Meta-Analysis of Genome-Wide Association Studies Identifies Genetic Risk Factors for Stroke in African Americans
Year: 2015
Type: review
Abstract: BACKGROUND AND PURPOSE: The majority of genome-wide association studies (GWAS) of stroke have focused on European-ancestry populations; however, none has been conducted in African Americans, despite the disproportionately high burden of stroke in this population. The Consortium of Minority Population Genome-Wide Association Studies of Stroke (COMPASS) was established to identify stroke susceptibility loci in minority populations. METHODS: Using METAL, we conducted meta-analyses of GWAS in 14 746 African Americans (1365 ischemic and 1592 total stroke cases) from COMPASS, and tested genetic variants with P<10(-6) for validation in METASTROKE, a consortium of ischemic stroke genetic studies in European-ancestry populations. We also evaluated stroke loci previously identified in European-ancestry populations. RESULTS: The 15q21.3 locus linked with lipid levels and hypertension was associated with total stroke (rs4471613; P=3.9×10(-8)) in African Americans. Nominal associations (P<10(-6)) for total or ischemic stroke were observed for 18 variants in or near genes implicated in cell cycle/mRNA presplicing (PTPRG, CDC5L), platelet function (HPS4), blood-brain barrier permeability (CLDN17), immune response (ELTD1, WDFY4, and IL1F10-IL1RN), and histone modification (HDAC9). Two of these loci achieved nominal significance in METASTROKE: 5q35.2 (P=0.03), and 1p31.1 (P=0.018). Four of 7 previously reported ischemic stroke loci (PITX2, HDAC9, CDKN2A/CDKN2B, and ZFHX3) were nominally associated (P<0.05) with stroke in COMPASS. CONCLUSIONS: We identified a novel genetic variant associated with total stroke in African Americans and found that ischemic stroke loci identified in European-ancestry populations may also be relevant for African Americans. Our findings support investigation of diverse populations to identify and characterize genetic risk factors, and the importance of shared genetic risk across populations.
Source: Stroke
Authors: Cara L. Carty, Keith L. Keene, Yu-Ching Cheng, James F. Meschia, Wei-Min Chen, Mike Nalls, Joshua C. Bis, Steven J. Kittner, Stephen S. Rich, Salman Tajuddin, Alan B. Zonderman, Michele K. Evans, Carl D. Langefeld, Rebecca Gottesman, Thomas H. Mosley, Eyal Shahar, Daniel Woo, Kristine Yaffe, Yongmei Liu, Michèle M. Sale, Martin Dichgans, Rainer Malik, W.T. Longstreth, Braxton D. Mitchell, Bruce M. Psaty, Charles Kooperberg, Alexander Reiner, Bradford B. Worrall, Myriam Fornage
Language: English
Subfield: Genetics
Domain: Life Sciences
Open Access status: green
Funders: U.S. Department of Veterans Affairs, National Institutes of Health, National Institute on Aging, National Heart, Lung, and Blood Institute, National Human Genome Research Institute, National Cancer Institute, National Institute of Diabetes and Digestive and Kidney Diseases, National Institute of Neurological Disorders and Stroke, National Center for Research Resources, National Center for Advancing Translational Sciences
Awards: G1052397333, FHCRC High-Performance Computing Cluster, G1135917780, G1220223050, G1243299691, CORONARY HEART DISEASE AND STROKE, CORONARY HEART DISEASE &STROKE IN PEOPLE AGED 65-84, G1527150935, CORONARY HEART DISEASE AND STROKE, G1691174148, G173303992, G1941623656, Rare variants and NHLBI traits in deeply phenotyped cohorts, G2194386449, CORONARY HEART DISEASE &STROKE IN PEOPLE AGED 65-84, G232264632, G2391884931, Institute for Clinical and Translational Research (UL1), CORONARY HEART DISEASE &STROKE IN THE ELDERLY, G2818629771, G3045517347, WGA Study to Identify Genetic Variants Associated with CV Events in CHS, Siblings With Ischemic Stroke Study (SWISS), G3114902838, Prospective meta-analyses of drug-gene interactions: CHARGE GWAS consortium, G3220743633, UCLA Clinical and Translational Science Institute, G3410686264, G3462919067, GWA for Gene-Environment Interaction Effects Influencing CHD, CENTRAL BLOOD ANALYSIS LABORATORY FOR CHS, G4157251650, COORDINATING CENTER FOR WOMEN'S HEALTH INITIATIVE, G457330776, Genetics Of Stroke, Genome-Wide Association for Loci Influencing CHD and Other Heart, Lung and Blood, G5479317095, Epidemiology of Venous Thrombosis and Pulmonary Embolism, Pharmacogenomic studies in VISP: results & implications for clinical trial design, G567847597, G573982542, A Genome-Wide Association Study of Ischemic Brain Vascular Injury, G581887176, CHARGE consortium: omics discovery for CVD and aging phenotypes, Genetic Risk to Stroke in Smokers and Nonsmokers in Two Ethnic Groups, CHS Events Follow-up Study, G6226795708, G6548750934, CHS-Transition Phase, Mid-Atlantic Nutrition Obesity Research Center, G7176672723, ISGS: The Ischemic Stroke Genetics Study, Exceptional Survival: Trajectories to Functional Aging (CHS All Stars), An Integrated Genetic and Epigenetic Approach to Cerebral Small Vessel Disease, Vitamin Intervention for Stroke Prevention (VISP), Genetics of Early Onset-Stroke, The NINDS International Stroke Genetics Consortium Study, G9000072420, G9000204923, Cancer Center Support Grant, Diabetes Research Center (DRC), From GWAS loci to blood pressure genes, variants & mechanisms - Renewal
OpenAlex ID: W1922859108