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

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Item Type:	Article
Title:	Interpreting type 1 diabetes risk with genetics and single-cell epigenomics
Creators Name:	Chiou, J., Geusz, R.J., Okino, M.L., Han, J.Y., Miller, M., Melton, R., Beebe, E., Benaglio, P., Huang, S., Korgaonkar, K., Heller, S., Kleger, A., Preissl, S., Gorkin, D.U., 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
Source:	Nature
ISSN:	0028-0836
Publisher:	Nature Publishing Group
Volume:	594
Number:	7863
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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