{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,21]],"date-time":"2025-11-21T05:18:02Z","timestamp":1763702282918,"version":"3.45.0"},"reference-count":29,"publisher":"MDPI AG","issue":"22","license":[{"start":{"date-parts":[[2025,11,19]],"date-time":"2025-11-19T00:00:00Z","timestamp":1763510400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["R01HD083323","R01HD033852"],"award-info":[{"award-number":["R01HD083323","R01HD033852"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"name":"a Penn State College of Medicine Bridge Grant"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Polycystic ovary syndrome (PCOS) is a complex endocrine disorder affecting reproductive-aged women. Previous studies have identified genomic associations at chromosome 12q13.2, but the functional mechanisms underlying these associations remain unclear. We integrated three complementary datasets: (1) WES-identified single nucleotide variants (SNVs) from PCOS and normal theca cells with association testing for forskolin-stimulated androgen production, (2) STARR-seq enhancer activity data with eQTL colocalization analysis, and (3) scRNA-seq expression data comparing forskolin-stimulated PCOS and normal theca cells. We previously identified haplotypes involving 10 SNVs at 12q13.2 containing RPS26\/RAB5B\/SUOX that are significantly associated with forskolin-stimulated androgen production. The identified haplotypes were further shown to associate with PCOS in a whole genome sequencing (WGS) cohort. Other studies have recently found the enhancer variant rs1081975 demonstrated perfect colocalization (PP = 1.0) with RPS26\/RAB5B\/SUOX eQTLs. Our scRNA-seq analysis revealed differential expression patterns for key genes. RAB5B showed a forskolin response upregulation in normal cells but an impaired response in PCOS. SUOX exhibited opposite forskolin responses between normal and PCOS cells. PA2G4, an androgen corepressor in the locus, was upregulated in normal untreated cells. ERBB3, an epidermal growth factor receptor in the locus, was downregulated in normal forskolin treated cells. The integration of multimodal genomic data provides functional validation of PCOS-associated variants at 12q13.2, revealing coordinated dysregulation of vesicular trafficking (RAB5B), androgen receptor regulation (PA2G4), and metabolic processes (SUOX) in PCOS theca cells.<\/jats:p>","DOI":"10.3390\/ijms262211184","type":"journal-article","created":{"date-parts":[[2025,11,19]],"date-time":"2025-11-19T15:03:15Z","timestamp":1763564595000},"page":"11184","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Multimodal Integration of Genomic Data Reveals Regulatory Mechanisms at the Polycystic Ovary Syndrome (PCOS)-Associated 12q13.2 Locus"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7333-4752","authenticated-orcid":false,"given":"R. Alan","family":"Harris","sequence":"first","affiliation":[{"name":"Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA"},{"name":"Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6910-2801","authenticated-orcid":false,"given":"Jan M.","family":"McAllister","sequence":"additional","affiliation":[{"name":"Departments of Pathology and Ob\/Gyn, Penn State Hershey College of Medicine, Hershey, PA 17033, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6199-0480","authenticated-orcid":false,"suffix":"III","given":"Jerome F.","family":"Strauss","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,11,19]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"927","DOI":"10.1210\/endrev\/bnac001","article-title":"Deconstructing a Syndrome: Genomic Insights into PCOS Causal Mechanisms and Classification","volume":"43","author":"Dapas","year":"2022","journal-title":"Endocr. 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