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

Item Type:Article
Title:Interpreting type 1 diabetes risk with genetics and single-cell epigenomics
Creators Name:Chiou, J. and Geusz, R.J. and Okino, M.L. and Han, J.Y. and Miller, M. and Melton, R. and Beebe, E. and Benaglio, P. and Huang, S. and Korgaonkar, K. and Heller, S. and Kleger, A. and Preissl, S. and Gorkin, D.U. and Sander, M. and Gaulton, K.J.
Abstract:Genetic risk variants that have been identified in genome-wide association studies of complex diseases are primarily non-coding. Translating these risk variants into mechanistic insights requires detailed maps of gene regulation in disease-relevant cell types. 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.
Keywords:Chromatin, Cystic Fibrosis Transmembrane Conductance Regulator, Epigenomics, Gene Expression Regulation, Genetic Predisposition to Disease, Genome-Wide Association Study, Immunity, Pancreatic Ducts, Single-Cell Analysis, Type 1 Diabetes Mellitus
Publisher:Nature Publishing Group
Page Range:398-402
Date:17 June 2021
Official Publication:https://doi.org/10.1038/s41586-021-03552-w
PubMed:View item in PubMed

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