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.
Subscribe to Journal
Get full journal access for 1 year
only $4.92 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Tax calculation will be finalised during checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Bouatia-Naji, N. et al. A variant near MTNR1B is associated with increased fasting plasma glucose levels and type 2 diabetes risk. Nat. Genet. 41, 89–94 (2009).
Prokopenko, I. et al. Variants in MTNR1B influence fasting glucose levels. Nat. Genet. 41, 77–81 (2009).
Voight, B.F. et al. Twelve type 2 diabetes susceptibility loci identified through large-scale association analysis. Nat. Genet. 42, 579–589 (2010).
Bass, J. & Takahashi, J.S. Circadian integration of metabolism and energetics. Science 330, 1349–1354 (2010).
Marcheva, B. et al. Disruption of the clock components CLOCK and BMAL1 leads to hypoinsulinaemia and diabetes. Nature 466, 627–631 (2010).
Dubocovich, M.L. et al. International Union of Basic and Clinical Pharmacology. LXXV. Nomenclature, classification, and pharmacology of G protein–coupled melatonin receptors. Pharmacol. Rev. 62, 343–380 (2010).
Jockers, R., Maurice, P., Boutin, J.A. & Delagrange, P. Melatonin receptors, heterodimerization, signal transduction and binding sites: what′s new? Br. J. Pharmacol. 154, 1182–1195 (2008).
Manolio, T.A. et al. Finding the missing heritability of complex diseases. Nature 461, 747–753 (2009).
Schork, N.J., Murray, S.S., Frazer, K.A. & Topol, E.J. Common vs. rare allele hypotheses for complex diseases. Curr. Opin. Genet. Dev. 19, 212–219 (2009).
Nejentsev, S., Walker, N., Riches, D., Egholm, M. & Todd, J.A. Rare variants of IFIH1, a gene implicated in antiviral responses, protect against type 1 diabetes. Science 324, 387–389 (2009).
Downes, K. et al. Reduced expression of IFIH1 is protective for type 1 diabetes. PLoS ONE 5, e12646 (2010).
Johansen, C.T. et al. Excess of rare variants in genes identified by genome-wide association study of hypertriglyceridemia. Nat. Genet. 42, 684–687 (2010).
Coventry, A. et al. Deep resequencing reveals excess rare recent variants consistent with explosive population growth. Nat. Commun. 1, 131 (2010).
Liu, D.J. & Leal, S.M. A novel adaptive method for the analysis of next-generation sequencing data to detect complex trait associations with rare variants due to gene main effects and interactions. PLoS Genet. 6, e1001156 (2010).
Nygaard, R., Frimurer, T.M., Holst, B., Rosenkilde, M.M. & Schwartz, T.W. Ligand binding and micro-switches in 7TM receptor structures. Trends Pharmacol. Sci. 30, 249–259 (2009).
Adzhubei, I.A. et al. A method and server for predicting damaging missense mutations. Nat. Methods 7, 248–249 (2010).
Andersson, E.A. et al. MTNR1B G24E variant associates with BMI and fasting plasma glucose in the general population in studies of 22,142 Europeans. Diabetes 59, 1539–1548 (2010).
Lyssenko, V. et al. Common variant in MTNR1B associated with increased risk of type 2 diabetes and impaired early insulin secretion. Nat. Genet. 41, 82–88 (2009).
Peschke, E. & Muhlbauer, E. New evidence for a role of melatonin in glucose regulation. Best Pract. Res. Clin. Endocrinol. Metab. 24, 829–841 (2010).
Dubovsky, S.L. & Warren, C. Agomelatine, a melatonin agonist with antidepressant properties. Expert Opin. Investig. Drugs 18, 1533–1540 (2009).
Balkau, B. An epidemiologic survey from a network of French Health Examination Centres (D.E.S.I.R.): epidemiologic data on the insulin resistance syndrome. Rev. Epidemiol. Sante Publique 44, 373–375 (1996).
Williams, D.R. et al. Undiagnosed glucose intolerance in the community: the Isle of Ely Diabetes Project. Diabet. Med. 12, 30–35 (1995).
Syddall, H.E. et al. Cohort profile: the Hertfordshire cohort study. Int. J. Epidemiol. 34, 1234–1242 (2005).
Meyre, D. et al. A genome-wide scan for childhood obesity-associated traits in French families shows significant linkage on chromosome 6q22.31-q23.2. Diabetes 53, 803–811 (2004).
Hercberg, S. et al. A primary prevention trial using nutritional doses of antioxidant vitamins and minerals in cardiovascular diseases and cancers in a general population: the SU.VI.MAX study—design, methods, and participant characteristics. Supplementation en VItamines et Mineraux Antioxydants. Control. Clin. Trials 19, 336–351 (1998).
Sladek, R. et al. A genome-wide association study identifies novel risk loci for type 2 diabetes. Nature 445, 881–885 (2007).
Hadjadj, S. et al. Prognostic value of the insertion/deletion polymorphism of the ACE gene in type 2 diabetic subjects: results from the non-insulin-dependent Diabetes, Hypertension, Microalbuminuria or Proteinuria, Cardiovascular Events, and Ramipril (DIABHYCAR), Diabete de type 2, Nephropathie et Genetique (DIAB2NEPHROGENE), and Survie, Diabete de type 2 et Genetique (SURDIAGENE) studies. Diabetes Care 31, 1847–1852 (2008).
American Diabetes Association. Standards of medical care in diabetes. Diabetes Care 31, (suppl.), S12–S54 (2008).
Ayoub, M.A. et al. Monitoring of ligand-independent dimerization and ligand-induced conformational changes of melatonin receptors in living cells by bioluminescence resonance energy transfer. J. Biol. Chem. 277, 21522–21528 (2002).
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.
The authors declare no competing financial interests.
A list of members is provided in the Supplementary Note.
About this article
Cite this article
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
Association between MTNR1B polymorphisms and obesity in African American: findings from the Jackson Heart Study
BMC Medical Genomics (2021)
Melatonin ameliorates cardiac remodelling in fructose-induced metabolic syndrome rat model by using genes encoding cardiac potassium ion channels
Molecular Biology Reports (2021)
Analysis of Evolution and Ethnic Diversity at Glucose-Associated SNPs of Circadian Clock-Related Loci with Cryptochrome 1, Cryptochrome 2, and Melatonin receptor 1B
Biochemical Genetics (2021)
CRISPR/Cas9 mediated mutation of the mtnr1a melatonin receptor gene causes rod photoreceptor degeneration in developing Xenopus tropicalis
Scientific Reports (2020)
Nature Reviews Endocrinology (2020)