Showing papers by "Daniel I. Chasman published in 2016"
TL;DR: Among participants at high genetic risk, a favorable lifestyle was associated with a nearly 50% lower relative risk of coronary artery disease than was an unfavorable lifestyle, and across four studies involving 55,685 participants, genetic and lifestyle factors were independently associated with susceptibility to coronary arteries disease.
Abstract: BackgroundBoth genetic and lifestyle factors contribute to individual-level risk of coronary artery disease. The extent to which increased genetic risk can be offset by a healthy lifestyle is unknown. MethodsUsing a polygenic score of DNA sequence polymorphisms, we quantified genetic risk for coronary artery disease in three prospective cohorts — 7814 participants in the Atherosclerosis Risk in Communities (ARIC) study, 21,222 in the Women’s Genome Health Study (WGHS), and 22,389 in the Malmo Diet and Cancer Study (MDCS) — and in 4260 participants in the cross-sectional BioImage Study for whom genotype and covariate data were available. We also determined adherence to a healthy lifestyle among the participants using a scoring system consisting of four factors: no current smoking, no obesity, regular physical activity, and a healthy diet. ResultsThe relative risk of incident coronary events was 91% higher among participants at high genetic risk (top quintile of polygenic scores) than among those at low gen...
915 citations
Broad Institute1, Harvard University2, Oslo University Hospital3, University of Oslo4, University of Helsinki5, Boston Children's Hospital6, University of Tartu7, Illumina8, Brigham and Women's Hospital9, Charité10, deCODE genetics11, Medical Research Council12, VU University Amsterdam13, Leiden University14, Helsinki University Central Hospital15, Ludwig Maximilian University of Munich16, University of Tübingen17, Karolinska Institutet18, QIMR Berghofer Medical Research Institute19, University of Ulm20, University of Oulu21, King's College London22, Erasmus University Medical Center23, University of Tampere24, University of Duisburg-Essen25, Washington University in St. Louis26, University Medical Center Groningen27, Wellcome Trust Sanger Institute28, University of Oxford29, John Radcliffe Hospital30, Max Planck Society31, University of Kiel32, Technische Universität München33, National Institutes of Health34, Norwegian Institute of Public Health35, University of Copenhagen36, Mental Health Services37, Lundbeck38, University of Turku39, Turku University Hospital40, University of Hamburg41, St George's, University of London42, University of Iceland43, Queensland University of Technology44
TL;DR: For example, the authors identified 44 independent single-nucleotide polymorphisms (SNPs) significantly associated with migraine risk (P < 5 × 10−8) that mapped to 38 distinct genomic loci, including 28 loci not previously reported and a locus that to date is the first to be identified on chromosome X.
Abstract: Migraine is a debilitating neurological disorder affecting around one in seven people worldwide, but its molecular mechanisms remain poorly understood. There is some debate about whether migraine is a disease of vascular dysfunction or a result of neuronal dysfunction with secondary vascular changes. Genome-wide association (GWA) studies have thus far identified 13 independent loci associated with migraine. To identify new susceptibility loci, we carried out a genetic study of migraine on 59,674 affected subjects and 316,078 controls from 22 GWA studies. We identified 44 independent single-nucleotide polymorphisms (SNPs) significantly associated with migraine risk (P < 5 × 10−8) that mapped to 38 distinct genomic loci, including 28 loci not previously reported and a locus that to our knowledge is the first to be identified on chromosome X. In subsequent computational analyses, the identified loci showed enrichment for genes expressed in vascular and smooth muscle tissues, consistent with a predominant theory of migraine that highlights vascular etiologies.
471 citations
TL;DR: A meta-analysis of genome-wide association studies for estimated glomerular filtration rate suggests that genetic determinants of eGFR are mediated largely through direct effects within the kidney and highlight important cell types and biological pathways.
Abstract: Reduced glomerular filtration rate defines chronic kidney disease and is associated with cardiovascular and all-cause mortality. We conducted a meta-analysis of genome-wide association studies for estimated glomerular filtration rate (eGFR), combining data across 133,413 individuals with replication in up to 42,166 individuals. We identify 24 new and confirm 29 previously identified loci. Of these 53 loci, 19 associate with eGFR among individuals with diabetes. Using bioinformatics, we show that identified genes at eGFR loci are enriched for expression in kidney tissues and in pathways relevant for kidney development and transmembrane transporter activity, kidney structure, and regulation of glucose metabolism. Chromatin state mapping and DNase I hypersensitivity analyses across adult tissues demonstrate preferential mapping of associated variants to regulatory regions in kidney but not extra-renal tissues. These findings suggest that genetic determinants of eGFR are mediated largely through direct effects within the kidney and highlight important cell types and biological pathways.
409 citations
University of Washington1, University of Cambridge2, University of Leicester3, University of Lübeck4, University of Copenhagen5, University of Wisconsin–Milwaukee6, University of Michigan7, Montreal Heart Institute8, University of Oxford9, Broad Institute10, Samsung Medical Center11, University of Amsterdam12, Queen Mary University of London13, University of Göttingen14, University of Dundee15, University of Verona16, Vanderbilt University17, University of Kiel18, University of Bonn19, University of Basel20, Norwegian University of Science and Technology21, Umeå University22, University of Duisburg-Essen23, Technische Universität München24, University of Tartu25, Lund University26, University of Ottawa27, King Abdulaziz University28, Merck & Co.29, Ohio State University30, National Institutes of Health31, Johns Hopkins University32, Harvard University33, University of Insubria34, University of Glasgow35, Leiden University36, Queen's University Belfast37, Pierre-and-Marie-Curie University38, Wellcome Trust Sanger Institute39, University of Leeds40, Duke University41, University of Pennsylvania42
TL;DR: It was found that carriers of loss-of-function mutations in ANGPTL4 had triglyceride levels that were lower than those among noncarriers; these mutations were also associated with protection from coronary artery disease.
Abstract: BACKGROUND The discovery of low-frequency coding variants affecting the risk of coronary artery disease has facilitated the identification of therapeutic targets. METHODS Through DNA genotyping, we ...
339 citations
TL;DR: In this article, the authors identified 66 blood pressure-associated loci, of which 17 were new; 15 harbored multiple distinct association signals, and 66 index SNPs were enriched for cis-regulatory elements, particularly in vascular endothelial cells, consistent with a primary role in blood pressure control through modulation of vascular tone across multiple tissues.
Abstract: To dissect the genetic architecture of blood pressure and assess effects on target organ damage, we analyzed 128,272 SNPs from targeted and genome-wide arrays in 201,529 individuals of European ancestry, and genotypes from an additional 140,886 individuals were used for validation. We identified 66 blood pressure-associated loci, of which 17 were new; 15 harbored multiple distinct association signals. The 66 index SNPs were enriched for cis-regulatory elements, particularly in vascular endothelial cells, consistent with a primary role in blood pressure control through modulation of vascular tone across multiple tissues. The 66 index SNPs combined in a risk score showed comparable effects in 64,421 individuals of non-European descent. The 66-SNP blood pressure risk score was significantly associated with target organ damage in multiple tissues but with minor effects in the kidney. Our findings expand current knowledge of blood pressure-related pathways and highlight tissues beyond the classical renal system in blood pressure regulation.
332 citations
01 Jan 2016
TL;DR: The 66-SNP blood pressure risk score was significantly associated with target organ damage in multiple tissues but with minor effects in the kidney, expanding current knowledge of blood pressure–related pathways and highlighting tissues beyond the classical renal system in blood pressure regulation.
272 citations
TL;DR: In this article, the authors reported a large genome-wide association study of both sexes including 251,151 individuals for AB and 343,072 individuals for NEB and identified 12 independent loci that are significantly associated with AB and NEB.
Abstract: The genetic architecture of human reproductive behavior-age at first birth (AFB) and number of children ever born (NEB)-has a strong relationship with fitness, human development, infertility and risk of neuropsychiatric disorders However, very few genetic loci have been identified, and the underlying mechanisms of AFB and NEB are poorly understood We report a large genome-wide association study of both sexes including 251,151 individuals for AFB and 343,072 individuals for NEB We identified 12 independent loci that are significantly associated with AFB and/or NEB in a SNP-based genome-wide association study and 4 additional loci associated in a gene-based effort These loci harbor genes that are likely to have a role, either directly or by affecting non-local gene expression, in human reproduction and infertility, thereby increasing understanding of these complex traits
237 citations
Boston University1, Washington University in St. Louis2, University of Michigan3, University of Washington4, University of North Carolina at Chapel Hill5, University of Texas Health Science Center at Houston6, Icahn School of Medicine at Mount Sinai7, University of Greifswald8, Los Angeles Biomedical Research Institute9, Columbia University Medical Center10, George Washington University11, University of Cambridge12, University of Bristol13, University College London14, University of Liverpool15, University of Leicester16, University of Wisconsin–Milwaukee17, Brigham and Women's Hospital18, Vanderbilt University Medical Center19, Wake Forest University20, Erasmus University Rotterdam21, University of Mississippi Medical Center22, Bill & Melinda Gates Foundation23, University of Iceland24, Harvard University25, Broad Institute26, Glenfield Hospital27, Technische Universität München28, King Abdulaziz University29, Queen Mary University of London30, European Academy of Bozen31, University of Regensburg32, National Institutes of Health33, Pennington Biomedical Research Center34, Cedars-Sinai Medical Center35, Northwestern University36, Johns Hopkins University School of Medicine37, Greifswald University Hospital38, National Yang-Ming University39, Chung Shan Medical University40, Wake Forest Baptist Medical Center41, Geneva College42
TL;DR: This large collection of blood pressure–associated loci suggests new therapeutic strategies for hypertension, emphasizing a link with cardiometabolic risk.
Abstract: Meta-analyses of association results for blood pressure using exome-centric single-variant and gene-based tests identified 31 new loci in a discovery stage among 146,562 individuals, with follow-up and meta-analysis in 180,726 additional individuals (total n = 327,288). These blood pressure-associated loci are enriched for known variants for cardiometabolic traits. Associations were also observed for the aggregation of rare and low-frequency missense variants in three genes, NPR1, DBH, and PTPMT1. In addition, blood pressure associations at 39 previously reported loci were confirmed. The identified variants implicate biological pathways related to cardiometabolic traits, vascular function, and development. Several new variants are inferred to have roles in transcription or as hubs in protein-protein interaction networks. Genetic risk scores constructed from the identified variants were strongly associated with coronary disease and myocardial infarction. This large collection of blood pressure-associated loci suggests new therapeutic strategies for hypertension, emphasizing a link with cardiometabolic risk.
218 citations
TL;DR: A novel locus (G allele at rs12122341) at 1p13.2 near TSPAN2 that was associated with large artery atherosclerosis-related stroke was identified and supported robust associations with ischaemic stroke for four other loci that have been reported in previous studies.
Abstract: Summary Background The discovery of disease-associated loci through genome-wide association studies (GWAS) is the leading genetic approach to the identification of novel biological pathways underlying diseases in humans. Until recently, GWAS in ischaemic stroke have been limited by small sample sizes and have yielded few loci associated with ischaemic stroke. We did a large-scale GWAS to identify additional susceptibility genes for stroke and its subtypes. Methods To identify genetic loci associated with ischaemic stroke, we did a two-stage GWAS. In the first stage, we included 16 851 cases with state-of-the-art phenotyping data and 32 473 stroke-free controls. Cases were aged 16 to 104 years, recruited between 1989 and 2012, and subtypes of ischaemic stroke were recorded by centrally trained and certified investigators who used the web-based protocol, Causative Classification of Stroke (CCS). We constructed case-control strata by identifying samples that were genotyped on nearly identical arrays and were of similar genetic ancestral background. We cleaned and imputed data by use of dense imputation reference panels generated from whole-genome sequence data. We did genome-wide testing to identify stroke-associated loci within each stratum for each available phenotype, and we combined summary-level results using inverse variance-weighted fixed-effects meta-analysis. In the second stage, we did in-silico lookups of 1372 single nucleotide polymorphisms identified from the first stage GWAS in 20 941 cases and 364 736 unique stroke-free controls. The ischaemic stroke subtypes of these cases had previously been established with the Trial of Org 10 172 in Acute Stroke Treatment (TOAST) classification system, in accordance with local standards. Results from the two stages were then jointly analysed in a final meta-analysis. Findings We identified a novel locus (G allele at rs12122341) at 1p13.2 near TSPAN2 that was associated with large artery atherosclerosis-related stroke (first stage odds ratio [OR] 1·21, 95% CI 1·13–1·30, p=4·50 × 10 −8 ; joint OR 1·19, 1·12–1·26, p=1·30 × 10 −9 ). Our results also supported robust associations with ischaemic stroke for four other loci that have been reported in previous studies, including PITX2 (first stage OR 1·39, 1·29–1·49, p=3·26 × 10 −19 ; joint OR 1·37, 1·30–1·45, p=2·79 × 10 −32 ) and ZFHX3 (first stage OR 1·19, 1·11–1·27, p=2·93 × 10 −7 ; joint OR 1·17, 1·11–1·23, p=2·29 × 10 −10 ) for cardioembolic stroke, and HDAC9 (first stage OR 1·29, 1·18–1·42, p=3·50 × 10 −8 ; joint OR 1·24, 1·15–1·33, p=4·52 × 10 −9 ) for large artery atherosclerosis stroke. The 12q24 locus near ALDH2 , which has previously been associated with all ischaemic stroke but not with any specific subtype, exceeded genome-wide significance in the meta-analysis of small artery stroke (first stage OR 1·20, 1·12–1·28, p=6·82 × 10 −8 ; joint OR 1·17, 1·11–1·23, p=2·92 × 10 −9 ). Other loci associated with stroke in previous studies, including NINJ2 , were not confirmed. Interpretation Our results suggest that all ischaemic stroke-related loci previously implicated by GWAS are subtype specific. We identified a novel gene associated with large artery atherosclerosis stroke susceptibility. Follow-up studies will be necessary to establish whether the locus near TSPAN2 can be a target for a novel therapeutic approach to stroke prevention. In view of the subtype-specificity of the associations detected, the rich phenotyping data available in the Stroke Genetics Network (SiGN) are likely to be crucial for further genetic discoveries related to ischaemic stroke. Funding US National Institute of Neurological Disorders and Stroke, National Institutes of Health.
210 citations
TL;DR: It is shown that brain-specific β-Klotho KO mice have an increased alcohol preference and that FGF21 inhibits alcohol drinking by acting on the brain, suggesting that a liver–brain endocrine axis may play an important role in the regulation of alcohol drinking behavior and provide a unique pharmacologic target for reducing alcohol consumption.
Abstract: Excessive alcohol consumption is a major public health problem worldwide. Although drinking habits are known to be inherited, few genes have been identified that are robustly linked to alcohol drinking. We conducted a genome-wide association metaanalysis and replication study among >105,000 individuals of European ancestry and identified β-Klotho (KLB) as a locus associated with alcohol consumption (rs11940694; P = 9.2 × 10−12). β-Klotho is an obligate coreceptor for the hormone FGF21, which is secreted from the liver and implicated in macronutrient preference in humans. We show that brain-specific β-Klotho KO mice have an increased alcohol preference and that FGF21 inhibits alcohol drinking by acting on the brain. These data suggest that a liver–brain endocrine axis may play an important role in the regulation of alcohol drinking behavior and provide a unique pharmacologic target for reducing alcohol consumption.
205 citations
Case Western Reserve University1, Harvard University2, Duke University3, QIMR Berghofer Medical Research Institute4, National University of Singapore5, Agency for Science, Technology and Research6, University of Tasmania7, Flinders University8, King's College London9, Marshfield Clinic10, University of Geneva11, University of North Carolina at Chapel Hill12, Singapore National Eye Center13, Boston University14, University of Iowa15, Moorfields Eye Hospital16, University College London17, University of California, San Diego18, University of Melbourne19, University of Cambridge20, University of Miami21, University of Michigan22, Menzies Research Institute23, University of Western Australia24, University of Sydney25, Yeshiva University26, West Virginia University27, New York Eye and Ear Infirmary28, Pennsylvania State University29, University of Pittsburgh30, Stanford University31, Mayo Clinic32, Aristotle University of Thessaloniki33, University of Tübingen34, Genentech35, Johns Hopkins University36, Georgia Regents University37
TL;DR: New pathways underlying POAG susceptibility are identified and new targets for preventative therapies are suggested, including TXNRD2 and ATXN2 expression in retinal ganglion cells and the optic nerve head.
Abstract: Primary open-angle glaucoma (POAG) is a leading cause of blindness worldwide. To identify new susceptibility loci, we performed meta-analysis on genome-wide association study (GWAS) results from eight independent studies from the United States (3,853 cases and 33,480 controls) and investigated the most significantly associated SNPs in two Australian studies (1,252 cases and 2,592 controls), three European studies (875 cases and 4,107 controls) and a Singaporean Chinese study (1,037 cases and 2,543 controls). A meta-analysis of the top SNPs identified three new associated loci: rs35934224[T] in TXNRD2 (odds ratio (OR) = 0.78, P = 4.05 × 10(-11)) encoding a mitochondrial protein required for redox homeostasis; rs7137828[T] in ATXN2 (OR = 1.17, P = 8.73 × 10(-10)); and rs2745572[A] upstream of FOXC1 (OR = 1.17, P = 1.76 × 10(-10)). Using RT-PCR and immunohistochemistry, we show TXNRD2 and ATXN2 expression in retinal ganglion cells and the optic nerve head. These results identify new pathways underlying POAG susceptibility and suggest new targets for preventative therapies.
22 Dec 2016
Tuomas O. Kilpeläinen1, Tuomas O. Kilpeläinen2, Tuomas O. Kilpeläinen3, Jayne F. Martin Carli4 +224 more•Institutions (71)
TL;DR: In this article, the authors performed a genome-wide association study (GWAS) of circulating leptin levels from 32,161 individuals and identified five loci robustly associated with leptin levels in/near LEP, SLC32A1, GCKR, CCNL1 and FTO.
Abstract: Leptin is an adipocyte-secreted hormone, the circulating levels of which correlate closely with overall adiposity. Although rare mutations in the leptin (LEP) gene are well known to cause leptin deficiency and severe obesity, no common loci regulating circulating leptin levels have been uncovered. Therefore, we performed a genome-wide association study (GWAS) of circulating leptin levels from 32,161 individuals and followed up loci reaching P<10(-6) in 19,979 additional individuals. We identify five loci robustly associated (P<5 × 10(-8)) with leptin levels in/near LEP, SLC32A1, GCKR, CCNL1 and FTO. Although the association of the FTO obesity locus with leptin levels is abolished by adjustment for BMI, associations of the four other loci are independent of adiposity. The GCKR locus was found associated with multiple metabolic traits in previous GWAS and the CCNL1 locus with birth weight. Knockdown experiments in mouse adipose tissue explants show convincing evidence for adipogenin, a regulator of adipocyte differentiation, as the novel causal gene in the SLC32A1 locus influencing leptin levels. Our findings provide novel insights into the regulation of leptin production by adipose tissue and open new avenues for examining the influence of variation in leptin levels on adiposity and metabolic health.
TL;DR: The ages of puberty, first sexual intercourse and first birth signify the onset of reproductive ability, behavior and success, respectively and Mendelian randomization analyses infer causal influences of earlier puberty timing on earlier firstSexual intercourse, earlier first birth and lower educational attainment.
Abstract: The ages of puberty, first sexual intercourse and first birth signify the onset of reproductive ability, behavior and success, respectively. In a genome-wide association study of 125,667 UK Biobank participants, we identify 38 loci associated (P < 5 × 10(-8)) with age at first sexual intercourse. These findings were taken forward in 241,910 men and women from Iceland and 20,187 women from the Women's Genome Health Study. Several of the identified loci also exhibit associations (P < 5 × 10(-8)) with other reproductive and behavioral traits, including age at first birth (variants in or near ESR1 and RBM6-SEMA3F), number of children (CADM2 and ESR1), irritable temperament (MSRA) and risk-taking propensity (CADM2). Mendelian randomization analyses infer causal influences of earlier puberty timing on earlier first sexual intercourse, earlier first birth and lower educational attainment. In turn, likely causal consequences of earlier first sexual intercourse include reproductive, educational, psychiatric and cardiometabolic outcomes.
TL;DR: Empirical and experimental data suggest that FOXF2 mediates this association, potentially via differentiation defects of cerebral vascular mural cells, and further expression studies in appropriate human tissues are needed to fully understand the underlying mechanisms.
Abstract: Summary Background Genetic determinants of stroke, the leading neurological cause of death and disability, are poorly understood and have seldom been explored in the general population. Our aim was to identify additional loci for stroke by doing a meta-analysis of genome-wide association studies. Methods For the discovery sample, we did a genome-wide analysis of common genetic variants associated with incident stroke risk in 18 population-based cohorts comprising 84 961 participants, of whom 4348 had stroke. Stroke diagnosis was ascertained and validated by the study investigators. Mean age at stroke ranged from 45·8 years to 76·4 years, and data collection in the studies took place between 1948 and 2013. We did validation analyses for variants yielding a significant association (at p −6 ) with all-stroke, ischaemic stroke, cardioembolic ischaemic stroke, or non-cardioembolic ischaemic stroke in the largest available cross-sectional studies (70 804 participants, of whom 19 816 had stroke). Summary-level results of discovery and follow-up stages were combined using inverse-variance weighted fixed-effects meta-analysis, and in-silico lookups were done in stroke subtypes. For genome-wide significant findings (at p −8 ), we explored associations with additional cerebrovascular phenotypes and did functional experiments using conditional (inducible) deletion of the probable causal gene in mice. We also studied the expression of orthologs of this probable causal gene and its effects on cerebral vasculature in zebrafish mutants. Findings We replicated seven of eight known loci associated with risk for ischaemic stroke, and identified a novel locus at chromosome 6p25 (rs12204590, near FOXF2 ) associated with risk of all-stroke (odds ratio [OR] 1·08, 95% CI 1·05–1·12, p=1·48 × 10 −8 ; minor allele frequency 21%). The rs12204590 stroke risk allele was also associated with increased MRI-defined burden of white matter hyperintensity—a marker of cerebral small vessel disease—in stroke-free adults (n=21 079; p=0·0025). Consistently, young patients (aged 2–32 years) with segmental deletions of FOXF2 showed an extensive burden of white matter hyperintensity. Deletion of Foxf2 in adult mice resulted in cerebral infarction, reactive gliosis, and microhaemorrhage. The orthologs of FOXF2 in zebrafish (foxf2b and foxf2a ) are expressed in brain pericytes and mutant foxf2b −/− cerebral vessels show decreased smooth muscle cell and pericyte coverage. Interpretation We identified common variants near FOXF2 that are associated with increased stroke susceptibility. Epidemiological and experimental data suggest that FOXF2 mediates this association, potentially via differentiation defects of cerebral vascular mural cells. Further expression studies in appropriate human tissues, and further functional experiments with long follow-up periods are needed to fully understand the underlying mechanisms. Funding NIH, NINDS, NHMRC, CIHR, European national research institutions, Fondation Leducq.
Erasmus University Rotterdam1, University of Texas Health Science Center at Houston2, University of Iceland3, University of Washington4, University of Edinburgh5, Leiden University6, University of Michigan7, Max Planck Society8, Harvard University9, Wake Forest University10, Medical University of Graz11, University of Split12, Trinity College, Dublin13, University of Basel14, University of Bonn15, University of Groningen16, University of Helsinki17, University of Exeter18, Greifswald University Hospital19, University of New South Wales20, Lille University of Science and Technology21, National Institutes of Health22, University of Newcastle23, University of Dundee24, Boston University25, University of Pittsburgh26, University of Glasgow27, Mayo Clinic28, University of California, San Francisco29, University of Mississippi30, University of North Carolina at Chapel Hill31, University of Aberdeen32, Baylor College of Medicine33, Taipei Medical University34, Johns Hopkins University35, Rush University Medical Center36, University of California, Los Angeles37, Cedars-Sinai Medical Center38, German Center for Neurodegenerative Diseases39, University College Cork40, Group Health Cooperative41
TL;DR: This article conducted a GWAS of executive functioning and information processing speed in non-demented older adults from the CHARGE (Cohorts for Heart and Aging Research in Genomic Epidemiology) consortium.
Abstract: To identify common variants contributing to normal variation in two specific domains of cognitive functioning, we conducted a genome-wide association study (GWAS) of executive functioning and information processing speed in non-demented older adults from the CHARGE (Cohorts for Heart and Aging Research in Genomic Epidemiology) consortium. Neuropsychological testing was available for 5429-32,070 subjects of European ancestry aged 45 years or older, free of dementia and clinical stroke at the time of cognitive testing from 20 cohorts in the discovery phase. We analyzed performance on the Trail Making Test parts A and B, the Letter Digit Substitution Test (LDST), the Digit Symbol Substitution Task (DSST), semantic and phonemic fluency tests, and the Stroop Color and Word Test. Replication was sought in 1311-21860 subjects from 20 independent cohorts. A significant association was observed in the discovery cohorts for the single-nucleotide polymorphism (SNP) rs17518584 (discovery P-value=3.12 × 10(-8)) and in the joint discovery and replication meta-analysis (P-value=3.28 × 10(-9) after adjustment for age, gender and education) in an intron of the gene cell adhesion molecule 2 (CADM2) for performance on the LDST/DSST. Rs17518584 is located about 170 kb upstream of the transcription start site of the major transcript for the CADM2 gene, but is within an intron of a variant transcript that includes an alternative first exon. The variant is associated with expression of CADM2 in the cingulate cortex (P-value=4 × 10(-4)). The protein encoded by CADM2 is involved in glutamate signaling (P-value=7.22 × 10(-15)), gamma-aminobutyric acid (GABA) transport (P-value=1.36 × 10(-11)) and neuron cell-cell adhesion (P-value=1.48 × 10(-13)). Our findings suggest that genetic variation in the CADM2 gene is associated with individual differences in information processing speed.
17 Mar 2016
TL;DR: A genome-wide association study of executive functioning and information processing speed in non-demented older adults from the CHARGE consortium suggests that genetic variation in the CADM2 gene is associated with individual differences in informationprocessing speed.
Abstract: To identify common variants contributing to normal variation in two specific domains of cognitive functioning, we conducted a genome-wide association study (GWAS) of executive functioning and information processing speed in non-demented older adults from the CHARGE (Cohorts for Heart and Aging Research in Genomic Epidemiology) consortium. Neuropsychological testing was available for 5429–32 070 subjects of European ancestry aged 45 years or older, free of dementia and clinical stroke at the time of cognitive testing from 20 cohorts in the discovery phase. We analyzed performance on the Trail Making Test parts A and B, the Letter Digit Substitution Test (LDST), the Digit Symbol Substitution Task (DSST), semantic and phonemic fluency tests, and the Stroop Color and Word Test. Replication was sought in 1311-21860 subjects from 20 independent cohorts. A significant association was observed in the discovery cohorts for the single-nucleotide polymorphism (SNP) rs17518584 (discovery P-value=3.12 × 10−8) and in the joint discovery and replication meta-analysis (P-value=3.28 × 10−9 after adjustment for age, gender and education) in an intron of the gene cell adhesion molecule 2 (CADM2) for performance on the LDST/DSST. Rs17518584 is located about 170 kb upstream of the transcription start site of the major transcript for the CADM2 gene, but is within an intron of a variant transcript that includes an alternative first exon. The variant is associated with expression of CADM2 in the cingulate cortex (P-value=4 × 10−4). The protein encoded by CADM2 is involved in glutamate signaling (P-value=7.22 × 10−15), gamma-aminobutyric acid (GABA) transport (P-value=1.36 × 10−11) and neuron cell-cell adhesion (P-value=1.48 × 10−13). Our findings suggest that genetic variation in the CADM2 gene is associated with individual differences in information processing speed.
01 Jun 2016
TL;DR: For example, the authors identified 45 independent single nucleotide polymorphisms (SNPs) significantly associated with migraine risk that map to 38 distinct genomic loci, including 28 loci not previously reported and the first locus identified on chromosome X.
Abstract: Migraine is a debilitating neurological disorder affecting around 1 in 7 people worldwide, but its molecular mechanisms remain poorly understood. Some debate exists over whether migraine is a disease of vascular dysfunction, or a result of neuronal dysfunction with secondary vascular changes. Genome-wide association (GWA) studies have thus far identified 13 independent loci associated with migraine. To identify new susceptibility loci, we performed the largest genetic study of migraine to date, comprising 59,674 cases and 316,078 controls from 22 GWA studies. We identified 45 independent single nucleotide polymorphisms (SNPs) significantly associated with migraine risk ( P -8 ) that map to 38 distinct genomic loci, including 28 loci not previously reported and the first locus identified on chromosome X. Furthermore, a subset analysis for migraine without aura (MO) identified seven of the same loci as from the full sample, whereas no loci reached genome-wide significance in the migraine with aura (MA) subset. In subsequent computational analyzes, the identified loci showed enrichment for genes expressed in vascular and smooth muscle tissues, consistent with a predominant theory of migraine that highlights vascular etiologies.
Brigham and Women's Hospital1, Harvard University2, Boston University3, National Institutes of Health4, University of Queensland5, VU University Amsterdam6, Ludwig Maximilian University of Munich7, Heidelberg University8, Los Angeles Biomedical Research Institute9, University of Sydney10, University of Wisconsin–Milwaukee11, Johns Hopkins University School of Medicine12, University of Copenhagen13, King's College London14, University of Michigan15, Pierre-and-Marie-Curie University16, University of Minnesota17, Wellcome Trust Centre for Human Genetics18, Mashhad University of Medical Sciences19, Fred Hutchinson Cancer Research Center20, University College Dublin21, Royal College of Surgeons in Ireland22, Frederiksberg Hospital23, University of Texas Health Science Center at Houston24, Science for Life Laboratory25, Royal North Shore Hospital26, University of Glasgow27, University of Cambridge28, Wellcome Trust Sanger Institute29, University of California, Davis30, University of Newcastle31, University of Helsinki32, Erasmus University Rotterdam33, University of Bristol34, Leiden University Medical Center35, University of Hamburg36, Technische Universität München37, Group Health Research Institute38, Cedars-Sinai Medical Center39, University of Split40, Aix-Marseille University41, Novo Nordisk Foundation42, University of Edinburgh43, Medical University of Graz44, Greifswald University Hospital45, University of Mainz46, University of Vermont47, University of Washington48, St George's, University of London49
TL;DR: A genome-wide association analysis of 34 studies imputed to the 1000 Genomes Project reference panel and including ∼120 000 participants of European ancestry identified 41 genome- wide significant fibrinogen loci; of which, 18 were newly identified.
Abstract: Genome-wide association studies have previously identified 23 genetic loci associated with circulating fibrinogen concentration. These studies used HapMap imputation and did not examine the X-chromosome. 1000 Genomes imputation provides better coverage of uncommon variants, and includes indels. We conducted a genome-wide association analysis of 34 studies imputed to the 1000 Genomes Project reference panel and including ∼120 000 participants of European ancestry (95 806 participants with data on the X-chromosome). Approximately 10.7 million single-nucleotide polymorphisms and 1.2 million indels were examined. We identified 41 genome-wide significant fibrinogen loci; of which, 18 were newly identified. There were no genome-wide significant signals on the X-chromosome. The lead variants of five significant loci were indels. We further identified six additional independent signals, including three rare variants, at two previously characterized loci: FGB and IRF1. Together the 41 loci explain 3% of the variance in plasma fibrinogen concentration.
TL;DR: The results of the analysis show that inflammatory responses initiate from within the cross-talk of the three identified endophenotypic modules, and are also enriched with differentially expressed genes linked to cardiovascular disease (risk).
Abstract: Historically, human diseases have been differentiated and categorized based on the organ system in which they primarily manifest. Recently, an alternative view is emerging that emphasizes that different diseases often have common underlying mechanisms and shared intermediate pathophenotypes, or endo(pheno)types. Within this framework, a specific disease's expression is a consequence of the interplay between the relevant endophenotypes and their local, organ-based environment. Important examples of such endophenotypes are inflammation, fibrosis, and thrombosis and their essential roles in many developing diseases. In this study, we construct endophenotype network models and explore their relation to different diseases in general and to cardiovascular diseases in particular. We identify the local neighborhoods (module) within the interconnected map of molecular components, i.e., the subnetworks of the human interactome that represent the inflammasome, thrombosome, and fibrosome. We find that these neighborhoods are highly overlapping and significantly enriched with disease-associated genes. In particular they are also enriched with differentially expressed genes linked to cardiovascular disease (risk). Finally, using proteomic data, we explore how macrophage activation contributes to our understanding of inflammatory processes and responses. The results of our analysis show that inflammatory responses initiate from within the cross-talk of the three identified endophenotypic modules.
Erasmus University Medical Center1, University of Washington2, Boston University3, University of Iceland4, University of Texas Health Science Center at Houston5, Leiden University6, Brigham and Women's Hospital7, University of Auckland8, Greifswald University Hospital9, University College Cork10, Wake Forest University11, Harvard University12, University of Minnesota13, University of North Carolina at Chapel Hill14, Merck & Co.15, Robertson Centre for Biostatistics16, National Institutes of Health17, Erasmus University Rotterdam18, Fred Hutchinson Cancer Research Center19, Pasteur Institute of Lille20, University of Strasbourg21, Group Health Research Institute22, University of Toulouse23, United States Department of Veterans Affairs24, Novartis25, New York Academy of Medicine26, Umeå University27, University of California, Los Angeles28, Queen's University Belfast29, University of Jyväskylä30, University of Helsinki31, University of Glasgow32, Leiden University Medical Center33, University of Hamburg34, Baylor College of Medicine35
TL;DR: The association of the 9p21 locus both with increased risk of first myocardial infarction and longer survival after MI highlights the importance of study design in investigating genetic determinants of complex disorders.
Abstract: Background Data are limited on genome-wide association studies (GWAS) for incident coronary heart disease (CHD). Moreover, it is not known whether genetic variants identified to date also associate with risk of CHD in a prospective setting. Methods We performed a two-stage GWAS analysis of incident myocardial infarction (MI) and CHD in a total of 64,297 individuals (including 3898 MI cases, 5465 CHD cases). SNPs that passed an arbitrary threshold of 5x10(-6) in Stage I were taken to Stage II for further discovery. Furthermore, in an analysis of prognosis, we studied whether known SNPs from former GWAS were associated with total mortality in individuals who experienced MI during follow-up. Results In Stage I 15 loci passed the threshold of 5x10(-6); 8 loci for MI and 8 loci for CHD, for which one locus overlapped and none were reported in previous GWAS meta-analyses. We took 60 SNPs representing these 15 loci to Stage II of discovery. Four SNPs near QKI showed nominally significant association with MI (p-value<8.8x10(-3)) and three exceeded the genome-wide significance threshold when Stage I and Stage II results were combined (top SNP rs6941513: p = 6.2x10(-9)). Despite excellent power, the 9p21 locus SNP (rs1333049) was only modestly associated with MI (HR = 1.09, p-value = 0.02) and marginally with CHD (HR = 1.06, p-value = 0.08). Among an inception cohort of those who experienced MI during follow-up, the risk allele of rs1333049 was associated with a decreased risk of subsequent mortality (HR = 0.90, p-value = 3.2x10(-3)). Conclusions QKI represents a novel locus that may serve as a predictor of incident CHD in prospective studies. The association of the 9p21 locus both with increased risk of first myocardial infarction and longer survival after MI highlights the importance of study design in investigating genetic determinants of complex disorders.
Janina S. Ried, Janina M. Jeff1, Audrey Y. Chu2, Jennifer L. Bragg-Gresham3 +327 more•Institutions (76)
TL;DR: In this paper, the authors examined whether genetic variants affect body shape as a composite phenotype that is represented by a combination of anthropometric traits, and identified six novel loci: LEMD2 and CD47 for AvPC1, RPS6KA5/C14orf159 and GANAB for AVPC3, and ARL15 and ANP32 for Avpc4.
Abstract: Large consortia have revealed hundreds of genetic loci associated with anthropometric traits, one trait at a time. We examined whether genetic variants affect body shape as a composite phenotype that is represented by a combination of anthropometric traits. We developed an approach that calculates averaged PCs (AvPCs) representing body shape derived from six anthropometric traits (body mass index, height, weight, waist and hip circumference, waist-to-hip ratio). The first four AvPCs explain >99% of the variability, are heritable, and associate with cardiometabolic outcomes. We performed genome-wide association analyses for each body shape composite phenotype across 65 studies and meta-analysed summary statistics. We identify six novel loci: LEMD2 and CD47 for AvPC1, RPS6KA5/C14orf159 and GANAB for AvPC3, and ARL15 and ANP32 for AvPC4. Our findings highlight the value of using multiple traits to define complex phenotypes for discovery, which are not captured by single-trait analyses, and may shed light onto new pathways.
Harvard University1, National Institutes of Health2, Dresden University of Technology3, Erasmus University Rotterdam4, University of Minnesota5, Vanderbilt University6, University of Wisconsin–Milwaukee7, Fred Hutchinson Cancer Research Center8, University of Ulm9, Brigham and Women's Hospital10, University of Kiel11, University Health Network12, University of Copenhagen13, Herlev Hospital14, Massachusetts Eye and Ear Infirmary15, Greifswald University Hospital16
TL;DR: A large-scale, meta-analysis of GWASs of individuals of European ancestry with available prior genotype data identified 4 loci in genes that have putative functions in cholesterol metabolism and transport, and sulfonylation of bile acids or hydroxysteroids.
TL;DR: The observed polygenic overlap between CAD and cardiometabolic risk factors indicates a pathogenic relation that warrants further investigation.
Abstract: Rationale: Coronary Artery Disease (CAD) is a critical determinant of morbidity and mortality. Previous studies have identified several cardiovascular disease (CVD) risk factors, which may partly arise from a shared genetic basis with CAD, and thus be useful for discovery of CAD genes.
Objective: We aimed to improve discovery of CAD genes, and inform the etiologic relationship between CAD and several CVD risk factors using a shared polygenic signal-informed statistical framework.
Methods and Results: Using genome-wide association studies (GWAS) summary statistics and shared polygenic pleiotropy-informed conditional and conjunctional false discovery rate (FDR) methodology, we systematically investigated genetic overlap between CAD and 8 traits related to CVD risk factors: low density lipoprotein (LDL) cholesterol, high density lipoprotein (HDL) cholesterol, triglycerides (TG), type 2 diabetes (T2D), C-reactive protein (CRP), body mass index (BMI), systolic blood pressure (SBP) and type 1 diabetes (T1D). We found significant enrichment of single nucleotide polymorphisms (SNPs) associated with CAD as a function of their association with LDL, HDL, TG, T2D, CRP, BMI, SBP and T1D. Applying the conditional FDR method to the enriched phenotypes, we identified 67 novel loci associated with CAD (overall conditional FDR < 0.01). Further, we identified 53 loci with significant effects in both CAD and at least one of LDL, HDL, TG, T2D, CRP, SBP and T1D.
Conclusions: The observed polygenic overlap between CAD and cardio-metabolic risk factors indicates an etiological relation that warrants further investigation. The new gene loci identified implicate novel genetic mechanisms related to CAD.
Leiden University Medical Center1, Delft University of Technology2, Harvard University3, Broad Institute4, Oslo University Hospital5, Charité6, Erasmus University Rotterdam7, University of Tübingen8, Ludwig Maximilian University of Munich9, University of Helsinki10, VU University Amsterdam11, Imperial College London12, University of Oulu13, Oulu University Hospital14, King's College London15, St George's, University of London16, University of Hamburg17, University of Bristol18, deCODE genetics19, University of Iceland20, QIMR Berghofer Medical Research Institute21, Queensland University of Technology22
TL;DR: This work integrated migraine GWAS data with high-resolution spatial gene expression data of normal adult brains from the Allen Human Brain Atlas to identify specific brain regions and molecular pathways that are possibly involved in migraine pathophysiology and used the high-confidence genes from the GWAS as a basis to construct local migraine-related co-expression gene networks.
Abstract: Migraine is a common disabling neurovascular brain disorder typically characterised by attacks of severe headache and associated with autonomic and neurological symptoms. Migraine is caused by an interplay of genetic and environmental factors. Genome-wide association studies (GWAS) have identified over a dozen genetic loci associated with migraine. Here, we integrated migraine GWAS data with high-resolution spatial gene expression data of normal adult brains from the Allen Human Brain Atlas to identify specific brain regions and molecular pathways that are possibly involved in migraine pathophysiology. To this end, we used two complementary methods. In GWAS data from 23,285 migraine cases and 95,425 controls, we first studied modules of co-expressed genes that were calculated based on human brain expression data for enrichment of genes that showed association with migraine. Enrichment of a migraine GWAS signal was found for five modules that suggest involvement in migraine pathophysiology of: (i) neurotransmission, protein catabolism and mitochondria in the cortex; (ii) transcription regulation in the cortex and cerebellum; and (iii) oligodendrocytes and mitochondria in subcortical areas. Second, we used the high-confidence genes from the migraine GWAS as a basis to construct local migraine-related co-expression gene networks. Signatures of all brain regions and pathways that were prominent in the first method also surfaced in the second method, thus providing support that these brain regions and pathways are indeed involved in migraine pathophysiology.
QIMR Berghofer Medical Research Institute1, Leiden University2, Harvard University3, University of Oslo4, French Institute of Health and Medical Research5, deCODE genetics6, Helsinki University Central Hospital7, Ludwig Maximilian University of Munich8, Erasmus University Rotterdam9, VU University Amsterdam10, University of Bonn11, Max Planck Society12, University of Kiel13, Technische Universität München14, National Institutes of Health15, King's College London16, University of Hamburg17, University of Iceland18, Queensland University of Technology19, University of Helsinki20
TL;DR: In this paper, it is unclear whether patients diagnosed according to International Classification of Headache Disorders criteria for migraine with aura (MA) and migraine without aura (MO) experience d...
Abstract: IntroductionIt is unclear whether patients diagnosed according to International Classification of Headache Disorders criteria for migraine with aura (MA) and migraine without aura (MO) experience d...
01 Oct 2016
TL;DR: A large genome-wide association study of both sexes including 251,151 individuals for AFB and 343,072 individuals for NEB finds 12 independent loci that are significantly associated with AFB and/or NEB in a SNP-based genome- wide association study and 4 additional loci associated in a gene-based effort.
Abstract: The genetic architecture of human reproductive behavior—age at first birth (AFB) and number of children ever born (NEB)—has a strong relationship with fitness, human development, infertility and risk of neuropsychiatric disorders. However, very few genetic loci have been identified, and the underlying mechanisms of AFB and NEB are poorly understood. We report a large genome-wide association study of both sexes including 251,151 individuals for AFB and 343,072 individuals for NEB. We identified 12 independent loci that are significantly associated with AFB and/or NEB in a SNP-based genome-wide association study and 4 additional loci associated in a gene-based effort. These loci harbor genes that are likely to have a role, either directly or by affecting non-local gene expression, in human reproduction and infertility, thereby increasing understanding of these complex traits.
Georgia Regents University1, Case Western Reserve University2, Duke University3, Marshfield Clinic4, University of North Carolina at Chapel Hill5, Harvard University6, University of Iowa7, University of California, San Diego8, Washington University in St. Louis9, University of Miami10, University of Michigan11, West Virginia University12, New York Eye and Ear Infirmary13, University of Pittsburgh14, Stanford University15, Mayo Clinic16, Johns Hopkins University17, Vanderbilt University18
TL;DR: This integrative study is the first to associate rs76481776 with POAG via elevated miR-182 expression using miRNA sequencing and ddPCR, and it is unclear whether this association was primarily in the HTG subset.
Abstract: Author(s): Liu, Yutao; Bailey, Jessica Cooke; Helwa, Inas; Dismuke, W Michael; Cai, Jingwen; Drewry, Michelle; Brilliant, Murray H; Budenz, Donald L; Christen, William G; Chasman, Daniel I; Fingert, John H; Gaasterland, Douglas; Gaasterland, Terry; Gordon, Mae O; Igo, Robert P; Kang, Jae H; Kass, Michael A; Kraft, Peter; Lee, Richard K; Lichter, Paul; Moroi, Sayoko E; Realini, Anthony; Richards, Julia E; Ritch, Robert; Schuman, Joel S; Scott, William K; Singh, Kuldev; Sit, Arthur J; Song, Yeunjoo E; Vollrath, Douglas; Weinreb, Robert; Medeiros, Felipe; Wollstein, Gadi; Zack, Donald J; Zhang, Kang; Pericak-Vance, Margaret A; Gonzalez, Pedro; Stamer, W Daniel; Kuchtey, John; Kuchtey, Rachel W; Allingham, R Rand; Hauser, Michael A; Pasquale, Louis R; Haines, Jonathan L; Wiggs, Janey L | Abstract: PurposeNoncoding microRNAs (miRNAs) have been implicated in the pathogenesis of glaucoma. We aimed to identify common variants in miRNA coding genes (MIR) associated with primary open-angle glaucoma (POAG).MethodsUsing the NEIGHBORHOOD data set (3853 cases/33,480 controls with European ancestry), we first assessed the relation between 85 variants in 76 MIR genes and overall POAG. Subtype-specific analyses were performed in high-tension glaucoma (HTG) and normal-tension glaucoma subsets. Second, we examined the expression of miR-182, which was associated with POAG, in postmortem human ocular tissues (ciliary body, cornea, retina, and trabecular meshwork [TM]), using miRNA sequencing (miRNA-Seq) and droplet digital PCR (ddPCR). Third, miR-182 expression was also examined in human aqueous humor (AH) by using miRNA-Seq. Fourth, exosomes secreted from primary human TM cells were examined for miR-182 expression by using miRNA-Seq. Fifth, using ddPCR we compared miR-182 expression in AH between five HTG cases and five controls.ResultsOnly rs76481776 in MIR182 gene was associated with POAG after adjustment for multiple comparisons (odds ratio [OR] = 1.23, 95% confidence interval [CI]: 1.11-1.42, P = 0.0002). Subtype analysis indicated that the association was primarily in the HTG subset (OR = 1.26, 95% CI: 1.08-1.47, P = 0.004). The risk allele T has been associated with elevated miR-182 expression in vitro. Data from ddPCR and miRNA-Seq confirmed miR-182 expression in all examined ocular tissues and TM-derived exosomes. Interestingly, miR-182 expression in AH was 2-fold higher in HTG patients than nonglaucoma controls (P = 0.03) without controlling for medication treatment.ConclusionsOur integrative study is the first to associate rs76481776 with POAG via elevated miR-182 expression.
Washington University in St. Louis1, Research Triangle Park2, Johns Hopkins University3, University of Washington4, Erasmus University Rotterdam5, University of Alabama at Birmingham6, Columbia University Medical Center7, Icahn School of Medicine at Mount Sinai8, University of Texas Health Science Center at Houston9, Brigham and Women's Hospital10, Harvard University11, University of Mississippi Medical Center12, University of North Carolina at Chapel Hill13, UCLA Medical Center14, University of Michigan15, Group Health Research Institute16, Fred Hutchinson Cancer Research Center17, Jackson State University18, Michigan State University19, University of Minnesota20, University of Colorado Boulder21
TL;DR: It is indicated that common, low frequency and rare CHRNA5 coding variants are independently associated with nicotine dependence risk and likely influence the risk for smoking-related diseases such as lung cancer.
Abstract: The common nonsynonymous variant rs16969968 in the α5 nicotinic receptor subunit gene (CHRNA5) is the strongest genetic risk factor for nicotine dependence in European Americans and contributes to risk in African Americans. To comprehensively examine whether other CHRNA5 coding variation influences nicotine dependence risk, we performed targeted sequencing on 1582 nicotine-dependent cases (Fagerstrom Test for Nicotine Dependence score⩾4) and 1238 non-dependent controls, with independent replication of common and low frequency variants using 12 studies with exome chip data. Nicotine dependence was examined using logistic regression with individual common variants (minor allele frequency (MAF)⩾0.05), aggregate low frequency variants (0.05>MAF⩾0.005) and aggregate rare variants (MAF<0.005). Meta-analysis of primary results was performed with replication studies containing 12 174 heavy and 11 290 light smokers. Next-generation sequencing with 180 × coverage identified 24 nonsynonymous variants and 2 frameshift deletions in CHRNA5, including 9 novel variants in the 2820 subjects. Meta-analysis confirmed the risk effect of the only common variant (rs16969968, European ancestry: odds ratio (OR)=1.3, P=3.5 × 10(-11); African ancestry: OR=1.3, P=0.01) and demonstrated that three low frequency variants contributed an independent risk (aggregate term, European ancestry: OR=1.3, P=0.005; African ancestry: OR=1.4, P=0.0006). The remaining 22 rare coding variants were associated with increased risk of nicotine dependence in the European American primary sample (OR=12.9, P=0.01) and in the same risk direction in African Americans (OR=1.5, P=0.37). Our results indicate that common, low frequency and rare CHRNA5 coding variants are independently associated with nicotine dependence risk. These newly identified variants likely influence the risk for smoking-related diseases such as lung cancer.