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

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

doi:10.1038/s41588-021-00880-5

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

Nat Genet. 2021 Jul;53(7):962-971. doi: 10.1038/s41588-021-00880-5. Epub 2021 Jun 14.

Authors

Catherine C Robertson^#^{1

2}, Jamie R J Inshaw^#³, Suna Onengut-Gumuscu^{1

4}, Wei-Min Chen^{1

4}, David Flores Santa Cruz³, Hanzhi Yang¹, Antony J Cutler³, Daniel J M Crouch³, Emily Farber¹, S Louis Bridges Jr^{5

6}, Jeffrey C Edberg⁷, Robert P Kimberly⁷, Jane H Buckner⁸, Panos Deloukas^{9

10}, Jasmin Divers¹¹, Dana Dabelea¹², Jean M Lawrence¹³, Santica Marcovina^{14

15}, Amy S Shah¹⁶, Carla J Greenbaum^{17

18}, Mark A Atkinson¹⁹, Peter K Gregersen²⁰, Jorge R Oksenberg²¹, Flemming Pociot^{22

23

24}, Marian J Rewers²⁵, Andrea K Steck²⁵, David B Dunger^{26

27}; Type 1 Diabetes Genetics Consortium; Linda S Wicker³, Patrick Concannon^{19

28}, John A Todd²⁹, Stephen S Rich^{1

4}

Affiliations

¹ Center for Public Health Genomics, University of Virginia, Charlottesville, VA, USA.
² Department of Biochemistry and Molecular Genetics, University of Virginia, Charlottesville, VA, USA.
³ JDRF/Wellcome Diabetes and Inflammation Laboratory, Wellcome Centre for Human Genetics, Nuffield Department of Medicine, NIHR Oxford Biomedical Research Centre, University of Oxford, Oxford, UK.
⁴ Department of Public Health Sciences, University of Virginia, Charlottesville, VA, USA.
⁵ Division of Rheumatology, Department of Medicine, Hospital for Special Surgery, New York, NY, USA.
⁶ Division of Rheumatology, Department of Medicine, Weill Cornell Medical College, New York, NY, USA.
⁷ Division of Clinical Immunology and Rheumatology, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA.
⁸ Center for Translational Immunology, Benaroya Research Institute, Seattle, WA, USA.
⁹ Clinical Pharmacology, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
¹⁰ Princess Al-Jawhara Al-Brahim Centre of Excellence in Research of Hereditary Disorders (PACER-HD), King Abdulaziz University, Jeddah, Saudi Arabia.
¹¹ Division of Health Services Research, Department of Foundations of Medicine, New York University Long Island School of Medicine, Mineola, NY, USA.
¹² Colorado School of Public Health and Lifecourse Epidemiology of Adiposity and Diabetes (LEAD) Center, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
¹³ Department of Research and Evaluation, Kaiser Permanente Southern California, Pasadena, CA, USA.
¹⁴ Northwest Lipid Metabolism and Diabetes Research Laboratories, University of Washington, Seattle, WA, USA.
¹⁵ Medpace Reference Laboratories, Cincinnati, OH, USA.
¹⁶ Cincinnati Children's Hospital Medical Center and the University of Cincinnati, Cincinnati, OH, USA.
¹⁷ Center for Interventional Immunology, Benaroya Research Institute, Seattle, WA, USA.
¹⁸ Diabetes Program, Benaroya Research Institute, Seattle, WA, USA.
¹⁹ Department of Pathology, Immunology, and Laboratory Medicine, University of Florida, Gainesville, FL, USA.
²⁰ Robert S. Boas Center for Genomics and Human Genetics, Feinstein Institutes for Medical Research, Northwell Health, Manhasset, NY, USA.
²¹ Department of Neurology and Weill Institute for Neurosciences, University of California at San Francisco, San Francisco, CA, USA.
²² Department of Pediatrics, Herlev University Hospital, Copenhagen, Denmark.
²³ Institute of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
²⁴ Type 1 Diabetes Biology, Department of Clinical Research, Steno Diabetes Center Copenhagen, Gentofte, Denmark.
²⁵ Barbara Davis Center for Diabetes, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
²⁶ Department of Paediatrics, University of Cambridge, Cambridge, UK.
²⁷ Wellcome Trust Medical Research Council Institute of Metabolic Science, University of Cambridge, Cambridge, UK.
²⁸ Genetics Institute, University of Florida, Gainesville, FL, USA.
²⁹ JDRF/Wellcome Diabetes and Inflammation Laboratory, Wellcome Centre for Human Genetics, Nuffield Department of Medicine, NIHR Oxford Biomedical Research Centre, University of Oxford, Oxford, UK. jatodd@well.ox.ac.uk.

^# Contributed equally.

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S.

MeSH terms

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

Abstract

Publication types

MeSH terms

Grants and funding