Rare MTNR1B variants impairing melatonin receptor 1B function contribute to type 2 diabetes.
Bonnefond A., Clément N., Fawcett K., Yengo L., Vaillant E., Guillaume JL., Dechaume A., Payne F., Roussel R., Czernichow S., Hercberg S., Hadjadj S., Balkau B., Marre M., Lantieri O., Langenberg C., Bouatia-Naji N., Meta-Analysis of Glucose and Insulin-Related Traits Consortium (MAGIC) None., Charpentier G., Vaxillaire M., Rocheleau G., Wareham NJ., Sladek R., McCarthy MI., Dina C., Barroso I., Jockers R., Froguel P.
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.