Journal
NATURE GENETICS
Volume 44, Issue 3, Pages 297-U98Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/ng.1053
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Funding
- French Agence Nationale de la Recherche [ANR-08-GENOPAT, ANR-11-blanc 'MLT2D', ANR-11-META 'MELA-BETES']
- Contrat de Projects Etat-Region Nord-Pas-De-Calais (CPER)
- Societe Francophone du Diabete
- Fondation Recherche Medicale
- Inserm
- CNRS
- Wellcome Trust [077016/Z/05/Z]
- UK National Institute for Health Research (NIHR) Cambridge Biomedical Research Centre
- MRC Centre for Obesity and Related Metabolic Diseases
- Medical Research Council [MC_U106179471, G0600717B] Funding Source: researchfish
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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) risk(1,2). Although the strongest association signal was highly significant (P < 1 x 10(-20)), its contribution to T2D risk was modest (odds ratio (OR) of similar to 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 x 10(-4)). A four-tiered functional investigation of all 40 mutants revealed that 14 were nonfunctional 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 x 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 x 10(-3)). This study establishes a firm functional link between MTNR1B and T2D risk.
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