Background: Polycystic ovary syndrome (PCOS) is a heterogeneous endocrine disorder that is influenced by both genetic and environmental factors. However, the etiology of PCOS remains unclear. Methods: We conducted a two-sample Mendelian randomization (MR) analysis to assess the causal effects of genetically determined metabolites (GDMs) on the risk of PCOS. We used summary level data of a genome-wide association study (GWAS) on 486 metabolites (n = 7,824) as exposure and a PCOS GWAS consisting of 4,138 cases and 20,129 controls as the outcome. Both datasets were obtained from publicly published databases. For each metabolite, a genetic instrumental variable was generated to assess the relationship between the metabolite and PCOS. For MR analysis, we primarily used the standard inverse variance weighted (IVW) method, while three additional methods-the MR-Egger, weighted median, and MR-PRESSO (pleiotropy residual sum and outlier) methods-were performed as sensitivity analyses. Results: Using genetic variants as predictors, we observed a robust relationship between epiandrosterone sulfate (EPIA-S) and PCOS (P IVW = 0.0186, P MR−Egger = 0.0111; P Weighted−median = 0.0154, and P MR−PRESSO = 0.0290). Similarly, 3-dehydrocarnitine, 4-hydroxyhippurate, hexadecanedioate, and β-hydroxyisovalerate may also have causal effects on PCOS development. Conclusions: We identified metabolites that might have causal effects on PCOS development. Our study emphasizes the role of genetic factors underlying the causal relationships between metabolites and PCOS and provides novel insights through the integration of metabolomics and genomics to better understand the mechanisms involved in human disease pathogenesis.
Human blood cells (HBCs) play essential roles in multiple biological processes but their roles in development of uterine polyps are unknown. Here we implemented a Mendelian randomization (MR) analysis to investigate the effects of 36 HBC traits on endometrial polyps (EPs) and cervical polyps (CPs). The random-effect inverse-variance weighted method was adopted as standard MR analysis and three additional MR methods (MR-Egger, weighted median, and MR-PRESSO) were used for sensitivity analyses. Genetic instruments of HBC traits was extracted from a large genome-wide association study of 173,480 individuals, while data for EPs and CPs were obtained from the UK Biobank. All samples were Europeans. Using genetic variants as instrumental variables, our study found that both eosinophil count (OR 0.85, 95% CI 0.79–0.93, P = 1.06 × 10−4) and eosinophil percentage of white cells (OR 0.84, 95% CI 0.77–0.91, P = 2.43 × 10−5) were associated with decreased risk of EPs. The results were robust in sensitivity analyses and no evidences of horizontal pleiotropy were observed. While we found no significant associations between HBC traits and CPs. Our findings suggested eosinophils might play important roles in the pathogenesis of EPs. Besides, out study provided novel insight into detecting uterine polyps biomarkers using genetic epidemiology approaches.
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