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

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 novel. We define credible sets of T1D-associated variants and show 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 (caQTLs) and identify five regions where T1D risk variants colocalize with caQTLs. 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.