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

• Published in: Nature genetics Vol. 44; no. 3; pp. 297 - 301
• Main Authors: Bonnefond, Amélie, Clément, Nathalie, Fawcett, Katherine, Yengo, Loïc, Vaillant, Emmanuel, Guillaume, Jean-Luc, Dechaume, Aurélie, Payne, Felicity, Roussel, Ronan, Czernichow, Sébastien, Hercberg, Serge, Hadjadj, Samy, Balkau, Beverley, Marre, Michel, Lantieri, Olivier, Langenberg, Claudia, Bouatia-Naji, Nabila, Charpentier, Guillaume, Vaxillaire, Martine, Rocheleau, Ghislain, Wareham, Nicholas J, Sladek, Robert, McCarthy, Mark I, Dina, Christian, Barroso, Inês, Jockers, Ralf, Froguel, Philippe
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01-03-2012; Nature Publishing Group
• Subjects: 631/208/205/2138; 631/208/2489/144; 692/699/2743/137/773; Agriculture; Amino Acid Sequence; Amino Acid Substitution; Animal Genetics and Genomics; Base Sequence; Binding sites; Biological and medical sciences; Biomedical and Life Sciences; Biomedical research; Biomedicine; Body Mass Index; Cancer Research; Cell receptors; Cell structures and functions; Circadian rhythm; Confidence intervals; Diabetes; Diabetes Mellitus, Type 2 - genetics; Diabetes Mellitus, Type 2 - metabolism; Diabetes. Impaired glucose tolerance; Disease; Drug receptors; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Etiopathogenesis. Screening. Investigations. Target tissue resistance; Exons - genetics; Fundamental and applied biological sciences. Psychology; Gene Frequency; Gene Function; Genetic aspects; Genetic Variation; Genetics of eukaryotes. Biological and molecular evolution; Genome-Wide Association Study; Health aspects; Human Genetics; Humans; letter; Life Sciences; Logistic Models; Medical research; Medical sciences; Melatonin; Metabolic disorders; Miscellaneous; Models, Molecular; Molecular and cellular biology; Molecular Sequence Data; Odds Ratio; Physiological aspects; Receptor, Melatonin, MT2 - genetics; Risk factors; Sequence Analysis, DNA; Type 2 diabetes; White People - genetics; France; United Kingdom; Endocrinopathy; Type 2 diabetes; Variant; Melatonin; Metabolic diseases; Pineal hormone; Biological receptor; EXCESS; FASTING PLASMA-GLUCOSE; GENERAL-POPULATION; DISEASES; RISK; LOCI; GENOME-WIDE ASSOCIATION
• ISSN: 1061-4036; 1546-1718
• DOI: 10.1038/ng.1053

Philippe Froguel, Ralf Jockers and colleagues report the functional characterization of 40 rare protein-coding variants of the
MTNR1B
gene (encoding melatonin receptor 1B, also known as MT
2
). They find that functionally impaired MT
2
melatonin receptors confer higher risk to type 2 diabetes in Europeans.
Genome-wide association studies have revealed that common noncoding variants in
MTNR1B
(encoding melatonin receptor 1B, also known as MT
2
) increase type 2 diabetes (T2D) risk
1
,
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.