Understanding pancreatic mechanisms of diabetes risk with genetic association and single cell epigenome data

Although genome-wide association studies (GWAS) have demonstrated the importance of the pancreas in diabetes risk, mechanistic insight remains challenging in part due to the non-coding nature of risk variants and the lack of cell type-resolved regulatory annotations. Beta cells within pancreatic islets are central to both forms of diabetes and are destroyed by autoimmune mechanisms in T1D or dysfunctional due to insulin resistance in T2D. However, the relevance of beta cell states or other pancreatic cell types to diabetes is relatively unknown. Here I present two studies, both of which use single cell chromatin accessibility to annotate cell type-specific genetic risk mechanisms of diabetes. In the first study, I use snATAC-seq of pancreatic islets to show that endocrine cell types are heterogenous at the gene regulation level, and beta cell states are differently enriched for T2D risk. I highlight a causal T2D variant (rs231361) at the KCNQ1 locus that was predicted to have state-specific effects on regulatory function, was located in a beta cell enhancer co-accessible with INS, and affected expression levels of INS in embryonic stem cell-derived beta cells. In the second study, I generate the largest-to-date GWAS of T1D in 520k samples to enable comprehensive fine mapping of T1D risk signals. I show that pancreatic exocrine cells are causal contributors of T1D through integration of fine mapping with a snATAC-seq reference map of pancreatic and immune cell types. I highlight a likely-causal T1D risk variant (rs7795896) at the CFTR locus that mapped within a ductal-specific enhancer co-accessible with the CFTR promoter, had allele-specific effects on enhancer activity and transcription factor binding in ductal cell models, and was associated with decreased CFTR expression in ductal cells. These two studies highlight the power of integrating comprehensive GWAS fine mapping with single cell epigenomics to understand how pancreatic cell types contribute to diabetes risk