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 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.

• Authors: Catherine C Robertson, Jamie R J Inshaw, Suna Onengut-Gumuscu, Wei-Min Chen, David Flores Santa Cruz, Hanzhi Yang, Antony J Cutler, Daniel J M Crouch, Emily Farber, S Louis Bridges Jr, Jeffrey C Edberg, Robert P Kimberly, Jane H Buckner, Panos Deloukas, Jasmin Divers, Dana Dabelea, Jean M Lawrence, Santica Marcovina, Amy S Shah, Carla J Greenbaum, Mark A Atkinson, Peter K Gregersen, Jorge R Oksenberg, Flemming Pociot, Marian J Rewers, Andrea K Steck, David B Dunger, Type 1 Diabetes Genetics Consortium, Linda S Wicker, Patrick Concannon, John A Todd, Stephen S Rich
• Journal: Nature genetics (Nat Genet) Vol. 53 Issue 7 Pg. 962-971 (07 2021) ISSN: 1546-1718 [Electronic] United States
• PMID: 34127860 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)
• Copyright: © 2021. Crown.

Topics

• Alleles
• Autoimmunity (genetics)
• CD4-Positive T-Lymphocytes (immunology, metabolism)
• Chromosome Mapping
• Diabetes Mellitus, Type 1 (drug therapy, genetics, metabolism)
• Drug Discovery
• Gene Expression
• Genetic Predisposition to Disease
• Genetic Variation
• Genomics (methods)
• Humans
• Molecular Targeted Therapy
• Protein Interaction Mapping