Genome-Wide Association Study Meta-Analysis of Stroke in 22 000 Individuals of African Descent Identifies Novel Associations With Stroke
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abstract
Background and Purpose: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.Methods: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.Results:
In meta-analyses, we identified one single nucleotide polymorphism (rs55931441) near the
HNF1A
gene that reached genome-wide significance (
P
=4.62×10
−8
) and an additional 29 variants with suggestive evidence of association (
P
<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
P
value of 2.08×10
−3
(0.05/24 unique loci), we were able to validate associations at the
HNF1A
locus in both SiGN (
P
=8.18×10
−4
) and METASTROKE (
P
=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
HNF1A
gene and lipids, C-reactive protein, and risk of coronary artery disease and stroke. Suggestive associations with variants in the
SFXN4
and
TMEM108
genes represent potential novel ischemic stroke loci.
Conclusions:These findings represent the most thorough investigation of genetic determinants of stroke in individuals of African descent, to date.
