THU640 Clustering Of Genetic Loci Identifies 4 Distinct Polycystic Ovarian Syndrome Physiologic Pathways

Disclosure: M. Stamou: None. K.T. Smith: None. H. Kim: None. R. Balasubramanian: None. K. Gray: None. M. Udler: Other; Self; Dr. Udler receives royalties from UpToDate, Inc and is part of an unpaid research collaboration with AstraZeneca, Inc. Introduction: Genome-wide association studies (GWAS) have implicated severe genetic loci with polycystic ovarian syndrome (PCOS), with disease pathogenesis remaining largely unknown. Methods: To group PCOS GWAS loci into genetic clusters driven by disease physiology we performed a cluster analysis for 60 PCOS-associated genetic variants and 49 traits using GWAS summary statistics. Cluster-specific PCOS partitioned polygenic scores (pPS) were generated and tested for association with clinical phenotypes in the Mass General Brigham Biobank (MGBB, N=62,252). Associations with clinical outcomes (type 2 diabetes/T2D, coronary artery disease/CAD and female reproductive traits) were assessed using both GWAS-based pPS (DIAMANTE, N=898,130, CARDIOGRAM/UKBB, N=547,261) and individual-level pPS in MGBB.Results: Four PCOS genetic clusters were identified with top loci indicated as following: (i) Cluster 1, obesity (FTO); (ii) Cluster 2, hormonal changes (FSHB); (iii) Cluster 3, inflammatory markers (ATXN2/SH2B3); (iv) Cluster 4, insulin resistance/liver enzymes (MAF, SLC38A11). Cluster pPS’s were associated with distinct clinical traits in MGBB females: Cluster 1 with increased body mass index (BMI; p=6.63x10(-29)); Cluster 2 with increased age of menarche (p= p=1.5x10(-4)); Cluster 3 with decreased mean platelet volume (MPV; p= p=3.07 x10(-6)); and Cluster 4 with increased ALP & ALT (p=0.007 & 0.02). Cluster 1 pPS was associated with increased T2D (OR 1.067; p=7.31x10(-50)) in GWAS, with replication in MGBB all participants (OR 1.088, p=7.63x10(-7)) and females only (OR 1.107, 9.59x10(-5)).Conclusions: Distinct genetic clusters in PCOS individuals may underlie the clinical heterogeneity of the disease. Presentation: Thursday, June 15, 2023