SAT-189 - Genetic Determinants of Reproductive and Metabolic Endocrine Dysfunction in Polycystic Ovary Syndrome

Polycystic Ovary Syndrome (PCOS) is a prevalent endocrine and metabolic disorder affecting over 10% of women. PCOS has been stratified into subtypes based on hormonal and metabolic traits, including hyperandrogenism, sex hormone–binding globulin, luteinizing hormone levels, and obesity. Genome-wide association studies (GWAS) have identified numerous PCOS risk variants, yet the relationship between risk variants and subtype-specific endocrine dysfunction remains unclear. We hypothesize that reproductive and metabolic subtypes of PCOS are driven by unique and overlapping genetic architectures in a cell-type-specific manner. The functional mechanisms by which predominantly non-coding PCOS risk variants contribute to endocrine dysfunction remain poorly defined, as most risk variants are predicted to act by altering cell-type-specific gene regulation, often through long-range chromatin interactions. We curated 354 PCOS risk loci from published GWAS, NIH All of Us, and an exploratory GWAS in the UCLA Atlas, and expanded these loci through linkage disequilibrium analysis to 4993 candidate variants. To functionally assess variant regulatory activity, we generated a lentivirally mediated massively parallel reporter assay (MPRA) library with sequences representing risk and non-risk alleles, cloned into a barcoded library that has been successfully constructed and validated. While prior functional studies have largely focused on ovarian models, PCOS involves extensive metabolic dysregulation; therefore, we extend functional analyses to metabolic endocrine tissues. We focus on ovarian granulosa cells, pancreatic β-cells, and adipocytes, key endocrine cell types regulating estrogen synthesis, insulin secretion, and metabolic homeostasis that are disrupted in PCOS. We use induced pluripotent stem cell (iPSC)-derived models across developmental timepoints, complemented by established endocrine cell models, to capture disease-relevant regulatory programs. In parallel, we generated RNA-seq and ATAC-seq datasets in iPSC-derived adipocytes, enabling integrative mapping of PCOS-risk variants to cell-type-specific transcriptional and chromatin accessibility landscapes. Ongoing MPRA screens will systematically prioritize functional variants, and multi-omics analyses will link them to target genes and endocrine pathways, advancing mechanistic understanding of PCOS heterogeneity in reproductive and metabolic endocrine dysfunction.