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

Joshua Chiou (), Ryan J. Geusz, Mei-Lin Okino, Jee Yun Han, Michael Miller, Rebecca Melton, Elisha Beebe, Paola Benaglio, Serina Huang, Katha Korgaonkar, Sandra Heller, Alexander Kleger, Sebastian Preissl, David U. Gorkin, Maike Sander and Kyle J. Gaulton ()
Additional contact information
Joshua Chiou: University of California San Diego
Ryan J. Geusz: University of California San Diego
Mei-Lin Okino: University of California San Diego
Jee Yun Han: University of California San Diego
Michael Miller: University of California San Diego
Rebecca Melton: University of California San Diego
Elisha Beebe: University of California San Diego
Paola Benaglio: University of California San Diego
Serina Huang: University of California San Diego
Katha Korgaonkar: University of California San Diego
Sandra Heller: Ulm University
Alexander Kleger: Ulm University
Sebastian Preissl: University of California San Diego
David U. Gorkin: University of California San Diego
Maike Sander: University of California San Diego
Kyle J. Gaulton: University of California San Diego

Nature, 2021, vol. 594, issue 7863, 398-402

Abstract: Abstract Genetic risk variants that have been identified in genome-wide association studies of complex diseases are primarily non-coding1. Translating these risk variants into mechanistic insights requires detailed maps of gene regulation in disease-relevant cell types2. 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.

Date: 2021
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DOI: 10.1038/s41586-021-03552-w

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