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Rare MTNR1B variants impairing melatonin receptor 1B function contribute to type 2 diabetes

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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Figure 1: Distribution of the 40 nonsynonymous MT2 variants identified by exon resequencing.
Figure 2: Functional characterization of wild-type and mutant MT2 receptors.
Figure 3: Odds ratio estimates of partial or total loss-of-function variants compared to neutral very rare (MAF <0.1%) variants for T2D risk determined on the basis of MTNR1B sequencing data.

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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.

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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.

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Correspondence to Ralf Jockers or Philippe Froguel.

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The authors declare no competing financial interests.

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A list of members is provided in the Supplementary Note.

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Supplementary Tables 1–4, Supplementary Figures 1–4 and Supplementary Note (PDF 707 kb)

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Bonnefond, A., Clément, N., Fawcett, K. et al. Rare MTNR1B variants impairing melatonin receptor 1B function contribute to type 2 diabetes. Nat Genet 44, 297–301 (2012). https://doi.org/10.1038/ng.1053

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