Abstract
Background: Genome-wide association studies (GWAS) have improved our understanding of the genetic basis of coronary artery disease (CAD). While sex-differences in CAD have been observed, little is known about the role of sex hormones in CAD genetics. Accounting for sex hormone levels may help identify CAD-risk loci and extend our knowledge of its genetic architecture. Methods: We performed a GWAS to identify CAD risk loci by incorporating gene-sex hormone interactions in 365,662 individuals of European ancestry enrolled in the UK Biobank (UKB). Genetic interactions of total testosterone (TT), bioavailable testosterone (BAT) and sex-hormone binding globulin (SHBG) were evaluated. GEM software was used to conduct sex-stratified genome-wide interaction analysis with prevalent CAD. Enrollment age and principal components 1-10 were model covariates. The online post-GWAS tool FUMA was used to annotate the biological functions of marginal, interaction, and joint effects summary statistics. Results: We identified 64 loci in males and 8 loci in females that reached genome-wide significance (p < 5х10 -8 ) for CAD ( Table 1 ). Among males, 3 significant loci were identified for BAT, one for TT and one for SHBG using joint effect model that did not overlap with those identified with marginal effect. Among females, 5 significant loci were identified, all for TT using joint effect that that did not overlap with those identified with marginal effect. Of these 5 loci, two loci were independently identified with significant SNP-TT interaction. These loci were mapped close to the TRDN and THADA genes that have been implicated in congenital ventricular tachycardia and polycystic ovarian syndrome, respectively. Conclusion: This Genome-wide gene-sex hormone interaction study identified genomic-risk loci that may contribute to the differential CAD risk between men and women, which would otherwise not have been discovered in traditional GWAS only including marginal genetic effect.
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