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; 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; Linda S Wicker; Patrick Concannon; John A Todd; Stephen S Rich; Type 1 Diabetes Genetics Consortium

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

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, 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 GreenbaumMark A Atkinson, Peter K Gregersen, Jorge R Oksenberg, Flemming Pociot, Marian J Rewers, Andrea K Steck, David B Dunger, Linda S Wicker, Patrick Concannon, John A Todd, Stephen S Rich, Type 1 Diabetes Genetics Consortium

219 Citations (Scopus)

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.

Original language	English
Journal	Nature Genetics
Volume	53
Issue number	7
Pages (from-to)	962-971
Number of pages	10
ISSN	1061-4036
DOIs	https://doi.org/10.1038/s41588-021-00880-5
Publication status	Published - Jul 2021

Keywords

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

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10.1038/s41588-021-00880-5

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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., ... Type 1 Diabetes Genetics Consortium (2021). Fine-mapping, trans-ancestral and genomic analyses identify causal variants, cells, genes and drug targets for type 1 diabetes. Nature Genetics, 53(7), 962-971. https://doi.org/10.1038/s41588-021-00880-5

Robertson, CC, Inshaw, JRJ, Onengut-Gumuscu, S, Chen, W-M, Santa Cruz, DF, Yang, H, Cutler, AJ, Crouch, DJM, Farber, E, Bridges, SL, Edberg, JC, Kimberly, RP, Buckner, JH, Deloukas, P, Divers, J, Dabelea, D, Lawrence, JM, Marcovina, S, Shah, AS, Greenbaum, CJ, Atkinson, MA, Gregersen, PK, Oksenberg, JR, Pociot, F, Rewers, MJ, Steck, AK, Dunger, DB, Wicker, LS, Concannon, P, Todd, JA, Rich, SS & Type 1 Diabetes Genetics Consortium 2021, 'Fine-mapping, trans-ancestral and genomic analyses identify causal variants, cells, genes and drug targets for type 1 diabetes', Nature Genetics, vol. 53, no. 7, pp. 962-971. https://doi.org/10.1038/s41588-021-00880-5

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

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.",

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

author = "Robertson, \{Catherine C\} and Inshaw, \{Jamie R J\} and Suna Onengut-Gumuscu and Wei-Min Chen and \{Santa Cruz\}, \{David Flores\} and Hanzhi Yang and Cutler, \{Antony J\} and Crouch, \{Daniel J M\} and Emily Farber and Bridges, \{S Louis\} and Edberg, \{Jeffrey C\} and Kimberly, \{Robert P\} and Buckner, \{Jane H\} and Panos Deloukas and Jasmin Divers and Dana Dabelea and Lawrence, \{Jean M\} and Santica Marcovina and Shah, \{Amy S\} and Greenbaum, \{Carla J\} and Atkinson, \{Mark A\} and Gregersen, \{Peter K\} and Oksenberg, \{Jorge R\} and Flemming Pociot and Rewers, \{Marian J\} and Steck, \{Andrea K\} and Dunger, \{David B\} and Wicker, \{Linda S\} and Patrick Concannon and Todd, \{John A\} and Rich, \{Stephen S\} and \{Type 1 Diabetes Genetics Consortium\}",

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year = "2021",

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doi = "10.1038/s41588-021-00880-5",

language = "English",

volume = "53",

pages = "962--971",

journal = "Nature Genetics",

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T1 - Fine-mapping, trans-ancestral and genomic analyses identify causal variants, cells, genes and drug targets for type 1 diabetes

AU - Robertson, Catherine C

AU - Inshaw, Jamie R J

AU - Onengut-Gumuscu, Suna

AU - Chen, Wei-Min

AU - Santa Cruz, David Flores

AU - Yang, Hanzhi

AU - Cutler, Antony J

AU - Crouch, Daniel J M

AU - Farber, Emily

AU - Bridges, S Louis

AU - Edberg, Jeffrey C

AU - Kimberly, Robert P

AU - Buckner, Jane H

AU - Deloukas, Panos

AU - Divers, Jasmin

AU - Dabelea, Dana

AU - Lawrence, Jean M

AU - Marcovina, Santica

AU - Shah, Amy S

AU - Greenbaum, Carla J

AU - Atkinson, Mark A

AU - Gregersen, Peter K

AU - Oksenberg, Jorge R

AU - Pociot, Flemming

AU - Rewers, Marian J

AU - Steck, Andrea K

AU - Dunger, David B

AU - Wicker, Linda S

AU - Concannon, Patrick

AU - Todd, John A

AU - Rich, Stephen S

AU - Type 1 Diabetes Genetics Consortium

PY - 2021/7

Y1 - 2021/7

N2 - 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.

AB - 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.

KW - Alleles

KW - Autoimmunity/genetics

KW - CD4-Positive T-Lymphocytes/immunology

KW - Chromosome Mapping

KW - Diabetes Mellitus, Type 1/drug therapy

KW - Drug Discovery

KW - Gene Expression

KW - Genetic Predisposition to Disease

KW - Genetic Variation

KW - Genomics/methods

KW - Humans

KW - Molecular Targeted Therapy

KW - Protein Interaction Mapping

UR - https://www.scopus.com/pages/publications/85108915214

U2 - 10.1038/s41588-021-00880-5

DO - 10.1038/s41588-021-00880-5

M3 - Journal article

C2 - 34127860

SN - 1061-4036

VL - 53

SP - 962

EP - 971

JO - Nature Genetics

JF - Nature Genetics

IS - 7

ER -

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

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Keywords

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