title: 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 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)(1-3). 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.
authors.affiliation: Centre National de la Recherche Scientifique Unité Mixte de Recherche, Lille Pasteur Institute, France.
authors.forename: Amélie
authors.initials: A
authors.lastname: Bonnefond
authors.forename: Nathalie
authors.initials: N
authors.lastname: Clément
authors.forename: Katherine
authors.initials: K
authors.lastname: Fawcett
authors.forename: Loïc
authors.initials: L
authors.lastname: Yengo
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Vaillant
authors.forename: Jean-Luc
authors.initials: JL
authors.lastname: Guillaume
authors.forename: Aurélie
authors.initials: A
authors.lastname: Dechaume
authors.forename: Felicity
authors.initials: F
authors.lastname: Payne
authors.forename: Ronan
authors.initials: R
authors.lastname: Roussel
authors.forename: Sébastien
authors.initials: S
authors.lastname: Czernichow
authors.forename: Serge
authors.initials: S
authors.lastname: Hercberg
authors.forename: Samy
authors.initials: S
authors.lastname: Hadjadj
authors.forename: Beverley
authors.initials: B
authors.lastname: Balkau
authors.forename: Michel
authors.initials: M
authors.lastname: Marre
authors.forename: Olivier
authors.initials: O
authors.lastname: Lantieri
authors.forename: Claudia
authors.initials: C
authors.lastname: Langenberg
authors.forename: Nabila
authors.initials: N
authors.lastname: Bouatia-Naji
authors.forename: Guillaume
authors.initials: G
authors.lastname: Charpentier
authors.forename: Martine
authors.initials: M
authors.lastname: Vaxillaire
authors.forename: Ghislain
authors.initials: G
authors.lastname: Rocheleau
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Wareham
authors.forename: Robert
authors.initials: R
authors.lastname: Sladek
authors.forename: Mark I
authors.initials: MI
authors.lastname: McCarthy
authors.forename: Christian
authors.initials: C
authors.lastname: Dina
authors.forename: Inês
authors.initials: I
authors.lastname: Barroso
authors.forename: Ralf
authors.initials: R
authors.lastname: Jockers
authors.forename: Philippe
authors.initials: P
authors.lastname: Froguel
mesh_terms: D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D001483:Base Sequence; D015992:Body Mass Index; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics* / Q000378:metabolism; D005091:Exons / Q000235:genetics; D005787:Gene Frequency; D014644:Genetic Variation; D055106:Genome-Wide Association Study; D006801:Humans; D016015:Logistic Models; D008958:Models, Molecular; D008969:Molecular Sequence Data; D016017:Odds Ratio; D044123:Receptor, Melatonin, MT2 / Q000235:genetics*; D017422:Sequence Analysis, DNA; D044465:White People / Q000235:genetics
chemical_list: D044123:Receptor, Melatonin, MT2