Common variants at 6p21.1 are associated with large artery atherosclerotic stroke

Abstract

Genome-wide association studies (GWAS) have not consistently detected replicable genetic risk factors for ischemic stroke, potentially due to etiological heterogeneity of this trait. We performed GWAS of ischemic stroke and a major ischemic stroke subtype (large artery atherosclerosis, LAA) using 1,162 ischemic stroke cases (including 421 LAA cases) and 1,244 population controls from Australia. Evidence for a genetic influence on ischemic stroke risk was detected, but this influence was higher and more significant for the LAA subtype. We identified a new LAA susceptibility locus on chromosome 6p21.1 (rs556621: odds ratio (OR)=1.62, P=3.9×10(-8)) and replicated this association in 1,715 LAA cases and 52,695 population controls from 10 independent population cohorts (meta-analysis replication OR=1.15, P=3.9×10(-4); discovery and replication combined OR=1.21, P=4.7×10(-8)). This study identifies a genetic risk locus for LAA and shows how analyzing etiological subtypes may better identify genetic risk alleles for ischemic stroke.

Figure 1

Genome-wide association results. (a,b) Data are shown for ischemic stroke (a) and LAA (b). The plots show −log₁₀-transformed P values for genotyped and imputed SNPs with respect to their physical positions. The threshold for association at genome-wide significance (P = 5 × 10⁻⁸) is shown by the upper dashed line, and the lower dashed line corresponds to P = 1 × 10⁻⁵.

Figure 2

Regional association results for the chromosome 6p21.1 locus showing association at genome-wide significance with LAA. The index associated SNP is labeled (rs556621: P = 3.9 × 10⁻⁸).

Figure 3

Forest plot showing association of rs556621 with LAA across the ten replication cohorts. For each cohort, the square and horizontal line show the estimated OR and 95% CI, respectively, representing the effect of each additional copy of the risk (A) allele on the odds of disease. The size of the square is inversely proportional to the standard error of the estimated allelic effect. A fixed-effects, inverse variance–weighted meta-analysis was used to combine association evidence across cohorts. There was no evidence of effect size heterogeneity across the ten cohorts (P = 0.5).