Associations between Type 2 Diabetes Partitioned/Process-Specific Polygenic Scores and Metabolic Traits

Polygenic scores (PS) for type 2 diabetes (T2D) associate strongly with disease status. Since T2D is heterogenous, using “partitioned” PS (pPS) that capture distinct etiological processes may improve clinical utility. A previous study in Europeans identified 6 pPS from genetic clusters (GCs) based on association patterns across traits, among 3T2D-associated variants: adiposity (GC1) , lipids (GC2) , insulin action (GC3) , beta cell function (GC4, GC5) , and mixed features (GC6) . Few data exist on how pPS associate with T2D and subphenotypes in non-European populations. The current analysis reconstructed these pPS using genotypes for 245 of the 3variants captured in a genome-wide association study in an Indigenous study population from the Southwest US. pPS associations were analyzed with T2D (N=7659) , % body fat (PFAT, non-diabetic only, n=557) , insulin action from hyperinsulinemic-euglycemic “clamp” (logM, non-diabetic only, n=557) , and acute insulin response from an IVGTT (lgAIR, normal glucose tolerance only, n=404) . Results (table) show that T2D pPS strongly associate with the subphenotype corresponding to the putative etiologic mechanism. These results demonstrate transferability of the phenotypic classifications of the T2D pPS and suggest that genetic influences on adiposity, insulin action, and insulin secretion contribute to development of T2D in this population. Disclosure L.E.Wedekind: None. W.Hsueh: None. S.Kobes: None. L.Baier: None. C.Bogardus: None. W.C.Knowler: None. A.Mahajan: Employee; Genentech, Inc. M.Mccarthy: Employee; Genentech, Inc. R.L.Hanson: None.