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

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 (1,365 ischemic and 1,592 total stroke cases) from COMPASS, and tested SNPs 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 pre-splicing (PTPRG, CDC5L), platelet function (HPS4), blood-brain barrier permeability (CLDN17), immune response (ELTD1, WDFY4, 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 SNP 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.

Ethnic Minorities and Coronary Heart Disease: an Update and Future Directions

“…With the identification of different pathways between races, it is important to consider generalizability while developing new anti-platelet drugs [73]. As technology improves, it becomes easier to perform larger studies in genomics using genome-wide association studies (GWAS) [74]. A recent GWAS by Qayyum identified novel loci which were associated with agonist-mediation platelet aggregation in African-Americans but not European Americans [75].…”

Genetic Risk Factors for Ischemic and Hemorrhagic Stroke

“…However, analysis of shared genetic variation across stroke subtypes has also shown high genetic correlation between some stroke subtypes, such as the large-artery atherosclerosis and small artery disease subtypes of ischemic stroke [24]. Moreover, with increasing sample size through large collaborative efforts, more recently multiple studies have also reported loci associated with all ischemic stroke and all stroke [33•, 34, 39•, 40•, 41•, 42•]. Genetic risk variants associated with all stroke are expected to be either acting at the upstream end of the pathophysiological cascade, by modulating the risk of medical conditions increasing the risk of all types of stroke (such as hypertension) or at the downstream end by modulating the brain’s susceptibility to ischemic injury (e.g., via increased risk of thrombosis) or the brain’s tolerance to brain injury at large (e.g., through affecting neuroprotective pathways, Fig.…”

Advancing stroke genomic research in the age of Trans-Omics big data science: Emerging priorities and opportunities

“…20, 22 Furthermore, the novel locus 15q21.3 [AQP9-LIPC gene region] was associated with both ischemic and hemorrhagic stroke in African Americans. 24 …”

“…It is essential that positive associations are replicated in independent (but similar) populations, 24 and appropriate methodology is used in such studies. 74 Top priorities identified for global stroke genomic research include greater sample size and research within subtypes of stroke to aid discoveries, translation of existing findings, and utilization of novel techniques.…”

“…29, 47, 84, 85 Secondly, variants discovered in continental Africans can be validated among African Americans within the Consortium of Minority Population Genome-Wide Association Studies of Stroke (COMPASS) 24 , International Stroke Genetics Consortium (ISGC) and other consortia.…”