Progesterone is essential for female reproduction, but the causal relationship between its signaling pathway and infertility remains uncharacterized. We applied a multi-omics Mendelian randomization (MR) framework to investigate the causal effect of progesterone receptor (PGR) signaling on female infertility risk. Genetic instruments for circulating PGR protein levels were obtained from a genome-wide association study (GWAS) of 47,745 individuals. Outcome data came from the FinnGen consortium (18,718 infertility cases, 501,254 controls). Genetic predisposition to higher PGR levels was associated with a reduced risk of female infertility (inverse variance weighted OR = 0.87, 95% CI: 0.76–0.99). Bidirectional MR suggested a potential feedback loop, with genetic liability to infertility associated with lower PGR levels. Multi-tissue expression quantitative trait locus (eQTL) mapping identified 213 significant associations affecting 60 genes. Strikingly, 8 of 12 ovary-specific candidate genes (67%) were located in the HLA/MHC locus. Functional enrichment analysis revealed overwhelming dominance of immune pathways. Protein-protein interaction network analysis highlighted HLA-DRB1, HLA-C, and SIRPB1 as central hubs. This integrative genomic study provides novel evidence that progesterone receptor signaling protects against female infertility primarily through immune modulation mechanisms, with HLA genes playing a central role.

Keywords: Progesterone receptor · Female infertility · Mendelian randomization · Immunology · HLA genes · Immune modulation

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