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

Nature. 2021 Jun;594(7863):398-402. doi: 10.1038/s41586-021-03552-w. Epub 2021 May 19.

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Chromatin / genetics
  • Cystic Fibrosis Transmembrane Conductance Regulator / genetics
  • Diabetes Mellitus, Type 1 / genetics*
  • Epigenomics*
  • Female
  • Gene Expression Regulation
  • Genetic Predisposition to Disease*
  • Genome-Wide Association Study
  • Humans
  • Immunity / genetics
  • Male
  • Pancreatic Ducts / metabolism
  • Pancreatic Ducts / pathology
  • Single-Cell Analysis*

Substances

  • CFTR protein, human
  • Chromatin
  • Cystic Fibrosis Transmembrane Conductance Regulator