TY - JOUR
T1 - Rare MTNR1B variants impairing melatonin receptor 1B function contribute to type 2 diabetes
AU - Bonnefond, Amélie
AU - Clément, Nathalie
AU - Fawcett, Katherine
AU - Yengo, Loic
AU - Vaillant, Emmanuel
AU - Guillaume, Jean Luc
AU - Dechaume, Aurélie
AU - Payne, Felicity
AU - Roussel, Ronan
AU - Czernichow, Sébastien
AU - Hercberg, Serge
AU - Hadjadj, Samy
AU - Balkau, Beverley
AU - Marre, Michel
AU - Lantieri, Olivier
AU - Langenberg, Claudia
AU - Bouatia-Naji, Nabila
AU - Charpentier, Guillaume
AU - Vaxillaire, Martine
AU - Rocheleau, Ghislain
AU - Wareham, Nicholas J.
AU - Sladek, Robert
AU - McCarthy, Mark I.
AU - Dina, Christian
AU - Barroso, Ins
AU - Jockers, Ralf
AU - Froguel, Philippe
N1 - Funding Information:
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.
PY - 2012/3
Y1 - 2012/3
N2 - 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. Although the strongest association signal was highly significant (P < 1 - 10 g 20), its contribution to T2D risk was modest (odds ratio (OR) of g1/41.10g1.15). 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) = 1.78g6.18; P = 1.64 - 10 g 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 = 2.17g14.82; P = 4.09 - 10 g4). 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 = 1.49g10.07; P = 5.37 - 10 g 3). This study establishes a firm functional link between MTNR1B and T2D risk.
AB - 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. Although the strongest association signal was highly significant (P < 1 - 10 g 20), its contribution to T2D risk was modest (odds ratio (OR) of g1/41.10g1.15). 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) = 1.78g6.18; P = 1.64 - 10 g 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 = 2.17g14.82; P = 4.09 - 10 g4). 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 = 1.49g10.07; P = 5.37 - 10 g 3). This study establishes a firm functional link between MTNR1B and T2D risk.
UR - http://www.scopus.com/inward/record.url?scp=84857654651&partnerID=8YFLogxK
U2 - 10.1038/ng.1053
DO - 10.1038/ng.1053
M3 - Article
C2 - 22286214
AN - SCOPUS:84857654651
SN - 1061-4036
VL - 44
SP - 297
EP - 301
JO - Nature Genetics
JF - Nature Genetics
IS - 3
ER -