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

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 x 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. A large-scale genetic analysis of type 1 diabetes identifies new susceptibility variants, highlights potential regulatory mechanisms and provides genetic support for therapeutic targets for immune intervention.

Automated summary

A large-scale genetic analysis of type 1 diabetes identifies new susceptibility variants, highlights potential regulatory mechanisms, and provides genetic support for therapeutic targets for immune intervention.