Mendelian randomization Identifies RSPO3 in Serum as a Potential Target for Endometriosis

Abstract

Abstract Objective Endometriosis lacks effective early intervention and treatment. Our objective is to explore potential protein drug targets in serum for endometriosis and different subtypes of endometriosis, using Mendelian randomization and Bayesian colocalization to provide support for clinical intervention. Design Multi-validated two-sample Mendelian randomization study, combined with Bayesian co-localization analysis to determine drug targets. Setting Summary statistics from published GWAS in European ancestry populations. Population or Sample Instrumental variants for serum proteins of finding cohort were obtained from a study on 3301 people, and instrumental variants for endometriosis and different subtypes of endometriosis of finding cohort were obtained from FinnGen cohort. Data of endometriosis of replicated cohort including 191747 people were obtained from UK biobank, and data of serum proteins of replicated cohort were obtained from a study including 35559 people. Methods Using Mendelian randomization, we explored and discovered a significant causal association between certain serum proteins and endometriosis. This finding was validated using data on endometriosis and serum proteins from a validation cohort. Finally, Bayesian colocalization analysis was applied to identify potential drug targets. Additionally, Mendelian randomization analysis was conducted on different subtypes of endometriosis to identify proteins potentially associated with these subtypes. Main outcome measures Data for the endometriosis discovery cohort were obtained from the FinnGen cohort, and data for the endometriosis validation cohort were obtained from the UK Biobank. Results Results from the MR analysis in the finding cohort indicated ten protein–Endometriosis pairs, including Intercellular adhesion molecule 2, R-spondin-3, Intercellular adhesion molecule 4, Endoglin, OX-2 membrane glycoprotein, Leukemia inhibitory factor receptor, Insulin-like growth factor 1 receptor, Hydroxycarboxylic acid receptor 2, Tryptase gamma, Alpha-(1,3)-fucosyltransferase 9 in the plasma. After validation analysis and Bayesian co-localization analysis, RSPO3 was identified as a potential drug target for endometriosis. Conclusions We conducted Mendelian Randomization analysis on GWAS data from a large population, confirming a causal relationship between serum levels of RSPO3 and endometriosis. This suggests that RSPO3 may influence the onset and progression of endometriosis, providing a protective effect. This finding supports its potential as a preventive and therapeutic approach for endometriosis. Funding The study was supported by funding from the projects of Chengdu Science and Technology Bureau, (Y.Z., Grant No. 2021-YF05-02110-SN), China Postdoctoral Science Foundation (Y.Z., Grant No. 2020M680149, 2020T130087ZX).