Genome-Wide Association Study Meta-Analysis of Stroke in 22 000 Individuals of African Descent Identifies Novel Associations With Stroke.

Abstract

Stroke is a complex disease with multiple genetic and environmental risk factors. Blacks endure a nearly 2-fold greater risk of stroke and are 2× to 3× more likely to die from stroke than European Americans. The COMPASS (Consortium of Minority Population Genome-Wide Association Studies of Stroke) has conducted a genome-wide association meta-analysis of stroke in >22 000 individuals of African ancestry (3734 cases, 18 317 controls) from 13 cohorts. In meta-analyses, we identified one single nucleotide polymorphism (rs55931441) near the <i>HNF1A</i> gene that reached genome-wide significance (<i>P</i>=4.62×10^-8) and an additional 29 variants with suggestive evidence of association (<i>P</i><1×10^-6), representing 24 unique loci. For validation, a look-up analysis for a 100 kb region flanking the COMPASS single nucleotide polymorphism was performed in SiGN (Stroke Genetics Network) Europeans, SiGN Hispanics, and METASTROKE (Europeans). Using a stringent Bonferroni correction <i>P</i> value of 2.08×10^-3 (0.05/24 unique loci), we were able to validate associations at the <i>HNF1A</i> locus in both SiGN (<i>P</i>=8.18×10^-4) and METASTROKE (<i>P</i>=1.72×10^-3) European populations. Overall, 16 of 24 loci showed evidence for validation across multiple populations. Previous studies have reported associations between variants in the <i>HNF1A</i> gene and lipids, C-reactive protein, and risk of coronary artery disease and stroke. Suggestive associations with variants in the <i>SFXN4</i> and <i>TMEM108</i> genes represent potential novel ischemic stroke loci. These findings represent the most thorough investigation of genetic determinants of stroke in individuals of African descent, to date.