1267-P: Fine-Mapping Type 1 Diabetes Risk at the MHC Locus

The Major Histocompatibility Complex (MHC) locus regulates the adaptive immune response and self-recognition and is the largest contributor to genetic risk of type 1 diabetes (T1D) . Protein-coding alleles in MHC class II and class I genes have long been known to contribute substantial T1D risk, yet whether additional variants affect T1D risk at this locus particularly in the non-coding genome has not been exhaustively evaluated. We therefore performed high-resolution fine-mapping of the MHC locus to identify additional coding and non-coding variants that contribute to T1D risk. We imputed genotypes for 39,270 samples from six European or American cohorts of T1D cases and controls into the T1DGC reference panel using SNP2HLA. We then performed two analyses to fine-map causal variants, first, stepwise conditional analysis using Firth bias-corrected logistic likelihood ratio test and second, iterative Bayesian stepwise selection analysis using the Sum of Single Effects (SuSiE) method. We identified 33 signals in stepwise conditional analysis with p<1×10-6 and 30 signals in SuSiE, where the results were highly concordant between methods. Both methods identified the known high-risk amino acid residue 57 of HLA-DQB1 as the top signal, as well as most known and several novel protein-coding risk and protective alleles in MHC class I and II genes. In addition, we identified multiple signals where the likely causal variant was non-coding and not linked to a protein-coding variant, including those that mapped to the LST1, HLA-DRA and NOTCH4 genes. We further annotated these non-coding signals using accessible chromatin, and several likely causal variants mapped in immune cell and/or pancreatic islet accessible chromatin. In ongoing analyses, we are replicating these signals in independent cohorts and performing molecular validation studies of their regulatory effects in relevant cell types. In total, high-resolution fine-mapping of the MHC locus identified additional T1D risk including in the non-coding genome. Disclosure C.Mcgrail: None. J.Chiou: Employee; Pfizer Inc. P.Benaglio: None. K.J.Gaulton: Consultant; Genentech, Inc., Stock/Shareholder; Neurocrine Biosciences, Inc., Vertex Pharmaceuticals Incorporated. Funding National Institutes of Health (DK120429) National Institutes of Health (DK122607)