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Fine-mapping, trans-ancestral and genomic analyses identify causal variants, cells, genes and drug targets for type 1 diabetes.
Robertson, Catherine C; Inshaw, Jamie R J; Onengut-Gumuscu, Suna; Chen, Wei-Min; Santa Cruz, David Flores; Yang, Hanzhi; Cutler, Antony J; Crouch, Daniel J M; Farber, Emily; Bridges, S Louis; Edberg, Jeffrey C; 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.
Afiliación
  • Robertson CC; Center for Public Health Genomics, University of Virginia, Charlottesville, VA, USA.
  • Inshaw JRJ; Department of Biochemistry and Molecular Genetics, University of Virginia, Charlottesville, VA, USA.
  • Onengut-Gumuscu S; 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.
  • Chen WM; Center for Public Health Genomics, University of Virginia, Charlottesville, VA, USA.
  • Santa Cruz DF; Department of Public Health Sciences, University of Virginia, Charlottesville, VA, USA.
  • Yang H; Center for Public Health Genomics, University of Virginia, Charlottesville, VA, USA.
  • Cutler AJ; Department of Public Health Sciences, University of Virginia, Charlottesville, VA, USA.
  • Crouch DJM; 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.
  • Farber E; Center for Public Health Genomics, University of Virginia, Charlottesville, VA, USA.
  • Bridges SL; 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.
  • Edberg JC; 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.
  • Kimberly RP; Center for Public Health Genomics, University of Virginia, Charlottesville, VA, USA.
  • Buckner JH; Division of Rheumatology, Department of Medicine, Hospital for Special Surgery, New York, NY, USA.
  • Deloukas P; Division of Rheumatology, Department of Medicine, Weill Cornell Medical College, New York, NY, USA.
  • Divers J; Division of Clinical Immunology and Rheumatology, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA.
  • Dabelea D; Division of Clinical Immunology and Rheumatology, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA.
  • Lawrence JM; Center for Translational Immunology, Benaroya Research Institute, Seattle, WA, USA.
  • Marcovina S; Clinical Pharmacology, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
  • Shah AS; Princess Al-Jawhara Al-Brahim Centre of Excellence in Research of Hereditary Disorders (PACER-HD), King Abdulaziz University, Jeddah, Saudi Arabia.
  • Greenbaum CJ; Division of Health Services Research, Department of Foundations of Medicine, New York University Long Island School of Medicine, Mineola, NY, USA.
  • Atkinson MA; Colorado School of Public Health and Lifecourse Epidemiology of Adiposity and Diabetes (LEAD) Center, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
  • Gregersen PK; Department of Research and Evaluation, Kaiser Permanente Southern California, Pasadena, CA, USA.
  • Oksenberg JR; Northwest Lipid Metabolism and Diabetes Research Laboratories, University of Washington, Seattle, WA, USA.
  • Pociot F; Medpace Reference Laboratories, Cincinnati, OH, USA.
  • Rewers MJ; Cincinnati Children's Hospital Medical Center and the University of Cincinnati, Cincinnati, OH, USA.
  • Steck AK; Center for Interventional Immunology, Benaroya Research Institute, Seattle, WA, USA.
  • Dunger DB; Diabetes Program, Benaroya Research Institute, Seattle, WA, USA.
  • Wicker LS; Robert S. Boas Center for Genomics and Human Genetics, Feinstein Institutes for Medical Research, Northwell Health, Manhasset, NY, USA.
  • Concannon P; Department of Neurology and Weill Institute for Neurosciences, University of California at San Francisco, San Francisco, CA, USA.
  • Todd JA; Department of Pediatrics, Herlev University Hospital, Copenhagen, Denmark.
  • Rich SS; Institute of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
Nat Genet ; 53(7): 962-971, 2021 07.
Article en En | MEDLINE | ID: mdl-34127860
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.
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Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Variación Genética / Mapeo Cromosómico / Predisposición Genética a la Enfermedad / Genómica / Diabetes Mellitus Tipo 1 / Alelos Tipo de estudio: Prognostic_studies Límite: Humans Idioma: En Revista: Nat Genet Asunto de la revista: GENETICA MEDICA Año: 2021 Tipo del documento: Article País de afiliación: Estados Unidos
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Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Variación Genética / Mapeo Cromosómico / Predisposición Genética a la Enfermedad / Genómica / Diabetes Mellitus Tipo 1 / Alelos Tipo de estudio: Prognostic_studies Límite: Humans Idioma: En Revista: Nat Genet Asunto de la revista: GENETICA MEDICA Año: 2021 Tipo del documento: Article País de afiliación: Estados Unidos