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

Tytuł:: Fine-mapping, trans-ancestral and genomic analyses identify causal variants, cells, genes and drug targets for type 1 diabetes.
Autorzy:: Robertson CC; Center for Public Health Genomics, University of Virginia, Charlottesville, VA, USA.; Department of Biochemistry and Molecular Genetics, University of Virginia, Charlottesville, VA, USA.
Inshaw JRJ; 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.
Onengut-Gumuscu S; Center for Public Health Genomics, University of Virginia, Charlottesville, VA, USA.; Department of Public Health Sciences, University of Virginia, Charlottesville, VA, USA.
Chen WM; Center for Public Health Genomics, University of Virginia, Charlottesville, VA, USA.; Department of Public Health Sciences, University of Virginia, Charlottesville, VA, USA.
Santa Cruz DF; 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.
Yang H; Center for Public Health Genomics, University of Virginia, Charlottesville, VA, USA.
Cutler AJ; 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.
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 Jr; Division of Rheumatology, Department of Medicine, Hospital for Special Surgery, New York, NY, USA.; Division of Rheumatology, Department of Medicine, Weill Cornell Medical College, New York, NY, USA.
Edberg JC; Division of Clinical Immunology and Rheumatology, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA.
Kimberly RP; Division of Clinical Immunology and Rheumatology, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA.
Buckner JH; Center for Translational Immunology, Benaroya Research Institute, Seattle, WA, USA.
Deloukas P; Clinical Pharmacology, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK.; Princess Al-Jawhara Al-Brahim Centre of Excellence in Research of Hereditary Disorders (PACER-HD), King Abdulaziz University, Jeddah, Saudi Arabia.
Divers J; Division of Health Services Research, Department of Foundations of Medicine, New York University Long Island School of Medicine, Mineola, NY, USA.
Dabelea D; Colorado School of Public Health and Lifecourse Epidemiology of Adiposity and Diabetes (LEAD) Center, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
Lawrence JM; Department of Research and Evaluation, Kaiser Permanente Southern California, Pasadena, CA, USA.
Marcovina S; Northwest Lipid Metabolism and Diabetes Research Laboratories, University of Washington, Seattle, WA, USA.; Medpace Reference Laboratories, Cincinnati, OH, USA.
Shah AS; Cincinnati Children's Hospital Medical Center and the University of Cincinnati, Cincinnati, OH, USA.
Greenbaum CJ; Center for Interventional Immunology, Benaroya Research Institute, Seattle, WA, USA.; Diabetes Program, Benaroya Research Institute, Seattle, WA, USA.
Atkinson MA; Department of Pathology, Immunology, and Laboratory Medicine, University of Florida, Gainesville, FL, USA.
Gregersen PK; Robert S. Boas Center for Genomics and Human Genetics, Feinstein Institutes for Medical Research, Northwell Health, Manhasset, NY, USA.
Oksenberg JR; Department of Neurology and Weill Institute for Neurosciences, University of California at San Francisco, San Francisco, CA, USA.
Pociot F; Department of Pediatrics, Herlev University Hospital, Copenhagen, Denmark.; Institute of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.; Type 1 Diabetes Biology, Department of Clinical Research, Steno Diabetes Center Copenhagen, Gentofte, Denmark.
Rewers MJ; Barbara Davis Center for Diabetes, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
Steck AK; Barbara Davis Center for Diabetes, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
Dunger DB; Department of Paediatrics, University of Cambridge, Cambridge, UK.; Wellcome Trust Medical Research Council Institute of Metabolic Science, University of Cambridge, Cambridge, UK.
Wicker LS; 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.
Concannon P; Department of Pathology, Immunology, and Laboratory Medicine, University of Florida, Gainesville, FL, USA.; Genetics Institute, University of Florida, Gainesville, FL, USA.
Todd JA; 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. .
Rich SS; Center for Public Health Genomics, University of Virginia, Charlottesville, VA, USA.; Department of Public Health Sciences, University of Virginia, Charlottesville, VA, USA.
Corporate Authors:: Type 1 Diabetes Genetics Consortium
Źródło:: Nature genetics [Nat Genet] 2021 Jul; Vol. 53 (7), pp. 962-971. Date of Electronic Publication: 2021 Jun 14.
Typ publikacji:: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S.
Język:: English
Imprint Name(s):: Original Publication: New York, NY : Nature Pub. Co., c1992-
MeSH Terms:: Alleles*
Chromosome Mapping*
Genetic Predisposition to Disease*
Genetic Variation*
Genomics*/methods
Diabetes Mellitus, Type 1/*genetics
Autoimmunity/genetics ; CD4-Positive T-Lymphocytes/immunology ; CD4-Positive T-Lymphocytes/metabolism ; Diabetes Mellitus, Type 1/drug therapy ; Diabetes Mellitus, Type 1/metabolism ; Drug Discovery ; Gene Expression ; Humans ; Molecular Targeted Therapy ; Protein Interaction Mapping
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Grant Information:: UL1 TR003096 United States TR NCATS NIH HHS; U01 DK061010 United States DK NIDDK NIH HHS; U18 DP002710 United States DP NCCDPHP CDC HHS; DP3 DK111906 United States DK NIDDK NIH HHS; U01 DK127404 United States DK NIDDK NIH HHS; U01 DK061036 United States DK NIDDK NIH HHS; U18 DP002709 United States DP NCCDPHP CDC HHS; U01 DK061042 United States DK NIDDK NIH HHS; R01 DK032493 United States DK NIDDK NIH HHS; HIR 10-001 United States HX HSRD VA; P01 AI042288 United States AI NIAID NIH HHS; R01 HL120393 United States HL NHLBI NIH HHS; 203141 United Kingdom WT_ Wellcome Trust; N01AR62278 United States HL NHLBI NIH HHS; U01 DP000247 United States DP NCCDPHP CDC HHS; U01 DK061040 United States DK NIDDK NIH HHS; R01 DK116954 United States DK NIDDK NIH HHS; N01AR02247 United States AR NIAMS NIH HHS; U01 DK085466 United States DK NIDDK NIH HHS; 095219 United Kingdom WT_ Wellcome Trust; U01 DK061058 United States DK NIDDK NIH HHS; U01 DK085505 United States DK NIDDK NIH HHS; U01 DK085453 United States DK NIDDK NIH HHS; United Kingdom DH_ Department of Health; UL1 TR000154 United States TR NCATS NIH HHS; U18 DP002714 United States DP NCCDPHP CDC HHS; G1001799 United Kingdom MRC_ Medical Research Council; U01 DP000248 United States DP NCCDPHP CDC HHS; U01 DK085499 United States DK NIDDK NIH HHS; U01 DK085463 United States DK NIDDK NIH HHS; R01 DK115694 United States DK NIDDK NIH HHS; T32 LM012416 United States LM NLM NIH HHS; U01 DP000244 United States DP NCCDPHP CDC HHS; P30 DK116073 United States DK NIDDK NIH HHS; U01 DK062418 United States DK NIDDK NIH HHS; U01 DK061055 United States DK NIDDK NIH HHS; HHSN268201800001C United States HL NHLBI NIH HHS; UM1 HG008853 United States HG NHGRI NIH HHS; U01 DK103282 United States DK NIDDK NIH HHS; 107212 United Kingdom WT_ Wellcome Trust; U01 DK061034 United States DK NIDDK NIH HHS; U01 DK085461 United States DK NIDDK NIH HHS; U01 DK085509 United States DK NIDDK NIH HHS; United Kingdom WT_ Wellcome Trust; UL1 TR001417 United States TR NCATS NIH HHS; R01 DK127208 United States DK NIDDK NIH HHS; U01 DK061041 United States DK NIDDK NIH HHS; R01 HL117626 United States HL NHLBI NIH HHS; U01 DP000250 United States DP NCCDPHP CDC HHS; P01 AR049084 United States AR NIAMS NIH HHS; U01 DP000246 United States DP NCCDPHP CDC HHS; U01 DP000254 United States DP NCCDPHP CDC HHS; U18 DP002708 United States DP NCCDPHP CDC HHS; 108439 United Kingdom WT_ Wellcome Trust
Entry Date(s):: Date Created: 20210615 Date Completed: 20210830 Latest Revision: 20231107
Update Code:: 20240104
PubMed Central ID:: PMC8273124
DOI:: 10.1038/s41588-021-00880-5
PMID:: 34127860
: Czasopismo naukowe

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.
(© 2021. Crown.)

Comment in: Nat Rev Endocrinol. 2021 Sep;17(9):515. (PMID: 34194009)

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