Abstract
Despite widely acknowledged sex differences in lipid metabolism and risks for cardiovascular disease, genetic associations contributing to such differences remain incompletely characterized. Here, we performed a sex-stratified genome-wide association study (GWAS) for four lipid profiles to identify loci exhibiting differential effects between males and females. Using whole-genome sequencing data from All of Us Research Program comprising 124,920 participants of diverse ancestry, we conducted GWAS analyses separately in males, females, and a pooled cohort. Our analyses validated previous findings on genes associated with lipid metabolism. In addition, we have found 5 genes showing significant sex-heterogeneous effects, including CELSR2 showing stronger association in males for HDL-C (β (female) : -0.022, β (male) : -0.045); GPAM in females for HDL-C (β (female) : 0.042, β (male) : 0.013); PLTP in females for LDL-C (β (female) : 0.06, β (male) : 0.02); ZPR1 in females for LDL-C (β (female) : 0.050, β (male) : 0.014); and CMIP in females for TG (β (female) : 0.037, β (male) : 0.019). These findings highlight sex-specific genetic contributions to lipid metabolism and underscore the importance of including sex in evaluating cardiovascular risk.