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Fine-mapping, trans-ancestral and genomic analyses identify causal variants, cells, genes and drug targets for type 1 diabetes
Open accessPublished version of a preprint
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. 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.
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Metadata
- Authors
- Robertson, C. C., Inshaw, J. R. J., Onengut-Gumuscu, S., Chen, W.-M., Santa Cruz, D. F., Yang, H., Cutler, A. J., Crouch, D. J. M., Farber, E., Bridges, S. L., Edberg, J. C., Kimberly, R. P., Buckner, J. H., Deloukas, P., Divers, J., Dabelea, D., Lawrence, J. M., Marcovina, S., Shah, A. S., Greenbaum, C. J., Atkinson, M. A., Gregersen, P. K., Oksenberg, J. R., Pociot, F., Rewers, M. J., Steck, A. K., Dunger, D. B., Type 1 Diabetes Genetics Consortium, Wicker, L. S., Concannon, P., Todd, J. A., & Rich, S. S.
- Affiliations
- University of Virginia (US)
- Centre for Human Genetics (GB)
- Hospital for Special Surgery (US)
- University of Alabama at Birmingham (US)
- Benaroya Research Institute (US)
- Queen Mary University of London (GB)
- NYU Grossman Long Island School of Medicine (US)
- Colorado School of Public Health (US)
- Kaiser Permanente (US)
- Medpace (United States) (US)
- Cincinnati Children's Hospital Medical Center (US)
- University of Florida (US)
- Northwell Health (US)
- University of California, San Francisco (US)
- University of Copenhagen (DK)
- University of Colorado Anschutz (US)
- University of Cambridge (GB)
- Corresponding author
- Todd, John A.
- ORCID
- Robertson, Catherine C.
- Inshaw, Jamie R. J.
- Onengut-Gumuscu, Suna
- Chen, Wei-Min
- Yang, Hanzhi
- Cutler, Antony J.
- Crouch, Daniel J. M.
- Farber, Emily
- Bridges, S. Louis
- Kimberly, Robert P.
- Buckner, Jane H.
- Deloukas, Panos
- Divers, Jasmin
- Dabelea, Dana
- Lawrence, Jean M.
- Marcovina, Santica
- Shah, Amy S.
- Greenbaum, Carla J.
- Atkinson, Mark A.
- Gregersen, Peter K.
- Oksenberg, Jorge R.
- Pociot, Flemming
- Rewers, Marian J.
- Steck, Andrea K.
- Dunger, David B.
- Wicker, Linda S.
- Concannon, Patrick
- Todd, John A.
- Rich, Stephen S.
- Venue
- Nature Genetics
- Published
- 2021-06-14
- Volume
- 53
- Issue
- 7
- Pages
- 962-971
- ISSN
- 1061-4036 (ISSN-L)
- 1546-1718
- PMC
- PMC8273124
- OpenAlex
- W3171115266
- Semantic Scholar
- e41e3ba0695f1da1b7c897ccfd64b223b9963243
- Cited by
- 302
- References
- 107
- Citations by year
- 2026: 42 · 2025: 63 · 2024: 66 · 2023: 65 · 2022: 39 · 2021: 26
- FWCI
- 27.56
- Type
- journal article
- Language
- en
- Open access
- green
- doi.org
- Locations
- Nature Genetics (publishedVersion)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Research at the University of Copenhagen (University of Copenhagen) (submittedVersion)
- Funders
- Juvenile Diabetes Research Foundation (4-SRA-2017-473-A-A)
- Wellcome Trust (107212/A/15/Z)
- U.S. Department of Health & Human Services | NIH | U.S. National Library of Medicine (5T32LM012416)
- University of Virginia
- U.S. Department of Health & Human Services | NIH | National Institute of Arthritis and Musculoskeletal and Skin Diseases (N01-AR-0-2247, N01 AR-6-2278)
- U.S. Department of Health & Human Services | National Institutes of Health (UL1-TR001417)
- U.S. Department of Health & Human Services | NIH | National Institute of Diabetes and Digestive and Kidney Diseases (U48/CCU919219, U01 DP000250, 107212/A/15/Z, U01 DP000247, U18DP000247-06A1, U01 DP000246, U58/CCU019235-4, U01 DP000244, U18DP002710-01, U48/CCU519239, U01 DP000248, 1U18DP002709, U01 DK103282, U01 DK127404, R01 DK032493, P30 DK116073, DK-115694, DP3-111906, U01 DK-062418)
- U.S. Department of Health & Human Services | Centers for Disease Control and Prevention (200-2010-35171)
- U.S. Department of Health & Human Services | NIH | National Institute of Allergy and Infectious Diseases (P01AI042288)
- National Multiple Sclerosis Society (SI-2001-35701)
- U.S. Department of Health & Human Services | NIH | National Center for Advancing Translational Sciences (UL1 TR000154)
- JDRF
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Diabetes and associated disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Keywords
- type 1 diabetes, genetic risk variants, fine mapping, chromatin accessibility, CD4+ T cells, BACH2, enhancer accessibility, causal variants, therapeutic target, immune cells
- MeSH terms
- Alleles, Chromosome Mapping, Diabetes Mellitus, Type 1, Humans, Genetic Variation, CD4-Positive T-Lymphocytes, Autoimmunity, Gene Expression, Genetic Predisposition to Disease, Genomics, Protein Interaction Mapping, Drug Discovery, Molecular Targeted Therapy
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