2390-P: Genetic Clusters Elucidate Heterogeneity in Type 1 Diabetes

Introduction and Objective: Type 1 diabetes (T1D) is characterized by autoimmune destruction of pancreatic beta cells. However, the clinical presentation of T1D is heterogeneous, with variation in age of onset, rate of beta-cell loss, and predisposition to other autoimmune conditions. In this study, we generated T1D genetic clusters and analyzed whether these clusters could identify distinct mechanisms in T1D pathogenesis. Methods: We assembled summary statistics from recent genome-wide association studies for T1D and related traits, including glycemic indices, cardiometabolic phenotypes, and immune cell markers. We applied Bayesian nonnegative matrix factorization (bNMF) to generate soft clusters that link T1D loci with associated traits. We calculated cluster-specific partitioned polygenic scores (pPS) in the Mass General Brigham Biobank, and we used regression models to analyze the association between pPS and various clinical phenotypes. Results: After removing highly correlated loci and traits, we analyzed 205 variants associated with T1D at genome-wide significance (including 79 major histocompatibility complex [MHC] variants) and 91 T1D-related traits. We identified eight clusters, which were distinguished by variation in immune cell markers and clinical phenotypes. For example, one cluster was associated with HLA-DRB1*03:01-DQA1*05:01-DQB1*02:01, was characterized by decreased lymphocyte count, and conferred increased risk of celiac disease (odds ratio [OR] 1.46 per standard deviation of pPS, P = 1.2x10-33). Another cluster was associated with multiple HLA variants, was characterized by increased expression of CD20, and conferred decreased risk of celiac disease (OR 0.75, P = 1.4x10-19). Outside of the MHC, two clusters were associated with altered measures of beta-cell function, such as HOMA-B; one cluster was linked to variation near GLIS3, while the other was linked to INS. Conclusion: Genetic clustering methods provide insight into the heterogeneity of T1D. Further studies should validate the clinical implications of these genetic clusters. Disclosure A.J. Deutsch: None. K. Smith: None. J.C. Florez: Research Support; Current; Novo Nordisk. Consultant; Current; Alveus Therapeutics. M. Udler: Advisory Panel; Ended; Novo Nordisk. Research Support; Current; Novo Nordisk. Funding NIH/NIDDK (K23 DK140643)