Sex-stratified genetic architecture of coronary artery calcification

Abstract Background Coronary artery calcification (CAC) is a direct quantitative marker of atherosclerotic plaque burden and a robust predictor of coronary heart disease. Development of atherosclerosis shows marked sex differences, with men typically exhibiting higher CAC scores and earlier onset compared with women. Purpose To characterize the sex-specific genetic architecture of CAC by performing a sex-stratified genome-wide association study (GWAS) and evaluating potential sex differences in the genetic determinants and causal drivers of CAC. Methods We included eight international cohorts with available genotyping and CAC measurements (10, 612 men and 11, 887 women), of whom 80% were of European ancestry. GWAS was conducted within each cohort using an additive linear model adjusted for age and up to 10 principal components, followed by an inverse-variance-weighted meta-analysis. Gene-strata (G×S) interaction analyses were performed to identify loci with sex-differential effects. Genetic correlations (rg) between CAC and cardiovascular traits, including coronary artery disease (CAD) and lipid measurements, were estimated separately in men and women. Two-sample Mendelian randomization (MR) was applied to evaluate sex-specific causal effects of lipid traits on CAC. Results At the genome-wide significant level (P 5×10−8), two loci (PHACTR1 and RP11-145E5. 5) were associated with CAC in both men and women (Figure 1) with same direction. The G×S interaction analyses identified two loci that demonstrated genome-wide suggestive (P 5×10−6) sex-differential effects: CCSER1 (lead variant rs76883688, Pdiff = 2. 03×10−7) and MICAL3 (lead variant rs45572336, Pdiff = 1. 82×10−7). Genetic correlation analyses showed sex-specific patterns between CAC and CAD (men: rg = 0. 66, SE = 0. 12, P = 6. 11×10−8; women: rg = 1. 14, SE = 0. 59, P = 0. 05), carotid plaque (men: rg = 0. 51, SE = 0. 20, P = 0. 01; women: rg = 0. 33, SE = 0. 26, P = 0. 20), and triglycerides (men: rg = 0. 23, SE = 0. 07, P = 8. 0×10−4; women: rg = 0. 07, SE = 0. 08, P = 0. 39). MR analyses further supported sex-differential causal effects of high-density lipoprotein (HDL) cholesterol (men: Beta = -0. 27, SE = 0. 11, P = 0. 01; women: Beta = -0. 15, SE= 0. 10, P = 0. 13) and triglycerides (men: Beta = 0. 23, SE = 0. 14, P = 0. 10; women: Beta: 0. 36, SE = 0. 10, P = 3. 14×10−4) on CAC. Conclusion In this multi-ancestry, sex-stratified GWAS of CAC, we identified distinct genetic loci associated with CAC in men and women and found two loci (CCSER1 and MICAL3) exhibiting significant sex heterogeneity. Genetic correlation and MR analyses revealed sex-specific genetic and causal relationships between cardiovascular traits and CAC, particularly HDL cholesterol and triglycerides. These findings highlight important biological differences in the genetic determinants of CAC between men and women. Sex-stratified CAC GWASFor image description, please refer to the figure legend and surrounding text.