Metabolites and Polycystic Ovarian Syndrome: A Mendelian Randomization Study

Introduction: Polycystic ovarian syndrome (PCOS) is a common reproductive disorder that affects a considerable number of women worldwide. Nevertheless, the causal relationship between metabolites and PCOS remains undetermined. Methods: We utilized a comprehensive two-sample Mendelian randomization (MR) analysis, a genetic epidemiological approach that uses genetic variants as instrumental variables to assess causal relationships between exposures and outcomes, to examine the causal link between 1352 metabolites and PCOS. We employed complementary MR methods, such as the inverse-variance weighted (IVW) method, and conducted sensitivity analyses to evaluate the reliability of the outcomes. Reverse MR analysis was performed to evaluate the possibility of reverse causation. Results: Five metabolites were identified to be significantly associated with PCOS risk: Methionine sulfoxide levels (IVW: OR [95%]: 1.549[1.274 to 1.883], p = 1.154E-5), Theophylline levels (IVW: OR [95%]: 0.725[0.589 to 0.890], p = 0.002), 4-hydroxycoumarin levels (IVW: OR [95%]: 0.786[0.658 to 0.940], p = 0.008), Tyramine O-sulfate levels (IVW: OR [95%]: 0.699[0.568 to 0.862], p = 0.0008), and Sulfate of piperine metabolite C16H19NO3 (3) levels (IVW: OR [95%]: 1.296[1.064 to 1.579], p = 0.009). We found PCOS was significantly associated with decreased Tyramine O-sulfate levels using the IVW method (OR [95%]: 0.953[0.917 to 0.991], p = 0.015) in the reverse MR analysis. The results of the sensitivity analyses were consistent with the main findings. Discussion: This study establishes causal relationships between specific metabolites and PCOS, highlighting the significant roles of oxidative stress (methionine sulfoxide), dietary components (theophylline, piperine metabolite), and gut microbiome-derived metabolites. These findings provide novel insights into PCOS pathogenesis and identify potential targets for prevention and treatment. However, the study's limitation to European populations necessitates further validation in diverse ethnic groups. Conclusion: Our MR analysis provides strong evidence supporting a causal association between metabolites and the susceptibility of PCOS.