sc-eQTL unveil Immunogenetic Architecture of Polycystic Ovary Syndrome

Abstract Polycystic ovary syndrome (PCOS) is a complex endocrine disorder characterized by metabolic, inflammatory, and reproductive dysfunction. We integrated genome-wide association study (GWAS) data, and single-cell expression quantitative trait loci (sc-eQTL) across various immune cells to elucidate the genetic and immune mechanisms underlying PCOS at the cellular level. Finally, we identified 20 19 risk loci for PCOS, prioritizing 16 candidate causal genes, approximately 30% of these genes are immune-related. Pathway analysis revealed 15 PCOS-associated signaling pathways, spanning hormonal regulation and immune function, notably T cell-mediated responses. Single-cell RNA sequencing analysis implicated NK cells, CD8 T cells, and CD4 T cells play a crucial role in PCOS pathogenesis, with the highest trait-relevant scores. sc-eQTL colocalization analysis identified IRF1 and MAPRE1 as causal genes with regulatory effects in specific T cell subsets and NK cells, which were obscured by bulk eQTL analysis. Moreover, MAPRE1 showing a discordant effect in NK cells, suggesting immune dysregulation. Our findings underscore the pivotal roles of metabolic and immune-related genes in PCOS and the importance of immune cell-specific mechanisms, enhancing our understanding of its pathophysiology and potential therapeutic targets.