Fine-mapping, trans-ancestral and genomic analyses identify causal variants, cells, genes and drug targets for type 1 diabetes

Academic Article

Abstract

  • We report the largest and most diverse genetic study of type 1 diabetes (T1D) to date (61,427 participants), yielding 78 genome-wide-significant (P < 5 × 10−8) regions, including 36 that are new. We define credible sets of T1D-associated variants and show that they are enriched in immune-cell accessible chromatin, particularly CD4+ effector T cells. Using chromatin-accessibility profiling of CD4+ T cells from 115 individuals, we map chromatin-accessibility quantitative trait loci and identify five regions where T1D risk variants co-localize with chromatin-accessibility quantitative trait loci. We highlight rs72928038 in BACH2 as a candidate causal T1D variant leading to decreased enhancer accessibility and BACH2 expression in T cells. Finally, we prioritize potential drug targets by integrating genetic evidence, functional genomic maps and immune protein–protein interactions, identifying 12 genes implicated in T1D that have been targeted in clinical trials for autoimmune diseases. These findings provide an expanded genomic landscape for T1D.
  • Published In

  • Nature Genetics  Journal
  • Digital Object Identifier (doi)

    Author List

  • Robertson CC; Inshaw JRJ; Onengut-Gumuscu S; Chen WM; Santa Cruz DF; Yang H; Cutler AJ; Crouch DJM; Farber E; Bridges SL
  • Start Page

  • 962
  • End Page

  • 971
  • Volume

  • 53
  • Issue

  • 7