The Sex‐Stratified Effects of RSPO3 Expression on Body Fat and Blood Lipids: An Omics Mendelian Randomization Study

OBJECTIVE: This study examined sex-stratified effects of R-spondin 3 (RSPO3) expression levels on body fat and blood lipids and their potential mediation effects through sex hormones. METHODS: We performed a sex-stratified genome-wide association study (GWAS) of RSPO3 protein (N = 18,529 men and 21,323 women). We used two-sample Mendelian randomization (MR) to examine associations of RSPO3 expression with the outcomes. Sex-stratified MR estimates were compared using the pairwise z score test and Cochran's Q test. We conducted two-step MR analyses to explore mediation effects through sex hormones. RESULTS: Sex-stratified GWAS identified nine loci associated with RSPO3 protein levels, including three novel signals and four female-stratified loci. In women, RSPO3 protein levels were associated with visceral adipose tissue (β = 0.22, 95% CI = 0.10 to 0.34), waist circumference (0.10, 0.05 to 0.15), hip circumference (0.10, 0.05 to 0.15), triglycerides (0.22, 0.18 to 0.26), high-density lipoprotein cholesterol (-0.17, -0.21 to -0.13), and apolipoprotein A (-0.11, -0.15 to -0.06). We also observed sex differences in these associations. Two-step MR showed that RSPO3 protein levels affected six outcomes via sex hormone-binding globulin in women, with little evidence in men. CONCLUSIONS: Our findings indicated that RSPO3 could be a drug target for regulating body fat distribution and blood lipids in women.