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To address this, we integrated molecular and epigenomic annotations from proposed causal cell types and employed a deep learning (DL) framework to predict cell type\u2013specific regulatory effects of PCOS-risk variants. Our analysis revealed that these variants affect key transcription factor\u2013binding sites, including NR4A1\/2, NHLH2, FOXA1, and WT1, which regulate gonadotropin signaling, folliculogenesis, and steroidogenesis across brain and endocrine cell types. The DL model, which showed strong concordance with reporter assay data, identified enhancer-disrupting activity in \u223c20% of risk variants. Notably, many of these variants disrupt transcription factors involved in androgen-mediated signaling, providing molecular insights into hyperandrogenemia in PCOS. Variants prioritized by the model were more pleiotropic and exerted stronger regulatory effects on gene expression compared with other risk variants. Using the IRX3-FTO locus as a case study, we demonstrate how regulatory disruptions in tissues such as the fetal brain, pancreas, adipocytes, and endothelial cells may link obesity-associated mechanisms to PCOS pathogenesis via neuronal development, metabolic dysfunction, and impaired folliculogenesis. Collectively, our findings highlight the utility of integrating DL models with epigenomic data to uncover disease-relevant variants, reveal cross-tissue regulatory effects, and refine mechanistic understanding of PCOS.<\/jats:p>","DOI":"10.1210\/jendso\/bvag083","type":"journal-article","created":{"date-parts":[[2026,4,1]],"date-time":"2026-04-01T11:40:21Z","timestamp":1775043621000},"source":"Crossref","is-referenced-by-count":1,"title":["Regulatory risk loci link disrupted androgen response to the pathophysiology of polycystic ovary syndrome"],"prefix":"10.1210","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1657-4004","authenticated-orcid":false,"given":"Jaya","family":"Srivastava","sequence":"first","affiliation":[{"name":"Division of Intramural Research, National Library of Medicine, National Institutes of Health , Bethesda, MD 20892 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