Interpreting type 1 diabetes risk with genetics and single-cell epigenomics

Genetic risk variants that have been identified in genome-wide association studies of complex diseases are primarily non-coding(1). Translating these risk variants into mechanistic insights requires detailed maps of gene regulation in disease-relevant cell types(2). Here we combined two approaches: a genome-wide association study of type 1 diabetes (T1D) using 520,580 samples, and the identification of candidate cis-regulatory elements (cCREs) in pancreas and peripheral blood mononuclear cells using single-nucleus assay for transposase-accessible chromatin with sequencing (snATAC-seq) of 131,554 nuclei. Risk variants for T1D were enriched in cCREs that were active in T cells and other cell types, including acinar and ductal cells of the exocrine pancreas. Risk variants at multiple T1D signals overlapped with exocrine-specific cCREs that were linked to genes with exocrine-specific expression. At the CFTR locus, the T1D risk variant rs7795896 mapped to a ductal-specific cCRE that regulated CFTR; the risk allele reduced transcription factor binding, enhancer activity and CFTR expression in ductal cells. These findings support a role for the exocrine pancreas in the pathogenesis of T1D and highlight the power of large-scale genome-wide association studies and single-cell epigenomics for understanding the cellular origins of complex disease.

Automated summary

Genome-wide association studies of type 1 diabetes identified risk variants that were enriched in specific cell types, including cells of the exocrine pancreas. The study highlights the role of the exocrine pancreas in the pathogenesis of T1D and underscores the importance of large-scale genetic studies and single-cell epigenomics in understanding complex diseases.