Polycystic Ovary Syndrome Physiologic Pathways Implicated Through Clustering of Genetic Loci.
J Clin Endocrinol Metab
; 109(4): 968-977, 2024 Mar 15.
Article
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| MEDLINE
| ID: mdl-37967238
ABSTRACT
CONTEXT Polycystic ovary syndrome (PCOS) is a heterogeneous disorder, with disease loci identified from genome-wide association studies (GWAS) having largely unknown relationships to disease pathogenesis. OBJECTIVE:
This work aimed to group PCOS GWAS loci into genetic clusters associated with disease pathophysiology.METHODS:
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.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 (P = 6.6 × 10-29); cluster 2 with increased age of menarche (P = 1.5 × 10-4); cluster 3 with multiple decreased blood markers, including mean platelet volume (P = 3.1 ×10-5); and cluster 4 with increased alkaline phosphatase (P = .007). PCOS genetic clusters GWAS-pPSs were also associated with diseaseoutcomes:
cluster 1 pPS with increased T2D (odds ratio [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).CONCLUSION:
Distinct genetic backgrounds in individuals with PCOS may underlie clinical heterogeneity and disease outcomes.Palabras clave
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Bases de datos:
MEDLINE
Asunto principal:
Síndrome del Ovario Poliquístico
/
Diabetes Mellitus Tipo 2
/
Mitoguazona
Límite:
Female
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Humans
Idioma:
En
Revista:
J Clin Endocrinol Metab
Año:
2024
Tipo del documento:
Article
País de afiliación:
Estados Unidos