Interpreting type 1 diabetes risk with genetics and single cell epigenomics

• 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
• Journal Title: Nature
• Volume: Volume 594, Number 7863
• Publisher: Springer Nature | 2021-05-19, Pages 398-402
• Type of Work: Article | Post-print: After Peer Review
• Publisher DOI: http://doi.org/10.1038/s41586-021-03552-w
• Subjects: Biology, Genetics; Biology, Cell
• Keywords: genome-wide association studies; type 1 diabetes; cis-regulatory elements; CFTR locus

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.