OR26-06 Molecular underpinnings of Polycystic Ovary Syndrome inferred from regulatory disease loci

Abstract Disclosure: J. Srivastava: None. I. Ovcharenko: None. A longstanding challenge in understanding the complex genetic architecture of PCOS is the lack of insight into the molecular mechanisms orchestrated by variants in the risk loci, most of which are non-coding. In this study, we functionally evaluated the regulatory features of PCOS risk loci by integrating epigenomic data, functional assays, and a deep learning (DL)-based approach to identify causal variants that disrupt enhancer activity and investigate molecular mechanisms by which they mediate PCOS pathophysiology. We propose that disruption in biosynthesis of reproductive hormones in pathogenic cell types, such as the pituitary, adrenal glands, and granulosa cells (GCs), dysregulates downstream pathways in affected cell types—cells that are responsive to these hormones through expression of their receptors such as AR, ESR1, etc. Based on phenotypic associations of risk loci in GWAS studies, we categorized variants into metabolic and reproductive subtypes. We identified key transcription factor binding sites (TFBSs) enriched in risk loci of metabolic subtype, including that of RXRB, IRX3, and ONECUT1, associated with adipocyte/pancreatic development and differentiation. Conversely, in the reproductive subtype, we identified ESR1, NR5A1, and other TFs that play crucial roles in folliculogenesis and steroidogenesis. Together with the observation that reproductive traits (e.g., sex hormone levels, menopause) are enriched in the reproductive subtype, while obesity, BMI, cholesterol, etc., are enriched in the metabolic subtype, we propose that pathogenic cell types drive the reproductive subtype of PCOS, whereas affected cell types mediate metabolic manifestations. Moreover, given AR's broad expression across multiple cell types, including liver, adipose, and muscle, we used it as an example to illustrate how TFs enriched in the two subtypes may form distinct interaction networks with AR, potentially leading to the simultaneous manifestation of reproductive and metabolic phenotypes. Further, by prioritizing causal variants in the regulatory locus of IRX3 located in the intron of FTO using DL scores and their overlap with TFs enriched in risk loci, we discuss plausible cell type specific responses in fetal brain, pancreas, adipocytes and GCs. These findings suggest that disruptions in IRX3 regulation may contribute to PCOS through diverse cellular mechanisms, including neuronal development, metabolic regulation, and folliculogenesis. In conclusion, our findings highlight the pleiotropic impact of PCOS risk loci. These insights will stimulate further studies investigating cross-cell type regulatory interactions and help dissect the role of unexplored risk genes in PCOS pathophysiology. Presentation: Monday, July 14, 2025