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Genome-wide association study and meta-analysis find that over 40 loci affect risk of type 1 diabetes

Abstract

Type 1 diabetes (T1D) is a common autoimmune disorder that arises from the action of multiple genetic and environmental risk factors. We report the findings of a genome-wide association study of T1D, combined in a meta-analysis with two previously published studies. The total sample set included 7,514 cases and 9,045 reference samples. Forty-one distinct genomic locations provided evidence for association with T1D in the meta-analysis (P < 10−6). After excluding previously reported associations, we further tested 27 regions in an independent set of 4,267 cases, 4,463 controls and 2,319 affected sib-pair (ASP) families. Of these, 18 regions were replicated (P < 0.01; overall P < 5 × 10−8) and 4 additional regions provided nominal evidence of replication (P < 0.05). The many new candidate genes suggested by these results include IL10, IL19, IL20, GLIS3, CD69 and IL27.

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Figure 1: Genome-wide plots of −log10 P values from stratified 1-d.f.

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Acknowledgements

This research utilizes resources provided by the Type 1 Diabetes Genetics Consortium, a collaborative clinical study sponsored by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Institute of Allergy and Infectious Diseases (NIAID), National Human Genome Research Institute (NHGRI), National Institute of Child Health and Human Development (NICHD) and Juvenile Diabetes Research Foundation International (JDRF) and supported by U01 DK062418. Further support was provided by a grant from the NIDDK (DK46635) to P.C. and a joint JDRF and Wellcome Trust grant to the Diabetes and Inflammation Laboratory at Cambridge, which also received support from the National Institute for Health Research Cambridge Biomedical Research Centre. D.C. is the recipient of a Wellcome Trust Principal Research Fellowship.

We acknowledge the contributions of the following individuals: J. Alipaz, A. Simpson, J. Brown and J. Garsetti for assistance with project management; M. Hardy and K. Downes for genotyping; M. Maisuria for DNA sample coordination and quality control; J. Hilner and J. Pierce for managing T1DGC Data and DNA resources; J. Allen, N. Ovington, V. Everett, G. Dolman and M. Brown for data services and computing; and L. Smink, O. Burren, J. Mychaleckyj and N. Goodman for bioinformatics support.

We gratefully acknowledge the following groups and individuals who provided biological samples or data for this study. We obtained DNA samples from the British 1958 Birth Cohort collection, funded by the Medical Research Council and the Wellcome Trust. We thank The Avon Longitudinal Study of Parents and Children laboratory in Bristol and the British 1958 Birth Cohort team, including S. Ring, R. Jones, M. Pembrey, W. McArdle, D. Strachan and P. Burton for preparing and providing the control DNA samples. We thank the Human Biological Data Interchange and Diabetes UK for providing DNA samples from USA and UK multiplex families, respectively. Danish subjects were from the Danish Society of Childhood Diabetes (DSBD) and control DNA samples were provided by T. Hansen, O. Pedersen, K. Borch-Johnsen and T. Joergensen. This study makes use of data generated by the Wellcome Trust Case Control Consortium, funded by Wellcome Trust award 076113, and a full list of the investigators who contributed to the generation of the data are available from http://www.wtccc.org.uk.

We gratefully acknowledge the Genetics of Kidneys in Diabetes (GoKinD) study for generously allowing the use of their sample SNP allele intensity and genotype data, which was obtained from the Genetic Association Information Network (GAIN) database (dbGAP, phs000018.v1.p1)12.

We gratefully acknowledge the National Institute of Mental Health for generously allowing the use of their control CEL and genotype data. Control subjects from the National Institute of Mental Health Schizophrenia Genetics Initiative (NIMH-GI), data and biomaterials are being collected by the “Molecular Genetics of Schizophrenia II” (MGS-2) collaboration. The investigators and coinvestigators are as follows: ENH/Northwestern University, MH059571, P.V. Gejman (collaboration coordinator: PI) and A.R. Sanders; Emory University School of Medicine, MH59587, F. Amin (PI); Louisiana State University Health Sciences Center, MH067257, N. Buccola (PI); University of California-Irvine, MH60870, W. Byerley (PI); Washington University, St. Louis, U01, MH060879, C.R. Cloninger (PI); University of Iowa, MH59566, R. Crowe, (PI) and D. Black; University of Colorado, Denver, MH059565, R. Freedman (PI); University of Pennsylvania, MH061675, D. Levinson (PI); University of Queensland, MH059588, B. Mowry (PI); Mt. Sinai School of Medicine, MH59586, J. Silverman (PI). The samples were collected by V.L. Nimgaonkar's group at the University of Pittsburgh, as part of a multi-institutional collaborative research project with J. Smoller and P. Sklar (Massachusetts General Hospital) (grant MH 63420).

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J.C.B. and D.G.C. helped design the study, and carried out the statistical analyses. J.C.B., D.G.C. and P.C. drafted the manuscript. P.C. managed the editing of the manuscript. F.P., C.J., J.A.T., B.A., H.A.E., G.M., J.N., C.N., P.C. and S.S.R. (Chair) are members of the T1DGC Steering Committee, and contributed to the general planning and design of the study, and to the writing of the manuscript. F.P. and J.N. also coordinated the inclusion of the Danish case-control samples. N.M.W. and H. Schuilenburg provided data services. J.D.C. and V.P. assisted with data analyses. D.J.S. carried out genotyping, and H. Stevens provided DNA sample coordination and quality control. The T1DGC provided biospecimens and data from families with T1D.

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Correspondence to Patrick Concannon.

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A full list of members appears in the Supplementary Note.

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Supplementary Figures 1–4, Supplementary Tables 1–3, Supplementary Note and Supplementary Methods (PDF 377 kb)

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Barrett, J., Clayton, D., Concannon, P. et al. Genome-wide association study and meta-analysis find that over 40 loci affect risk of type 1 diabetes. Nat Genet 41, 703–707 (2009). https://doi.org/10.1038/ng.381

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