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

被引：70

作者：

Carty, Cara L. ^{[1
]}

Keene, Keith L. ^{[2
]}

Cheng, Yu-Ching ^{[3
,4
]}

Meschia, James F. ^{[5
]}

Chen, Wei-Min ^{[6
]}

Nalls, Mike ^{[7
]}

Bis, Joshua C. ^{[8
]}

Kittner, Steven J. ^{[3
,4
]}

Rich, Stephen S. ^{[6
]}

Tajuddin, Salman ^{[7
]}

Zonderman, Alan B. ^{[7
]}

Evans, Michele K. ^{[7
]}

Langefeld, Carl D. ^{[9
]}

Gottesman, Rebecca ^{[10
]}

Mosley, Thomas H. ^{[11
]}

Shahar, Eyal ^{[12
]}

Woo, Daniel ^{[13
]}

Yaffe, Kristine ^{[14
]}

Liu, Yongmei ^{[9
]}

Sale, Michele M. ^{[6
]}

Dichgans, Martin ^{[15
]}

Malik, Rainer ^{[15
]}

Longstreth, W. T., Jr. ^{[8
]}

Mitchell, Braxton D. ^{[4
]}

Psaty, Bruce M. ^{[8
,16
]}

Kooperberg, Charles ^{[1
]}

Reiner, Alexander ^{[1
,8
]}

Worrall, Bradford B. ^{[6
]}

Fornage, Myriam ^{[17
]}

机构：

[1] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, Seattle, WA 98104 USA

[2] E Carolina Univ, Ctr Hlth Dispar, Greenville, NC USA

[3] Baltimore Vet Adm Med Ctr, Baltimore, MD USA

[4] Univ Maryland, Sch Med, Baltimore, MD 21201 USA

[5] Mayo Clin Florida, Jacksonville, FL USA

[6] Univ Virginia, Publ Hlth Sci, Charlottesville, VA USA

[7] NIA, NIH, Bethesda, MD 20892 USA

[8] Univ Washington, Seattle, WA 98195 USA

[9] Wake Forest Univ, Winston Salem, NC 27109 USA

[10] Johns Hopkins Univ, Sch Med, Div Cerebrovasc Neurol, Baltimore, MD USA

[11] Univ Mississippi, Med Ctr, Dept Neurol, Jackson, MS USA

[12] Univ Arizona, Mel & Enid Zuckerman Coll Publ Hlth, Tucson, AZ USA

[13] Univ Cincinnati, Dept Neurol & Rehabil Med, Cincinnati, OH 45221 USA

[14] Univ Calif San Francisco, Dept Psychiat, San Francisco, CA USA

[15] Univ Munich, Inst Stroke & Dementia Res, Munich Cluster Syst Neurol Synergy, Klinikum Univ Munchen, Munich, Germany

[16] Grp Hlth Cooperat Puget Sound, Grp Hlth Res Unit, Seattle, WA USA

[17] Univ Texas Houston, Ctr Human Genet, Houston, TX USA

来源：

STROKE | 2015年 / 46卷 / 08期

基金：

美国国家卫生研究院;

关键词：

African Americans; genetic association studies; genome-wide association study; meta-analysis; stroke; ISCHEMIC-STROKE; ATHEROSCLEROTIC STROKE; HEART-ASSOCIATION; COMMON VARIANTS; SUBTYPES; DISEASE; DESIGN; BLACKS; UPDATE; HEALTH;

D O I：

10.1161/STROKEAHA.115.009044

中图分类号：

R74 [神经病学与精神病学];

学科分类号：

100204 [神经病学];

摘要：

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=3.9x10(-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.

引用

页码：2063 / 2068

页数：6

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