Genetic association and machine learning improves discovery and prediction of type 1 diabetes

Type 1 diabetes (T1D) has a large genetic component, and expanded genetic studies of T1D can lead to novel biological and therapeutic discovery and improved risk prediction. In this study, we performed genetic association and fine-mapping analyses in 817,718 European ancestry samples genome-wide and 29,746 samples at the MHC locus, which identified 165 independent risk signals for T1D of which 19 were novel. We used risk variants to train a machine learning model (named T1GRS) to predict T1D, which highly differentiated T1D from non-disease and type 2 diabetes (T2D) in Europeans as well as African Americans at or beyond the level of current standards. We identified extensive non-linear interactions between risk loci in T1GRS, for example between HLA-DQB1*57 and INS, coding and non-coding HLA alleles, and DEXI, INS and other beta cell loci, that provided mechanistic insight and improved risk prediction. T1D individuals formed distinct clusters based on genetic features from T1GRS which had significant differences in age of onset, HbA1c, and renal disease severity. Finally, we provided T1GRS in formats to enhance accessibility of risk prediction to any user and computing environment. Overall, the improved genetic discovery and prediction of T1D will have wide clinical, therapeutic, and research applications.