Abstract
BACKGROUND: Evidence concerning the causal effects of blood metabolites on polycystic ovary syndrome (PCOS) risk remains scarce. A two-sample Mendelian randomization (MR) analysis was performed among individuals of European ancestry to establish a causal relationship between plasma metabolites and the risk of PCOS. OBJECTIVE: To determine causal associations between 1400 blood metabolites and PCOS. METHODS: Utilizing data from a GWAS, which encompasses over 1400 blood metabolites, bidirectional MR was employed to explore the potential causal associations between PCOS and these metabolites. Causal inference methods included inverse variance weighting, MR-Egger regression, weighted median, weighted mode, and simple mode approaches. Sensitivity analyses were performed to validate the robustness of the results. Reverse MR analyzed 1400 blood metabolites as outcomes and PCOS as the exposure. RESULTS: Fifteen plasma metabolites, including methionine sulfoxide, N-acetylserine, and glycine, exhibited positive causal effects on PCOS risk. In contrast, 13 metabolites, including threonate, 7-methylguanine, and theophylline, demonstrated protective effects. Leave-one-out analysis confirmed the stability of the results, with no influential instrumental variables, and eliminated the impacts of heterogeneity and horizontal pleiotropy. Reverse MR revealed no evidence of causal associations between PCOS and the metabolites. CONCLUSION: Thirteen plasma metabolites were identified as protective factors for PCOS. Targeted modulation of these metabolites may improve metabolic dysfunction in patients, alleviating symptoms and enhancing quality of life. Further exploration of metabolite dynamics could advance mechanistic insights into PCOS pathogenesis and inform therapeutic development.