Causal Genes and Immune-Epigenetic Mechanisms Underlying Polycystic Ovary Syndrome: A Multi-Omics Mendelian Randomization Study

Background Polycystic ovary syndrome (PCOS) is a common endocrine-metabolic disorder, yet its genetic basis remains incompletely understood. This study aimed to identify causal genes and elucidate upstream epigenetic and immune cell–specific regulatory mechanisms using a multi-omics Mendelian randomization (MR) framework. Methods We performed two-sample MR analyses using expression quantitative trait loci (eQTLs) from the eQTLGen consortium and protein QTLs (pQTLs) from the UK Biobank to assess the causal effects of gene expression and protein levels on PCOS risk. Genes significant in both datasets were retained as candidate genes and further evaluated using summary-data-based Mendelian randomization (SMR) with GTEx whole-blood eQTLs to determine colocalized genetic signals. To investigate upstream regulation, we conducted mediation MR analysis using methylation QTLs (mQTLs) from the GoDMC database to identify CpG sites potentially mediating gene expression and PCOS risk. Finally, we performed cell-type–specific MR using single-cell eQTLs (sc-eQTLs) from the OneK1K project across 14 immune cell types. Results MR identified 1,715 eQTL- and 182 pQTL-associated genes, with 60 overlapping candidates. SMR prioritized six causal genes: CRELD1, NSFL1C, ITIH4, IL6R, SNAP29, and PON2. Mediation MR revealed a borderline-significant effect for cg20688791 upstream of IL6R and suggestive mediation at cg00335892 within SNAP29 . sc-eQTL analysis showed that CRELD1 , ITIH4 , PON2 , and SNAP29 had significant causal effects in CD8⁺ T cells, CD4⁺ T cells, monocytes, and NK cells, respectively. Conclusion This integrative analysis identifies multi-omics-supported causal genes for PCOS and reveals epigenetic and immune cell–specific regulatory mechanisms, offering novel insights into pathogenesis and potential therapeutic targets.