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Common variants in WFS1 confer risk of type 2 diabetes

Nature Genetics volume 39, pages 951–953 (2007)Cite this article

Abstract

We studied genes involved in pancreatic β cell function and survival, identifying associations between SNPs in WFS1 and diabetes risk in UK populations that we replicated in an Ashkenazi population and in additional UK studies. In a pooled analysis comprising 9,533 cases and 11,389 controls, SNPs in WFS1 were strongly associated with diabetes risk. Rare mutations in WFS1 cause Wolfram syndrome; using a gene-centric approach, we show that variation in WFS1 also predisposes to common type 2 diabetes.

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Acknowledgements

We thank all study participants. We acknowledge use of DNA from the British 1958 Birth Cohort collection, funded by the UK Medical Research Council (MRC) grant G0000934 and the Wellcome Trust grant 068545/Z/02. The Ashkenazi population was collected by the Israeli Diabetes Research Group, funded by the Russell Berrie Foundation, D-Cure, Diabetes Care in Israel, Israel Ministry of Health and an unrestricted research grant from Novo-Nordisk. The Wellcome Trust and Diabetes UK funded the Warren 2 study. The work on the Cambridgeshire case-control, Ely, ADDITION and EPIC-Norfolk studies was funded by support from the Wellcome Trust and MRC. We are grateful to S. Griffin, MRC Epidemiology Unit for assistance with the ADDITION study and to S. O'Rahilly and M. Sampson for their contribution to the Warren 2 study. The UK type 2 diabetes case/control collection (Go-DARTS2) was funded by the Wellcome Trust. C.N.A.P. and A.D.M. are supported by the Scottish Executive Chief Scientist's Office as part of the Generation Scotland initiative. Illumina genotyping was done by P. Deloukas's laboratory at the Wellcome Trust Sanger Institute. I. Blech. and K.A.F. are funded by the Wellcome Trust. I.B. acknowledges support from EU FP6 funding (contract number LSHM-CT-2003-503041). A.T.H. is a Wellcome Trust Research Leave Fellow. M.N.W. is a Vandervell Foundation Research Fellow. S.L.D. is funded by the British Heart Foundation. None of the sponsors or funders had any role in the design and conduct of the study, in the collection, analysis and interpretation of the data or in the preparation, review or approval of the manuscript.

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Author notes

  1. Manjinder S Sandhu and Michael N Weedon: These authors contributed equally to this work.

Authors and Affiliations

  1. UK Medical Research Council (MRC) Epidemiology Unit, Strangeways Research Laboratory, Cambridge, CB1 8RN, UK

    Manjinder S Sandhu & Nicholas J Wareham

  2. Department of Public Health and Primary Care, Institute of Public Health, University of Cambridge, Cambridge, CB2 0SR, UK

    Manjinder S Sandhu & Sally L Debenham

  3. Institute of Biomedical and Clinical Science, Peninsula Medical School, Exeter, EX1 2LU, UK

    Michael N Weedon, Hana Lango, Timothy M Frayling & Andrew T Hattersley

  4. Metabolic Disease Group, Wellcome Trust Sanger Institute, Hinxton, Cambridge, CB10 1SA, UK

    Katherine A Fawcett, Allan Daly & Inês Barroso

  5. Washington University School of Medicine, St. Louis, 63110, Missouri, USA

    Jon Wasson, Rosalind J Neumann, Richard Sherva & M Alan Permutt

  6. Endocrine and Metabolism Service, The Hadassah Hebrew University Medical Center, Jerusalem, 91120, Israel

    Ilana Blech & Benjamin Glaser

  7. Cancer Research UK Department of Oncology, Strangeways Research Laboratory, University of Cambridge, Cambridge, CB1 8RN, UK

    Paul D Pharoah

  8. Population Pharmacogenetics Group, Biomedical Research Centre, University of Dundee, Dundee, DD1 9SY, UK

    Colin N A Palmer, Charlotte Kimber & Roger Tavendale

  9. Division of Medicine and Therapeutics, Diabetes Research Group, Ninewells Hospital and Medical School, University of Dundee, Dundee, DD1 9SY, UK

    Andrew D Morris

  10. Oxford Centre for Diabetes, Endocrinology and Metabolism, Oxford, OX3 7LJ, UK

    Mark I McCarthy

  11. Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, OX3 7BN, UK

    Mark I McCarthy

  12. Diabetes Research Group, School of Clinical Medical Sciences, Newcastle University, Newcastle upon Tyne, NE2 4HH, UK

    Mark Walker

  13. Centre for Diabetes and Metabolic Medicine, Barts and the London, Queen Mary's School of Medicine and Dentistry, University of London, London, E1 1BB, UK

    Graham Hitman

Authors
  1. Manjinder S Sandhu
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  2. Michael N Weedon
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  3. Katherine A Fawcett
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  4. Jon Wasson
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  5. Sally L Debenham
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  6. Allan Daly
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  7. Hana Lango
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  8. Timothy M Frayling
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  9. Rosalind J Neumann
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  10. Richard Sherva
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  11. Ilana Blech
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  12. Paul D Pharoah
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  13. Colin N A Palmer
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  14. Charlotte Kimber
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  15. Roger Tavendale
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  16. Andrew D Morris
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  17. Mark I McCarthy
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  18. Mark Walker
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  19. Graham Hitman
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  20. Benjamin Glaser
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  21. M Alan Permutt
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  22. Andrew T Hattersley
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  23. Nicholas J Wareham
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  24. Inês Barroso
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Contributions

I. Barroso, A.T.H., M.A.P., N.J.W. and M.S.S. designed this study; M.S.S. did the statistical analysis, supported by I. Barroso, A.D., S.L.D., K.A.F., H.L., R.J.N., P.D.P., R.S. and M.N.W. M.S.S. wrote the manuscript with I. Barroso, S.L.D. and K.A.F.; A.D. conducted the bioinformatic analysis; I. Blech., S.L.D., K.A.F. and C.K. arrayed and genotyped the replication studies; B.G., A.T.H., G.H., C.K., A.D.M., M.I.M., C.N.A.P., M.W., R.T., J.W. and N.J.W. provided study samples and all authors contributed to data interpretation and commented on the final manuscript.

Corresponding authors

Correspondence to Manjinder S Sandhu or Inês Barroso.

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Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–2, Supplementary Tables 1–4, Supplementary Methods (PDF 377 kb)

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Sandhu, M., Weedon, M., Fawcett, K. et al. Common variants in WFS1 confer risk of type 2 diabetes. Nat Genet 39, 951–953 (2007). https://doi.org/10.1038/ng2067

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