SUN-164 Expanding the Genetic Landscape of PCOS: Novel and Shared Risk Loci in African Ancestry Populations

Abstract Disclosure: S. Patel*: None. K. Brewer*: None. R.K. Sisk: None. A.E. Dunaif: None. Polycystic ovary syndrome (PCOS) is a common endocrine disorder affecting 5-15% of women globally. Genomic studies have implicated neuroendocrine, reproductive, and metabolic pathways in its pathogenesis, yet research has largely focused on European (EUR) and East Asian (EAS) populations. Despite known phenotypic differences, no genome-wide association studies (GWAS) have been published in African ancestry (AFR) individuals. Expanding genetic studies to diverse populations is essential for refining risk models and identifying shared and ancestry-specific genetic factors. We conducted a GWAS and meta-analysis in three AFR ancestry cohorts: cohort 1 (388 cases, 120 controls) included fully phenotyped individuals; cases in cohorts 2 (289 cases, BioMe) and 3 (431 cases, All of Us) were identified via ICD-9/10 codes. Controls were unrelated females without PCOS or hyperandrogenic ICD codes matched for ancestry: 1157 from BioMe, 1747 from All of Us, and 1373 additional BioMe controls in cohort 1. Meta-analysis (1108 cases, 4396 controls) was restricted to variants shared across cohorts, adjusting for five principal components. We identified a novel genome-wide significant locus, rs12190604 (P=4.30E-08), near SYNCRIP, a gene upregulated during the follicular phase. Two additional loci showed suggestive associations: rs62484646 (P=8.50E-08) near CSMD1, linked to age at menarche and BMI, and rs59276959 (P=9.70E-07) near BRINP1, associated with male pattern baldness. Nine of 36 (25%) previously reported EUR/EAS PCOS loci were associated with AFR PCOS, exceeding chance expectations. Notably, DENND1A (rs3945628, P=1.81E-04) remained significant after multiple testing correction (0.05/36=0.0014), replicating this gene regulating androgen biosynthesis in AFR ancestry. Other associated loci included ZBTB16 (rs1784692, P=0.002), MYO10 (rs9312937, P=0.009), TOX3 (rs11075468, P=0.013), INHBB (rs6712151, P=0.019), C9orf3 (rs2183958, P=0.023), GATA4/NEIL2 (rs804263, P=0.034), and YAP1 (EUR: rs7925543, P=0.035; EAS: rs1894116, P=0.047). Our study, the first GWAS of PCOS exclusively in individuals of AFR ancestry, identifies novel genetic loci and demonstrates both shared and ancestry-specific risk variants. The replication of the DENND1A locus in AFR PCOS, previously the strongest signal in the largest EUR PCOS GWAS meta-analysis, underscores its central role in disease susceptibility across ancestries. These findings not only expand our understanding of PCOS genetic architecture but also emphasize the importance of including diverse populations in genetic research. By addressing gaps in representation, this work lays the foundation for more accurate risk prediction and the development of targeted precision medicine approaches for underrepresented populations, ultimately contributing to reducing health disparities in PCOS diagnosis and management. Presentation: Sunday, July 13, 2025