 human ageing-related genes and a dataset with >2000 genes associated with ageing or longevity in model organisms; (ii) the AnAge database of animal ageing and longevity, featuring >4000 species; (iii) the GenDR database with >200 genes associated with the life-extending effects of dietary restriction; (iv) the LongevityMap database of human genetic association studies of longevity with >500 entries; (v) the DrugAge database with >400 ageing or longevity-associated drugs or compounds; (vi) the CellAge database with >200 genes associated with cell senescence. All our databases are manually curated by experts and regularly updated to ensure a high quality data. Cross-links across our databases and to external resources help researchers locate and integrate relevant information. HAGR is freely available online (http://genomics.senescence.info/).", - "journal_title": "Nucleic acids research", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/29121237/" - } - ], - "aef3b1d1-d19b-4060-9c24-88adc47523f1": [ - { - "pub_id": "28602509", - "title": "NeuroChip, an updated version of the NeuroX genotyping platform to rapidly screen for variants associated with neurological diseases.", - "authors": "Cornelis Blauwendraat,Faraz Faghri,Lasse Pihlstrom,Joshua T Geiger,Alexis Elbaz,Suzanne Lesage,Jean-Christophe Corvol,Patrick May,Aude Nicolas,Yevgeniya Abramzon,Natalie A Murphy,J Raphael Gibbs,Mina Ryten,Raffaele Ferrari,Jose Bras,Rita Guerreiro,Julie Williams,Rebecca Sims,Steven Lubbe,Dena G Hernandez,Kin Y Mok,Laurie Robak,Roy H Campbell,Ekaterina Rogaeva,Bryan J Traynor,Ruth Chia,Sun Ju Chung, ,John A Hardy,Alexis Brice,Nicholas W Wood,Henry Houlden,Joshua M Shulman,Huw R Morris,Thomas Gasser,Rejko Kr\u00fcger,Peter Heutink,Manu Sharma,Javier Sim\u00f3n-S\u00e1nchez,Mike A Nalls,Andrew B Singleton,Sonja W Scholz", - "abstract": "Genetics has proven to be a powerful approach in neurodegenerative diseases research, resulting in the identification of numerous causal and risk variants. Previously, we introduced the NeuroX Illumina genotyping array, a fast and efficient genotyping platform designed for the investigation of genetic variation in neurodegenerative diseases. Here, we present its updated version, named NeuroChip. The NeuroChip is a low-cost, custom-designed array containing a tagging variant backbone of about 306,670 variants complemented with a manually curated custom content comprised of 179,467 variants implicated in diverse neurological diseases, including Alzheimer's disease, Parkinson's disease, Lewy body dementia, amyotrophic lateral sclerosis, frontotemporal dementia, progressive supranuclear palsy, corticobasal degeneration, and multiple system atrophy. The tagging backbone was chosen because of the low cost and good genome-wide resolution; the custom content can be combined with other backbones, like population or drug development arrays. Using the NeuroChip, we can accurately identify rare variants and impute over 5.3 million common SNPs from the latest release of the Haplotype Reference Consortium. In summary, we describe the design and usage of the NeuroChip array and show its capability for detecting rare pathogenic variants in numerous neurodegenerative diseases. The NeuroChip has a more comprehensive and improved content, which makes it a reliable, high-throughput, cost-effective screening tool for genetic research and molecular diagnostics in neurodegenerative diseases.", - "journal_title": "Neurobiology of aging", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/28602509/" - } - ], - "f7ab9d4f-add7-4534-8714-367a338a09d2": [ - { - "pub_id": "31578549", - "title": "Genome aging: somatic mutation in the brain links age-related decline with disease and nominates pathogenic mechanisms.", - "authors": "Michael A Lodato,Christopher A Walsh", - "abstract": "Aging is a mysterious process, not only controlled genetically but also subject to random damage that can accumulate over time. While DNA damage and subsequent mutation in somatic cells were first proposed as drivers of aging more than 60\u00a0years ago, whether and to what degree these processes shape the neuronal genome in the human brain could not be tested until recent technological breakthroughs related to single-cell whole-genome sequencing. Indeed, somatic single-nucleotide variants (SNVs) increase with age in the human brain, in a somewhat stochastic process that may nonetheless be controlled by underlying genetic programs. Evidence from the literature suggests that in addition to demonstrated increases in somatic SNVs during aging in normal brains, somatic mutation may also play a role in late-onset, sporadic neurodegenerative diseases, such as Alzheimer's disease and Parkinson's disease. In this review, we will discuss somatic mutation in the human brain, mechanisms by which somatic mutations occur and can be controlled, and how this process can impact human health.", - "journal_title": "Human molecular genetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/31578549/" - } - ], - "f4f4d7de-2089-46ac-8e89-dd6e5734649d": [ - { - "pub_id": "36864178", - "title": "Methods and applications for single-cell and spatial multi-omics.", - "authors": "Katy Vandereyken,Alejandro Sifrim,Bernard Thienpont,Thierry Voet", - "abstract": "The joint analysis of the genome, epigenome, transcriptome, proteome and/or metabolome from single cells is transforming our understanding of cell biology in health and disease. In less than a decade, the field has seen tremendous technological revolutions that enable crucial new insights into the interplay between intracellular and intercellular molecular mechanisms that govern development, physiology and pathogenesis. In this Review, we highlight advances in the fast-developing field of single-cell and spatial multi-omics technologies (also known as multimodal omics approaches), and the computational strategies needed to integrate information across these molecular layers. We demonstrate their impact on fundamental cell biology and translational research, discuss current challenges and provide an outlook to the future.", - "journal_title": "Nature reviews. Genetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/36864178/" - } - ], - "0eeae7ac-b00c-4012-aae8-152382ecaf9b": [ - { - "pub_id": "31014230", - "title": "Aging in the Drosophila ovary: contrasting changes in the expression of the piRNA machinery and mitochondria but no global release of transposable elements.", - "authors": "Alexandra A Erwin,Justin P Blumenstiel", - "abstract": "Evolutionary theory indicates that the dynamics of aging in the soma and reproductive tissues may be distinct. This difference arises from the fact that only the germline lineage establishes future generations. In the soma, changes in the landscape of heterochromatin have been proposed to have an important role in aging. This is because redistribution of heterochromatin during aging has been linked to the derepression of transposable elements and an overall loss of somatic gene regulation. A role for changes in the chromatin landscape in the aging of reproductive tissues is less well established. Whether or not epigenetic factors, such as heterochromatin marks, are perturbed in aging reproductive tissues is of interest because, in special cases, epigenetic variation may be heritable. Using mRNA sequencing data from late-stage egg chambers in Drosophila melanogaster, we characterized the landscape of altered gene and transposable element expression in aged reproductive tissues. This allowed us to test the hypothesis that reproductive tissues may differ from somatic tissues in their response to aging. We show that age-related expression changes in late-stage egg chambers tend to occur in genes residing in heterochromatin, particularly on the largely heterochromatic 4th chromosome. However, these expression differences are seen as both decreases and increases during aging, inconsistent with a general loss of heterochromatic silencing. We also identify an increase in expression of the piRNA machinery, suggesting an age-related increased investment in the maintenance of genome stability. We further identify a strong age-related reduction in the expression of mitochondrial transcripts. However, we find no evidence for global TE derepression in reproductive tissues. Rather, the observed effects of aging on TEs are primarily strain and family specific. These results identify unique responses in somatic versus reproductive tissue with regards to aging. As in somatic tissues, female reproductive tissues show reduced expression of mitochondrial genes. In contrast, the piRNA machinery shows increased expression during aging. Overall, these results also indicate that global loss of TE control observed in other studies may be unique to the soma and sensitive to genetic background and TE family.", - "journal_title": "BMC genomics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/31014230/" - } - ], - "41036c17-1873-41ba-8880-cc659722640e": [ - { - "pub_id": "31845735", - "title": "The DNA methylation landscape in cancer.", - "authors": "Ksenia Skvortsova,Clare Stirzaker,Phillippa Taberlay", - "abstract": "As one of the most abundant and well-studied epigenetic modifications, DNA methylation plays an essential role in normal development and cellular biology. Global alterations to the DNA methylation landscape contribute to alterations in the transcriptome and deregulation of cellular pathways. Indeed, improved methods to study DNA methylation patterning and dynamics at base pair resolution and across individual DNA molecules on a genome-wide scale has highlighted the scope of change to the DNA methylation landscape in disease states, particularly during tumorigenesis. More recently has been the development of DNA hydroxymethylation profiling techniques, which allows differentiation between 5mC and 5hmC profiles and provides further insights into DNA methylation dynamics and remodeling in tumorigenesis. In this review, we describe the distribution of DNA methylation and DNA hydroxymethylation in different genomic contexts, first in normal cells, and how this is altered in cancer. Finally, we discuss DNA methylation profiling technologies and the most recent advances in single-cell methods, bisulfite-free approaches and ultra-long read sequencing techniques.", - "journal_title": "Essays in biochemistry", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/31845735/" - } - ], - "236f046c-e69d-4aca-98fa-6ecf65c426c6": [ - { - "pub_id": "31958187", - "title": "Penetrance of Parkinson's Disease in LRRK2 p.G2019S Carriers Is Modified by a Polygenic Risk Score.", - "authors": "Hirotaka Iwaki,Cornelis Blauwendraat,Mary B Makarious,Sara Bandr\u00e9s-Ciga,Hampton L Leonard,J Raphael Gibbs,Dena G Hernandez,Sonja W Scholz,Faraz Faghri, ,Mike A Nalls,Andrew B Singleton", - "abstract": "Although the leucine-rich repeat kinase 2 p.G2019S mutation has been demonstrated to be a strong risk factor for PD, factors that contribute to penetrance among carriers, other than aging, have not been well identified. To evaluate whether a cumulative genetic risk identified in the recent genome-wide study is associated with penetrance of PD among p.G2019S mutation carriers. We included p.G2019S heterozygote carriers with European ancestry in three genetic cohorts in which the mutation carriers with and without PD were selectively recruited. We also included the carriers from two data sets: one from a case-control setting without selection of mutation carriers and the other from a population sampling. Associations between polygenic risk score constructed from 89 variants reported recently and PD were tested and meta-analyzed. We also explored the interaction of age and PRS. After excluding eight homozygotes, 833 p.G2019S heterozygote carriers (439 PD and 394 unaffected) were analyzed. Polygenic risk score was associated with a higher penetrance of PD (odds ratio: 1.34; 95% confidence interval: [1.09, 1.64] per +1 standard deviation; P = 0.005). In addition, associations with polygenic risk score and penetrance were stronger in the younger participants (main effect: odds ratio 1.28 [1.04, 1.58] per +1 standard deviation; P = 0.022; interaction effect: odds ratio 0.78 [0.64, 0.94] per +1 standard deviation and\u2009+\u200910\u2009years of age; P = 0.008). Our results suggest that there is a genetic contribution for penetrance of PD among p.G2019S carriers. These results have important etiological consequences and potential impact on the selection of subjects for clinical trials. \u00a9 2020 International Parkinson and Movement Disorder Society.", - "journal_title": "Movement disorders : official journal of the Movement Disorder Society", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/31958187/" - } - ], - "02b1c922-a9cf-470d-b036-52c367fc1ca9": [ - { - "pub_id": "30355600", - "title": "Selfish mutations dysregulating RAS-MAPK signaling are pervasive in aged human testes.", - "authors": "Geoffrey J Maher,Hannah K Ralph,Zhihao Ding,Nils Koelling,Hana Mlcochova,Eleni Giannoulatou,Pawan Dhami,Dirk S Paul,Stefan H Stricker,Stephan Beck,Gilean McVean,Andrew O M Wilkie,Anne Goriely", - "abstract": "Mosaic mutations present in the germline have important implications for reproductive risk and disease transmission. We previously demonstrated a phenomenon occurring in the male germline, whereby specific mutations arising spontaneously in stem cells (spermatogonia) lead to clonal expansion, resulting in elevated mutation levels in sperm over time. This process, termed \"selfish spermatogonial selection,\" explains the high spontaneous birth prevalence and strong paternal age-effect of disorders such as achondroplasia and Apert, Noonan and Costello syndromes, with direct experimental evidence currently available for specific positions of six genes (<i>FGFR2</i>, <i>FGFR3</i>, <i>RET</i>, <i>PTPN11</i>, <i>HRAS</i>, and <i>KRAS</i>). We present a discovery screen to identify novel mutations and genes showing evidence of positive selection in the male germline, by performing massively parallel simplex PCR using RainDance technology to interrogate mutational hotspots in 67 genes (51.5 kb in total) in 276 biopsies of testes from five men (median age, 83 yr). Following ultradeep sequencing (about 16,000\u00d7), development of a low-frequency variant prioritization strategy, and targeted validation, we identified 61 distinct variants present at frequencies as low as 0.06%, including 54 variants not previously directly associated with selfish selection. The majority (80%) of variants identified have previously been implicated in developmental disorders and/or oncogenesis and include mutations in six newly associated genes (<i>BRAF</i>, <i>CBL</i>, <i>MAP2K1</i>, <i>MAP2K2</i>, <i>RAF1</i>, and <i>SOS1</i>), all of which encode components of the RAS-MAPK pathway and activate signaling. Our findings extend the link between mutations dysregulating the RAS-MAPK pathway and selfish selection, and show that the aging male germline is a repository for such deleterious mutations.", - "journal_title": "Genome research", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/30355600/" - } - ], - "d70fa4ef-9c42-4bdd-ac01-fc2b94fe9de6": [ - { - "pub_id": "32726628", - "title": "Dissecting Murine Muscle Stem Cell Aging through Regeneration Using Integrative Genomic Analysis.", - "authors": "Anna Shcherbina,Jacqueline Larouche,Paula Fraczek,Benjamin A Yang,Lemuel A Brown,James F Markworth,Carolina H Chung,Mehwish Khaliq,Kanishka de Silva,Jeongmoon J Choi,Mohammad Fallahi-Sichani,Sriram Chandrasekaran,Young C Jang,Susan V Brooks,Carlos A Aguilar", - "abstract": "During aging, there is a progressive loss of volume and function in skeletal muscle that impacts mobility and quality of life. The repair of skeletal muscle is regulated by tissue-resident stem cells called satellite cells (or muscle stem cells [MuSCs]), but in aging, MuSCs decrease in numbers and regenerative capacity. The transcriptional networks and epigenetic changes that confer diminished regenerative function in MuSCs as a result of natural aging are only partially understood. Herein, we use an integrative genomics approach to profile MuSCs from young and aged animals before and after injury. Integration of these datasets reveals aging impacts multiple regulatory changes through significant differences in gene expression, metabolic flux, chromatin accessibility, and patterns of transcription factor (TF) binding activities. Collectively, these datasets facilitate a deeper understanding of the regulation tissue-resident stem cells use during aging and healing.", - "journal_title": "Cell reports", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/32726628/" - } - ], - "b2738553-3bf2-4c8c-9660-52e939bf82a1": [ - { - "pub_id": "31443728", - "title": "Improved precision of epigenetic clock estimates across tissues and its implication for biological ageing.", - "authors": "Qian Zhang,Costanza L Vallerga,Rosie M Walker,Tian Lin,Anjali K Henders,Grant W Montgomery,Ji He,Dongsheng Fan,Javed Fowdar,Martin Kennedy,Toni Pitcher,John Pearson,Glenda Halliday,John B Kwok,Ian Hickie,Simon Lewis,Tim Anderson,Peter A Silburn,George D Mellick,Sarah E Harris,Paul Redmond,Alison D Murray,David J Porteous,Christopher S Haley,Kathryn L Evans,Andrew M McIntosh,Jian Yang,Jacob Gratten,Riccardo E Marioni,Naomi R Wray,Ian J Deary,Allan F McRae,Peter M Visscher", - "abstract": "DNA methylation changes with age. Chronological age predictors built from DNA methylation are termed 'epigenetic clocks'. The deviation of predicted age from the actual age ('age acceleration residual', AAR) has been reported to be associated with death. However, it is currently unclear how a better prediction of chronological age affects such association. In this study, we build multiple predictors based on training DNA methylation samples selected from 13,661 samples (13,402 from blood and 259 from saliva). We use the Lothian Birth Cohorts of 1921 (LBC1921) and 1936 (LBC1936) to examine whether the association between AAR (from these predictors) and death is affected by (1) improving prediction accuracy of an age predictor as its training sample size increases (from 335 to 12,710) and (2) additionally correcting for confounders (i.e., cellular compositions). In addition, we investigated the performance of our predictor in non-blood tissues. We found that in principle, a near-perfect age predictor could be developed when the training sample size is sufficiently large. The association between AAR and mortality attenuates as prediction accuracy increases. AAR from our best predictor (based on Elastic Net, https://github.com/qzhang314/DNAm-based-age-predictor ) exhibits no association with mortality in both LBC1921 (hazard ratio\u2009=\u20091.08, 95% CI 0.91-1.27) and LBC1936 (hazard ratio\u2009=\u20091.00, 95% CI 0.79-1.28). Predictors based on small sample size are prone to confounding by cellular compositions relative to those from large sample size. We observed comparable performance of our predictor in non-blood tissues with a multi-tissue-based predictor. This study indicates that the epigenetic clock can be improved by increasing the training sample size and that its association with mortality attenuates with increased prediction of chronological age.", - "journal_title": "Genome medicine", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/31443728/" - } - ], - "d4b27764-77a9-43b0-982b-cec8d5e016cb": [ - { - "pub_id": "35471657", - "title": "Coming of Age: Human Genomics and the Cancer-Immune Set Point.", - "authors": "Christian Hammer,Ira Mellman", - "abstract": "Cancer is largely a disease of the tumor cell genome. As a result, the majority of genetics research in oncology has concentrated on the role of tumor somatic mutations, as well as inherited risk variants, in disease susceptibility and response to targeted treatments. The advent and success of cancer immunotherapies, however, have opened new perspectives for the investigation of the role of inherited genetic variation in codetermining outcome and safety. It is increasingly likely that the entirety of germline genetic variation involved in regulating immune responses accounts for a significant fraction of the observed variability in responses to cancer immunotherapies. Although germline genetic data from patients treated with cancer immunotherapies are still scarce, this line of research benefits from a vast body of knowledge derived from studies into autoimmune and infectious disease phenotypes, thus not requiring a start from a blank slate. Here, we discuss how a thorough investigation of genomic variation relevant for individuals' variability in (auto)immune responses can contribute to the discovery of novel treatment approaches and drug targets, and yield predictive biomarkers to stratify cancer patient populations in precision and personalized medicine settings.", - "journal_title": "Cancer immunology research", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/35471657/" - } - ], - "99a35e24-bbd2-495b-82dc-53d7e2075191": [ - { - "pub_id": "29925262", - "title": "Nuclear Genomic Instability and Aging.", - "authors": "Laura J Niedernhofer,Aditi U Gurkar,Yinsheng Wang,Jan Vijg,Jan H J Hoeijmakers,Paul D Robbins", - "abstract": "The nuclear genome decays as organisms age. Numerous studies demonstrate that the burden of several classes of DNA lesions is greater in older mammals than in young mammals. More challenging is proving this is a cause rather than a consequence of aging. The DNA damage theory of aging, which argues that genomic instability plays a causal role in aging, has recently gained momentum. Support for this theory stems partly from progeroid syndromes in which inherited defects in DNA repair increase the burden of DNA damage leading to accelerated aging of one or more organs. Additionally, growing evidence shows that DNA damage accrual triggers cellular senescence and metabolic changes that promote a decline in tissue function and increased susceptibility to age-related diseases. Here, we examine multiple lines of evidence correlating nuclear DNA damage with aging. We then consider how, mechanistically, nuclear genotoxic stress could promote aging. We conclude that the evidence, in toto, supports a role for DNA damage as a nidus of aging.", - "journal_title": "Annual review of biochemistry", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/29925262/" - } - ], - "f7dfab8c-2887-42d8-9035-c7460128553a": [ - { - "pub_id": "29739406", - "title": "DNA methylation in the APOE genomic region is associated with cognitive function in African Americans.", - "authors": "Jiaxuan Liu,Wei Zhao,Erin B Ware,Stephen T Turner,Thomas H Mosley,Jennifer A Smith", - "abstract": "Genetic variations in apolipoprotein E (APOE) and proximal genes (PVRL2, TOMM40, and APOC1) are associated with cognitive function and dementia, particularly Alzheimer's disease. Epigenetic mechanisms such as DNA methylation play a central role in the regulation of gene expression. Recent studies have found evidence that DNA methylation may contribute to the pathogenesis of dementia, but its association with cognitive function in populations without dementia remains unclear. We assessed DNA methylation levels of 48 CpG sites in the APOE genomic region in peripheral blood leukocytes collected from 289 African Americans (mean age\u2009=\u200967\u00a0years) from the Genetic Epidemiology Network of Arteriopathy (GENOA) study. Using linear regression, we examined the relationship between methylation in the APOE genomic region and multiple cognitive measures including learning, memory, processing speed, concentration, language and global cognitive function. We identified eight CpG sites in three genes (PVRL2, TOMM40, and APOE) that showed an inverse association between methylation level and delayed recall, a measure of memory, after adjusting for age and sex (False Discovery Rate q-value\u2009<\u20090.1). All eight CpGs are located in either CpG islands (CGIs) or CGI shelves, and six of them are in promoter regions. Education and APOE \u03b54 carrier status significantly modified the effect of methylation in cg08583001 (PVRL2) and cg22024783 (TOMM40), respectively. Together, methylation of the eight CpGs explained an additional 8.7% of the variance in delayed recall, after adjustment for age, sex, education, and APOE \u03b54 carrier status. Methylation was not significantly associated with any other cognitive measures. Our results suggest that methylation levels at multiple CpGs in the APOE genomic region are inversely associated with delayed recall during normal cognitive aging, even after accounting for known genetic predictors for cognition. Our findings highlight the important role of epigenetic mechanisms in influencing cognitive performance, and suggest that changes in blood methylation may be an early indicator of individuals at risk for dementia as well as potential targets for intervention in asymptomatic populations.", - "journal_title": "BMC medical genomics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/29739406/" - } - ], - "920f00c8-4c5d-48f9-9fef-fc882e13ceb1": [ - { - "pub_id": "29081693", - "title": "Editorial: Genomics and Epigenomics of Tumor and Aging Cells.", - "authors": "Gjumrakch Aliev,George E Barreto,Ram\u00f3n Cacabelos", - "abstract": "", - "journal_title": "Current genomics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/29081693/" - } - ], - "595489bf-eea2-47be-a1d2-485b73bc1819": [ - { - "pub_id": "28556790", - "title": "DNA Methylation Profiling of Human Prefrontal Cortex Neurons in Heroin Users Shows Significant Difference between Genomic Contexts of Hyper- and Hypomethylation and a Younger Epigenetic Age.", - "authors": "Alexey Kozlenkov,Andrew E Jaffe,Alisa Timashpolsky,Pasha Apontes,Sergei Rudchenko,Mihaela Barbu,William Byne,Yasmin L Hurd,Steve Horvath,Stella Dracheva", - "abstract": "We employed Illumina 450 K Infinium microarrays to profile DNA methylation (DNAm) in neuronal nuclei separated by fluorescence-activated sorting from the postmortem orbitofrontal cortex (OFC) of heroin users who died from heroin overdose (<i>N</i> = 37), suicide completers (<i>N</i> = 22) with no evidence of heroin use and from control subjects who did not abuse illicit drugs and died of non-suicide causes (<i>N</i> = 28). We identified 1298 differentially methylated CpG sites (DMSs) between heroin users and controls, and 454 DMSs between suicide completers and controls (<i>p</i> < 0.001). DMSs and corresponding genes (DMGs) in heroin users showed significant differences in the preferential context of hyper and hypo DM. HyperDMSs were enriched in gene bodies and exons but depleted in promoters, whereas hypoDMSs were enriched in promoters and enhancers. In addition, hyperDMGs showed preference for genes expressed specifically by glutamatergic as opposed to GABAergic neurons and enrichment for axonogenesis- and synaptic-related gene ontology categories, whereas hypoDMGs were enriched for transcription factor activity- and gene expression regulation-related terms. Finally, we found that the DNAm-based \"epigenetic age\" of neurons from heroin users was younger than that in controls. Suicide-related results were more difficult to interpret. Collectively, these findings suggest that the observed DNAm differences could represent functionally significant marks of heroin-associated plasticity in the OFC.", - "journal_title": "Genes", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/28556790/" - } - ], - "b21c0391-b441-4842-a2df-8d2f2fca6485": [ - { - "pub_id": "33597750", - "title": "Million-year-old DNA sheds light on the genomic history of mammoths.", - "authors": "Tom van der Valk,Patr\u00edcia Pe\u010dnerov\u00e1,David D\u00edez-Del-Molino,Anders Bergstr\u00f6m,Jonas Oppenheimer,Stefanie Hartmann,Georgios Xenikoudakis,Jessica A Thomas,Marianne Dehasque,Ekin Sa\u011fl\u0131can,Fatma Rabia Fidan,Ian Barnes,Shanlin Liu,Mehmet Somel,Peter D Heintzman,Pavel Nikolskiy,Beth Shapiro,Pontus Skoglund,Michael Hofreiter,Adrian M Lister,Anders G\u00f6therstr\u00f6m,Love Dal\u00e9n", - "abstract": "Temporal genomic data hold great potential for studying evolutionary processes such as speciation. However, sampling across speciation events would, in many cases, require genomic time series that stretch well back into the Early Pleistocene subepoch. Although theoretical models suggest that DNA should survive on this timescale<sup>1</sup>, the oldest genomic data recovered so far are from a horse specimen dated to 780-560\u00a0thousand years ago<sup>2</sup>. Here we report the recovery of genome-wide data from three mammoth specimens dating to the Early and Middle Pleistocene subepochs, two of which are more than one million years old. We find that two distinct mammoth lineages were present in eastern Siberia during the Early Pleistocene. One of these lineages gave rise to the woolly mammoth and the other represents a previously unrecognized lineage that was ancestral to the first mammoths to colonize North America. Our analyses reveal that the Columbian mammoth of North America traces its ancestry to a Middle Pleistocene hybridization between these two lineages, with roughly equal admixture proportions. Finally, we show that the majority of protein-coding changes associated with cold adaptation in woolly mammoths were already present one million years ago. These findings highlight the potential of deep-time palaeogenomics to expand our understanding of speciation and long-term adaptive evolution.", - "journal_title": "Nature", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/33597750/" - } - ], - "c172e7ea-3a3a-4970-9e00-ad720177264f": [ - { - "pub_id": "33975542", - "title": "Disentangling the aging gene expression network of termite queens.", - "authors": "Jos\u00e9 Manuel Monroy Kuhn,Karen Meusemann,Judith Korb", - "abstract": "Most insects are relatively short-lived, with a maximum lifespan of a few weeks, like the aging model organism, the fruit-fly Drosophila melanogaster. By contrast, the queens of many social insects (termites, ants and some bees) can live from a few years to decades. This makes social insects promising models in aging research providing insights into how a long reproductive life can be achieved. Yet, aging studies on social insect reproductives are hampered by a lack of quantitative data on age-dependent survival and time series analyses that cover the whole lifespan of such long-lived individuals. We studied aging in queens of the drywood termite Cryptotermes secundus by determining survival probabilities over a period of 15 years and performed transcriptome analyses for queens of known age that covered their whole lifespan. The maximum lifespan of C. secundus queens was 13 years, with a median maximum longevity of 11.0 years. Time course and co-expression network analyses of gene expression patterns over time indicated a non-gradual aging pattern. It was characterized by networks of genes that became differentially expressed only late in life, namely after ten years, which associates well with the median maximum lifespan for queens. These old-age gene networks reflect processes of physiological upheaval. We detected strong signs of stress, decline, defense and repair at the transcriptional level of epigenetic control as well as at the post-transcriptional level with changes in transposable element activity and the proteostasis network. The latter depicts an upregulation of protein degradation, together with protein synthesis and protein folding, processes which are often down-regulated in old animals. The simultaneous upregulation of protein synthesis and autophagy is indicative of a stress-response mediated by the transcription factor cnc, a homolog of human nrf genes. Our results show non-linear senescence with a rather sudden physiological upheaval at old-age. Most importantly, they point to a re-wiring in the proteostasis network and stress as part of the aging process of social insect queens, shortly before queens die.", - "journal_title": "BMC genomics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/33975542/" - } - ], - "be3bfb7f-565c-49c9-8565-e6e1f95ed211": [ - { - "pub_id": "27105872", - "title": "Genome instability in Alzheimer disease.", - "authors": "Yujun Hou,Hyundong Song,Deborah L Croteau,Mansour Akbari,Vilhelm A Bohr", - "abstract": "Alzheimer's disease (AD) is a progressive neurodegenerative disorder and the most common form of dementia. Autosomal dominant, familial AD (fAD) is very rare and caused by mutations in amyloid precursor protein (APP), presenilin-1 (PSEN-1), and presenilin-2 (PSEN-2) genes. The pathogenesis of sporadic AD (sAD) is more complex and variants of several genes are associated with an increased lifetime risk of AD. Nuclear and mitochondrial DNA integrity is pivotal during neuronal development, maintenance and function. DNA damage and alterations in cellular DNA repair capacity have been implicated in the aging process and in age-associated neurodegenerative diseases, including AD. These findings are supported by research using animal models of AD and in DNA repair deficient animal models. In recent years, novel mechanisms linking DNA damage to neuronal dysfunction have been identified and have led to the development of noninvasive treatment strategies. Further investigations into the molecular mechanisms connecting DNA damage to AD pathology may help to develop novel treatment strategies for this debilitating disease. Here we provide an overview of the role of genome instability and DNA repair deficiency in AD pathology and discuss research strategies that include genome instability as a component.", - "journal_title": "Mechanisms of ageing and development", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/27105872/" - } - ], - "7afe318e-a854-4e06-90e9-73ef0a8a8917": [ - { - "pub_id": "32927008", - "title": "Age-related gene expression and DNA methylation changes in rhesus macaque.", - "authors": "Min Zhou,Liang Zhang,Qiao Yang,Chaochao Yan,Peng Jiang,Yue Lan,Jiao Wang,Ruixiang Tang,Miao He,Guanglun Lei,Pan Sun,Na Su,Megan Price,Jing Li,Fangzhao Lin,Bisong Yue,Zhenxin Fan", - "abstract": "Aging is a very complicated biological process that can change gene expressions. The Chinese rhesus macaque (Macaca mulatta lasiota; CR) is closely related to humans. We explored gene expression with increasing age and DNA methylation changes in young and old CRs. Results showed blood transcriptome and DNA methylome significantly changed from young to old CRs. The age-associated differentially expressed genes (DEGs) and differentially methylated regions (DMRs) were associated with age-related biological features, such as immunity, blood coagulation, and biosynthetic process. The measurements of coagulation indicators confirmed old CRs had shorter coagulation time than young CRs, and the activities of coagulation factor II (FII) and factor VIII (FVIII) were enhanced in old CRs. Humans and CRs exhibited the same enhanced blood coagulation with age phenotype. Our study found aging is a critical factor affecting gene expression in CRs, and also provided new insights into the blood coagulation changes in non-human primates.", - "journal_title": "Genomics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/32927008/" - } - ], - "1bcec33b-75bd-46e0-836e-dc13c7ab6f94": [ - { - "pub_id": "30252044", - "title": "A C6orf10/LOC101929163 locus is associated with age of onset in C9orf72 carriers.", - "authors": "Ming Zhang,Raffaele Ferrari,Maria Carmela Tartaglia,Julia Keith,Ezequiel I Surace,Uri Wolf,Christine Sato,Mark Grinberg,Yan Liang,Zhengrui Xi,Kyle Dupont,Philip McGoldrick,Anna Weichert,Paul M McKeever,Raphael Schneider,Michael D McCorkindale,Claudia Manzoni,Rosa Rademakers,Neill R Graff-Radford,Dennis W Dickson,Joseph E Parisi,Bradley F Boeve,Ronald C Petersen,Bruce L Miller,William W Seeley,John C van Swieten,Jeroen van Rooij,Yolande Pijnenburg,Julie van der Zee,Christine Van Broeckhoven,Isabelle Le Ber,Vivianna Van Deerlin,EunRan Suh,Jonathan D Rohrer,Simon Mead,Caroline Graff,Linn \u00d6ijerstedt,Stuart Pickering-Brown,Sara Rollinson,Giacomina Rossi,Fabrizio Tagliavini,William S Brooks,Carol Dobson-Stone,Glenda M Halliday,John R Hodges,Olivier Piguet,Giuliano Binetti,Luisa Benussi,Roberta Ghidoni,Benedetta Nacmias,Sandro Sorbi,Amalia C Bruni,Daniela Galimberti,Elio Scarpini,Innocenzo Rainero,Elisa Rubino,Jordi Clarimon,Alberto Lle\u00f3,Agustin Ruiz,Isabel Hern\u00e1ndez,Pau Pastor,Monica Diez-Fairen,Barbara Borroni,Florence Pasquier,Vincent Deramecourt,Thibaud Lebouvier,Robert Perneczky,Janine Diehl-Schmid,Jordan Grafman,Edward D Huey,Richard Mayeux,Michael A Nalls,Dena Hernandez,Andrew Singleton,Parastoo Momeni,Zhen Zeng,John Hardy,Janice Robertson,Lorne Zinman,Ekaterina Rogaeva, ", - "abstract": "The G4C2-repeat expansion in C9orf72 is the most common known cause of amyotrophic lateral sclerosis and frontotemporal dementia. The high phenotypic heterogeneity of C9orf72 patients includes a wide range in age of onset, modifiers of which are largely unknown. Age of onset could be influenced by environmental and genetic factors both of which may trigger DNA methylation changes at CpG sites. We tested the hypothesis that age of onset in C9orf72 patients is associated with some common single nucleotide polymorphisms causing a gain or loss of CpG sites and thus resulting in DNA methylation alterations. Combined analyses of epigenetic and genetic data have the advantage of detecting functional variants with reduced likelihood of false negative results due to excessive correction for multiple testing in genome-wide association studies. First, we estimated the association between age of onset in C9orf72 patients (n = 46) and the DNA methylation levels at all 7603 CpG sites available on the 450 k BeadChip that are mapped to common single nucleotide polymorphisms. This was followed by a genetic association study of the discovery (n = 144) and replication (n = 187) C9orf72 cohorts. We found that age of onset was reproducibly associated with polymorphisms within a 124.7 kb linkage disequilibrium block tagged by top-significant variation, rs9357140, and containing two overlapping genes (LOC101929163 and C6orf10). A meta-analysis of all 331 C9orf72 carriers revealed that every A-allele of rs9357140 reduced hazard by 30% (P = 0.0002); and the median age of onset in AA-carriers was 6 years later than GG-carriers. In addition, we investigated a cohort of C9orf72 negative patients (n = 2634) affected by frontotemporal dementia and/or amyotrophic lateral sclerosis; and also found that the AA-genotype of rs9357140 was associated with a later age of onset (adjusted P = 0.007 for recessive model). Phenotype analyses detected significant association only in the largest subgroup of patients with frontotemporal dementia (n = 2142, adjusted P = 0.01 for recessive model). Gene expression studies of frontal cortex tissues from 25 autopsy cases affected by amyotrophic lateral sclerosis revealed that the G-allele of rs9357140 is associated with increased brain expression of LOC101929163 (a non-coding RNA) and HLA-DRB1 (involved in initiating immune responses), while the A-allele is associated with their reduced expression. Our findings suggest that carriers of the rs9357140 GG-genotype (linked to an earlier age of onset) might be more prone to be in a pro-inflammatory state (e.g. by microglia) than AA-carriers. Further, investigating the functional links within the C6orf10/LOC101929163/HLA-DRB1 pathway will be critical to better define age-dependent pathogenesis of frontotemporal dementia and amyotrophic lateral sclerosis.", - "journal_title": "Brain : a journal of neurology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/30252044/" - } - ], - "53b0c014-8502-4883-8808-d796e80fc24f": [ - { - "pub_id": "33167850", - "title": "Uterine transcriptome analysis reveals mRNA expression changes associated with the ultrastructure differences of eggshell in young and aged laying hens.", - "authors": "Jia Feng,Hai-Jun Zhang,Shu-Geng Wu,Guang-Hai Qi,Jing Wang", - "abstract": "Lower eggshell quality in the late laying period leads to economic loss. It is a major threat to the quality and safety of egg products. Age-related variations in ultrastructure were thought to induce this deterioration. Eggshell formation is a highly complex process under precise regulation of genes and biological pathways in uterus of laying hens. Herein, we evaluated the physical, mechanical and ultrastructure properties of eggshell and conducted RNA sequencing to learn the transcriptomic differences in uterus between laying hens in the peak (young hens) and late phase (aged hens) of production. The declined breaking strength and fracture toughness of eggshell were observed in aged hen group compared to those in young hen group, accompanied with ultrastructure variations including the increased thickness of mammillary layer and the decreased incidence of early fusion. During the initial stage of eggshell formation, a total of 183 differentially expressed genes (DEGs; 125 upregulated and 58 downregulated) were identified in uterus of laying hens in the late phase in relative to those at peak production. The DEGs annotated to Gene Ontology terms related to antigen processing and presentation were downregulated in aged hens compared to young hens. The contents of proinflammatory cytokine IL-1\u03b2 in uterus were higher in aged hens relative to those in young hens. Besides, the genes of some matrix proteins potentially involved in eggshell mineralization, such as ovalbumin, versican and glypican 3, were also differentially expressed between two groups. Altered gene expression of matrix proteins along with the compromised immune function in uterus of laying hens in the late phase of production may conduce to age-related impairments of eggshell ultrastructure and mechanical properties. The current study enhances our understanding of the age-related deteriorations in eggshell ultrastructure and provides potential targets for improvement of eggshell quality in the late laying period.", - "journal_title": "BMC genomics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/33167850/" - } - ], - "76e0f906-ebff-46d2-9680-a8e1f9d97acf": [ - { - "pub_id": "35526740", - "title": "RETRACTED: Parallel bimodal single-cell sequencing of transcriptome\u00a0and\u00a0methylome provides molecular and translational\u00a0insights\u00a0on oocyte maturation and maternal aging.", - "authors": "Fa-Li Zhang,Wei-Dong Li,Ho Ting Chu,Alfred Chun Sui Luk,Shun Wa Tsang,Wai Kit Lee,Patrick Ming-Kuen Tang,Wai-Yee Chan,King Lau Chow,David Yiu Leung Chan,Tin Chiu Li,Wei Shen,Tin-Lap Lee", - "abstract": "This article has been retracted: please see Elsevier Policy on Article Withdrawal (http://www.elsevier.com/locate/withdrawalpolicy). This article has been retracted at the request of the Editor-in-Chief. It has been brought to our attention that the authors of the article \"Parallel bimodal single-cell sequencing of transcriptome and methylome provides molecular and translational insights on oocyte maturation and maternal aging\" cannot agree on who should be listed as an author of the article. Further inquiry by the journal revealed that the authorship was also changed at the revision stages of the article without notifying the handling Editor, which is contrary to the journal policy on changes to authorship. The journal considers this unacceptable practice, and the Editor-in-Chief decided to retract the article.", - "journal_title": "Genomics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/35526740/" - } - ], - "f9f5fac9-b1df-41b3-ad49-e413209510bd": [ - { - "pub_id": "28959963", - "title": "Parental influence on human germline de novo mutations in 1,548 trios from Iceland.", - "authors": "H\u00e1kon J\u00f3nsson,Patrick Sulem,Birte Kehr,Snaedis Kristmundsdottir,Florian Zink,Eirikur Hjartarson,Marteinn T Hardarson,Kristjan E Hjorleifsson,Hannes P Eggertsson,Sigurjon Axel Gudjonsson,Lucas D Ward,Gudny A Arnadottir,Einar A Helgason,Hannes Helgason,Arnaldur Gylfason,Adalbjorg Jonasdottir,Aslaug Jonasdottir,Thorunn Rafnar,Mike Frigge,Simon N Stacey,Olafur Th Magnusson,Unnur Thorsteinsdottir,Gisli Masson,Augustine Kong,Bjarni V Halldorsson,Agnar Helgason,Daniel F Gudbjartsson,Kari Stefansson", - "abstract": "The characterization of mutational processes that generate sequence diversity in the human genome is of paramount importance both to medical genetics and to evolutionary studies. To understand how the age and sex of transmitting parents affect de novo mutations, here we sequence 1,548 Icelanders, their parents, and, for a subset of 225, at least one child, to 35\u00d7 genome-wide coverage. We find 108,778 de novo mutations, both single nucleotide polymorphisms and indels, and determine the parent of origin of 42,961. The number of de novo mutations from mothers increases by 0.37 per year of age (95% CI 0.32-0.43), a quarter of the 1.51 per year from fathers (95% CI 1.45-1.57). The number of clustered mutations increases faster with the mother's age than with the father's, and the genomic span of maternal de novo mutation clusters is greater than that of paternal ones. The types of de novo mutation from mothers change substantially with age, with a 0.26% (95% CI 0.19-0.33%) decrease in cytosine-phosphate-guanine to thymine-phosphate-guanine (CpG>TpG) de novo mutations and a 0.33% (95% CI 0.28-0.38%) increase in C>G de novo mutations per year, respectively. Remarkably, these age-related changes are not distributed uniformly across the genome. A striking example is a 20 megabase region on chromosome 8p, with a maternal C>G mutation rate that is up to 50-fold greater than the rest of the genome. The age-related accumulation of maternal non-crossover gene conversions also mostly occurs within these regions. Increased sequence diversity and linkage disequilibrium of C>G variants within regions affected by excess maternal mutations indicate that the underlying mutational process has persisted in humans for thousands of years. Moreover, the regional excess of C>G variation in humans is largely shared by chimpanzees, less by gorillas, and is almost absent from orangutans. This demonstrates that sequence diversity in humans results from evolving interactions between age, sex, mutation type, and genomic location.", - "journal_title": "Nature", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/28959963/" - } - ], - "63066483-f708-4376-8121-f76dff8423e1": [ - { - "pub_id": "30348084", - "title": "Paternal germ line aging: DNA methylation age prediction from human sperm.", - "authors": "Timothy G Jenkins,Kenneth I Aston,Bradley Cairns,Andrew Smith,Douglas T Carrell", - "abstract": "The relationship between aging and epigenetic profiles has been highlighted in many recent studies. Models using somatic cell methylomes to predict age have been successfully constructed. However, gamete aging is quite distinct and as such age prediction using sperm methylomes is ineffective with current techniques. We have produced a model that utilizes human sperm DNA methylation signatures to predict chronological age by utilizing methylation array data from a total of 329 samples. The dataset used for model construction includes infertile patients, sperm donors, and individuals from the general population. Our model is capable predicting age with an R2 of 0.89, a mean absolute error (MAE) of 2.04\u00a0years, and a mean absolute percent error (MAPE) of 6.28% in our data set. We additionally investigated the reproducibility of prediction with our model in an independent cohort where 6 technical replicates of 10 individual samples were tested on different arrays. We found very similar age prediction accuracy (MAE\u2009=\u20092.37\u00a0years; MAPE\u2009=\u20097.05%) with a high degree of precision between replicates (standard deviation of only 0.877\u00a0years). Additionally, we found that smokers trended toward increased age profiles when compared to 'never smokers' though this pattern was only striking in a portion of the samples screened. The predictive model described herein was built to offer researchers the ability to assess \"germ line age\" by accessing sperm DNA methylation signatures at genomic regions affected by age. Our data suggest that this model can predict an individual's chronological age with a high degree of accuracy regardless of fertility status and with a high degree of repeatability. Additionally, our data suggest that the aging process in sperm may be impacted by environmental factors, though this effect appears to be quite subtle and future work is needed to establish this relationship.", - "journal_title": "BMC genomics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/30348084/" - } - ], - "cc42391c-97ac-42df-a7c2-9b707d7fd238": [ - { - "pub_id": "32114984", - "title": "Epigenome-wide meta-analysis of blood DNA methylation in newborns and children identifies numerous loci related to gestational age.", - "authors": "Simon Kebede Merid,Alexei Novoloaca,Gemma C Sharp,Leanne K K\u00fcpers,Alvin T Kho,Ritu Roy,Lu Gao,Isabella Annesi-Maesano,Pooja Jain,Michelle Plusquin,Manolis Kogevinas,Catherine Allard,Florianne O Vehmeijer,Nabila Kazmi,Lucas A Salas,Faisal I Rezwan,Hongmei Zhang,Sylvain Sebert,Darina Czamara,Sheryl L Rifas-Shiman,Phillip E Melton,Debbie A Lawlor,G\u00f6ran Pershagen,Carrie V Breton,Karen Huen,Nour Baiz,Luigi Gagliardi,Tim S Nawrot,Eva Corpeleijn,Patrice Perron,Liesbeth Duijts,Ellen Aagaard Nohr,Mariona Bustamante,Susan L Ewart,Wilfried Karmaus,Shanshan Zhao,Christian M Page,Zdenko Herceg,Marjo-Riitta Jarvelin,Jari Lahti,Andrea A Baccarelli,Denise Anderson,Priyadarshini Kachroo,Caroline L Relton,Anna Bergstr\u00f6m,Brenda Eskenazi,Munawar Hussain Soomro,Paolo Vineis,Harold Snieder,Luigi Bouchard,Vincent W Jaddoe,Thorkild I A S\u00f8rensen,Martine Vrijheid,S Hasan Arshad,John W Holloway,Siri E H\u00e5berg,Per Magnus,Terence Dwyer,Elisabeth B Binder,Dawn L DeMeo,Judith M Vonk,John Newnham,Kelan G Tantisira,Inger Kull,Joseph L Wiemels,Barbara Heude,Jordi Sunyer,Wenche Nystad,Monica C Munthe-Kaas,Katri R\u00e4ikk\u00f6nen,Emily Oken,Rae-Chi Huang,Scott T Weiss,Josep Maria Ant\u00f3,Jean Bousquet,Ashish Kumar,Cilla S\u00f6derh\u00e4ll,Catarina Almqvist,Andres Cardenas,Olena Gruzieva,Cheng-Jian Xu,Sarah E Reese,Juha Kere,Petter Brodin,Olivia Solomon,Matthias Wielscher,Nina Holland,Akram Ghantous,Marie-France Hivert,Janine F Felix,Gerard H Koppelman,Stephanie J London,Erik Mel\u00e9n", - "abstract": "Preterm birth and shorter duration of pregnancy are associated with increased morbidity in neonatal and later life. As the epigenome is known to have an important role during fetal development, we investigated associations between gestational age and blood DNA methylation in children. We performed meta-analysis of Illumina's HumanMethylation450-array associations between gestational age and cord blood DNA methylation in 3648 newborns from 17 cohorts without common pregnancy complications, induced delivery or caesarean section. We also explored associations of gestational age with DNA methylation measured at 4-18\u2009years in additional pediatric cohorts. Follow-up analyses of DNA methylation and gene expression correlations were performed in cord blood. DNA methylation profiles were also explored in tissues relevant for gestational age health effects: fetal brain and lung. We identified 8899 CpGs in cord blood that were associated with gestational age (range 27-42\u2009weeks), at Bonferroni significance, P\u2009<\u20091.06\u2009\u00d7\u200910<sup>-\u20097</sup>, of which 3343 were novel. These were annotated to 4966 genes. After restricting findings to at least three significant adjacent CpGs, we identified 1276 CpGs annotated to 325 genes. Results were generally consistent when analyses were restricted to term births. Cord blood findings tended not to persist into childhood and adolescence. Pathway analyses identified enrichment for biological processes critical to embryonic development. Follow-up of identified genes showed correlations between gestational age and DNA methylation levels in fetal brain and lung tissue, as well as correlation with expression levels. We identified numerous CpGs differentially methylated in relation to gestational age at birth that appear to reflect fetal developmental processes across tissues. These findings may contribute to understanding mechanisms linking gestational age to health effects.", - "journal_title": "Genome medicine", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/32114984/" - } - ], - "1e92aeb2-376b-48da-87b1-21e29b31a863": [ - { - "pub_id": "30894217", - "title": "Transcriptome-wide analysis of differentially expressed chemokine receptors, SNPs, and SSRs in the age-related macular degeneration.", - "authors": "Madhu Sudhana Saddala,Anton Lennikov,Anthony Mukwaya,Lijuan Fan,Zhengmao Hu,Hu Huang", - "abstract": "Age-related macular degeneration (AMD) is the most common, progressive, and polygenic cause of irreversible visual impairment in the world. The molecular pathogenesis of the primary events of AMD is poorly understood. We have investigated a transcriptome-wide analysis of differential gene expression, single-nucleotide polymorphisms (SNPs), indels, and simple sequence repeats (SSRs) in datasets of the human peripheral retina and RPE-choroid-sclera control and AMD. Adaptors and unbiased components were removed and checked to ensure the quality of the data sets. Molecular function, biological process, cellular component, and pathway analyses were performed on differentially expressed genes. Analysis of the gene expression datasets identified 5011 upregulated genes, 11,800 downregulated genes, 42,016 SNPs, 1141 indels, and 6668 SRRs between healthy controls and AMD donor material. Enrichment categories for gene ontology included chemokine activity, cytokine activity, cytokine receptor binding, immune system process, and signal transduction respectively. A functional pathways analysis identified that chemokine receptors bind chemokines, complement cascade genes, and create cytokine signaling in immune system pathway genes (p value <\u20090.001). Finally, allele-specific expression was found to be significant for Chemokine (C-C motif) ligand (CCL) 2, 3, 4, 13, 19, 21; C-C chemokine receptor (CCR) 1, 5; chemokine (C-X-C motif) ligand (CXCL) 9, 10, 16; C-X-C chemokine receptor type (CXCR) 6; as well as atypical chemokine receptor (ACKR) 3,4 and pro-platelet basic protein (PPBP). Our results improve our overall understanding of the chemokine receptors' signaling pathway in AMD conditions, which may lead to potential new diagnostic and therapeutic targets.", - "journal_title": "Human genomics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/30894217/" - } - ], - "a7f21808-dce3-4110-8e7c-ceb2437e72ff": [ - { - "pub_id": "28209587", - "title": "Genome surgery using Cas9 ribonucleoproteins for the treatment of age-related macular degeneration.", - "authors": "Kyoungmi Kim,Sung Wook Park,Jin Hyoung Kim,Seung Hwan Lee,Daesik Kim,Taeyoung Koo,Kwang-Eun Kim,Jeong Hun Kim,Jin-Soo Kim", - "abstract": "RNA-guided genome surgery using CRISPR-Cas9 nucleases has shown promise for the treatment of diverse genetic diseases. Yet, the potential of such nucleases for therapeutic applications in nongenetic diseases is largely unexplored. Here, we focus on age-related macular degeneration (AMD), a leading cause of blindness in adults, which is associated with retinal overexpression of, rather than mutations in, the <i>VEGFA</i> gene. Subretinal injection of preassembled, <i>Vegfa</i> gene-specific Cas9 ribonucleoproteins (RNPs) into the adult mouse eye gave rise to mutagenesis at the target site in the retinal pigment epithelium. Furthermore, Cas9 RNPs effectively reduced the area of laser-induced choroidal neovascularization (CNV) in a mouse model of AMD. Genome-wide profiling of Cas9 off-target effects via Digenome-seq showed that off-target mutations were rarely induced in the human genome. Because Cas9 RNPs can function immediately after in vivo delivery and are rapidly degraded by endogenous proteases, their activities are unlikely to be hampered by antibody- and cell-mediated adaptive immune systems. Our results demonstrate that in vivo genome editing with Cas9 RNPs has the potential for the local treatment for nongenetic degenerative diseases, expanding the scope of RNA-guided genome surgery to a new dimension.", - "journal_title": "Genome research", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/28209587/" - } - ], - "3221196c-3a63-4cb3-9d8b-c16b755375ff": [ - { - "pub_id": "37596440", - "title": "Dynamic 3D genome reorganization during senescence: defining cell states through chromatin.", - "authors": "Haitham A Shaban,Susan M Gasser", - "abstract": "Cellular senescence, a cell state characterized by growth arrest and insensitivity to growth stimulatory hormones, is accompanied by a massive change in chromatin organization. Senescence can be induced by a range of physiological signals and pathological stresses and was originally thought to be an irreversible state, implicated in normal development, wound healing, tumor suppression and aging. Recently cellular senescence was shown to be reversible in some cases, with exit being triggered by the modulation of the cell's transcriptional program by the four Yamanaka factors, the suppression of p53 or H3K9me3, PDK1, and/or depletion of AP-1. Coincident with senescence reversal are changes in chromatin organization, most notably the loss of senescence-associated heterochromatin foci (SAHF) found in oncogene-induced senescence. In addition to fixed-cell imaging, chromatin conformation capture and multi-omics have been used to examine chromatin reorganization at different spatial resolutions during senescence. They identify determinants of SAHF formation and other key features that differentiate distinct types of senescence. Not surprisingly, multiple factors, including the time of induction, the type of stress experienced, and the type of cell involved, influence the global reorganization of chromatin in senescence. Here we discuss how changes in the three-dimensional organization of the genome contribute to the regulation of transcription at different stages of senescence. In particular, the distinct contributions of heterochromatin- and lamina-mediated interactions, changes in gene expression, and other cellular control mechanisms are discussed. We propose that high-resolution temporal and spatial analyses of the chromatin landscape during senescence will identify early markers of the different senescence states to help guide clinical diagnosis.", - "journal_title": "Cell death and differentiation", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/37596440/" - } - ], - "58f36772-b82e-437e-a5dd-2442277089f5": [ - { - "pub_id": "27663196", - "title": "Variation of global DNA methylation levels with age and in autistic children.", - "authors": "Shui-Ying Tsang,Tanveer Ahmad,Flora W K Mat,Cunyou Zhao,Shifu Xiao,Kun Xia,Hong Xue", - "abstract": "The change in epigenetic signatures, in particular DNA methylation, has been proposed as risk markers for various age-related diseases. However, the course of variation in methylation levels with age, the difference in methylation between genders, and methylation-disease association at the whole genome level is unclear. In the present study, genome-wide methylation levels in DNA extracted from peripheral blood for 2116 healthy Chinese in the 2-97 age range and 280 autistic trios were examined using the fluorescence polarization-based genome-wide DNA methylation quantification method developed by us. Genome-wide or global DNA methylation levels proceeded through multiple phases of variation with age, consisting of a steady increase from age 2 to 25 (r\u2009=\u20090.382) and another rise from age 41 to 55 to reach a peak level of ~80\u00a0% (r\u2009=\u20090.265), followed by a sharp decrease to ~40\u00a0% in the mid-1970s (age 56 to 75; r\u2009=\u2009-0.395) and leveling off thereafter. Significant gender effect in methylation levels was observed only for the 41-55 age group in which methylation in females was significantly higher than in males (p\u2009=\u20090.010). In addition, global methylation level was significantly higher in autistic children than in age-matched healthy children (p\u2009<\u20090.001). The multiphasic nature of changes in global methylation levels with age was delineated, and investigation into the factors underlying this profile will be essential to a proper understanding of the aging process. Furthermore, this first report of global hypermethylation in autistic children also illustrates the importance of age-matched controls in characterization of disease-associated variations in DNA methylation.", - "journal_title": "Human genomics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/27663196/" - } - ], - "38971a48-9ad6-4719-b99b-b327ca12f543": [ - { - "pub_id": "32424311", - "title": "Phylogenetic tree building in the genomic age.", - "authors": "Paschalia Kapli,Ziheng Yang,Maximilian J Telford", - "abstract": "Knowing phylogenetic relationships among species is fundamental for many studies in biology. An accurate phylogenetic tree underpins our understanding of the major transitions in evolution, such as the emergence of new body plans or metabolism, and is key to inferring the origin of new genes, detecting molecular adaptation, understanding morphological character evolution and reconstructing demographic changes in recently diverged species. Although data are ever more plentiful and powerful analysis methods are available, there remain many challenges to reliable tree building. Here, we discuss the major steps of phylogenetic analysis, including identification of orthologous genes or proteins, multiple sequence alignment, and choice of substitution models and inference methodologies. Understanding the different sources of errors and the strategies to mitigate them is essential for assembling an accurate tree of life.", - "journal_title": "Nature reviews. Genetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/32424311/" - } - ], - "b014e368-d0d5-4eff-a9af-abd4a4ed6d29": [ - { - "pub_id": "28961822", - "title": "Human female meiosis revised: new insights into the mechanisms of chromosome segregation and aneuploidies from advanced genomics and time-lapse imaging.", - "authors": "Antonio Capalbo,Eva R Hoffmann,Danilo Cimadomo,Filippo Maria Ubaldi,Laura Rienzi", - "abstract": "The unbalanced transmission of chromosomes in human gametes and early preimplantation embryos causes aneuploidy, which is a major cause of infertility and pregnancy failure. A baseline of 20% of human oocytes are estimated to be aneuploid and this increases exponentially from 30 to 35 years, reaching on average 80% by 42 years. As a result, reproductive senescence in human females is predominantly determined by the accelerated decline in genetic quality of oocytes from 30 years of age. Understanding mechanisms of chromosome segregation and aneuploidies in the female germline is a crucial step towards the development of new diagnostic approaches and, possibly, for the development of therapeutic targets and molecules. Here, we have reviewed emerging mechanisms that may drive human aneuploidy, in particular the maternal age effect. We conducted a systematic search in PubMed Central of the primary literature from 1990 through 2016 following the PRISMA guidelines, using MeSH terms related to human aneuploidy. For model organism research, we conducted a literature review based on references in human oocytes manuscripts and general reviews related to chromosome segregation in meiosis and mitosis. Advances in genomic and imaging technologies are allowing unprecedented insight into chromosome segregation in human oocytes. This includes the identification of a novel chromosome segregation error, termed reverse segregation, as well as sister kinetochore configurations that were not predicted based on murine models. Elucidation of mechanisms that result in errors in chromosome segregation in meiosis may lead to therapeutic developments that could improve reproductive outcomes by reducing aneuploidy.", - "journal_title": "Human reproduction update", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/28961822/" - } - ], - "f55a0a7f-aac4-4fa1-941a-0f929e779d9a": [ - { - "pub_id": "36037356", - "title": "Comparative genomics of mortal and immortal cnidarians unveils novel keys behind rejuvenation.", - "authors": "Maria Pascual-Torner,Dido Carrero,Jos\u00e9 G P\u00e9rez-Silva,Diana \u00c1lvarez-Puente,David Roiz-Valle,Gabriel Bretones,David Rodr\u00edguez,Daniel Maeso,Elena Mateo-Gonz\u00e1lez,Yaiza Espa\u00f1ol,Guillermo Mari\u00f1o,Jos\u00e9 Luis Acu\u00f1a,V\u00edctor Quesada,Carlos L\u00f3pez-Ot\u00edn", - "abstract": "<i>Turritopsis dohrnii</i> is the only metazoan able to rejuvenate repeatedly after its medusae reproduce, hinting at biological immortality and challenging our understanding of aging. We present and compare whole-genome assemblies of <i>T. dohrnii</i> and the nonimmortal <i>Turritopsis rubra</i> using automatic and manual annotations, together with the transcriptome of life cycle reversal (LCR) process of <i>T. dohrnii.</i> We have identified variants and expansions of genes associated with replication, DNA repair, telomere maintenance, redox environment, stem cell population, and intercellular communication. Moreover, we have found silencing of polycomb repressive complex 2 targets and activation of pluripotency targets during LCR, which points to these transcription factors as pluripotency inducers in <i>T. dohrnii</i>. Accordingly, we propose these factors as key elements in the ability of <i>T. dohrnii</i> to undergo rejuvenation.", - "journal_title": "Proceedings of the National Academy of Sciences of the United States of America", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/36037356/" - } - ], - "a538ceb8-32c0-49d2-ace9-6f949f94b6fc": [ - { - "pub_id": "31980526", - "title": "Precision medicine integrating whole-genome sequencing, comprehensive metabolomics, and advanced imaging.", - "authors": "Ying-Chen Claire Hou,Hung-Chun Yu,Rick Martin,Elizabeth T Cirulli,Natalie M Schenker-Ahmed,Michael Hicks,Isaac V Cohen,Thomas J J\u00f6nsson,Robyn Heister,Lori Napier,Christine Leon Swisher,Saints Dominguez,Haibao Tang,Weizhong Li,Bradley A Perkins,Jaime Barea,Christina Rybak,Emily Smith,Keegan Duchicela,Michael Doney,Pamila Brar,Nathaniel Hernandez,Ewen F Kirkness,Andrew M Kahn,J Craig Venter,David S Karow,C Thomas Caskey", - "abstract": "Genome sequencing has established clinical utility for rare disease diagnosis. While increasing numbers of individuals have undergone elective genome sequencing, a comprehensive study surveying genome-wide disease-associated genes in adults with deep phenotyping has not been reported. Here we report the results of a 3-y precision medicine study with a goal to integrate whole-genome sequencing with deep phenotyping. A cohort of 1,190 adult participants (402 female [33.8%]; mean age, 54 y [range 20 to 89+]; 70.6% European) had whole-genome sequencing, and were deeply phenotyped using metabolomics, advanced imaging, and clinical laboratory tests in addition to family/medical history. Of 1,190 adults, 206 (17.3%) had at least 1 genetic variant with pathogenic (P) or likely pathogenic (LP) assessment that suggests a predisposition of genetic risk. A multidisciplinary clinical team reviewed all reportable findings for the assessment of genotype and phenotype associations, and 137 (11.5%) had genotype and phenotype associations. A high percentage of genotype and phenotype associations (>75%) was observed for dyslipidemia (<i>n</i> = 24), cardiomyopathy, arrhythmia, and other cardiac diseases (<i>n</i> = 42), and diabetes and endocrine diseases (<i>n</i> = 17). A lack of genotype and phenotype associations, a potential burden for patient care, was observed in 69 (5.8%) individuals with P/LP variants. Genomics and metabolomics associations identified 61 (5.1%) heterozygotes with phenotype manifestations affecting serum metabolite levels in amino acid, lipid and cofactor, and vitamin pathways. Our descriptive analysis provides results on the integration of whole-genome sequencing and deep phenotyping for clinical assessments in adults.", - "journal_title": "Proceedings of the National Academy of Sciences of the United States of America", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/31980526/" - } - ], - "9fb05e3b-1422-48f7-8db9-8476336accdb": [ - { - "pub_id": "28351387", - "title": "Dietary restriction protects from age-associated DNA methylation and induces epigenetic reprogramming of lipid metabolism.", - "authors": "Oliver Hahn,Sebastian Gr\u00f6nke,Thomas M Stubbs,Gabriella Ficz,Oliver Hendrich,Felix Krueger,Simon Andrews,Qifeng Zhang,Michael J Wakelam,Andreas Beyer,Wolf Reik,Linda Partridge", - "abstract": "Dietary restriction (DR), a reduction in food intake without malnutrition, increases most aspects of health during aging and extends lifespan in diverse species, including rodents. However, the mechanisms by which DR interacts with the aging process to improve health in old age are poorly understood. DNA methylation could play an important role in mediating the effects of DR because it is sensitive to the effects of nutrition and can affect gene expression memory over time. Here, we profile genome-wide changes in DNA methylation, gene expression and lipidomics in response to DR and aging in female mouse liver. DR is generally strongly protective against age-related changes in DNA methylation. During aging with DR, DNA methylation becomes targeted to gene bodies and is associated with reduced gene expression, particularly of genes involved in lipid metabolism. The lipid profile of the livers of DR mice is correspondingly shifted towards lowered triglyceride content and shorter chain length of triglyceride-associated fatty acids, and these effects become more pronounced with age. Our results indicate that DR remodels genome-wide patterns of DNA methylation so that age-related changes are profoundly delayed, while changes at loci involved in lipid metabolism affect gene expression and the resulting lipid profile.", - "journal_title": "Genome biology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/28351387/" - } - ], - "4d871970-9d84-47e8-8de3-66fd0d7d5b8b": [ - { - "pub_id": "30355081", - "title": "Epigenetic Modifications in Cardiovascular Aging and Diseases.", - "authors": "Weiqi Zhang,Moshi Song,Jing Qu,Guang-Hui Liu", - "abstract": "Aging is associated with a progressive decline in cardiovascular structure and function. Accumulating evidence links cardiovascular aging to epigenetic alterations encompassing a complex interplay of DNA methylation, histone posttranslational modifications, and dynamic nucleosome occupancy governed by numerous epigenetic factors. Advances in genomics technology have led to a profound understanding of chromatin reorganization in both cardiovascular aging and diseases. This review summarizes recent discoveries in epigenetic mechanisms involved in cardiovascular aging and diseases and discusses potential therapeutic strategies to retard cardiovascular aging and conquer related diseases through the rejuvenation of epigenetic signatures to a young state.", - "journal_title": "Circulation research", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/30355081/" - } - ], - "a8c4b4d7-b31d-46cc-9676-a2123b975428": [ - { - "pub_id": "35420638", - "title": "Expansion of Cancer Risk Profile for BRCA1 and BRCA2 Pathogenic Variants.", - "authors": "Yukihide Momozawa,Rumi Sasai,Yoshiaki Usui,Kouya Shiraishi,Yusuke Iwasaki,Yukari Taniyama,Michael T Parsons,Keijiro Mizukami,Yuya Sekine,Makoto Hirata,Yoichiro Kamatani,Mikiko Endo,Chihiro Inai,Sadaaki Takata,Hidemi Ito,Takashi Kohno,Koichi Matsuda,Seigo Nakamura,Kokichi Sugano,Teruhiko Yoshida,Hidewaki Nakagawa,Keitaro Matsuo,Yoshinori Murakami,Amanda B Spurdle,Michiaki Kubo", - "abstract": "The clinical importance of genetic testing of BRCA1 and BRCA2 in breast, ovarian, prostate, and pancreatic cancers is widely recognized. However, there is insufficient evidence to include other cancer types that are potentially associated with BRCA1 and BRCA2 in clinical management guidelines. To evaluate the association of BRCA1 and BRCA2 pathogenic variants with additional cancer types and their clinical characteristics in 100\u202f914 individuals across 14 cancer types. This case-control analysis to identify cancer types and clinical characteristics associated with pathogenic variants in BRCA1 and BRCA2 included DNA samples and clinical information from 63\u202f828 patients with 14 common cancer types and 37\u202f086 controls that were sourced from a multi-institutional hospital-based registry, BioBank Japan, between April 2003 and March 2018. The data were analyzed between August 2019 and October 2021. Germline pathogenic variants in coding regions and 2 bp flanking intronic sequences in BRCA1 and BRCA2 were identified by a multiplex polymerase chain reaction-based target sequence method. Associations of (likely) pathogenic variants with each cancer type were assessed by comparing pathogenic variant carrier frequency between patients in each cancer type and controls. A total of 65\u202f108 patients (mean [SD] age at diagnosis, 64.1 [11.6] years; 27 531 [42.3%] female) and 38 153 controls (mean [SD] age at registration, 61.8 [14.6] years; 17\u202f911 [46.9%] female) were included in this study. A total of 315 unique pathogenic variants were identified. Pathogenic variants were associated with P\u2009<\u20091\u2009\u00d7\u200910-4 with an odds ratio (OR) of greater than 4.0 in biliary tract cancer (OR, 17.4; 95% CI, 5.8-51.9) in BRCA1, esophageal cancer (OR, 5.6; 95% CI, 2.9-11.0) in BRCA2, and gastric cancer (OR, 5.2; 95% CI, 2.6-10.5) in BRCA1, and (OR, 4.7; 95% CI, 3.1-7.1) in BRCA2 in addition to the 4 established cancer types. We also observed an association with 2 and 4 other cancer types in BRCA1 and BRCA2, respectively. Biliary tract, female breast, ovarian, and prostate cancers showed enrichment of carrier patients according to the increased number of reported cancer types in relatives. The results of this large-scale registry-based case-control study suggest that pathogenic variants in BRCA1 and BRCA2 were associated with the risk of 7 cancer types. These results indicate broader clinical relevance of BRCA1 and BRCA2 genetic testing.", - "journal_title": "JAMA oncology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/35420638/" - } - ], - "27b471ec-acc3-4624-9050-57516328da07": [ - { - "pub_id": "32483115", - "title": "Ancient genomes from northern China suggest links between subsistence changes and human migration.", - "authors": "Chao Ning,Tianjiao Li,Ke Wang,Fan Zhang,Tao Li,Xiyan Wu,Shizhu Gao,Quanchao Zhang,Hai Zhang,Mark J Hudson,Guanghui Dong,Sihao Wu,Yanming Fang,Chen Liu,Chunyan Feng,Wei Li,Tao Han,Ruo Li,Jian Wei,Yonggang Zhu,Yawei Zhou,Chuan-Chao Wang,Shengying Fan,Zenglong Xiong,Zhouyong Sun,Maolin Ye,Lei Sun,Xiaohong Wu,Fawei Liang,Yanpeng Cao,Xingtao Wei,Hong Zhu,Hui Zhou,Johannes Krause,Martine Robbeets,Choongwon Jeong,Yinqiu Cui", - "abstract": "Northern China harbored the world's earliest complex societies based on millet farming, in two major centers in the Yellow (YR) and West Liao (WLR) River basins. Until now, their genetic histories have remained largely unknown. Here we present 55 ancient genomes dating to 7500-1700 BP from the YR, WLR, and Amur River (AR) regions. Contrary to the genetic stability in the AR, the YR and WLR genetic profiles substantially changed over time. The YR populations show a monotonic increase over time in their genetic affinity with present-day southern Chinese and Southeast Asians. In the\u00a0WLR, intensification of farming in the Late Neolithic is correlated with increased YR affinity while the inclusion of a pastoral economy in the Bronze Age was correlated with increased AR affinity. Our results suggest a link between changes in subsistence strategy and human migration, and fuel the debate about archaeolinguistic signatures of past human migration.", - "journal_title": "Nature communications", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/32483115/" - } - ], - "896b3cbd-0799-4305-9acd-79f163e2bdff": [ - { - "pub_id": "35366793", - "title": "Predict the role of lncRNA in kidney aging based on RNA sequencing.", - "authors": "Jie Li,Fanfan Gao,Limin Wei,Lei Chen,Ning Qu,Lu Zeng,Yulong Luo,Xinmei Huang,Hongli Jiang", - "abstract": "Long noncoding RNAs (lncRNAs) are involved in physiological and pathological processes. However, no studies have been conducted on the relationship between lncRNAs and renal aging. First, we evaluated the histopathology of young (3-month-old) and old (24-month-old) C57BL/6J mouse kidneys. Masson trichrome staining and PAS staining showed interstitial collagen deposition and fibrosis, mesangial matrix expansion, a thicker basement membrane and renal interstitial fibrosis in old mouse kidneys. Senescence-associated \u03b2-galactosidase (SA-\u03b2-gal)-positive areas in the kidneys of old mice were significantly elevated compared to those of young mice. Then, we analyzed the differential expression of lncRNAs and mRNAs in the kidneys of young and old mouse kidneys by RNA-seq analysis. 42 known and 179 novel differentially expressed lncRNAs and 702 differential mRNAs were detected in the mouse kidney. Next, we focused on the differentially expressed mRNAs and lncRNAs by RNA-seq.\u00a0GO and KEGG analyses were performed based on differentially expressed mRNAs between young and old mouse kidneys. Transregulation based on RIsearch and the correlation coefficient of mRNA-lncRNA were also calculated. The mRNA-lncRNA network was constructed by choosing a Spearman correlation coefficient\u2009>\u20090.9 or <-0.9. GO and KEGG pathway enrichment analyses revealed that differentially expressed mRNAs participated in aging-related pathways. A total of 10 lncRNAs and trans-regulated mRNAs were constructed. Finally, we validated the role of lncRNA Gm43360 by CCK-8, flow cytometry, western blot and SA-\u03b2-gal staining. The expression level of Adra1a was positively correlated and Csnk1a1 was negatively correlated with lncRNA Gm43360. The cell counting kit-8 (CCK-8) results showed that lncRNA Gm43360 promoted cell viability. LncRNA Gm43360 increased the percentage of S phase cells and decreased the percentage of G1 phase cells compared with the negative control. LncRNA Gm43360 decreased the expression of p53, p21 and SA-\u03b2-gal. LncRNA Gm43360 may play a protective role in kidney aging.", - "journal_title": "BMC genomics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/35366793/" - } - ], - "29d09d03-fd2f-48b3-a020-ea574d583dc4": [ - { - "pub_id": "33401659", - "title": "Epigenetics of Aging and Aging-Associated Diseases.", - "authors": "Dominik Saul,Robyn Laura Kosinsky", - "abstract": "Aging represents the multifactorial decline in physiological function of every living organism. Over the past decades, several hallmarks of aging have been defined, including epigenetic deregulation. Indeed, multiple epigenetic events were found altered across different species during aging. Epigenetic changes directly contributing to aging and aging-related diseases include the accumulation of histone variants, changes in chromatin accessibility, loss of histones and heterochromatin, aberrant histone modifications, and deregulated expression/activity of miRNAs. As a consequence, cellular processes are affected, which results in the development or progression of several human pathologies, including cancer, diabetes, osteoporosis, and neurodegenerative disorders. In this review, we focus on epigenetic mechanisms underlying aging-related processes in various species and describe how these deregulations contribute to human diseases.", - "journal_title": "International journal of molecular sciences", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/33401659/" - } - ], - "98725edc-19e7-4bbc-bf28-7566de590791": [ - { - "pub_id": "30651069", - "title": "RiboTag translatomic profiling of Drosophila oenocytes under aging and induced oxidative stress.", - "authors": "Kerui Huang,Wenhao Chen,Fang Zhu,Patrick Wai-Lun Li,Pankaj Kapahi,Hua Bai", - "abstract": "Aging is accompanied with loss of tissue homeostasis and accumulation of cellular damages. As one of the important metabolic centers, liver shows age-related dysregulation of lipid metabolism, impaired detoxification pathway, increased inflammation and oxidative stress response. However, the mechanisms for these age-related changes still remain unclear. In the fruit fly, Drosophila melanogaster, liver-like functions are controlled by two distinct tissues, fat body and oenocytes. Compared to fat body, little is known about how oenocytes age and what are their roles in aging regulation. To characterize age- and stress-regulated gene expression in oenocytes, we performed cell-type-specific ribosome profiling (RiboTag) to examine the impacts of aging and oxidative stress on oenocyte translatome in Drosophila. We show that aging and oxidant paraquat significantly increased the levels of reactive oxygen species (ROS) in adult oenocytes of Drosophila, and aged oenocytes exhibited reduced sensitivity to paraquat treatment. Through RiboTag sequencing, we identified 3324 and 949 differentially expressed genes in oenocytes under aging and paraquat treatment, respectively. Aging and paraquat exhibit both shared and distinct regulations on oenocyte translatome. Among all age-regulated genes, oxidative phosphorylation, ribosome, proteasome, fatty acid metabolism, and cytochrome P450 pathways were down-regulated, whereas DNA replication and immune response pathways were up-regulated. In addition, most of the peroxisomal genes were down-regulated in aged oenocytes, including genes involved in peroxisomal biogenesis factors and fatty acid beta-oxidation. Many age-related mRNA translational changes in oenocytes are similar to aged mammalian liver, such as up-regulation of innate immune response and Ras/MAPK signaling pathway and down-regulation of peroxisome and fatty acid metabolism. Furthermore, oenocytes highly expressed genes involving in liver-like processes (e.g., ketogenesis). Our oenocyte-specific translatome analysis identified many genes and pathways that are shared between Drosophila oenocytes and mammalian liver, highlighting the molecular and functional similarities between the two tissues. Many of these genes were altered in both oenocytes and liver during aging. Thus, our translatome analysis provide important genomic resource for future dissection of oenocyte function and its role in lipid metabolism, stress response and aging regulation.", - "journal_title": "BMC genomics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/30651069/" - } - ], - "b4e5d2bd-8a65-4315-a13b-9376cebed8a8": [ - { - "pub_id": "30108127", - "title": "A Large Multiethnic Genome-Wide Association Study of Adult Body Mass Index Identifies Novel Loci.", - "authors": "Thomas J Hoffmann,H\u00e9l\u00e8ne Choquet,Jie Yin,Yambazi Banda,Mark N Kvale,Maria Glymour,Catherine Schaefer,Neil Risch,Eric Jorgenson", - "abstract": "Body mass index (BMI), a proxy measure for obesity, is determined by both environmental (including ethnicity, age, and sex) and genetic factors, with > 400 BMI-associated loci identified to date. However, the impact, interplay, and underlying biological mechanisms among BMI, environment, genetics, and ancestry are not completely understood. To further examine these relationships, we utilized 427,509 calendar year-averaged BMI measurements from 100,418 adults from the single large multiethnic Genetic Epidemiology Research on Adult Health and Aging (GERA) cohort. We observed substantial independent ancestry and nationality differences, including ancestry principal component interactions and nonlinear effects. To increase the list of BMI-associated variants before assessing other differences, we conducted a genome-wide association study (GWAS) in GERA, with replication in the Genetic Investigation of Anthropomorphic Traits (GIANT) consortium combined with the UK Biobank (UKB), followed by GWAS in GERA combined with GIANT, with replication in the UKB. We discovered 30 novel independent BMI loci (<i>P</i> < 5.0 \u00d7 10<sup>-8</sup>) that replicated. We then assessed the proportion of BMI variance explained by sex in the UKB using previously identified loci compared to previously and newly identified loci and found slight increases: from 3.0 to 3.3% for males and from 2.7 to 3.0% for females. Further, the variance explained by previously and newly identified variants decreased with increasing age in the GERA and UKB cohorts, echoed in the variance explained by the entire genome, which also showed gene-age interaction effects. Finally, we conducted a tissue expression QTL enrichment analysis, which revealed that GWAS BMI-associated variants were enriched in the cerebellum, consistent with prior work in humans and mice.", - "journal_title": "Genetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/30108127/" - } - ], - "9919b119-c026-4b78-9b56-ba54239834b3": [ - { - "pub_id": "32444850", - "title": "Visualizing and interpreting cancer genomics data via the Xena platform.", - "authors": "Mary J Goldman,Brian Craft,Mim Hastie,Kristupas Repe\u010dka,Fran McDade,Akhil Kamath,Ayan Banerjee,Yunhai Luo,Dave Rogers,Angela N Brooks,Jingchun Zhu,David Haussler", - "abstract": "", - "journal_title": "Nature biotechnology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/32444850/" - } - ], - "1ac23aae-2a51-4846-81ec-6db70ab6e5a4": [ - { - "pub_id": "28575157", - "title": "Sex Differences in Aging: Genomic Instability.", - "authors": "Kathleen E Fischer,Nicole C Riddle", - "abstract": "Aging is characterized by decreasing physiological integration, reduced function, loss of resilience, and increased risk of death. Paradoxically, although women live longer, they suffer greater morbidity particularly late in life. These sex differences in human lifespan and healthspan are consistently observed in all countries and during every era for which reliable data exist. While these differences are ubiquitous in humans, evidence of sex differences in longevity and health for other species is more equivocal. Among fruit flies, nematodes, and mice, sex differences in lifespan vary depending on strain and treatment. In this review, we focus on sex differences in age-related alterations in DNA damage and mutation rates, telomere attrition, epigenetics, and nuclear architecture. We find that robust sex differences exist, eg, the higher incidence of DNA damage in men compared to women, but sex differences are not often conserved between species. For most mechanisms reviewed here, there are insufficient data to make a clear determination regarding the impact of sex, largely because sex differences have not been analyzed. Overall, our findings reveal an urgent need for well-designed studies that explicitly examine sex differences in molecular drivers of aging.", - "journal_title": "The journals of gerontology. Series A, Biological sciences and medical sciences", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/28575157/" - } - ], - "78e2b7dd-40e5-4e23-b696-49b9ef950486": [ - { - "pub_id": "31257224", - "title": "Integrated multi-omics analysis of genomics, epigenomics, and transcriptomics in ovarian carcinoma.", - "authors": "Mingjun Zheng,Yuexin Hu,Rui Gou,Jing Wang,Xin Nie,Xiao Li,Qing Liu,Juanjuan Liu,Bei Lin", - "abstract": "In this study, we identified prognostic biomarkers in ovarian carcinoma by integrating multi-omics DNA copy number variation (CNV) and methylation variation (MET) data. CNV, MET, and messenger RNA (mRNA) expression were examined in 351 ovarian carcinoma patients. Genes for which expression was correlated with DNA copy-number or DNA methylation were identified; three ovarian carcinoma gene subtypes were defined based on these correlations. Overall survival and B cell scores were lower, while the macrophage cell score was higher, in the DNA imprinting centre 1 (iC1) subtype than in the iC2 and iC3 subtypes. Comparison of CNV, MET, and mRNA expression among the subtypes identified two genes, ubiquitin B (UBB) and interleukin 18 binding protein (IL18BP), that were associated with prognosis. Mutation spectrum results based on subtype indicated that UBB and IL18BP expression may be influenced by mutation loci. Mutation levels were higher in iC1 samples than in iC2 or iC3 samples, indicating that the iC1 subtype is associated with disease progression. This integrated multi-omics analysis of genomics, epigenomics, and transcriptomics provides new insight into the molecular mechanisms of ovarian carcinoma and may help identify biomolecular markers for early disease diagnosis.", - "journal_title": "Aging", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/31257224/" - } - ], - "39613edb-cfdb-4103-8c9a-c90c1bc9f802": [ - { - "pub_id": "33402207", - "title": "N6-methyladenosine dynamics in neurodevelopment and aging, and its potential role in Alzheimer's disease.", - "authors": "Andrew M Shafik,Feiran Zhang,Zhenxing Guo,Qing Dai,Kinga Pajdzik,Yangping Li,Yunhee Kang,Bing Yao,Hao Wu,Chuan He,Emily G Allen,Ranhui Duan,Peng Jin", - "abstract": "N6-methyladenosine (m<sup>6</sup>A) modification is known to impact many aspects of RNA metabolism, including mRNA stability and translation, and is highly prevalent in the brain. We show that m<sup>6</sup>A modification displays temporal and spatial dynamics during neurodevelopment and aging. Genes that are temporally differentially methylated are more prone to have mRNA expression changes and affect many pathways associated with nervous system development. Furthermore, m<sup>6</sup>A shows a distinct tissue-specific methylation profile, which is most pronounced in the hypothalamus. Tissue-specific methylation is associated with an increase in mRNA expression and is associated with tissue-specific developmental processes. During the aging process, we observe significantly more m<sup>6</sup>A sites as age increases, in both mouse and human. We show a high level of overlap between mouse and human; however, humans at both young and old ages consistently show more m<sup>6</sup>A sites compared to mice. Differential m<sup>6</sup>A sites are found to be enriched in alternative untranslated regions of genes that affect aging-related pathways. These m<sup>6</sup>A sites are associated with a strong negative effect on mRNA expression. We also show that many Alzheimer-related transcripts exhibit decreased m<sup>6</sup>A methylation in a mouse model of Alzheimer's disease, which is correlated with reduced protein levels. Our results suggest that m<sup>6</sup>A exerts a critical function in both early and late brain development in a spatio-temporal fashion. Furthermore, m<sup>6</sup>A controls protein levels of key genes involved in Alzheimer's disease-associated pathways, suggesting that m<sup>6</sup>A plays an important role in aging and neurodegenerative disease.", - "journal_title": "Genome biology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/33402207/" - } - ], - "9ca7f8e9-056f-498b-a932-f94d6936eb3b": [ - { - "pub_id": "30820047", - "title": "Genetic meta-analysis of diagnosed Alzheimer's disease identifies new risk loci and implicates A\u03b2, tau, immunity and lipid processing.", - "authors": "Brian W Kunkle,Benjamin Grenier-Boley,Rebecca Sims,Joshua C Bis,Vincent Damotte,Adam C Naj,Anne Boland,Maria Vronskaya,Sven J van der Lee,Alexandre Amlie-Wolf,C\u00e9line Bellenguez,Aura Frizatti,Vincent Chouraki,Eden R Martin,Kristel Sleegers,Nandini Badarinarayan,Johanna Jakobsdottir,Kara L Hamilton-Nelson,Sonia Moreno-Grau,Robert Olaso,Rachel Raybould,Yuning Chen,Amanda B Kuzma,Mikko Hiltunen,Taniesha Morgan,Shahzad Ahmad,Badri N Vardarajan,Jacques Epelbaum,Per Hoffmann,Merce Boada,Gary W Beecham,Jean-Guillaume Garnier,Denise Harold,Annette L Fitzpatrick,Otto Valladares,Marie-Laure Moutet,Amy Gerrish,Albert V Smith,Liming Qu,Delphine Bacq,Nicola Denning,Xueqiu Jian,Yi Zhao,Maria Del Zompo,Nick C Fox,Seung-Hoan Choi,Ignacio Mateo,Joseph T Hughes,Hieab H Adams,John Malamon,Florentino Sanchez-Garcia,Yogen Patel,Jennifer A Brody,Beth A Dombroski,Maria Candida Deniz Naranjo,Makrina Daniilidou,Gudny Eiriksdottir,Shubhabrata Mukherjee,David Wallon,James Uphill,Thor Aspelund,Laura B Cantwell,Fabienne Garzia,Daniela Galimberti,Edith Hofer,Mariusz Butkiewicz,Bertrand Fin,Elio Scarpini,Chloe Sarnowski,Will S Bush,St\u00e9phane Meslage,Johannes Kornhuber,Charles C White,Yuenjoo Song,Robert C Barber,Sebastiaan Engelborghs,Sabrina Sordon,Dina Voijnovic,Perrie M Adams,Rik Vandenberghe,Manuel Mayhaus,L Adrienne Cupples,Marilyn S Albert,Peter P De Deyn,Wei Gu,Jayanadra J Himali,Duane Beekly,Alessio Squassina,Annette M Hartmann,Adelina Orellana,Deborah Blacker,Eloy Rodriguez-Rodriguez,Simon Lovestone,Melissa E Garcia,Rachelle S Doody,Carmen Munoz-Fernadez,Rebecca Sussams,Honghuang Lin,Thomas J Fairchild,Yolanda A Benito,Clive Holmes,Hata Karamuji\u0107-\u010comi\u0107,Matthew P Frosch,Hakan Thonberg,Wolfgang Maier,Gennady Roshchupkin,Bernardino Ghetti,Vilmantas Giedraitis,Amit Kawalia,Shuo Li,Ryan M Huebinger,Lena Kilander,Susanne Moebus,Isabel Hern\u00e1ndez,M Ilyas Kamboh,RoseMarie Brundin,James Turton,Qiong Yang,Mindy J Katz,Letizia Concari,Jenny Lord,Alexa S Beiser,C Dirk Keene,Seppo Helisalmi,Iwona Kloszewska,Walter A Kukull,Anne Maria Koivisto,Aoibhinn Lynch,Llu\u00eds Tarraga,Eric B Larson,Annakaisa Haapasalo,Brian Lawlor,Thomas H Mosley,Richard B Lipton,Vincenzo Solfrizzi,Michael Gill,W T Longstreth,Thomas J Montine,Vincenza Frisardi,Monica Diez-Fairen,Fernando Rivadeneira,Ronald C Petersen,Vincent Deramecourt,Ignacio Alvarez,Francesca Salani,Antonio Ciaramella,Eric Boerwinkle,Eric M Reiman,Nathalie Fievet,Jerome I Rotter,Joan S Reisch,Olivier Hanon,Chiara Cupidi,A G Andre Uitterlinden,Donald R Royall,Carole Dufouil,Raffaele Giovanni Maletta,Itziar de Rojas,Mary Sano,Alexis Brice,Roberta Cecchetti,Peter St George-Hyslop,Karen Ritchie,Magda Tsolaki,Debby W Tsuang,Bruno Dubois,David Craig,Chuang-Kuo Wu,Hilkka Soininen,Despoina Avramidou,Roger L Albin,Laura Fratiglioni,Antonia Germanou,Liana G Apostolova,Lina Keller,Maria Koutroumani,Steven E Arnold,Francesco Panza,Olymbia Gkatzima,Sanjay Asthana,Didier Hannequin,Patrice Whitehead,Craig S Atwood,Paolo Caffarra,Harald Hampel,In\u00e9s Quintela,\u00c1ngel Carracedo,Lars Lannfelt,David C Rubinsztein,Lisa L Barnes,Florence Pasquier,Lutz Fr\u00f6lich,Sandra Barral,Bernadette McGuinness,Thomas G Beach,Janet A Johnston,James T Becker,Peter Passmore,Eileen H Bigio,Jonathan M Schott,Thomas D Bird,Jason D Warren,Bradley F Boeve,Michelle K Lupton,James D Bowen,Petra Proitsi,Adam Boxer,John F Powell,James R Burke,John S K Kauwe,Jeffrey M Burns,Michelangelo Mancuso,Joseph D Buxbaum,Ubaldo Bonuccelli,Nigel J Cairns,Andrew McQuillin,Chuanhai Cao,Gill Livingston,Chris S Carlson,Nicholas J Bass,Cynthia M Carlsson,John Hardy,Regina M Carney,Jose Bras,Minerva M Carrasquillo,Rita Guerreiro,Mariet Allen,Helena C Chui,Elizabeth Fisher,Carlo Masullo,Elizabeth A Crocco,Charles DeCarli,Gina Bisceglio,Malcolm Dick,Li Ma,Ranjan Duara,Neill R Graff-Radford,Denis A Evans,Angela Hodges,Kelley M Faber,Martin Scherer,Kenneth B Fallon,Matthias Riemenschneider,David W Fardo,Reinhard Heun,Martin R Farlow,Heike K\u00f6lsch,Steven Ferris,Markus Leber,Tatiana M Foroud,Isabella Heuser,Douglas R Galasko,Ina Giegling,Marla Gearing,Michael H\u00fcll,Daniel H Geschwind,John R Gilbert,John Morris,Robert C Green,Kevin Mayo,John H Growdon,Thomas Feulner,Ronald L Hamilton,Lindy E Harrell,Dmitriy Drichel,Lawrence S Honig,Thomas D Cushion,Matthew J Huentelman,Paul Hollingworth,Christine M Hulette,Bradley T Hyman,Rachel Marshall,Gail P Jarvik,Alun Meggy,Erin Abner,Georgina E Menzies,Lee-Way Jin,Ganna Leonenko,Luis M Real,Gyungah R Jun,Clinton T Baldwin,Detelina Grozeva,Anna Karydas,Giancarlo Russo,Jeffrey A Kaye,Ronald Kim,Frank Jessen,Neil W Kowall,Bruno Vellas,Joel H Kramer,Emma Vardy,Frank M LaFerla,Karl-Heinz J\u00f6ckel,James J Lah,Martin Dichgans,James B Leverenz,David Mann,Allan I Levey,Stuart Pickering-Brown,Andrew P Lieberman,Norman Klopp,Kathryn L Lunetta,H-Erich Wichmann,Constantine G Lyketsos,Kevin Morgan,Daniel C Marson,Kristelle Brown,Frank Martiniuk,Christopher Medway,Deborah C Mash,Markus M N\u00f6then,Eliezer Masliah,Nigel M Hooper,Wayne C McCormick,Antonio Daniele,Susan M McCurry,Anthony Bayer,Andrew N McDavid,John Gallacher,Ann C McKee,Hendrik van den Bussche,Marsel Mesulam,Carol Brayne,Bruce L Miller,Steffi Riedel-Heller,Carol A Miller,Joshua W Miller,Ammar Al-Chalabi,John C Morris,Christopher E Shaw,Amanda J Myers,Jens Wiltfang,Sid O'Bryant,John M Olichney,Victoria Alvarez,Joseph E Parisi,Andrew B Singleton,Henry L Paulson,John Collinge,William R Perry,Simon Mead,Elaine Peskind,David H Cribbs,Martin Rossor,Aimee Pierce,Natalie S Ryan,Wayne W Poon,Benedetta Nacmias,Huntington Potter,Sandro Sorbi,Joseph F Quinn,Eleonora Sacchinelli,Ashok Raj,Gianfranco Spalletta,Murray Raskind,Carlo Caltagirone,Paola Boss\u00f9,Maria Donata Orfei,Barry Reisberg,Robert Clarke,Christiane Reitz,A David Smith,John M Ringman,Donald Warden,Erik D Roberson,Gordon Wilcock,Ekaterina Rogaeva,Amalia Cecilia Bruni,Howard J Rosen,Maura Gallo,Roger N Rosenberg,Yoav Ben-Shlomo,Mark A Sager,Patrizia Mecocci,Andrew J Saykin,Pau Pastor,Michael L Cuccaro,Jeffery M Vance,Julie A Schneider,Lori S Schneider,Susan Slifer,William W Seeley,Amanda G Smith,Joshua A Sonnen,Salvatore Spina,Robert A Stern,Russell H Swerdlow,Mitchell Tang,Rudolph E Tanzi,John Q Trojanowski,Juan C Troncoso,Vivianna M Van Deerlin,Linda J Van Eldik,Harry V Vinters,Jean Paul Vonsattel,Sandra Weintraub,Kathleen A Welsh-Bohmer,Kirk C Wilhelmsen,Jennifer Williamson,Thomas S Wingo,Randall L Woltjer,Clinton B Wright,Chang-En Yu,Lei Yu,Yasaman Saba,Alberto Pilotto,Maria J Bullido,Oliver Peters,Paul K Crane,David Bennett,Paola Bosco,Eliecer Coto,Virginia Boccardi,Phil L De Jager,Alberto Lleo,Nick Warner,Oscar L Lopez,Martin Ingelsson,Panagiotis Deloukas,Carlos Cruchaga,Caroline Graff,Rhian Gwilliam,Myriam Fornage,Alison M Goate,Pascual Sanchez-Juan,Patrick G Kehoe,Najaf Amin,Nilifur Ertekin-Taner,Claudine Berr,St\u00e9phanie Debette,Seth Love,Lenore J Launer,Steven G Younkin,Jean-Francois Dartigues,Chris Corcoran,M Arfan Ikram,Dennis W Dickson,Gael Nicolas,Dominique Campion,JoAnn Tschanz,Helena Schmidt,Hakon Hakonarson,Jordi Clarimon,Ron Munger,Reinhold Schmidt,Lindsay A Farrer,Christine Van Broeckhoven,Michael C O'Donovan,Anita L DeStefano,Lesley Jones,Jonathan L Haines,Jean-Francois Deleuze,Michael J Owen,Vilmundur Gudnason,Richard Mayeux,Valentina Escott-Price,Bruce M Psaty,Alfredo Ramirez,Li-San Wang,Agustin Ruiz,Cornelia M van Duijn,Peter A Holmans,Sudha Seshadri,Julie Williams,Phillippe Amouyel,Gerard D Schellenberg,Jean-Charles Lambert,Margaret A Pericak-Vance, , , , ", - "abstract": "Risk for late-onset Alzheimer's disease (LOAD), the most prevalent dementia, is partially driven by genetics. To identify LOAD risk loci, we performed a large genome-wide association meta-analysis of clinically diagnosed LOAD (94,437 individuals). We confirm 20 previous LOAD risk loci and identify five new genome-wide loci (IQCK, ACE, ADAM10, ADAMTS1, and WWOX), two of which (ADAM10, ACE) were identified in a recent genome-wide association (GWAS)-by-familial-proxy of Alzheimer's or dementia. Fine-mapping of the human leukocyte antigen (HLA) region confirms the neurological and immune-mediated disease haplotype HLA-DR15 as a risk factor for LOAD. Pathway analysis implicates immunity, lipid metabolism, tau binding proteins, and amyloid precursor protein (APP) metabolism, showing that genetic variants affecting APP and A\u03b2 processing are associated not only with early-onset autosomal dominant Alzheimer's disease but also with LOAD. Analyses of risk genes and pathways show enrichment for rare variants (P\u2009=\u20091.32\u2009\u00d7\u200910<sup>-7</sup>), indicating that additional rare variants remain to be identified. We also identify important genetic correlations between LOAD and traits such as family history of dementia and education.", - "journal_title": "Nature genetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/30820047/" - } - ], - "20b466c6-004b-484f-96a1-c1b4651bc856": [ - { - "pub_id": "30158665", - "title": "Y chromosome mosaicism is associated with age-related macular degeneration.", - "authors": "Felix Grassmann,Christina Kiel,Anneke I den Hollander,Daniel E Weeks,Andrew Lotery,Valentina Cipriani,Bernhard H F Weber, ", - "abstract": "Age-related macular degeneration (AMD) is the leading cause of blindness in industrialised countries, and thereby a major individual but also a socio-economic burden. Y chromosome loss in nucleated blood cells has been implicated in age-related diseases such as Alzheimer disease and was shown to be caused by increasing age, smoking and genetic factors. Mosaic loss of Y chromosome (mLOY) in peripheral blood was estimated from normalised dosages of genotyping chip data covering the male-specific region of the Y chromosome. After quality control, we assessed the association of mLOY on AMD risk in 5772 male cases and 6732 male controls. In controls the prevalence of mLOY increased significantly with age, which is consistent with previous reports. Importantly, mLOY was associated with late-stage AMD with genome-wide significance (OR: 1.332 [95% CI: 1.206; 1.472], P\u2009=\u20091.60e-08), independent of age, the AMD genetic risk score and the first two principle components of ancestry. Additionally conditioning on smoking behaviour had no influence on the observed association strength. mLOY was strongest associated in individuals aged between 65 and 75 years. Taken together, mLOY is significantly associated with risk for AMD, independent of known and potential confounding factors.", - "journal_title": "European journal of human genetics : EJHG", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/30158665/" - } - ], - "1a1132fa-f194-4b7d-b66d-5c8f97d84154": [ - { - "pub_id": "32249012", - "title": "Comprehensive assessment of PINK1 variants in Parkinson's disease.", - "authors": "Lynne Krohn,Francis P Grenn,Mary B Makarious,Jonggeol Jeffrey Kim,Sara Bandres-Ciga,Dorien A Roosen,Ziv Gan-Or,Mike A Nalls,Andrew B Singleton,Cornelis Blauwendraat, ", - "abstract": "Multiple genes have been associated with monogenic Parkinson's disease and Parkinsonism syndromes. Mutations in PINK1 (PARK6) have been shown to result in autosomal recessive early-onset Parkinson's disease. In the past decade, several studies have suggested that carrying a single heterozygous PINK1 mutation is associated with increased risk for Parkinson's disease. Here, we comprehensively assess the role of PINK1 variants in Parkinson's disease susceptibility using several large data sets totalling 376,558 individuals including 13,708 cases with Parkinson's disease and 362,850 control subjects. After combining these data, we did not find evidence to support a role for heterozygous PINK1 mutations as a robust risk factor for Parkinson's disease.", - "journal_title": "Neurobiology of aging", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/32249012/" - } - ], - "7194da7c-b022-4f43-9007-e057e6a53b0a": [ - { - "pub_id": "31829291", - "title": "Downregulation of miR-542-3p promotes osteogenic transition of vascular smooth muscle cells in the aging rat by targeting BMP7.", - "authors": "Huan Liu,Hongwei Wang,Sijin Yang,Dehui Qian", - "abstract": "Aging is believed to have a close association with cardiovascular diseases, resulting in various pathological alterations in blood vessels, including vascular cell phenotypic shifts. In aging vessels, the microRNA(miRNA)-mediated mechanism regulating the vascular smooth muscle cell (VSMC) phenotype remains unclarified. MiRNA microarray was used to compare the expressions of miRNAs in VSMCs from old rats (oVSMCs) and young rats (yVSMCs). Quantitative reverse transcription real-time PCR (qRT-PCR) and small RNA transfection were used to explore the miR-542-3p expression in oVSMCs and yVSMCs in vitro. Calcification induction of yVSMCs was conducted by the treatment of \u03b2-glycerophosphate (\u03b2-GP). Alizarin red staining was used to detect calcium deposition. Western blot and qRT-PCR were used to investigate the expression of the smooth muscle markers, smooth muscle 22\u03b1 (SM22\u03b1) and calponin, and the osteogenic markers, osteopontin (OPN), and runt-related transcription factor 2 (Runx2). Lentivirus was used to overexpress miR-542-3p and bone morphogenetic protein 7 (BMP7) in yVMSCs. Luciferase reporter assay was conducted to identify the target of miR-542-3p. Compared with yVSMCs, 28 downregulated and 34 upregulated miRNAs were identified in oVSMCs. It was confirmed by qRT-PCR that oVSMC expressed four times lower miR-542-3p than yVSMCs. Overexpressing miR-542-3p in yVSMCs suppressed the osteogenic differentiation induced by \u03b2-GP. Moreover, miR-542-3p targets BMP7 and overexpressing BMP7 in miR-542-3p-expressing yVSMCs reverses miR-542-3p's inhibition of osteogenic differentiation. miR-542-3p regulates osteogenic differentiation of VSMCs through targeting BMP7, suggesting that the downregulation of miR-542-3p in oVSMCs plays a crucial role in osteogenic transition in the aging rat.", - "journal_title": "Human genomics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/31829291/" - } - ], - "f534f9da-64a3-4037-b8b9-0a101f6c71ee": [ - { - "pub_id": "34509618", - "title": "Transcriptional features of biological age maintained in human cultured cardiac interstitial cells.", - "authors": "Oscar Echeagaray,Taeyong Kim,Alex Casillas,Megan Monsanto,Mark Sussman", - "abstract": "Ex vivo expansion of cells is necessary in regenerative medicine to generate large populations for therapeutic use. Adaptation to culture conditions prompt an increase in transcriptome diversity and decreased population heterogeneity in cKit+ cardiac interstitial cells (cCICs). The \"transcriptional memory\" influenced by cellular origin remained unexplored and is likely to differ between neonatal versus senescent input cells undergoing culture expansion. Transcriptional profiles derived from single cell RNASEQ platforms characterized human cCIC derived from neonatal and adult source tissue. Bioinformatic analysis revealed contrasting imprint of age influencing targets of 1) cell cycle, 2) senescence associated secretory phenotype (SASP), 3) RNA transport, and 4) ECM-receptor/fibrosis. A small subset of cCICs exist in a transcriptional continuum between \"youthful\" phenotype and the damaged microenvironment of LVAD tissue in which they were embedded. The connate transcriptional phenotypes offer fundamental biological insight and highlights cellular input as a consideration in culture expansion and adoptive transfer protocols.", - "journal_title": "Genomics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/34509618/" - } - ], - "f5efe2cf-7b2b-4622-b9f1-8a6085616db1": [ - { - "pub_id": "29227476", - "title": "The molecular landscape of pediatric acute myeloid leukemia reveals recurrent structural alterations and age-specific mutational interactions.", - "authors": "Hamid Bolouri,Jason E Farrar,Timothy Triche,Rhonda E Ries,Emilia L Lim,Todd A Alonzo,Yussanne Ma,Richard Moore,Andrew J Mungall,Marco A Marra,Jinghui Zhang,Xiaotu Ma,Yu Liu,Yanling Liu,Jaime M Guidry Auvil,Tanja M Davidsen,Patee Gesuwan,Leandro C Hermida,Bodour Salhia,Stephen Capone,Giridharan Ramsingh,Christian Michel Zwaan,Sanne Noort,Stephen R Piccolo,E Anders Kolb,Alan S Gamis,Malcolm A Smith,Daniela S Gerhard,Soheil Meshinchi", - "abstract": "We present the molecular landscape of pediatric acute myeloid leukemia (AML) and characterize nearly 1,000 participants in Children's Oncology Group (COG) AML trials. The COG-National Cancer Institute (NCI) TARGET AML initiative assessed cases by whole-genome, targeted DNA, mRNA and microRNA sequencing and CpG methylation profiling. Validated DNA variants corresponded to diverse, infrequent mutations, with fewer than 40 genes mutated in >2% of cases. In contrast, somatic structural variants, including new gene fusions and focal deletions of MBNL1, ZEB2 and ELF1, were disproportionately prevalent in young individuals as compared to adults. Conversely, mutations in DNMT3A and TP53, which were common in adults, were conspicuously absent from virtually all pediatric cases. New mutations in GATA2, FLT3 and CBL and recurrent mutations in MYC-ITD, NRAS, KRAS and WT1 were frequent in pediatric AML. Deletions, mutations and promoter DNA hypermethylation convergently impacted Wnt signaling, Polycomb repression, innate immune cell interactions and a cluster of zinc finger-encoding genes associated with KMT2A rearrangements. These results highlight the need for and facilitate the development of age-tailored targeted therapies for the treatment of pediatric AML.", - "journal_title": "Nature medicine", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/29227476/" - } - ], - "35f6efe9-dff7-40e0-becb-c7b1e704a9fc": [ - { - "pub_id": "30673605", - "title": "Neurons with Complex Karyotypes Are Rare in Aged Human Neocortex.", - "authors": "William D Chronister,Ian E Burbulis,Margaret B Wierman,Matthew J Wolpert,Mark F Haakenson,Aiden C B Smith,Joel E Kleinman,Thomas M Hyde,Daniel R Weinberger,Stefan Bekiranov,Michael J McConnell", - "abstract": "A subset of human neocortical neurons harbors complex karyotypes wherein megabase-scale copy-number variants (CNVs) alter allelic diversity. Divergent levels of neurons with complex karyotypes (CNV neurons) are reported in different individuals, yet genome-wide and familial studies implicitly assume a single brain genome when assessing the genetic risk architecture of neurological disease. We assembled a brain CNV atlas using a robust computational approach applied to a new dataset (>800 neurons from 5 neurotypical individuals) and to published data from 10 additional neurotypical individuals. The atlas reveals that the frequency of neocortical neurons with complex karyotypes varies widely among individuals, but this variability is not readily accounted for by tissue quality or CNV detection approach. Rather, the age of the individual is anti-correlated with CNV neuron frequency. Fewer CNV neurons are observed in aged individuals than in young individuals.", - "journal_title": "Cell reports", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/30673605/" - } - ], - "4ca8d070-8b58-4bd5-86be-127089b70324": [ - { - "pub_id": "33609361", - "title": "Career Retrospective: Tom Johnson-Genetics, Genomics, Stress, Stochastic Variation, and Aging.", - "authors": "Alexander R Mendenhall,Gordon J Lithgow,Stuart Kim,David Friedman,Breanne L Newell-Stamper,Thomas E Johnson", - "abstract": "", - "journal_title": "The journals of gerontology. Series A, Biological sciences and medical sciences", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/33609361/" - } - ], - "e7f715f5-b543-4cf0-8105-a856d6bffb8c": [ - { - "pub_id": "29875488", - "title": "Genomic atlas of the human plasma proteome.", - "authors": "Benjamin B Sun,Joseph C Maranville,James E Peters,David Stacey,James R Staley,James Blackshaw,Stephen Burgess,Tao Jiang,Ellie Paige,Praveen Surendran,Clare Oliver-Williams,Mihir A Kamat,Bram P Prins,Sheri K Wilcox,Erik S Zimmerman,An Chi,Narinder Bansal,Sarah L Spain,Angela M Wood,Nicholas W Morrell,John R Bradley,Nebojsa Janjic,David J Roberts,Willem H Ouwehand,John A Todd,Nicole Soranzo,Karsten Suhre,Dirk S Paul,Caroline S Fox,Robert M Plenge,John Danesh,Heiko Runz,Adam S Butterworth", - "abstract": "Although plasma proteins have important roles in biological processes and are the direct targets of many drugs, the genetic factors that control inter-individual variation in plasma protein levels are not well understood. Here we characterize the genetic architecture of the human plasma proteome in healthy blood donors from the INTERVAL study. We identify 1,927 genetic associations with 1,478 proteins, a fourfold increase on existing knowledge, including trans associations for 1,104 proteins. To understand the consequences of perturbations in plasma protein levels, we apply an integrated approach that links genetic variation with biological pathway, disease, and drug databases. We show that protein quantitative trait loci overlap with gene\u00a0expression quantitative trait loci, as well as with disease-associated loci, and find evidence that protein biomarkers have causal roles in disease using Mendelian randomization analysis. By linking genetic factors to diseases via specific proteins, our analyses highlight potential therapeutic targets, opportunities for matching existing drugs with new disease indications, and potential safety concerns for drugs under development.", - "journal_title": "Nature", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/29875488/" - } - ], - "e1adc142-658a-4b67-8629-eedf66eb2989": [ - { - "pub_id": "29670042", - "title": "Long Non-Coding RNAs in Neuronal Aging.", - "authors": "Diana Pereira Fernandes,Main\u00e1 Bitar,Frank M J Jacobs,Guy Barry", - "abstract": "The expansion of long non-coding RNAs (lncRNAs) in organismal genomes has been associated with the emergence of sophisticated regulatory networks that may have contributed to more complex neuronal processes, such as higher-order cognition. In line with the important roles of lncRNAs in the normal functioning of the human brain, dysregulation of lncRNA expression has been implicated in aging and age-related neurodegenerative disorders. In this paper, we discuss the function and expression of known neuronal-associated lncRNAs, their impact on epigenetic changes, the contribution of transposable elements to lncRNA expression, and the implication of lncRNAs in maintaining the 3D nuclear architecture in neurons. Moreover, we discuss how the complex molecular processes that are orchestrated by lncRNAs in the aged brain may contribute to neuronal pathogenesis by promoting protein aggregation and neurodegeneration. Finally, this review explores the possibility that age-related disturbances of lncRNA expression change the genomic and epigenetic regulatory landscape of neurons, which may affect neuronal processes such as neurogenesis and synaptic plasticity.", - "journal_title": "Non-coding RNA", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/29670042/" - } - ], - "c3ae2186-ef48-46a5-b214-dc944366df8f": [ - { - "pub_id": "29056297", - "title": "Virus-Mediated Genome Editing via Homology-Directed Repair in Mitotic and Postmitotic Cells in Mammalian Brain.", - "authors": "Jun Nishiyama,Takayasu Mikuni,Ryohei Yasuda", - "abstract": "Precise genome editing via homology-directed repair (HDR) in targeted cells, particularly in\u00a0vivo, provides an invaluable tool for biomedical research. However, HDR has been considered to be largely restricted to dividing cells, making it challenging to apply the technique in postmitotic neurons. Here we show that precise genome editing via HDR is possible in mature postmitotic neurons as well as mitotic cells in mice brain by combining CRISPR-Cas9-mediated DNA cleavage and the efficient delivery of donor template with adeno-associated virus (AAV). Using this strategy, we achieved efficient tagging of endogenous proteins in primary and organotypic cultures in\u00a0vitro and developing, adult, aged, and pathological brains in\u00a0vivo. Thus, AAV- and CRISPR-Cas9-mediated HDR will be broadly useful for precise genome editing in basic and translational neuroscience.", - "journal_title": "Neuron", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/29056297/" - } - ], - "f7c05225-4e5a-4aac-90a5-f658b6ea70a9": [ - { - "pub_id": "31504802", - "title": "EANO guideline on the diagnosis and treatment of vestibular schwannoma.", - "authors": "Roland Goldbrunner,Michael Weller,Jean Regis,Morten Lund-Johansen,Pantelis Stavrinou,David Reuss,D Gareth Evans,Florence Lefranc,Kita Sallabanda,Andrea Falini,Patrick Axon,Olivier Sterkers,Laura Fariselli,Wolfgang Wick,Joerg-Christian Tonn", - "abstract": "The level of evidence to provide treatment recommendations for vestibular schwannoma is low compared with other intracranial neoplasms. Therefore, the vestibular schwannoma task force of the European Association of Neuro-Oncology assessed the data available in the literature and composed a set of recommendations for health care professionals. The radiological diagnosis of vestibular schwannoma is made by magnetic resonance imaging. Histological verification of the diagnosis is not always required. Current treatment options include observation, surgical resection, fractionated radiotherapy, and radiosurgery. The choice of treatment depends on clinical presentation, tumor size, and expertise of the treating center. In small tumors, observation has to be weighed against radiosurgery, in large tumors surgical decompression is mandatory, potentially followed by fractionated radiotherapy or radiosurgery. Except for bevacizumab in neurofibromatosis type 2, there is no role for pharmacotherapy.", - "journal_title": "Neuro-oncology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/31504802/" - } - ], - "332293e6-ab80-4a52-bd95-2d3c6b3a8a1d": [ - { - "pub_id": "27875856", - "title": "Antimicrobial resistance surveillance in the genomic age.", - "authors": "Andrew G McArthur,Kara K Tsang", - "abstract": "The loss of effective antimicrobials is reducing our ability to protect the global population from infectious disease. However, the field of antibiotic drug discovery and the public health monitoring of antimicrobial resistance (AMR) is beginning to exploit the power of genome and metagenome sequencing. The creation of novel AMR bioinformatics tools and databases and their continued development will advance our understanding of the molecular mechanisms and threat severity of antibiotic resistance, while simultaneously improving our ability to accurately predict and screen for antibiotic resistance genes within environmental, agricultural, and clinical settings. To do so, efforts must be focused toward exploiting the advancements of genome sequencing and information technology. Currently, AMR bioinformatics software and databases reflect different scopes and functions, each with its own strengths and weaknesses. A review of the available tools reveals common approaches and reference data but also reveals gaps in our curated data, models, algorithms, and data-sharing tools that must be addressed to conquer the limitations and areas of unmet need within the AMR research field before DNA sequencing can be fully exploited for AMR surveillance and improved clinical outcomes.", - "journal_title": "Annals of the New York Academy of Sciences", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/27875856/" - } - ], - "37acd7d4-e934-4920-8043-aaa13f7b4258": [ - { - "pub_id": "35668551", - "title": "Understanding climate change response in the age of genomics.", - "authors": "Lesley T Lancaster,Zachary L Fuller,David Berger,Matthew A Barbour,Sissel Jentoft,Maren Wellenreuther", - "abstract": "", - "journal_title": "The Journal of animal ecology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/35668551/" - } - ], - "ca76f85d-9f72-4e15-8ba9-3bf94308c449": [ - { - "pub_id": "32511191", - "title": "Genomics of aging: Genes, adducts, and telomeres.", - "authors": "Kenneth Wysocki,Diane Seibert", - "abstract": "Genomics influences the aging process in many different ways. This 10-part series of articles describes what is known about genetics and aging, including genes, adducts, and telomeres, decreased immune defenses, oxidation and inefficient mitochondria, toxins and radiation, glycosylation, caloric intake and sirtuin production, neurotransmitter imbalance, hormone mechanisms, reduced nitric oxide, and stem cell slowdown. This first article explores gene adducts as an epigenetic \"sludge,\" the influence of telomeres and other mutations that contribute to DNA dysfunction, cell stress, and premature aging. Factors that contribute to adduct formation and reduced telomere length are presented along with some changes in behavior, environmental exposure, food/supplement use, weight, sleep, and exercise that have been found to reduce damage, potentially increasing longevity. Adherence to a Mediterranean diet that contains fruits and whole grains along with fiber, antioxidants (e.g., beta-carotene, vitamins C and E), omega-3 fatty acids, and soy protein may reduce DNA adducts and protect telomeres. So providers may want to recommend these simple but key clinical and individual changes to enhance DNA health, wellness, and longevity.", - "journal_title": "Journal of the American Association of Nurse Practitioners", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/32511191/" - } - ], - "15d2da46-ff2e-4400-a2ae-ec2d9a067cde": [ - { - "pub_id": "36353993", - "title": "Genomic Aging, Clonal Hematopoiesis, and Cardiovascular Disease.", - "authors": "Pradeep Natarajan", - "abstract": "Chronologic age is the dominant risk factor for coronary artery disease but the features of aging promoting coronary artery disease are poorly understood. Advances in human genetics and population-based genetic profiling of blood cells have uncovered the surprising role of age-related subclinical leukemogenic mutations in blood cells, termed \"clonal hematopoiesis of indeterminate potential,\" in coronary artery disease. Such mutations typically occur in <i>DNMT3A</i>, <i>TET2</i>, <i>ASXL1</i>, and <i>JAK2</i>. Murine and human studies prioritize the role of key inflammatory pathways linking clonal hematopoiesis with coronary artery disease. Increasingly larger, longitudinal, multiomics analyses are enabling further dissection into mechanistic insights. These observations expand the genetic architecture of coronary artery disease, now linking hallmark features of hematologic neoplasia with a much more common cardiovascular condition. Implications of these studies include the prospect of novel precision medicine paradigms for coronary artery disease.", - "journal_title": "Arteriosclerosis, thrombosis, and vascular biology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/36353993/" - } - ], - "7c2732db-ed6e-419a-8256-537b4dc68072": [ - { - "pub_id": "33728458", - "title": "Genome-wide screens in yeast models towards understanding chronological lifespan regulation.", - "authors": "Luc Legon,Charalampos Rallis", - "abstract": "Cellular models such as yeasts are a driving force in biogerontology studies. Their simpler genome, short lifespans and vast genetic and genomics resources make them ideal to characterise pro-ageing and anti-ageing genes and signalling pathways. Over the last three decades, yeasts have contributed to the understanding of fundamental aspects of lifespan regulation including the roles of nutrient response, global protein translation rates and quality, DNA damage, oxidative stress, mitochondrial function and dysfunction as well as autophagy. In this short review, we focus on approaches used for competitive and non-competitive cell-based screens using the budding yeast Saccharomyces cerevisiae, and the fission yeast Schizosaccharomyces pombe, for deciphering the molecular mechanisms underlying chronological ageing. Automation accompanied with appropriate computational tools allowed manipulation of hundreds of thousands of colonies, generation, processing and analysis of genome-wide lifespan data. Together with barcoding and modern mutagenesis technologies, these approaches have allowed to take decisive steps towards a global, comprehensive view of cellular ageing.", - "journal_title": "Briefings in functional genomics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/33728458/" - } - ], - "ca19d030-1ebd-422e-b1ab-310e3b1c7f55": [ - { - "pub_id": "28068899", - "title": "Maternal BMI as a predictor of methylation of obesity-related genes in saliva samples from preschool-age Hispanic children at-risk for obesity.", - "authors": "Kathryn Tully Oelsner,Yan Guo,Sophie Bao-Chieu To,Amy L Non,Shari L Barkin", - "abstract": "The study of epigenetic processes and mechanisms present a dynamic approach to assess complex individual variation in obesity susceptibility. However, few studies have examined epigenetic patterns in preschool-age children at-risk for obesity despite the relevance of this developmental stage to trajectories of weight gain. We hypothesized that salivary DNA methylation patterns of key obesogenic genes in Hispanic children would 1) correlate with maternal BMI and 2) allow for identification of pathways associated with children at-risk for obesity. Genome-wide DNA methylation was conducted on 92 saliva samples collected from Hispanic preschool children using the Infinium Illumina HumanMethylation 450\u00a0K BeadChip (Illumina, San Diego, CA, USA), which interrogates >484,000 CpG sites associated with ~24,000 genes. The analysis was limited to 936 genes that have been associated with obesity in a prior GWAS Study. Child DNA methylation at 17 CpG sites was found to be significantly associated with maternal BMI, with increased methylation at 12 CpG sites and decreased methylation at 5 CpG sites. Pathway analysis revealed methylation at these sites related to homocysteine and methionine degradation as well as cysteine biosynthesis and circadian rhythm. Furthermore, eight of the 17 CpG sites reside in genes (FSTL1, SORCS2, NRF1, DLC1, PPARGC1B, CHN2, NXPH1) that have prior known associations with obesity, diabetes, and the insulin pathway. Our study confirms that saliva is a practical human tissue to obtain in community settings and in pediatric populations. These salivary findings indicate potential epigenetic differences in Hispanic preschool children at risk for pediatric obesity. Identifying early biomarkers and understanding pathways that are epigenetically regulated during this critical stage of child development may present an opportunity for prevention or early intervention for addressing childhood obesity. The clinical trial protocol is available at ClinicalTrials.gov ( NCT01316653 ). Registered 3 March 2011.", - "journal_title": "BMC genomics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/28068899/" - } - ], - "253fad94-3be6-4362-b56f-f00c9c5705e6": [ - { - "pub_id": "31997134", - "title": "Mitonuclear genomics and aging.", - "authors": "Joseph C Reynolds,Conscience P Bwiza,Changhan Lee", - "abstract": "Our cells operate based on two distinct genomes that are enclosed in the nucleus and mitochondria. The mitochondrial genome presumably originates from endosymbiotic bacteria. With time, a large portion of the original genes in the bacterial genome is considered to have been lost or transferred to the nuclear genome, leaving a reduced 16.5\u00a0Kb circular mitochondrial DNA (mtDNA). Traditionally only 37 genes, including 13 proteins, were thought to be encoded within mtDNA, its genetic repertoire is expanding with the identification of mitochondrial-derived peptides (MDPs). The biology of aging has been largely unveiled to be regulated by genes that are encoded in the nuclear genome, whereas the mitochondrial genome remained more cryptic. However, recent studies position mitochondria and mtDNA as an important counterpart to the nuclear genome, whereby the two organelles constantly regulate each other. Thus, the genomic network that regulates lifespan and/or healthspan is likely constituted by two unique, yet co-evolved, genomes. Here, we will discuss aspects of mitochondrial biology, especially mitochondrial communication that may add substantial momentum to aging research by accounting for both mitonuclear genomes to more comprehensively and inclusively map the genetic and molecular networks that govern aging and age-related diseases.", - "journal_title": "Human genetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/31997134/" - } - ], - "78a43a45-84b0-4d73-9396-95b99cfd3983": [ - { - "pub_id": "30642433", - "title": "Genomics of 1 million parent lifespans implicates novel pathways and common diseases and distinguishes survival chances.", - "authors": "Paul Rhj Timmers,Ninon Mounier,Kristi Lall,Krista Fischer,Zheng Ning,Xiao Feng,Andrew D Bretherick,David W Clark, ,Xia Shen,T\u00f5nu Esko,Zolt\u00e1n Kutalik,James F Wilson,Peter K Joshi", - "abstract": "We use a genome-wide association of 1 million parental lifespans of genotyped subjects and data on mortality risk factors to validate previously unreplicated findings near <i>CDKN2B-AS1</i>, <i>ATXN2/BRAP</i>, <i>FURIN/FES</i>, <i>ZW10</i>, <i>PSORS1C3</i>, and 13q21.31, and identify and replicate novel findings near <i>ABO</i>, <i>ZC3HC1</i>, and <i>IGF2R</i>. We also validate previous findings near 5q33.3/<i>EBF1</i> and <i>FOXO3</i>, whilst finding contradictory evidence at other loci. Gene set and cell-specific analyses show that expression in foetal brain cells and adult dorsolateral prefrontal cortex is enriched for lifespan variation, as are gene pathways involving lipid proteins and homeostasis, vesicle-mediated transport, and synaptic function. Individual genetic variants that increase dementia, cardiovascular disease, and lung cancer - but not other cancers - explain the most variance. Resulting polygenic scores show a mean lifespan difference of around five years of life across the deciles. This article has been through an editorial process in which the authors decide how to respond to the issues raised during peer review. The Reviewing Editor's assessment is that all the issues have been addressed (see decision letter).", - "journal_title": "eLife", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/30642433/" - } - ], - "79ae7122-3716-498b-9b9a-dd0960e33f99": [ - { - "pub_id": "28067908", - "title": "Genome-wide association study implicates immune activation of multiple integrin genes in inflammatory bowel disease.", - "authors": "Katrina M de Lange,Loukas Moutsianas,James C Lee,Christopher A Lamb,Yang Luo,Nicholas A Kennedy,Luke Jostins,Daniel L Rice,Javier Gutierrez-Achury,Sun-Gou Ji,Graham Heap,Elaine R Nimmo,Cathryn Edwards,Paul Henderson,Craig Mowat,Jeremy Sanderson,Jack Satsangi,Alison Simmons,David C Wilson,Mark Tremelling,Ailsa Hart,Christopher G Mathew,William G Newman,Miles Parkes,Charlie W Lees,Holm Uhlig,Chris Hawkey,Natalie J Prescott,Tariq Ahmad,John C Mansfield,Carl A Anderson,Jeffrey C Barrett", - "abstract": "Genetic association studies have identified 215 risk loci for inflammatory bowel disease, thereby uncovering fundamental aspects of its molecular biology. We performed a genome-wide association study of 25,305 individuals and conducted a meta-analysis with published summary statistics, yielding a total sample size of 59,957 subjects. We identified 25 new susceptibility loci, 3 of which contain integrin genes that encode proteins in pathways that have been identified as important therapeutic targets in inflammatory bowel disease. The associated variants are correlated with expression changes in response to immune stimulus at two of these genes (ITGA4 and ITGB8) and at previously implicated loci (ITGAL and ICAM1). In all four cases, the expression-increasing allele also increases disease risk. We also identified likely causal missense variants in a gene implicated in primary immune deficiency, PLCG2, and a negative regulator of inflammation, SLAMF8. Our results demonstrate that new associations at common variants continue to identify genes relevant to therapeutic target identification and prioritization.", - "journal_title": "Nature genetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/28067908/" - } - ], - "da113334-5b9d-46f6-b47d-b51c2070eb78": [ - { - "pub_id": "30260295", - "title": "Reconceptualizing harms and benefits in the genomic age.", - "authors": "Anya E R Prince,Benjamin E Berkman", - "abstract": "As new, high-powered sequencing technologies are increasingly incorporated into genomics research, we believe that there has been a break point in how risks and benefits associated with genetic information are being characterized and understood. Genomic sequencing provides the potential benefit of a wealth of information, but also has the potential to alter how we conceptualize risks of sequencing. Until now, our conceptions of risks and benefits have been generally static, arising out of the early ethical, legal and social implications studies conducted in the context of targeted genetics. This paper investigates how the increasing availability of genetic information is changing views about risks and benefits, particularly examining our evolving understanding of psychosocial harms and our expanding conception of benefit. We argue that the lack of robust empirical evidence of psychosocial harms and the expanding view that benefits of genomic research include indirect familial benefit necessitate continued ethical, legal and social implications research.", - "journal_title": "Personalized medicine", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/30260295/" - } - ], - "b83fc539-d909-4569-84cb-cd5d9d837e3c": [ - { - "pub_id": "28628103", - "title": "A common haplotype lowers PU.1 expression in myeloid cells and delays onset of Alzheimer's disease.", - "authors": "Kuan-Lin Huang,Edoardo Marcora,Anna A Pimenova,Antonio F Di Narzo,Manav Kapoor,Sheng Chih Jin,Oscar Harari,Sarah Bertelsen,Benjamin P Fairfax,Jake Czajkowski,Vincent Chouraki,Benjamin Grenier-Boley,C\u00e9line Bellenguez,Yuetiva Deming,Andrew McKenzie,Towfique Raj,Alan E Renton,John Budde,Albert Smith,Annette Fitzpatrick,Joshua C Bis,Anita DeStefano,Hieab H H Adams,M Arfan Ikram,Sven van der Lee,Jorge L Del-Aguila,Maria Victoria Fernandez,Laura Iba\u00f1ez, , ,Rebecca Sims,Valentina Escott-Price,Richard Mayeux,Jonathan L Haines,Lindsay A Farrer,Margaret A Pericak-Vance,Jean Charles Lambert,Cornelia van Duijn,Lenore Launer,Sudha Seshadri,Julie Williams,Philippe Amouyel,Gerard D Schellenberg,Bin Zhang,Ingrid Borecki,John S K Kauwe,Carlos Cruchaga,Ke Hao,Alison M Goate", - "abstract": "A genome-wide survival analysis of 14,406 Alzheimer's disease (AD) cases and 25,849 controls identified eight previously reported AD risk loci and 14 novel loci associated with age at onset. Linkage disequilibrium score regression of 220 cell types implicated the regulation of myeloid gene expression in AD risk. The minor allele of rs1057233 (G), within the previously reported CELF1 AD risk locus, showed association with delayed AD onset and lower expression of SPI1 in monocytes and macrophages. SPI1 encodes PU.1, a transcription factor critical for myeloid cell development and function. AD heritability was enriched within the PU.1 cistrome, implicating a myeloid PU.1 target gene network in AD. Finally, experimentally altered PU.1 levels affected the expression of mouse orthologs of many AD risk genes and the phagocytic activity of mouse microglial cells. Our results suggest that lower SPI1 expression reduces AD risk by regulating myeloid gene expression and cell function.", - "journal_title": "Nature neuroscience", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/28628103/" - } - ], - "cc1d0153-590d-434b-a1cd-0046213417ac": [ - { - "pub_id": "37658851", - "title": "A noninvasive method for whole-genome skin methylome profiling.", - "authors": "Cristiana Banila,Daniel Green,Dimitris Katsanos,Joana Viana,Alice Osmaston,Angel Menendez Vazquez,Magnus Lynch,Shakiba Kaveh", - "abstract": "Ageing, disease and malignant transformation of the skin are associated with changes in DNA methylation. So far, mostly invasive methodologies such as biopsies have been applied in collecting DNA methylation signatures. Tape stripping offers a noninvasive option for skin diagnostics. It enables the easy but robust capture of biologic material in large numbers of participants without the need for specialized medical personnel. To design and validate a methodology for noninvasive skin sample collection using tape stripping for subsequent DNA -methylation analysis. A total of 175 participants were recruited and provided tape-stripping samples from a sun-exposed area; 92 provided matched tape-stripping samples from a sun-protected area, and an additional 5 provided matched skin-shave biopsies from the same area. Using -enzymatic conversion and whole-genome Illumina sequencing, we generated genome-wide DNA methylation profiles that were used to evaluate the feasibility of noninvasive data acquisition, to compare with established sampling approaches and to investigate biomarker identification for age and ultraviolet (UV) exposure. We found that tape-stripping samples showed strong concordance in their global DNA methylation landscapes to those of conventional invasive biopsies. Moreover, we showed sample reproducibility and consistent global methylation profiles in skin tape-stripping samples collected from different areas of the body. Using matched samples from sun-protected and sun-exposed areas of the body we were able to validate the capacity of our method to capture the effects of environmental changes and ageing in a cohort covering various ages, ethnicities and skin types. We found DNA methylation changes on the skin resulting from UV exposure and identified significant age-related hypermethylation of CpG islands, with a pronounced peak effect at 50-55\u2005years of age, including methylation changes in well-described markers of ageing. These data demonstrate the feasibility of using tape stripping combined with whole-genome sequencing as a noninvasive approach to measuring DNA methylation changes in the skin. In addition, they outline a viable experimental framework for the use of skin tape stripping, particularly when it is performed in large cohorts of patients to identify biomarkers of skin ageing, UV damage and, possibly, to track treatment response to therapeutic interventions.", - "journal_title": "The British journal of dermatology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/37658851/" - } - ], - "7f926324-f561-4292-8681-643978127d92": [ - { - "pub_id": "28347358", - "title": "Genetic pleiotropy between age-related macular degeneration and 16 complex diseases and traits.", - "authors": "Felix Grassmann,Christina Kiel,Martina E Zimmermann,Mathias Gorski,Veronika Grassmann,Klaus Stark, ,Iris M Heid,Bernhard H F Weber", - "abstract": "Age-related macular degeneration (AMD) is a common condition of vision loss with disease development strongly influenced by environmental and genetic factors. Recently, 34 loci were associated with AMD at genome-wide significance. So far, little is known about a genetic overlap between AMD and other complex diseases or disease-relevant traits. For each of 60 complex diseases/traits with publicly available genome-wide significant association data, the lead genetic variant per independent locus was extracted and a genetic score was calculated for each disease/trait as the weighted sum of risk alleles. The association with AMD was estimated based on 16,144 AMD cases and 17,832 controls using logistic regression. Of the respective disease/trait variance, the 60 genetic scores explained on average 4.8% (0.27-20.69%) and 16 of them were found to be significantly associated with AMD (Q-values\u2009<\u20090.01, p values from\u2009<\u20091.0\u2009\u00d7\u200910<sup>-16</sup> to 1.9\u2009\u00d7\u200910<sup>-3</sup>). Notably, an increased risk for AMD was associated with reduced risk for cardiovascular diseases, increased risk for autoimmune diseases, higher HDL and lower LDL levels in serum, lower bone-mineral density as well as an increased risk for skin cancer. By restricting the analysis to 1824 variants initially used to compute the 60 genetic scores, we identified 28 novel AMD risk variants (Q-values\u2009<\u20090.01, p values from 1.1\u2009\u00d7\u200910<sup>-7</sup> to 3.0\u2009\u00d7\u200910<sup>-4</sup>), known to be involved in cardiovascular disorders, lipid metabolism, autoimmune diseases, anthropomorphic traits, ocular disorders, and neurological diseases. The latter variants represent 20 novel AMD-associated, pleiotropic loci. Genes in the novel loci reinforce previous findings strongly implicating the complement system in AMD pathogenesis. We demonstrate a substantial overlap of the genetics of several complex diseases/traits with AMD and provide statistically significant evidence for an additional 20 loci associated with AMD. This highlights the possibility that so far unrelated pathologies may have disease pathways in common.", - "journal_title": "Genome medicine", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/28347358/" - } - ], - "c23e7f99-6e3a-4150-854e-f5a4a8abf21d": [ - { - "pub_id": "28884802", - "title": "A female Viking warrior confirmed by genomics.", - "authors": "Charlotte Hedenstierna-Jonson,Anna Kjellstr\u00f6m,Torun Zachrisson,Maja Krzewi\u0144ska,Veronica Sobrado,Neil Price,Torsten G\u00fcnther,Mattias Jakobsson,Anders G\u00f6therstr\u00f6m,Jan Stor\u00e5", - "abstract": "The objective of this study has been to confirm the sex and the affinity of an individual buried in a well-furnished warrior grave (Bj 581) in the Viking Age town of Birka, Sweden. Previously, based on the material and historical records, the male sex has been associated with the gender of the warrior and such was the case with Bj 581. An earlier osteological classification of the individual as female was considered controversial in a historical and archaeological context. A genomic confirmation of the biological sex of the individual was considered necessary to solve the issue. Genome-wide sequence data was generated in order to confirm the biological sex, to support skeletal integrity, and to investigate the genetic relationship of the individual to ancient individuals as well as modern-day groups. Additionally, a strontium isotope analysis was conducted to highlight the mobility of the individual. The genomic results revealed the lack of a Y-chromosome and thus a female biological sex, and the mtDNA analyses support a single-individual origin of sampled elements. The genetic affinity is close to present-day North Europeans, and within Sweden to the southern and south-central region. Nevertheless, the Sr values are not conclusive as to whether she was of local or nonlocal origin. The identification of a female Viking warrior provides a unique insight into the Viking society, social constructions, and exceptions to the norm in the Viking time-period. The results call for caution against generalizations regarding social orders in past societies.", - "journal_title": "American journal of physical anthropology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/28884802/" - } - ], - "3a9e80fc-b20d-4828-aaed-1a6ad490020a": [ - { - "pub_id": "32264951", - "title": "A multidimensional systems biology analysis of cellular senescence in aging and disease.", - "authors": "Roberto A Avelar,Javier G\u00f3mez Ortega,Robi Tacutu,Eleanor J Tyler,Dominic Bennett,Paolo Binetti,Arie Budovsky,Kasit Chatsirisupachai,Emily Johnson,Alex Murray,Samuel Shields,Daniela Tejada-Martinez,Daniel Thornton,Vadim E Fraifeld,Cleo L Bishop,Jo\u00e3o Pedro de Magalh\u00e3es", - "abstract": "Cellular senescence, a permanent state of replicative arrest in otherwise proliferating cells, is a hallmark of aging and has been linked to aging-related diseases. Many genes play a role in cellular senescence, yet a comprehensive understanding of its pathways is still lacking. We develop\u00a0CellAge (http://genomics.senescence.info/cells), a manually curated database of 279 human genes driving cellular senescence, and perform various integrative analyses. Genes inducing cellular senescence tend to be overexpressed with age in human tissues and are significantly overrepresented in anti-longevity and tumor-suppressor genes, while genes inhibiting cellular senescence overlap with pro-longevity and oncogenes. Furthermore, cellular senescence genes are strongly conserved in mammals but not in invertebrates. We also build cellular senescence protein-protein interaction and co-expression networks. Clusters in the networks are enriched for cell cycle and immunological processes. Network topological parameters also reveal novel potential cellular senescence regulators. Using siRNAs, we observe that all 26 candidates tested induce at least one marker of senescence with 13 genes (C9orf40, CDC25A, CDCA4, CKAP2, GTF3C4, HAUS4, IMMT, MCM7, MTHFD2, MYBL2, NEK2, NIPA2, and TCEB3) decreasing cell number, activating p16/p21, and undergoing morphological changes that resemble cellular senescence. Overall, our work provides a benchmark resource for researchers to study cellular senescence, and our systems biology analyses reveal new insights and gene regulators of cellular senescence.", - "journal_title": "Genome biology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/32264951/" - } - ], - "bb15afa8-8165-4d45-899f-7f00c4e465b6": [ - { - "pub_id": "34418496", - "title": "Co-expression of the SARS-CoV-2 entry molecules ACE2 and TMPRSS2 in human ovaries: Identification of cell types and trends with age.", - "authors": "Meng Wu,Lingwei Ma,Liru Xue,Qingqing Zhu,Su Zhou,Jun Dai,Wei Yan,Jinjin Zhang,Shixuan Wang", - "abstract": "The high rate of SARS-CoV-2 infection poses a serious threat to public health. Previous studies have suggested that SARS-CoV-2 can infect human ovary, the core organ of the female reproductive system. However, it remains unclear which type of ovarian cells are easily infected by SARS-CoV-2 and whether ovarian infectivity differs from puberty to menopause. In this study, public datasets containing bulk and single-cell RNA-Seq data derived from ovarian tissues were analyzed to demonstrate the mRNA expression and protein distribution of the two key entry receptors for SARS-CoV-2-angiotensin-converting enzyme 2 (ACE2) and type II transmembrane serine protease (TMPRSS2). Furthermore, an immunohistochemical study of ACE2 and TMPRSS2 in human ovaries of different ages was conducted. Differentially expressed gene (DEG) analysis of ovaries of different ages and with varying ovarian reserves was conducted to explore the potential functions of ACE2 and TMPRSS2 in the ovary. The analysis of the public datasets indicated that the co-expression of ACE2 and TMPRSS2 was observed mostly in oocytes and partially in granulosa cells. However, no marked difference was observed in ACE2 or TMPRSS2 expression between young and old ovaries and ovaries with low and high reserves. Correspondingly, ACE2 and TMPRSS2 were detected in the human ovarian cortex and medulla, especially in oocytes of different stages, with no observed variations in their expression level in ovaries of different ages, which was consistent with the results of bioinformatic analyses. Remarkably, DEG analysis showed that a series of viral infection-related pathways were more enriched in ACE2-positive ovarian cells than in ACE2-negative ovarian cells, suggesting that SARS-CoV-2 may potentially target specific ovarian cells and affect ovarian function. However, further fundamental and clinical research is still needed to monitor the process of SARS-CoV-2 entry into ovarian cells and the long-term effects of SARS-CoV-2 infection on the ovarian function in recovered females.", - "journal_title": "Genomics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/34418496/" - } - ], - "9551c76a-d296-43cc-b3c2-5be11bc17d72": [ - { - "pub_id": "32694684", - "title": "NAD<sup>+</sup> homeostasis in health and disease.", - "authors": "Elena Katsyuba,Mario Romani,Dina Hofer,Johan Auwerx", - "abstract": "The conceptual evolution of nicotinamide adenine dinucleotide (NAD<sup>+</sup>) from being seen as a simple metabolic cofactor to a pivotal cosubstrate for proteins regulating metabolism and longevity, including the sirtuin family of protein deacylases, has led to a new wave of scientific interest in NAD<sup>+</sup>. NAD<sup>+</sup> levels decline during ageing, and alterations in NAD<sup>+</sup> homeostasis can be found in virtually all age-related diseases, including neurodegeneration, diabetes and cancer. In preclinical settings, various strategies to increase NAD<sup>+</sup> levels have shown beneficial effects, thus starting a competitive race to discover marketable NAD<sup>+</sup> boosters to improve healthspan and lifespan. Here, we review the basics of NAD<sup>+</sup> biochemistry and metabolism, and its roles in health and disease, and we discuss current challenges and the future translational potential of NAD<sup>+</sup> research.", - "journal_title": "Nature metabolism", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/32694684/" - } - ], - "85a1c882-0cf4-4843-84df-3fba96d27d6c": [ - { - "pub_id": "30486438", - "title": "Genomics: New Light on Alzheimer's Disease Research.", - "authors": "Yeong Ju Jung,Yoon Ha Kim,Mridula Bhalla,Sung Bae Lee,Jinsoo Seo", - "abstract": "Alzheimer's disease (AD) is a progressive neurodegenerative disease that represents a major cause of death in many countries. AD is characterized by profound memory loss, disruptions in thinking and reasoning, and changes in personality and behavior followed by malfunctions in various bodily systems. Although AD was first identified over 100 years ago, and tremendous efforts have been made to cure the disease, the precise mechanisms underlying the onset of AD remain unclear. The recent development of next-generation sequencing tools and bioinformatics has enabled us to investigate the role of genetics in the pathogenesis of AD. In this review, we discuss novel discoveries in this area, including the results of genome-wide association studies (GWAS) that have implicated a number of novel genes as risk factors, as well as the identification of epigenetic regulators strongly associated with the onset and progression of AD. We also review how genetic risk factors may interact with age-associated, progressive decreases in cognitive function in patients with AD.", - "journal_title": "International journal of molecular sciences", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/30486438/" - } - ], - "7e22bd8c-7c81-445a-a964-ed9ead149c7a": [ - { - "pub_id": "31486122", - "title": "A comprehensive biomedical variant catalogue based on whole genome sequences of 582 dogs and eight wolves.", - "authors": "V Jagannathan,C Dr\u00f6gem\u00fcller,T Leeb, ", - "abstract": "The domestic dog serves as an excellent model to investigate the genetic basis of disease. More than 400 heritable traits analogous to human diseases have been described in dogs. To further canine medical genetics research, we established the Dog Biomedical Variant Database Consortium (DBVDC) and present a comprehensive list of functionally annotated genome variants that were identified with whole genome sequencing of 582 dogs from 126 breeds and eight wolves. The genomes used in the study have a minimum coverage of 10\u00d7 and an average coverage of ~24\u00d7. In total, we identified 23\u00a0133\u00a0692 single-nucleotide variants (SNVs) and 10\u00a0048\u00a0038 short indels, including 93% undescribed variants. On average, each individual dog genome carried \u223c4.1\u00a0million single-nucleotide and ~1.4\u00a0million short-indel variants with respect to the reference genome assembly. About 2% of the variants were located in coding regions of annotated genes and loci. Variant effect classification showed 247\u00a0141 SNVs and 99\u00a0562 short indels having moderate or high impact on 11\u00a0267 protein-coding genes. On average, each genome contained heterozygous loss-of-function variants in 30 potentially embryonic lethal genes and 97 genes associated with developmental disorders. More than 50 inherited disorders and traits have been unravelled using the DBVDC variant catalogue, enabling genetic testing for breeding and diagnostics. This resource of annotated variants and their corresponding genotype frequencies constitutes a highly useful tool for the identification of potential variants causative for rare inherited disorders in dogs.", - "journal_title": "Animal genetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/31486122/" - } - ], - "c4f336ea-a7c0-4c53-8f39-2ac74279b61c": [ - { - "pub_id": "29232479", - "title": "Metabolomic Pathways to Osteoporosis in Middle-Aged Women: A Genome-Metabolome-Wide Mendelian Randomization Study.", - "authors": "Alireza Moayyeri,Ching-Lung Cheung,Kathryn Cb Tan,John A Morris,Agustin Cerani,Robert P Mohney,J Brent Richards,Christopher Hammond,Tim D Spector,Cristina Menni", - "abstract": "The metabolic state of the body can be a major determinant of bone health. We used a Mendelian randomization approach to identify metabolites causally associated with bone mass to better understand the biological mechanisms of osteoporosis. We tested bone phenotypes (femoral neck, total hip, and lumbar spine bone mineral density [BMD]) for association with 280 fasting blood metabolites in 6055 women from TwinsUK cohort with genomewide genotyping scans. Causal associations between metabolites and bone phenotypes were further assessed in a bidirectional Mendelian randomization study using genetic markers/scores as instrumental variables. Significant associations were replicated in 624 participants from the Hong Kong Osteoporosis Study (HKOS). Fifteen metabolites showed direct associations with bone phenotypes after adjusting for covariates and multiple testing. Using genetic instruments, four of these metabolites were found to be causally associated with hip or spine BMD. These included androsterone sulfate, epiandrosterone sulfate, 5alpha-androstan-3beta17beta-diol disulfate (encoded by CYP3A5), and 4-androsten-3beta17beta-diol disulfate (encoded by SULT2A1). In the HKOS population, all four metabolites showed significant associations with hip and spine BMD in the expected directions. No causal reverse association between BMD and any of the metabolites were found. In the first metabolome-genomewide Mendelian randomization study of human bone mineral density, we identified four novel biomarkers causally associated with BMD. Our findings reveal novel biological pathways involved in the pathogenesis of osteoporosis. \u00a9 2017 American Society for Bone and Mineral Research.", - "journal_title": "Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/29232479/" - } - ], - "e6b18c09-2ad7-42d9-9dba-d9c3cfc52950": [ - { - "pub_id": "30417088", - "title": "Ancient genomes suggest the eastern Pontic-Caspian steppe as the source of western Iron Age nomads.", - "authors": "Maja Krzewi\u0144ska,G\u00fcl\u015fah Merve K\u0131l\u0131n\u00e7,Anna Juras,Dilek Koptekin,Maciej Chyle\u0144ski,Alexey G Nikitin,Nikolai Shcherbakov,Iia Shuteleva,Tatiana Leonova,Liudmila Kraeva,Flarit A Sungatov,Alfija N Sultanova,Inna Potekhina,Sylwia \u0141ukasik,Marta Krenz-Niedba\u0142a,Love Dal\u00e9n,Vitaly Sinika,Mattias Jakobsson,Jan Stor\u00e5,Anders G\u00f6therstr\u00f6m", - "abstract": "For millennia, the Pontic-Caspian steppe was a connector between the Eurasian steppe and Europe. In this scene, multidirectional and sequential movements of different populations may have occurred, including those of the Eurasian steppe nomads. We sequenced 35 genomes (low to medium coverage) of Bronze Age individuals (Srubnaya-Alakulskaya) and Iron Age nomads (Cimmerians, Scythians, and Sarmatians) that represent four distinct cultural entities corresponding to the chronological sequence of cultural complexes in the region. Our results suggest that, despite genetic links among these peoples, no group can be considered a direct ancestor of the subsequent group. The nomadic populations were heterogeneous and carried genetic affinities with populations from several other regions including the Far East and the southern Urals. We found evidence of a stable shared genetic signature, making the eastern Pontic-Caspian steppe a likely source of western nomadic groups.", - "journal_title": "Science advances", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/30417088/" - } - ], - "9fed8fd1-fce5-4fc1-9911-05d312f88521": [ - { - "pub_id": "32678081", - "title": "Multivariate genomic scan implicates novel loci and haem metabolism in human ageing.", - "authors": "Paul R H J Timmers,James F Wilson,Peter K Joshi,Joris Deelen", - "abstract": "Ageing phenotypes, such as years lived in good health (healthspan), total years lived (lifespan), and survival until an exceptional old age (longevity), are of interest to us all but require exceptionally large sample sizes to study genetically. Here we combine existing genome-wide association summary statistics for healthspan,\u00a0parental lifespan, and longevity in a multivariate framework, increasing statistical power, and identify 10 genomic loci which influence all three phenotypes, of which five (near FOXO3, SLC4A7, LINC02513, ZW10, and FGD6) have not been reported previously at genome-wide significance. The majority of these 10 loci are associated with cardiovascular disease and some affect the expression of genes known to change their\u00a0activity with age. In total, we implicate 78 genes, and find these to be enriched for ageing pathways previously highlighted in model organisms, such as the response to DNA damage, apoptosis, and homeostasis. Finally, we identify a pathway worthy of further study: haem metabolism.", - "journal_title": "Nature communications", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/32678081/" - } - ], - "bc192876-83b8-4d58-9c71-e16a4fe0d210": [ - { - "pub_id": "31865598", - "title": "Obesity paradox and aging.", - "authors": "Ottavio Bosello,Angiola Vanzo", - "abstract": "In association with the rapid lengthening of life expectancy and the ever-rising prevalence of obesity, many studies explored in the elderly the phenomenon usually defined as the obesity paradox. This article is a narrative overview of seventy-two papers (1999-2019) that investigated the obesity paradox during the aging process. Twenty-nine documents are examined more in detail. The majority of studies suggesting the existence of an obesity paradox have evaluated just BMI as an index of obesity. Some aspects are often not assessed or are underestimated, in particular body composition and visceral adiposity, sarcopenic obesity, and cardio fitness. Many studies support that central fat and relative loss of fat-free mass may become relatively more important than BMI in determining the health risk associated with obesity in older ages. Inaccurate assessments may lead to a systematic underestimation of the impact of obesity on morbidity and premature mortality and, consequently, to clinical behaviors that are not respectful of the health of elderly patients. Knowledge of the changes in\u00a0body composition and fat distribution will help to better understand the relationship between obesity, morbidity, and mortality in the elderly. Level V, narrative overview.", - "journal_title": "Eating and weight disorders : EWD", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/31865598/" - } - ], - "7e84354b-8a0a-4e1b-9691-86dde5c86f0e": [ - { - "pub_id": "37511197", - "title": "Genomic Instability Evolutionary Footprints on Human Health: Driving Forces or Side Effects?", - "authors": "Laura Veschetti,Mirko Treccani,Elisa De Tomi,Giovanni Malerba", - "abstract": "In this work, we propose a comprehensive perspective on genomic instability comprising not only the accumulation of mutations but also telomeric shortening, epigenetic alterations and other mechanisms that could contribute to genomic information conservation or corruption. First, we present mechanisms playing a role in genomic instability across the kingdoms of life. Then, we explore the impact of genomic instability on the human being across its evolutionary history and on present-day human health, with a particular focus on aging and complex disorders. Finally, we discuss the role of non-coding RNAs, highlighting future approaches for a better living and an expanded healthy lifespan.", - "journal_title": "International journal of molecular sciences", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/37511197/" - } - ], - "15f38c8b-b864-4b96-87c0-acb9223622fb": [ - { - "pub_id": "32761644", - "title": "Genomics to accelerate genetic improvement in tilapia.", - "authors": "J M Y\u00e1\u00f1ez,R Joshi,G M Yoshida", - "abstract": "Selective breeding of tilapia populations started in the early 1990s and over the past three decades tilapia has become one of the most important farmed freshwater species, being produced in more than 125 countries around the globe. Although genome assemblies have been available since 2011, most of the tilapia industry still depends on classical selection techniques using mass spawning or pedigree information to select for growth traits with reported genetic gains of up to 20% per generation. The involvement of international breeding companies and research institutions has resulted in the rapid development and application of genomic resources in the last few years. GWAS and genomic selection are expected to contribute to uncovering the genetic variants involved in economically relevant traits and increasing the genetic gain in selective breeding programs, respectively. Developments over the next few years will probably focus on achieving a deep understanding of genetic architecture of complex traits, as well as accelerating genetic progress in the selection for growth-, quality- and robustness-related traits. Novel phenotyping technologies (i.e. phenomics), lower-cost whole-genome sequencing approaches, functional genomics and gene editing tools will be crucial in future developments for the improvement of tilapia aquaculture.", - "journal_title": "Animal genetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/32761644/" - } - ], - "f60ba055-fc78-4903-a34e-68a52724d9d4": [ - { - "pub_id": "30661755", - "title": "Extensive Unexplored Human Microbiome Diversity Revealed by Over 150,000 Genomes from Metagenomes Spanning Age, Geography, and Lifestyle.", - "authors": "Edoardo Pasolli,Francesco Asnicar,Serena Manara,Moreno Zolfo,Nicolai Karcher,Federica Armanini,Francesco Beghini,Paolo Manghi,Adrian Tett,Paolo Ghensi,Maria Carmen Collado,Benjamin L Rice,Casey DuLong,Xochitl C Morgan,Christopher D Golden,Christopher Quince,Curtis Huttenhower,Nicola Segata", - "abstract": "The body-wide human microbiome plays a role in health, but its full diversity remains uncharacterized, particularly outside of the gut and in international populations. We leveraged 9,428 metagenomes to reconstruct 154,723 microbial genomes (45% of high quality) spanning body sites, ages, countries, and lifestyles. We recapitulated 4,930 species-level genome bins (SGBs), 77% without genomes in public repositories (unknown SGBs [uSGBs]). uSGBs are prevalent (in 93% of well-assembled samples), expand underrepresented phyla, and are enriched in non-Westernized populations (40% of the total SGBs). We annotated 2.85\u00a0M genes in SGBs, many associated with conditions including infant development (94,000) or Westernization (106,000). SGBs and uSGBs permit deeper microbiome analyses and increase the average mappability of metagenomic reads from 67.76% to 87.51% in the gut (median 94.26%) and 65.14% to 82.34% in the mouth. We thus identify thousands of microbial genomes from yet-to-be-named species, expand the pangenomes of human-associated microbes, and allow better exploitation of metagenomic technologies.", - "journal_title": "Cell", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/30661755/" - } - ], - "f28111d5-fe88-4668-8699-f02f907af80a": [ - { - "pub_id": "28346895", - "title": "Wheat genomics comes of age.", - "authors": "Cristobal Uauy", - "abstract": "Advances in wheat genomics have lagged behind other major cereals (e.g., rice and maize) due to its highly repetitive and large polyploid genome. Recent technological developments in sequencing and assembly methods, however, have largely overcome these barriers. The community now moves to an era centred on functional characterisation of the genome. This includes understanding sequence and structural variation as well as how information is integrated across multiple homoeologous genomes. This understanding promises to uncover variation previously hidden from natural and human selection due to the often observed functional redundancy between homoeologs. Key functional genomic resources will enable this, including sequenced mutant populations and gene editing technologies which are now available in wheat. Training the next-generation of genomics-enabled researchers will be essential to ensure these advances are quickly translated into farmers' fields.", - "journal_title": "Current opinion in plant biology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/28346895/" - } - ], - "64ecf4a8-193f-4811-ac82-85573b0d6bc9": [ - { - "pub_id": "31847894", - "title": "Genomics of circadian rhythms in health and disease.", - "authors": "Filipa Rijo-Ferreira,Joseph S Takahashi", - "abstract": "Circadian clocks are endogenous oscillators that control 24-h physiological and behavioral processes. The central circadian clock exerts control over myriad aspects of mammalian physiology, including the regulation of sleep, metabolism, and the immune system. Here, we review advances in understanding the genetic regulation of sleep through the circadian system, as well as the impact of dysregulated gene expression on metabolic function. We also review recent studies that have begun to unravel the circadian clock's role in controlling the cardiovascular and nervous systems, gut microbiota, cancer, and aging. Such circadian control of these systems relies, in part, on transcriptional regulation, with recent evidence for genome-wide regulation of the clock through circadian chromosome organization. These novel insights into the genomic regulation of human physiology provide opportunities for the discovery of improved treatment strategies and new understanding of the biological underpinnings of human disease.", - "journal_title": "Genome medicine", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/31847894/" - } - ], - "395a51ba-bd2a-4160-8396-b13a3bf762ff": [ - { - "pub_id": "30544645", - "title": "Repetitive Fragile Sites: Centromere Satellite DNA As a Source of Genome Instability in Human Diseases.", - "authors": "Elizabeth M Black,Simona Giunta", - "abstract": "Maintenance of an intact genome is essential for cellular and organismal homeostasis. The centromere is a specialized chromosomal locus required for faithful genome inheritance at each round of cell division. Human centromeres are composed of large tandem arrays of repetitive alpha-satellite DNA, which are often sites of aberrant rearrangements that may lead to chromosome fusions and genetic abnormalities. While the centromere has an essential role in chromosome segregation during mitosis, the long and repetitive nature of the highly identical repeats has greatly hindered in-depth genetic studies, and complete annotation of all human centromeres is still lacking. Here, we review our current understanding of human centromere genetics and epigenetics as well as recent investigations into the role of centromere DNA in disease, with a special focus on cancer, aging, and human immunodeficiency\u207bcentromeric instability\u207bfacial anomalies (ICF) syndrome. We also highlight the causes and consequences of genomic instability at these large repetitive arrays and describe the possible sources of centromere fragility. The novel connection between alpha-satellite DNA instability and human pathological conditions emphasizes the importance of obtaining a truly complete human genome assembly and accelerating our understanding of centromere repeats' role in physiology and beyond.", - "journal_title": "Genes", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/30544645/" - } - ], - "0942fb8b-731c-4d6e-9b5a-8a303012eec6": [ - { - "pub_id": "33673725", - "title": "Genetics and Epigenetics in Asthma.", - "authors": "Polyxeni Ntontsi,Andreas Photiades,Eleftherios Zervas,Georgina Xanthou,Konstantinos Samitas", - "abstract": "Asthma is one of the most common respiratory disease that affects both children and adults worldwide, with diverse phenotypes and underlying pathogenetic mechanisms poorly understood. As technology in genome sequencing progressed, scientific efforts were made to explain and predict asthma's complexity and heterogeneity, and genome-wide association studies (GWAS) quickly became the preferred study method. Several gene markers and loci associated with asthma susceptibility, atopic and childhood-onset asthma were identified during the last few decades. Markers near the <i>ORMDL3/GSDMB</i> genes were associated with childhood-onset asthma, interleukin (IL)33 and <i>IL1RL1</i> SNPs were associated with atopic asthma, and the <i>Thymic Stromal Lymphopoietin (TSLP)</i> gene was identified as protective against the risk to TH2-asthma. The latest efforts and advances in identifying and decoding asthma susceptibility are focused on epigenetics, heritable characteristics that affect gene expression without altering DNA sequence, with DNA methylation being the most described mechanism. Other less studied epigenetic mechanisms include histone modifications and alterations of miR expression. Recent findings suggest that the DNA methylation pattern is tissue and cell-specific. Several studies attempt to describe DNA methylation of different types of cells and tissues of asthmatic patients that regulate airway remodeling, phagocytosis, and other lung functions in asthma. In this review, we attempt to briefly present the latest advancements in the field of genetics and mainly epigenetics concerning asthma susceptibility.", - "journal_title": "International journal of molecular sciences", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/33673725/" - } - ], - "c553328b-fc5a-47e0-8e2a-7456004fa218": [ - { - "pub_id": "28204942", - "title": "Molecular modeling in the age of clinical genomics, the enterprise of the next generation.", - "authors": "Jeremy W Prokop,Jozef Lazar,Gabrielle Crapitto,D Casey Smith,Elizabeth A Worthey,Howard J Jacob", - "abstract": "Protein modeling and molecular dynamics hold a unique toolset to aide in the characterization of clinical variants that may result in disease. Not only do these techniques offer the ability to study under characterized proteins, but they do this with the speed that is needed for time-sensitive clinical cases. In this paper we retrospectively study a clinical variant in the XIAP protein, C203Y, while addressing additional variants seen in patients with similar gastrointestinal phenotypes as the C203Y mutation. In agreement with the clinical tests performed on the C203Y patient, protein modeling and molecular dynamics suggest that direct interactions with RIPK2 and Caspase3 are altered by the C203Y mutation and subsequent loss of Zn coordination in the second BIR domain of XIAP. Interestingly, the variant does not appear to alter interactions with SMAC, resulting in further damage to the caspase and NOD2 pathways. To expand the computational strategy designed when studying XIAP, we have applied the molecular modeling tools to a list of 140 variants seen in CFTR associated with cystic fibrosis, and a list of undiagnosed variants in 17 different genes. This paper shows the exciting applications of molecular modeling in the classification and characterization of genetic variants identified in next generation sequencing. Graphical abstract XIAP in Caspase 3 and NOD2 signaling pathways.", - "journal_title": "Journal of molecular modeling", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/28204942/" - } - ], - "b119b2dd-14f2-439d-b42a-c37541d64391": [ - { - "pub_id": "33835452", - "title": "Single-Cell RNA Sequencing Analysis: A Step-by-Step Overview.", - "authors": "Shaked Slovin,Annamaria Carissimo,Francesco Panariello,Antonio Grimaldi,Valentina Bouch\u00e9,Gennaro Gambardella,Davide Cacchiarelli", - "abstract": "Thanks to innovative sample-preparation and sequencing technologies, gene expression in individual cells can now be measured for thousands of cells in a single experiment. Since its introduction, single-cell RNA sequencing (scRNA-seq) approaches have revolutionized the genomics field as they created unprecedented opportunities for resolving cell heterogeneity by exploring gene expression profiles at a single-cell resolution. However, the rapidly evolving field of scRNA-seq invoked the emergence of various analytics approaches aimed to maximize the full potential of this novel strategy. Unlike population-based RNA sequencing approaches, scRNA seq necessitates comprehensive computational tools to address high data complexity and keep up with the emerging single-cell associated challenges. Despite the vast number of analytical methods, a universal standardization is lacking. While this reflects the fields' immaturity, it may also encumber a newcomer to blend in.In this review, we aim to bridge over the abovementioned hurdle and propose four ready-to-use pipelines for scRNA-seq analysis easily accessible by a newcomer, that could fit various biological data types. Here we provide an overview of the currently available single-cell technologies for cell isolation and library preparation and a step by step guide that covers the entire canonical analytic workflow to analyse scRNA-seq data including read mapping, quality controls, gene expression quantification, normalization, feature selection, dimensionality reduction, and cell clustering useful for trajectory inference and differential expression. Such workflow guidelines will escort novices as well as expert users in the analysis of complex scRNA-seq datasets, thus further expanding the research potential of single-cell approaches in basic science, and envisaging its future implementation as best practice in the field.", - "journal_title": "Methods in molecular biology (Clifton, N.J.)", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/33835452/" - } - ], - "4ef81e6c-5a77-4800-9cfb-30af590d32f5": [ - { - "pub_id": "32864809", - "title": "The Parkinson's Disease Genome-Wide Association Study Locus Browser.", - "authors": "Francis P Grenn,Jonggeol J Kim,Mary B Makarious,Hirotaka Iwaki,Anastasia Illarionova,Kajsa Brolin,Jillian H Kluss,Artur F Schumacher-Schuh,Hampton Leonard,Faraz Faghri,Kimberley Billingsley,Lynne Krohn,Ashley Hall,Monica Diez-Fairen,Maria Teresa Peri\u00f1\u00e1n,Jia Nee Foo,Cynthia Sandor,Caleb Webber,Brian K Fiske,J Raphael Gibbs,Mike A Nalls,Andrew B Singleton,Sara Bandres-Ciga,Xylena Reed,Cornelis Blauwendraat, ", - "abstract": "Parkinson's disease (PD) is a neurodegenerative disease with an often complex component identifiable by genome-wide association studies. The most recent large-scale PD genome-wide association studies have identified more than 90 independent risk variants for PD risk and progression across more than 80 genomic regions. One major challenge in current genomics is the identification of the causal gene(s) and variant(s) at each genome-wide association study locus. The objective of the current study was to create a tool that would display data for relevant PD risk loci and provide guidance with the prioritization of causal genes and potential mechanisms at each locus. We included all significant genome-wide signals from multiple recent PD genome-wide association studies including themost recent PD risk genome-wide association study, age-at-onset genome-wide association study, progression genome-wide association study, and Asian population PD risk genome-wide association study. We gathered data for all genes 1 Mb up and downstream of each variant to allow users to assess which gene(s) are most associated with the variant of interest based on a set of self-ranked criteria. Multiple databases were queried for each gene to collect additional causal data. We created a PD genome-wide association study browser tool (https://pdgenetics.shinyapps.io/GWASBrowser/) to assist the PD research community with the prioritization of genes for follow-up functional studies to identify potential therapeutic targets. Our PD genome-wide association study browser tool provides users with a useful method of identifying potential causal genes at all known PD risk loci from large-scale PD genome-wide association studies. We plan to update this tool with new relevant data as sample sizes increase and new PD risk loci are discovered. \u00a9 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. This article has been contributed to by US Government employees and their work is in the public domain in the USA.", - "journal_title": "Movement disorders : official journal of the Movement Disorder Society", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/32864809/" - } - ], - "cac4696c-511a-448f-ae7c-b91ec64be2be": [ - { - "pub_id": "28263867", - "title": "Mutation and catastrophe in the aging genome.", - "authors": "Brandon Milholland,Yousin Suh,Jan Vijg", - "abstract": "In the 1960s, Leslie Orgel proposed what is now known as the error catastrophe theory of aging, arguing that errors in protein translation that reduce the fidelity of the protein-translating enzymes would lead to a feedback loop of increasingly inaccurate protein synthesis, terminating in the death of the organism. This mechanism of aging would be consistent with the exponential increase of mortality observed in humans, but the error catastrophe theory of aging has been generally disregarded by researchers due to a lack of evidence for an age-related increase in protein errors. Another theory of aging, proposed at roughly the same time, is Leo Szilard's two-hit model of somatic mutation accumulation, which assumed a linear increase in mutations over time but explained the nonlinear pattern of human mortality through a mechanism of genetic and cellular redundancy which kept mortality low until the redundancy was exhausted, at which point mortality rapidly rose. Here, we synthesize the two theories, along with the latest advances in genomics research. We propose a new catastrophe theory of aging, this time with somatic mutations as the primary agent of the feedback loop. Similar to protein errors affecting translation itself, somatic mutations in genes involved in DNA replication and repair would lead to a feedback loop of exponentially increasing mutation load. The difference from protein errors is that somatic mutations would mainly affect gene regulatory regions rather than the much smaller part of the genome encoding protein-coding information. Although the self-stimulating accumulation of somatic mutations is not mutually exclusive with the Szilard-based loss of redundancy, we present evidence that suggests that the accumulated mutations themselves could be numerous enough to cause mortality. Finally, we acknowledge the limits of our current knowledge and propose a course of research practices that will help to confirm or refute our model and advance the field of aging research as a whole.", - "journal_title": "Experimental gerontology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/28263867/" - } - ], - "49e78c89-14fd-4c52-8710-51a023bbb3b4": [ - { - "pub_id": "31810449", - "title": "Human gene expression variability and its dependence on methylation and aging.", - "authors": "Nasser Bashkeel,Theodore J Perkins,Mads K\u00e6rn,Jonathan M Lee", - "abstract": "Phenotypic variability of human populations is partly the result of gene polymorphism and differential gene expression. As such, understanding the molecular basis for diversity requires identifying genes with both high and low population expression variance and identifying the mechanisms underlying their expression control. Key issues remain unanswered with respect to expression variability in human populations. The role of gene methylation as well as the contribution that age, sex and tissue-specific factors have on expression variability are not well understood. Here we used a novel method that accounts for sampling error to classify human genes based on their expression variability in normal human breast and brain tissues. We find that high expression variability is almost exclusively unimodal, indicating that variance is not the result of segregation into distinct expression states. Genes with high expression variability differ markedly between tissues and we find that genes with high population expression variability are likely to have age-, but not sex-dependent expression. Lastly, we find that methylation likely has a key role in controlling expression variability insofar as genes with low expression variability are likely to be non-methylated. We conclude that gene expression variability in the human population is likely to be important in tissue development and identity, methylation, and in natural biological aging. The expression variability of a gene is an important functional characteristic of the gene itself and the classification of a gene as one with Hyper-Variability or Hypo-Variability in a human population or in a specific tissue should be useful in the identification of important genes that functionally regulate development or disease.", - "journal_title": "BMC genomics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/31810449/" - } - ], - "30eabd29-2f48-459a-b162-bd90d99f1411": [ - { - "pub_id": "34967848", - "title": "Cancer Incidence, Mortality, Years of Life Lost, Years Lived With Disability, and Disability-Adjusted Life Years for 29 Cancer Groups From 2010 to 2019: A Systematic Analysis for the Global Burden of Disease Study 2019.", - "authors": " ,Jonathan M Kocarnik,Kelly Compton,Frances E Dean,Weijia Fu,Brian L Gaw,James D Harvey,Hannah Jacqueline Henrikson,Dan Lu,Alyssa Pennini,Rixing Xu,Emad Ababneh,Mohsen Abbasi-Kangevari,Hedayat Abbastabar,Sherief M Abd-Elsalam,Amir Abdoli,Aidin Abedi,Hassan Abidi,Hassan Abolhassani,Isaac Akinkunmi Adedeji,Qorinah Estiningtyas Sakilah Adnani,Shailesh M Advani,Muhammad Sohail Afzal,Mohammad Aghaali,Bright Opoku Ahinkorah,Sajjad Ahmad,Tauseef Ahmad,Ali Ahmadi,Sepideh Ahmadi,Tarik Ahmed Rashid,Yusra Ahmed Salih,Gizachew Taddesse Akalu,Addis Aklilu,Tayyaba Akram,Chisom Joyqueenet Akunna,Hanadi Al Hamad,Fares Alahdab,Ziyad Al-Aly,Saqib Ali,Yousef Alimohamadi,Vahid Alipour,Syed Mohamed Aljunid,Motasem Alkhayyat,Amir Almasi-Hashiani,Nihad A Almasri,Sadeq Ali Ali Al-Maweri,Sami Almustanyir,Nivaldo Alonso,Nelson Alvis-Guzman,Hubert Amu,Etsay Woldu Anbesu,Robert Ancuceanu,Fereshteh Ansari,Alireza Ansari-Moghaddam,Maxwell Hubert Antwi,Davood Anvari,Anayochukwu Edward Anyasodor,Muhammad Aqeel,Jalal Arabloo,Morteza Arab-Zozani,Olatunde Aremu,Hany Ariffin,Timur Aripov,Muhammad Arshad,Al Artaman,Judie Arulappan,Zatollah Asemi,Mohammad Asghari Jafarabadi,Tahira Ashraf,Prince Atorkey,Avinash Aujayeb,Marcel Ausloos,Atalel Fentahun Awedew,Beatriz Paulina Ayala Quintanilla,Temesgen Ayenew,Mohammed A Azab,Sina Azadnajafabad,Amirhossein Azari Jafari,Ghasem Azarian,Ahmed Y Azzam,Ashish D Badiye,Saeed Bahadory,Atif Amin Baig,Jennifer L Baker,Senthilkumar Balakrishnan,Maciej Banach,Till Winfried B\u00e4rnighausen,Francesco Barone-Adesi,Fabio Barra,Amadou Barrow,Masoud Behzadifar,Uzma Iqbal Belgaumi,Woldesellassie M Mequanint Bezabhe,Yihienew Mequanint Bezabih,Devidas S Bhagat,Akshaya Srikanth Bhagavathula,Nikha Bhardwaj,Pankaj Bhardwaj,Sonu Bhaskar,Krittika Bhattacharyya,Vijayalakshmi S Bhojaraja,Sadia Bibi,Ali Bijani,Antonio Biondi,Catherine Bisignano,Tone Bj\u00f8rge,Archie Bleyer,Oleg Blyuss,Obasanjo Afolabi Bolarinwa,Srinivasa Rao Bolla,Dejana Braithwaite,Amanpreet Brar,Hermann Brenner,Maria Teresa Bustamante-Teixeira,Nadeem Shafique Butt,Zahid A Butt,Florentino Luciano Caetano Dos Santos,Yin Cao,Giulia Carreras,Ferr\u00e1n Catal\u00e1-L\u00f3pez,Francieli Cembranel,Ester Cerin,Achille Cernigliaro,Raja Chandra Chakinala,Soosanna Kumary Chattu,Vijay Kumar Chattu,Pankaj Chaturvedi,Odgerel Chimed-Ochir,Daniel Youngwhan Cho,Devasahayam J Christopher,Dinh-Toi Chu,Michael T Chung,Joao Conde,Sanda Cort\u00e9s,Paolo Angelo Cortesi,Vera Marisa Costa,Amanda Ramos Cunha,Omid Dadras,Amare Belachew Dagnew,Saad M A Dahlawi,Xiaochen Dai,Lalit Dandona,Rakhi Dandona,Aso Mohammad Darwesh,Jos\u00e9 das Neves,Fernando Pio De la Hoz,Asmamaw Bizuneh Demis,Edgar Denova-Guti\u00e9rrez,Deepak Dhamnetiya,Mandira Lamichhane Dhimal,Meghnath Dhimal,Mostafa Dianatinasab,Daniel Diaz,Shirin Djalalinia,Huyen Phuc Do,Saeid Doaei,Fariba Dorostkar,Francisco Winter Dos Santos Figueiredo,Tim Robert Driscoll,Hedyeh Ebrahimi,Sahar Eftekharzadeh,Maha El Tantawi,Hassan El-Abid,Iffat Elbarazi,Hala Rashad Elhabashy,Muhammed Elhadi,Shaimaa I El-Jaafary,Babak Eshrati,Sharareh Eskandarieh,Firooz Esmaeilzadeh,Arash Etemadi,Sayeh Ezzikouri,Mohammed Faisaluddin,Emerito Jose A Faraon,Jawad Fares,Farshad Farzadfar,Abdullah Hamid Feroze,Simone Ferrero,Lorenzo Ferro Desideri,Irina Filip,Florian Fischer,James L Fisher,Masoud Foroutan,Takeshi Fukumoto,Peter Andras Gaal,Mohamed M Gad,Muktar A Gadanya,Silvano Gallus,Mariana Gaspar Fonseca,Abera Getachew Obsa,Mansour Ghafourifard,Ahmad Ghashghaee,Nermin Ghith,Maryam Gholamalizadeh,Syed Amir Gilani,Themba G Ginindza,Abraham Tamirat T Gizaw,James C Glasbey,Mahaveer Golechha,Pouya Goleij,Ricardo Santiago Gomez,Sameer Vali Gopalani,Giuseppe Gorini,Houman Goudarzi,Giuseppe Grosso,Mohammed Ibrahim Mohialdeen Gubari,Maximiliano Ribeiro Guerra,Avirup Guha,D Sanjeeva Gunasekera,Bhawna Gupta,Veer Bala Gupta,Vivek Kumar Gupta,Reyna Alma Guti\u00e9rrez,Nima Hafezi-Nejad,Mohammad Rifat Haider,Arvin Haj-Mirzaian,Rabih Halwani,Randah R Hamadeh,Sajid Hameed,Samer Hamidi,Asif Hanif,Shafiul Haque,Netanja I Harlianto,Josep Maria Haro,Ahmed I Hasaballah,Soheil Hassanipour,Roderick J Hay,Simon I Hay,Khezar Hayat,Golnaz Heidari,Mohammad Heidari,Brenda Yuliana Herrera-Serna,Claudiu Herteliu,Kamal Hezam,Ramesh Holla,Md Mahbub Hossain,Mohammad Bellal Hossain Hossain,Mohammad-Salar Hosseini,Mostafa Hosseini,Mehdi Hosseinzadeh,Mihaela Hostiuc,Sorin Hostiuc,Mowafa Househ,Mohamed Hsairi,Junjie Huang,Fernando N Hugo,Rabia Hussain,Nawfal R Hussein,Bing-Fang Hwang,Ivo Iavicoli,Segun Emmanuel Ibitoye,Fidelia Ida,Kevin S Ikuta,Olayinka Stephen Ilesanmi,Irena M Ilic,Milena D Ilic,Lalu Muhammad Irham,Jessica Y Islam,Rakibul M Islam,Sheikh Mohammed Shariful Islam,Nahlah Elkudssiah Ismail,Gaetano Isola,Masao Iwagami,Louis Jacob,Vardhmaan Jain,Mihajlo B Jakovljevic,Tahereh Javaheri,Shubha Jayaram,Seyed Behzad Jazayeri,Ravi Prakash Jha,Jost B Jonas,Tamas Joo,Nitin Joseph,Farahnaz Joukar,Mikk J\u00fcrisson,Ali Kabir,Danial Kahrizi,Leila R Kalankesh,Rohollah Kalhor,Feroze Kaliyadan,Yogeshwar Kalkonde,Ashwin Kamath,Nawzad Kameran Al-Salihi,Himal Kandel,Neeti Kapoor,Andr\u00e9 Karch,Ayele Semachew Kasa,Srinivasa Vittal Katikireddi,Joonas H Kauppila,Taras Kavetskyy,Sewnet Adem Kebede,Pedram Keshavarz,Mohammad Keykhaei,Yousef Saleh Khader,Rovshan Khalilov,Gulfaraz Khan,Maseer Khan,Md Nuruzzaman Khan,Moien A B Khan,Young-Ho Khang,Amir M Khater,Maryam Khayamzadeh,Gyu Ri Kim,Yun Jin Kim,Adnan Kisa,Sezer Kisa,Katarzyna Kissimova-Skarbek,Jacek A Kopec,Rajasekaran Koteeswaran,Parvaiz A Koul,Sindhura Lakshmi Koulmane Laxminarayana,Ai Koyanagi,Burcu Kucuk Bicer,Nuworza Kugbey,G Anil Kumar,Narinder Kumar,Nithin Kumar,Om P Kurmi,Tezer Kutluk,Carlo La Vecchia,Faris Hasan Lami,Iv\u00e1n Landires,Paolo Lauriola,Sang-Woong Lee,Shaun Wen Huey Lee,Wei-Chen Lee,Yo Han Lee,James Leigh,Elvynna Leong,Jiarui Li,Ming-Chieh Li,Xuefeng Liu,Joana A Loureiro,Raimundas Lunevicius,Muhammed Magdy Abd El Razek,Azeem Majeed,Alaa Makki,Shilpa Male,Ahmad Azam Malik,Mohammad Ali Mansournia,Santi Martini,Seyedeh Zahra Masoumi,Prashant Mathur,Martin McKee,Ravi Mehrotra,Walter Mendoza,Ritesh G Menezes,Endalkachew Worku Mengesha,Mohamed Kamal Mesregah,Tomislav Mestrovic,Junmei Miao Jonasson,Bartosz Miazgowski,Tomasz Miazgowski,Irmina Maria Michalek,Ted R Miller,Hamed Mirzaei,Hamid Reza Mirzaei,Sanjeev Misra,Prasanna Mithra,Masoud Moghadaszadeh,Karzan Abdulmuhsin Mohammad,Yousef Mohammad,Mokhtar Mohammadi,Seyyede Momeneh Mohammadi,Abdollah Mohammadian-Hafshejani,Shafiu Mohammed,Nagabhishek Moka,Ali H Mokdad,Mariam Molokhia,Lorenzo Monasta,Mohammad Ali Moni,Mohammad Amin Moosavi,Yousef Moradi,Paula Moraga,Joana Morgado-da-Costa,Shane Douglas Morrison,Abbas Mosapour,Sumaira Mubarik,Lillian Mwanri,Ahamarshan Jayaraman Nagarajan,Shankar Prasad Nagaraju,Chie Nagata,Mukhammad David Naimzada,Vinay Nangia,Atta Abbas Naqvi,Sreenivas Narasimha Swamy,Rawlance Ndejjo,Sabina O Nduaguba,Ionut Negoi,Serban Mircea Negru,Sandhya Neupane Kandel,Cuong Tat Nguyen,Huong Lan Thi Nguyen,Robina Khan Niazi,Chukwudi A Nnaji,Nurulamin M Noor,Virginia Nu\u00f1ez-Samudio,Chimezie Igwegbe Nzoputam,Bogdan Oancea,Chimedsuren Ochir,Oluwakemi Ololade Odukoya,Felix Akpojene Ogbo,Andrew T Olagunju,Babayemi Oluwaseun Olakunde,Emad Omar,Ahmed Omar Bali,Abidemi E Emmanuel Omonisi,Sokking Ong,Obinna E Onwujekwe,Hans Orru,Doris V Ortega-Altamirano,Nikita Otstavnov,Stanislav S Otstavnov,Mayowa O Owolabi,Mahesh P A,Jagadish Rao Padubidri,Keyvan Pakshir,Adrian Pana,Demosthenes Panagiotakos,Songhomitra Panda-Jonas,Shahina Pardhan,Eun-Cheol Park,Eun-Kee Park,Fatemeh Pashazadeh Kan,Harsh K Patel,Jenil R Patel,Siddhartha Pati,Sanjay M Pattanshetty,Uttam Paudel,David M Pereira,Renato B Pereira,Arokiasamy Perianayagam,Julian David Pillay,Saeed Pirouzpanah,Farhad Pishgar,Indrashis Podder,Maarten J Postma,Hadi Pourjafar,Akila Prashant,Liliana Preotescu,Mohammad Rabiee,Navid Rabiee,Amir Radfar,Raghu Anekal Radhakrishnan,Venkatraman Radhakrishnan,Ata Rafiee,Fakher Rahim,Shadi Rahimzadeh,Mosiur Rahman,Muhammad Aziz Rahman,Amir Masoud Rahmani,Nazanin Rajai,Aashish Rajesh,Ivo Rakovac,Pradhum Ram,Kiana Ramezanzadeh,Kamal Ranabhat,Priyanga Ranasinghe,Chythra R Rao,Sowmya J Rao,Reza Rawassizadeh,Mohammad Sadegh Razeghinia,Andre M N Renzaho,Negar Rezaei,Nima Rezaei,Aziz Rezapour,Thomas J Roberts,Jefferson Antonio Buendia Rodriguez,Peter Rohloff,Michele Romoli,Luca Ronfani,Gholamreza Roshandel,Godfrey M Rwegerera,Manjula S,Siamak Sabour,Basema Saddik,Umar Saeed,Amirhossein Sahebkar,Harihar Sahoo,Sana Salehi,Marwa Rashad Salem,Hamideh Salimzadeh,Mehrnoosh Samaei,Abdallah M Samy,Juan Sanabria,Senthilkumar Sankararaman,Milena M Santric-Milicevic,Yaeesh Sardiwalla,Arash Sarveazad,Brijesh Sathian,Monika Sawhney,Mete Saylan,Ione Jayce Ceola Schneider,Mario Sekerija,Allen Seylani,Omid Shafaat,Zahra Shaghaghi,Masood Ali Shaikh,Erfan Shamsoddin,Mohammed Shannawaz,Rajesh Sharma,Aziz Sheikh,Sara Sheikhbahaei,Adithi Shetty,Jeevan K Shetty,Pavanchand H Shetty,Kenji Shibuya,Reza Shirkoohi,K M Shivakumar,Velizar Shivarov,Soraya Siabani,Sudeep K Siddappa Malleshappa,Diego Augusto Santos Silva,Jasvinder A Singh,Yitagesu Sintayehu,Valentin Yurievich Skryabin,Anna Aleksandrovna Skryabina,Matthew J Soeberg,Ahmad Sofi-Mahmudi,Houman Sotoudeh,Paschalis Steiropoulos,Kurt Straif,Ranjeeta Subedi,Mu'awiyyah Babale Sufiyan,Iyad Sultan,Saima Sultana,Daniel Sur,Vikt\u00f3ria Szerencs\u00e9s,Mikl\u00f3s Sz\u00f3cska,Rafael Tabar\u00e9s-Seisdedos,Takahiro Tabuchi,Hooman Tadbiri,Amir Taherkhani,Ken Takahashi,Iman M Talaat,Ker-Kan Tan,Vivian Y Tat,Bemnet Amare A Tedla,Yonas Getaye Tefera,Arash Tehrani-Banihashemi,Mohamad-Hani Temsah,Fisaha Haile Tesfay,Gizachew Assefa Tessema,Rekha Thapar,Aravind Thavamani,Viveksandeep Thoguluva Chandrasekar,Nihal Thomas,Hamid Reza Tohidinik,Mathilde Touvier,Marcos Roberto Tovani-Palone,Eugenio Traini,Bach Xuan Tran,Khanh Bao Tran,Mai Thi Ngoc Tran,Jaya Prasad Tripathy,Biruk Shalmeno Tusa,Irfan Ullah,Saif Ullah,Krishna Kishore Umapathi,Bhaskaran Unnikrishnan,Era Upadhyay,Marco Vacante,Maryam Vaezi,Sahel Valadan Tahbaz,Diana Zuleika Velazquez,Massimiliano Veroux,Francesco S Violante,Vasily Vlassov,Bay Vo,Victor Volovici,Giang Thu Vu,Yasir Waheed,Richard G Wamai,Paul Ward,Yi Feng Wen,Ronny Westerman,Andrea Sylvia Winkler,Lalit Yadav,Seyed Hossein Yahyazadeh Jabbari,Lin Yang,Sanni Yaya,Taklo Simeneh Yazie Yazie,Yigizie Yeshaw,Naohiro Yonemoto,Mustafa Z Younis,Zabihollah Yousefi,Chuanhua Yu,Deniz Yuce,Ismaeel Yunusa,Vesna Zadnik,Fariba Zare,Mikhail Sergeevich Zastrozhin,Anasthasia Zastrozhina,Jianrong Zhang,Chenwen Zhong,Linghui Zhou,Cong Zhu,Arash Ziapour,Ivan R Zimmermann,Christina Fitzmaurice,Christopher J L Murray,Lisa M Force", - "abstract": "The Global Burden of Diseases, Injuries, and Risk Factors Study 2019 (GBD 2019) provided systematic estimates of incidence, morbidity, and mortality to inform local and international efforts toward reducing cancer burden. To estimate cancer burden and trends globally for 204 countries and territories and by Sociodemographic Index (SDI) quintiles from 2010 to 2019. The GBD 2019 estimation methods were used to describe cancer incidence, mortality, years lived with disability, years of life lost, and disability-adjusted life years (DALYs) in 2019 and over the past decade. Estimates are also provided by quintiles of the SDI, a composite measure of educational attainment, income per capita, and total fertility rate for those younger than 25 years. Estimates include 95% uncertainty intervals (UIs). In 2019, there were an estimated 23.6 million (95% UI, 22.2-24.9 million) new cancer cases (17.2 million when excluding nonmelanoma skin cancer) and 10.0 million (95% UI, 9.36-10.6 million) cancer deaths globally, with an estimated 250 million (235-264 million) DALYs due to cancer. Since 2010, these represented a 26.3% (95% UI, 20.3%-32.3%) increase in new cases, a 20.9% (95% UI, 14.2%-27.6%) increase in deaths, and a 16.0% (95% UI, 9.3%-22.8%) increase in DALYs. Among 22 groups of diseases and injuries in the GBD 2019 study, cancer was second only to cardiovascular diseases for the number of deaths, years of life lost, and DALYs globally in 2019. Cancer burden differed across SDI quintiles. The proportion of years lived with disability that contributed to DALYs increased with SDI, ranging from 1.4% (1.1%-1.8%) in the low SDI quintile to 5.7% (4.2%-7.1%) in the high SDI quintile. While the high SDI quintile had the highest number of new cases in 2019, the middle SDI quintile had the highest number of cancer deaths and DALYs. From 2010 to 2019, the largest percentage increase in the numbers of cases and deaths occurred in the low and low-middle SDI quintiles. The results of this systematic analysis suggest that the global burden of cancer is substantial and growing, with burden differing by SDI. These results provide comprehensive and comparable estimates that can potentially inform efforts toward equitable cancer control around the world.", - "journal_title": "JAMA oncology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/34967848/" - } - ], - "3d015864-19e0-428f-ad32-a96c8c1d33bd": [ - { - "pub_id": "28757201", - "title": "Continuity and Admixture in the Last Five Millennia of Levantine History from Ancient Canaanite and Present-Day Lebanese Genome Sequences.", - "authors": "Marc Haber,Claude Doumet-Serhal,Christiana Scheib,Yali Xue,Petr Danecek,Massimo Mezzavilla,Sonia Youhanna,Rui Martiniano,Javier Prado-Martinez,Micha\u0142 Szpak,Elizabeth Matisoo-Smith,Holger Schutkowski,Richard Mikulski,Pierre Zalloua,Toomas Kivisild,Chris Tyler-Smith", - "abstract": "The Canaanites inhabited the Levant region during the Bronze Age and established a culture that became influential in the Near East and beyond. However, the Canaanites, unlike most other ancient Near Easterners of this period, left few surviving textual records and thus their origin and relationship to ancient and present-day populations remain unclear. In this study, we sequenced five whole genomes from \u223c3,700-year-old individuals from the city of Sidon, a major Canaanite city-state on the Eastern Mediterranean coast. We also sequenced the genomes of 99 individuals from present-day Lebanon to catalog modern Levantine genetic diversity. We find that a Bronze Age Canaanite-related ancestry was widespread in the region, shared among urban populations inhabiting the coast (Sidon) and inland populations (Jordan) who likely lived in farming societies or were pastoral nomads. This Canaanite-related ancestry derived from mixture between local Neolithic populations and eastern migrants genetically related to Chalcolithic Iranians. We estimate, using linkage-disequilibrium decay patterns, that admixture occurred 6,600-3,550 years ago, coinciding with recorded massive population movements in Mesopotamia during the mid-Holocene. We show that present-day Lebanese derive most of their ancestry from a Canaanite-related population, which therefore implies substantial genetic continuity in the Levant since at least the Bronze Age. In addition, we find Eurasian ancestry in the Lebanese not present in Bronze Age or earlier Levantines. We estimate that this Eurasian ancestry arrived in the Levant around 3,750-2,170 years ago during a period of successive conquests by distant populations.", - "journal_title": "American journal of human genetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/28757201/" - } - ], - "b688664f-f506-4a4a-b5fd-0b352b8d492b": [ - { - "pub_id": "32066974", - "title": "An immune-cell signature of bacterial sepsis.", - "authors": "Miguel Reyes,Michael R Filbin,Roby P Bhattacharyya,Kianna Billman,Thomas Eisenhaure,Deborah T Hung,Bruce D Levy,Rebecca M Baron,Paul C Blainey,Marcia B Goldberg,Nir Hacohen", - "abstract": "Dysregulation of the immune response to bacterial infection can lead to sepsis, a condition with high mortality. Multiple whole-blood gene-expression studies have defined sepsis-associated molecular signatures, but have not resolved changes in transcriptional states of specific cell types. Here, we used single-cell RNA-sequencing to profile the blood of people with sepsis (n\u2009=\u200929) across three clinical cohorts with corresponding controls (n\u2009=\u200936). We profiled total peripheral blood mononuclear cells (PBMCs, 106,545 cells) and dendritic cells (19,806 cells) across all subjects and, on the basis of clustering of their gene-expression profiles, defined 16 immune-cell states. We identified a unique CD14<sup>+</sup> monocyte state that is expanded in people with sepsis and validated its power in distinguishing these individuals from controls using public transcriptomic data from subjects with different disease etiologies and from multiple geographic locations (18 cohorts, n\u2009=\u20091,467 subjects). We identified a panel of surface markers for isolation and quantification of the monocyte state and characterized its epigenomic and functional phenotypes, and propose a model for its induction from human bone marrow. This study demonstrates the utility of single-cell genomics in discovering disease-associated cytologic signatures and provides insight into the cellular basis of immune dysregulation in bacterial sepsis.", - "journal_title": "Nature medicine", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/32066974/" - } - ], - "3ae91519-34e6-4c06-8126-1156eb9da47b": [ - { - "pub_id": "35120664", - "title": "Genomic characterization of metastatic patterns from prospective clinical sequencing of 25,000 patients.", - "authors": "Bastien Nguyen,Christopher Fong,Anisha Luthra,Shaleigh A Smith,Renzo G DiNatale,Subhiksha Nandakumar,Henry Walch,Walid K Chatila,Ramyasree Madupuri,Ritika Kundra,Craig M Bielski,Brooke Mastrogiacomo,Mark T A Donoghue,Adrienne Boire,Sarat Chandarlapaty,Karuna Ganesh,James J Harding,Christine A Iacobuzio-Donahue,Pedram Razavi,Ed Reznik,Charles M Rudin,Dmitriy Zamarin,Wassim Abida,Ghassan K Abou-Alfa,Carol Aghajanian,Andrea Cercek,Ping Chi,Darren Feldman,Alan L Ho,Gopakumar Iyer,Yelena Y Janjigian,Michael Morris,Robert J Motzer,Eileen M O'Reilly,Michael A Postow,Nitya P Raj,Gregory J Riely,Mark E Robson,Jonathan E Rosenberg,Anton Safonov,Alexander N Shoushtari,William Tap,Min Yuen Teo,Anna M Varghese,Martin Voss,Rona Yaeger,Marjorie G Zauderer,Nadeem Abu-Rustum,Julio Garcia-Aguilar,Bernard Bochner,Abraham Hakimi,William R Jarnagin,David R Jones,Daniela Molena,Luc Morris,Eric Rios-Doria,Paul Russo,Samuel Singer,Vivian E Strong,Debyani Chakravarty,Lora H Ellenson,Anuradha Gopalan,Jorge S Reis-Filho,Britta Weigelt,Marc Ladanyi,Mithat Gonen,Sohrab P Shah,Joan Massague,Jianjiong Gao,Ahmet Zehir,Michael F Berger,David B Solit,Samuel F Bakhoum,Francisco Sanchez-Vega,Nikolaus Schultz", - "abstract": "Metastatic progression is the main cause of death in cancer patients, whereas the underlying genomic mechanisms driving metastasis remain largely unknown. Here, we assembled MSK-MET, a pan-cancer cohort of over 25,000 patients with metastatic diseases. By analyzing genomic and clinical data from this cohort, we identified associations between genomic alterations and patterns of metastatic dissemination across 50 tumor types. We found that chromosomal instability is strongly correlated with metastatic burden in some tumor types, including prostate adenocarcinoma, lung adenocarcinoma, and HR+/HER2+ breast ductal carcinoma, but not in others, including colorectal cancer and high-grade serous ovarian cancer, where copy-number alteration patterns may be established early in tumor development. We also identified somatic alterations associated with metastatic burden and specific target organs. Our data offer a valuable resource for the investigation of the biological basis for metastatic spread and highlight the complex role of chromosomal instability in cancer progression.", - "journal_title": "Cell", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/35120664/" - } - ], - "e44ac473-04c5-4568-97c7-6f2f622e5690": [ - { - "pub_id": "33575316", - "title": "Methylation of 45S Ribosomal DNA (rDNA) Is Associated with Cancer and Aging in Humans.", - "authors": "Fengqing Shao,Xiaoqi Liu,Xianzhi Zhang,Qi Wang,Wencai Wang", - "abstract": "Cancer and aging, two distinct processes of cell development, are two major problems threatening our human health and life in current days. Epigenetic studies, especially DNA methylation, have been intensively investigated on them over the years, though a lot of unanswered issues remain. In the human genome, rDNA is a highly conserved tandem repeat family playing critical roles in protein synthesis, genome stability and integrity, etc. More importantly, rDNA is the significant target of DNA methylation, and a potential association between rDNA methylation and cancer and aging has emerged recently. However, whether there is a general trend that rDNA methylation is associated with cancer and aging remains an open issue. In this study, the involvement of rDNA methylation in a series of records of cancer and aging was investigated and summarized, upon which perspectives about rDNA methylation in cancer and aging were proposed. The results showed that rDNA methylation in most cancer cases displayed a consistent pattern with hypermethylation in the coding region but with hypomethylation in the promoter region, which likely facilitates the proliferation and metastasis of cancerous cells. Distinctively, both the coding and promoter regions of rDNA become increasingly methylated during the process of aging, indicating the decline of rDNA activity. The finding of rDNA methylation also implies its potential application as an epigenetic biomarker in the diagnosis of cancer and aging. This work will shed light on our understanding of the pathogenesis, diagnosis, and treatment of cancer and aging from the perspective of rDNA methylation.", - "journal_title": "International journal of genomics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/33575316/" - } - ], - "4e12ee96-7532-4fc7-b836-a21f68a8f8d6": [ - { - "pub_id": "36925638", - "title": "Comprehensive genomics analysis of aging related gene signature to predict the prognosis and drug resistance of colon adenocarcinoma.", - "authors": "Jubin Feng,Fengyihuan Fu,Yuqiang Nie", - "abstract": "<b>Background:</b> Colon adenocarcinoma (COAD) is a heterogeneous tumor and senescence is crucial in the occurrence of cancer. This study aimed to identify senescence-based subtypes and construct a prognostic signature to predict the prognosis and guide immunotherapy or chemotherapy decisions for COAD patients. <b>Methods:</b> Based on the single-cell RNA sequencing (scRNA-seq) data of 13 samples from the Gene Expression Omnibus (GEO) database, we assessed cellular senescence characteristics. Transcriptome data, copy number variations (CNVs) and single nucleotide variations (SNVs) data were obtained from The Cancer Genome Atlas (TCGA) database. GSE39582 and GSE17537 were used for validation. Senescence subtypes were identified using unsupervised consensus clustering analysis, and a prognostic signature was developed using univariate Cox analysis and least absolute shrinkage and selection operator (LASSO). Response of risk groups to chemotherapy was predicted using the half-maximal inhibitory concentration (IC50) values. We further analyzed the relationship between risk gene expression and methylation level. The prediction performance was assessed by nomogram. <b>Results:</b> Senescence-related pathways were highly enriched in malignant cells and bulk RNA-seq verified cellular senescence. Three senescence subtypes were identified, in which patients in clust3 had poorest prognosis and higher T stage, accompanied with higher tumor mutation burden (TMB) and mutations, activated inflammatory response, more immune cell infiltration, and higher immune escape tendency. A senescence-based signature using 11 genes (MFNG, GPRC5B, TNNT1, CCL22, NOXA1, PABPC1L, PCOLCE2, MID2, CPA3, HSPA1A, and CALB1) was established, and accurately predicted a lower prognosis in high risk patients. Its robustness was validated by external cohort. Low risk patients were more sensitive to small molecule drugs including Erlotinib, Sunitinib, MG-132, CGP-082996, AZ628, Sorafenib, VX-680, and Z-LLNle-CHO. Risk score was an independent prognostic factor and nomogram confirmed its reliability. Four risk genes (CALB1, CPA3, NOXA1, and TNNT1) had significant positive correlation with their methylation level, while six genes (CCL22, GPRC5B, HSPA1A, MFNG, PABPC1L, and PCOLCE2) were negatively correlated with their methylation level. <b>Conclusion:</b> This study provides novel understanding of heterogeneity in COAD from the perspective of senescence, and develops signatures for prognosis prediction in COAD.", - "journal_title": "Frontiers in pharmacology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/36925638/" - } - ], - "88855917-864e-4b74-bc7e-e4fedbae829a": [ - { - "pub_id": "29743675", - "title": "137 ancient human genomes from across the Eurasian steppes.", - "authors": "Peter de Barros Damgaard,Nina Marchi,Simon Rasmussen,Micha\u00ebl Peyrot,Gabriel Renaud,Thorfinn Korneliussen,J V\u00edctor Moreno-Mayar,Mikkel Winther Pedersen,Amy Goldberg,Emma Usmanova,Nurbol Baimukhanov,Valeriy Loman,Lotte Hedeager,Anders Gorm Pedersen,Kasper Nielsen,Gennady Afanasiev,Kunbolot Akmatov,Almaz Aldashev,Ashyk Alpaslan,Gabit Baimbetov,Vladimir I Bazaliiskii,Arman Beisenov,Bazartseren Boldbaatar,Bazartseren Boldgiv,Choduraa Dorzhu,Sturla Ellingvag,Diimaajav Erdenebaatar,Rana Dajani,Evgeniy Dmitriev,Valeriy Evdokimov,Karin M Frei,Andrey Gromov,Alexander Goryachev,Hakon Hakonarson,Tatyana Hegay,Zaruhi Khachatryan,Ruslan Khaskhanov,Egor Kitov,Alina Kolbina,Tabaldiev Kubatbek,Alexey Kukushkin,Igor Kukushkin,Nina Lau,Ashot Margaryan,Inga Merkyte,Ilya V Mertz,Viktor K Mertz,Enkhbayar Mijiddorj,Vyacheslav Moiyesev,Gulmira Mukhtarova,Bekmukhanbet Nurmukhanbetov,Z Orozbekova,Irina Panyushkina,Karol Pieta,V\u00e1clav Smr\u010dka,Irina Shevnina,Andrey Logvin,Karl-G\u00f6ran Sj\u00f6gren,Tereza \u0160tolcov\u00e1,Angela M Taravella,Kadicha Tashbaeva,Alexander Tkachev,Turaly Tulegenov,Dmitriy Voyakin,Levon Yepiskoposyan,Sainbileg Undrakhbold,Victor Varfolomeev,Andrzej Weber,Melissa A Wilson Sayres,Nikolay Kradin,Morten E Allentoft,Ludovic Orlando,Rasmus Nielsen,Martin Sikora,Evelyne Heyer,Kristian Kristiansen,Eske Willerslev", - "abstract": "For thousands of years the Eurasian steppes have been a centre of human migrations and cultural change. Here we sequence the genomes of 137 ancient humans (about 1\u00d7 average coverage), covering a period of 4,000 years, to understand the population history of the Eurasian steppes after the Bronze Age migrations. We find that the genetics of the Scythian groups that dominated the Eurasian steppes throughout the Iron Age were highly structured, with diverse origins comprising Late Bronze Age herders, European farmers and southern Siberian hunter-gatherers. Later, Scythians admixed with the eastern steppe nomads who formed the Xiongnu confederations, and moved westward in about the second or third century BC, forming the Hun traditions in the fourth-fifth century AD, and carrying with them plague that was basal to the Justinian plague. These nomads were further admixed with East Asian groups during several short-term khanates in the Medieval period. These historical events transformed the Eurasian steppes from being inhabited by Indo-European speakers of largely West Eurasian ancestry to the mostly Turkic-speaking groups of the present day, who are primarily of East Asian ancestry.", - "journal_title": "Nature", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/29743675/" - } - ], - "cfe77366-42e2-4960-bf96-01a3e0a61ff4": [ - { - "pub_id": "31645730", - "title": "The landscape of somatic mutation in normal colorectal epithelial cells.", - "authors": "Henry Lee-Six,Sigurgeir Olafsson,Peter Ellis,Robert J Osborne,Mathijs A Sanders,Luiza Moore,Nikitas Georgakopoulos,Franco Torrente,Ayesha Noorani,Martin Goddard,Philip Robinson,Tim H H Coorens,Laura O'Neill,Christopher Alder,Jingwei Wang,Rebecca C Fitzgerald,Matthias Zilbauer,Nicholas Coleman,Kourosh Saeb-Parsy,Inigo Martincorena,Peter J Campbell,Michael R Stratton", - "abstract": "The colorectal adenoma-carcinoma sequence has provided a paradigmatic framework for understanding the successive somatic genetic changes and consequent clonal expansions that lead to cancer<sup>1</sup>. However, our understanding of the earliest phases of colorectal neoplastic changes-which may occur in morphologically normal tissue-is comparatively limited, as for most cancer types. Here we use whole-genome sequencing to analyse hundreds of normal crypts from 42 individuals. Signatures of multiple mutational processes were revealed; some of these were ubiquitous and continuous, whereas others were only found in some individuals, in some crypts or during certain periods of life. Probable driver mutations were present in around 1% of normal colorectal crypts in middle-aged individuals, indicating that adenomas and carcinomas are rare outcomes of a pervasive process of neoplastic change across morphologically normal colorectal epithelium. Colorectal cancers exhibit substantially increased mutational burdens relative to normal cells. Sequencing normal colorectal cells provides quantitative insights into the genomic and clonal evolution of cancer.", - "journal_title": "Nature", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/31645730/" - } - ], - "f12f0ae0-db63-40cd-826b-b4fb1d704f1c": [ - { - "pub_id": "31951611", - "title": "Dating genomic variants and shared ancestry in population-scale sequencing data.", - "authors": "Patrick K Albers,Gil McVean", - "abstract": "The origin and fate of new mutations within species is the fundamental process underlying evolution. However, while much attention has been focused on characterizing the presence, frequency, and phenotypic impact of genetic variation, the evolutionary histories of most variants are largely unexplored. We have developed a nonparametric approach for estimating the date of origin of genetic variants in large-scale sequencing data sets. The accuracy and robustness of the approach is demonstrated through simulation. Using data from two publicly available human genomic diversity resources, we estimated the age of more than 45 million single-nucleotide polymorphisms (SNPs) in the human genome and release the Atlas of Variant Age as a public online database. We characterize the relationship between variant age and frequency in different geographical regions and demonstrate the value of age information in interpreting variants of functional and selective importance. Finally, we use allele age estimates to power a rapid approach for inferring the ancestry shared between individual genomes and to quantify genealogical relationships at different points in the past, as well as to describe and explore the evolutionary history of modern human populations.", - "journal_title": "PLoS biology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/31951611/" - } - ], - "60a48b32-ac3c-461b-9add-b48fb75af25e": [ - { - "pub_id": "32527937", - "title": "Transposable elements, circular RNAs and mitochondrial transcription in age-related genomic regulation.", - "authors": "Juan I Bravo,S\u00e9verine Nozownik,Prakroothi S Danthi,B\u00e9r\u00e9nice A Benayoun", - "abstract": "Our understanding of the molecular regulation of aging and age-related diseases is still in its infancy, requiring in-depth characterization of the molecular landscape shaping these complex phenotypes. Emerging classes of molecules with promise as aging modulators include transposable elements, circRNAs and the mitochondrial transcriptome. Analytical complexity means that these molecules are often overlooked, even though they exhibit strong associations with aging and, in some cases, may directly contribute to its progress. Here, we review the links between these novel factors and age-related phenotypes, and we suggest tools that can be easily incorporated into existing pipelines to better understand the aging process.", - "journal_title": "Development (Cambridge, England)", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/32527937/" - } - ], - "c4962ed0-1d95-4763-bdac-752eb2ba743e": [ - { - "pub_id": "30819113", - "title": "A modular analysis of microglia gene expression, insights into the aged phenotype.", - "authors": "Christine E Cho,Sagar S Damle,Edward V Wancewicz,Swagatam Mukhopadhyay,Christopher E Hart,Curt Mazur,Eric E Swayze,Fredrik Kamme", - "abstract": "Microglia are multifunctional cells that are key players in brain development and homeostasis. Recent years have seen tremendous growth in our understanding of the role microglia play in neurodegeneration, CNS injury, and developmental disorders. Given that microglia show diverse functional phenotypes, there is a need for more precise tools to characterize microglial states. Here, we experimentally define gene modules as the foundation for describing microglial functional states. In an effort to develop a comprehensive classification scheme, we profiled transcriptomes of mouse microglia in a stimulus panel with 96 different conditions. Using the transcriptomic data, we generated fine-resolution gene modules that are robustly preserved across datasets. These modules served as the basis for a combinatorial code that we then used to characterize microglial activation under various inflammatory stimulus conditions. The microglial gene modules described here were robustly preserved, and could be applied to in vivo as well as in vitro conditions to dissociate the signaling pathways that distinguish acutely inflamed microglia from aged microglia. The microglial gene modules presented here are a novel resource for classifying and characterizing microglial states in health and disease.", - "journal_title": "BMC genomics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/30819113/" - } - ], - "4cf93c52-524e-48ab-b485-77928ca67b40": [ - { - "pub_id": "29674453", - "title": "Multiple large-scale gene and genome duplications during the evolution of hexapods.", - "authors": "Zheng Li,George P Tiley,Sally R Galuska,Chris R Reardon,Thomas I Kidder,Rebecca J Rundell,Michael S Barker", - "abstract": "Polyploidy or whole genome duplication (WGD) is a major contributor to genome evolution and diversity. Although polyploidy is recognized as an important component of plant evolution, it is generally considered to play a relatively minor role in animal evolution. Ancient polyploidy is found in the ancestry of some animals, especially fishes, but there is little evidence for ancient WGDs in other metazoan lineages. Here we use recently published transcriptomes and genomes from more than 150 species across the insect phylogeny to investigate whether ancient WGDs occurred during the evolution of Hexapoda, the most diverse clade of animals. Using gene age distributions and phylogenomics, we found evidence for 18 ancient WGDs and six other large-scale bursts of gene duplication during insect evolution. These bursts of gene duplication occurred in the history of lineages such as the Lepidoptera, Trichoptera, and Odonata. To further corroborate the nature of these duplications, we evaluated the pattern of gene retention from putative WGDs observed in the gene age distributions. We found a relatively strong signal of convergent gene retention across many of the putative insect WGDs. Considering the phylogenetic breadth and depth of the insect phylogeny, this observation is consistent with polyploidy as we expect dosage balance to drive the parallel retention of genes. Together with recent research on plant evolution, our hexapod results suggest that genome duplications contributed to the evolution of two of the most diverse lineages of eukaryotes on Earth.", - "journal_title": "Proceedings of the National Academy of Sciences of the United States of America", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/29674453/" - } - ], - "f4dd6a1d-062b-42bc-8e22-83fcb3135578": [ - { - "pub_id": "32649873", - "title": "Pathogenic Mechanisms of Somatic Mutation and Genome Mosaicism in Aging.", - "authors": "Jan Vijg,Xiao Dong", - "abstract": "Age-related accumulation of postzygotic DNA mutations results in tissue genetic heterogeneity known as somatic mosaicism. Although implicated in aging as early as the 1950s, somatic mutations in normal tissue have been difficult to study because of their low allele fractions. With the recent emergence of cost-effective high-throughput sequencing down to the single-cell level, enormous progress has been made in our capability to quantitatively analyze somatic mutations in human tissue in relation to aging and disease. Here we first review how recent technological progress has opened up this field, providing the first broad sets of quantitative information on somatic mutations in\u00a0vivo necessary to gain insight into their possible causal role in human aging and disease. We then propose three major mechanisms that can lead from accumulated de novo mutations across tissues to cell functional loss and human disease.", - "journal_title": "Cell", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/32649873/" - } - ], - "40397283-906e-4c54-933c-336648fb1ba0": [ - { - "pub_id": "31564434", - "title": "GWAS Identifies 44 Independent Associated Genomic Loci for Self-Reported Adult Hearing Difficulty in UK Biobank.", - "authors": "Helena R R Wells,Maxim B Freidin,Fatin N Zainul Abidin,Antony Payton,Piers Dawes,Kevin J Munro,Cynthia C Morton,David R Moore,Sally J Dawson,Frances M K Williams", - "abstract": "Age-related hearing impairment (ARHI) is the most common sensory impairment in the aging population; a third of individuals are affected by disabling hearing loss by the age of 65. It causes social isolation and depression and has recently been identified as a risk factor for dementia. The genetic risk factors and underlying pathology of ARHI are largely unknown, meaning that targets for new therapies remain elusive, yet heritability estimates range between 35% and 55%. We performed genome-wide association studies (GWASs) for two self-reported hearing phenotypes, using more than 250,000\u00a0UK Biobank (UKBB) volunteers aged between 40 and 69\u00a0years. Forty-four independent genome-wide significant loci (p < 5E-08) were identified, considerably increasing the number of established\u00a0trait loci. Thirty-four loci are novel associations with hearing loss of any form, and only one of the ten known hearing loci has a previously reported association with an ARHI-related trait. Gene sets from these loci are enriched in auditory processes such as synaptic activities, nervous system processes, inner ear morphology, and cognition, while genetic correlation analysis revealed strong positive correlations with multiple personality and psychological traits for the first time. Immunohistochemistry for protein localization in adult mouse cochlea implicate metabolic, sensory, and neuronal functions for NID2, CLRN2, and ARHGEF28. These results provide insight into the genetic landscape underlying ARHI, opening up novel therapeutic targets for further investigation. In a wider context, our study also highlights the viability of using self-report phenotypes for genetic discovery in very large samples when deep phenotyping is unavailable.", - "journal_title": "American journal of human genetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/31564434/" - } - ], - "6d77ee5f-f4b7-412b-abd6-527666af6bbf": [ - { - "pub_id": "29298683", - "title": "Global accumulation of circRNAs during aging in Caenorhabditis elegans.", - "authors": "Mariela Cort\u00e9s-L\u00f3pez,Matthew R Gruner,Daphne A Cooper,Hannah N Gruner,Alexandru-Ioan Voda,Alexander M van der Linden,Pedro Miura", - "abstract": "Circular RNAs (CircRNAs) are a newly appreciated class of RNAs that lack free 5' and 3' ends, are expressed by the thousands in diverse forms of life, and are mostly of enigmatic function. Ostensibly due to their resistance to exonucleases, circRNAs are known to be exceptionally stable. Previous work in Drosophila and mice have shown that circRNAs increase during aging in neural tissues. Here, we examined the global profile of circRNAs in C. elegans during aging by performing ribo-depleted total RNA-seq from the fourth larval stage (L4) through 10-day old adults. Using stringent bioinformatic criteria and experimental validation, we annotated a high-confidence set of 1166 circRNAs, including 575 newly discovered circRNAs. These circRNAs were derived from 797 genes with diverse functions, including genes involved in the determination of lifespan. A massive accumulation of circRNAs during aging was uncovered. Many hundreds of circRNAs were significantly increased among the aging time-points and increases of select circRNAs by over 40-fold during aging were quantified by RT-qPCR. The expression of 459 circRNAs was determined to be distinct from the expression of linear RNAs from the same host genes, demonstrating host gene independence of circRNA age-accumulation. We attribute the global scale of circRNA age-accumulation to the high composition of post-mitotic cells in adult C. elegans, coupled with the high resistance of circRNAs to decay. These findings suggest that the exceptional stability of circRNAs might explain age-accumulation trends observed from neural tissues of other organisms, which also have a high composition of post-mitotic cells. Given the suitability of C. elegans for aging research, it is now poised as an excellent model system to determine whether there are functional consequences of circRNA accumulation during aging.", - "journal_title": "BMC genomics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/29298683/" - } - ], - "4fc73c30-054c-4e22-a8c3-7c38812a21d4": [ - { - "pub_id": "33893045", - "title": "Designing Future Crops: Genomics-Assisted Breeding Comes of Age.", - "authors": "Rajeev K Varshney,Abhishek Bohra,Jianming Yu,Andreas Graner,Qifa Zhang,Mark E Sorrells", - "abstract": "Over the past decade, genomics-assisted breeding (GAB) has been instrumental in harnessing the potential of modern genome resources and characterizing and exploiting allelic variation for germplasm enhancement and cultivar development. Sustaining GAB in the future (GAB 2.0) will rely upon a suite of new approaches that fast-track targeted manipulation of allelic variation for creating novel diversity and facilitate their rapid and efficient incorporation in crop improvement programs. Genomic breeding strategies that optimize crop genomes with accumulation of beneficial alleles and purging of deleterious alleles will be indispensable for designing future crops. In coming decades, GAB 2.0 is expected to play a crucial role in breeding more climate-smart crop cultivars with higher nutritional value in a cost-effective and timely manner.", - "journal_title": "Trends in plant science", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/33893045/" - } - ], - "35a178e9-6bb8-46a9-a720-a726a9d2c439": [ - { - "pub_id": "28096526", - "title": "Telomeres in cancer: tumour suppression and genome instability.", - "authors": "John Maciejowski,Titia de Lange", - "abstract": "The shortening of human telomeres has two opposing effects during cancer development. On the one hand, telomere shortening can exert a tumour-suppressive effect through the proliferation arrest induced by activating the kinases ATM and ATR at unprotected chromosome ends. On the other hand, loss of telomere protection can lead to telomere crisis, which is a state of extensive genome instability that can promote cancer progression. Recent data, reviewed here, provide new evidence for the telomere tumour suppressor pathway and has revealed that telomere crisis can induce numerous cancer-relevant changes, including chromothripsis, kataegis and tetraploidization.", - "journal_title": "Nature reviews. Molecular cell biology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/28096526/" - } - ], - "cdcd26cf-e76a-4e00-88ea-235c46bddf31": [ - { - "pub_id": "29333609", - "title": "Runs of homozygosity reveal genome-wide autozygosity in Italian sheep breeds.", - "authors": "S Mastrangelo,E Ciani,M T Sardina,G Sottile,F Pilla,B Portolano, ", - "abstract": "The availability of dense single nucleotide polymorphism (SNP) assays allows for the determination of autozygous segments based on runs of consecutive homozygous genotypes (ROH). The aim of the present study was to investigate the occurrence and distribution of ROH in 21 Italian sheep breeds using medium-density SNP genotypes in order to characterize autozygosity and identify genomic regions that frequently appeared in ROH within individuals, namely ROH islands. After filtering, the final number of animals and SNPs retained for analyses were 502 and 46\u00a0277 respectively. A total of 12\u00a0302 ROH were identified. The mean number of ROH per breed ranged from 10.58 (Comisana) to 44.54 (Valle del Belice). The average length of ROH across breeds was 4.55\u00a0Mb and ranged from 3.85\u00a0Mb (Biellese) to 5.51\u00a0Mb (Leccese). Valle del Belice showed the highest value of inbreeding on the basis of ROH (F<sub>ROH</sub> \u00a0=\u00a00.099), whereas Comisana showed the lowest (F<sub>ROH</sub> \u00a0=\u00a00.016), and high standard deviation values revealed high variability in autozygosity levels within each breed. Differences also existed in the length of ROH. Analysis of the distribution of ROH according to their size showed that, for all breeds, the majority of the detected ROH were <10\u00a0Mb in length, with a few long ROH\u00a0>25\u00a0Mb. The levels of ROH that we estimated here reflect the inbreeding history of the investigated sheep breeds. These results also highlight that ancient and recent inbreeding have had an impact on the genome of the Italian sheep breeds and suggest that several animals have experienced recent autozygosity events. Comisana and Bergamasca appeared as the less consanguineous breeds, whereas Barbaresca, Leccese and Valle del Belice showed ROH patterns typically produced by recent inbreeding. Moreover, within the genomic regions most commonly associated with ROH, several candidate genes were detected.", - "journal_title": "Animal genetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/29333609/" - } - ], - "80e1b2af-be79-4d9b-852f-46bf3e23c963": [ - { - "pub_id": "35329812", - "title": "AMD Genomics: Non-Coding RNAs as Biomarkers and Therapeutic Targets.", - "authors": "Charles Zhang,Leah A Owen,John H Lillvis,Sarah X Zhang,Ivana K Kim,Margaret M DeAngelis", - "abstract": "Age-related macular degeneration (AMD) is a progressive neurodegenerative disease that is the world's leading cause of blindness in the aging population. Although the clinical stages and forms of AMD have been elucidated, more specific prognostic tools are required to determine when patients with early and intermediate AMD will progress into the advanced stages of AMD. Another challenge in the field has been the appropriate development of therapies for intermediate AMD and advanced atrophic AMD. After numerous negative clinical trials, an anti-C5 agent and anti-C3 agent have recently shown promising results in phase 3 clinical trials, in terms of slowing the growth of geographic atrophy, an advanced form of AMD. Interestingly, both drugs appear to be associated with an increased incidence of wet AMD, another advanced form of the disease, and will require frequent intravitreal injections. Certainly, there remains a need for other therapeutic agents with the potential to prevent progression to advanced stages of the disease. Investigation of the role and clinical utility of non-coding RNAs (ncRNAs) is a major advancement in biology that has only been minimally applied to AMD. In the following review, we discuss the clinical relevance of ncRNAs in AMD as both biomarkers and therapeutic targets.", - "journal_title": "Journal of clinical medicine", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/35329812/" - } - ], - "4c2f8dcb-02a1-4968-a117-bdf505cad02f": [ - { - "pub_id": "28240269", - "title": "Connecting genetic risk to disease end points through the human blood plasma proteome.", - "authors": "Karsten Suhre,Matthias Arnold,Aditya Mukund Bhagwat,Richard J Cotton,Rudolf Engelke,Johannes Raffler,Hina Sarwath,Gaurav Thareja,Annika Wahl,Robert Kirk DeLisle,Larry Gold,Marija Pezer,Gordan Lauc,Mohammed A El-Din Selim,Dennis O Mook-Kanamori,Eman K Al-Dous,Yasmin A Mohamoud,Joel Malek,Konstantin Strauch,Harald Grallert,Annette Peters,Gabi Kastenm\u00fcller,Christian Gieger,Johannes Graumann", - "abstract": "Genome-wide association studies (GWAS) with intermediate phenotypes, like changes in metabolite and protein levels, provide functional evidence to map disease associations and translate them into clinical applications. However, although hundreds of genetic variants have been associated with complex disorders, the underlying molecular pathways often remain elusive. Associations with intermediate traits are key in establishing functional links between GWAS-identified risk-variants and disease end points. Here we describe a GWAS using a highly multiplexed aptamer-based affinity proteomics platform. We quantify 539 associations between protein levels and gene variants (pQTLs) in a German cohort and replicate over half of them in an Arab and Asian cohort. Fifty-five of the replicated pQTLs are located in trans. Our associations overlap with 57 genetic risk loci for 42 unique disease end points. We integrate this information into a genome-proteome network and provide an interactive web-tool for interrogations. Our results provide a basis for novel approaches to pharmaceutical and diagnostic applications.", - "journal_title": "Nature communications", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/28240269/" - } - ], - "f58f52a1-a704-49c1-b3b6-fde6ebdec9fc": [ - { - "pub_id": "33057201", - "title": "Inherited causes of clonal haematopoiesis in 97,691 whole genomes.", - "authors": "Alexander G Bick,Joshua S Weinstock,Satish K Nandakumar,Charles P Fulco,Erik L Bao,Seyedeh M Zekavat,Mindy D Szeto,Xiaotian Liao,Matthew J Leventhal,Joseph Nasser,Kyle Chang,Cecelia Laurie,Bala Bharathi Burugula,Christopher J Gibson,Amy E Lin,Margaret A Taub,Francois Aguet,Kristin Ardlie,Braxton D Mitchell,Kathleen C Barnes,Arden Moscati,Myriam Fornage,Susan Redline,Bruce M Psaty,Edwin K Silverman,Scott T Weiss,Nicholette D Palmer,Ramachandran S Vasan,Esteban G Burchard,Sharon L R Kardia,Jiang He,Robert C Kaplan,Nicholas L Smith,Donna K Arnett,David A Schwartz,Adolfo Correa,Mariza de Andrade,Xiuqing Guo,Barbara A Konkle,Brian Custer,Juan M Peralta,Hongsheng Gui,Deborah A Meyers,Stephen T McGarvey,Ida Yii-Der Chen,M Benjamin Shoemaker,Patricia A Peyser,Jai G Broome,Stephanie M Gogarten,Fei Fei Wang,Quenna Wong,May E Montasser,Michelle Daya,Eimear E Kenny,Kari E North,Lenore J Launer,Brian E Cade,Joshua C Bis,Michael H Cho,Jessica Lasky-Su,Donald W Bowden,L Adrienne Cupples,Angel C Y Mak,Lewis C Becker,Jennifer A Smith,Tanika N Kelly,Stella Aslibekyan,Susan R Heckbert,Hemant K Tiwari,Ivana V Yang,John A Heit,Steven A Lubitz,Jill M Johnsen,Joanne E Curran,Sally E Wenzel,Daniel E Weeks,Dabeeru C Rao,Dawood Darbar,Jee-Young Moon,Russell P Tracy,Erin J Buth,Nicholas Rafaels,Ruth J F Loos,Peter Durda,Yongmei Liu,Lifang Hou,Jiwon Lee,Priyadarshini Kachroo,Barry I Freedman,Daniel Levy,Lawrence F Bielak,James E Hixson,James S Floyd,Eric A Whitsel,Patrick T Ellinor,Marguerite R Irvin,Tasha E Fingerlin,Laura M Raffield,Sebastian M Armasu,Marsha M Wheeler,Ester C Sabino,John Blangero,L Keoki Williams,Bruce D Levy,Wayne Huey-Herng Sheu,Dan M Roden,Eric Boerwinkle,JoAnn E Manson,Rasika A Mathias,Pinkal Desai,Kent D Taylor,Andrew D Johnson, ,Paul L Auer,Charles Kooperberg,Cathy C Laurie,Thomas W Blackwell,Albert V Smith,Hongyu Zhao,Ethan Lange,Leslie Lange,Stephen S Rich,Jerome I Rotter,James G Wilson,Paul Scheet,Jacob O Kitzman,Eric S Lander,Jesse M Engreitz,Benjamin L Ebert,Alexander P Reiner,Siddhartha Jaiswal,Gon\u00e7alo Abecasis,Vijay G Sankaran,Sekar Kathiresan,Pradeep Natarajan", - "abstract": "Age is the dominant risk factor for most chronic human diseases, but the mechanisms through which ageing confers this risk are largely unknown<sup>1</sup>. The age-related acquisition of somatic mutations that lead to clonal expansion in regenerating haematopoietic stem cell populations has recently been associated with both haematological cancer<sup>2-4</sup> and coronary heart disease<sup>5</sup>-this phenomenon is\u00a0termed clonal haematopoiesis of indeterminate potential (CHIP)<sup>6</sup>. Simultaneous analyses of germline and somatic whole-genome sequences provide the opportunity to identify root causes of CHIP. Here we analyse high-coverage whole-genome sequences from 97,691 participants of diverse ancestries in the National Heart, Lung, and Blood Institute Trans-omics for Precision Medicine (TOPMed) programme, and identify 4,229 individuals with CHIP. We identify associations with blood cell, lipid and inflammatory traits that are specific to different CHIP\u00a0driver genes. Association of a genome-wide set of germline genetic variants enabled the identification of three genetic loci associated with CHIP status, including one locus at TET2 that was specific to individuals of African ancestry. In silico-informed in vitro evaluation of the TET2 germline locus enabled the identification of a causal variant that disrupts a TET2 distal enhancer, resulting in increased self-renewal of haematopoietic stem cells. Overall, we observe that germline genetic variation shapes haematopoietic stem cell function, leading to CHIP through mechanisms that are specific to clonal haematopoiesis as well as shared mechanisms that lead to somatic mutations across tissues.", - "journal_title": "Nature", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/33057201/" - } - ], - "48fc05db-21f8-4493-897b-1ee2c6cec417": [ - { - "pub_id": "32118628", - "title": "Genomic and Clinicopathologic Characteristics of PRKAR1A-inactivated Melanomas: Toward Genetic Distinctions of Animal-type Melanoma/Pigment Synthesizing Melanoma.", - "authors": "Jarish N Cohen,Iwei Yeh,Thaddeus W Mully,Philip E LeBoit,Timothy H McCalmont", - "abstract": "Melanocytic tumors with inactivation of protein kinase A regulatory subunit-\u03b1 (PRKAR1A) have large oval nuclei and intense pigmentation. Historically, these tumors have been categorized under various names, including epithelioid blue nevus, pigmented epithelioid melanocytoma (PEM) and animal-type melanoma. Although a subset of PEM harbor BRAF activating mutations and biallelic inactivation of PRKAR1A, there are only a few reports of melanomas, or of tumors with genomic alterations beyond those of PEMs. Herein, we describe the clinicopathologic and genetic features of 8 melanomas and tumors that lack PRKAR1\u03b1 expression by immunohistochemistry but do not fit with conventional PRKAR1A-inactivated melanocytomas. These tumors tended to affect younger patients than conventional melanomas (median age=38\u2009y) and presented as dark brown/black papules and nodules. Histopathologically, they demonstrated nodularity, sometimes in a background of conventional melanoma, and large vesicular nuclei with prominent nucleoli. With the exception of 1 case, the mitotic index was not significantly elevated. Immunohistochemically, all cases showed loss of PRKAR1\u03b1 and of p16 expression. Seven tumors underwent massively parallel short read (next-generation) sequencing of a panel of 480 cancer-associated genes. Five tumors demonstrated truncating mutations of PRKAR1A and the 2 in which such mutations were not identified demonstrated loss of heterozygosity of the PRKAR1A locus. Four of the tumors harbored BRAF V600E mutations, and 1 harbored a FAM39B-BRAF gene fusion. Another harbored a GNA11 activating mutation. A MAP kinase activating mutation was not identified in the remaining case. Four tumors displayed TERT promoter mutations and chromosomal copy number changes supporting the diagnosis of melanoma. Two cases without these alterations and were classified as \"high-grade PRKAR1A-inactivated melanocytomas\". The 1 case with widespread metastases demonstrated mutations in TP53 and RB1. Overall, we provide the first genetic characterization of PRKAR1A-inactivated melanomas, discuss the differential diagnosis of heavily pigmented epithelioid melanocytic neoplasms, and propose a new nomenclature for such tumors.", - "journal_title": "The American journal of surgical pathology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/32118628/" - } - ], - "aa48c641-3db1-4cf4-bb71-b1d57c24e13f": [ - { - "pub_id": "36658433", - "title": "Genome-wide RNA polymerase stalling shapes the transcriptome during aging.", - "authors": "Akos Gyenis,Jiang Chang,Joris J P G Demmers,Serena T Bruens,Sander Barnhoorn,Renata M C Brandt,Marjolein P Baar,Marko Raseta,Kasper W J Derks,Jan H J Hoeijmakers,Joris Pothof", - "abstract": "Gene expression profiling has identified numerous processes altered in aging, but how these changes arise is largely unknown. Here we combined nascent RNA sequencing and RNA polymerase II chromatin immunoprecipitation followed by sequencing to elucidate the underlying mechanisms triggering gene expression changes in wild-type aged mice. We found that in 2-year-old liver, 40% of elongating RNA polymerases are stalled, lowering productive transcription and skewing transcriptional output in a gene-length-dependent fashion. We demonstrate that this transcriptional stress is caused by endogenous DNA damage and explains the majority of gene expression changes in aging in most mainly postmitotic organs, specifically affecting aging hallmark pathways such as nutrient sensing, autophagy, proteostasis, energy metabolism, immune function and cellular stress resilience. Age-related transcriptional stress is evolutionary conserved from nematodes to humans. Thus, accumulation of stochastic endogenous DNA damage during aging deteriorates basal transcription, which establishes the age-related transcriptome and causes dysfunction of key aging hallmark pathways, disclosing how DNA damage functionally underlies major aspects of normal aging.", - "journal_title": "Nature genetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/36658433/" - } - ], - "104a9a2e-c356-44d9-8d64-83f0d34a258b": [ - { - "pub_id": "30573846", - "title": "Reliability of human cortical organoid generation.", - "authors": "Se-Jin Yoon,Lubayna S Elahi,Anca M Pa\u0219ca,Rebecca M Marton,Aaron Gordon,Omer Revah,Yuki Miura,Elisabeth M Walczak,Gwendolyn M Holdgate,H Christina Fan,John R Huguenard,Daniel H Geschwind,Sergiu P Pa\u0219ca", - "abstract": "The differentiation of pluripotent stem cells in three-dimensional cultures can recapitulate key aspects of brain development, but protocols are prone to variable results. Here we differentiated multiple human pluripotent stem cell lines for over 100 d using our previously developed approach to generate brain-region-specific organoids called cortical spheroids and, using several assays, found that spheroid generation was highly reliable and consistent. We anticipate the use of this approach for large-scale differentiation experiments and disease modeling.", - "journal_title": "Nature methods", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/30573846/" - } - ], - "5a147c5d-3723-4075-93c7-abd6db7cec85": [ - { - "pub_id": "30971729", - "title": "Genomic prediction of cognitive traits in childhood and adolescence.", - "authors": "A G Allegrini,S Selzam,K Rimfeld,S von Stumm,J B Pingault,R Plomin", - "abstract": "Recent advances in genomics are producing powerful DNA predictors of complex traits, especially cognitive abilities. Here, we leveraged summary statistics from the most recent genome-wide association studies of intelligence and educational attainment, with highly genetically correlated traits, to build prediction models of general cognitive ability and educational achievement. To this end, we compared the performances of multi-trait genomic and polygenic scoring methods. In a representative UK sample of 7,026 children at ages 12 and 16, we show that we can now predict up to 11% of the variance in intelligence and 16% in educational achievement. We also show that predictive power increases from age 12 to age 16 and that genomic predictions do not differ for girls and boys. We found that multi-trait genomic methods were effective in boosting predictive power. Prediction accuracy varied across polygenic score approaches, however results were similar for different multi-trait and polygenic score methods. We discuss general caveats of multi-trait methods and polygenic score prediction, and conclude that polygenic scores for educational attainment and intelligence are currently the most powerful predictors in the behavioural sciences.", - "journal_title": "Molecular psychiatry", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/30971729/" - } - ], - "6e834383-7260-4601-b5b3-e33a99f2796a": [ - { - "pub_id": "31208334", - "title": "Whole-genome mapping identified novel \"QTL hotspots regions\" for seed storability in soybean (Glycine max L.).", - "authors": "Xi Zhang,Aiman Hina,Shiyu Song,Jiejie Kong,Javaid Akhter Bhat,Tuanjie Zhao", - "abstract": "Seed aging in soybean is a serious challenge for agronomic production and germplasm preservation. However, its genetic basis remains largely unclear in soybean. Unraveling the genetic mechanism involved in seed aging, and enhancing seed storability is an imperative goal for soybean breeding. The aim of this study is to identify quantitative trait loci (QTLs) using high-density genetic linkage maps of soybean for seed storability. In this regard, two recombinant inbred line (RIL) populations derived from Zhengyanghuangdou \u00d7 Meng 8206 (ZM6) and Linhefenqingdou \u00d7 Meng 8206 (LM6) crosses were evaluated for three seed-germination related traits viz., germination rate (GR), normal seedling length (SL) and normal seedling fresh weight (FW) under natural and artificial aging conditions to map QTLs for seed storability. A total of 34 QTLs, including 13 QTLs for GR, 11 QTLs for SL and 10 QTLs for FW, were identified on 11 chromosomes with the phenotypic variation ranged from 7.30 to 23.16% under both aging conditions. All these QTLs were novel, and 21 of these QTLs were clustered in five QTL-rich regions on four different chromosomes viz., Chr3, Chr5, Chr17 &Chr18, among them the highest concentration of seven and six QTLs were found in \"QTL hotspot A\" (Chr17) and \"QTL hotspot B\" (Chr5), respectively. Furthermore, QTLs within all the five QTL clusters are linked to at least two studied traits, which is also supported by highly significant correlation between the three germination-related traits. QTLs for seed-germination related traits in \"QTL hotspot B\" were found in both RIL populations and aging conditions, and also QTLs underlying \"QTL hotspot A\" are identified in both RIL populations under artificial aging condition. These are the stable genomic regions governing the inheritance of seed storability in soybean, and will be the main focus for soybean breeders. This study uncovers the genetic basis of seed storability in soybean. The newly identified QTLs provides valuable information, and will be main targets for fine mapping, candidate gene identification and marker-assisted breeding. Hence, the present study is the first report for the comprehensive and detailed investigation of genetic architecture of seed storability in soybean.", - "journal_title": "BMC genomics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/31208334/" - } - ], - "369947e3-fcda-43ac-a7f6-a847ef802b04": [ - { - "pub_id": "34612543", - "title": "Genetic Stratification of Age-Dependent Parkinson's Disease Risk by Polygenic Hazard Score.", - "authors": "Lasse Pihlstr\u00f8m,Chun C Fan,Oleksandr Frei,Manuela Tan,Roshan A Karunamuni,Cornelis Blauwendraat,Sara Bandres-Ciga,Ziv Gan-Or,Donald G Grosset, ,Anders M Dale,Tyler M Seibert,Ole A Andreassen", - "abstract": "Parkinson's disease (PD) is a highly age-related disorder, where common genetic risk variants affect both disease risk and age at onset. A statistical approach that integrates these effects across all common variants may be clinically useful for individual risk stratification. A polygenic hazard score methodology, leveraging a time-to-event framework, has recently been successfully applied in other age-related disorders. We aimed to develop and validate a polygenic hazard score model in sporadic PD. Using a Cox regression framework, we modeled the polygenic hazard score in a training data set of 11,693 PD patients and 9841 controls. The score was then validated in an independent test data set of 5112 PD patients and 5372 controls and a small single-study sample of 360 patients and 160 controls. A polygenic hazard score predicts the onset of PD with a hazard ratio of 3.78 (95% confidence interval 3.49-4.10) when comparing the highest to the lowest risk decile. Combined with epidemiological data on incidence rate, we apply the score to estimate genetically stratified instantaneous PD risk across age groups. We demonstrate the feasibility of a polygenic hazard approach in PD, integrating the genetic effects on disease risk and age at onset in a single model. In combination with other predictive biomarkers, the approach may hold promise for risk stratification in future clinical trials of disease-modifying therapies, which aim at postponing the onset of PD. \u00a9 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.", - "journal_title": "Movement disorders : official journal of the Movement Disorder Society", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/34612543/" - } - ], - "cec1b19a-112a-4dd1-bbc3-6c9a6b761a4a": [ - { - "pub_id": "32873436", - "title": "Analysis of DNM3 and VAMP4 as genetic modifiers of LRRK2 Parkinson's disease.", - "authors": "Emmeline E Brown,Cornelis Blauwendraat,Joanne Trinh,Mie Rizig,Mike A Nalls,Etienne Leveille,Jennifer A Ruskey,Hallgeir Jonvik,Manuela M X Tan,Sara Bandres-Ciga,Sharon Hassin-Baer,Kathrin Brockmann,Jon Infante,Eduardo Tolosa,Mario Ezquerra,Sawssan Ben Romdhan,Mustapha Benmahdjoub,Mohamed Arezki,Chokri Mhiri,John Hardy,Andrew B Singleton,Roy N Alcalay,Thomas Gasser,Donald G Grosset,Nigel M Williams,Alan Pittman,Ziv Gan-Or,Ruben Fernandez-Santiago,Alexis Brice,Suzanne Lesage,Matthew Farrer,Nicholas Wood,Huw R Morris, ", - "abstract": "The LRRK2 gene has rare (p.G2019S) and common risk variants for Parkinson's disease (PD). DNM3 has previously been reported as a genetic modifier of the age at onset in PD patients carrying the LRRK2 p.G2019S mutation. We analyzed this effect in a new cohort of LRRK2 p.G2019S heterozygotes (n\u00a0= 724) and meta-analyzed our data with previously published data (n\u00a0= 754). VAMP4 is in close proximity to DNM3, and was associated with PD in a recent study, so it is possible that variants in this gene may be important. We also analyzed the effect of VAMP4 rs11578699 on LRRK2 penetrance. Our analysis of DNM3 in previously unpublished data does not show an effect on age at onset in LRRK2 p.G2019S carriers; however, the inter-study heterogeneity may indicate ethnic or population-specific effects of DNM3. There was no evidence for linkage disequilibrium between DNM3 and VAMP4. Analysis of sporadic patients stratified by the risk variant LRRK2 rs10878226 indicates a possible interaction between common variation in LRRK2 and VAMP4 in disease risk.", - "journal_title": "Neurobiology of aging", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/32873436/" - } - ], - "267a769c-6cd2-4a78-9e30-c2a4d7fc421f": [ - { - "pub_id": "33888599", - "title": "Radiation-related genomic profile of papillary thyroid carcinoma after the Chernobyl accident.", - "authors": "Lindsay M Morton,Danielle M Karyadi,Chip Stewart,Tetiana I Bogdanova,Eric T Dawson,Mia K Steinberg,Jieqiong Dai,Stephen W Hartley,Sara J Schonfeld,Joshua N Sampson,Yosef E Maruvka,Vidushi Kapoor,Dale A Ramsden,Juan Carvajal-Garcia,Charles M Perou,Joel S Parker,Marko Krznaric,Meredith Yeager,Joseph F Boland,Amy Hutchinson,Belynda D Hicks,Casey L Dagnall,Julie M Gastier-Foster,Jay Bowen,Olivia Lee,Mitchell J Machiela,Elizabeth K Cahoon,Alina V Brenner,Kiyohiko Mabuchi,Vladimir Drozdovitch,Sergii Masiuk,Mykola Chepurny,Liudmyla Yu Zurnadzhy,Maureen Hatch,Amy Berrington de Gonzalez,Gerry A Thomas,Mykola D Tronko,Gad Getz,Stephen J Chanock", - "abstract": "The 1986 Chernobyl nuclear power plant accident increased papillary thyroid carcinoma (PTC) incidence in surrounding regions, particularly for radioactive iodine (<sup>131</sup>I)-exposed children. We analyzed genomic, transcriptomic, and epigenomic characteristics of 440 PTCs from Ukraine (from 359 individuals with estimated childhood <sup>131</sup>I exposure and 81 unexposed children born after 1986). PTCs displayed radiation dose-dependent enrichment of fusion drivers, nearly all in the mitogen-activated protein kinase pathway, and increases in small deletions and simple/balanced structural variants that were clonal and bore hallmarks of nonhomologous end-joining repair. Radiation-related genomic alterations were more pronounced for individuals who were younger at exposure. Transcriptomic and epigenomic features were strongly associated with driver events but not radiation dose. Our results point to DNA double-strand breaks as early carcinogenic events that subsequently enable PTC growth after environmental radiation exposure.", - "journal_title": "Science (New York, N.Y.)", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/33888599/" - } - ], - "98d443c7-8d99-4139-a27d-e447b0f6630f": [ - { - "pub_id": "31036433", - "title": "Shared and distinct genetic risk factors for childhood-onset and adult-onset asthma: genome-wide and transcriptome-wide studies.", - "authors": "Milton Pividori,Nathan Schoettler,Dan L Nicolae,Carole Ober,Hae Kyung Im", - "abstract": "Childhood-onset and adult-onset asthma differ with respect to severity and comorbidities. Whether they also differ with respect to genetic risk factors has not been previously investigated in large samples. The goals of this study were to identify shared and distinct genetic risk loci for childhood-onset and adult-onset asthma, and to identify the genes that might mediate the effects of associated variation. We did genome-wide and transcriptome-wide studies, using data from the UK Biobank, in individuals with asthma, including adults with childhood-onset asthma (onset before 12 years of age), adults with adult-onset asthma (onset between 26 and 65 years of age), and adults without asthma (controls; aged older than 38 years). We did genome-wide association studies (GWAS) for childhood-onset asthma and adult-onset asthma each compared with shared controls, and for age of asthma onset in all asthma cases, with a genome-wide significance threshold of p<5\u2008\u00d7\u200810<sup>-8</sup>. Enrichment studies determined the tissues in which genes at GWAS loci were most highly expressed, and PrediXcan, a transcriptome-wide gene-based test, was used to identify candidate risk genes. Of 376\u2008358 British white individuals from the UK Biobank, we included 37\u2008846 with self-reports of doctor-diagnosed asthma: 9433 adults with childhood-onset asthma; 21\u2008564 adults with adult-onset asthma; and an additional 6849 young adults with asthma with onset between 12 and 25 years of age. For the first and second GWAS analyses, 318\u2008237 individuals older than 38 years without asthma were used as controls. We detected 61 independent asthma loci: 23 were childhood-onset specific, one was adult-onset specific, and 37 were shared. 19 loci were associated with age of asthma onset. The most significant asthma-associated locus was at 17q12 (odds ratio 1\u00b7406, 95% CI 1\u00b7365-1\u00b7448; p=1\u00b745\u2008\u00d7\u200810<sup>-111</sup>) in the childhood-onset GWAS. Genes at the childhood onset-specific loci were most highly expressed in skin, blood, and small intestine; genes at the adult onset-specific loci were most highly expressed in lung, blood, small intestine, and spleen. PrediXcan identified 113 unique candidate genes at 22 of the 61 GWAS loci. Single-nucleotide polymorphism-based heritability estimates were more than three times larger for childhood-onset asthma (0\u00b7327) than for adult-onset disease (0\u00b7098). The onset of disease in childhood was associated with additional genes with relatively large effect sizes, with the largest odds ratio observed at the FLG locus at 1q21.3 (1\u00b7970, 95% CI 1\u00b7823-2\u00b7129). Genetic risk factors for adult-onset asthma are largely a subset of the genetic risk for childhood-onset asthma but with overall smaller effects, suggesting a greater role for non-genetic risk factors in adult-onset asthma. Combined with gene expression and tissue enrichment patterns, we suggest that the establishment of disease in children is driven more by dysregulated allergy and epithelial barrier function genes, whereas the cause of adult-onset asthma is more lung-centred and environmentally determined, but with immune-mediated mechanisms driving disease progression in both children and adults. US National Institutes of Health.", - "journal_title": "The Lancet. Respiratory medicine", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/31036433/" - } - ], - "3577a2ff-34c0-47c4-98ea-830bfc5f7c83": [ - { - "pub_id": "36108770", - "title": "Systems genomics in age-related macular degeneration.", - "authors": "Anneke I den Hollander,Robert F Mullins,Luz D Orozco,Andrew P Voigt,Hsu-Hsin Chen,Tobias Strunz,Felix Grassmann,Jonathan L Haines,Jonas J W Kuiper,Santa J Tumminia,Rando Allikmets,Gregory S Hageman,Dwight Stambolian,Caroline C W Klaver,Jef D Boeke,Hao Chen,Lee Honigberg,Suresh Katti,Kelly A Frazer,Bernhard H F Weber,Michael B Gorin", - "abstract": "Genomic studies in age-related macular degeneration (AMD) have identified genetic variants that account for the majority of AMD risk. An important next step is to understand the functional consequences and downstream effects of the identified AMD-associated genetic variants. Instrumental for this next step are 'omics' technologies, which enable high-throughput characterization and quantification of biological molecules, and subsequent integration of genomics with these omics datasets, a field referred to as systems genomics. Single cell sequencing studies of the retina and choroid demonstrated that the majority of candidate AMD genes identified through genomic studies are expressed in non-neuronal cells, such as the retinal pigment epithelium (RPE), glia, myeloid and choroidal cells, highlighting that many different retinal and choroidal cell types contribute to the pathogenesis of AMD. Expression quantitative trait locus (eQTL) studies in retinal tissue have identified putative causal genes by demonstrating a genetic overlap between gene regulation and AMD risk. Linking genetic data to complement measurements in the systemic circulation has aided in understanding the effect of AMD-associated genetic variants in the complement system, and supports that protein QTL (pQTL) studies in plasma or serum samples may aid in understanding the effect of genetic variants and pinpointing causal genes in AMD. A recent epigenomic study fine-mapped AMD causal variants by determing regulatory regions in RPE cells differentiated from induced pluripotent stem cells (iPSC-RPE). Another approach that is being employed to pinpoint causal AMD genes is to produce synthetic DNA assemblons representing risk and protective haplotypes, which are then delivered to cellular or animal model systems. Pinpointing causal genes and understanding disease mechanisms is crucial for the next step towards clinical translation. Clinical trials targeting proteins encoded by the AMD-associated genomic loci C3, CFB, CFI, CFH, and ARMS2/HTRA1 are currently ongoing, and a phase III clinical trial for C3 inhibition recently showed a modest reduction of lesion growth in geographic atrophy. The EYERISK consortium recently developed a genetic test for AMD that allows genotyping of common and rare variants in AMD-associated genes. Polygenic risk scores (PRS) were applied to quantify AMD genetic risk, and may aid in predicting AMD progression. In conclusion, genomic studies represent a turning point in our exploration of AMD. The results of those studies now serve as a driving force for several clinical trials. Expanding to omics and systems genomics will further decipher function and causality from the associations that have been reported, and will enable the development of therapies that will lessen the burden of AMD.", - "journal_title": "Experimental eye research", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/36108770/" - } - ], - "e2d5bf4e-e581-43ee-ab78-c7e374d2a582": [ - { - "pub_id": "31925558", - "title": "Cognitive Genomics: Recent Advances and Current Challenges.", - "authors": "Joan Fitzgerald,Derek W Morris,Gary Donohoe", - "abstract": "We review recent progress in uncovering the complex genetic architecture of cognition, arising primarily from genome-wide association studies (GWAS). We explore the genetic correlations between cognitive performance and neuropsychiatric disorders, the genetic and environmental factors associated with age-related cognitive decline, and speculate about the future role of genomics in the understanding of cognitive processes. Improvements in genomic methods, and the increasing availability of large datasets via consortia cooperation, have led to a greater understanding of the role played by common and rare variants in the genomics of cognition, the highly polygenic basis of cognitive function and dysfunction, and the multiple biological processes involved. Recent research has aided in our understanding of the complex biological nature of genomics of cognition. Further development of data banks and techniques to analyze this data hold significant promise for understanding cognitive ability, and for treating cognitively related disability.", - "journal_title": "Current psychiatry reports", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/31925558/" - } - ], - "fb4a3fbd-61b7-492e-b0f7-8cdd2ab559d6": [ - { - "pub_id": "31537915", - "title": "Data privacy in the age of personal genomics.", - "authors": "Dennis Grishin,Kamal Obbad,George M Church", - "abstract": "", - "journal_title": "Nature biotechnology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/31537915/" - } - ], - "7e93a30f-cc3d-4334-a09f-f0ab6b488b0e": [ - { - "pub_id": "29719834", - "title": "Genomic Instabilities, Cellular Senescence, and Aging: <i>In Vitro, In Vivo</i> and Aging-Like Human Syndromes.", - "authors": "Gabriel Lidzbarsky,Danielle Gutman,Huda Adwan Shekhidem,Lital Sharvit,Gil Atzmon", - "abstract": "As average life span and elderly people prevalence in the western world population is gradually increasing, the incidence of age-related diseases such as cancer, heart diseases, diabetes, and dementia is increasing, bearing social and economic consequences worldwide. Understanding the molecular basis of aging-related processes can help extend the organism's health span, i.e., the life period in which the organism is free of chronic diseases or decrease in basic body functions. During the last few decades, immense progress was made in the understanding of major components of aging and healthy aging biology, including genomic instability, telomere attrition, epigenetic changes, proteostasis, nutrient sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, and intracellular communications. This progress has been made by three spear-headed strategies: <i>in vitro</i> (cell and tissue culture from various sources), <i>in vivo</i> (includes diverse model and non-model organisms), both can be manipulated and translated to human biology, and the study of aging-like human syndromes and human populations. Herein, we will focus on current repository of genomic \"senescence\" stage of aging, which includes health decline, structural changes of the genome, faulty DNA damage response and DNA damage, telomere shortening, and epigenetic alterations. Although aging is a complex process, many of the \"hallmarks\" of aging are directly related to DNA structure and function. This review will illustrate the variety of these studies, done in <i>in vitro, in vivo</i> and human levels, and highlight the unique potential and contribution of each research level and eventually the link between them.", - "journal_title": "Frontiers in medicine", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/29719834/" - } - ], - "1a4db3fb-f4eb-475f-bed9-b2b8413f707f": [ - { - "pub_id": "33759814", - "title": "Functional genomics study of protein inhibitor of activated STAT1 in mouse hippocampal neuronal cells revealed by RNA sequencing.", - "authors": "Kan He,Jian Zhang,Justin Liu,Yandi Cui,Leyna G Liu,Shoudong Ye,Qian Ban,Ruolan Pan,Dahai Liu", - "abstract": "Protein inhibitor of activated STAT1 (PIAS1), a small ubiquitin-like modifier (SUMO) E3 ligase, was considered to be an inhibitor of STAT1 by inhibiting the DNA-binding activity of STAT1 and blocking STAT1-mediated gene transcription in response to cytokine stimulation. PIAS1 has been determined to be involved in modulating several biological processes such as cell proliferation, DNA damage responses, and inflammatory responses, both <i>in vivo</i> and <i>in vitro</i>. However, the role played by PIAS1 in regulating neurodegenerative diseases, including Alzheimer's disease (AD), has not been determined. In our study, significantly different expression levels of PIAS1 between normal controls and AD patients were detected in four regions of the human brain. Based on a functional analysis of <i>Pias1</i> in undifferentiated mouse hippocampal neuronal HT-22 cells, we observed that the expression levels of several AD marker genes could be inhibited by <i>Pias1</i> overexpression. Moreover, the proliferation ability of HT-22 cells could be promoted by the overexpression of <i>Pias1</i>. Furthermore, we performed RNA sequencing (RNA-seq) to evaluate and quantify the gene expression profiles in response to <i>Pias1</i> overexpression in HT-22 cells. As a result, 285 significantly dysregulated genes, including 79 upregulated genes and 206 downregulated genes, were identified by the comparison of <i>Pias1</i>/+ cells with WT cells. Among these genes, five overlapping genes, including early growth response 1 (<i>Egr1</i>), early growth response 2 (<i>Egr2</i>), early growth response 3 (<i>Egr3</i>), FBJ osteosarcoma oncogene (<i>Fos</i>) and fos-like antigen 1 (<i>Fosl1</i>), were identified by comparison of the transcription factor binding site (TFBS) prediction results for STAT1, whose expression was evaluated by qPCR. Three cell cycle inhibitors, p53, p18 and p21, were significantly downregulated with the overexpression of <i>Pias1</i>. Analysis of functional enrichment and expression levels showed that basic region leucine zipper domain-containing transcription factors including zinc finger C2H2 (zf-C2H2), homeobox and basic/helix-loop-helix (bHLH) in several signaling pathways were significantly involved in PIAS1 regulation in HT-22 cells. A reconstructed regulatory network under PIAS1 overexpression demonstrated that there were 43 related proteins, notably Nr3c2, that directly interacted with PIAS1.", - "journal_title": "Aging", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/33759814/" - } - ], - "d05f2105-e665-426c-8a7b-1ee57c89f23d": [ - { - "pub_id": "31917080", - "title": "Protecting the Aging Genome.", - "authors": "Michael A Petr,Tulika Tulika,Lina M Carmona-Marin,Morten Scheibye-Knudsen", - "abstract": "Mounting evidence suggests that DNA damage plays a central role in aging. Multiple tiers of defense have evolved to reduce the accumulation of DNA damage, including reducing damaging molecules, repairing DNA damage, and inducing senescence or apoptosis in response to persistent DNA damage. Mutations in or failure of these pathways can lead to accelerated or premature aging and age-related decline in vital organs, supporting the hypothesis that maintaining a pristine genome is paramount for human health. Understanding how we cope with DNA damage could inform on the aging process and further on how deficient DNA maintenance manifests in age-related phenotypes. This knowledge may lead to the development of novel interventions promoting healthspan.", - "journal_title": "Trends in cell biology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/31917080/" - } - ], - "3fa77aa5-669d-4fe6-9d41-ddc6d7b81488": [ - { - "pub_id": "29872864", - "title": "Prevalence of Clonal Hematopoiesis Mutations in Tumor-Only Clinical Genomic Profiling of Solid Tumors.", - "authors": "Ryan N Ptashkin,Diana L Mandelker,Catherine C Coombs,Kelly Bolton,Zarina Yelskaya,David M Hyman,David B Solit,Jos\u00e9 Baselga,Maria E Arcila,Marc Ladanyi,Liying Zhang,Ross L Levine,Michael F Berger,Ahmet Zehir", - "abstract": "Although clonal hematopoiesis (CH) is well described in aging healthy populations, few studies have addressed the practical clinical implications of these alterations in solid-tumor sequencing. To identify and quantify CH-related mutations in patients with solid tumors using matched tumor-blood sequencing, and to establish the proportion that would be misattributed to the tumor based on tumor-only sequencing (unmatched analysis). Retrospective analysis of samples from 17\u202f469 patients with solid cancers who underwent prospective clinical sequencing of DNA isolated from tumor tissue and matched peripheral blood using the MSK-IMPACT assay between January 2014 and August 2017. We identified the presence of CH-related mutations in each patient's blood leukocytes and quantified the fraction of DNA molecules harboring the mutation in the corresponding matched tumor sample. The mean age of the 17\u202f469 patients with cancer at sample collection was 59.2 years (range, 0.3-98.9 years); 53.6% were female. We identified 7608 CH-associated mutations in the blood of 4628 (26.5%) patients. A total of 1075 (14.1%) CH-associated mutations were also detectable in the matched tumor above established thresholds for calling somatic mutations. Overall, 912 (5.2%) patients would have had at least 1 CH-associated mutation erroneously called as tumor derived in the absence of matched blood sequencing. A total of 1061 (98.7%) of these mutations were absent from population scale databases of germline polymorphisms and therefore would have been challenging to filter informatically. Annotating variants with OncoKB classified 534 (49.7%) as oncogenic or likely oncogenic. This study demonstrates how CH-derived mutations could lead to erroneous reporting and treatment recommendations when tumor-only sequencing is used.", - "journal_title": "JAMA oncology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/29872864/" - } - ], - "80d88597-0ee7-4987-96b1-e3f0a8553810": [ - { - "pub_id": "29884871", - "title": "Analysis of 3800-year-old Yersinia pestis genomes suggests Bronze Age origin for bubonic plague.", - "authors": "Maria A Spyrou,Rezeda I Tukhbatova,Chuan-Chao Wang,Aida Andrades Valtue\u00f1a,Aditya K Lankapalli,Vitaly V Kondrashin,Victor A Tsybin,Aleksandr Khokhlov,Denise K\u00fchnert,Alexander Herbig,Kirsten I Bos,Johannes Krause", - "abstract": "The origin of Yersinia pestis and the early stages of its evolution are fundamental subjects of investigation given its high virulence and mortality that resulted from past pandemics. Although the earliest evidence of Y. pestis infections in humans has been identified in Late Neolithic/Bronze Age Eurasia (LNBA 5000-3500y BP), these strains lack key genetic components required for flea adaptation, thus making their mode of transmission and disease presentation in humans unclear. Here, we reconstruct ancient Y. pestis genomes from individuals associated with the Late Bronze Age period (~3800 BP) in the Samara region of modern-day Russia. We show clear distinctions between our new strains and the LNBA lineage, and suggest that the full ability for flea-mediated transmission causing bubonic plague evolved more than 1000 years earlier than previously suggested. Finally, we propose that several Y. pestis lineages were established during the Bronze Age, some of which persist to the present day.", - "journal_title": "Nature communications", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/29884871/" - } - ], - "f199fa4c-bee6-4377-a099-bb6e2f01a40e": [ - { - "pub_id": "31754020", - "title": "Murine single-cell RNA-seq reveals cell-identity- and tissue-specific trajectories of aging.", - "authors": "Jacob C Kimmel,Lolita Penland,Nimrod D Rubinstein,David G Hendrickson,David R Kelley,Adam Z Rosenthal", - "abstract": "Aging is a pleiotropic process affecting many aspects of mammalian physiology. Mammals are composed of distinct cell type identities and tissue environments, but the influence of these cell identities and environments on the trajectory of aging in individual cells remains unclear. Here, we performed single-cell RNA-seq on >50,000 individual cells across three tissues in young and old mice to allow for direct comparison of aging phenotypes across cell types. We found transcriptional features of aging common across many cell types, as well as features of aging unique to each type. Leveraging matrix factorization and optimal transport methods, we found that both cell identities and tissue environments exert influence on the trajectory and magnitude of aging, with cell identity influence predominating. These results suggest that aging manifests with unique directionality and magnitude across the diverse cell identities in mammals.", - "journal_title": "Genome research", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/31754020/" - } - ], - "df13fc2f-7b11-4e56-bde6-cf5e232dfdad": [ - { - "pub_id": "35290801", - "title": "Spatial CRISPR genomics identifies regulators of the tumor microenvironment.", - "authors": "Maxime Dhainaut,Samuel A Rose,Guray Akturk,Aleksandra Wroblewska,Sebastian R Nielsen,Eun Sook Park,Mark Buckup,Vladimir Roudko,Luisanna Pia,Robert Sweeney,Jessica Le Berichel,C Matthias Wilk,Anela Bektesevic,Brian H Lee,Nina Bhardwaj,Adeeb H Rahman,Alessia Baccarini,Sacha Gnjatic,Dana Pe'er,Miriam Merad,Brian D Brown", - "abstract": "While CRISPR screens are helping uncover genes regulating many cell-intrinsic processes, existing approaches are suboptimal for identifying extracellular gene functions, particularly in the tissue context. Here, we developed an approach for spatial functional genomics called Perturb-map. We applied Perturb-map to knock out dozens of genes in parallel in a mouse model of lung cancer and simultaneously assessed how each knockout influenced tumor growth, histopathology, and immune composition. Moreover, we paired Perturb-map and spatial transcriptomics for unbiased analysis of CRISPR-edited tumors. We found that in Tgfbr2 knockout tumors, the tumor microenvironment (TME) was converted to a fibro-mucinous state, and T\u00a0cells excluded, concomitant with upregulated TGF\u03b2 and TGF\u03b2-mediated fibroblast activation, indicating that TGF\u03b2-receptor loss on cancer cells increased TGF\u03b2 bioavailability and its immunosuppressive effects on the TME. These studies establish Perturb-map for functional genomics within the tissue at single-cell resolution with spatial architecture preserved and provide insight into how TGF\u03b2 responsiveness of cancer cells can affect the TME.", - "journal_title": "Cell", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/35290801/" - } - ], - "14cad5a7-e53a-4ab8-9d4f-8f0b827ae427": [ - { - "pub_id": "32031400", - "title": "To Cleave or Not To Cleave in XL-MS?", - "authors": "B Steigenberger,P Albanese,A J R Heck,R A Scheltema", - "abstract": "Cross-linking mass spectrometry (XL-MS) is an efficient technique for uncovering structural features and interactions of the in-solution state of the proteins under investigation. Distance constraints obtained by this technique are highly complementary to classical structural biology approaches like X-ray crystallography and cryo-EM and have successfully been leveraged to shed light on protein structures of increasing size and complexity. To accomplish this, small reagents are used that typically incorporate two amine reactive moieties connected by a spacer arm and that can be applied in solution to protein structures of any size. Over the years, many reagents initially developed for different applications were adopted, and others were specifically developed for XL-MS. This has resulted in a vast array of options, making it difficult to make the right choice for specific experiments. Here, we delve into the previous decade of published XL-MS literature to uncover which workflows have been predominantly applied. We focus on application papers as these represent proof that biologically valid results can be extracted. This ignores some more recent approaches that did not have sufficient time to become more widely applied, for which we supply a separate discussion. From our selection, we extract information on the types of samples, cross-linking reagent, prefractionation, instruments, and data analysis, to highlight widely used workflows. All of the results are summarized in an easy-to-use flow chart defined by selection points resulting from our analysis. Although potentially biased by our own experiences, we expect this overview to be useful for novices stepping into this rapidly expanding field.", - "journal_title": "Journal of the American Society for Mass Spectrometry", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/32031400/" - } - ], - "34640a37-31e0-481a-8207-930a9773fd72": [ - { - "pub_id": "33109080", - "title": "Blood-based epigenetic estimators of chronological age in human adults using DNA methylation data from the Illumina MethylationEPIC array.", - "authors": "Yunsung Lee,Kristine L Haftorn,William R P Denault,Haakon E Nustad,Christian M Page,Robert Lyle,Sindre Lee-\u00d8deg\u00e5rd,Gunn-Helen Moen,Rashmi B Prasad,Leif C Groop,Line Sletner,Christine Sommer,Maria C Magnus,H\u00e5kon K Gjessing,Jennifer R Harris,Per Magnus,Siri E H\u00e5berg,Astanand Jugessur,Jon Bohlin", - "abstract": "Epigenetic clocks have been recognized for their precise prediction of chronological age, age-related diseases, and all-cause mortality. Existing epigenetic clocks are based on CpGs from the Illumina HumanMethylation450 BeadChip (450\u2009K) which has now been replaced by the latest platform, Illumina MethylationEPIC BeadChip (EPIC). Thus, it remains unclear to what extent EPIC contributes to increased precision and accuracy in the prediction of chronological age. We developed three blood-based epigenetic clocks for human adults using EPIC-based DNA methylation (DNAm) data from the Norwegian Mother, Father and Child Cohort Study (MoBa) and the Gene Expression Omnibus (GEO) public repository: 1) an Adult Blood-based EPIC Clock (ABEC) trained on DNAm data from MoBa (n\u2009=\u20091592, age-span: 19 to 59\u2009years), 2) an extended ABEC (eABEC) trained on DNAm data from MoBa and GEO (n\u2009=\u20092227, age-span: 18 to 88\u2009years), and 3) a common ABEC (cABEC) trained on the same training set as eABEC but restricted to CpGs common to 450\u2009K and EPIC. Our clocks showed high precision (Pearson correlation between chronological and epigenetic age (r)\u2009>\u20090.94) in independent cohorts, including GSE111165 (n\u2009=\u200915), GSE115278 (n\u2009=\u2009108), GSE132203 (n\u2009=\u2009795), and the Epigenetics in Pregnancy (EPIPREG) study of the STORK Groruddalen Cohort (n\u2009=\u2009470). This high precision is unlikely due to the use of EPIC, but rather due to the large sample size of the training set. Our ABECs predicted adults' chronological age precisely in independent cohorts. As EPIC is now the dominant platform for measuring DNAm, these clocks will be useful in further predictions of chronological age, age-related diseases, and mortality.", - "journal_title": "BMC genomics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/33109080/" - } - ], - "e6477600-b71b-4c02-b64a-d2c87b65ea79": [ - { - "pub_id": "33002439", - "title": "Genetic risk, incident gastric cancer, and healthy lifestyle: a meta-analysis of genome-wide association studies and prospective cohort study.", - "authors": "Guangfu Jin,Jun Lv,Ming Yang,Mengyun Wang,Meng Zhu,Tianpei Wang,Caiwang Yan,Canqing Yu,Yanbing Ding,Gang Li,Chuanli Ren,Jing Ni,Ruoxin Zhang,Yu Guo,Zheng Bian,Yan Zheng,Nasha Zhang,Yue Jiang,Jiaping Chen,Yanong Wang,Dazhi Xu,Hong Zheng,Ling Yang,Yiping Chen,Robin Walters,Iona Y Millwood,Juncheng Dai,Hongxia Ma,Kexin Chen,Zhengming Chen,Zhibin Hu,Qingyi Wei,Hongbing Shen,Liming Li", - "abstract": "Genetic variants and lifestyle factors have been associated with gastric cancer risk, but the extent to which an increased genetic risk can be offset by a healthy lifestyle remains unknown. We aimed to establish a genetic risk model for gastric cancer and assess the benefits of adhering to a healthy lifestyle in individuals with a high genetic risk. In this meta-analysis and prospective cohort study, we first did a fixed-effects meta-analysis of the association between genetic variants and gastric cancer in six independent genome-wide association studies (GWAS) with a case-control study design. These GWAS comprised 21\u2008168 Han Chinese individuals, of whom 10\u2008254 had gastric cancer and 10\u2008914 geographically matched controls did not. Using summary statistics from the meta-analysis, we constructed five polygenic risk scores in a range of thresholds (p=5\u2008\u00d7\u200810<sup>-4</sup> p=5\u2008\u00d7\u200810<sup>-5</sup> p=5\u2008\u00d7\u200810<sup>-6</sup> p=5\u2008\u00d7\u200810<sup>-7</sup>, and p=5\u2008\u00d7\u200810<sup>-8</sup>) for gastric cancer. We then applied these scores to an independent, prospective, nationwide cohort of 100\u2008220 individuals from the China Kadoorie Biobank (CKB), with more than 10 years of follow-up. The relative and absolute risk of incident gastric cancer associated with healthy lifestyle factors (defined as not smoking, never consuming alcohol, the low consumption of preserved foods, and the frequent intake of fresh fruits and vegetables), was assessed and stratified by genetic risk (low [quintile 1 of the polygenic risk score], intermediate [quintile 2-4 of the polygenic risk score], and high [quintile 5 of the polygenic risk score]). Individuals with a favourable lifestyle were considered as those who adopted all four healthy lifestyle factors, those with an intermediate lifestyle adopted two or three factors, and those with an unfavourable lifestyle adopted none or one factor. The polygenic risk score derived from 112 single-nucleotide polymorphisms (p<5\u2008\u00d7\u200810<sup>-5</sup>) showed the strongest association with gastric cancer risk (p=7\u00b756\u2008\u00d7\u200810<sup>-10</sup>). When this polygenic risk score was applied to the CKB cohort, we found that there was a significant increase in the relative risk of incident gastric cancer across the quintiles of the polygenic risk score (p<sub>trend</sub><0\u00b70001). Compared with individuals who had a low genetic risk, those with an intermediate genetic risk (hazard ratio [HR] 1\u00b754 [95% CI 1\u00b722-1\u00b794], p=2\u00b767\u2008\u00d7\u200810<sup>-4</sup>) and a high genetic risk (2\u00b708 [1\u00b761-2\u00b769], p<0\u00b70001) had a greater risk of gastric cancer. A similar increase in the relative risk of incident gastric cancer was observed across the lifestyle categories (p<sub>trend</sub><0\u00b70001), with a higher risk of gastric cancer in those with an unfavourable lifestyle than those with a favourable lifestyle (2\u00b703 [1\u00b746-2\u00b783], p<0\u00b70001). Participants with a high genetic risk and a favourable lifestyle had a lower risk of gastric cancer than those with a high genetic risk and an unfavourable lifestyle (0\u00b753 [0\u00b729-0\u00b799], p=0\u00b7048), with an absolute risk reduction of 1\u00b712% (95% CI 0\u00b762-1\u00b756). Chinese individuals at an increased risk of incident gastric cancer could be identified by use of our newly developed polygenic risk score. Compared with individuals at a high genetic risk who adopt an unhealthy lifestyle, those who adopt a healthy lifestyle could substantially reduce their risk of incident gastric cancer. National Key R&D Program of China, National Natural Science Foundation of China, 333 High-Level Talents Cultivation Project of Jiangsu Province, and China Postdoctoral Science Foundation.", - "journal_title": "The Lancet. Oncology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/33002439/" - } - ], - "8bc64d64-8b96-44ff-992b-8d1cbb6d2e52": [ - { - "pub_id": "31234232", - "title": "SNCA and mTOR Pathway Single Nucleotide Polymorphisms Interact to Modulate the Age at Onset of Parkinson's Disease.", - "authors": "Rub\u00e9n Fern\u00e1ndez-Santiago,N\u00faria Mart\u00edn-Flores,Francesca Antonelli,Catalina Cerquera,Ver\u00f3nica Moreno,Sara Bandres-Ciga,Elisabetta Manduchi,Eduard Tolosa,Andrew B Singleton,Jason H Moore, ,Mar\u00eda-Josep Mart\u00ed,Mario Ezquerra,Cristina Malagelada", - "abstract": "Single nucleotide polymorphisms (SNPs) in the \u03b1-synuclein (SNCA) gene are associated with differential risk and age at onset (AAO) of both idiopathic and Leucine-rich repeat kinase 2 (LRRK2)-associated Parkinson's disease (PD). Yet potential combinatory or synergistic effects among several modulatory SNPs for PD risk or AAO remain largely underexplored. The mechanistic target of rapamycin (mTOR) signaling pathway is functionally impaired in PD. Here we explored whether SNPs in the mTOR pathway, alone or by epistatic interaction with known susceptibility factors, can modulate PD risk and AAO. Based on functional relevance, we selected a total of 64 SNPs mapping to a total of 57 genes from the mTOR pathway and genotyped a discovery series cohort encompassing 898 PD patients and 921 controls. As a replication series, we screened 4170 PD and 3014 controls available from the International Parkinson's Disease Genomics Consortium. In the discovery series cohort, we found a 4-loci interaction involving STK11 rs8111699, FCHSD1 rs456998, GSK3B rs1732170, and SNCA rs356219, which was associated with an increased risk of PD (odds ratio = 2.59, P <\u2009.001). In addition, we also found a 3-loci epistatic combination of RPTOR rs11868112 and RPS6KA2 rs6456121 with SNCA rs356219, which was associated (odds ratio = 2.89; P <\u2009.0001) with differential AAO. The latter was further validated (odds ratio = 1.56; P =\u20090.046-0.047) in the International Parkinson's Disease Genomics Consortium cohort. These findings indicate that genetic variability in the mTOR pathway contributes to SNCA effects in a nonlinear epistatic manner to modulate differential AAO in PD, unraveling the contribution of this cascade in the pathogenesis of the disease. \u00a9 2019 International Parkinson and Movement Disorder Society.", - "journal_title": "Movement disorders : official journal of the Movement Disorder Society", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/31234232/" - } - ], - "87542bdd-1a9a-470f-857f-5d62abed0446": [ - { - "pub_id": "29581585", - "title": "The dTAG system for immediate and target-specific protein degradation.", - "authors": "Behnam Nabet,Justin M Roberts,Dennis L Buckley,Joshiawa Paulk,Shiva Dastjerdi,Annan Yang,Alan L Leggett,Michael A Erb,Matthew A Lawlor,Amanda Souza,Thomas G Scott,Sarah Vittori,Jennifer A Perry,Jun Qi,Georg E Winter,Kwok-Kin Wong,Nathanael S Gray,James E Bradner", - "abstract": "Dissection of complex biological systems requires target-specific control of the function or abundance of proteins. Genetic perturbations are limited by off-target effects, multicomponent complexity, and irreversibility. Most limiting is the requisite delay between modulation to experimental measurement. To enable the immediate and selective control of single protein abundance, we created a chemical biology system that leverages the potency of cell-permeable heterobifunctional degraders. The dTAG system pairs a novel degrader of FKBP12<sup>F36V</sup> with expression of FKBP12<sup>F36V</sup> in-frame with a protein of interest. By transgene expression or CRISPR-mediated locus-specific knock-in, we exemplify a generalizable strategy to study the immediate consequence of protein loss. Using dTAG, we observe an unexpected superior antiproliferative effect of pan-BET bromodomain degradation over selective BRD4 degradation, characterize immediate effects of KRAS<sup>G12V</sup> loss on proteomic signaling, and demonstrate rapid degradation in vivo. This technology platform will confer kinetic resolution to biological investigation and provide target validation in the context of drug discovery.", - "journal_title": "Nature chemical biology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/29581585/" - } - ], - "46ab6068-b9d7-49d2-817d-024c3da50866": [ - { - "pub_id": "36368318", - "title": "High-resolution single-cell atlas reveals diversity and plasticity of tissue-resident neutrophils in non-small cell lung cancer.", - "authors": "Stefan Salcher,Gregor Sturm,Lena Horvath,Gerold Untergasser,Christiane Kuempers,Georgios Fotakis,Elisa Panizzolo,Agnieszka Martowicz,Manuel Trebo,Georg Pall,Gabriele Gamerith,Martina Sykora,Florian Augustin,Katja Schmitz,Francesca Finotello,Dietmar Rieder,Sven Perner,Sieghart Sopper,Dominik Wolf,Andreas Pircher,Zlatko Trajanoski", - "abstract": "Non-small cell lung cancer (NSCLC) is characterized by molecular heterogeneity with diverse immune cell infiltration patterns, which has been linked to therapy sensitivity and resistance. However, full understanding of how immune cell phenotypes vary across different patient subgroups is lacking. Here, we dissect the NSCLC tumor microenvironment at high resolution by integrating 1,283,972 single cells from 556 samples and 318 patients across 29 datasets, including our dataset capturing cells with low mRNA content. We stratify patients into immune-deserted, B cell, T\u00a0cell, and myeloid cell subtypes. Using bulk samples with genomic and clinical information, we identify cellular components associated with tumor histology and genotypes. We then focus on the analysis of tissue-resident neutrophils (TRNs) and uncover distinct subpopulations that acquire new functional properties in the tissue microenvironment, providing evidence for the plasticity of TRNs. Finally, we show that a TRN-derived gene signature is associated with anti-programmed cell death ligand 1 (PD-L1) treatment failure.", - "journal_title": "Cancer cell", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/36368318/" - } - ], - "98af081d-5ee4-45ad-aa7d-007fbda7a0b0": [ - { - "pub_id": "32601912", - "title": "Large-scale pathway specific polygenic risk and transcriptomic community network analysis identifies novel functional pathways in Parkinson disease.", - "authors": "S Bandres-Ciga,S Saez-Atienzar,J J Kim,M B Makarious,F Faghri,M Diez-Fairen,H Iwaki,H Leonard,J Botia,M Ryten,D Hernandez,J R Gibbs,J Ding,Z Gan-Or,A Noyce,L Pihlstrom,A Torkamani,A R Soltis,C L Dalgard, ,S W Scholz,B J Traynor,D Ehrlich,C R Scherzer,M Bookman,M Cookson,C Blauwendraat,M A Nalls,A B Singleton, ", - "abstract": "Polygenic inheritance plays a central role in Parkinson disease (PD). A priority in elucidating PD etiology lies in defining the biological basis of genetic risk. Unraveling how risk leads to disruption will yield disease-modifying therapeutic targets that may be effective. Here, we utilized a high-throughput and hypothesis-free approach to determine biological processes underlying PD using the largest currently available cohorts of genetic and gene expression data from International Parkinson's Disease Genetics Consortium (IPDGC) and the Accelerating Medicines Partnership-Parkinson's disease initiative (AMP-PD), among other sources. We applied large-scale gene-set specific polygenic risk score (PRS) analyses to assess the role of common variation on PD risk focusing on publicly annotated gene sets representative of curated pathways. We nominated specific molecular sub-processes underlying protein misfolding and aggregation, post-translational protein modification, immune response, membrane and intracellular trafficking, lipid and vitamin metabolism, synaptic transmission, endosomal-lysosomal dysfunction, chromatin remodeling and apoptosis mediated by caspases among the main contributors to PD etiology. We assessed the impact of rare variation on PD risk in an independent cohort of whole-genome sequencing data and found evidence for a burden of rare damaging alleles in a range of processes, including neuronal transmission-related pathways and immune response. We explored enrichment linked to expression cell specificity patterns using single-cell gene expression data and demonstrated a significant risk pattern for dopaminergic neurons, serotonergic neurons, hypothalamic GABAergic neurons, and neural progenitors. Subsequently, we created a novel way of building de novo pathways by constructing a network expression community map using transcriptomic data derived from the blood of PD patients, which revealed functional enrichment in inflammatory signaling pathways, cell death machinery related processes, and dysregulation of mitochondrial homeostasis. Our analyses highlight several specific promising pathways and genes for functional prioritization and provide a cellular context in which such work should be done.", - "journal_title": "Acta neuropathologica", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/32601912/" - } - ], - "7e78b25e-b8c7-4bd6-87d8-0b745a5d0829": [ - { - "pub_id": "37331566", - "title": "Genome-Wide Methylation Profiling in 229 Patients With Crohn's Disease Requiring Intestinal Resection: Epigenetic Analysis of the Trial of Prevention of Post-operative Crohn's Disease (TOPPIC).", - "authors": "Nicholas T Ventham,Nicholas A Kennedy,Rahul Kalla,Alex T Adams,Alexandra Noble,Holly Ennis, , ,Craig Mowat,Malcolm G Dunlop,Jack Satsangi", - "abstract": "DNA methylation alterations may provide important insights into gene-environment interaction in cancer, aging, and complex diseases, such as inflammatory bowel disease (IBD). We aim first to determine whether the circulating DNA methylome in patients requiring surgery may predict Crohn's disease (CD) recurrence following intestinal resection; and second to compare the circulating methylome seen in patients with established CD with that we had reported in a series of inception cohorts. TOPPIC was a placebo-controlled, randomized controlled trial of 6-mercaptopurine at 29 UK centers in patients with CD undergoing ileocolic resection between 2008 and 2012. Genomic DNA was extracted from whole blood samples from 229 of the 240 patients taken before intestinal surgery and analyzed using 450KHumanMethylation and Infinium Omni Express Exome arrays (Illumina, San Diego, CA). Coprimary objectives were to determine whether methylation alterations may predict clinical disease recurrence; and to assess whether the epigenetic alterations previously reported in newly diagnosed IBD were present in the patients with CD recruited into the TOPPIC study. Differential methylation and variance analysis was performed comparing patients with and without clinical evidence of recurrence. Secondary analyses included investigation of methylation associations with smoking, genotype (MeQTLs), and chronologic age. Validation of our previously published case-control observation of the methylome was performed using historical control data (CD, n\u00a0= 123; Control, n\u00a0= 198). CD recurrence in patients following surgery is associated with 5 differentially methylated positions (Holm P < .05), including probes mapping to WHSC1 (P\u00a0= 4.1\u00a0\u00d7 10<sup>-9</sup>, Holm P\u00a0= .002) and EFNA3 (P\u00a0= 4.9\u00a0\u00d7 10<sup>-8</sup>, Holm P\u00a0= .02). Five differentially variable positions are demonstrated in the group of patients with evidence of disease recurrence including a probe mapping to MAD1L1 (P\u00a0= 6.4\u00a0\u00d7 10<sup>-5</sup>). DNA methylation clock analyses demonstrated significant age acceleration in CD compared with control subjects (GrimAge\u00a0+ 2 years; 95% confidence interval, 1.2-2.7 years), with some evidence for accelerated aging in patients with CD with disease recurrence following surgery (GrimAge\u00a0+1.04 years; 95% confidence interval, -0.04 to 2.22). Significant methylation differences between CD cases and control subjects were seen by comparing this cohort in conjunction with previously published control data, including validation of our previously described differentially methylated positions (RPS6KA2 P\u00a0= 1.2\u00a0\u00d7 10<sup>-19</sup>, SBNO2\u00a0= 1.2\u00a0\u00d7 10<sup>-11</sup>) and regions (TXK [false discovery rate, P\u00a0= 3.6\u00a0\u00d7 10<sup>-14</sup>], WRAP73 [false discovery rate, P\u00a0= 1.9\u00a0\u00d7 10<sup>-9</sup>], VMP1 [false discovery rate, P\u00a0= 1.7\u00a0\u00d7 10<sup>-7</sup>], and ITGB2 [false discovery rate, P\u00a0= 1.4\u00a0\u00d7 10<sup>-7</sup>]). We demonstrate differential methylation and differentially variable methylation in patients developing clinical recurrence within 3 years of surgery. Moreover, we report replication of the CD-associated methylome, previously characterized only in adult and pediatric inception cohorts, in patients with medically refractory disease needing surgery.", - "journal_title": "Cellular and molecular gastroenterology and hepatology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/37331566/" - } - ], - "0915838e-097d-4347-a500-55b011556eab": [ - { - "pub_id": "33848428", - "title": "Plant Pan-Genomics Comes of Age.", - "authors": "Li Lei,Eugene Goltsman,David Goodstein,Guohong Albert Wu,Daniel S Rokhsar,John P Vogel", - "abstract": "A pan-genome is the nonredundant collection of genes and/or DNA sequences in a species. Numerous studies have shown that plant pan-genomes are typically much larger than the genome of any individual and that a sizable fraction of the genes in any individual are present in only some genomes. The construction and interpretation of plant pan-genomes are challenging due to the large size and repetitive content of plant genomes. Most pan-genomes are largely focused on nontransposable element protein coding genes because they are more easily analyzed and defined than noncoding and repetitive sequences. Nevertheless, noncoding and repetitive DNA play important roles in determining the phenotype and genome evolution. Fortunately, it is now feasible to make multiple high-quality genomes that can be used to construct high-resolution pan-genomes that capture all the variation. However, assembling, displaying, and interacting with such high-resolution pan-genomes will require the development of new tools.", - "journal_title": "Annual review of plant biology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/33848428/" - } - ], - "a07c987b-1969-4437-b0f8-81b411e7716f": [ - { - "pub_id": "34930919", - "title": "Finding genetically-supported drug targets for Parkinson's disease using Mendelian randomization of the druggable genome.", - "authors": "Catherine S Storm,Demis A Kia,Mona M Almramhi,Sara Bandres-Ciga,Chris Finan, ,Aroon D Hingorani,Nicholas W Wood", - "abstract": "Parkinson's disease is a neurodegenerative movement disorder that currently has no disease-modifying treatment, partly owing to inefficiencies in drug target identification and validation. We use Mendelian randomization to investigate over 3,000 genes that encode druggable proteins and predict their efficacy as drug targets for Parkinson's disease. We use expression and protein quantitative trait loci to mimic exposure to medications, and we examine the causal effect on Parkinson's disease risk (in two large cohorts), age at onset and progression. We propose 23 drug-targeting mechanisms for Parkinson's disease, including four possible drug repurposing opportunities and two drugs which may increase Parkinson's disease risk. Of these, we put forward six drug targets with the strongest Mendelian randomization evidence. There is remarkably little overlap between our drug targets to reduce Parkinson's disease risk versus progression, suggesting different molecular mechanisms. Drugs with genetic support are considerably more likely to succeed in clinical trials, and we provide compelling genetic evidence and an analysis pipeline to prioritise Parkinson's disease drug development.", - "journal_title": "Nature communications", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/34930919/" - } - ], - "29677e8a-16e6-41d3-aba6-e47ba55da611": [ - { - "pub_id": "30971107", - "title": "Biomarkers of Dietary Omega-6 Fatty Acids and Incident Cardiovascular Disease and Mortality.", - "authors": "Matti Marklund,Jason H Y Wu,Fumiaki Imamura,Liana C Del Gobbo,Amanda Fretts,Janette de Goede,Peilin Shi,Nathan Tintle,Maria Wennberg,Stella Aslibekyan,Tzu-An Chen,Marcia C de Oliveira Otto,Yoichiro Hirakawa,Helle H\u00f8jmark Eriksen,Janine Kr\u00f6ger,Federica Laguzzi,Maria Lankinen,Rachel A Murphy,Kiesha Prem,C\u00e9cilia Samieri,Jyrki Virtanen,Alexis C Wood,Kerry Wong,Wei-Sin Yang,Xia Zhou,Ana Baylin,Jolanda M A Boer,Ingeborg A Brouwer,Hannia Campos,Paulo H M Chaves,Kuo-Liong Chien,Ulf de Faire,Luc Djouss\u00e9,Gudny Eiriksdottir,Naglaa El-Abbadi,Nita G Forouhi,J Michael Gaziano,Johanna M Geleijnse,Bruna Gigante,Graham Giles,Eliseo Guallar,Vilmundur Gudnason,Tamara Harris,William S Harris,Catherine Helmer,Mai-Lis Hellenius,Allison Hodge,Frank B Hu,Paul F Jacques,Jan-H\u00e5kan Jansson,Anya Kalsbeek,Kay-Tee Khaw,Woon-Puay Koh,Markku Laakso,Karin Leander,Hung-Ju Lin,Lars Lind,Robert Luben,Juhua Luo,Barbara McKnight,Jaakko Mursu,Toshiharu Ninomiya,Kim Overvad,Bruce M Psaty,Eric Rimm,Matthias B Schulze,David Siscovick,Michael Skjelbo Nielsen,Albert V Smith,Brian T Steffen,Lyn Steffen,Qi Sun,Johan Sundstr\u00f6m,Michael Y Tsai,Hugh Tunstall-Pedoe,Matti I J Uusitupa,Rob M van Dam,Jenna Veenstra,W M Monique Verschuren,Nick Wareham,Walter Willett,Mark Woodward,Jian-Min Yuan,Renata Micha,Rozenn N Lemaitre,Dariush Mozaffarian,Ulf Ris\u00e9rus, ", - "abstract": "Global dietary recommendations for and cardiovascular effects of linoleic acid, the major dietary omega-6 fatty acid, and its major metabolite, arachidonic acid, remain controversial. To address this uncertainty and inform international recommendations, we evaluated how in vivo circulating and tissue levels of linoleic acid (LA) and arachidonic acid (AA) relate to incident cardiovascular disease (CVD) across multiple international studies. We performed harmonized, de novo, individual-level analyses in a global consortium of 30 prospective observational studies from 13 countries. Multivariable-adjusted associations of circulating and adipose tissue LA and AA biomarkers with incident total CVD and subtypes (coronary heart disease, ischemic stroke, cardiovascular mortality) were investigated according to a prespecified analytic plan. Levels of LA and AA, measured as the percentage of total fatty acids, were evaluated linearly according to their interquintile range (ie, the range between the midpoint of the first and fifth quintiles), and categorically by quintiles. Study-specific results were pooled using inverse-variance-weighted meta-analysis. Heterogeneity was explored by age, sex, race, diabetes mellitus, statin use, aspirin use, omega-3 levels, and fatty acid desaturase 1 genotype (when available). In 30 prospective studies with medians of follow-up ranging 2.5 to 31.9 years, 15\u2009198 incident cardiovascular events occurred among 68\u2009659 participants. Higher levels of LA were significantly associated with lower risks of total CVD, cardiovascular mortality, and ischemic stroke, with hazard ratios per interquintile range of 0.93 (95% CI, 0.88-0.99), 0.78 (0.70-0.85), and 0.88 (0.79-0.98), respectively, and nonsignificantly with lower coronary heart disease risk (0.94; 0.88-1.00). Relationships were similar for LA evaluated across quintiles. AA levels were not associated with higher risk of cardiovascular outcomes; in a comparison of extreme quintiles, higher levels were associated with lower risk of total CVD (0.92; 0.86-0.99). No consistent heterogeneity by population subgroups was identified in the observed relationships. In pooled global analyses, higher in vivo circulating and tissue levels of LA and possibly AA were associated with lower risk of major cardiovascular events. These results support a favorable role for LA in CVD prevention.", - "journal_title": "Circulation", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/30971107/" - } - ], - "213afab9-b2fb-40ed-abb7-d80853a0fbf3": [ - { - "pub_id": "34737426", - "title": "A generalized linear mixed model association tool for biobank-scale data.", - "authors": "Longda Jiang,Zhili Zheng,Hailing Fang,Jian Yang", - "abstract": "Compared with linear mixed model-based genome-wide association (GWA) methods, generalized linear mixed model (GLMM)-based methods have better statistical properties when applied to binary traits but are computationally much slower. In the present study, leveraging efficient sparse matrix-based algorithms, we developed a GLMM-based GWA tool, fastGWA-GLMM, that is severalfold to orders of magnitude faster than the state-of-the-art tools when applied to the UK Biobank (UKB) data and scalable to cohorts with millions of individuals. We show by simulation that the fastGWA-GLMM test statistics of both common and rare variants are well calibrated under the null, even for traits with extreme case-control ratios. We applied fastGWA-GLMM to the UKB data of 456,348 individuals, 11,842,647 variants and 2,989 binary traits (full summary statistics available at http://fastgwa.info/ukbimpbin ), and identified 259 rare variants associated with 75 traits, demonstrating the use of imputed genotype data in a large cohort to discover rare variants for binary complex traits.", - "journal_title": "Nature genetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/34737426/" - } - ], - "a13e2333-f810-4266-b967-250dd80c98dc": [ - { - "pub_id": "29319699", - "title": "Precision oncology in the age of integrative genomics.", - "authors": "Chandan Kumar-Sinha,Arul M Chinnaiyan", - "abstract": "Precision oncology applies genomic and other molecular analyses of tumor biopsies to improve the diagnosis and treatment of cancers. In addition to identifying therapeutic options, precision oncology tracks the response of a tumor to an intervention at the molecular level and detects drug resistance and the mechanisms by which it occurs. Integrative genomics can include sequencing specific panels of genes, exomes, or the entire triad of the patient's germline, tumor exome, and tumor transcriptome. Although the capabilities of sequencing technologies continue to improve, widespread adoption of genomics-driven precision oncology in the clinic has been held back by logistical, regulatory, financial, and ethical considerations. Nevertheless, integrative clinical sequencing programs applied at the point of care have the potential to improve the clinical management of cancer patients.", - "journal_title": "Nature biotechnology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/29319699/" - } - ], - "0db70db5-a507-449c-8e4e-9e1af08ff510": [ - { - "pub_id": "30784661", - "title": "Uncovering genetic mechanisms of kidney aging through transcriptomics, genomics, and epigenomics.", - "authors": "Joshua Rowland,Artur Akbarov,James Eales,Xiaoguang Xu,John P Dormer,Hui Guo,Matthew Denniff,Xiao Jiang,Parisa Ranjzad,Alicja Nazgiewicz,Priscilla Ribeiro Prestes,Andrzej Antczak,Monika Szulinska,Ingrid A Wise,Ewa Zukowska-Szczechowska,Pawel Bogdanski,Adrian S Woolf,Nilesh J Samani,Fadi J Charchar,Maciej Tomaszewski", - "abstract": "Nephrons scar and involute during aging, increasing the risk of chronic kidney disease. Little is known, however, about genetic mechanisms of kidney aging. We sought to define the signatures of age on the renal transcriptome using 563 human kidneys. The initial discovery analysis of 260 kidney transcriptomes from the TRANScriptome of renaL humAn TissuE Study (TRANSLATE) and the Cancer Genome Atlas identified 37 age-associated genes. For 19 of those genes, the association with age was replicated in 303 kidney transcriptomes from the Nephroseq resource. Surveying 42 nonrenal tissues from the Genotype-Tissue Expression project revealed that, for approximately a fifth of the replicated genes, the association with age was kidney-specific. Seventy-three percent of the replicated genes were associated with functional or histological parameters of age-related decline in kidney health, including glomerular filtration rate, glomerulosclerosis, interstitial fibrosis, tubular atrophy, and arterial narrowing. Common genetic variants in four of the age-related genes, namely LYG1, PPP1R3C, LTF and TSPYL5, correlated with the trajectory of age-related changes in their renal expression. Integrative analysis of genomic, epigenomic, and transcriptomic information revealed that the observed age-related decline in renal TSPYL5 expression was determined both genetically and epigenetically. Thus, this study revealed robust molecular signatures of the aging kidney and new regulatory mechanisms of age-related change in the kidney transcriptome.", - "journal_title": "Kidney international", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/30784661/" - } - ], - "78660b91-b9cf-431c-a025-02c8c576d2c3": [ - { - "pub_id": "34563268", - "title": "Protective chromosome 1q32 haplotypes mitigate risk for age-related macular degeneration associated with the CFH-CFHR5 and ARMS2/HTRA1 loci.", - "authors": "Chris M Pappas,Moussa A Zouache,Stacie Matthews,Caitlin D Faust,Jill L Hageman,Brandi L Williams,Burt T Richards,Gregory S Hageman", - "abstract": "Single-variant associations with age-related macular degeneration (AMD), one of the most prevalent causes of irreversible vision loss worldwide, have been studied extensively. However, because of a lack of refinement of these associations, there remains considerable ambiguity regarding what constitutes genetic risk and/or protection for this disease, and how genetic combinations affect this risk. In this study, we consider the two most common and strongly AMD-associated loci, the CFH-CFHR5 region on chromosome 1q32 (Chr1 locus)\u00a0and ARMS2/HTRA1 gene on chromosome 10q26 \u00a0(Chr10 locus). By refining associations within the CFH-CFHR5 locus, we show that all genetic protection against the development of AMD in this region is described by the combination of the amino acid-altering variant CFH I62V (rs800292) and genetic deletion of CFHR3/1. Haplotypes based on CFH I62V, a CFHR3/1 deletion tagging SNP and the risk variant CFH Y402H are associated with either risk, protection or neutrality for AMD and capture more than 99% of control- and case-associated chromosomes. We find that genetic combinations of CFH-CFHR5 haplotypes (diplotypes) strongly influence AMD susceptibility and that individuals with risk/protective diplotypes are substantially protected against the development of disease. Finally, we demonstrate that AMD risk in the ARMS2/HTRA1 locus is also mitigated by combinations of CFH-CFHR5 haplotypes, with Chr10\u00a0risk variants essentially neutralized by protective CFH-CFHR5 haplotypes. Our study highlights the importance of considering protective CFH-CFHR5 haplotypes when assessing genetic susceptibility for AMD. It establishes a framework that describes the full spectrum of AMD susceptibility using an optimal set of single-nucleotide polymorphisms with known functional consequences. It also indicates that protective or preventive complement-directed therapies targeting AMD driven by CFH-CFHR5 risk haplotypes may also be effective when AMD is driven by ARMS2/HTRA1 risk variants.", - "journal_title": "Human genomics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/34563268/" - } - ], - "7c27cf21-f894-4963-8c8c-f01c3a5b1d94": [ - { - "pub_id": "31624012", - "title": "Primary ciliary dyskinesia in the genomics age.", - "authors": "Jane S Lucas,Stephanie D Davis,Heymut Omran,Amelia Shoemark", - "abstract": "Primary ciliary dyskinesia is a genetically and clinically heterogeneous syndrome. Impaired function of motile cilia causes failure of mucociliary clearance. Patients typically present with neonatal respiratory distress of unknown cause and then continue to have a daily wet cough, recurrent chest infections, perennial rhinosinusitis, otitis media with effusion, and bronchiectasis. Approximately 50% of patients have situs inversus, and infertility is common. While understanding of the underlying genetics and disease mechanisms have substantially advanced in recent years, there remains a paucity of evidence for treatment. Next-generation sequencing has increased gene discovery, and mutations in more than 40 genes have been reported to cause primary ciliary dyskinesia, with many other genes likely to be discovered. Increased knowledge of cilia genes is challenging perceptions of the clinical phenotype, as some genes reported in the last 5 years are associated with mild respiratory disease. Developments in genomics and molecular medicine are rapidly improving diagnosis, and a genetic cause can be identified in approximately 70% of patients known to have primary ciliary dyskinesia. Groups are now investigating novel and personalised treatments, although gene therapies are unlikely to be available in the near future.", - "journal_title": "The Lancet. Respiratory medicine", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/31624012/" - } - ], - "102dd64c-5038-445b-b076-5dbb5a94a20a": [ - { - "pub_id": "31243121", - "title": "Comprehensive Genomic Landscapes in Early and Later Onset Colorectal Cancer.", - "authors": "Christopher H Lieu,Erica A Golemis,Ilya G Serebriiskii,Justin Newberg,Amanda Hemmerich,Caitlin Connelly,Wells A Messersmith,Cathy Eng,S Gail Eckhardt,Garrett Frampton,Matthew Cooke,Joshua E Meyer", - "abstract": "The incidence rates of colorectal cancers are increasing in young adults. The objective of this study was to investigate genomic differences between tumor samples collected from younger and older patients with colorectal cancer. DNA was extracted from 18,218 clinical specimens, followed by hybridization capture of 3,769 exons from 403 cancer-related genes and 47 introns of 19 genes commonly rearranged in cancer. Genomic alterations (GA) were determined, and association with patient age and microsatellite stable/microsatellite instability high (MSS/MSI-H) status established. Overall genomic alteration rates in the younger (<40) and older (\u226550) cohorts were similar in the majority of the genes analyzed. Gene alteration rates in the microsatellite stable (MSS) younger and older cohorts were largely similar, with several notable differences. In particular, <i>TP53</i> (FDR < 0.01) and <i>CTNNB1</i> (FDR = 0.01) alterations were more common in younger patients with colorectal cancer, and <i>APC</i> (FDR < 0.01), <i>KRAS</i> (FDR < 0.01), <i>BRAF</i> (FDR < 0.01), and <i>FAM123B</i> (FDR < 0.01) were more commonly altered in older patients with colorectal cancer. In the MSI-H cohort, the majority of genes showed similar rate of alterations in all age groups, but with significant differences seen in <i>APC</i> (FDR < 0.01), <i>BRAF</i> (FDR < 0.01), and KRAS (FDR < 0.01). Tumors from younger and older patients with colorectal cancer demonstrated similar overall rates of genomic alteration. However, differences were noted in several genes relevant to biology and response to therapy. Further study will need to be conducted to determine whether the differences in gene alteration rates can be leveraged to provide personalized therapies for young patients with early-onset sporadic colorectal cancer.", - "journal_title": "Clinical cancer research : an official journal of the American Association for Cancer Research", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/31243121/" - } - ], - "b1656249-5f62-428f-8b71-7549cc2886ff": [ - { - "pub_id": "30901550", - "title": "Genomic Analysis in the Age of Human Genome Sequencing.", - "authors": "Tuuli Lappalainen,Alexandra J Scott,Margot Brandt,Ira M Hall", - "abstract": "Affordable genome sequencing technologies promise to revolutionize the field of human genetics by enabling comprehensive studies that interrogate all classes of genome variation, genome-wide, across the entire allele frequency spectrum. Ongoing projects worldwide are sequencing many thousands-and soon millions-of human genomes as part of various gene mapping studies, biobanking efforts, and clinical programs. However, while genome sequencing data production has become routine, genome analysis and interpretation remain challenging endeavors with many limitations and caveats. Here, we review the current state of technologies for genetic variant discovery, genotyping, and functional interpretation and discuss the prospects for future advances. We focus on germline variants discovered by whole-genome sequencing, genome-wide functional genomic approaches for predicting and measuring variant functional effects, and implications for studies of common and rare human disease.", - "journal_title": "Cell", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/30901550/" - } - ], - "05527d81-7242-43ce-821f-7e86460c3288": [ - { - "pub_id": "31552249", - "title": "Sexual Dimorphism in the Age of Genomics: How, When, Where.", - "authors": "Daniel F Deegan,Nora Engel", - "abstract": "In mammals, sex chromosomes start to program autosomal gene expression and epigenetic patterns very soon after fertilization. Yet whether the resulting sex differences are perpetuated throughout development and how they connect to the sex-specific expression patterns in adult tissues is not known. There is a dearth of information on the timing and continuity of sex biases during development. It is also unclear whether sex-specific selection operates during embryogenesis. On the other hand, there is mounting evidence that all adult tissues exhibit sex-specific expression patterns, some of which are independent of hormonal influence and due to intrinsic regulatory effects of the sex chromosome constitution. There are many diseases with origins during embryogenesis that also exhibit sex biases. Epigenetics has provided us with viable mechanisms to explain how the genome stores the memory of developmental events. We propose that some of these marks can be traced back to the sex chromosomes, which interact with the autosomes and establish sex-specific epigenetic features soon after fertilization. Sex-biased epigenetic marks that linger after reprograming may reveal themselves at the transcriptional level at later developmental stages and possibly, throughout the lifespan. Detailed molecular information on the ontogeny of sex biases would also elucidate the sex-specific selective pressures operating on embryos and how compensatory mechanisms evolved to resolve sexual conflict.", - "journal_title": "Frontiers in cell and developmental biology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/31552249/" - } - ], - "b0e49b4c-954d-476a-ba3a-0215e63c98b6": [ - { - "pub_id": "34163529", - "title": "Footprints in the Sand: Deep Taxonomic Comparisons in Vertebrate Genomics to Unveil the Genetic Programs of Human Longevity.", - "authors": "Stephen Treaster,David Karasik,Matthew P Harris", - "abstract": "With the modern quality, quantity, and availability of genomic sequencing across species, as well as across the expanse of human populations, we can screen for shared signatures underlying longevity and lifespan. Knowledge of these mechanisms would be medically invaluable in combating aging and age-related diseases. The diversity of longevities across vertebrates is an opportunity to look for patterns of genetic variation that may signal how this life history property is regulated, and ultimately how it can be modulated. Variation in human longevity provides a unique window to look for cases of extreme lifespan within a population, as well as associations across populations for factors that influence capacity to live longer. Current large cohort studies support the use of population level analyses to identify key factors associating with human lifespan. These studies are powerful in concept, but have demonstrated limited ability to resolve signals from background variation. In parallel, the expanding catalog of sequencing and annotation from diverse species, some of which have evolved longevities well past a human lifespan, provides independent cases to look at the genomic signatures of longevity. Recent comparative genomic work has shown promise in finding shared mechanisms associating with longevity among distantly related vertebrate groups. Given the genetic constraints between vertebrates, we posit that a combination of approaches, of parallel meta-analysis of human longevity along with refined analysis of other vertebrate clades having exceptional longevity, will aid in resolving key regulators of enhanced lifespan that have proven to be elusive when analyzed in isolation.", - "journal_title": "Frontiers in genetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/34163529/" - } - ], - "efdc861a-4758-4d2d-9d09-f19f0be32c2f": [ - { - "pub_id": "30585859", - "title": "Mosaicism, aging and cancer.", - "authors": "Mitchell J Machiela", - "abstract": "Genetic mosaicism is the presence of a somatic mutation in a subset of cells that differs from the inherited germline genome. Detectable genetic mosaicism is attractive as a potential early biomarker for cancer risk because of its established relationship with aging, introduction of potentially deleterious mutations, and clonal selection and expansion of mutated cells. The aim of this review is to survey shared risk factors associated with genetic mosaicism, aging and cancer risk. Studies have associated aging, cigarette smoking and several genetic susceptibility loci with increased risk of acquiring genetic mosaicism. Genetic mosaicism has also been associated with numerous outcomes including cancer risk and cancer mortality; however, the level of evidence supporting these associations varies considerably. Ample evidence exists for shared risk factors for genetic mosaicism and cancer risk as well as abundant support linking genetic mosaicism in leukocytes to hematologic malignancies. The relationship between genetic mosaicism in circulating leukocytes and solid malignancies remains an active area of research.", - "journal_title": "Current opinion in oncology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/30585859/" - } - ], - "463527bf-6270-40f6-a76d-460bab1cdf38": [ - { - "pub_id": "30419258", - "title": "The role of DNA methylation in epigenetics of aging.", - "authors": "Archana Unnikrishnan,Willard M Freeman,Jordan Jackson,Jonathan D Wren,Hunter Porter,Arlan Richardson", - "abstract": "Recent research suggests that epigenetics, especially DNA methylation, plays a mechanistic role in aging. Epigenetic clocks, which measure changes in a few hundred specific CpG sites, can accurately predict chronological age in a variety of species, including humans. These clocks are currently the best biomarkers for predicting mortality in humans. Additionally, several studies have characterized the effects of aging across the methylome in a wide variety of tissues from humans and mice. A small fraction (~2%) of the CpG sites show age-related changes, either hypermethylation or hypomethylation with aging. Evaluation of non-CpG site methylation has only been examined in a few studies, with about ~0.5% of these sites showing a change with age. Therefore, while only a small fraction of cytosines in the genome show changes in DNA methylation with age, this represents 2 to 3 million cytosines in the genome. Importantly, the only study to compare the effect of aging on DNA methylation in male and female mice and humans found that >95% of the age-related changes in DNA methylation in the hippocampus were sexually divergent, i.e., the methylation did not differ between males and females at young age but age-related changes occurred in one sex but not the other. The age-related changes in DNA methylation tend to be enriched and under-represented in specific genomic contexts, with some commonalities between tissues and species that require further investigation. The strongest evidence that the age-related changes in DNA methylation play a role in aging comes from studies of anti-aging interventions (e.g., caloric restriction, dwarfism, and rapamycin treatment) in mice. These anti-aging interventions deaccelerate the epigenetic clocks and reverse/prevent 20 to 40% of the age-related changes in DNA methylation. It will be important in the future to demonstrate that at least some of the age-related changes in DNA methylation directly lead to alterations in the transcriptome of cells/tissues that could potentially contribute to aging.", - "journal_title": "Pharmacology & therapeutics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/30419258/" - } - ], - "73eb0686-a14c-4ed4-a705-8a7c1ae168cf": [ - { - "pub_id": "32470401", - "title": "Genomic History of Neolithic to Bronze Age Anatolia, Northern Levant, and Southern Caucasus.", - "authors": "Eirini Skourtanioti,Yilmaz S Erdal,Marcella Frangipane,Francesca Balossi Restelli,K Asl\u0131han Yener,Frances Pinnock,Paolo Matthiae,Rana \u00d6zbal,Ulf-Dietrich Schoop,Farhad Guliyev,Tufan Akhundov,Bertille Lyonnet,Emily L Hammer,Selin E Nugent,Marta Burri,Gunnar U Neumann,Sandra Penske,Tara Ingman,Murat Akar,Rula Shafiq,Giulio Palumbi,Stefanie Eisenmann,Marta D'Andrea,Adam B Rohrlach,Christina Warinner,Choongwon Jeong,Philipp W Stockhammer,Wolfgang Haak,Johannes Krause", - "abstract": "Here, we report genome-wide data analyses from 110 ancient Near Eastern individuals spanning the Late Neolithic to Late Bronze Age, a period characterized by intense interregional interactions for the Near East. We find that 6<sup>th</sup> millennium BCE populations of North/Central Anatolia and the Southern Caucasus shared mixed ancestry on a genetic cline that formed during the Neolithic between Western Anatolia and regions in today's Southern Caucasus/Zagros. During the Late Chalcolithic and/or the Early Bronze Age, more than half of the Northern Levantine gene pool was replaced, while in the rest of Anatolia and the Southern Caucasus, we document genetic continuity with only transient gene flow. Additionally, we reveal a genetically distinct individual within the Late Bronze Age Northern Levant. Overall, our study uncovers multiple scales of population dynamics through time, from extensive admixture during the Neolithic period to long-distance mobility within the globalized societies of the Late Bronze Age. VIDEO ABSTRACT.", - "journal_title": "Cell", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/32470401/" - } - ], - "a16d0947-4bc8-4086-84bb-395a2e127eb4": [ - { - "pub_id": "34565328", - "title": "Accelerated hematopoietic mitotic aging measured by DNA methylation, blood cell lineage, and Parkinson's disease.", - "authors": "Kimberly C Paul,Alexandra M Binder,Steve Horvath,Cynthia Kusters,Qi Yan,Irish Del Rosario,Yu Yu,Jeff Bronstein,Beate Ritz", - "abstract": "Aging and inflammation are important components of Parkinson's disease (PD) pathogenesis and both are associated with changes in hematopoiesis and blood cell composition. DNA methylation (DNAm) presents a mechanism to investigate inflammation, aging, and hematopoiesis in PD, using epigenetic mitotic aging and aging clocks. Here, we aimed to define the influence of blood cell lineage on epigenetic mitotic age and then investigate mitotic age acceleration with PD, while considering epigenetic age acceleration biomarkers. We estimated epigenetic mitotic age using the \"epiTOC\" epigenetic mitotic clock in 10 different blood cell populations and in a population-based study of PD with whole-blood. Within subject analysis of the flow-sorted purified blood cell types DNAm showed a clear separation of epigenetic mitotic age by cell lineage, with the mitotic age significantly lower in myeloid versus lymphoid cells (p\u2009=\u20092.1e-11). PD status was strongly associated with accelerated epigenetic mitotic aging (AccelEpiTOC) after controlling for cell composition (OR\u2009=\u20092.11, 95\u2009% CI\u2009=\u20091.56, 2.86, p\u2009=\u20091.6e-6). AccelEpiTOC was also positively correlated with extrinsic epigenetic age acceleration, a DNAm aging biomarker related to immune system aging (with cell composition adjustment: R\u2009=\u20090.27, p\u2009=\u20096.5e-14), and both were independently associated with PD. Among PD patients, AccelEpiTOC measured at baseline was also associated with longitudinal motor and cognitive symptom decline. The current study presents a first look at epigenetic mitotic aging in PD and our findings suggest accelerated hematopoietic cell mitosis, possibly reflecting immune pathway imbalances, in early PD that may also be related to motor and cognitive progression.", - "journal_title": "BMC genomics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/34565328/" - } - ], - "f862901e-b2ae-4f2f-b162-ed5cf1e50704": [ - { - "pub_id": "33690792", - "title": "Functional genomics of inflamm-aging and immunosenescence.", - "authors": "Ryan J Lu,Emily K Wang,B\u00e9r\u00e9nice A Benayoun", - "abstract": "The aging population is at a higher risk for age-related diseases and infections. This observation could be due to immunosenescence: the decline in immune efficacy of both the innate and the adaptive immune systems. Age-related immune decline also links to the concept of 'inflamm-aging,' whereby aging is accompanied by sterile chronic inflammation. Along with a decline in immune function, aging is accompanied by a widespread of 'omics' remodeling. Transcriptional landscape changes linked to key pathways of immune function have been identified across studies, such as macrophages having decreased expression of genes associated to phagocytosis, a major function of macrophages. Therefore, a key mechanism underlying innate immune cell dysfunction during aging may stem from dysregulation of youthful genomic networks. In this review, we discuss both molecular and cellular phenotypes of innate immune cells that contribute to age-related inflammation.", - "journal_title": "Briefings in functional genomics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/33690792/" - } - ], - "dfac5bad-5587-4fa8-a547-ccd6b9914176": [ - { - "pub_id": "29386101", - "title": "Learning and Age-Related Changes in Genome-wide H2A.Z Binding in the Mouse Hippocampus.", - "authors": "Gilda Stefanelli,Amber B Azam,Brandon J Walters,Mark A Brimble,Caroline P Gettens,Pascale Bouchard-Cannon,Hai-Ying M Cheng,Andrew M Davidoff,Klotilda Narkaj,Jeremy J Day,Andrew J Kennedy,Iva B Zovkic", - "abstract": "Histone variants were recently discovered to regulate neural plasticity, with H2A.Z emerging as a memory suppressor. Using whole-genome sequencing of the mouse hippocampus, we show that basal H2A.Z occupancy is positively associated with steady-state\u00a0transcription, whereas learning-induced H2A.Z removal is associated with learning-induced gene expression. AAV-mediated H2A.Z depletion enhanced fear memory and resulted in gene-specific alterations of learning-induced transcription, reinforcing the role of H2A.Z as a memory suppressor. H2A.Z accumulated with age, although it remained sensitive to learning-induced eviction. Learning-related H2A.Z removal occurred at largely distinct genes in young versus aged mice, suggesting that H2A.Z is subject to regulatory shifts in the aged brain despite similar memory performance. When combined with prior evidence of H3.3 accumulation in neurons, our data suggest that nucleosome composition in the brain is reorganized with age.", - "journal_title": "Cell reports", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/29386101/" - } - ], - "9bcf8a0d-af94-4d86-9b64-018ffd4ea6bb": [ - { - "pub_id": "36147920", - "title": "Surgical approaches to intramedullary spinal cord astrocytomas in the age of genomics.", - "authors": "Andrew M Hersh,George I Jallo,Nir Shimony", - "abstract": "Intramedullary astrocytomas represent approximately 30%-40% of all intramedullary tumors and are the most common intramedullary tumor in children. Surgical resection is considered the mainstay of treatment in symptomatic patients with neurological deficits. Gross total resection (GTR) can be difficult to achieve as astrocytomas frequently present as diffuse lesions that infiltrate the cord. Therefore, GTR carries a substantial risk of new post-operative deficits. Consequently, subtotal resection and biopsy are often the only surgical options attempted. A midline or paramedian sulcal myelotomy is frequently used for surgical resection, although a dorsal root entry zone myelotomy can be used for lateral tumors. Intra-operative neuromonitoring using D-wave integrity, somatosensory, and motor evoked potentials is critical to facilitating a safe resection. Adjuvant radiation and chemotherapy, such as temozolomide, are often administered for high-grade recurrent or progressive lesions; however, consensus is lacking on their efficacy. Biopsied tumors can be analyzed for molecular markers that inform clinicians about the tumor's prognosis and response to conventional as well as targeted therapeutic treatments. Stratification of intramedullary tumors is increasingly based on molecular features and mutational status. The landscape of genetic and epigenetic mutations in intramedullary astrocytomas is not equivalent to their intracranial counterparts, with important difference in frequency and type of mutations. Therefore, dedicated attention is needed to cohorts of patients with intramedullary tumors. Targeted therapeutic agents can be designed and administered to patients based on their mutational status, which may be used in coordination with traditional surgical resection to improve overall survival and functional status.", - "journal_title": "Frontiers in oncology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/36147920/" - } - ], - "c5ccc4c8-ef81-4059-a889-7b5b0922a040": [ - { - "pub_id": "32272900", - "title": "Lung transcriptomic clock predicts premature aging in cigarette smoke-exposed mice.", - "authors": "Mohamed-Amin Choukrallah,Julia Hoeng,Manuel C Peitsch,Florian Martin", - "abstract": "Lung aging is characterized by a number of structural alterations including fibrosis, chronic inflammation and the alteration of inflammatory cell composition. Chronic exposure to cigarette smoke (CS) is known to induce similar alterations and may contribute to premature lung aging. Additionally, aging and CS exposure are associated with transcriptional alterations in the lung. The current work aims to explore the interaction between age- and CS- associated transcriptomic perturbations and develop a transcriptomic clock able to predict the biological age and the impact of external factors on lung aging. Our investigations revealed a substantial overlap between transcriptomic response to CS exposure and age-related transcriptomic alterations in the murine lung. Of particular interest is the strong upregulation of immunoglobulin genes with increased age and in response to CS exposure, indicating an important implication of B-cells in lung inflammation associated with aging and smoking. Furthermore, we used a machine learning approach based on Lasso regression to build a transcriptomic age model that can accurately predict chronological age in untreated mice and the deviations associated with certain exposures. Interestingly, CS-exposed-mice were predicted to be prematurely aged in contrast to mice exposed to fresh air or to heated tobacco products (HTPs). The accelerated aging rate associated with CS was reversed upon smoking cessation or switching to HTPs. Additionally, our model was able to predict premature aging associated with thoracic irradiation from an independent public dataset. Aging and CS exposure share common transcriptional alteration patterns in the murine lung. The massive upregulation of B-cell restricted genes during these processes shed light on the contribution of cell composition and particularly immune cells to the measured transcriptomic signal. Through machine learning approach, we show that gene expression changes can be used to accurately monitor the biological age and the modulations associated with certain exposures. Our findings also suggest that the premature lung aging is reversible upon the reduction of harmful exposures.", - "journal_title": "BMC genomics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/32272900/" - } - ], - "c8befe34-3270-4c99-81cb-ee1d63c66045": [ - { - "pub_id": "31806903", - "title": "Undulating changes in human plasma proteome profiles across the lifespan.", - "authors": "Benoit Lehallier,David Gate,Nicholas Schaum,Tibor Nanasi,Song Eun Lee,Hanadie Yousef,Patricia Moran Losada,Daniela Berdnik,Andreas Keller,Joe Verghese,Sanish Sathyan,Claudio Franceschi,Sofiya Milman,Nir Barzilai,Tony Wyss-Coray", - "abstract": "Aging is a predominant risk factor for several chronic diseases that limit healthspan<sup>1</sup>. Mechanisms of aging are thus increasingly recognized as potential therapeutic targets. Blood from young mice reverses aspects of aging and disease across multiple tissues<sup>2-10</sup>, which supports a hypothesis that age-related molecular changes in blood could provide new insights into age-related disease biology. We measured 2,925 plasma proteins from 4,263 young adults to nonagenarians (18-95 years old) and developed a new bioinformatics approach that uncovered marked non-linear alterations in the human plasma proteome with age. Waves of changes in the proteome in the fourth, seventh and eighth decades of life reflected distinct biological pathways and revealed differential associations with the genome and proteome of age-related diseases and phenotypic traits. This new approach to the study of aging led to the identification of unexpected signatures and pathways that might offer potential targets for age-related diseases.", - "journal_title": "Nature medicine", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/31806903/" - } - ], - "9a606159-b219-4a1a-a06e-387ebb884357": [ - { - "pub_id": "37527159", - "title": "Genome-Scale Methylation Analysis Identifies Immune Profiles and Age Acceleration Associations with Bladder Cancer Outcomes.", - "authors": "Ji-Qing Chen,Lucas A Salas,John K Wiencke,Devin C Koestler,Annette M Molinaro,Angeline S Andrew,John D Seigne,Margaret R Karagas,Karl T Kelsey,Brock C Christensen", - "abstract": "Immune profiles have been associated with bladder cancer outcomes and may have clinical applications for prognosis. However, associations of detailed immune cell subtypes with patient outcomes remain underexplored and may contribute crucial prognostic information for better managing bladder cancer recurrence and survival. Bladder cancer case peripheral blood DNA methylation was measured using the Illumina HumanMethylationEPIC array. Extended cell-type deconvolution quantified 12 immune cell-type proportions, including memory, na\u00efve T and B cells, and granulocyte subtypes. DNA methylation clocks determined biological age. Cox proportional hazards models tested associations of immune cell profiles and age acceleration with bladder cancer outcomes. The partDSA algorithm discriminated 10-year overall survival groups from clinical variables and immune cell profiles, and a semi-supervised recursively partitioned mixture model (SS-RPMM) with DNA methylation data was applied to identify a classifier for 10-year overall survival. Higher CD8T memory cell proportions were associated with better overall survival [HR = 0.95, 95% confidence interval (CI) = 0.93-0.98], while higher neutrophil-to-lymphocyte ratio (HR = 1.36, 95% CI = 1.23-1.50), CD8T na\u00efve (HR = 1.21, 95% CI = 1.04-1.41), neutrophil (HR = 1.04, 95% CI = 1.03-1.06) proportions, and age acceleration (HR = 1.06, 95% CI = 1.03-1.08) were associated with worse overall survival in patient with bladder cancer. partDSA and SS-RPMM classified five groups of subjects with significant differences in overall survival. We identified associations between immune cell subtypes and age acceleration with bladder cancer outcomes. The findings of this study suggest that bladder cancer outcomes are associated with specific methylation-derived immune cell-type proportions and age acceleration, and these factors could be potential prognostic biomarkers.", - "journal_title": "Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/37527159/" - } - ], - "32693e00-d7b1-40b0-8700-462d0fd3d5a3": [ - { - "pub_id": "20800221", - "title": "Genome-wide association scan of trait depression.", - "authors": "Antonio Terracciano,Toshiko Tanaka,Angelina R Sutin,Serena Sanna,Barbara Deiana,Sandra Lai,Manuela Uda,David Schlessinger,Gon\u00e7alo R Abecasis,Luigi Ferrucci,Paul T Costa", - "abstract": "Independent of temporal circumstances, some individuals have greater susceptibility to depressive affects, such as feelings of guilt, sadness, hopelessness, and loneliness. Identifying the genetic variants that contribute to these individual differences can point to biological pathways etiologically involved in psychiatric disorders. Genome-wide association scans for the depression scale of the Revised NEO Personality Inventory in community-based samples from a genetically homogeneous area of Sardinia, Italy (n = 3972) and from the Baltimore Longitudinal Study of Aging in the United States (n = 839). Meta-analytic results for genotyped or imputed single nucleotide polymorphisms indicate that the strongest association signals for trait depression were found in RORA (rs12912233; p = 6 \u00d7 10\u207b\u2077), a gene involved in circadian rhythm. A plausible biological association was also found with single nucleotide polymorphisms within GRM8 (rs17864092; p = 5 \u00d7 10\u207b\u2076), a metabotropic receptor for glutamate, a major excitatory neurotransmitter in the central nervous system. These findings suggest shared genetic basis underlying the continuum from personality traits to psychopathology.", - "journal_title": "Biological psychiatry", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/20800221/" - } - ], - "100a4670-4b27-4528-bdba-5b5e38c82c8a": [ - { - "pub_id": "18662770", - "title": "A locus on distal chromosome 11 (ahl8) and its interaction with Cdh23 ahl underlie the early onset, age-related hearing loss of DBA/2J mice.", - "authors": "Kenneth R Johnson,Chantal Longo-Guess,Leona H Gagnon,Heping Yu,Qing Yin Zheng", - "abstract": "The DBA/2J inbred strain of mice is used extensively in hearing research, yet little is known about the genetic basis for its early onset, progressive hearing loss. To map underlying genetic factors we analyzed recombinant inbred strains and linkage backcrosses. Analysis of 213 mice from 31 BXD recombinant inbred strains detected linkage of auditory brain-stem response thresholds with a locus on distal chromosome 11, which we designate ahl8. Analysis of 225 N2 mice from a backcross of (C57BL/6JxDBA/2J) F1 hybrids to DBA/2J mice confirmed this linkage (LOD>50) and refined the ahl8 candidate gene interval. Analysis of 214 mice from a backcross of (B6.CAST-Cdh23 Ahl+ xDBA/2J) F1 hybrids to DBA/2J mice demonstrated a genetic interaction of Cdh23 with ahl8. We conclude that ahl8 is a major contributor to the hearing loss of DBA/2J mice and that its effects are dependent on the predisposing Cdh23 ahl genotype of this strain.", - "journal_title": "Genomics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/18662770/" - } - ], - "5b2f5728-7e9d-42d8-a2f4-23dcab32364f": [ - { - "pub_id": "26686632", - "title": "Stem Cell-Specific Mechanisms Ensure Genomic Fidelity within HSCs and upon Aging of HSCs.", - "authors": "Bettina M Moehrle,Kalpana Nattamai,Andreas Brown,Maria C Florian,Marnie Ryan,Mona Vogel,Corinna Bliederhaeuser,Karin Soller,Daniel R Prows,Amir Abdollahi,David Schleimer,Dagmar Walter,Michael D Milsom,Peter Stambrook,Matthew Porteus,Hartmut Geiger", - "abstract": "Whether aged hematopoietic stem and progenitor cells (HSPCs) have impaired DNA damage repair is controversial. Using a combination of DNA mutation indicator assays, we observe a 2- to 3-fold increase in the number of DNA mutations in the hematopoietic system upon aging. Young and aged hematopoietic stem cells (HSCs) and hematopoietic progenitor cells (HPCs) do not show an increase in mutation upon irradiation-induced DNA damage repair, and young and aged HSPCs respond very similarly to DNA damage with respect to cell-cycle checkpoint activation and apoptosis. Both young and aged HSPCs show impaired activation of the DNA-damage-induced G1-S checkpoint. Induction of chronic DNA double-strand breaks by zinc-finger nucleases suggests that HSPCs undergo apoptosis rather than faulty repair. These data reveal a protective mechanism in both the young and aged hematopoietic system against accumulation of mutations in response to DNA damage.", - "journal_title": "Cell reports", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/26686632/" - } - ], - "7f3e13d3-d0a2-4aee-8705-c6802009d850": [ - { - "pub_id": "36411412", - "title": "Proteomic analysis reveals that aging rabbit vocal folds are more vulnerable to changes caused by systemic dehydration.", - "authors": "Naila C do Nascimento,Taylor W Bailey,Andrea P Santos,Chenwei Duan,Rodrigo Mohallem,Jackeline Franco,Uma K Aryal,Jun Xie,Abigail Cox,M Preeti Sivasankar", - "abstract": "Older adults are more prone to develop systemic dehydration. Systemic dehydration has implications for vocal fold biology by affecting gene and protein expression. The objective of this study was to quantify vocal fold protein changes between two age groups and hydration status, and to investigate the interaction of age and hydration status on protein expression, which has not been investigated in the context of vocal folds before. Comparative proteomics was used to analyze the vocal fold proteome of 6.5-month-old and\u2009>\u20093-year-old rabbits subjected to water ad libitum or water volume restriction protocol. Young and older adult rabbits (n\u2009=\u200922) were either euhydrated (water ad libitum) or dehydrated by water volume restriction. Dehydration was confirmed by body weight loss of -\u20095.4% and\u2009-\u20094.6% in young and older groups, respectively, and a 1.7-fold increase of kidney renin gene expression in the young rabbits. LC-MS/MS identified 2286 proteins in the rabbit vocal folds of young and older adult rabbits combined. Of these, 177, 169, and 81 proteins were significantly (p\u2009\u2264\u20090.05) affected by age, hydration status, or the interaction of both factors, respectively. Analysis of the interaction effect revealed 32 proteins with opposite change patterns after dehydration between older and young rabbit vocal folds, while 31 proteins were differentially regulated only in the older adult rabbits and ten only in the young rabbits in response to systemic dehydration. The magnitude of changes for either up or downregulated proteins was higher in the older rabbits. These proteins are predominantly related to structural components of the extracellular matrix and muscle layer, suggesting a disturbance in the viscoelastic properties of aging vocal fold tissue, especially when subjected to systemic dehydration. Water restriction is a laboratory protocol to assess systemic dehydration-related changes in the vocal fold tissue that is translatable to human subjects. Our findings showed a higher number of proteins differentially regulated with a greater magnitude of change in the vocal folds of older adult rabbits in the presence of systemic dehydration compared to younger rabbits. The association of these proteins with vocal fold structure and biomechanical properties suggests that older human subjects may be more vulnerable to the effects of systemic dehydration on vocal function. The clinical implications of these protein changes warrant more investigation, but age should be taken into consideration when evaluating vocal treatment recommendations that interfere with body fluid balance.", - "journal_title": "BMC genomics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/36411412/" - } - ], - "e2bf7711-6ec5-4f8a-a79b-ea4a2e58a94b": [ - { - "pub_id": "25633388", - "title": "DNA methylation age of blood predicts all-cause mortality in later life.", - "authors": "Riccardo E Marioni,Sonia Shah,Allan F McRae,Brian H Chen,Elena Colicino,Sarah E Harris,Jude Gibson,Anjali K Henders,Paul Redmond,Simon R Cox,Alison Pattie,Janie Corley,Lee Murphy,Nicholas G Martin,Grant W Montgomery,Andrew P Feinberg,M Daniele Fallin,Michael L Multhaup,Andrew E Jaffe,Roby Joehanes,Joel Schwartz,Allan C Just,Kathryn L Lunetta,Joanne M Murabito,John M Starr,Steve Horvath,Andrea A Baccarelli,Daniel Levy,Peter M Visscher,Naomi R Wray,Ian J Deary", - "abstract": "DNA methylation levels change with age. Recent studies have identified biomarkers of chronological age based on DNA methylation levels. It is not yet known whether DNA methylation age captures aspects of biological age. Here we test whether differences between people's chronological ages and estimated ages, DNA methylation age, predict all-cause mortality in later life. The difference between DNA methylation age and chronological age (\u0394age) was calculated in four longitudinal cohorts of older people. Meta-analysis of proportional hazards models from the four cohorts was used to determine the association between \u0394age and mortality. A 5-year higher \u0394age is associated with a 21% higher mortality risk, adjusting for age and sex. After further adjustments for childhood IQ, education, social class, hypertension, diabetes, cardiovascular disease, and APOE e4 status, there is a 16% increased mortality risk for those with a 5-year higher \u0394age. A pedigree-based heritability analysis of \u0394age was conducted in a separate cohort. The heritability of \u0394age was 0.43. DNA methylation-derived measures of accelerated aging are heritable traits that predict mortality independently of health status, lifestyle factors, and known genetic factors.", - "journal_title": "Genome biology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/25633388/" - } - ], - "d7a4ce3a-9bd0-4f31-b27f-e425e2298b9f": [ - { - "pub_id": "35881546", - "title": "Targeting the DNA Damage Response Pathways and Replication Stress in Colorectal Cancer.", - "authors": "Erika Durinikova,Nicole M Reilly,Kristi Buzo,Elisa Mariella,Rosaria Chil\u00e0,Annalisa Lorenzato,Jo\u00e3o M L Dias,Gaia Grasso,Federica Pisati,Simona Lamba,Giorgio Corti,Andrea Degasperi,Carlotta Cancelliere,Gianluca Mauri,Pietro Andrei,Michael Linnebacher,Silvia Marsoni,Salvatore Siena,Andrea Sartore-Bianchi,Serena Nik-Zainal,Federica Di Nicolantonio,Alberto Bardelli,Sabrina Arena", - "abstract": "Genomic instability is a hallmark of cancer and targeting DNA damage response (DDR) is emerging as a promising therapeutic strategy in different solid tumors. The effectiveness of targeting DDR in colorectal cancer has not been extensively explored. We challenged 112 cell models recapitulating the genomic landscape of metastatic colorectal cancer with ATM, ATR, CHK1, WEE1, and DNA-PK inhibitors, in parallel with chemotherapeutic agents. We focused then on ATR inhibitors (ATRi) and, to identify putative biomarkers of response and resistance, we analyzed at multiple levels colorectal cancer models highly sensitive or resistant to these drugs. We found that around 30% of colorectal cancers, including those carrying KRAS and BRAF mutations and unresponsive to targeted agents, are sensitive to at least one DDR inhibitor. By investigating potential biomarkers of response to ATRi, we found that ATRi-sensitive cells displayed reduced phospho-RPA32 foci at basal level, while ATRi-resistant cells showed increased RAD51 foci formation in response to replication stress. Lack of ATM and RAD51C expression was associated with ATRi sensitivity. Analysis of mutational signatures and HRDetect score identified a subgroup of ATRi-sensitive models. Organoids derived from patients with metastatic colorectal cancer recapitulated findings obtained in cell lines. In conclusion, a subset of colorectal cancers refractory to current therapies could benefit from inhibitors of DDR pathways and replication stress. A composite biomarker involving phospho-RPA32 and RAD51 foci, lack of ATM and RAD51C expression, as well as analysis of mutational signatures could be used to identify colorectal cancers likely to respond to ATRi.", - "journal_title": "Clinical cancer research : an official journal of the American Association for Cancer Research", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/35881546/" - } - ], - "5e6ad994-9cad-4b8b-903d-2d5c350e25dc": [ - { - "pub_id": "37561875", - "title": "DNA methylation networks underlying mammalian traits.", - "authors": "Amin Haghani,Caesar Z Li,Todd R Robeck,Joshua Zhang,Ake T Lu,Julia Ablaeva,Victoria A Acosta-Rodr\u00edguez,Danielle M Adams,Abdulaziz N Alagaili,Javier Almunia,Ajoy Aloysius,Nabil M S Amor,Reza Ardehali,Adriana Arneson,C Scott Baker,Gareth Banks,Katherine Belov,Nigel C Bennett,Peter Black,Daniel T Blumstein,Eleanor K Bors,Charles E Breeze,Robert T Brooke,Janine L Brown,Gerald Carter,Alex Caulton,Julie M Cavin,Lisa Chakrabarti,Ioulia Chatzistamou,Andreas S Chavez,Hao Chen,Kaiyang Cheng,Priscila Chiavellini,Oi-Wa Choi,Shannon Clarke,Joseph A Cook,Lisa N Cooper,Marie-Laurence Cossette,Joanna Day,Joseph DeYoung,Stacy Dirocco,Christopher Dold,Jonathan L Dunnum,Erin E Ehmke,Candice K Emmons,Stephan Emmrich,Ebru Erbay,Claire Erlacher-Reid,Chris G Faulkes,Zhe Fei,Steven H Ferguson,Carrie J Finno,Jennifer E Flower,Jean-Michel Gaillard,Eva Garde,Livia Gerber,Vadim N Gladyshev,Rodolfo G Goya,Matthew J Grant,Carla B Green,M Bradley Hanson,Daniel W Hart,Martin Haulena,Kelsey Herrick,Andrew N Hogan,Carolyn J Hogg,Timothy A Hore,Taosheng Huang,Juan Carlos Izpisua Belmonte,Anna J Jasinska,Gareth Jones,Eve Jourdain,Olga Kashpur,Harold Katcher,Etsuko Katsumata,Vimala Kaza,Hippokratis Kiaris,Michael S Kobor,Pawel Kordowitzki,William R Koski,Michael Kr\u00fctzen,Soo Bin Kwon,Brenda Larison,Sang-Goo Lee,Marianne Lehmann,Jean-Fran\u00e7ois Lema\u00eetre,Andrew J Levine,Xinmin Li,Cun Li,Andrea R Lim,David T S Lin,Dana M Lindemann,Schuyler W Liphardt,Thomas J Little,Nicholas Macoretta,Dewey Maddox,Craig O Matkin,Julie A Mattison,Matthew McClure,June Mergl,Jennifer J Meudt,Gisele A Montano,Khyobeni Mozhui,Jason Munshi-South,William J Murphy,Asieh Naderi,Martina Nagy,Pritika Narayan,Peter W Nathanielsz,Ngoc B Nguyen,Christof Niehrs,Batsaikhan Nyamsuren,Justine K O'Brien,Perrie O'Tierney Ginn,Duncan T Odom,Alexander G Ophir,Steve Osborn,Elaine A Ostrander,Kim M Parsons,Kimberly C Paul,Amy B Pedersen,Matteo Pellegrini,Katharina J Peters,Jessica L Petersen,Darren W Pietersen,Gabriela M Pinho,Jocelyn Plassais,Jesse R Poganik,Natalia A Prado,Pradeep Reddy,Benjamin Rey,Beate R Ritz,Jooke Robbins,Magdalena Rodriguez,Jennifer Russell,Elena Rydkina,Lindsay L Sailer,Adam B Salmon,Akshay Sanghavi,Kyle M Schachtschneider,Dennis Schmitt,Todd Schmitt,Lars Schomacher,Lawrence B Schook,Karen E Sears,Ashley W Seifert,Aaron B A Shafer,Anastasia V Shindyapina,Melanie Simmons,Kavita Singh,Ishani Sinha,Jesse Slone,Russel G Snell,Elham Soltanmohammadi,Matthew L Spangler,Maria Spriggs,Lydia Staggs,Nancy Stedman,Karen J Steinman,Donald T Stewart,Victoria J Sugrue,Balazs Szladovits,Joseph S Takahashi,Masaki Takasugi,Emma C Teeling,Michael J Thompson,Bill Van Bonn,Sonja C Vernes,Diego Villar,Harry V Vinters,Ha Vu,Mary C Wallingford,Nan Wang,Gerald S Wilkinson,Robert W Williams,Qi Yan,Mingjia Yao,Brent G Young,Bohan Zhang,Zhihui Zhang,Yang Zhao,Peng Zhao,Wanding Zhou,Joseph A Zoller,Jason Ernst,Andrei Seluanov,Vera Gorbunova,X William Yang,Ken Raj,Steve Horvath", - "abstract": "Using DNA methylation profiles (<i>n</i> = 15,456) from 348 mammalian species, we constructed phyloepigenetic trees that bear marked similarities to traditional phylogenetic ones. Using unsupervised clustering across all samples, we identified 55 distinct cytosine modules, of which 30 are related to traits such as maximum life span, adult weight, age, sex, and human mortality risk. Maximum life span is associated with methylation levels in <i>HOXL</i> subclass homeobox genes and developmental processes and is potentially regulated by pluripotency transcription factors. The methylation state of some modules responds to perturbations such as caloric restriction, ablation of growth hormone receptors, consumption of high-fat diets, and expression of Yamanaka factors. This study reveals an intertwined evolution of the genome and epigenome that mediates the biological characteristics and traits of different mammalian species.", - "journal_title": "Science (New York, N.Y.)", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/37561875/" - } - ], - "d1ef18b1-ee0b-487f-9c81-c21c26d6c9c8": [ - { - "pub_id": "22922032", - "title": "Divergent whole-genome methylation maps of human and chimpanzee brains reveal epigenetic basis of human regulatory evolution.", - "authors": "Jia Zeng,Genevieve Konopka,Brendan G Hunt,Todd M Preuss,Dan Geschwind,Soojin V Yi", - "abstract": "DNA methylation is a pervasive epigenetic DNA modification that strongly affects chromatin regulation and gene expression. To date, it remains largely unknown how patterns of DNA methylation differ between closely related species and whether such differences contribute to species-specific phenotypes. To investigate these questions, we generated nucleotide-resolution whole-genome methylation maps of the prefrontal cortex of multiple humans and chimpanzees. Levels and patterns of DNA methylation vary across individuals within species according to the age and the sex of the individuals. We also found extensive species-level divergence in patterns of DNA methylation and that hundreds of genes exhibit significantly lower levels of promoter methylation in the human brain than in the chimpanzee brain. Furthermore, we investigated the functional consequences of methylation differences in humans and chimpanzees by integrating data on gene expression generated with next-generation sequencing methods, and we found a strong relationship between differential methylation and gene expression. Finally, we found that differentially methylated genes are strikingly enriched with loci associated with neurological disorders, psychological disorders, and cancers. Our results demonstrate that differential DNA methylation might be an important molecular mechanism driving gene-expression divergence between human and chimpanzee brains and might potentially contribute to the evolution of disease vulnerabilities. Thus, comparative studies of humans and chimpanzees stand to identify key epigenomic modifications underlying the evolution of human-specific traits.", - "journal_title": "American journal of human genetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/22922032/" - } - ], - "54ba3fb1-7ed0-4211-8f15-9c45fea8d3e3": [ - { - "pub_id": "18598106", - "title": "Molecular profiling in the age of cancer genomics.", - "authors": "Jimmy Lin,Meng Li", - "abstract": "In this new era of cancer genomics, large-scale queries of whole genomic characteristics are now possible not only for research and biological understanding, but also for molecular profiling in the context of patient management and care. Here, we will examine genomic, transcriptomic and proteomic methods of characterizing tumors that may play a role in early diagnosis, classification, prognosis, therapeutic guidance and recurrence surveillance during the entire progression of the disease and treatment cycle. We examine all the technological advances and biological discoveries that enable new exciting frontiers of molecular profiling, and also provide a glimpse of emerging and future applications of these methods in a clinical setting.", - "journal_title": "Expert review of molecular diagnostics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/18598106/" - } - ], - "612a70c6-2f42-492f-9f23-0d5e9296919e": [ - { - "pub_id": "6307991", - "title": "Mitochondrial DNA in mortal and immortal human cells. Genome number, integrity, and methylation.", - "authors": "R J Shmookler Reis,S Goldstein", - "abstract": "Mitochondrial DNA was quantitated in total DNA of various normal and mutant strains of human diploid fibroblasts (finite replicative lifespan) and permanent cell lines, using Southern-transfer hybridization to 32P-labeled pure mtDNA probe and saturation hybridization to 3H-labeled cRNA copied from mtDNA. In six normal fibroblast strains, mtDNA copy number increased during serial passage roughly in proportion to cell volume or protein content, whereas normalized mtDNA content per pg of protein depended upon in vivo donor age but not passage level (\"in vitro\" age). Copy numbers for mtDNA varied much more widely in individual fibroblast clones than in mass cultures, but were not well correlated with longevity or growth rate. Five mutant fibroblast strains associated with reduced replicative lifespan, and four permanent cell lines, were also examined; in each group, mtDNA values were observed both lower and higher than any obtained for normal fibroblasts. No evidence was found of petite-type deletions from human mtDNA, either at late passage or in individual clones of fibroblasts. Methylation of mtDNA genomes was strikingly non-random and apparently decreased with culture age.", - "journal_title": "The Journal of biological chemistry", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/6307991/" - } - ], - "b1ffece8-f805-4d99-8e3b-402df309f1ed": [ - { - "pub_id": "23039964", - "title": "GeneFriends: an online co-expression analysis tool to identify novel gene targets for aging and complex diseases.", - "authors": "Sipko van Dam,Rui Cordeiro,Thomas Craig,Jesse van Dam,Shona H Wood,Jo\u00e3o Pedro de Magalh\u00e3es", - "abstract": "Although many diseases have been well characterized at the molecular level, the underlying mechanisms are often unknown. Nearly half of all human genes remain poorly studied, yet these genes may contribute to a number of disease processes. Genes involved in common biological processes and diseases are often co-expressed. Using known disease-associated genes in a co-expression analysis may help identify and prioritize novel candidate genes for further study. We have created an online tool, called GeneFriends, which identifies co-expressed genes in over 1,000 mouse microarray datasets. GeneFriends can be used to assign putative functions to poorly studied genes. Using a seed list of disease-associated genes and a guilt-by-association method, GeneFriends allows users to quickly identify novel genes and transcription factors associated with a disease or process. We tested GeneFriends using seed lists for aging, cancer, and mitochondrial complex I disease. We identified several candidate genes that have previously been predicted as relevant targets. Some of the genes identified are already being tested in clinical trials, indicating the effectiveness of this approach. Co-expressed transcription factors were investigated, identifying C/ebp genes as candidate regulators of aging. Furthermore, several novel candidate genes, that may be suitable for experimental or clinical follow-up, were identified. Two of the novel candidates of unknown function that were co-expressed with cancer-associated genes were selected for experimental validation. Knock-down of their human homologs (C1ORF112 and C12ORF48) in HeLa cells slowed growth, indicating that these genes of unknown function, identified by GeneFriends, may be involved in cancer. GeneFriends is a resource for biologists to identify and prioritize novel candidate genes involved in biological processes and complex diseases. It is an intuitive online resource that will help drive experimentation. GeneFriends is available online at: http://genefriends.org/.", - "journal_title": "BMC genomics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/23039964/" - } - ], - "3859c73d-e251-4c17-81f1-a42fba99ace9": [ - { - "pub_id": "18195102", - "title": "Longevity mutation in SCH9 prevents recombination errors and premature genomic instability in a Werner/Bloom model system.", - "authors": "Federica Madia,Cristina Gattazzo,Min Wei,Paola Fabrizio,William C Burhans,Martin Weinberger,Abdoulaye Galbani,Jesse R Smith,Christopher Nguyen,Selina Huey,Lucio Comai,Valter D Longo", - "abstract": "Werner and Bloom syndromes are human diseases characterized by premature age-related defects including elevated cancer incidence. Using a novel Saccharomyces cerevisiae model system for aging and cancer, we show that cells lacking the RecQ helicase SGS1 (WRN and BLM homologue) undergo premature age-related changes, including reduced life span under stress and calorie restriction (CR), G1 arrest defects, dedifferentiation, elevated recombination errors, and age-dependent increase in DNA mutations. Lack of SGS1 results in a 110-fold increase in gross chromosomal rearrangement frequency during aging of nondividing cells compared with that generated during the initial population expansion. This underscores the central role of aging in genomic instability. The deletion of SCH9 (homologous to AKT and S6K), but not CR, protects against the age-dependent defects in sgs1Delta by inhibiting error-prone recombination and preventing DNA damage and dedifferentiation. The conserved function of Akt/S6k homologues in lifespan regulation raises the possibility that modulation of the IGF-I-Akt-56K pathway can protect against premature aging syndromes in mammals.", - "journal_title": "The Journal of cell biology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/18195102/" - } - ], - "c9f18682-826f-486c-a634-1ac8b27e0800": [ - { - "pub_id": "22930739", - "title": "Quantitative proteomic analysis reveals novel mitochondrial targets of estrogen deficiency in the aged female rat heart.", - "authors": "T S Lancaster,S J Jefferson,J Craig Hunter,Veronica Lopez,J E Van Eyk,E G Lakatta,D H Korzick", - "abstract": "The incidence of myocardial infarction rises sharply at menopause, implicating a potential role for estrogen (E(2)) loss in age-related increases in ischemic injury. We aimed to identify quantitative changes to the cardiac mitochondrial proteome of aging females, based on the hypothesis that E(2) deficiency exacerbates age-dependent disruptions in mitochondrial proteins. Mitochondria isolated from left ventricles of adult (6 mo) and aged (24 mo) F344 ovary-intact or ovariectomized (OVX) rats were labeled with 8plex isobaric tags for relative and absolute quantification (iTRAQ; n = 5-6/group). Groups studied were adult, adult OVX, aged, and aged OVX. In vivo coronary artery ligation and in vitro mitochondrial respiration studies were also performed in a subset of rats. We identified 965 proteins across groups and significant directional changes in 67 proteins of aged and/or aged OVX; 32 proteins were unique to aged OVX. Notably, only six proteins were similarly altered in adult OVX (voltage-dependent ion channel 1, adenine nucleotide translocator 1, cytochrome c oxidase subunits VIIc and VIc, catalase, and myosin binding protein C). Proteins affected by aging were primarily related to cellular metabolism, oxidative stress, and cell death. The largest change occurred in monoamine oxidase-A (MAO-A), a source of oxidative stress. While acute MAO-A inhibition induced mild uncoupling in aged mitochondria, reductions in infarct size were not observed. Age-dependent alterations in mitochondrial signaling indicate a highly selective myocardial response to E(2) deficiency. The combined proteomic and functional approaches described here offer possibility of new protein targets for experimentation and therapeutic intervention in the aged female population.", - "journal_title": "Physiological genomics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/22930739/" - } - ], - "ba779513-74ff-46e0-988e-72ed0355d173": [ - { - "pub_id": "19437452", - "title": "Arsenic exposure induces genomic hypermethylation.", - "authors": "Sunipa Majumdar,Sarmishtha Chanda,Bhaswati Ganguli,D N Guha Mazumder,Sarbari Lahiri,Uma B Dasgupta", - "abstract": "Gene-specific hypermethylation has previously been detected in Arsenic exposed persons. To monitor the level of whole genome methylation in persons exposed to different levels of Arsenic via drinking water, DNA was extracted from peripheral blood mononuclear cells of 64 persons. Uptake of methyl group from (3)H labeled S-Adenosyl Methionine after incubation of DNA with SssI methylase was measured. Results showed statistically significant (P = 0.0004) decrease in uptake of (3)H methyl group in the persons exposed to 250-500 microg/L arsenic, indicating genomic hypermethylation.", - "journal_title": "Environmental toxicology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/19437452/" - } - ], - "7eef5f7a-f18d-4793-b2aa-e0ccdfd779be": [ - { - "pub_id": "35680011", - "title": "First report on genome wide association study in western Indian population reveals host genetic factors for COVID-19 severity and outcome.", - "authors": "Ramesh Pandit,Indra Singh,Afzal Ansari,Janvi Raval,Zarna Patel,Raghav Dixit,Pranay Shah,Kamlesh Upadhyay,Naresh Chauhan,Kairavi Desai,Meenakshi Shah,Bhavesh Modi,Madhvi Joshi,Chaitanya Joshi", - "abstract": "Different human races across the globe responded in a different way to the SARS-CoV-2 infection leading to different disease severity. Therefore, it is anticipated that host genetic factors have a straight association with the COVID-19. We identified a total 6, 7, and 6 genomic loci for deceased-recovered, asymptomatic-recovered, and deceased-asymptomatic group comparison, respectively. Unfavourable alleles of the markers nearby the genes which are associated with lung and heart diseases such as Tumor necrosis factor superfamily (TNFSF4&18), showed noteworthy association with the disease severity and outcome for the COVID-19 patients in the western Indian population. The markers found with significant association with disease prognosis or recovery are of value in determining the individual's response to SARS-CoV-2 infection and can be used for the risk prediction in COVID-19. Besides, GWAS study in other populations from India may help to strengthen the outcome of this study.", - "journal_title": "Genomics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/35680011/" - } - ], - "e54182ac-551b-4293-95eb-3f235efa1ec5": [ - { - "pub_id": "32803238", - "title": "Integrative genomics approach identifies conserved transcriptomic networks in Alzheimer's disease.", - "authors": "Samuel Morabito,Emily Miyoshi,Neethu Michael,Vivek Swarup", - "abstract": "Alzheimer's disease (AD) is a devastating neurological disorder characterized by changes in cell-type proportions and consequently marked alterations of the transcriptome. Here we use a data-driven systems biology meta-analytical approach across three human AD cohorts, encompassing six cortical brain regions, and integrate with multi-scale datasets comprising of DNA methylation, histone acetylation, transcriptome- and genome-wide association studies and quantitative trait loci to further characterize the genetic architecture of AD. We perform co-expression network analysis across more than 1200 human brain samples, identifying robust AD-associated dysregulation of the transcriptome, unaltered in normal human aging. We assess the cell-type specificity of AD gene co-expression changes and estimate cell-type proportion changes in human AD by integrating co-expression modules with single-cell transcriptome data generated from 27\u2009321 nuclei from human postmortem prefrontal cortical tissue. We also show that genetic variants of AD are enriched in a microglial AD-associated module and identify key transcription factors regulating co-expressed modules. Additionally, we validate our results in multiple published human AD gene expression datasets, which can be easily accessed using our online resource (https://swaruplab.bio.uci.edu/consensusAD).", - "journal_title": "Human molecular genetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/32803238/" - } - ], - "14a15ff3-706d-44be-aca5-4bad24a5e4ec": [ - { - "pub_id": "32265525", - "title": "Animal domestication in the era of ancient genomics.", - "authors": "Laurent A F Frantz,Daniel G Bradley,Greger Larson,Ludovic Orlando", - "abstract": "The domestication of animals led to a major shift in human subsistence patterns, from a hunter-gatherer to a sedentary agricultural lifestyle, which ultimately resulted in the development of complex societies. Over the past 15,000 years, the phenotype and genotype of multiple animal species, such as dogs, pigs, sheep, goats, cattle and horses, have been substantially altered during their adaptation to the human niche. Recent methodological innovations, such as improved ancient DNA extraction methods and next-generation sequencing, have enabled the sequencing of whole ancient genomes. These genomes have helped reconstruct the process by which animals entered into domestic relationships with humans and were subjected to novel selection pressures. Here, we discuss and update key concepts in animal domestication in light of recent contributions from ancient genomics.", - "journal_title": "Nature reviews. Genetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/32265525/" - } - ], - "e3b8b9aa-9702-43a1-ac44-3d1198e04217": [ - { - "pub_id": "30849937", - "title": "Genome-wide methylation is modified by caloric restriction in Daphnia magna.", - "authors": "Jack Hearn,Marianne Pearson,Mark Blaxter,Philip J Wilson,Tom J Little", - "abstract": "The degradation of epigenetic control with age is associated with progressive diseases of ageing, including cancers, immunodeficiency and diabetes. Reduced caloric intake slows the effects of ageing and age-related disease in vertebrates and invertebrates, a process potentially mediated by the impact of caloric restriction on epigenetic factors such as DNA methylation. We used whole genome bisulphite sequencing to study how DNA methylation patterns change with diet in a small invertebrate, the crustacean Daphnia magna. Daphnia show the classic response of longer life under caloric restriction (CR), and they reproduce clonally, which permits the study of epigenetic changes in the absence of genetic variation. Global cytosine followed by guanine (CpG) methylation was 0.7-0.9%, and there was no difference in overall methylation levels between normal and calorie restricted replicates. However, 333 differentially methylated regions (DMRs) were evident between the normally fed and CR replicates post-filtering. Of these 65% were hypomethylated in the CR group, and 35% were hypermethylated in the CR group. Our results demonstrate an effect of CR on the genome-wide methylation profile. This adds to a growing body of research in Daphnia magna that demonstrate an epigenomic response to environmental stimuli. Specifically, gene Ontology (GO) term enrichment of genes associated with hyper and hypo-methylated DMRs showed significant enrichment for methylation and acyl-CoA dehydrogenase activity, which are linked to current understanding of their roles in CR in invertebrate model organisms.", - "journal_title": "BMC genomics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/30849937/" - } - ], - "cdeda6d2-1371-4ceb-bdcd-50375746d775": [ - { - "pub_id": "19880490", - "title": "A genome-wide association analysis of serum iron concentrations.", - "authors": "Toshiko Tanaka,Cindy N Roy,Wenliang Yao,Amy Matteini,Richard D Semba,Dan Arking,Jeremy D Walston,Linda P Fried,Andrew Singleton,Jack Guralnik,Gon\u00e7alo R Abecasis,Stefania Bandinelli,Dan L Longo,Luigi Ferrucci", - "abstract": "To investigate genetic variants that affect iron concentrations in persons not affected by overt genetic disorders of iron metabolism, a genome-wide association study was conducted in the InCHIANTI Study (N = 1206) and the Baltimore Longitudinal Study of Aging (N = 713). The top 2 single-nucleotide polymorphisms were examined for replication in the Women's Health and Aging Study (WHAS) I and II (N = 569). The single-nucleotide polymorphism most strongly associated with lower serum iron concentration was rs4820268 (P = 5.12 x 10(-9)), located in exon 13 of the transmembrane protease serine 6 (TMPRSS6) gene, an enzyme that promotes iron absorption and recycling by inhibiting hepcidin antimicrobial peptide transcription. The allele associated with lower iron concentrations was also associated with lower hemoglobin levels, smaller red cells, and more variability in red cell size (high red blood cell distribution width). Our results confirm the association of TMPRSS6 variants with iron level and provide further evidence of association with other anemia-related phenotypes.", - "journal_title": "Blood", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/19880490/" - } - ], - "94f15a3c-4099-4a5b-8280-b56c31d8876b": [ - { - "pub_id": "33050031", - "title": "Pleiotropic Locus 15q24.1 Reveals a Gender-Specific Association with Neovascular but Not Atrophic Age-Related Macular Degeneration (AMD).", - "authors": "Christina Kiel,Tobias Strunz, International Amd Genomics Consortium Project Manager Susan Blanton Iamdgc,Felix Grassmann,Bernhard H F Weber", - "abstract": "Genome-wide association studies (GWAS) have identified an abundance of genetic loci associated with complex traits and diseases. In contrast, in-depth characterization of an individual genetic signal is rarely available. Here, we focus on the genetic variant rs2168518 in 15q24.1 previously associated with age-related macular degeneration (AMD), but only with suggestive evidence. In a two-step procedure, we initially conducted a series of association analyses to further delineate the association of rs2168518 with AMD but also with other complex phenotypes by using large independent datasets from the International AMD Genomics Consortium (IAMDGC) and the UK Biobank. We then performed a functional annotation with reference to gene expression regulation based on data from the Genotype-Tissue Expression (GTEx) project and RegulomeDB. Association analysis revealed a gender-specific association with male AMD patients and an association predominantly with choroidal neovascularization. Further, the AMD association colocalizes with an association signal of several blood pressure-related phenotypes and with the gene expression regulation of <i>CYP1A1</i>, a member of the cytochrome P450 superfamily of monooxygenases. Functional annotation revealed altered transcription factor (TF) binding sites for gender-specific TFs, including SOX9 and SRY. In conclusion, the pleiotropic 15q24.1 association signal suggests a shared mechanism between blood pressure regulation and choroidal neovascularization with a potential involvement of CYP1A1.", - "journal_title": "Cells", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/33050031/" - } - ], - "96cb840e-747f-4849-8354-e8764aa0a1ce": [ - { - "pub_id": "30706680", - "title": "Turner syndrome: New insights from prenatal genomics and transcriptomics.", - "authors": "Diana W Bianchi", - "abstract": "In some parts of the world, prenatal screening using analysis of circulating cell-free (cf) DNA in the plasma of pregnant women has become part of routine prenatal care with limited professional guidelines and without significant input from the Turner syndrome community. In contrast to the very high positive predictive values (PPVs) achieved with cfDNA analysis for trisomy 21 (91% for high-risk and 82% for low-risk cases), the PPVs for monosomy X are much lower (~26%). This is because the maternal plasma sample contains both maternal cfDNA and placental DNA, which is a proxy for the fetal genome. Underlying biological mechanisms for false positive monosomy X screening results include confined placental mosaicism, co-twin demise, and maternal mosaicism. Somatic loss of a single X chromosome in the mother is a natural phenomenon that occurs with aging; this could explain many of the false positive cfDNA results. There is also increased awareness of women who have constitutional mosaicism for 45, X who are fertile. It is important to recognize that a positive cfDNA screen for 45, X does not mean that the fetus has Turner syndrome. A follow-up diagnostic test, either amniocentesis or neonatal karyotype/chromosome microarray, is recommended. Research studies on cell-free mRNA in second trimester amniotic fluid, which is almost exclusively fetal, demonstrate consistent dysregulation of genes involved in the hematologic, immune, and neurologic systems. This suggests that some of the pathophysiology of Turner syndrome occurs early in fetal life and presents novel opportunities for consideration of antenatal treatments.", - "journal_title": "American journal of medical genetics. Part C, Seminars in medical genetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/30706680/" - } - ], - "150c550c-5c6f-4f73-b2ed-62daba7a81ed": [ - { - "pub_id": "31296769", - "title": "Ancient cattle genomics, origins, and rapid turnover in the Fertile Crescent.", - "authors": "Marta Pereira Verdugo,Victoria E Mullin,Amelie Scheu,Valeria Mattiangeli,Kevin G Daly,Pierpaolo Maisano Delser,Andrew J Hare,Joachim Burger,Matthew J Collins,Ron Kehati,Paula Hesse,Deirdre Fulton,Eberhard W Sauer,Fatemeh A Mohaseb,Hossein Davoudi,Roya Khazaeli,Johanna Lhuillier,Claude Rapin,Saeed Ebrahimi,Mutalib Khasanov,S M Farhad Vahidi,David E MacHugh,Okan Ertu\u011frul,Chaido Koukouli-Chrysanthaki,Adamantios Sampson,George Kazantzis,Ioannis Kontopoulos,Jelena Bulatovic,Ivana Stojanovi\u0107,Abdesalam Mikdad,Norbert Benecke,J\u00f6rg Linst\u00e4dter,Mikhail Sablin,Robin Bendrey,Lionel Gourichon,Benjamin S Arbuckle,Marjan Mashkour,David Orton,Liora Kolska Horwitz,Matthew D Teasdale,Daniel G Bradley", - "abstract": "Genome-wide analysis of 67 ancient Near Eastern cattle, <i>Bos taurus,</i> remains reveals regional variation that has since been obscured by admixture in modern populations. Comparisons of genomes of early domestic cattle to their aurochs progenitors identify diverse origins with separate introgressions of wild stock. A later region-wide Bronze Age shift indicates rapid and widespread introgression of zebu, <i>Bos indicus,</i> from the Indus Valley. This process was likely stimulated at the onset of the current geological age, ~4.2 thousand years ago, by a widespread multicentury drought. In contrast to genome-wide admixture, mitochondrial DNA stasis supports that this introgression was male-driven, suggesting that selection of arid-adapted zebu bulls enhanced herd survival. This human-mediated migration of zebu-derived genetics has continued through millennia, altering tropical herding on each continent.", - "journal_title": "Science (New York, N.Y.)", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/31296769/" - } - ], - "9a12db75-1efa-46b1-9da4-d2fc8d828f42": [ - { - "pub_id": "33505962", - "title": "New Technologies to Study Functional Genomics of Age-Related Macular Degeneration.", - "authors": "Tu Nguyen,Daniel Urrutia-Cabrera,Roxanne Hsiang-Chi Liou,Chi D Luu,Robyn Guymer,Raymond Ching-Bong Wong", - "abstract": "Age-related macular degeneration (AMD) is the most common cause of irreversible vision loss in people over 50 years old in developed countries. Currently, we still lack a comprehensive understanding of the genetic factors contributing to AMD, which is critical to identify effective therapeutic targets to improve treatment outcomes for AMD patients. Here we discuss the latest technologies that can facilitate the identification and functional study of putative genes in AMD pathology. We review improved genomic methods to identify novel AMD genes, advances in single cell transcriptomics to profile gene expression in specific retinal cell types, and summarize recent development of <i>in vitro</i> models for studying AMD using induced pluripotent stem cells, organoids and biomaterials, as well as new molecular technologies using CRISPR/Cas that could facilitate functional studies of AMD-associated genes.", - "journal_title": "Frontiers in cell and developmental biology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/33505962/" - } - ], - "7025797f-8718-4dd5-a7f3-1fe68e08057e": [ - { - "pub_id": "30978202", - "title": "Integration of heterogeneous functional genomics data in gerontology research to find genes and pathway underlying aging across species.", - "authors": "Jason A Bubier,George L Sutphin,Timothy J Reynolds,Ron Korstanje,Axis Fuksman-Kumpa,Erich J Baker,Michael A Langston,Elissa J Chesler", - "abstract": "Understanding the biological mechanisms behind aging, lifespan and healthspan is becoming increasingly important as the proportion of the world's population over the age of 65 grows, along with the cost and complexity of their care. BigData oriented approaches and analysis methods enable current and future bio-gerontologists to synthesize, distill and interpret vast, heterogeneous data from functional genomics studies of aging. GeneWeaver is an analysis system for integration of data that allows investigators to store, search, and analyze immense amounts of data including user-submitted experimental data, data from primary publications, and data in other databases. Aging related genome-wide gene sets from primary publications were curated into this system in concert with data from other model-organism and aging-specific databases, and applied to several questions in genrontology using. For example, we identified Cd63 as a frequently represented gene among aging-related genome-wide results. To evaluate the role of Cd63 in aging, we performed RNAi knockdown of the C. elegans ortholog, tsp-7, demonstrating that this manipulation is capable of extending lifespan. The tools in GeneWeaver enable aging researchers to make new discoveries into the associations between the genes, normal biological processes, and diseases that affect aging, healthspan, and lifespan.", - "journal_title": "PloS one", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/30978202/" - } - ], - "04c5378f-40dc-4690-af03-e5205779b881": [ - { - "pub_id": "36484990", - "title": "Whole-Exome Sequencing Among Chinese Patients With Hereditary Diffuse Gastric Cancer.", - "authors": "Ze-Xian Liu,Xiao-Long Zhang,Qi Zhao,Yungchang Chen,Hui Sheng,Cai-Yun He,Yu-Ting Sun,Ming-Yu Lai,Min-Qing Wu,Zhi-Xiang Zuo,Wei Wang,Zhi-Wei Zhou,Feng-Hua Wang,Yu-Hong Li,Rui-Hua Xu,Miao-Zhen Qiu", - "abstract": "The E-cadherin gene, CDH1, and the \u03b1-E-catenin gene, CTNNA1, were previously identified as hereditary diffuse gastric cancer (HDGC) susceptibility genes, explaining 25% to 50% of HDGC cases. The genetic basis underlying disease susceptibility in the remaining 50% to 75% of patients with HDGC is still unknown. To assess the incidence rate of CDH1 germline alterations in HDGC, identify new susceptibility genes that can be used for screening of HDGC, and provide a genetic landscape for HDGC. This cohort study conducted retrospective whole-exome and targeted sequencing of 284 leukocyte samples and 186 paired tumor samples from Chinese patients with HDGC over a long follow-up period (median, 21.7 [range, 0.6-185.9] months). Among 10 431 patients diagnosed with gastric cancer between January 1, 2002, and August 31, 2018, 284 patients who met the criteria for HDGC were included. Data were analyzed from August 1 to 30, 2020. Incidence rate of CDH1 germline alterations, identification of new HDGC susceptibility genes, and genetic landscape of HDGC. Among 284 Chinese patients, 161 (56.7%) were female, and the median age was 35 (range, 20-75) years. The frequency of CDH1 germline alterations was 2.8%, whereas the frequency of CDH1 somatic alterations was 25.3%. The genes with the highest incidence (>10%) of private germline alterations (including insertions and deletions) in the HDGC cohort were MUC4, ABCA13, ZNF469, FCGBP, IGFN1, RNF213, and SSPO, whereas previously reported germline alterations of CTNNA1, BRCA2, STK11, PRSS1, ATM, MSR1, PALB2, BRCA1, and RAD51C were observed at low frequencies (median, 4 [range, 1-12] cases). Furthermore, enrichment of the somatic variant signature of exposure to aflatoxin suggested potential interaction between genetics and environment in HDGC. Double-hit events in genes such as CACNA1D were observed, which suggested that these events might serve as important mechanisms for HDGC tumorigenesis. In addition, germline variants of FSIP2, HSPG2, and NCKAP5 and somatic alterations of FGFR3, ASPSCR1, CIC, DGCR8, and LZTR1 were associated with poor overall survival among patients with HDGC. This study provided a genetic landscape for HDGC. The study's findings challenged the previously reported high germline alteration rate of CDH1 in HDGC and identified new potential susceptibility genes. Analyses of variant signatures and double-hit events revealed potentially important mechanisms for HDGC tumorigenesis. Findings from the present study may provide helpful information for further investigations of HDGC.", - "journal_title": "JAMA network open", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/36484990/" - } - ], - "84a43249-4f36-466a-88ad-c8bf23786fb9": [ - { - "pub_id": "30337457", - "title": "Somatic mutant clones colonize the human esophagus with age.", - "authors": "I\u00f1igo Martincorena,Joanna C Fowler,Agnieszka Wabik,Andrew R J Lawson,Federico Abascal,Michael W J Hall,Alex Cagan,Kasumi Murai,Krishnaa Mahbubani,Michael R Stratton,Rebecca C Fitzgerald,Penny A Handford,Peter J Campbell,Kourosh Saeb-Parsy,Philip H Jones", - "abstract": "The extent to which cells in normal tissues accumulate mutations throughout life is poorly understood. Some mutant cells expand into clones that can be detected by genome sequencing. We mapped mutant clones in normal esophageal epithelium from nine donors (age range, 20 to 75 years). Somatic mutations accumulated with age and were caused mainly by intrinsic mutational processes. We found strong positive selection of clones carrying mutations in 14 cancer genes, with tens to hundreds of clones per square centimeter. In middle-aged and elderly donors, clones with cancer-associated mutations covered much of the epithelium, with <i>NOTCH1</i> and <i>TP53</i> mutations affecting 12 to 80% and 2 to 37% of cells, respectively. Unexpectedly, the prevalence of <i>NOTCH1</i> mutations in normal esophagus was several times higher than in esophageal cancers. These findings have implications for our understanding of cancer and aging.", - "journal_title": "Science (New York, N.Y.)", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/30337457/" - } - ], - "805fb332-212e-494a-954c-89eb7d66589e": [ - { - "pub_id": "32298765", - "title": "Genome-wide association study of non-alcoholic fatty liver and steatohepatitis in a histologically characterised cohort<sup>\u2606</sup>.", - "authors": "Quentin M Anstee,Rebecca Darlay,Simon Cockell,Marica Meroni,Olivier Govaere,Dina Tiniakos,Alastair D Burt,Pierre Bedossa,Jeremy Palmer,Yang-Lin Liu,Guruprasad P Aithal,Michael Allison,Hannele Yki-J\u00e4rvinen,Michele Vacca,Jean-Francois Dufour,Pietro Invernizzi,Daniele Prati,Mattias Ekstedt,Stergios Kechagias,Sven Francque,Salvatore Petta,Elisabetta Bugianesi,Karine Clement,Vlad Ratziu,J\u00f6rn M Schattenberg,Luca Valenti,Christopher P Day,Heather J Cordell,Ann K Daly, ", - "abstract": "Genetic factors associated with non-alcoholic fatty liver disease (NAFLD) remain incompletely understood. To date, most genome-wide association studies (GWASs) have adopted radiologically assessed hepatic triglyceride content as the reference phenotype and so cannot address steatohepatitis or fibrosis. We describe a GWAS encompassing the full spectrum of histologically characterised NAFLD. The GWAS involved 1,483 European NAFLD cases and 17,781 genetically matched controls. A replication cohort of 559 NAFLD cases and 945 controls was genotyped to confirm signals showing genome-wide or close to genome-wide significance. Case-control analysis identified signals showing p values \u22645\u00a0\u00d7 10<sup>-8</sup> at 4 locations (chromosome [chr] 2 GCKR/C2ORF16; chr4 HSD17B13; chr19 TM6SF2; chr22 PNPLA3) together with 2 other signals with p <1\u00a0\u00d7 10<sup>-7</sup> (chr1 near LEPR and chr8 near IDO2/TC1). Case-only analysis of quantitative traits showed that the PNPLA3 signal (rs738409) had genome-wide significance for steatosis, fibrosis and NAFLD activity score and a new signal (PYGO1 rs62021874) had close to genome-wide significance for steatosis (p\u00a0= 8.2\u00a0\u00d7 10<sup>-8</sup>). Subgroup case-control analysis for NASH confirmed the PNPLA3 signal. The chr1 LEPR single nucleotide polymorphism also showed genome-wide significance for this phenotype. Considering the subgroup with advanced fibrosis (\u2265F3), the signals on chr2, chr19 and chr22 maintained their genome-wide significance. Except for GCKR/C2ORF16, the genome-wide significance signals were replicated. This study confirms PNPLA3 as a risk factor for the full histological spectrum of NAFLD at genome-wide significance levels, with important contributions from TM6SF2 and HSD17B13. PYGO1 is a novel steatosis modifier, suggesting that Wnt signalling pathways may be relevant in NAFLD pathogenesis. Non-alcoholic fatty liver disease is a common disease where excessive fat accumulates in the liver and may result in cirrhosis. To understand who is at risk of developing this disease and suffering liver damage, we undertook a genetic study to compare the genetic profiles of people suffering from fatty liver disease with genetic profiles seen in the general population. We found that particular sequences in 4 different areas of the human genome were seen at different frequencies in the fatty liver disease cases. These sequences may help predict an individual's risk of developing advanced disease. Some genes where these sequences are located may also be good targets for future drug treatments.", - "journal_title": "Journal of hepatology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/32298765/" - } - ], - "945b78ad-5465-4cd2-8dfa-1b1c879b5994": [ - { - "pub_id": "14519767", - "title": "Age-related changes in the transcriptional profile of mouse RPE/choroid.", - "authors": "Hisashi Ida,Sharon A Boylan,Andrea L Weigel,Leonard M Hjelmeland", - "abstract": "To evaluate the age-related changes in gene expression occurring in the complex of retinal pigmented epithelium, Bruch's membrane, and choroid (RPE/choroid), we examined the gene expression profiles of young adult (2 mo) and old (24 mo) male C57BL/6 mice. cDNA probe sets from individual animals were synthesized using total RNA isolated from the RPE/choroid of each animal. Probes were amplified using the Clontech SMART system, radioactively labeled, and hybridized to two different Clontech Atlas mouse cDNA arrays. From each age group, three independent triplicates were hybridized to the arrays. Statistical analyses were performed using the Significance Analysis of Microarrays program (SAM version 1.13; Stanford University). Selected array results were confirmed by semi-quantitative RT-PCR analysis. Of 2,340 genes represented on the arrays, approximately 60% were expressed in young and/or old mouse RPE/choroid. A moderate fraction (12%) of all expressed genes exhibited a statistically significant change in expression with age. Of these 150 genes, all but two, HMG14 and carboxypeptidase E, were upregulated with age. Many of these upregulated genes can be grouped into several broad functional categories: immune response, proteases and protease inhibitors, stress response, and neovascularization. RT-PCR results from six of six genes examined confirmed the differential change in expression with age of these genes. Our study provides likely candidate genes to further study their role in the development of age-related macular degeneration and other aging diseases affecting the RPE/choroid.", - "journal_title": "Physiological genomics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/14519767/" - } - ], - "ff9b57df-b8ae-419a-a9f8-72644d4f0360": [ - { - "pub_id": "23315237", - "title": "Increased paternal age and the influence on burden of genomic copy number variation in the general population.", - "authors": "Jacobine E Buizer-Voskamp,Hylke M Blauw,Marco P M Boks,Kristel R van Eijk,Jan H Veldink,Eric A M Hennekam,Jacob A S Vorstman,Flip Mulder,Henning Tiemeier,Andr\u00e9 G Uitterlinden,Lambertus A Kiemeney,Leonard H van den Berg,Ren\u00e9 S Kahn,Chiara Sabatti,Roel A Ophoff", - "abstract": "Genomic copy number variations (CNVs) and increased parental age are both associated with the risk to develop a variety of clinical neuropsychiatric disorders such as autism, schizophrenia and bipolar disorder. At the same time, it has been shown that the rate of transmitted de novo single nucleotide mutations is increased with paternal age. To address whether paternal age also affects the burden of structural genomic deletions and duplications, we examined various types of CNV burden in a large population sample from the Netherlands. Healthy participants with parental age information (n\u00a0=\u00a06,773) were collected at different University Medical Centers. CNVs were called with the PennCNV algorithm using Illumina genome-wide SNP array data. We observed no evidence in support of a paternal age effect on CNV load in the offspring. Our results were negative for global measures as well as several proxies for de novo CNV events in this unique sample. While recent studies suggest de novo single nucleotide mutation rate to be dominated by the age of the father at conception, our results strongly suggest that at the level of global CNV burden there is no influence of increased paternal age. While it remains possible that local genomic effects may exist for specific phenotypes, this study indicates that global CNV burden and increased father's age may be independent disease risk factors.", - "journal_title": "Human genetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/23315237/" - } - ], - "8d3493d8-aa00-440e-8a3d-8209d0b39d19": [ - { - "pub_id": "21946350", - "title": "Genome-wide association and large-scale follow up identifies 16 new loci influencing lung function.", - "authors": "Mar\u00eda Soler Artigas,Daan W Loth,Louise V Wain,Sina A Gharib,Ma'en Obeidat,Wenbo Tang,Guangju Zhai,Jing Hua Zhao,Albert Vernon Smith,Jennifer E Huffman,Eva Albrecht,Catherine M Jackson,David M Evans,Gemma Cadby,Myriam Fornage,Ani Manichaikul,Lorna M Lopez,Toby Johnson,Melinda C Aldrich,Thor Aspelund,In\u00eas Barroso,Harry Campbell,Patricia A Cassano,David J Couper,Gudny Eiriksdottir,Nora Franceschini,Melissa Garcia,Christian Gieger,Gauti Kjartan Gislason,Ivica Grkovic,Christopher J Hammond,Dana B Hancock,Tamara B Harris,Adaikalavan Ramasamy,Susan R Heckbert,Markku Heli\u00f6vaara,Georg Homuth,Pirro G Hysi,Alan L James,Stipan Jankovic,Bonnie R Joubert,Stefan Karrasch,Norman Klopp,Beate Koch,Stephen B Kritchevsky,Lenore J Launer,Yongmei Liu,Laura R Loehr,Kurt Lohman,Ruth J F Loos,Thomas Lumley,Khalid A Al Balushi,Wei Q Ang,R Graham Barr,John Beilby,John D Blakey,Mladen Boban,Vesna Boraska,Jonas Brisman,John R Britton,Guy G Brusselle,Cyrus Cooper,Ivan Curjuric,Santosh Dahgam,Ian J Deary,Shah Ebrahim,Mark Eijgelsheim,Clyde Francks,Darya Gaysina,Raquel Granell,Xiangjun Gu,John L Hankinson,Rebecca Hardy,Sarah E Harris,John Henderson,Amanda Henry,Aroon D Hingorani,Albert Hofman,Patrick G Holt,Jennie Hui,Michael L Hunter,Medea Imboden,Karen A Jameson,Shona M Kerr,Ivana Kolcic,Florian Kronenberg,Jason Z Liu,Jonathan Marchini,Tricia McKeever,Andrew D Morris,Anna-Carin Olin,David J Porteous,Dirkje S Postma,Stephen S Rich,Susan M Ring,Fernando Rivadeneira,Thierry Rochat,Avan Aihie Sayer,Ian Sayers,Peter D Sly,George Davey Smith,Akshay Sood,John M Starr,Andr\u00e9 G Uitterlinden,Judith M Vonk,S Goya Wannamethee,Peter H Whincup,Cisca Wijmenga,O Dale Williams,Andrew Wong,Massimo Mangino,Kristin D Marciante,Wendy L McArdle,Bernd Meibohm,Alanna C Morrison,Kari E North,Ernst Omenaas,Lyle J Palmer,Kirsi H Pietil\u00e4inen,Isabelle Pin,Ozren Pola Sbreve Ek,Anneli Pouta,Bruce M Psaty,Anna-Liisa Hartikainen,Taina Rantanen,Samuli Ripatti,Jerome I Rotter,Igor Rudan,Alicja R Rudnicka,Holger Schulz,So-Youn Shin,Tim D Spector,Ida Surakka,Veronique Vitart,Henry V\u00f6lzke,Nicholas J Wareham,Nicole M Warrington,H-Erich Wichmann,Sarah H Wild,Jemma B Wilk,Matthias Wjst,Alan F Wright,Lina Zgaga,Tatijana Zemunik,Craig E Pennell,Fredrik Nyberg,Diana Kuh,John W Holloway,H Marike Boezen,Debbie A Lawlor,Richard W Morris,Nicole Probst-Hensch, , ,Jaakko Kaprio,James F Wilson,Caroline Hayward,Mika K\u00e4h\u00f6nen,Joachim Heinrich,Arthur W Musk,Deborah L Jarvis,Sven Gl\u00e4ser,Marjo-Riitta J\u00e4rvelin,Bruno H Ch Stricker,Paul Elliott,George T O'Connor,David P Strachan,Stephanie J London,Ian P Hall,Vilmundur Gudnason,Martin D Tobin", - "abstract": "Pulmonary function measures reflect respiratory health and are used in the diagnosis of chronic obstructive pulmonary disease. We tested genome-wide association with forced expiratory volume in 1 second and the ratio of forced expiratory volume in 1 second to forced vital capacity in 48,201 individuals of European ancestry with follow up of the top associations in up to an additional 46,411 individuals. We identified new regions showing association (combined P < 5 \u00d7 10(-8)) with pulmonary function in or near MFAP2, TGFB2, HDAC4, RARB, MECOM (also known as EVI1), SPATA9, ARMC2, NCR3, ZKSCAN3, CDC123, C10orf11, LRP1, CCDC38, MMP15, CFDP1 and KCNE2. Identification of these 16 new loci may provide insight into the molecular mechanisms regulating pulmonary function and into molecular targets for future therapy to alleviate reduced lung function.", - "journal_title": "Nature genetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/21946350/" - } - ], - "39d31a16-b437-40d3-bef5-5b8c9b092c14": [ - { - "pub_id": "21545734", - "title": "Characterization of age-related gene expression profiling in bone marrow and epididymal adipocytes.", - "authors": "Li-Fen Liu,Wen-Jun Shen,Masami Ueno,Shailja Patel,Fredric B Kraemer", - "abstract": "While an increase in bone marrow adiposity is associated with age-related bone disease, the function of bone marrow adipocytes has not been studied. The aim of this study was to characterize and compare the age-related gene expression profiles in bone marrow adipocytes and epididymal adipocytes. A total of 3918 (13.7%) genes were differentially expressed in bone marrow adipocytes compared to epididymal adipocytes. Bone marrow adipocytes revealed a distinct gene profile with low expression of adipocyte-specific genes peroxisome proliferator-activated receptor gamma (PPAR\u03b3), fatty acid binding protein 4 (FABP4), perilipin (Plin1), adipsin (CFD) and high expression of genes associated with early adipocyte differentiation (CCAAT/enhancer binding protein beta (C/EBP\u03b2), regulator of G-protein signaling 2 (RGS2). In addition, a number of genes including secreted frizzled related protein 4 (SFRP4), tumor necrosis factor \u03b1 (TNF\u03b1), transforming growth factor beta 1(TGF\u03b21), G-protein coupled receptor 109A (GPR109A) and interleukin 6 (IL-6), that could affect adipose-derived signaling to bone are markedly increased in bone marrow adipocytes. Age had a substantial effect on genes associated with mitochondria function and inflammation in bone marrow adipocytes. Twenty seven genes were significantly changed with age in both adipocyte depots. Among these genes, IL6 and GPR109A were significantly reduced with age in both adipocyte depots. Overall, gene profiling reveals a unique phenotype for primary bone marrow adipocytes characterized by low adipose-specific gene expression and high expression of inflammatory response genes. Bone marrow and epididymal adipocytes share a common pathway in response to aging in mice, but age has a greater impact on global gene expression in epididymal than in bone marrow adipocytes. Genes that are differentially expressed at greater levels in the bone marrow are highly regulated with age.", - "journal_title": "BMC genomics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/21545734/" - } - ], - "52c101dd-4131-4e7d-b914-478836a05edf": [ - { - "pub_id": "30765617", - "title": "Ribosomal DNA harbors an evolutionarily conserved clock of biological aging.", - "authors": "Meng Wang,Bernardo Lemos", - "abstract": "The ribosomal DNA (rDNA) is the most evolutionarily conserved segment of the genome and gives origin to the nucleolus, an energy intensive nuclear organelle and major hub influencing myriad molecular processes from cellular metabolism to epigenetic states of the genome. The rDNA/nucleolus has been directly and mechanistically implicated in aging and longevity in organisms as diverse as yeasts, <i>Drosophila</i>, and humans. The rDNA is also a significant target of DNA methylation that silences supernumerary rDNA units and regulates nucleolar activity. Here, we introduce an age clock built exclusively with CpG methylation within the rDNA. The ribosomal clock is sufficient to accurately estimate individual age within species, is responsive to genetic and environmental interventions that modulate life-span, and operates across species as distant as humans, mice, and dogs. Further analyses revealed a significant excess of age-associated hypermethylation in the rDNA relative to other segments of the genome, and which forms the basis of the rDNA clock. Our observations identified an evolutionarily conserved marker of aging that is easily ascertained, grounded on nucleolar biology, and could serve as a universal marker to gauge individual age and response to interventions in humans as well as laboratory and wild organisms across a wide diversity of species.", - "journal_title": "Genome research", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/30765617/" - } - ], - "309bf5c6-d154-4a8e-8f8a-1bc67040fc1d": [ - { - "pub_id": "23792563", - "title": "Comprehensive molecular characterization of clear cell renal cell carcinoma.", - "authors": " ", - "abstract": "Genetic changes underlying clear cell renal cell carcinoma (ccRCC) include alterations in genes controlling cellular oxygen sensing (for example, VHL) and the maintenance of chromatin states (for example, PBRM1). We surveyed more than 400 tumours using different genomic platforms and identified 19 significantly mutated genes. The PI(3)K/AKT pathway was recurrently mutated, suggesting this pathway as a potential therapeutic target. Widespread DNA hypomethylation was associated with mutation of the H3K36 methyltransferase SETD2, and integrative analysis suggested that mutations involving the SWI/SNF chromatin remodelling complex (PBRM1, ARID1A, SMARCA4) could have far-reaching effects on other pathways. Aggressive cancers demonstrated evidence of a metabolic shift, involving downregulation of genes involved in the TCA cycle, decreased AMPK and PTEN protein levels, upregulation of the pentose phosphate pathway and the glutamine transporter genes, increased acetyl-CoA carboxylase protein, and altered promoter methylation of miR-21 (also known as MIR21) and GRB10. Remodelling cellular metabolism thus constitutes a recurrent pattern in ccRCC that correlates with tumour stage and severity and offers new views on the opportunities for disease treatment.", - "journal_title": "Nature", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/23792563/" - } - ], - "4680871d-7ef5-47e3-a1dd-8865b8142d1d": [ - { - "pub_id": "34726931", - "title": "<i>Listeria monocytogenes</i> infections: presentation, diagnosis and treatment.", - "authors": "Maria Valenti,Nisha Ranganathan,Luke Sp Moore,Stephen Hughes", - "abstract": "Listeriosis is an infective complication that primarily affects pregnant women, patients at extremes of age or those with weakened immune systems. Ingestion of food contaminated with <i>Listeria monocytogenes</i> is the most common source of infection, causing self-limiting illness in immunocompetent hosts but associated with invasive infection and high mortality in high-risk patient groups. Milder illness presents as gastroenteritis with fever, diarrhoea, nausea and vomiting common in the 7 days post exposure. Invasive infection, characterised by bacteraemia and encephalitis, can develop in high-risk patients. Fetal loss is a major complication of listeriosis during pregnancy. Penicillin-based therapy (high dose penicillin or amoxicillin) in combination with gentamicin is advised for invasive infection; co-trimoxazole may be considered for patients intolerant to penicillin. Vulnerable individuals, notably pregnant women, should be counseled on appropriate preventative strategies including avoiding foods commonly contaminated with <i>L. monocytogenes</i>, such as soft ripened cheeses, pate, cooked chilled meats, unpasteurised milk, and ready to eat poultry unless thoroughly cooked.", - "journal_title": "British journal of hospital medicine (London, England : 2005)", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/34726931/" - } - ], - "f2b8524b-501d-4ec7-a3d7-048aab67ce05": [ - { - "pub_id": "18986374", - "title": "The Human Ageing Genomic Resources: online databases and tools for biogerontologists.", - "authors": "Jo\u00e3o Pedro de Magalh\u00e3es,Arie Budovsky,Gilad Lehmann,Joana Costa,Yang Li,Vadim Fraifeld,George M Church", - "abstract": "Aging is a complex, challenging phenomenon that requires multiple, interdisciplinary approaches to unravel its puzzles. To assist basic research on aging, we developed the Human Ageing Genomic Resources (HAGR). This work provides an overview of the databases and tools in HAGR and describes how the gerontology research community can employ them. Several recent changes and improvements to HAGR are also presented. The two centrepieces in HAGR are GenAge and AnAge. GenAge is a gene database featuring genes associated with aging and longevity in model organisms, a curated database of genes potentially associated with human aging, and a list of genes tested for their association with human longevity. A myriad of biological data and information is included for hundreds of genes, making GenAge a reference for research that reflects our current understanding of the genetic basis of aging. GenAge can also serve as a platform for the systems biology of aging, and tools for the visualization of protein-protein interactions are also included. AnAge is a database of aging in animals, featuring over 4000 species, primarily assembled as a resource for comparative and evolutionary studies of aging. Longevity records, developmental and reproductive traits, taxonomic information, basic metabolic characteristics, and key observations related to aging are included in AnAge. Software is also available to aid researchers in the form of Perl modules to automate numerous tasks and as an SPSS script to analyse demographic mortality data. The HAGR are available online at http://genomics.senescence.info.", - "journal_title": "Aging cell", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/18986374/" - } - ], - "bc81ff69-8a8e-4909-8ec6-a76748048df9": [ - { - "pub_id": "11276429", - "title": "Fungal virulence studies come of age.", - "authors": "F C Odds,N A Gow,A J Brown", - "abstract": "Sophisticated molecular biological research has revealed many virulence attributes in at least four pathogenic fungi, but the future study of fungal virulence requires investigators to distinguish between molecules that directly interact with the host, molecules that regulate these, and molecules that are always required for fungal growth and survival, independent of the host.", - "journal_title": "Genome biology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/11276429/" - } - ], - "572e2eb6-2b8a-446c-a288-d4857bfd56b3": [ - { - "pub_id": "12547392", - "title": "Caloric restriction promotes genomic stability by induction of base excision repair and reversal of its age-related decline.", - "authors": "Diane C Cabelof,Sunitha Yanamadala,Julian J Raffoul,ZhongMao Guo,Abdulsalam Soofi,Ahmad R Heydari", - "abstract": "Caloric restriction is a potent experimental manipulation that extends mean and maximum life span and delays the onset and progression of tumors in laboratory rodents. While caloric restriction (CR) clearly protects the genome from deleterious damage, the mechanism by which genomic stability is achieved remains unclear. We provide evidence that CR promotes genomic stability by increasing DNA repair capacity, specifically base excision repair (BER). CR completely reverses the age-related decline in BER capacity (P<0.01) in all tissues tested (brain, liver, spleen and testes) providing aged, CR animals with the BER phenotype of young, ad libitum-fed animals. This CR-induced reversal of the aged BER phenotype is accompanied by a reversal in the age-related decline in DNA polymerase beta (beta-pol), a rate-limiting enzyme in the BER pathway. CR significantly reversed the age-related loss of beta-pol protein levels (P<0.01), mRNA levels (P<0.01) and enzyme activity (P<0.01) in all tissues tested. Additionally, in young (4-6-month-old) CR animals a significant up-regulation in BER capacity, beta-pol protein and beta-pol mRNA is observed (P<0.01), demonstrating an early effect of CR that may provide insight in distinguishing the anti-tumor from the anti-aging effects of CR. This up-regulation in BER by caloric restriction in young animals corresponds to increased protection from carcinogen exposure, as mutation frequency is significantly reduced in CR animals exposed to either DMS or 2-nitropropane (2-NP) (P<0.01). Overall the data suggest an important biological consequence of moderate BER up-regulation and provides support for the hormesis theory of caloric restriction.", - "journal_title": "DNA repair", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/12547392/" - } - ], - "1152aa3c-a9df-4745-b262-97c03ccf0e1a": [ - { - "pub_id": "12923532", - "title": "Mitochondrial DNA modifies cognition in interaction with the nuclear genome and age in mice.", - "authors": "Pierre L Roubertoux,Frans Sluyter,Mich\u00e8le Carlier,Brice Marcet,Fatima Maarouf-Veray,Chabane Ch\u00e9rif,Charlotte Marican,Patricia Arrechi,Fabienne Godin,Marc Jamon,Bernard Verrier,Charles Cohen-Salmon", - "abstract": "Several lines of evidence indicate an association between mitochondrial DNA (mtDNA) and the functioning of the nervous system. As neuronal development and structure as well as axonal and synaptic activity involve mitochondrial genes, it is not surprising that most mtDNA diseases are associated with brain disorders. Only one study has suggested an association between mtDNA and cognition, however. Here we provide direct evidence of mtDNA involvement in cognitive functioning. Total substitution of mtDNA was achieved by 20 repeated backcrosses in NZB/BlNJ (N) and CBA/H (H) mice with different mtDNA origins. All 13 mitochondrial genes were expressed in the brains of the congenic quartet. In interaction with nuclear DNA (nDNA), mtDNA modified learning, exploration, sensory development and the anatomy of the brain. The effects of mtDNA substitution persisted with age, increasing in magnitude as the mice got older. We observed different effects with input of mtDNA from N versus H mice, varying according to the phenotypes. Exchanges of mtDNA may produce phenotypes outside the range of scores observed in the original mitochondrial and nuclear combinations. These findings show that mitochondrial polymorphisms are not as neutral as was previously believed.", - "journal_title": "Nature genetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/12923532/" - } - ], - "870798fd-2c26-4819-9403-fe52836770eb": [ - { - "pub_id": "25837999", - "title": "The mechanism of ageing: primary role of transposable elements in genome disintegration.", - "authors": "\u00c1d\u00e1m Sturm,Zolt\u00e1n Ivics,Tibor Vellai", - "abstract": "Understanding the molecular basis of ageing remains a fundamental problem in biology. In multicellular organisms, while the soma undergoes a progressive deterioration over the lifespan, the germ line is essentially immortal as it interconnects the subsequent generations. Genomic instability in somatic cells increases with age, and accumulating evidence indicates that the disintegration of somatic genomes is accompanied by the mobilisation of transposable elements (TEs) that, when mobilised, can be mutagenic by disrupting coding or regulatory sequences. In contrast, TEs are effectively silenced in the germ line by the Piwi-piRNA system. Here, we propose that TE repression transmits the persistent proliferation capacity and the non-ageing phenotype (e.g., preservation of genomic integrity) of the germ line. The Piwi-piRNA pathway also operates in tumorous cells and in somatic cells of certain organisms, including hydras, which likewise exhibit immortality. However, in somatic cells lacking the Piwi-piRNA pathway, gradual chromatin decondensation increasingly allows the mobilisation of TEs as the organism ages. This can explain why the mortality rate rises exponentially throughout the adult life in most animal species, including humans.", - "journal_title": "Cellular and molecular life sciences : CMLS", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/25837999/" - } - ], - "10489887-2cc9-427a-b707-1fbbf8ddc7fb": [ - { - "pub_id": "18073271", - "title": "Aging alters gene expression of growth and remodeling factors in human skeletal muscle both at rest and in response to acute resistance exercise.", - "authors": "Richard A Dennis,Beata Przybyla,Cathy Gurley,Patrick M Kortebein,Pippa Simpson,Dennis H Sullivan,Charlotte A Peterson", - "abstract": "The purpose of this investigation was to compare expression of genes that function in inflammation and stress, cell structure and signaling, or remodeling and growth in skeletal muscle of young (32 +/- 7 yr, n = 15) and elderly (72 +/- 5 yr, n = 16) healthy subjects before and after a bout of resistance leg exercises. A real-time RT-PCR method was used to screen 100 transcripts in v. lateralis biopsies obtained before and 72 h postexercise. The screen identified 15 candidates for differential expression due to aging and/or exercise that were measured quantitatively. The median levels of four mRNAs (insulin-like growth factor-1 and its binding protein IGFBP5, ciliary neurotrophic factor, and the metallopeptidase MMP2) were significantly affected by aging and were greater (1.6- to 2.3-fold, P </= 0.05) in the young than elderly muscle at both time points. The median levels of three mRNAs were significantly (P </= 0.05) affected by exercise in the young. The metallopeptidase inhibitor TIMP1 and alpha-cardiac actin mRNAs increased 2-fold and 6.5-fold, respectively, and GDF8 (myostatin) mRNA decreased by 50%. However, elderly muscle did not display any significant changes in gene expression postexercise. Thus, aging muscle shows decreased levels at rest and an impaired response to exercise for a number of mRNAs for factors potentially involved in muscle growth and remodeling. Future studies must determine the functional importance of these gene expression changes to protein synthesis, satellite cell activity, and other processes that are directly involved in the mechanisms of muscle hypertrophy.", - "journal_title": "Physiological genomics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/18073271/" - } - ], - "5622b7c1-d1fd-4986-8df6-de681204e96d": [ - { - "pub_id": "20876843", - "title": "Aging and microRNA expression in human skeletal muscle: a microarray and bioinformatics analysis.", - "authors": "Micah J Drummond,John J McCarthy,Mala Sinha,Heidi M Spratt,Elena Volpi,Karyn A Esser,Blake B Rasmussen", - "abstract": "A common characteristic of aging is loss of skeletal muscle (sarcopenia), which can lead to falls and fractures. MicroRNAs (miRNAs) are novel posttranscriptional modulators of gene expression with potential roles as regulators of skeletal muscle mass and function. The purpose of this study was to profile miRNA expression patterns in aging human skeletal muscle with a miRNA array followed by in-depth functional and network analysis. Muscle biopsy samples from 36 men [young: 31 \u00b1 2 (n = 19); older: 73 \u00b1 3 (n = 17)] were 1) analyzed for expression of miRNAs with a miRNA array, 2) validated with TaqMan quantitative real-time PCR assays, and 3) identified (and later validated) for potential gene targets with the bioinformatics knowledge base software Ingenuity Pathways Analysis. Eighteen miRNAs were differentially expressed in older humans (P < 0.05 and >500 expression level). Let-7 family members Let-7b and Let-7e were significantly elevated and further validated in older subjects (P < 0.05). Functional and network analysis from Ingenuity determined that gene targets of the Let-7s were associated with molecular networks involved in cell cycle control such as cellular proliferation and differentiation. We confirmed with real-time PCR that mRNA expression of cell cycle regulators CDK6, CDC25A, and CDC34 were downregulated in older compared with young subjects (P < 0.05). In addition, PAX7 mRNA expression was lower in older subjects (P < 0.05). These data suggest that aging is characterized by a higher expression of Let-7 family members that may downregulate genes related to cellular proliferation. We propose that higher Let-7 expression may be an indicator of impaired cell cycle function possibly contributing to reduced muscle cell renewal and regeneration in older human muscle.", - "journal_title": "Physiological genomics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/20876843/" - } - ], - "f1176abf-031c-492d-8f2d-d8415096edbc": [ - { - "pub_id": "27007234", - "title": "Evidence for Genetic Overlap Between Schizophrenia and Age at First Birth in Women.", - "authors": "Divya Mehta,Felix C Tropf,Jacob Gratten,Andrew Bakshi,Zhihong Zhu,Silviu-Alin Bacanu,Gibran Hemani,Patrik K E Magnusson,Nicola Barban,T\u00f5nu Esko,Andres Metspalu,Harold Snieder,Bryan J Mowry,Kenneth S Kendler,Jian Yang,Peter M Visscher,John J McGrath,Melinda C Mills,Naomi R Wray,S Hong Lee, ,Ole A Andreassen,Elvira Bramon,Richard Bruggeman,Joseph D Buxbaum,Murray J Cairns,Rita M Cantor,C Robert Cloninger,David Cohen,Benedicto Crespo-Facorro,Ariel Darvasi,Lynn E DeLisi,Timothy Dinan,Srdjan Djurovic,Gary Donohoe,Elodie Drapeau,Valentina Escott-Price,Nelson B Freimer,Lyudmila Georgieva,Lieuwe de Haan,Frans A Henskens,Inge Joa,Antonio Juli\u00e0,Andrey Khrunin,Bernard Lerer,Svetlana Limborska,Carmel M Loughland,Milan Macek,Patrik K E Magnusson,Sara Marsal,Robert W McCarley,Andrew M McIntosh,Andrew McQuillin,Bela Melegh,Patricia T Michie,Derek W Morris,Kieran C Murphy,Inez Myin-Germeys,Ann Olincy,Jim Van Os,Christos Pantelis,Danielle Posthuma,Digby Quested,Ulrich Schall,Rodney J Scott,Larry J Seidman,Draga Toncheva,Paul A Tooney,John Waddington,Daniel R Weinberger,Mark Weiser,Jing Qin Wu", - "abstract": "A recently published study of national data by McGrath et al in 2014 showed increased risk of schizophrenia (SCZ) in offspring associated with both early and delayed parental age, consistent with a U-shaped relationship. However, it remains unclear if the risk to the child is due to psychosocial factors associated with parental age or if those at higher risk for SCZ tend to have children at an earlier or later age. To determine if there is a genetic association between SCZ and age at first birth (AFB) using genetically informative but independently ascertained data sets. This investigation used multiple independent genome-wide association study data sets. The SCZ sample comprised 18\u202f957 SCZ cases and 22\u202f673 controls in a genome-wide association study from the second phase of the Psychiatric Genomics Consortium, and the AFB sample comprised 12\u202f247 genotyped women measured for AFB from the following 4 community cohorts: Estonia (Estonian Genome Center Biobank, University of Tartu), the Netherlands (LifeLines Cohort Study), Sweden (Swedish Twin Registry), and the United Kingdom (TwinsUK). Schizophrenia genetic risk for each woman in the AFB community sample was estimated using genetic effects inferred from the SCZ genome-wide association study. We tested if SCZ genetic risk was a significant predictor of response variables based on published polynomial functions that described the relationship between maternal age and SCZ risk in offspring in Denmark. We substituted AFB for maternal age in these functions, one of which was corrected for the age of the father, and found that the fit was superior for the model without adjustment for the father's age. We observed a U-shaped relationship between SCZ risk and AFB in the community cohorts, consistent with the previously reported relationship between SCZ risk in offspring and maternal age when not adjusted for the age of the father. We confirmed that SCZ risk profile scores significantly predicted the response variables (coefficient of determination R2\u2009=\u20091.1E-03, P\u2009=\u20094.1E-04), reflecting the published relationship between maternal age and SCZ risk in offspring by McGrath et al in 2014. This study provides evidence for a significant overlap between genetic factors associated with risk of SCZ and genetic factors associated with AFB. It has been reported that SCZ risk associated with increased maternal age is explained by the age of the father and that de novo mutations that occur more frequently in the germline of older men are the underlying causal mechanism. This explanation may need to be revised if, as suggested herein and if replicated in future studies, there is also increased genetic risk of SCZ in older mothers.", - "journal_title": "JAMA psychiatry", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/27007234/" - } - ], - "969a6399-d5d3-46c8-99ee-ca3ce5c77c4f": [ - { - "pub_id": "19366437", - "title": "Gene expression profiling to characterize sediment toxicity--a pilot study using Caenorhabditis elegans whole genome microarrays.", - "authors": "Ralph Menzel,Suresh C Swain,Sebastian Hoess,Evelyn Claus,Stefanie Menzel,Christian Ew Steinberg,Georg Reifferscheid,Stephen R St\u00fcrzenbaum", - "abstract": "Traditionally, toxicity of river sediments is assessed using whole sediment tests with benthic organisms. The challenge, however, is the differentiation between multiple effects caused by complex contaminant mixtures and the unspecific toxicity endpoints such as survival, growth or reproduction. The use of gene expression profiling facilitates the identification of transcriptional changes at the molecular level that are specific to the bio-available fraction of pollutants. In this pilot study, we exposed the nematode Caenorhabditis elegans to three sediments of German rivers with varying (low, medium and high) levels of heavy metal and organic contamination. Beside chemical analysis, three standard bioassays were performed: reproduction of C. elegans, genotoxicity (Comet assay) and endocrine disruption (YES test). Gene expression was profiled using a whole genome DNA-microarray approach to identify overrepresented functional gene categories and derived cellular processes. Disaccharide and glycogen metabolism were found to be affected, whereas further functional pathways, such as oxidative phosphorylation, ribosome biogenesis, metabolism of xenobiotics, aging and several developmental processes were found to be differentially regulated only in response to the most contaminated sediment. This study demonstrates how ecotoxicogenomics can identify transcriptional responses in complex mixture scenarios to distinguish different samples of river sediments.", - "journal_title": "BMC genomics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/19366437/" - } - ], - "9c67c910-b78d-418a-b20a-50e680d282d6": [ - { - "pub_id": "15040813", - "title": "Evolutionary history of Oryza sativa LTR retrotransposons: a preliminary survey of the rice genome sequences.", - "authors": "Lizhi Gao,Eugene M McCarthy,Eric W Ganko,John F McDonald", - "abstract": "LTR Retrotransposons transpose through reverse transcription of an RNA intermediate and are ubiquitous components of all eukaryotic genomes thus far examined. Plant genomes, in particular, have been found to be comprised of a remarkably high number of LTR retrotransposons. There is a significant body of direct and indirect evidence that LTR retrotransposons have contributed to gene and genome evolution in plants. To explore the evolutionary history of long terminal repeat (LTR) retrotransposons and their impact on the genome of Oryza sativa, we have extended an earlier computer-based survey to include all identifiable full-length, fragmented and solo LTR elements in the rice genome database as of April 2002. A total of 1,219 retroelement sequences were identified, including 217 full-length elements, 822 fragmented elements, and 180 solo LTRs. In order to gain insight into the chromosomal distribution of LTR-retrotransposons in the rice genome, a detailed examination of LTR-retrotransposon sequences on Chromosome 10 was carried out. An average of 22.3 LTR-retrotransposons per Mb were detected in Chromosome 10. Gypsy-like elements were found to be >4 x more abundant than copia-like elements. Eleven of the thirty-eight investigated LTR-retrotransposon families displayed significant subfamily structure. We estimate that at least 46.5% of LTR-retrotransposons in the rice genome are older than the age of the species (< 680,000 years). LTR-retrotransposons present in the rice genome range in age from those just recently inserted up to nearly 10 million years old. Approximately 20% of LTR retrotransposon sequences lie within putative genes. The distribution of elements across chromosome 10 is non-random with the highest density (48 elements per Mb) being present in the pericentric region.", - "journal_title": "BMC genomics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/15040813/" - } - ], - "3c447365-bdf9-44f0-b518-10c8afdbfb60": [ - { - "pub_id": "18940004", - "title": "Gene expression analysis of glioblastomas identifies the major molecular basis for the prognostic benefit of younger age.", - "authors": "Yohan Lee,Adrienne C Scheck,Timothy F Cloughesy,Albert Lai,Jun Dong,Haumith K Farooqi,Linda M Liau,Steve Horvath,Paul S Mischel,Stanley F Nelson", - "abstract": "Glioblastomas are the most common primary brain tumour in adults. While the prognosis for patients is poor, gene expression profiling has detected signatures that can sub-classify GBMs relative to histopathology and clinical variables. One category of GBM defined by a gene expression signature is termed ProNeural (PN), and has substantially longer patient survival relative to other gene expression-based subtypes of GBMs. Age of onset is a major predictor of the length of patient survival where younger patients survive longer than older patients. The reason for this survival advantage has not been clear. We collected 267 GBM CEL files and normalized them relative to other microarrays of the same Affymetrix platform. 377 probesets on U133A and U133 Plus 2.0 arrays were used in a gene voting strategy with 177 probesets of matching genes on older U95Av2 arrays. Kaplan-Meier curves and Cox proportional hazard analyses were applied in distinguishing survival differences between expression subtypes and age. This meta-analysis of published data in addition to new data confirms the existence of four distinct GBM expression-signatures. Further, patients with PN subtype GBMs had longer survival, as expected. However, the age of the patient at diagnosis is not predictive of survival time when controlled for the PN subtype. The survival benefit of younger age is nullified when patients are stratified by gene expression group. Thus, the main cause of the age effect in GBMs is the more frequent occurrence of PN GBMs in younger patients relative to older patients.", - "journal_title": "BMC medical genomics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/18940004/" - } - ], - "9ba69cb9-b1c9-483d-87c5-011d8802a67b": [ - { - "pub_id": "26884461", - "title": "Age-dependent differences in microglial responses to systemic inflammation are evident as early as middle age.", - "authors": "Maria Nikodemova,Alissa L Small,Rebecca S Kimyon,Jyoti J Watters", - "abstract": "Whereas age increases microglial inflammatory activities and impairs their ability to effectively regulate their immune response, it is unclear at what age these exaggerated responses begin. We tested the hypotheses that augmented microglial responses to inflammatory challenge are present as early as middle age and that repeated stimulation of primed microglia in vivo would reveal microglial senescence. Microglial gene expression was investigated in a mouse model of repeated systemic inflammation induced by intraperitoneal injection of bacterial lipopolysaccharide (LPS). Following LPS, microglia from middle-aged mice (9-10 mo) displayed larger increases in Tnf\u03b1, Il-6, and Il-1\u03b2 gene expression compared with young adults (2 mo). Similar results were observed in the spleens of middle-aged mice, indicating that exaggeration of both central and peripheral immune responses are already evident at early middle age. Interestingly, despite greater proinflammatory responses to the first LPS challenge in the aged mice, there were no age-dependent differences in either microglia or spleen following a subsequent LPS dose, suggesting that animals at this age retain the ability to effectively control their immune response following repeated challenge. The exacerbated microglial immune response to systemic inflammation at early middle age suggests that the CNS may be vulnerable to age-dependent alterations earlier than previously appreciated.", - "journal_title": "Physiological genomics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/26884461/" - } - ], - "f116ee1c-b275-4239-98e9-c2032b8f05c5": [ - { - "pub_id": "26430063", - "title": "Single-cell RNA-seq reveals changes in cell cycle and differentiation programs upon aging of hematopoietic stem cells.", - "authors": "Monika S Kowalczyk,Itay Tirosh,Dirk Heckl,Tata Nageswara Rao,Atray Dixit,Brian J Haas,Rebekka K Schneider,Amy J Wagers,Benjamin L Ebert,Aviv Regev", - "abstract": "Both intrinsic cell state changes and variations in the composition of stem cell populations have been implicated as contributors to aging. We used single-cell RNA-seq to dissect variability in hematopoietic stem cell (HSC) and hematopoietic progenitor cell populations from young and old mice from two strains. We found that cell cycle dominates the variability within each population and that there is a lower frequency of cells in the G1 phase among old compared with young long-term HSCs, suggesting that they traverse through G1 faster. Moreover, transcriptional changes in HSCs during aging are inversely related to those upon HSC differentiation, such that old short-term (ST) HSCs resemble young long-term (LT-HSCs), suggesting that they exist in a less differentiated state. Our results indicate both compositional changes and intrinsic, population-wide changes with age and are consistent with a model where a relationship between cell cycle progression and self-renewal versus differentiation of HSCs is affected by aging and may contribute to the functional decline of old HSCs.", - "journal_title": "Genome research", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/26430063/" - } - ], - "f62cda8c-0758-4fab-bdbe-3639b7a86267": [ - { - "pub_id": "16174643", - "title": "Hypothetical LOC387715 is a second major susceptibility gene for age-related macular degeneration, contributing independently of complement factor H to disease risk.", - "authors": "Andrea Rivera,Sheila A Fisher,Lars G Fritsche,Claudia N Keilhauer,Peter Lichtner,Thomas Meitinger,Bernhard H F Weber", - "abstract": "Age-related macular degeneration (AMD) is a multifactorial disease and a prevalent cause of visual impairment in developed countries. Risk factors include environmental components and genetic determinants. The complement factor H (CFH) has been the first major susceptibility gene for AMD identified within 1q32. Here, we focused on a second region of interest in 10q26 where a recent meta-analysis revealed strongest evidence for linkage to AMD at a genome-wide significance level. Within an interval of 22 Mb, we have analyzed 93 single nucleotide polymorphisms for allelic association with AMD in two independent case-control cohorts of German origin (AMD(combined) n=1166; controls(combined) n=945). Significant association was found across a 60 kb region of high linkage disequilibrium harboring two genes PLEKHA1 and hypothetical LOC387715. The strongest association (P=10(-34)) centered over a frequent coding polymorphism, Ala69Ser, at LOC387715, strongly implicating this gene in the pathogenesis of AMD. Besides abundant expression in placenta, we demonstrate weak expression of LOC387715 in the human retina. At present, however, there is no functional information on this gene, which appears to have evolved recently within the primate lineage. The joint contribution of the common risk allele at LOC387715, Ala69Ser, and at CFH, Tyr402His, was assessed in our case-control population, which suggests an additive model indicating an independent contribution of the two gene loci to disease risk. Our data show a disease odds ratio of 57.6 (95% CI: 37.2, 89.0) conferred by homozygosity for risk alleles at both CFH and LOC387715 when compared with the baseline non-risk genotype.", - "journal_title": "Human molecular genetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/16174643/" - } - ], - "3c219a32-3e0b-45db-ad42-c4d00cede32d": [ - { - "pub_id": "26643944", - "title": "Genome-wide analysis of genetic correlation in dementia with Lewy bodies, Parkinson's and Alzheimer's diseases.", - "authors": "Rita Guerreiro,Valentina Escott-Price,Lee Darwent,Laura Parkkinen,Olaf Ansorge,Dena G Hernandez,Michael A Nalls,Lorraine Clark,Lawrence Honig,Karen Marder,Wiesje van der Flier,Henne Holstege,Eva Louwersheimer,Afina Lemstra,Philip Scheltens,Ekaterina Rogaeva,Peter St George-Hyslop,Elisabet Londos,Henrik Zetterberg,Sara Ortega-Cubero,Pau Pastor,Tanis J Ferman,Neill R Graff-Radford,Owen A Ross,Imelda Barber,Anne Braae,Kristelle Brown,Kevin Morgan,Walter Maetzler,Daniela Berg,Claire Troakes,Safa Al-Sarraj,Tammaryn Lashley,Yaroslau Compta,Tamas Revesz,Andrew Lees,Nigel J Cairns,Glenda M Halliday,David Mann,Stuart Pickering-Brown,John Powell,Katie Lunnon,Michelle K Lupton, ,Dennis Dickson,John Hardy,Andrew Singleton,Jose Bras", - "abstract": "The similarities between dementia with Lewy bodies (DLB) and both Parkinson's disease (PD) and Alzheimer's disease (AD) are many and range from clinical presentation, to neuropathological characteristics, to more recently identified, genetic determinants of risk. Because of these overlapping features, diagnosing DLB is challenging and has clinical implications since some therapeutic agents that are applicable in other diseases have adverse effects in DLB. Having shown that DLB shares some genetic risk with PD and AD, we have now quantified the amount of sharing through the application of genetic correlation estimates, and show that, from a purely genetic perspective, and excluding the strong association at the APOE locus, DLB is equally correlated to AD and PD.", - "journal_title": "Neurobiology of aging", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/26643944/" - } - ], - "a1d2b2eb-8466-42a8-8fb0-a6b5119039f1": [ - { - "pub_id": "26806129", - "title": "Mutational Strand Asymmetries in Cancer Genomes Reveal Mechanisms of DNA Damage and Repair.", - "authors": "Nicholas J Haradhvala,Paz Polak,Petar Stojanov,Kyle R Covington,Eve Shinbrot,Julian M Hess,Esther Rheinbay,Jaegil Kim,Yosef E Maruvka,Lior Z Braunstein,Atanas Kamburov,Philip C Hanawalt,David A Wheeler,Amnon Koren,Michael S Lawrence,Gad Getz", - "abstract": "Mutational processes constantly shape the somatic genome, leading to immunity, aging, cancer, and other diseases. When cancer is the outcome, we are afforded a glimpse into these processes by the clonal expansion of the malignant cell. Here, we characterize a less explored layer of the mutational landscape of cancer: mutational asymmetries between the two DNA strands. Analyzing whole-genome sequences of 590 tumors from 14 different cancer types, we reveal widespread asymmetries across mutagenic processes, with transcriptional (\"T-class\") asymmetry dominating UV-, smoking-, and liver-cancer-associated mutations and replicative (\"R-class\") asymmetry dominating POLE-, APOBEC-, and MSI-associated mutations. We report a striking phenomenon of transcription-coupled damage (TCD) on the non-transcribed DNA strand and provide evidence that APOBEC mutagenesis occurs on the lagging-strand template during DNA replication. As more genomes are sequenced, studying and classifying their asymmetries will illuminate the underlying biological mechanisms of DNA damage and repair.", - "journal_title": "Cell", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/26806129/" - } - ], - "7a8556d9-6e49-47e8-8f7b-9b3e7623e86a": [ - { - "pub_id": "25773351", - "title": "Polygenic risk of Parkinson disease is correlated with disease age at onset.", - "authors": "Valentina Escott-Price, ,Mike A Nalls,Huw R Morris,Steven Lubbe,Alexis Brice,Thomas Gasser,Peter Heutink,Nicholas W Wood,John Hardy,Andrew B Singleton,Nigel M Williams, ", - "abstract": "We have investigated the polygenic architecture of Parkinson disease (PD) and have also explored the potential relationship between an individual's polygenic risk score and their disease age at onset. This study used genotypic data from 4,294 cases and 10,340 controls obtained from the meta-analysis of PD genome-wide association studies. Polygenic score analysis was performed as previously described by the International Schizophrenia Consortium, testing whether the polygenic score alleles identified in 1 association study were significantly enriched in the cases relative to the controls of 3 independent studies. Linear regression was used to investigate the relationship between an individual's polygenic score for PD risk alleles and disease age at onset. Our polygenic score analysis has identified significant evidence for a polygenic component enriched in the cases of each of 3 independent PD genome-wide association cohorts (minimum p\u2009=\u20093.76 \u00d7 10(-6) ). Further analysis identified compelling evidence that the average polygenic score in patients with an early disease age at onset was significantly higher than in those with a late age at onset (p\u2009=\u20090.00014). This provides strong support for a large polygenic contribution to the overall heritable risk of PD and also suggests that early onset forms of the illness are not exclusively caused by highly penetrant Mendelian mutations, but can also be contributed to by an accumulation of common polygenic alleles with relatively low effect sizes.", - "journal_title": "Annals of neurology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/25773351/" - } - ], - "02349115-481d-40d2-a975-27f358934403": [ - { - "pub_id": "32219057", - "title": "The SARS-CoV-2 Vaccine Pipeline: an Overview.", - "authors": "Wen-Hsiang Chen,Ulrich Strych,Peter J Hotez,Maria Elena Bottazzi", - "abstract": "The goal of this review is to provide a timely overview on efforts to develop a vaccine for the 2019 novel coronavirus SARS-CoV-2, the causative agent of coronavirus disease (COVID-19). Previous research efforts to develop a severe acute respiratory syndrome coronavirus (SARS-CoV) vaccine in the years following the 2003 pandemic have opened the door for investigators to design vaccine concepts and approaches for the COVID-19 epidemic in China. Both SARS-CoV and SARS-CoV-2 exhibit a high degree of genetic similarity and bind to the same host cell ACE2 receptor. Based on previous experience with SARS-CoV vaccines, it is expected that all COVID-19 vaccines will require careful safety evaluations for immunopotentiation that could lead to increased infectivity or eosinophilic infiltration. Besides this, a COVID-19 vaccine target product profile must address vaccinating at-risk human populations including frontline healthcare workers, individuals over the age of 60, and those with underlying and debilitating chronic conditions. Among the vaccine technologies under evaluation are whole virus vaccines, recombinant protein subunit vaccines, and nucleic acid vaccines. Each current vaccine strategy has distinct advantages and disadvantages. Therefore, it is paramount that multiple strategies be advanced quickly and then evaluated for safety and efficacy. Ultimately, the safety studies to minimize undesired immunopotentiation will become the most significant bottleneck in terms of time.", - "journal_title": "Current tropical medicine reports", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/32219057/" - } - ], - "1386c8ad-297d-48b1-aa34-41659a9f6544": [ - { - "pub_id": "22303384", - "title": "Whole genome sequences of a male and female supercentenarian, ages greater than 114\u2009years.", - "authors": "Paola Sebastiani,Alberto Riva,Monty Montano,Phillip Pham,Ali Torkamani,Eugene Scherba,Gary Benson,Jacqueline N Milton,Clinton T Baldwin,Stacy Andersen,Nicholas J Schork,Martin H Steinberg,Thomas T Perls", - "abstract": "Supercentenarians (age 110+ years old) generally delay or escape age-related diseases and disability well beyond the age of 100 and this exceptional survival is likely to be influenced by a genetic predisposition that includes both common and rare genetic variants. In this report, we describe the complete genomic sequences of male and female supercentenarians, both age >114\u2009years old. We show that: (1) the sequence variant spectrum of these two individuals' DNA sequences is largely comparable to existing non-supercentenarian genomes; (2) the two individuals do not appear to carry most of the well-established human longevity enabling variants already reported in the literature; (3) they have a comparable number of known disease-associated variants relative to most human genomes sequenced to-date; (4) approximately 1% of the variants these individuals possess are novel and may point to new genes involved in exceptional longevity; and (5) both individuals are enriched for coding variants near longevity-associated variants that we discovered through a large genome-wide association study. These analyses suggest that there are both common and rare longevity-associated variants that may counter the effects of disease-predisposing variants and extend lifespan. The continued analysis of the genomes of these and other rare individuals who have survived to extremely old ages should provide insight into the processes that contribute to the maintenance of health during extreme aging.", - "journal_title": "Frontiers in genetics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/22303384/" - } - ], - "c6657ed9-ad01-4b8b-9f2b-6202b07fce82": [ - { - "pub_id": "3611071", - "title": "Genomic 5-methyldeoxycytidine decreases with age.", - "authors": "V L Wilson,R A Smith,S Ma,R G Cutler", - "abstract": "Significant losses of DNA 5-methyldeoxycytidine residues in old age could disrupt cellular gene expression and contribute to the physiological decline of the animal. Thus, the 5-methyldeoxycytidine content of DNAs, isolated from the tissues of two rodent species of various ages, were determined. Mus musculus lost DNA methylation sites at a rate of about 4.7 X 10(4) (approximately 0.012% of the newborn level)/month. Peromyscus leucopus lost DNA 5-methyldeoxycytidine residues at a rate of only 2.3 X 10(4) (approximately 0.006% of the newborn level)/month. Since P. leucopus generally live twice as long as M. musculus, the rate of loss of DNA 5-methyldeoxycytidine residues appears to be inversely related to life span. Similar losses in genomic 5-methyldeoxycytidine content were also observed to correlate with donor age in cultured normal human bronchial epithelial cells.", - "journal_title": "The Journal of biological chemistry", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/3611071/" - } - ], - "9ddecf72-cb4e-47ce-9f18-47f45a6e582e": [ - { - "pub_id": "17623811", - "title": "Temporal and spatial transcriptional profiles of aging in Drosophila melanogaster.", - "authors": "Ming Zhan,Haruyoshi Yamaza,Yu Sun,Jason Sinclair,Huai Li,Sige Zou", - "abstract": "Temporal and tissue-specific alterations in gene expression have profound effects on aging of multicellular organisms. However, much remains unknown about the patterns of molecular changes in different tissues and how different tissues interact with each other during aging. Previous genomic studies on invertebrate aging mostly utilized the whole body or body parts and limited age-points, and failed to address tissue-specific aging. Here we measured genome-wide expression profiles of aging in Drosophila melanogaster for seven tissues representing nervous, muscular, digestive, renal, reproductive, and storage systems at six adult ages. In each tissue, we identified hundreds of age-related genes exhibiting significant changes of transcript levels with age. The age-related genes showed clear tissue-specific patterns: <10% of them in each tissue were in common with any other tissue; <20% of the biological processes enriched with the age-related genes were in common between any two tissues. A significant portion of the age-related genes were those involved in physiological functions regulated by the corresponding tissue. Nevertheless, we identified some overlaps of the age-related functional groups among tissues, suggesting certain common molecular mechanisms that regulate aging in different tissues. This study is one of the first that defined global, temporal, and spatial changes associated with aging from multiple tissues at multiple ages, showing that different tissues age in different patterns in an organism. The spatial and temporal transcriptome data presented in this study provide a basis and a valuable resource for further genetic and genomic investigation of tissue-specific regulation of aging.", - "journal_title": "Genome research", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/17623811/" - } - ], - "8a8bea99-d3b9-4109-88e4-ad459dcd7173": [ - { - "pub_id": "17608836", - "title": "Functional genomic approach to identify novel genes involved in the regulation of oxidative stress resistance and animal lifespan.", - "authors": "Yongsoon Kim,Hong Sun", - "abstract": "Genetic studies in many organisms suggest that an increased animal lifespan phenotype is often accompanied by enhanced resistance toward reactive oxygen species (ROS). In Caenorhabditis elegans, mutations in daf-2, which encode an insulin/insulin-like growth factor 1 receptor-like molecule, lead to an extended animal lifespan and increased resistance to ROS. We have optimized an assay to monitor ROS resistance in worms using the ROS-generating chemical paraquat. We have employed this assay to screen the RNAi library along chromosomes III and IV for genes that, when silenced, confer paraquat resistance. The positive RNAi clones were subsequently screened for a lifespan extension phenotype. Using this approach, we have identified 84 genes that, when inactivated by RNAi, lead to significant increases in animal lifespan. Among the 84 genes, 29 were found to act in a manner dependent on daf-16. DAF-16, a forkhead transcription factor, is known to integrate signals from multiple pathways, including the daf-2 pathway, to regulate animal lifespan. Most of the 84 genes have not been previously linked to aging, and potentially participate in important cellular processes such as signal transduction, cell-cell interaction, gene expression, protein degradation, and energy metabolism. Our screen has also identified a group of genes that potentially function in a nutrient-sensing pathway to regulate lifespan in C. elegans. Our study provides a novel approach to identify genes involved in the regulation of aging.", - "journal_title": "Aging cell", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/17608836/" - } - ], - "0572247e-821d-4cdc-a417-c430d241c2d8": [ - { - "pub_id": "20725513", - "title": "Do different neurons age differently? Direct genome-wide analysis of aging in single identified cholinergic neurons.", - "authors": "Leonid L Moroz,Andrea B Kohn", - "abstract": "Aplysia californica is a powerful experimental system to study the entire scope of genomic and epigenomic regulation at the resolution of single functionally characterized neurons and is an emerging model in the neurobiology of aging. First, we have identified and cloned a number of evolutionarily conserved genes that are age-related, including components of apoptosis and chromatin remodeling. Second, we performed gene expression profiling of different identified cholinergic neurons between young and aged animals. Our initial analysis indicates that two cholinergic neurons (R2 and LPl1) revealed highly differential genome-wide changes following aging suggesting that on the molecular scale different neurons indeed age differently. Each of the neurons tested has a unique subset of genes differentially expressed in older animals, and the majority of differently expressed genes (including those related to apoptosis and Alzheimer's disease) are found in aging neurons of one but not another type. The performed analysis allows us to implicate (i) cell specific changes in histones, (ii) DNA methylation and (iii) regional relocation of RNAs as key processes underlying age-related changes in neuronal functions and synaptic plasticity. These mechanisms can fine-tune the dynamics of long-term chromatin remodeling, or control weakening and the loss of synaptic connections in aging. At the same time our genomic tests revealed evolutionarily conserved gene clusters associated with aging (e.g., apoptosis-, telomere- and redox-dependent processes, insulin and estrogen signaling and water channels).", - "journal_title": "Frontiers in aging neuroscience", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/20725513/" - } - ], - "4a5716f3-cd44-4c1c-a165-7dff0e077bd9": [ - { - "pub_id": "20421499", - "title": "Genome-wide association identifies OBFC1 as a locus involved in human leukocyte telomere biology.", - "authors": "Daniel Levy,Susan L Neuhausen,Steven C Hunt,Masayuki Kimura,Shih-Jen Hwang,Wei Chen,Joshua C Bis,Annette L Fitzpatrick,Erin Smith,Andrew D Johnson,Jeffrey P Gardner,Sathanur R Srinivasan,Nicholas Schork,Jerome I Rotter,Utz Herbig,Bruce M Psaty,Malinee Sastrasinh,Sarah S Murray,Ramachandran S Vasan,Michael A Province,Nicole L Glazer,Xiaobin Lu,Xiaojian Cao,Richard Kronmal,Massimo Mangino,Nicole Soranzo,Tim D Spector,Gerald S Berenson,Abraham Aviv", - "abstract": "Telomeres are engaged in a host of cellular functions, and their length is regulated by multiple genes. Telomere shortening, in the course of somatic cell replication, ultimately leads to replicative senescence. In humans, rare mutations in genes that regulate telomere length have been identified in monogenic diseases such as dyskeratosis congenita and idiopathic pulmonary fibrosis, which are associated with shortened leukocyte telomere length (LTL) and increased risk for aplastic anemia. Shortened LTL is observed in a host of aging-related complex genetic diseases and is associated with diminished survival in the elderly. We report results of a genome-wide association study of LTL in a consortium of four observational studies (n = 3,417 participants with LTL and genome-wide genotyping). SNPs in the regions of the oligonucleotide/oligosaccharide-binding folds containing one gene (OBFC1; rs4387287; P = 3.9 x 10(-9)) and chemokine (C-X-C motif) receptor 4 gene (CXCR4; rs4452212; P = 2.9 x 10(-8)) were associated with LTL at a genome-wide significance level (P < 5 x 10(-8)). We attempted replication of the top SNPs at these loci through de novo genotyping of 1,893 additional individuals and in silico lookup in another observational study (n = 2,876), and we confirmed the association findings for OBFC1 but not CXCR4. In addition, we confirmed the telomerase RNA component (TERC) as a gene associated with LTL (P = 1.1 x 10(-5)). The identification of OBFC1 through genome-wide association as a locus for interindividual variation in LTL in the general population advances the understanding of telomere biology in humans and may provide insights into aging-related disorders linked to altered LTL dynamics.", - "journal_title": "Proceedings of the National Academy of Sciences of the United States of America", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/20421499/" - } - ], - "f6429dfc-47a3-4635-beb4-35c05bee003a": [ - { - "pub_id": "16308694", - "title": "Constancy of organellar genome copy numbers during leaf development and senescence in higher plants.", - "authors": "Weimin Li,Stephanie Ruf,Ralph Bock", - "abstract": "In higher plants, plastid and mitochondrial genomes occur at high copy numbers per cell. Several recent publications have suggested that, in higher plants like Arabidopsis and maize, chloroplast DNA is virtually absent in mature and old leaves. This conclusion was mainly based on DAPI staining of isolated chloroplasts. If correct, the finding that chloroplasts in mature leaves lack DNA would change dramatically our understanding of gene expression, mRNA stability and protein stability in chloroplasts. In view of the wide implications that the disposal of chloroplast DNA during leaf development would have, we have reinvestigated the age dependency of genome copy numbers in chloroplasts and, in addition, tested for possible changes in mitochondrial genome copy number during plant development. Analyzing chloroplast and mitochondrial DNA amounts in Arabidopsis and tobacco plants, we find that organellar genome copy numbers remain remarkably constant during leaf development and are present in essentially unchanged numbers even in the senescing leaves. We conclude that, during leaf development, organellar gene expression in higher plants is not significantly regulated at the level of genome copy number and we discuss possible explanations for the failure to detect DNA in isolated chloroplasts stained with DAPI.", - "journal_title": "Molecular genetics and genomics : MGG", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/16308694/" - } - ], - "92004cb7-4f79-4dde-a8e7-d1e93a253dc3": [ - { - "pub_id": "29555771", - "title": "Precision medicine screening using whole-genome sequencing and advanced imaging to identify disease risk in adults.", - "authors": "Bradley A Perkins,C Thomas Caskey,Pamila Brar,Eric Dec,David S Karow,Andrew M Kahn,Ying-Chen Claire Hou,Naisha Shah,Debbie Boeldt,Erin Coughlin,Gabby Hands,Victor Lavrenko,James Yu,Andrea Procko,Julia Appis,Anders M Dale,Lining Guo,Thomas J J\u00f6nsson,Bryan M Wittmann,Istvan Bartha,Smriti Ramakrishnan,Axel Bernal,James B Brewer,Suzanne Brewerton,William H Biggs,Yaron Turpaz,J Craig Venter", - "abstract": "Reducing premature mortality associated with age-related chronic diseases, such as cancer and cardiovascular disease, is an urgent priority. We report early results using genomics in combination with advanced imaging and other clinical testing to proactively screen for age-related chronic disease risk among adults. We enrolled active, symptom-free adults in a study of screening for age-related chronic diseases associated with premature mortality. In addition to personal and family medical history and other clinical testing, we obtained whole-genome sequencing (WGS), noncontrast whole-body MRI, dual-energy X-ray absorptiometry (DXA), global metabolomics, a new blood test for prediabetes (Quantose IR), echocardiography (ECHO), ECG, and cardiac rhythm monitoring to identify age-related chronic disease risks. Precision medicine screening using WGS and advanced imaging along with other testing among active, symptom-free adults identified a broad set of complementary age-related chronic disease risks associated with premature mortality and strengthened WGS variant interpretation. This and other similarly designed screening approaches anchored by WGS and advanced imaging may have the potential to extend healthy life among active adults through improved prevention and early detection of age-related chronic diseases (and their risk factors) associated with premature mortality.", - "journal_title": "Proceedings of the National Academy of Sciences of the United States of America", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/29555771/" - } - ], - "9729da69-0a02-456b-aa99-80134d12ed9a": [ - { - "pub_id": "35234025", - "title": "Exercise-mediated reinnervation of skeletal muscle in elderly people: An update.", - "authors": "Claudia Coletti,Gilberto F Acosta,Stefan Keslacy,Dario Coletti", - "abstract": "Sarcopenia is defined by the loss of muscle mass and function. In aging sarcopenia is due to mild chronic inflammation but also to fiber-intrinsic defects, such as mitochondrial dysfunction. Age-related sarcopenia is associated with physical disability and lowered quality of life. In addition to skeletal muscle, the nervous tissue is also affected in elderly people. With aging, type 2 fast fibers preferentially undergo denervation and are reinnervated by slow-twitch motor neurons. They spread forming new neuro-muscular junctions with the denervated fibers: the result is an increased proportion of slow fibers that group together since they are associated in the same motor unit. Grouping and fiber type shifting are indeed major histological features of aging skeletal muscle. Exercise has been proposed as an intervention for age-related sarcopenia due to its numerous beneficial effects on muscle mechanical and biochemical features. In 2013, a precursor study in humans was published in the European Journal of Translation Myology (formerly known as Basic and Applied Myology), highlighting the occurrence of reinnervation in the musculature of aged, exercise-trained individuals as compared to the matching control. This paper, entitled \u00abReinnervation of Vastus lateralis is increased significantly in seniors (70-years old) with a lifelong history of high-level exercise\u00bb, is now being reprinted for the second issue of the \u00abEjtm Seminal Paper Series\u00bb. In this short review we discuss those results in the light of the most recent advances confirming the occurrence of exercise-mediated reinnervation, ultimately preserving muscle structure and function in elderly people who exercise.", - "journal_title": "European journal of translational myology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/35234025/" - } - ], - "be7b40f2-4d4a-41d5-9e58-19a30b63ee06": [ - { - "pub_id": "23098078", - "title": "The role of DNA methylation in aging, rejuvenation, and age-related disease.", - "authors": "Adiv A Johnson,Kemal Akman,Stuart R G Calimport,Daniel Wuttke,Alexandra Stolzing,Jo\u00e3o Pedro de Magalh\u00e3es", - "abstract": "DNA methylation is a major control program that modulates gene expression in a plethora of organisms. Gene silencing through methylation occurs through the activity of DNA methyltransferases, enzymes that transfer a methyl group from S-adenosyl-L-methionine to the carbon 5 position of cytosine. DNA methylation patterns are established by the de novo DNA methyltransferases (DNMTs) DNMT3A and DNMT3B and are subsequently maintained by DNMT1. Aging and age-related diseases include defined changes in 5-methylcytosine content and are generally characterized by genome-wide hypomethylation and promoter-specific hypermethylation. These changes in the epigenetic landscape represent potential disease biomarkers and are thought to contribute to age-related pathologies, such as cancer, osteoarthritis, and neurodegeneration. Some diseases, such as a hereditary form of sensory neuropathy accompanied by dementia, are directly caused by methylomic changes. Epigenetic modifications, however, are reversible and are therefore a prime target for therapeutic intervention. Numerous drugs that specifically target DNMTs are being tested in ongoing clinical trials for a variety of cancers, and data from finished trials demonstrate that some, such as 5-azacytidine, may even be superior to standard care. DNMTs, demethylases, and associated partners are dynamically shaping the methylome and demonstrate great promise with regard to rejuvenation.", - "journal_title": "Rejuvenation research", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/23098078/" - } - ], - "7a284237-8394-4cdb-9154-ebdbc55ea327": [ - { - "pub_id": "20231535", - "title": "Novel associations of multiple genetic loci with plasma levels of factor VII, factor VIII, and von Willebrand factor: The CHARGE (Cohorts for Heart and Aging Research in Genome Epidemiology) Consortium.", - "authors": "Nicholas L Smith,Ming-Huei Chen,Abbas Dehghan,David P Strachan,Saonli Basu,Nicole Soranzo,Caroline Hayward,Igor Rudan,Maria Sabater-Lleal,Joshua C Bis,Moniek P M de Maat,Ann Rumley,Xiaoxiao Kong,Qiong Yang,Frances M K Williams,Veronique Vitart,Harry Campbell,Anders M\u00e4larstig,Kerri L Wiggins,Cornelia M Van Duijn,Wendy L McArdle,James S Pankow,Andrew D Johnson,Angela Silveira,Barbara McKnight,Andre G Uitterlinden, ,Nena Aleksic,James B Meigs,Annette Peters,Wolfgang Koenig,Mary Cushman,Sekar Kathiresan,Jerome I Rotter,Edwin G Bovill,Albert Hofman,Eric Boerwinkle,Geoffrey H Tofler,John F Peden,Bruce M Psaty,Frank Leebeek,Aaron R Folsom,Martin G Larson,Timothy D Spector,Alan F Wright,James F Wilson,Anders Hamsten,Thomas Lumley,Jacqueline C M Witteman,Weihong Tang,Christopher J O'Donnell", - "abstract": "Plasma levels of coagulation factors VII (FVII), VIII (FVIII), and von Willebrand factor (vWF) influence risk of hemorrhage and thrombosis. We conducted genome-wide association studies to identify new loci associated with plasma levels. The setting of the study included 5 community-based studies for discovery comprising 23 608 European-ancestry participants: Atherosclerosis Risk In Communities Study, Cardiovascular Health Study, British 1958 Birth Cohort, Framingham Heart Study, and Rotterdam Study. All subjects had genome-wide single-nucleotide polymorphism (SNP) scans and at least 1 phenotype measured: FVII activity/antigen, FVIII activity, and vWF antigen. Each study used its genotype data to impute to HapMap SNPs and independently conducted association analyses of hemostasis measures using an additive genetic model. Study findings were combined by meta-analysis. Replication was conducted in 7604 participants not in the discovery cohort. For FVII, 305 SNPs exceeded the genome-wide significance threshold of 5.0x10(-8) and comprised 5 loci on 5 chromosomes: 2p23 (smallest P value 6.2x10(-24)), 4q25 (3.6x10(-12)), 11q12 (2.0x10(-10)), 13q34 (9.0x10(-259)), and 20q11.2 (5.7x10(-37)). Loci were within or near genes, including 4 new candidate genes and F7 (13q34). For vWF, 400 SNPs exceeded the threshold and marked 8 loci on 6 chromosomes: 6q24 (1.2x10(-22)), 8p21 (1.3x10(-16)), 9q34 (<5.0x10(-324)), 12p13 (1.7x10(-32)), 12q23 (7.3x10(-10)), 12q24.3 (3.8x10(-11)), 14q32 (2.3x10(-10)), and 19p13.2 (1.3x10(-9)). All loci were within genes, including 6 new candidate genes, as well as ABO (9q34) and VWF (12p13). For FVIII, 5 loci were identified and overlapped vWF findings. Nine of the 10 new findings were replicated. New genetic associations were discovered outside previously known biological pathways and may point to novel prevention and treatment targets of hemostasis disorders.", - "journal_title": "Circulation", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/20231535/" - } - ], - "2b93a596-0842-40ae-86bb-36edf9a2d23d": [ - { - "pub_id": "16600170", - "title": "Studies on genomic DNA topology and stability in brain regions of Parkinson's disease.", - "authors": "Muralidhar L Hegde,Veer Bala Gupta,M Anitha,T Harikrishna,S K Shankar,Uday Muthane,K Subba Rao,K S Jagannatha Rao", - "abstract": "DNA damage has been postulated as a mechanism of neuronal death in Parkinson's disease (PD). In the present study, genomic DNA was isolated from eight brain regions (frontal, temporal, and occipital cortex, hippocampus, caudate/putamen, thalamus, cerebellum, and midbrain) from five neuropathologically confirmed cases of Parkinson's disease and six control brains and analyzed for the presence of single and double strand breaks, melting temperature, EtBr intercalation, DNAse digestion pattern, and DNA conformations. The results showed that DNA from midbrain in PD accumulated significantly higher number of strand breaks than age-matched controls. Caudate nucleus/putamen, thalamus, and hippocampus also showed more DNA fragmentation compared to control brains. Circular dichroism studies showed that DNA conformation was altered with imprecise base stacking in midbrain, caudate nucleus/putamen, thalamus, and hippocampus in PD. However, DNA from frontal, temporal, and occipital cortex, and cerebellum was not affected significantly in PD group as compared to controls. This study provides a comprehensive database on stability, damage, and conformations of DNA in different regions in brains of PD patients.", - "journal_title": "Archives of biochemistry and biophysics", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/16600170/" - } - ], - "50146ca4-1b2c-4585-b797-61dbe573ae70": [ - { - "pub_id": "12548202", - "title": "High cumulative incidence of uterine leiomyoma in black and white women: ultrasound evidence.", - "authors": "Donna Day Baird,David B Dunson,Michael C Hill,Deborah Cousins,Joel M Schectman", - "abstract": "Uterine leiomyoma, or fibroid tumors, are the leading indication for hysterectomy in the United States, but the proportion of women in whom fibroid tumors develop is not known. This study screened for fibroid tumors, independently of clinical symptoms, to estimate the age-specific proportion of black and white women in whom fibroid tumors develop. Randomly selected members of an urban health plan who were 35 to 49 years old participated (n = 1364 women). Medical records and self-report were used to assess fibroid status for those women who were no longer menstruating (most of whom had had hysterectomies). Premenopausal women were screened by ultrasonography. We estimated the age-specific cumulative incidence of fibroid tumors for black and white women. Thirty-five percent of premenopausal women had a previous diagnosis of fibroid tumors. Fifty-one percent of the premenopausal women who had no previous diagnosis had ultrasound evidence of fibroid tumors. The estimated cumulative incidence of tumors by age 50 was >80% for black women and nearly 70% for white women. The difference between the age-specific cumulative incidence curves for black and white women was highly significant (odds ratio, 2.9; 95% CI, 2.5-3.4; P <.001). The results of this study suggest that most black and white women in the United States develop uterine fibroid tumors before menopause and that uterine fibroid tumors develop in black women at earlier ages than in white women.", - "journal_title": "American journal of obstetrics and gynecology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/12548202/" - } - ], - "b3c92c3b-7cbf-41af-bc0a-2b969b7c29ef": [ - { - "pub_id": "8389816", - "title": "Age distribution of latent herpes simplex virus 1 and varicella-zoster virus genome in human nervous tissue.", - "authors": "W Liedtke,B Opalka,C W Zimmermann,E Lignitz", - "abstract": "Latency in nervous tissue caused by herpes simplex virus 1 (HSV-1) and by varicella-zoster virus (VZV) is an intriguing feature of herpes-virus' neurotropism. HSV-1 and VZV latency are the causes of ophthalmic zoster and recurrent HSV infections in the distributions of the trigeminal branches. HSV-1 neuronal latency may play a role in the etiopathogenesis of HSV encephalitis. We attempted to determine the prevalence and age distribution of VZV and HSV latency. We applied nested polymerase chain reaction (PCR) assays to detect HSV-1 and VZV genome in trigeminal ganglia and olfactory bulbs which were obtained from 109 human corpses at forensic postmortems. HSV-1 latency was found in 72.5% of trigeminal ganglia and in 15.5% of olfactory bulbs. VZV latency was 63.3% in trigeminal ganglia and 1% in olfactory bulbs. Simultaneous latency of VZV and HSV genome occurs in 48.8% of trigeminal ganglia. The age-group specific prevalence of HSV neuronal latency increases from 18.2% in 0-20 years to reach finally 100% in persons older than 60 years. Age specific prevalences of VZV peaked for a first time with 82% between 21-30 years, fell to 50% for 40-50 years, and rose to 89% for 71-80 years. If the latent trigeminal ganglion HSV-1 genome were the source of endogenously acquired encephalitis, the peak incidence of HSV encephalitis in older subjects correlates with our findings. Increased VZV latency prevalence in nervous tissue of younger people without subsequent disease indicates sufficient immune surveillance.", - "journal_title": "Journal of the neurological sciences", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/8389816/" - } - ], - "448ebb84-7e31-4306-ba08-83c5f492a2ad": [ - { - "pub_id": "25733939", - "title": "The Human Genome Project, and recent advances in personalized genomics.", - "authors": "Brenda J Wilson,Stuart G Nicholls", - "abstract": "The language of \"personalized medicine\" and \"personal genomics\" has now entered the common lexicon. The idea of personalized medicine is the integration of genomic risk assessment alongside other clinical investigations. Consistent with this approach, testing is delivered by health care professionals who are not medical geneticists, and where results represent risks, as opposed to clinical diagnosis of disease, to be interpreted alongside the entirety of a patient's health and medical data. In this review we consider the evidence concerning the application of such personalized genomics within the context of population screening, and potential implications that arise from this. We highlight two general approaches which illustrate potential uses of genomic information in screening. The first is a narrowly targeted approach in which genetic profiling is linked with standard population-based screening for diseases; the second is a broader targeting of variants associated with multiple single gene disorders, performed opportunistically on patients being investigated for unrelated conditions. In doing so we consider the organization and evaluation of tests and services, the challenge of interpretation with less targeted testing, professional confidence, barriers in practice, and education needs. We conclude by discussing several issues pertinent to health policy, namely: avoiding the conflation of genetics with biological determinism, resisting the \"technological imperative\", due consideration of the organization of screening services, the need for professional education, as well as informed decision making and public understanding.", - "journal_title": "Risk management and healthcare policy", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/25733939/" - } - ], - "2d0d839d-e526-4fd0-8f20-7558f2eed389": [ - { - "pub_id": "19805033", - "title": "Evolution in health and medicine Sackler colloquium: Somatic evolutionary genomics: mutations during development cause highly variable genetic mosaicism with risk of cancer and neurodegeneration.", - "authors": "Steven A Frank", - "abstract": "Somatic mutations must happen often during development because of the large number of cell divisions to expand from a single-cell zygote to a full organism. A mutation in development carries forward to all descendant cells, causing genetic mosaicism. Widespread genetic mosaicism may influence diseases that derive from a few genetically altered cells, such as cancer. I show how to predict the expected amount of mosaicism and the variation in mosaicism between individuals. I then calculate the predicted risk of cancer derived from developmental mutations. The calculations show that a significant fraction of cancer in later life likely arises from developmental mutations in early life. In addition, much of the variation in the risk of cancer between individuals may arise from variation in the degree of genetic mosaicism set in early life. I also suggest that certain types of neurodegeneration, such as amyotrophic lateral sclerosis (ALS), may derive from a small focus of genetically altered cells. If so, then the risk of ALS would be influenced by developmental mutations and the consequent variation in genetic mosaicism. New technologies promise the ability to measure genetic mosaicism by sampling a large number of cellular genomes within an individual. The sampling of many genomes within an individual will eventually allow one to reconstruct the cell lineage history of genetic change in a single body. Somatic evolutionary genomics will follow from this technology, providing new insight into the origin and progression of disease with increasing age.", - "journal_title": "Proceedings of the National Academy of Sciences of the United States of America", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/19805033/" - } - ], - "b045a3ea-ed22-47d7-ae01-2e038f1f8fb0": [ - { - "pub_id": "11830352", - "title": "Roles of the Werner syndrome protein in pathways required for maintenance of genome stability.", - "authors": "Robert M Brosh,Vilhelm A Bohr", - "abstract": "Werners syndrome is a disease of premature aging where the patients appear much older than their chronological age. The gene codes for a protein that is a helicase and an exonuclease, and recently we have learned about some of its protein interactions. These interactions are being discussed as they shed light on the molecular pathways in which Werner protein participates. Insight into these pathways brings insight into the aging process.", - "journal_title": "Experimental gerontology", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/11830352/" - } - ], - "f8703b19-e43f-4a38-85c7-084d4ea23dee": [ - { - "pub_id": "8908510", - "title": "Livestock genomics comes of age.", - "authors": "M Georges,L Andersson", - "abstract": "", - "journal_title": "Genome research", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/8908510/" - } - ], - "0f75ea41-9d44-4374-ace4-8eab70be0960": [ - { - "pub_id": "31246715", - "title": "Methodological Recommendations for Menstrual Cycle Research in Sports and Exercise.", - "authors": "Xanne Janse DE Jonge,Belinda Thompson,Ahreum Han", - "abstract": "The aim of this review is to provide methodological recommendations for menstrual cycle research in exercise science and sports medicine based on a review of recent literature. Research in this area is growing but often reports conflicting results, and it is proposed that some of this may be explained by methodological issues. This review examined the menstrual cycle verification methods used in recent literature on exercise performance over the menstrual cycle identified through a literature search of PubMed and SportDiscus from 2008 until 2018. Potential changes over the menstrual cycle are likely related to hormone fluctuations; however, only 44% of the selected studies measured the actual concentrations of the female steroid hormones estrogen and progesterone. It was shown that the likely inclusion of participants with anovulatory or luteal phase-deficient cycles in combination with small participant numbers has affected results in recent menstrual cycle research and, consequently, our understanding of this area. To improve the quality of future menstrual cycle research, it is recommended that a combination of three methods is used to verify menstrual cycle phase: the calendar-based counting method combined with urinary luteinizing hormone surge testing and the measurement of serum estrogen and progesterone concentrations at the time of testing. A strict luteal phase verification limit of >16 nmol\u00b7L for progesterone should be set. It is also recommended that future research should focus on the inclusion of the late follicular estrogen peak. It is envisaged that these methodological recommendations will assist in clarifying some of the disagreement around the effects of the menstrual cycle on exercise performance and other aspects of exercise science and sports medicine.", - "journal_title": "Medicine and science in sports and exercise", - "languages": [ - "eng" - ], - "source": "https://pubmed.ncbi.nlm.nih.gov/31246715/" - } - ] -}
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