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Meta-analysis of genome-wide association study data identifies additional type 1 diabetes risk loci

Abstract

We carried out a meta-analysis of data from three genome-wide association (GWA) studies of type 1 diabetes (T1D), testing 305,090 SNPs in 3,561 T1D cases and 4,646 controls of European ancestry. We obtained further support for 4q27 (IL2-IL21, P = 1.9 × 10−8) and, after genotyping an additional 6,225 cases, 6,946 controls and 2,828 families, convincing evidence for four previously unknown and distinct risk loci in chromosome regions 6q15 (BACH2, P = 4.7 × 10−12), 10p15 (PRKCQ, P = 3.7 × 10−9), 15q24 (CTSH, P = 3.2 × 10−15) and 22q13 (C1QTNF6, P = 2.0 × 10−8).

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Acknowledgements

This work was funded by the Juvenile Diabetes Research Foundation International, the Wellcome Trust and the National Institute for Health Research Cambridge Biomedical Centre. The Cambridge Institute for Medical Research (CIMR) is in receipt of a Wellcome Trust Strategic Award (079895). We thank all study participants and family members. We gratefully acknowledge D. Clayton for methodology advice and comments on the manuscript. We acknowledge use of DNA 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 also thank H. Stevens, P. Clarke, G. Coleman, S. Duley, D. Harrison, S. Hawkins, M. Maisuria, T. Mistry and N. Taylor for preparation of DNA samples. We acknowledge use of DNA from the Human Biological Data Interchange and Diabetes UK for the USA and UK multiplex families, respectively; the Norwegian Study Group for Childhood Diabetes (D. Undlien and K. Ronningen) for the Norwegian families; D. Savage, C. Patterson, D. Carson and P. Maxwell for the Northern Irish families; the Genetics of Type 1 Diabetes in Finland (GET1FIN); J. Tuomilehto, L. Kinnunen, E. Tuomilehto-Wolf, V. Harjutsalo and T. Valle for the Finnish families; and C. Guja and C. Ionescu-Tirgoviste for the Romanian families. WTCCC: This study makes use of data generated by the Wellcome Trust Case Control Consortium. A full list of the investigators who contributed to the generation of the data are available from http://www.wtccc.org.uk/. Funding for the project was provided by the Wellcome Trust under award 076113 (see ref. 1). NIMH: 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 co-investigators are as follows: P.V. Gejman (Collaboration coordinator) and A.R. Sanders (ENH/Northwestern University, MH059571); F. Amin (Emory University School of Medicine, MH59587); N. Buccola (Louisiana State University Health Sciences Center, MH067257); W. Byerley (University of California-Irvine,MH60870); C.R. Cloninger (Washington University, St. Louis, U01, MH060879); R. Crowe (PI) and D. Black (University of Iowa, MH59566); R. Freedman (University of Colorado, MH059565); D. Levinson (University of Pennsylvania, MH061675); B. Mowry (University of Queensland, MH059588); and J. Silverman (Mt. Sinai School of Medicine, MH59586). 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). GoKinD: We acknowledge the National Institutes of Health for allowing the use of their control allele signal intensity and genotype data. The dataset(s) used for the analyses described in this manuscript were obtained from the GAIN Database, controlled through dbGaP accession number phs000018.v1.p1.

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Correspondence to Jason D Cooper.

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Supplementary Methods, Supplementary Note, Supplementary Tables 1–5 and Supplementary Figures 1–7 (PDF 445 kb)

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Cooper, J., Smyth, D., Smiles, A. et al. Meta-analysis of genome-wide association study data identifies additional type 1 diabetes risk loci. Nat Genet 40, 1399–1401 (2008). https://doi.org/10.1038/ng.249

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