Gene prioritization across ancestries uncovers distinct molecular pathophysiology and therapeutic landscape in polycystic ovary syndrome.

Polycystic ovary syndrome (PCOS) is a highly prevalent and heterogeneous endocrine disorder affecting women of reproductive age, with substantial reproductive, metabolic, and long-term health consequences. While genome-wide association studies (GWAS) have identified multiple PCOS-associated loci across diverse populations, the functional interpretation of these predominantly non-coding variants and their translation into clinically actionable targets remain unresolved. Here, we present an integrative population-aware framework that systematically combines regulatory functional genomics, long-range chromatin interactions, genome-wide quantitative trait loci, and protein-protein interaction networks to prioritize effector genes underlying PCOS susceptibility. Applying this framework to East Asian and European populations, we demonstrate robust performance relative to existing approaches and uncover both shared and population-specific functions. Notably, our analyses reveal a predominant enrichment of metabolic dysregulation-associated pathways in East Asian PCOS, whereas European PCOS exhibits a stronger inflammatory and immune-related signature. These population-specific molecular phenotypes were further supported by transcriptomic data from PCOS patient samples. Importantly, integration of genetic evidence with a network-based approach enabled the identification of druggable targets lacking direct genetic cues. Collectively, our study provides mechanistic insight into the ethnic heterogeneity of PCOS and establishes a scalable strategy for genetically informed, population-specific therapeutic prioritization, advancing precision medicine approaches for women's health.