Abstract
Stroke is the second leading cause of death and a major cause of severe disability worldwide. Experimental, epidemiological, and clinical studies have consistently documented differences between men and women in stroke incidence, prevalence, outcomes, and risk factors. Although stroke heritability has been reported to differ by sex, the genetic variants that may underlie these sex disparities are unknown. We performed a genome-wide association (GWA) analysis stratified on sex in 12,577 ischemic stroke cases (6811 men, 5766 women) and 25,643 stroke-free controls (12,179 men, 13,464 women ) from the Stroke Genetics Network (SiGN). Testing for heterogeneity of effects between the sexes was conducted using a 1-df Chi-square test. We identified a region on chromosome 19q13.2 harboring common SNPs (minor allele frequency (MAF)=0.11 to 0.25) associated with all ischemic stroke in men (lead SNP P=7.4x10
-8
; odds ratio (OR)=0.81) but not in women (P=0.38; OR=1.03). A common variant (MAF=0.19) on chromosome 10q22.2 showed evidence of heterogeneity by sex (P_het=7.7x10
-8
) with sex-specific associations in opposite direction (OR_men=0.86, P=4.4x10
-6
; OR_women=1.10, P=2.8x10
-3
). Subtype-specific analyses also identified several sex-specific associations. In this sex-stratified GWA analysis, we identified several loci with sex-specific effects on ischemic stroke and its subtypes. The majority of these loci were in intergenic regions of the genome, suggesting that sex-specific effects on stroke may occur via mechanisms acting on gene regulation. Replications and extension of these findings is planned.