Abstract
Background: Early onset ischemic stroke (IS) affects males and females unequally, but the etiologic background of the sex differences remains inadequately understood. We hypothesize that stratifying GWAS by sex provides an opportunity to 1) identify loci that shed light on mechanisms and pathways relevant to sex specific effects in IS and 2) discover novel IS loci.
Methods: We performed a sex-stratified transethnic GWAS meta-analysis in 6,879 female IS cases and 11,264 male cases < 60 years-old and > 700,000 sex-matched controls from the Early Onset Stroke Genetics Consortium. We tested for difference (p-diff) between the men- and women-specific beta-estimates with corresponding standard errors using the t statistics.
Results: We found genome-wide significant evidence for association (p < 5 х 10-8) at a locus near NYAP2 for females (chr2:225661726:C:CT, p = 2.11 х 10-8, OR = 1.38, p-diff = 1.69 х 10-4) and in PIAS4 for males (chr19:4013652:C:CA, p = 6.29 х 10-9, OR = 0.85, p-diff = 0.02) in transethnic analysis. NYAP2 has previously shown suggestive evidence for association with early onset menopause. PIAS4, a candidate gene for migraine, has shown sex-specific expression levels in migraine patients compared to controls. Additional loci with suggestive evidence (p < 1 х 10-6) for association in a sex-dependent manner included MMP1-MMP3-MMP12, a previously known stroke locus, for males (chr11:102822455:A:G, p = 3.99 х 10-7, OR = 1.17, p-diff = 0.02), and a novel stroke locus near TMX1, a transmembrane platelet protein, for females (chr14:51193174:G:C, p = 4.15 х 10-7, OR = 1.76, p-diff = 4.08 х 10-3). The known early onset IS locus ABO did not show evidence for sex-specific association despite suggestive association in the male stratified analysis (chr9:133274295:A:T, p = 3.15 х 10-7, OR = 1.17, p-diff = 0.81).
Conclusions: We identified potential novel stroke loci and evidence for sex differences at other biologically relevant loci by stratifying GWAS by sex. To our knowledge, our cohort represents the largest early onset IS GWAS cohort to date. However, our findings require verification in large sample sizes and also evaluation in older onset IS. Sex-specific association analysis is a potentially useful tool for characterizing the genetic basis of early onset IS.