Letter | Published:

Variants in MTNR1B influence fasting glucose levels

Nature Genetics volume 41, pages 7781 (2009) | Download Citation

Abstract

To identify previously unknown genetic loci associated with fasting glucose concentrations, we examined the leading association signals in ten genome-wide association scans involving a total of 36,610 individuals of European descent. Variants in the gene encoding melatonin receptor 1B (MTNR1B) were consistently associated with fasting glucose across all ten studies. The strongest signal was observed at rs10830963, where each G allele (frequency 0.30 in HapMap CEU) was associated with an increase of 0.07 (95% CI = 0.06–0.08) mmol/l in fasting glucose levels (P = 3.2 × 10−50) and reduced beta-cell function as measured by homeostasis model assessment (HOMA-B, P = 1.1 × 10−15). The same allele was associated with an increased risk of type 2 diabetes (odds ratio = 1.09 (1.05–1.12), per G allele P = 3.3 × 10−7) in a meta-analysis of 13 case-control studies totaling 18,236 cases and 64,453 controls. Our analyses also confirm previous associations of fasting glucose with variants at the G6PC2 (rs560887, P = 1.1 × 10−57) and GCK (rs4607517, P = 1.0 × 10−25) loci.

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Acknowledgements

The authors would like to thank the many colleagues who contributed to collection and phenotypic characterization of the clinical samples, as well as genotyping and analysis of the GWA data. They would also like to acknowledge those who agreed to participate in these studies. Major funding for the work described in this paper comes from Academy of Finland (124243); the Administration of Lanusei, Ilbono, Arzana and Elini (Sardinia, Italy); American Diabetes Association (1-05-RA-140); the Center for Inherited Disease Research; Clinical Research Institute (HUCH); Diabetes UK; the European Bioinformatics Institute; the European Commission (contracts LSHM-CT-2006-037197, LSHM-CT-2003-503041, QLK6-CT-2002-02629, QLG2-CT-2002-01254, HEALTH-F4-2007-201413, LSHG-CT-2004-512066, QLRT-2001-01254, LSHG-CT-2004-518153); the Faculty of Biology and Medicine of Lausanne; Finnish Diabetes Research Foundation; Folkhalsan Research Foundation; Foundation of the NIH (GAIN initiative); German Federal Ministry of Education and Research; German Federal Ministry of Health and Social Security; German National Genome Research Network; GlaxoSmithKline; GSF-National Research Center for Environment and Health; LMUinnovativ; Ministry of Science and Research of the State North-Rhine Westphalia; Municipality of Rotterdam; US National Institutes of Health (HG-02651, HL-084729, HL-087679, HC-25195, N02-HL-6-4278, DK-078616, DK-080140, DK-065978, RR-163736, MH059160, DK069922, DA-021519, DK-062370, DK-072193, US National Human Genome Research Institute intramural project HG-000024; and the Intramural Program of the National Institute on Aging); the UK National Institute for Health Research (Oxford Biomedical Research Centre and Guys and St. Thomas' Biomedical Research Centre); the Netherlands Ministry of Education, Culture and Science; the Netherlands Ministry of Health, Welfare and Sports; Novartis; NWO (904-61-090, 904-61-193, 480-04-004, 400-05-717); NWOGenomics; NWOInvestments; Research Institute for Diseases in the Elderly (RIDE); Sigrid Juselius Foundation; Spinozapremie; Swedish Research Council (349-2006-237); UK Medical Research Council (G0500539, G0000649, G016121); UK National Health Services Research and Development; the Wellcome Trust (including intramural support for the Wellcome Trust Sanger Institute, GR069224, Strategic Awards 076113 and 083948, Biomedical Collections Grant GR072960); and ZonMw (10-000-1002). A full list of acknowledgments is provided in the Supplementary Note.

Author information

Author notes

    • Inga Prokopenko
    • , Claudia Langenberg
    • , Jose C Florez
    • , Richa Saxena
    •  & Nicole Soranzo

    These authors contributed equally to this work.

Affiliations

  1. Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford OX3 7LJ, UK.

    • Inga Prokopenko
    •  & Mark I McCarthy
  2. Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK.

    • Inga Prokopenko
    • , Cecilia M Lindgren
    • , Joshua Randall
    • , Eleftheria Zeggini
    •  & Mark I McCarthy
  3. Medical Research Council Epidemiology Unit, Addenbrooke's Hospital, Cambridge CB2 0QQ, UK.

    • Claudia Langenberg
    • , Ruth J F Loos
    • , Stephen Sharp
    • , Jing Hua Zhao
    • , Manjinder Sandhu
    •  & Nicholas J Wareham
  4. Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, Massachusetts 02142, USA.

    • Jose C Florez
    • , Richa Saxena
    • , Benjamin F Voight
    •  & David Altshuler
  5. Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA.

    • Jose C Florez
    •  & James B Meigs
  6. Center for Human Genetic Research and Diabetes Unit, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.

    • Jose C Florez
  7. Center for Human Genetic Research, Department of Molecular Biology, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.

    • Richa Saxena
    • , Benjamin F Voight
    •  & David Altshuler
  8. Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SA, UK.

    • Nicole Soranzo
    • , Simon C Potter
    • , Eleanor Wheeler
    • , Panos Deloukas
    • , Sarah Hunt
    • , Michael Inouye
    • , Owen T McCann
    • , Leena Peltonen
    •  & Inês Barroso
  9. Twin Research and Genetic Epidemiology Department, King's College London, St. Thomas' Hospital Campus, Lambeth Palace Rd, London SE1 7EH, UK.

    • Nicole Soranzo
    • , Kourosh Ahmadi
    • , Alessandra Cervino
    •  & Tim D Spector
  10. deCODE genetics, 101 Reykjavík, Iceland.

    • Gudmar Thorleifsson
    • , Augustine Kong
    • , Valgerdur Steinthorsdottir
    • , Unnur Thorsteinsdottir
    •  & Kari Stefansson
  11. Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts 02118, USA.

    • Alisa K Manning
    • , L Adrienne Cupples
    •  & Josée Dupuis
  12. Center for Statistical Genetics, Department of Biostatistics, University of Michigan School of Public Health, Ann Arbor, Michigan 48109, USA.

    • Anne U Jackson
    • , Vesela Gateva
    • , Paul Scheet
    • , Laura J Scott
    • , Heather M Stringham
    • , Michael Boehnke
    •  & Gonçalo R Abecasis
  13. Department of Epidemiology, Erasmus MC Rotterdam, Postbus 2040, 3000 CA Rotterdam, The Netherlands.

    • Yurii Aulchenko
    • , Abbas Dehghan
    • , Albert Hofman
    • , Jacqueline C M Witteman
    •  & Cornelia Van Duijn
  14. Genome Technology Branch, National Human Genome Research Institute, Bethesda, Maryland 20892, USA.

    • Michael R Erdos
    • , Lori L Bonnycastle
    • , Francis S Collins
    •  & Angelo Scuteri
  15. Istituto di Neurogenetica e Neurofarmacologia (INN), Consiglio Nazionale delle Ricerche, c/o Cittadella Universitaria di Monserrato, Monserrato, Cagliari 09042, Italy.

    • Serena Sanna
    • , Antonio Cao
    • , Laura Crisponi
    • , Silvia Naitza
    • , Marco Orrù
    •  & Manuela Uda
  16. Department of Biological Psychology, VU University Amsterdam, van der Boechorstraat 1, 1081 BT Amsterdam, The Netherlands.

    • Jouke-Jan Hottenga
    • , Eco J C de Geus
    • , Gonneke Willemsen
    •  & Dorret I Boomsma
  17. Institute of Health Sciences and Biocenter Oulu, P.O. Box 5000, 90014 University of Oulu, Finland.

    • Marika Kaakinen
    •  & Marjo Riitta Jarvelin
  18. Department of Clinical Sciences, Diabetes and Endocrinology, Lund University, University Hospital Malmo, Malmo, Sweden.

    • Valeriya Lyssenko
    •  & Leif C Groop
  19. Center for Public Health Genomics, University of Virginia, Charlottesville, Virginia 22908, USA.

    • Wei-Min Chen
  20. Department of Public Health Sciences, University of Virginia, Charlottesville, Virginia 22908, USA.

    • Wei-Min Chen
  21. Department of Medical Genetics, University of Lausanne, Lausanne, 1005 Switzerland.

    • Jacques S Beckmann
    •  & Toby Johnson
  22. Service of Medical Genetics, Centre Hospitalier Universitaire Vaudois (CHUV), Lausanne, 1011 Switzerland.

    • Jacques S Beckmann
  23. Department of Physiology and Biophysics, Keck School of Medicine, University of Southern California, Los Angeles, California 90033, USA.

    • Richard N Bergman
    •  & Richard M Watanabe
  24. University Institute of Social and Preventive Medicine, Centre Hospitalier Universitaire Vaudois (CHUV), Lausanne, 1011 Switzerland.

    • Murielle Bochud
    •  & Toby Johnson
  25. Department of Medicine, Division of Endocrinology, Keck School of Medicine, University of Southern California, Los Angeles, California 90033, USA.

    • Thomas A Buchanan
  26. Department of Epidemiology and Public Health, Imperial College of London, Norfolk Place, London W2 1PG, UK.

    • Lachlan Coin
    • , Paul Elliott
    •  & Marjo Riitta Jarvelin
  27. Diabetes Research Group, Division of Medicine and Therapeutics, Ninewells Hospital and Medical School, Dundee, UK.

    • Alex S F Doney
    •  & Andrew D Morris
  28. Center for Neurobehavioral Genetics, University of California, 695 Charles E. Young Drive South, Los Angeles, California 90095, USA.

    • Nelson Freimer
  29. Institute for Clinical Diabetology, German Diabetes Center, Leibniz Institute at Heinrich-Heine-University, Düsseldorf, Germany.

    • Christian Herder
  30. Diabetes and Metabolism Disease Area, Novartis Institutes for BioMedical Research, 100 Technology Square, Cambridge, MA 02139, USA.

    • Thomas E Hughes
  31. Helmholtz Zentrum Muenchen, National Research Center for Environmental Health, Institute of Epidemiology, Neuherberg, Germany.

    • Thomas Illig
    •  & H-Erich Wichmann
  32. Malmska Municipal Health Center and Hospital, Jakobstad, Finland.

    • Bo Isomaa
  33. Swiss Institute of Bioinformatics, Switzerland.

    • Toby Johnson
  34. EMBL-EBI, European Bioinformatics Institute, Wellcome Trust Genome Campus, Hinxton, UK.

    • Maria Krestyaninova
  35. Department of Medicine, University of Kuopio and Kuopio University Hospital, Kuopio, Finland.

    • Johanna Kuusisto
    •  & Markku Laakso
  36. Medical Genetics/Clinical Pharmacology and Discovery Medicine, Glaxo SmithKline, King of Prussia, Pennsylvania, 19406 USA.

    • Noha Lim
    • , Kijoung Song
    • , Dawn Waterworth
    • , Xin Yuan
    •  & Vincent Mooser
  37. Skaraborg Institute, Skovde, Sweden.

    • Ulf Lindblad
  38. Department of Clinical Sciences, Community Medicine, Lund University, University Hospital Malmo, Malmo, Sweden.

    • Ulf Lindblad
  39. Department of Genetics, University of North Carolina, Chapel Hill, North Carolina 27599, USA.

    • Karen L Mohlke
  40. Population Pharmacogenetics Group, Biomedical Research Centre, Ninewells Hospital and Medical School, Dundee, UK.

    • Colin N A Palmer
  41. Department of Obstetrics and Gynaecology, Oulu University Hospital, Finland.

    • Anneli Pouta
  42. Department of Child and Adolescent Health, National Public Health Institute (KTL), Aapistie 1, P.O. Box 310, FIN-90101 Oulu, Finland.

    • Anneli Pouta
    •  & Marjo Riitta Jarvelin
  43. Institute of Biometrics and Epidemiology, German Diabetes Center, Leibniz Institute at Heinrich-Heine-University, Düsseldorf, Germany.

    • Wolfgang Rathmann
  44. Savitaipale Health Center, 54800 Savitaipale, Finland.

    • Jouko Saramies
  45. Unità Operativa Geriatria, Istituto per la Patologia Endocrina e Metabolica, Rome, Italy.

    • Angelo Scuteri
  46. Department of Internal Medicine, Erasmus MC, Postbus 2040, 3000 CA Rotterdam, The Netherlands.

    • Eric Sijbrands
    •  & André G Uitterlinden
  47. Department of Psychiatry, University Medical Center Groningen, Hanzeplein 1, 9713 GZ Groningen, The Netherlands.

    • Jan H Smit
  48. Department of Medicine, Helsinki University Hospital, University of Helsinki, Finland.

    • Tiinamaija Tuomi
  49. Diabetes Unit, Department of Health Promotion and Chronic Disease Prevention, National Public Health Institute, Helsinki, 00300 Finland.

    • Jaakko Tuomilehto
  50. South Ostrobothnia Central Hospital, Senäjoki 60220, Finland.

    • Jaakko Tuomilehto
  51. Institute of Medical Informatics, Biometry and Epidemiology, Ludwig Maximilians University, Munich, Germany.

    • H-Erich Wichmann
  52. Gerontology Research Center, National Institute on Aging, Baltimore, Maryland 21224, USA.

    • David Schlessinger
    •  & Edward Lakatta
  53. Department of Public Health and Primary Care, Strangeways Research Laboratory, University of Cambridge, Cambridge, UK.

    • Manjinder Sandhu
    •  & Brenda WJH Penninx
  54. Department of Psychiatry, Leiden University Medical Center, Postbus 9600, 2300 RC Leiden, the Netherlands.

    • Brenda WJH Penninx
  55. Department of Psychiatry, EMGO Institute, Institute of Neuroscience, VU University Medical Center, A.J. Ernstraat 887, 1081 HL Amsterdam, The Netherlands.

    • Brenda WJH Penninx
  56. Department of Internal Medicine, Centre Hospitalier Universitaire Vaudois (CHUV), Lausanne, 1011 Switzerland.

    • Peter Vollenweider
    •  & Gerard Waeber
  57. Division of Endocrinology, Diabetes, and Hypertension, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts USA.

    • Caroline S Fox
  58. The National Heart, Lung, and Blood Institute's Framingham Heart Study, Framingham, Massachusetts USA.

    • Caroline S Fox
  59. Institute of Molecular Medicine, Biomedicum, 00290, Helsinki Finland.

    • Leena Peltonen
  60. Massachusetts Institute of Technology, The Broad Institute, Cambridge, Massachusetts 02141, USA.

    • Leena Peltonen
  61. Faculty of Medicine, University of Iceland, 101 Reykjavík, Iceland.

    • Unnur Thorsteinsdottir
    •  & Kari Stefansson
  62. Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California 90089, USA.

    • Richard M Watanabe
  63. General Medicine Division, Massachusetts General Hospital, Boston, Massachusetts USA.

    • James B Meigs

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Contributions

Project management: DFS: R.N.B., A. Cao, F.S.C., K.L.M., J.T., D.S., M.U., E.L., L.C.G., M. Boehnke, G.R.A.; ENGAGE: P.E., A.H., J.H.S., H.-E.W., G. Willemsen, D.I.B., B.W.J.H.P., M.R.J., L.P., U.T., C.v.D., K. Stefansson, M.I.M.; FHS: J.D., J.B.M.; GEM: T.D.S., I.B., N.J.W.

Study design: DFS: R.S., V.L., R.N.B., T.A.B., A. Cao, F.S.C., K.L.M., L.J.S., J.T., D.S., M.U., E.L., M. Boehnke, R.M.W., G.R.A.; ENGAGE: L.P., A.H., U.T., C.v.D., K. Stefansson, M.I.M.; FHS: J.D., J.C.F., J.B.M.; GEM: C.L., N.S., R.J.F.L., J.S.B., M. Bochud, D.W., M.S., T.D.S., P.V., G. Waeber, V.M., I.B., N.J.W.

Genome-wide association sampling and genotyping: DFS: M.R.E., L.L.B., A. Cao, L. Crisponi, T.E.H., B.I., U.L., S.N., M.O., A.S., H.M.S., T.T., J.T., M.U., D.A., L.C.G.; ENGAGE: P.E., N.F., A.P., E.S., V.S., A.G.U., J.C.M.W., D.I.B., M.R.J., L.P., U.T., C.v.D., K. Stefansson, M.I.M.; FHS: C.S.F., L.A.C., J.D., J.B.M.; GEM: K.A., A. Cervino, P.D., M.I., O.T.M.

Statistical analysis and informatics: DFS: R.S., A.U.J., S. Sanna, W.-M.C., V.G., P.S., B.F.V., R.M.W.; ENGAGE: I.P., G.T., Y.A., J.-J.H., M. Kaakinen, L. Coin, E.J.C.d.G., A.D., C.H., A.K., M. Krestyaninova, C.M.L., J.R., V.S., E.Z., C.v.D.; FHS: A.K.M., J.D.; GEM: C.L., N.S., S.C.P., E.W., S.H., T.J., N.L., S. Sharp, K. Song, X.Y., J.H.Z.

Replication sampling and genotyping: A.S.F.D., A.H., T.I., M.L., A.D.M., C.N.A.P., W.R., J.S., H.E.W.

MAGIC management committee: I.P., C.L., J.C.F., R.S., N.S., G.T., R.J.F.L., A.U.J., Y.A., E.W., V.L., C.M.L., D.W., D.S., M.S., P.V., G. Waeber., L.C.G., V.M., U.T., M. Boehnke, I.B., J.D., R.M.W., M.I.M., N.J.W., J.B.M., G.R.A.

Writing team: I.P., C.L., J.C.F., R.S., N.S., G.T., M. Boehnke, I.B., C.v.D., J.D., R.M.W., K. Stefansson, M.I.M., N.J.W., J.B.M., G.R.A.

Competing interests

Dawn Waterworth and Vincent Mooser are full-time employees of GlaxoSmithKline. Inês Barroso owns stock in GlaxoSmithKline and Incyte. Drs. Thorleifsson, Kong, Steinsthorsdottir, Thorsteinsdottir, and Stefansson are employees at deCODE genetics, and own stock or stock options in the company. Dr. Meigs currently has research grants from GlaxoSmithKline and Sanofi-Aventis, and serves on consultancy boards for GlaxoSmithKline, Sanofi-Aventis, Interleukin Genetics, Kalypsis, and Outcomes Sciences. Dr. Florez has received consulting honoraria from Merck and from Publicis Healthcare Communications, an advertising agency for Amylin Pharmaceuticals.

Corresponding authors

Correspondence to Mark I McCarthy or Nicholas J Wareham or James B Meigs or Gonçalo R Abecasis.

Supplementary information

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    Supplementary Text and Figures

    Supplementary Note, Supplementary Methods, Supplementary Figure 1 and Supplementary Tables 1–6

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DOI

https://doi.org/10.1038/ng.290

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