Letter abstract


Nature Genetics 41, 77 - 81 (2008)
Published online: 7 December 2008 | doi:10.1038/ng.290

Variants in MTNR1B influence fasting glucose levels

Inga Prokopenko1,2,64, Claudia Langenberg3,64, Jose C Florez4,5,6,64, Richa Saxena4,7,64, Nicole Soranzo8,9,64, Gudmar Thorleifsson10, Ruth J F Loos3, Alisa K Manning11, Anne U Jackson12, Yurii Aulchenko13, Simon C Potter8, Michael R Erdos14, Serena Sanna15, Jouke-Jan Hottenga16, Eleanor Wheeler8, Marika Kaakinen17, Valeriya Lyssenko18, Wei-Min Chen19,20, Kourosh Ahmadi9, Jacques S Beckmann21,22, Richard N Bergman23, Murielle Bochud24, Lori L Bonnycastle14, Thomas A Buchanan25, Antonio Cao15, Alessandra Cervino9, Lachlan Coin26, Francis S Collins14, Laura Crisponi15, Eco J C de Geus16, Abbas Dehghan13, Panos Deloukas8, Alex S F Doney27, Paul Elliott26, Nelson Freimer28, Vesela Gateva12, Christian Herder29, Albert Hofman13, Thomas E Hughes30, Sarah Hunt8, Thomas Illig31, Michael Inouye8, Bo Isomaa32, Toby Johnson21,24,33, Augustine Kong10, Maria Krestyaninova34, Johanna Kuusisto35, Markku Laakso35, Noha Lim36, Ulf Lindblad37,38, Cecilia M Lindgren2, Owen T McCann8, Karen L Mohlke39, Andrew D Morris27, Silvia Naitza15, Marco Orrù15, Colin N A Palmer40, Anneli Pouta41,42, Joshua Randall2, Wolfgang Rathmann43, Jouko Saramies44, Paul Scheet12, Laura J Scott12, Angelo Scuteri14,45, Stephen Sharp3, Eric Sijbrands46, Jan H Smit47, Kijoung Song36, Valgerdur Steinthorsdottir10, Heather M Stringham12, Tiinamaija Tuomi48, Jaakko Tuomilehto49,50, André G Uitterlinden46, Benjamin F Voight4,7, Dawn Waterworth36, H-Erich Wichmann31,51, Gonneke Willemsen16, Jacqueline C M Witteman13, Xin Yuan36, Jing Hua Zhao3, Eleftheria Zeggini2, David Schlessinger52, Manjinder Sandhu3,53, Dorret I Boomsma16, Manuela Uda15, Tim D Spector9, Brenda WJH Penninx53,54,55, David Altshuler4,7, Peter Vollenweider56, Marjo Riitta Jarvelin17,26,42, Edward Lakatta52, Gerard Waeber56, Caroline S Fox57,58, Leena Peltonen8,59,60, Leif C Groop18, Vincent Mooser36, L Adrienne Cupples11, Unnur Thorsteinsdottir10,61, Michael Boehnke12, Inês Barroso8, Cornelia Van Duijn13, Josée Dupuis11, Richard M Watanabe23,62, Kari Stefansson10,61, Mark I McCarthy1,2, Nicholas J Wareham3, James B Meigs5,63 & Gonçalo R Abecasis12

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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 times 10-50) and reduced beta-cell function as measured by homeostasis model assessment (HOMA-B, P = 1.1 times 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 times 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 times 10-57) and GCK (rs4607517, P = 1.0 times 10-25) loci.

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  1. Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford OX3 7LJ, UK.
  2. Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK.
  3. Medical Research Council Epidemiology Unit, Addenbrooke's Hospital, Cambridge CB2 0QQ, UK.
  4. Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, Massachusetts 02142, USA.
  5. Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA.
  6. Center for Human Genetic Research and Diabetes Unit, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.
  7. Center for Human Genetic Research, Department of Molecular Biology, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.
  8. Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SA, UK.
  9. Twin Research and Genetic Epidemiology Department, King's College London, St. Thomas' Hospital Campus, Lambeth Palace Rd, London SE1 7EH, UK.
  10. deCODE genetics, 101 Reykjavík, Iceland.
  11. Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts 02118, USA.
  12. Center for Statistical Genetics, Department of Biostatistics, University of Michigan School of Public Health, Ann Arbor, Michigan 48109, USA.
  13. Department of Epidemiology, Erasmus MC Rotterdam, Postbus 2040, 3000 CA Rotterdam, The Netherlands.
  14. Genome Technology Branch, National Human Genome Research Institute, Bethesda, Maryland 20892, USA.
  15. Istituto di Neurogenetica e Neurofarmacologia (INN), Consiglio Nazionale delle Ricerche, c/o Cittadella Universitaria di Monserrato, Monserrato, Cagliari 09042, Italy.
  16. Department of Biological Psychology, VU University Amsterdam, van der Boechorstraat 1, 1081 BT Amsterdam, The Netherlands.
  17. Institute of Health Sciences and Biocenter Oulu, P.O. Box 5000, 90014 University of Oulu, Finland.
  18. Department of Clinical Sciences, Diabetes and Endocrinology, Lund University, University Hospital Malmo, Malmo, Sweden.
  19. Center for Public Health Genomics, University of Virginia, Charlottesville, Virginia 22908, USA.
  20. Department of Public Health Sciences, University of Virginia, Charlottesville, Virginia 22908, USA.
  21. Department of Medical Genetics, University of Lausanne, Lausanne, 1005 Switzerland.
  22. Service of Medical Genetics, Centre Hospitalier Universitaire Vaudois (CHUV), Lausanne, 1011 Switzerland.
  23. Department of Physiology and Biophysics, Keck School of Medicine, University of Southern California, Los Angeles, California 90033, USA.
  24. University Institute of Social and Preventive Medicine, Centre Hospitalier Universitaire Vaudois (CHUV), Lausanne, 1011 Switzerland.
  25. Department of Medicine, Division of Endocrinology, Keck School of Medicine, University of Southern California, Los Angeles, California 90033, USA.
  26. Department of Epidemiology and Public Health, Imperial College of London, Norfolk Place, London W2 1PG, UK.
  27. Diabetes Research Group, Division of Medicine and Therapeutics, Ninewells Hospital and Medical School, Dundee, UK.
  28. Center for Neurobehavioral Genetics, University of California, 695 Charles E. Young Drive South, Los Angeles, California 90095, USA.
  29. Institute for Clinical Diabetology, German Diabetes Center, Leibniz Institute at Heinrich-Heine-University, Düsseldorf, Germany.
  30. Diabetes and Metabolism Disease Area, Novartis Institutes for BioMedical Research, 100 Technology Square, Cambridge, MA 02139, USA.
  31. Helmholtz Zentrum Muenchen, National Research Center for Environmental Health, Institute of Epidemiology, Neuherberg, Germany.
  32. Malmska Municipal Health Center and Hospital, Jakobstad, Finland.
  33. Swiss Institute of Bioinformatics, Switzerland.
  34. EMBL-EBI, European Bioinformatics Institute, Wellcome Trust Genome Campus, Hinxton, UK.
  35. Department of Medicine, University of Kuopio and Kuopio University Hospital, Kuopio, Finland.
  36. Medical Genetics/Clinical Pharmacology and Discovery Medicine, Glaxo SmithKline, King of Prussia, Pennsylvania, 19406 USA.
  37. Skaraborg Institute, Skovde, Sweden.
  38. Department of Clinical Sciences, Community Medicine, Lund University, University Hospital Malmo, Malmo, Sweden.
  39. Department of Genetics, University of North Carolina, Chapel Hill, North Carolina 27599, USA.
  40. Population Pharmacogenetics Group, Biomedical Research Centre, Ninewells Hospital and Medical School, Dundee, UK.
  41. Department of Obstetrics and Gynaecology, Oulu University Hospital, Finland.
  42. Department of Child and Adolescent Health, National Public Health Institute (KTL), Aapistie 1, P.O. Box 310, FIN-90101 Oulu, Finland.
  43. Institute of Biometrics and Epidemiology, German Diabetes Center, Leibniz Institute at Heinrich-Heine-University, Düsseldorf, Germany.
  44. Savitaipale Health Center, 54800 Savitaipale, Finland.
  45. Unità Operativa Geriatria, Istituto per la Patologia Endocrina e Metabolica, Rome, Italy.
  46. Department of Internal Medicine, Erasmus MC, Postbus 2040, 3000 CA Rotterdam, The Netherlands.
  47. Department of Psychiatry, University Medical Center Groningen, Hanzeplein 1, 9713 GZ Groningen, The Netherlands.
  48. Department of Medicine, Helsinki University Hospital, University of Helsinki, Finland.
  49. Diabetes Unit, Department of Health Promotion and Chronic Disease Prevention, National Public Health Institute, Helsinki, 00300 Finland.
  50. South Ostrobothnia Central Hospital, Senäjoki 60220, Finland.
  51. Institute of Medical Informatics, Biometry and Epidemiology, Ludwig Maximilians University, Munich, Germany.
  52. Gerontology Research Center, National Institute on Aging, Baltimore, Maryland 21224, USA.
  53. Department of Public Health and Primary Care, Strangeways Research Laboratory, University of Cambridge, Cambridge, UK.
  54. Department of Psychiatry, Leiden University Medical Center, Postbus 9600, 2300 RC Leiden, the Netherlands.
  55. Department of Psychiatry, EMGO Institute, Institute of Neuroscience, VU University Medical Center, A.J. Ernstraat 887, 1081 HL Amsterdam, The Netherlands.
  56. Department of Internal Medicine, Centre Hospitalier Universitaire Vaudois (CHUV), Lausanne, 1011 Switzerland.
  57. Division of Endocrinology, Diabetes, and Hypertension, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts USA.
  58. The National Heart, Lung, and Blood Institute's Framingham Heart Study, Framingham, Massachusetts USA.
  59. Institute of Molecular Medicine, Biomedicum, 00290, Helsinki Finland.
  60. Massachusetts Institute of Technology, The Broad Institute, Cambridge, Massachusetts 02141, USA.
  61. Faculty of Medicine, University of Iceland, 101 Reykjavík, Iceland.
  62. Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California 90089, USA.
  63. General Medicine Division, Massachusetts General Hospital, Boston, Massachusetts USA.
  64. These authors contributed equally to this work.

Correspondence to: Gonçalo R Abecasis12 e-mail: goncalo@umich.edu

Correspondence to: James B Meigs5,63 e-mail: jmeigs@partners.org

Correspondence to: Nicholas J Wareham3 e-mail: nick.wareham@mrc-epid.cam.ac.uk

Correspondence to: Mark I McCarthy1,2 e-mail: mark.mccarthy@drl.ox.ac.uk