Letter | Published:

Meta-analysis of genome-wide association data and large-scale replication identifies additional susceptibility loci for type 2 diabetes

Nature Genetics volume 40, pages 638645 (2008) | Download Citation

Abstract

Genome-wide association (GWA) studies have identified multiple loci at which common variants modestly but reproducibly influence risk of type 2 diabetes (T2D)1,2,3,4,5,6,7,8,9,10,11. Established associations to common and rare variants explain only a small proportion of the heritability of T2D. As previously published analyses had limited power to identify variants with modest effects, we carried out meta-analysis of three T2D GWA scans comprising 10,128 individuals of European descent and 2.2 million SNPs (directly genotyped and imputed), followed by replication testing in an independent sample with an effective sample size of up to 53,975. We detected at least six previously unknown loci with robust evidence for association, including the JAZF1 (P = 5.0 × 10−14), CDC123-CAMK1D (P = 1.2 × 10−10), TSPAN8-LGR5 (P = 1.1 × 10−9), THADA (P = 1.1 × 10−9), ADAMTS9 (P = 1.2 × 10−8) and NOTCH2 (P = 4.1 × 10−8) gene regions. Our results illustrate the value of large discovery and follow-up samples for gaining further insights into the inherited basis of T2D.

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Acknowledgements

UK: Collection of the UK type 2 diabetes cases was supported by Diabetes UK, BDA Research and the UK Medical Research Council (Biomedical Collections Strategic Grant G0000649). The UK Type 2 Diabetes Genetics Consortium collection was supported by the Wellcome Trust (Biomedical Collections Grant GR072960). The GWA genotyping was supported by the Wellcome Trust (076113), and the replication genotyping was supported by the European Commission (EURODIA LSHG-CT-2004- 518153), MRC (Project Grant G0601261), Wellcome Trust, Peninsula Medical School and Diabetes UK. E.Z. is a Wellcome Trust Research Career Development Fellow. We acknowledge the contribution of M. Sampson and our team of research nurses. We acknowledge the efforts of J. Collier, P. Robinson, S. Asquith and others at KBiosciences for their rapid and accurate large-scale genotyping.

DGI: We thank the study participants who made this research possible. We thank colleagues in the Broad Genetic Analysis and Biological Samples Platforms for their expertise and contributions to genotyping, data and sample management, and analysis. The initial GWAS genotyping was supported by Novartis (to D.A.); support for additional analysis and genotyping in this report was provided by funding from the Broad Institute of Harvard and MIT, by the Richard and Susan Smith Family Foundation/American Diabetes Association Pinnacle Program Project Award (to D.A.), and by a Freedom to Discovery award of the Foundation of Bristol Myers Squibb (to D.A.). P.I.W.dB., M.J.D. and D.A. acknowledge support from US National Institutes of Health/National Heart, Lung, and Blood Institute grant (U01 HG004171). D.A. was a Burroughs Wellcome Fund Clinical Scholar in Translational Research and is a Distinguished Clinical Scholar of the Doris Duke Charitable Foundation. L.G., T.T., B.I. and M.R.T. and the Botnia Study are principally supported by the Sigrid Juselius Foundation, the Finnish Diabetes Research Foundation, The Folkhalsan Research Foundation and Clinical Research Institute HUCH Ltd; work in Malmö, Sweden was also funded by a Linné grant from the Swedish Research Council (349-2006-237). We thank the Botnia and Skara research teams for clinical contributions, and colleagues at MGH, Harvard, Broad, Novartis and Lund for helpful discussions throughout the course of this work.

FUSION: We thank the Finnish citizens who generously participated in this study and R.Welch for bioinformatics support. Support for this research was provided by US National Institutes of Health grants DK062370 (M.B.), DK072193 (K.L.M.), HL084729 (G.R.A.), HG002651 (G.R.A.) and U54 DA021519; National Human Genome Research Institute intramural project number 1 Z01 HG000024 (F.S.C.); and a postdoctoral fellowship award from the American Diabetes Association (C.J.W.). Genome-wide genotyping was performed by the Johns Hopkins University Genetic Resources Core Facility (GRCF) SNP Center at the Center for Inherited Disease Research (CIDR) with support from CIDR NIH Contract Number N01-HG-65403 and the GRCF SNP Center.

deCODE: We thank the Icelandic study participants whose contribution made this work possible. We also thank the nurses at Noatun (deCODE's sample recruitment center) and personnel at the deCODE core facilities.

KORA study: We thank C. Gieger and G. Fischer for expert data handling. The MONICA/KORA Augsburg studies were financed by the GSF-National Research Center for Environment and Health, Neuherberg, Germany and supported by grants from the German Federal Ministry of Education and Research (BMBF). Part of this work was financed by the German National Genome Research Network (NGFN). Our research was also supported within the Munich Center of Health Sciences (MC Health) as part of LMUinnovativ. We thank all members of field staffs who were involved in the planning and conduct of the MONICA/KORA Augsburg studies.

Danish study: This work was supported by the European Union (EUGENE2, grant no. LSHM-CT-2004-512013), Lundbeck Foundation centre of Applied Medical Genomics in Personalized Disease Prediction, Prevention and Care and The Danish Medical Research Council.

HUNT: The Nord-Trøndelag Health Study (The HUNT Study) is a collaboration between The HUNT Research Centre, Faculty of Medicine, Norwegian University of Science and Technology (NTNU), The National Institute of Public Health, The National Screening Service of Norway and The Nord-Trøndelag County Council.

NHS: The Nurses' Health Study is funded by National Cancer Institute grant CA87969. L.Q. is supported by an American Heart Association Scientist Development Grant. F.B.H. is supported by NIH grants DK58845 and U01 HG004399.

GEM Consortium: We thank all study participants. The work on the Cambridgeshire case-control, Ely, ADDITION and EPIC-Norfolk studies was funded by support from the Wellcome Trust and MRC. The Norfolk Diabetes study is funded by the MRC with support from NHS Research & Development and the Wellcome Trust. We are grateful to S. Griffin, MRC Epidemiology Unit, for assistance with the ADDITION study and M. Sampson and E. Young for help with the Norfolk Diabetes Study. We thank S. Bumpstead, W.E. Bottomley and A. Chaney for rapid and accurate genotyping and J. Ghori for assay design and informatics support. We are grateful to P. Deloukas for overall genotyping support. F.P. and I.B. are funded by the Wellcome Trust.

METSIM: The METSIM study has received grant support from the Academy of Finland (no. 124243).

Author information

Author notes

    • Eleftheria Zeggini
    • , Laura J Scott
    • , Richa Saxena
    •  & Benjamin F Voight

    These authors contributed equally to this work.

    • Mark I McCarthy
    • , Michael Boehnke
    •  & David Altshuler

    These authors contributed equally to this work.

Affiliations

  1. Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.

    • Eleftheria Zeggini
    • , Katherine S Elliott
    • , Cecilia M Lindgren
    • , Inga Prokopenko
    • , Nigel W Rayner
    • , Nicholas J Timpson
    •  & Mark I McCarthy
  2. Department of Biostatistics and Center for Statistical Genetics, University of Michigan, Ann Arbor, Michigan 48109, USA.

    • Laura J Scott
    • , Tianle Hu
    • , Gonçalo R Abecasis
    • , Chia-Jen Ding
    • , William L Duren
    • , Anne U Jackson
    • , Yun Li
    • , Heather M Stringham
    • , Cristen J Willer
    •  & Michael Boehnke
  3. Broad Institute of Harvard and Massachusetts Institute of Technology (MIT), Cambridge, Massachusetts 02142, USA.

    • Richa Saxena
    • , Benjamin F Voight
    • , Paul IW de Bakker
    • , Kristin Ardlie
    • , Noël P Burtt
    • , Mark J Daly
    • , Lauren Gianniny
    • , Candace Guiducci
    • , Finny G Kuruvilla
    •  & David Altshuler
  4. Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.

    • Richa Saxena
    • , Benjamin F Voight
    • , Mark J Daly
    • , Finny G Kuruvilla
    •  & David Altshuler
  5. Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.

    • Richa Saxena
    • , Benjamin F Voight
    •  & Mark J Daly
  6. Department of Molecular Biology, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.

    • Richa Saxena
    • , Finny G Kuruvilla
    •  & David Altshuler
  7. Department of Medicine, Harvard Medical School, Boston, Massachusetts 02115, USA.

    • Richa Saxena
    • , Benjamin F Voight
    • , Paul IW de Bakker
    • , Mark J Daly
    •  & David Altshuler
  8. Department of Genetics, Harvard Medical School, Boston, Massachusetts 02115, USA.

    • Richa Saxena
    •  & David Altshuler
  9. Department of Statistics, University of Oxford, Oxford, OX1 3TG, UK.

    • Jonathan L Marchini
  10. Division of Genetics, Brigham and Women's Hospital, Harvard-Partners Center for Genetics and Genomics, Boston, Massachusetts 02115, USA.

    • Paul IW de Bakker
  11. Department of Clinical Sciences, Diabetes and Endocrinology Research Unit, University Hospital Malmö, Lund University, S-205 02 Malmö, Sweden.

    • Peter Almgren
    • , Valeriya Lyssenko
    • , Peter Nilsson
    • , Marketa Sjögren
    •  & Leif Groop
  12. Steno Diabetes Center, Copenhagen, DK-2820, Denmark.

    • Gitte Andersen
    • , Knut Borch-Johnsen
    • , Niels Grarup
    • , Torben Hansen
    •  & Oluf Pedersen
  13. Skaraborg Institute, S-541 30 Skövde, Sweden.

    • Kristina Bengtsson Boström
  14. Department of Physiology and Biophysics, Keck School of Medicine, University of Southern California, Los Angeles, California 90033, USA.

    • Richard N Bergman
  15. Genome Technology Branch, National Human Genome Research Institute, Bethesda, Maryland 20892, USA.

    • Lori L Bonnycastle
    • , Peter S Chines
    • , Parimal Deodhar
    • , Michael R Erdos
    • , Kari Kubalanza
    • , Mario A Morken
    • , Narisu Narisu
    • , Matthew Rees
    • , Amy J Swift
    •  & Francis S Collins
  16. Faculty of Health Science, University of Aarhus, Aarhus, DK-8000, Denmark.

    • Knut Borch-Johnsen
    • , Anelli Sandbæk
    •  & Oluf Pedersen
  17. Diabetes and Metabolism Disease Area, Novartis Institutes for BioMedical Research, 100 Technology Square, Cambridge, Massachusetts 02139, USA.

    • Hong Chen
    • , Thomas E Hughes
    •  & Jeffrey J Roix
  18. Diabetes Research Group, Division of Medicine and Therapeutics, Ninewells Hospital and Medical School, Dundee, DD1 9SY, UK.

    • Alex S F Doney
    •  & Andrew D Morris
  19. Genetics of Complex Traits, Institute of Biomedical and Clinical Science, Peninsula Medical School, Magdalen Road, Exeter, EX1 2LU, UK.

    • Timothy M Frayling
    • , Rachel M Freathy
    • , Hana Lango
    • , John R B Perry
    • , Michael N Weedon
    •  & Andrew T Hattersley
  20. Diabetes Genetics, Institute of Biomedical and Clinical Science, Peninsula Medical School, Barrack Road, Exeter, EX2 5DW, UK.

    • Timothy M Frayling
    • , Rachel M Freathy
    • , Hana Lango
    • , John R B Perry
    • , Beverley Shields
    • , Michael N Weedon
    •  & Andrew T Hattersley
  21. Gesellschaft für Strahlenforschung-National Research Center for Environment and Health, Institute of Epidemiology, D-85764 Neuherberg, Germany.

    • Harald Grallert
    • , Christa Meisinger
    •  & Thomas Illig
  22. Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, OX3 7LJ, UK.

    • Christopher J Groves
    • , Cecilia M Lindgren
    • , Katharine R Owen
    • , Inga Prokopenko
    • , Nigel W Rayner
    •  & Mark I McCarthy
  23. Institute for Clinical Diabetes Research, German Diabetes Center, Leibniz Institute at Heinrich Heine University, D-40225 Düsseldorf, Germany.

    • Christian Herder
  24. Centre for Diabetes and Metabolic Medicine, Barts and The London, Royal London Hospital, Whitechapel, London, E1 1BB, UK.

    • Graham A Hitman
  25. Malmska Municipal Health Center and Hospital, FIN-68601 Jakobstad, Finland.

    • Bo Isomaa
  26. Folkhälsan Research Center, FIN-00014 Helsinki, Finland.

    • Bo Isomaa
    •  & Tiinamaija Tuomi
  27. Research Centre for Prevention and Health, Glostrup University Hospital, DK-2600 Glostrup, Denmark.

    • Torben Jørgensen
  28. deCODE genetics, Sturlugata 8, IS-101 Reykjavik, Iceland.

    • Augustine Kong
    • , Valgerdur Steinthorsdottir
    • , Gudmar Thorleifsson
    • , Unnur Thorsteinsdottir
    •  & Kari Stefansson
  29. Department of Medicine, University of Kuopio and Kuopio University Hospital, 70210, Kuopio, Finland.

    • Johanna Kuusisto
    •  & Markku Laakso
  30. MRC Epidemiology Unit, Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge CB2 0QQ, UK.

    • Claudia Langenberg
    •  & Nicholas J Wareham
  31. Department of General Practice, University of Aarhus, DK-8000 Aarhus, Denmark.

    • Torsten Lauritzen
  32. Department of Genetics, University of North Carolina, Chapel Hill, North Carolina 27599, USA.

    • Amanda F Marvelle
    • , Karen L Mohlke
    •  & Li Qin
  33. HUNT Research Centre, Department of Public Health and General Practice, Faculty of Medicine, Norwegian University of Science and Technology (NTNU), 7650 Verdal, Norway.

    • Kristian Midthjell
    • , Carl Platou
    •  & Kristian Hveem
  34. Population Pharmacogenetics Group, Biomedical Research Centre, Ninewells Hospital and Medical School, Dundee, DD1 9SY, UK.

    • Colin NA Palmer
  35. Metabolic Disease Group, Wellcome Trust Sanger Institute, Hinxton, Cambridge, CB10 1SA, UK.

    • Felicity Payne
    •  & Inês Barroso
  36. Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology (NTNU), N-7600 Levanger, Norway.

    • Elin Pettersen
  37. Departments of Nutrition and Epidemiology, Harvard School of Public Health, Boston, Massachusetts 02115, USA.

    • Lu Qi
    •  & Frank B Hu
  38. Channing Laboratory, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA.

    • Lu Qi
    •  & Frank B Hu
  39. The MRC Centre for Causal Analyses in Translational Epidemiology, Bristol University, Canynge Hall, Whiteladies Road, Bristol, BS2 8PR, UK.

    • Nicholas J Timpson
  40. Department of Medicine, Helsinki University Hospital, University of Helsinki, FIN-00300 Helsinki, Finland.

    • Tiinamaija Tuomi
    •  & Leif Groop
  41. Diabetes Unit, Department of Epidemiology and Health Promotion, National Public Health Institute, 00300 Helsinki, Finland.

    • Jaakko Tuomilehto
  42. Department of Public Health, University of Helsinki, 00014 Helsinki, Finland.

    • Jaakko Tuomilehto
  43. South Ostrobothnia Central Hospital, 60220 Seinäjoki, Finland.

    • Jaakko Tuomilehto
  44. Diabetes Research Group, School of Clinical Medical Sciences, Newcastle University, Framlington Place, Newcastle upon Tyne, NE2 4HH, UK.

    • Mark Walker
  45. Department of Preventative Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California 90033, USA.

    • Richard M Watanabe
  46. Diabetes Unit, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.

    • David Altshuler

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Contributions

Writing team and project management: L.J.S., E.Z., R.S., B.F.V., D.A., M.B. & M.I.M. Study design: R.S., B.F.V., E.Z., L.J.S., T.E.H., F.B.H., J.J.R., H.C., K.S., O.P., T.I., K.H., M.L., A.T.H., I.B., N.J.W., F.S.C., L.G., D.A., M.I.M. & M.B. Analysis: K.S.E., R.M.F., H.L., C.M.L., J.R.B.P., I.P., N.W.R., N.J.T., M.N.W., J.L.M. & E.Z. (UK), P.S.C., C.-J.D., W.L.D., T. Hu, A.U.J., Y.L., H.M.S., C.J.W., G.R.A. & L.J.S. (FUSION), R.S., B.F.V., P.I.W.dB., F.G.K., P.A. & M.J.D. (DGI), U.T. & A.K. (deCODE), N.G., G.A., T.H. & O.P. (Danish), K.M. (HUNT), L. Qi (NHS), C.L. (GEM Consortium), M.L. (Metsim). Clinical samples and genotyping: WTCCC, A.S.F.D., T.M.F., C.J.G., G.A.H., K.R.O., C.N.A.P., B.S., M.W., A.D.M., A.T.H. & M.I.M. (UK), L.L.B., P.D., M.R.E., K.K., M.A.M., N.N., M.R., A.J.S., R.N.B., K.L.M., J.T., A.F.M., L. Qin & R.M.W. (FUSION), K.A., K.B.B., N.P.B., L. Gianniny, C.G., B.I., V.L., P.N., M.S., T.T. & L. Groop (DGI), V.S., G.T. & K.S. (deCODE), H.G., C.H., C.M. & T.I. (KORA), G.A., N.G., T.H., T.J., T.L., A.S., K.B.-J. & O.P. (Danish), K.M., E.P., C.P. & K.H. (HUNT), F.B.H. (NHS), F.P., I.B. & N.J.W. (GEM Consortium), J.K. (METSIM).

Competing interests

G.T., V.S., A.K., K.S. and U.T. are employees at deCODE genetics, and own stock or stock options in the company. J.J.R., T.E.H. and H.C. are employees and shareholders of Novartis Institute of Biomedical Research, Inc. O.P. K.B.-J., G.A., N.G. and T.H. are employees of the Steno Diabetes Center, a hospital providing health service for the public health care system but owned by Novo Nordisk A/S, Bagsværd, Denmark. O.P., K.B.-J., N.G. and T.H. hold equity in Novo Nordisk A/S. I.B. holds equity in GlaxoSmithKline and Incyte.

Corresponding authors

Correspondence to Mark I McCarthy or Michael Boehnke or David Altshuler.

Supplementary information

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  1. 1.

    Supplementary Text and Figures

    Supplementary Methods, Supplementary Figures 1–4, Supplementary Tables 1–4 and 6–10 , Supplementary Note

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  1. 1.

    Supplementary Table 5

    Details of stage 1, 2, 3 and meta-analysis results for the set of SNPs followed-up after stage 1 meta-analysis

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DOI

https://doi.org/10.1038/ng.120

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