Meta-Analysis of Genome-Wide Association Studies Identifies Genetic Risk Factors for Stroke in African Americans

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 Jr; Braxton D Mitchell; Bruce M Psaty; Charles Kooperberg; Alexander Reiner; Bradford B Worrall; Myriam Fornage; COMPASS and METASTROKE Consortia

doi:10.1161/STROKEAHA.115.009044

Meta-Analysis of Genome-Wide Association Studies Identifies Genetic Risk Factors for Stroke in African Americans

Stroke. 2015 Aug;46(8):2063-8. doi: 10.1161/STROKEAHA.115.009044. Epub 2015 Jun 18.

Authors

Cara L Carty¹, Keith L Keene², Yu-Ching Cheng², James F Meschia², Wei-Min Chen², Mike Nalls², Joshua C Bis², Steven J Kittner², Stephen S Rich², Salman Tajuddin², Alan B Zonderman², Michele K Evans², Carl D Langefeld², Rebecca Gottesman², Thomas H Mosley², Eyal Shahar², Daniel Woo², Kristine Yaffe², Yongmei Liu², Michèle M Sale², Martin Dichgans², Rainer Malik², W T Longstreth Jr², Braxton D Mitchell², Bruce M Psaty², Charles Kooperberg², Alexander Reiner², Bradford B Worrall², Myriam Fornage²; COMPASS and METASTROKE Consortia

Affiliations

¹ Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA (C.L.C., C.K., A.R.); Center for Health Disparities, East Carolina University, Greenville, NC (K.L.K.); Baltimore Veterans Administration Medical Center, MD (Y.-C.C., S.J.K.); University of Maryland School of Medicine, Baltimore (Y.-C.C., S.J.K., B.D.M.); Mayo Clinic Florida, Jacksonville, FL (J.F.M.); Public Health Sciences, University of Virginia, Charlottesville (W.-M.C., S.S.R., M.M.S., B.B.W.); National Institute of Aging, NIH, Bethesda, MD (M.N., S.T., A.B.Z., M.K.E.); University of Washington, Seattle (J.C.B., W.T.L., B.M.P., A.R.); Wake Forest University, Winston-Salem, NC (C.D.L., Y.L.); Division of Cerebrovascular Neurology, Johns Hopkins University School of Medicine, Baltimore, MD (R.G.); Department of Neurology, University of Mississippi Medical Center, Jackson (T.H.M.); Mel and Enid Zuckerman College of Public Health, University of Arizona, Tucson (E.S.); Department of Neurology and Rehabilitation Medicine, University of Cincinnati, OH (D.W.); Department of Psychiatry, University of California, San Francisco (K.Y.); Institute for Stroke and Dementia Research, Munich Cluster for Systems Neurology (Synergy), Klinikum der Universität München, Ludwig-Maximilians-Universität; Munich, Germany (M.D., R.M.); Group Health Research Unit, Group Health Cooperative, Seattle, WA (B.M.P.); and Center for Human Genetics, University of Texas, Houston (M.F.). ccarty@cnmc.org.
² Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA (C.L.C., C.K., A.R.); Center for Health Disparities, East Carolina University, Greenville, NC (K.L.K.); Baltimore Veterans Administration Medical Center, MD (Y.-C.C., S.J.K.); University of Maryland School of Medicine, Baltimore (Y.-C.C., S.J.K., B.D.M.); Mayo Clinic Florida, Jacksonville, FL (J.F.M.); Public Health Sciences, University of Virginia, Charlottesville (W.-M.C., S.S.R., M.M.S., B.B.W.); National Institute of Aging, NIH, Bethesda, MD (M.N., S.T., A.B.Z., M.K.E.); University of Washington, Seattle (J.C.B., W.T.L., B.M.P., A.R.); Wake Forest University, Winston-Salem, NC (C.D.L., Y.L.); Division of Cerebrovascular Neurology, Johns Hopkins University School of Medicine, Baltimore, MD (R.G.); Department of Neurology, University of Mississippi Medical Center, Jackson (T.H.M.); Mel and Enid Zuckerman College of Public Health, University of Arizona, Tucson (E.S.); Department of Neurology and Rehabilitation Medicine, University of Cincinnati, OH (D.W.); Department of Psychiatry, University of California, San Francisco (K.Y.); Institute for Stroke and Dementia Research, Munich Cluster for Systems Neurology (Synergy), Klinikum der Universität München, Ludwig-Maximilians-Universität; Munich, Germany (M.D., R.M.); Group Health Research Unit, Group Health Cooperative, Seattle, WA (B.M.P.); and Center for Human Genetics, University of Texas, Houston (M.F.).

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.

Keywords: African Americans; genetic association studies; genome-wide association study; meta-analysis; stroke.

Publication types

Meta-Analysis

MeSH terms

Black or African American / genetics*
Case-Control Studies
Cohort Studies
Genetic Predisposition to Disease / epidemiology
Genetic Predisposition to Disease / genetics*
Genome-Wide Association Study / methods*
Humans
Polymorphism, Single Nucleotide / genetics
Risk Factors
Stroke / diagnosis
Stroke / epidemiology
Stroke / genetics*

Abstract

Publication types

MeSH terms

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