A sex-specific genome-wide association study of blood lipid levels in All of Us

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 ({beta}female: -0.022, {beta}male: -0.045); GPAM in females for HDL-C ({beta}female: 0.042, {beta}male: 0.013); PLTP in females for HDL-C ({beta}female: 0.06, {beta}male: 0.02); ZPR1 in females for LDL-C ({beta}female: 0.050, {beta}male: 0.014); and CMIP in females for TG ({beta}female: 0.037, {beta}male: 0.019). These findings highlight sex-specific genetic contributions to lipid metabolism and underscore the importance of including sex in evaluating cardiovascular risk.