The Sex‐Stratified Effects of <scp>RSPO3</scp> Expression on Body Fat and Blood Lipids: An Omics Mendelian Randomization Study
Obesity, 2026
Guo Y., Chen Z., Huang L., Zhang Z., Gong Y., Yang Q., Wang J., Zheng J.
| Disease area | Application area | Sample type | Products |
|---|---|---|---|
Metabolic Diseases | Pathophysiology | Plasma |  Olink Explore 3072/384 |
Abstract
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.