Interpreting type 1 diabetes risk with genetics and single cell epigenomics

• Type of Material: Article
• Authors: 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 Gorkin, Emory University; Maike Sander, University of California, San Diego; Kyle J. Gaulton, University of California, San Diego
• Language: English
• Date: 2021-05-19
• Publisher: Springer Nature
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2021, The Author(s), under exclusive licence to Springer Nature Limited
• Final Published Version (URL): https://doi.org/10.1038/s41586-021-03552-w
• Title of Journal or Parent Work: Nature
• Volume: 594
• Issue: 7863
• Start Page: 398
• End Page: 402
• Grant/Funding Information: This work was supported by NIH grants DK112155, DK120429 and DK122607 to K.J.G and M.S., and T32 GM008666 to R.G.
• Keywords: type 1 diabetes; cis-regulatory elements; CFTR locus; genome-wide association studies
• Research Categories: Biology, Genetics; Biology, Cell

Abstract

Genetic risk variants identified in genome-wide association studies (GWAS) of complex disease are primarily non-coding1, and translating risk variants into mechanistic insight requires detailed gene regulatory maps in disease-relevant cell types2. Here, we combined a GWAS of type 1 diabetes (T1D) in 520,580 samples with candidate cis-regulatory elements (cCREs) in pancreas and peripheral blood mononuclear cell types defined using single nucleus ATAC-seq (snATAC-seq) of 131,554 nuclei. T1D risk variants were enriched in cCREs active in T cells and additional cell types, including acinar and ductal cells of the exocrine pancreas. Risk variants at multiple T1D signals overlapped exocrine-specific cCREs linked to genes with exocrine-specific expression. At the CFTR locus, T1D risk variant rs7795896 mapped in a ductal-specific cCRE which regulated CFTR, and 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 T1D pathogenesis and highlight the power of large-scale GWAS and single cell epigenomics for understanding the cellular origins of complex disease.