Abstract

Genome-wide association studies have revealed that common noncoding variants in MTNR1B (encoding melatonin receptor 1B, also known as MT2) increase type 2 diabetes (T2D) risk1,2. Although the strongest association signal was highly significant (P < 1 × 10−20), its contribution to T2D risk was modest (odds ratio (OR) of 1.10–1.15)1,2,3. We performed large-scale exon resequencing in 7,632 Europeans, including 2,186 individuals with T2D, and identified 40 nonsynonymous variants, including 36 very rare variants (minor allele frequency (MAF) <0.1%), associated with T2D (OR = 3.31, 95% confidence interval (CI) = 1.78–6.18; P = 1.64 × 10−4). A four-tiered functional investigation of all 40 mutants revealed that 14 were non-functional and rare (MAF < 1%), and 4 were very rare with complete loss of melatonin binding and signaling capabilities. Among the very rare variants, the partial- or total-loss-of-function variants but not the neutral ones contributed to T2D (OR = 5.67, CI = 2.17–14.82; P = 4.09 × 10−4). Genotyping the four complete loss-of-function variants in 11,854 additional individuals revealed their association with T2D risk (8,153 individuals with T2D and 10,100 controls; OR = 3.88, CI = 1.49–10.07; P = 5.37 × 10−3). This study establishes a firm functional link between MTNR1B and T2D risk.

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Acknowledgements

We are sincerely indebted to all participants in the genetic study. We thank M. Deweirder and F. Allegaert for their technical assistance and their invaluable management of DNA samples and B. Gardiola-Lemaître for her invaluable advice. This study was supported by the French Agence Nationale de la Recherche (ANR-08-GENOPAT to P.F. and ANR-11-blanc 'MLT2D' and ANR-11-META 'MELA-BETES' to R.J. and P.F.), the Contrat de Projets Etat-Région Nord-Pas-De-Calais (CPER 2007-2013 'Axe Cardio-Diabète' to P.F.), the Société Francophone du Diabète (to A.B.), the Fondation Recherche Médicale ('Equipe FRM' to R.J.), Inserm and CNRS. I.B. acknowledges funding from the Wellcome Trust (077016/Z/05/Z) and from the UK National Institute for Health Research (NIHR) Cambridge Biomedical Research Centre and the MRC Centre for Obesity and Related Metabolic Diseases.

Author information

Author notes

    • Amélie Bonnefond
    •  & Nathalie Clément

    These authors contributed equally to this work.

    • Ralf Jockers
    •  & Philippe Froguel

    These authors jointly directed this work.

Affiliations

  1. Centre National de la Recherche Scientifique (CNRS) Unité Mixte de Recherche (UMR) 8199, Lille Pasteur Institute, Lille, France.

    • Amélie Bonnefond
    • , Loïc Yengo
    • , Emmanuel Vaillant
    • , Aurélie Dechaume
    • , Nabila Bouatia-Naji
    • , Martine Vaxillaire
    •  & Philippe Froguel
  2. Ecole Doctorale de Biologie–Santé, Lille Nord de France University, Lille, France.

    • Amélie Bonnefond
    • , Loïc Yengo
    • , Emmanuel Vaillant
    • , Aurélie Dechaume
    • , Nabila Bouatia-Naji
    • , Martine Vaxillaire
    •  & Philippe Froguel
  3. Institut National de la Santé et de la Recherche Médicale (Inserm) U1016, Institut Cochin, Paris, France.

    • Nathalie Clément
    • , Jean-Luc Guillaume
    •  & Ralf Jockers
  4. CNRS UMR 8104, Paris, France.

    • Nathalie Clément
    • , Jean-Luc Guillaume
    •  & Ralf Jockers
  5. Department of Medicine, Paris Descartes University, Paris, France.

    • Nathalie Clément
    • , Jean-Luc Guillaume
    •  & Ralf Jockers
  6. Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK.

    • Katherine Fawcett
    • , Felicity Payne
    •  & Inês Barroso
  7. Department of Endocrinology, Diabetology and Nutrition, Bichat-Claude Bernard University Hospital, Assistance Publique des Hôpitaux de Paris (AP-HP), Paris, France.

    • Ronan Roussel
    •  & Michel Marre
  8. Inserm U695, Paris 7 University, Paris, France.

    • Ronan Roussel
    •  & Michel Marre
  9. Department of Nutrition, Ambroise Paré Hospital, AP-HP, Boulogne-Billancourt, France.

    • Sébastien Czernichow
  10. Unité de Formation et de Recherche (UFR) des Sciences de la Santé, University of Versailles Saint-Quentin, Boulogne-Billancourt, France.

    • Sébastien Czernichow
  11. Inserm U557, Institut National de la Recherche Agronomique Unit 1125, Conservatoire National des Arts et Métiers, Centre de Recherches en Nutrition Humaine, Paris 13 University, Bobigny, France.

    • Serge Hercberg
  12. Department of Public Health, Avicenne Hospital, AP-HP, Bobigny, France.

    • Serge Hercberg
  13. Department of Endocrinology and Diabetology, Centre Hospitalier Universitaire Poitiers, Poitiers, France.

    • Samy Hadjadj
  14. Inserm U927, Clinical Investigation Centre of Poitiers (Biotheque CIC0802), Poitiers, France.

    • Samy Hadjadj
  15. Inserm U780, Centre for Research in Epidemiology and Population Health, Villejuif, France.

    • Beverley Balkau
  16. Santé Publique, Paris-Sud 11 University, Orsay, France.

    • Beverley Balkau
  17. Institut Inter-Régional pour la Santé (IRSA), La Riche, France.

    • Olivier Lantieri
  18. Medical Research Council (MRC) Epidemiology Unit, Institute of Metabolic Science, University of Cambridge, Cambridge, UK.

    • Claudia Langenberg
    •  & Nicholas J Wareham
  19. Department of Endocrinology and Diabetology, Corbeil-Essonnes Hospital, Essonnes, France.

    • Guillaume Charpentier
  20. Centre de Recherche, Centre Hospitalier de l′Université de Montreal, Montreal, Quebec, Canada.

    • Ghislain Rocheleau
  21. Prognomix, Montreal, Quebec, Canada.

    • Ghislain Rocheleau
  22. Department of Human Genetics, Faculty of Medicine, McGill University, Montreal, Quebec, Canada.

    • Robert Sladek
  23. Genome Quebec Innovation Centre, Montreal, Quebec, Canada.

    • Robert Sladek
  24. Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, UK.

    • Mark I McCarthy
  25. Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.

    • Mark I McCarthy
  26. Inserm U915, Institut du Thorax, Nantes, France.

    • Christian Dina
  27. CNRS Equipe de Recherche Labellisée 3147, Nantes, France.

    • Christian Dina
  28. Department of Biology, Medicine and Health, Nantes University, Nantes, France.

    • Christian Dina
  29. Metabolic Research Labs, Institute of Metabolic Science, Addenbrooke's Hospital, University of Cambridge, Cambridge, UK.

    • Inês Barroso
  30. Department of Genomics of Common Disease, School of Public Health, Imperial College London, Hammersmith Hospital, London, UK.

    • Philippe Froguel

Consortia

  1. The Meta-Analysis of Glucose and Insulin-Related Traits Consortium (MAGIC)

    A list of members is provided in the Supplementary Note.

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Contributions

A.B., R.J. and P.F. wrote the manuscript, and N.C., J.-L.G., M.V., C.D., R.S., M.I.M. and I.B. reviewed and/or edited the manuscript and contributed to discussion. R.J. and P.F. managed the project. L.Y. performed the statistical analyses, and A.B., G.R. and C.D. contributed to statistical analyses. A.B. and K.F. performed the sequencing. E.V. performed the genotyping. A.B., N.C., E.V., J.-L.G. and A.D. performed the functional analyses. F.P., R.R., S.C., S. Hercberg, S. Hadjadj, B.B., M.M., O.L., C.L., N.B.-N., MAGIC, G.C., N.J.W., M.I.M. and I.B. contributed to cohort study samples and researched data.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Ralf Jockers or Philippe Froguel.

Supplementary information

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    Supplementary Text and Figures

    Supplementary Tables 1–4, Supplementary Figures 1–4 and Supplementary Note

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DOI

https://doi.org/10.1038/ng.1053

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