Abstract

The Wellcome Trust Case Control Consortium (WTCCC) primary genome-wide association (GWA) scan1 on seven diseases, including the multifactorial autoimmune disease type 1 diabetes (T1D), shows associations at P < 5 × 10−7 between T1D and six chromosome regions: 12q24, 12q13, 16p13, 18p11, 12p13 and 4q27. Here, we attempted to validate these and six other top findings in 4,000 individuals with T1D, 5,000 controls and 2,997 family trios independent of the WTCCC study. We confirmed unequivocally the associations of 12q24, 12q13, 16p13 and 18p11 (Pfollow-up ≤ 1.35 × 10−9; Poverall ≤ 1.15 × 10−14), leaving eight regions with small effects or false-positive associations. We also obtained evidence for chromosome 18q22 (Poverall = 1.38 × 10−8) from a GWA study of nonsynonymous SNPs. Several regions, including 18q22 and 18p11, showed association with autoimmune thyroid disease. This study increases the number of T1D loci with compelling evidence from six to at least ten.

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Acknowledgements

This work was funded by the Juvenile Diabetes Research Foundation International and the Wellcome Trust. We gratefully acknowledge the participation of all the patients, control subjects and family members and thank the Human Biological Data Interchange and Diabetes UK for the USA and UK multiplex families, respectively, the Norwegian Study Group for Childhood Diabetes for the collection of Norwegian families (D. Undlien and K. Rønningen), D. Savage, C. Patterson, D. Carson and P. Maxwell for the Northern Irish samples. GET1FIN (J. Tuomilehto, L. Kinnunen, E. Tuomilehto-Wolf, V. Harjutsalo and T. Valle) thank the Academy of Finland, the Sigrid Juselius Foundation and the JDRF for funding. We acknowledge use of the DNA from the 1958 British Birth Cohort collection, funded by the Medical Research Council and Wellcome Trust, and we thank D. Strachan and P. Burton for their help. We also thank The Avon Longitudinal Study of Parents and Children laboratory in Bristol, including S. Ring, R. Jones, M. Pembrey and W. McArdle for preparing and providing the control DNA samples. We thank colleagues at Affymetrix for help and advice in genotyping and T. Willis, M. Faham and P. Hardenbol for the molecular inversion probe technology. We thank the Wellcome Trust for funding the AITD UK national collection; all doctors and nurses in Birmingham, Bournemouth, Cambridge, Cardiff, Exeter, Leeds, Newcastle and Sheffield for recruitment of patients and J. Franklyn, S. Pearce (Newcastle) and P. Newby (Birmingham) for preparing and providing DNA samples on Graves' disease patients. We thank V. Everett, G. Scholz and G. Dolman for information technology support. T1D DNA samples were prepared by K. Bourget, S. Duley, M. Hardy, S. Hawkins, S. Hood, E. King, T. Mistry, A. Simpson, S. Wood, P. Lauder, S. Clayton, F. Wright and C. Collins. We thank L. Peterson for helpful discussions. C.W. is supported by the British Heart Foundation. S. Nejentsev is a Diabetes Research and Wellness Foundation Non-Clinical Fellow.

Author information

Author notes

    • Adrian Vella

    Current address: Endocrine Research Unit, Mayo Clinic College of Medicine, Rochester, Minnesota 55905, USA.

    • Neil M Walker
    • , Jason D Cooper
    •  & Deborah J Smyth

    These authors contributed equally to this work.

Affiliations

  1. Juvenile Diabetes Research Foundation/Wellcome Trust Diabetes and Inflammation Laboratory, Department of Medical Genetics, Cambridge Institute for Medical Research, University of Cambridge, Addenbrooke's Hospital, Cambridge CB2 0XY, UK.

    • John A Todd
    • , Neil M Walker
    • , Jason D Cooper
    • , Deborah J Smyth
    • , Kate Downes
    • , Vincent Plagnol
    • , Rebecca Bailey
    • , Sergey Nejentsev
    • , Sarah F Field
    • , Felicity Payne
    • , Christopher E Lowe
    • , Jeffrey S Szeszko
    • , Jason P Hafler
    • , Lauren Zeitels
    • , Jennie H M Yang
    • , Adrian Vella
    • , Sarah Nutland
    • , Helen E Stevens
    • , Helen Schuilenburg
    • , Gillian Coleman
    • , Meeta Maisuria
    • , William Meadows
    • , Luc J Smink
    • , Barry Healy
    • , Oliver S Burren
    • , Alex A C Lam
    • , Nigel R Ovington
    • , James Allen
    • , Ellen Adlem
    • , Hin-Tak Leung
    • , Joanna M M Howson
    • , Linda S Wicker
    •  & David G Clayton
  2. Department of Clinical Pharmacology, William Harvey Research Institute, Bart's and The London School of Medicine and Dentistry, Charterhouse Square, London EC1M 6BQ, UK.

    • Chris Wallace
  3. Clinic of Diabetes, Institute of Diabetes, Nutrition and Metabolic Disease 'N. Paulescu', Bucharest 79811, Romania.

    • Cristian Guja
    •  & Constantin Ionescu-Tîrgovişte
  4. Genetics of Type 1 Diabetes in Finland (GET1FIN), Diabetes Unit, Department of Health Promotion and Chronic Disease Prevention, National Public Health Institute, Helsinki, Finland.

  5. Division of Medical Sciences, University of Birmingham, Birmingham B15 2TT, UK.

    • Matthew J Simmonds
    • , Joanne M Heward
    •  & Stephen C L Gough
  6. Department of Paediatrics, University of Cambridge, Addenbrooke's Hospital, Cambridge CB2 0XY, UK.

    • David B Dunger

Consortia

  1. Genetics of Type 1 Diabetes in Finland

    1. Genetics of Type 1 Diabetes in Finland (GET1FIN), Diabetes Unit, Department of Health Promotion and Chronic Disease Prevention, National Public Health Institute
  2. the Wellcome Trust Case Control Consortium

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Contributions

Members of the WTCCC are listed in the Supplementary Note. J.A.T. participated in the conception, design and coordination of the study; data analysis and drafting of the manuscript. N.M.W. managed the data and helped coordinate the study. J.D.C. analyzed data and drafted the manuscript. D.J.S. genotyped the nsSNP study and contributed to follow-up genotyping of the nsSNP and WTCCC studies, sequencing and genotyping of IL2 and SOCS1, data analysis and drafting of the manuscript. K.D. contributed to follow-up genotyping of the nsSNP and WTCCC studies, sequencing and genotyping of PTPN2 and data analysis. V.P. developed the nsSNP scoring algorithm and contributed to data analysis. R.B. genotyped the nsSNP study and contributed to follow-up genotyping of the nsSNP study. S. Nejentsev sequenced KIAA0350 and contributed to its bioinformatics analysis, participated in the follow-up genotyping of the WTCCC study and genotyped and analyzed 12q24 SNPs. S.F.F. genotyped the nsSNP study and contributed to follow-up genotyping of the nsSNP study. F.P. sequenced and genotyped CIITA. C.E.L. sequenced and genotyped IL21. J.S.S. genotyped and analyzed the gvSNPs. J.P.H. genotyped CD226 SNPs. L.Z. contributed to follow-up genotyping of the WTCCC scan and bioinformatics analysis. J.H.M.Y. contributed to follow-up genotyping of the WTCCC study. A.V. genotyped the IL2RB tag SNPs. S. Nutland, H.E.S., H.S., G.C., M.M. and W.M. were responsible for the DNA. L.J.S., B.H., O.S.B. and A.A.C.L. provided bioinformatics support. N.R.O. managed subject exclusions and SNP exclusions and the database for the nsSNP study. J.A. and E.A. provided T1DBase support. H.-T.L. and C.W. produced Supplementary Figure 1 and provided statistical support. J.M.M.H. performed statistical analysis; C.G. and C.I.-T. collected the Romanian families; J. Tuomilehto, L. Kinnunen, E. Tuomilehto-Wolf, V. Harjutsalo and T. Valle of GET1FIN collected the Finnish families; M.J.S., J.M.H. and S.C.L.G. provided the Graves' disease cases and genotyping of rs1990760; WTCCC carried out the 500,000-SNP GWA study; D.B.D collected the T1D cases; L.S.W. discovered the CD226 nsSNP splice sequence alterations and contributed to the overall planning of the study and D.G.C. participated in the conception, design and coordination of the study; data analysis and drafting of the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to John A Todd.

Supplementary information

PDF files

  1. 1.

    Supplementary Fig. 1

    Association localization plots.

  2. 2.

    Supplementary Fig. 2

    Cross-species alignment of KIAA0350.

  3. 3.

    Supplementary Table 1

    The locus-specific sibling recurrence-risk ratio of type 1 diabetes susceptibility variants.

  4. 4.

    Supplementary Table 2

    Type 1 diabetes association analyses of SNPs chosen for follow-up from the WTCCC and nsSNP studies in case-controls and families.

  5. 5.

    Supplementary Table 3

    Further genotyping from the 18p11 and 12q24 regions.

  6. 6.

    Supplementary Table 4

    A summary of geographically variable nsSNPs and association analyses in type 1 diabetes.

  7. 7.

    Supplementary Table 5

    Graves' disease case-control association analyses.

  8. 8.

    Supplementary Table 6

    DNA collections and references.

  9. 9.

    Supplementary Table 7

    Concordance between the two GWA studies and TaqMan genotyping.

  10. 10.

    Supplementary Note

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DOI

https://doi.org/10.1038/ng2068

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