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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, Jr, 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

Nature genetics, 2021-07, Vol.53 (7), p.962-971 [Periódico revisado por pares]

United States: Nature Publishing Group

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Fine-mapping, trans-ancestral and genomic analyses identify causal variants, cells, genes and drug targets for type 1 diabetes
Autor: 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, Jr, 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
Assuntos: Accessibility ; Alleles ; Autoimmune diseases ; Autoimmunity - genetics ; CD4 antigen ; CD4-Positive T-Lymphocytes - immunology ; CD4-Positive T-Lymphocytes - metabolism ; Chromatin ; Chromosome Mapping ; Chromosomes ; Clinical trials ; Diabetes ; Diabetes mellitus ; Diabetes mellitus (insulin dependent) ; Diabetes Mellitus, Type 1 - drug therapy ; Diabetes Mellitus, Type 1 - genetics ; Diabetes Mellitus, Type 1 - metabolism ; Drug Discovery ; Effector cells ; Gene Expression ; Gene mapping ; Genes ; Genetic aspects ; Genetic diversity ; Genetic Predisposition to Disease ; Genetic research ; Genetic Variation ; Genomes ; Genomic analysis ; Genomics - methods ; Health aspects ; Health risk assessment ; Humans ; Lymphocytes ; Lymphocytes T ; Molecular Targeted Therapy ; Protein interaction ; Protein Interaction Mapping ; Proteins ; Quantitative trait loci ; Risk factors ; T cells ; Therapeutic targets ; Transcription factors ; Type 1 diabetes
É parte de: Nature genetics, 2021-07, Vol.53 (7), p.962-971
Notas: ObjectType-Article-1
SourceType-Scholarly Journals-1
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content type line 23
Consortia
Patrick Concannon18,27, Flemming Pociot21,22,23, Stephen S. Rich1,4§, John A. Todd3
Present address
These authors jointly supervised this work
Santica Marcovina, Medpace Reference Laboratories, Cincinnati, Ohio, USA
The study was conceptually designed by P.C., J.A.T. and S.S.R. The study was implemented by S.O.-G., P.C., J.A.T. and S.S.R. DNA samples for genotyping were managed by S.O.-G and E.F. L.W.S. contributed to data interpretation. D.J.M.C. provided statistical advice. Frozen T1DGC PBMC samples for chromatin accessibility profiling (ATAC-seq) were managed by P.C. and S.O.-G. ATAC-seq data generation at University of Virginia was led by S.O.-G. ATAC-seq data generation at University of Oxford was led by A.J.C. Genotype data processing, quality control, imputation, and statistical analyses were performed by W.-M.C., S.O.-G., J.R.J.I. and C.C.R. Chromatin accessibility data processing and analysis was performed by A.J.C., D.F.S.C., J.R.J.I., and C.C.R. EMSA assays were performed by H.Y., with supervision from S.O.-G. D.B.D. provided samples for genotyping through the Genetic Resource Investigating Diabetes (GRID). P.D. provided ImmunoChip genotyping data through the UK Blood Service (UKBS). J.H.B. provided samples for genotyping and data from the Benaroya Research Institute (BRI). S.L.B. provided samples for genotyping through the Consortium for the Longitudinal Evaluation of African-Americans with Early Rheumatoid Arthritis (CLEAR). P.K.G. provided samples for genotyping through the New York Cancer Project (NYCP). J.D., D.D., J.M.L., S.M., and A.S.S. provided samples for genotyping and data through the SEARCH for Diabetes in Youth study (SEARCH). C.J.G. and M.A.A. provided samples for genotyping through the Type 1 Diabetes TrialNet study (TrialNet). R.P.K., J.C.E., M.J.R., A.K.S., J.R.O., and F.P. provided samples for genotyping through their affiliated institutions and research programs. The manuscript was written by J.R.J.I. (under supervision by J.A.T.) and C.C.R. (under supervision by S.S.R.). All authors reviewed and approved the manuscript.
Type 1 Diabetes Genetics Consortium (T1DGC)
Author contributions
Descrição: 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 ) 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.
Editor: United States: Nature Publishing Group
Idioma: Inglês

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

United States: Nature Publishing Group

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