J Clin Endocrinol Metab. 2023 Nov 15:dgad664. doi: 10.1210/clinem/dgad664. Online ahead of print.


CONTEXT: Polycystic ovarian syndrome (PCOS) is a heterogeneous disorder, with disease loci identified from genome-wide association studies (GWAS) having largely unknown relationships to disease pathogenesis.

OBJECTIVE: To group PCOS GWAS loci into genetic clusters associated with disease pathophysiology.

DESIGN/SETTING/PATIENTS OR OTHER PARTICIPANTS: Cluster analysis was performed 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.

INTERVENTIONS/MAIN OUTCOME MEASURES/RESULTS: Four PCOS genetic clusters were identified with top loci indicated as following: (i) Cluster 1/Obesity/insulin resistance (FTO); (ii) Cluster 2/Hormonal/menstrual cycle changes (FSHB); (iii) Cluster 3/Blood markers/inflammation (ATXN2/SH2B3); (iv) Cluster 4/Metabolic changes (MAF, SLC38A11). Cluster pPS were associated with distinct clinical traits: Cluster 1 with increased body mass index (BMI; p=6.6×10-29); Cluster 2 with increased age of menarche (p= p=1.5×10-4); Cluster 3 with multiple decreased blood markers, including mean platelet volume (MPV; p=3.1 x10-5); and Cluster 4 with increased ALP (p=0.007). PCOS genetic clusters GWAS-pPS’s were also associated with disease outcomes: Cluster 1 pPS with increased T2D (OR 1.07; p=7.3×10-50), with replication in MGBB all participants (OR 1.09, p=2.7×10-7) and females only (OR 1.11, 4.8×10-5).

CONCLUSIONS: Distinct genetic backgrounds in individuals with PCOS may underlie clinical heterogeneity and disease outcomes.

PMID:37967238 | DOI:10.1210/clinem/dgad664