Genetic Link Identified Between Rare MTNR1B Variants and Type 2 Diabetes

Although genome-wide association studies have been very successful in identifying novel single nucleotide polymorphisms (SNPs) associated with many common diseases, including type 2 diabetes (T2D), a limitation of many of these studies has been the inability to unequivocally identify the true functional variant that is marked by the associated SNP and the gene or pathway in which the functional variant falls. Moreover, even if the relevant gene or pathway is known, the associated variant often only modestly perturbs gene function so that the total impact of the gene on disease susceptibility cannot be determined. A recent study by Bonnefond et al. builds on previous findings of robust but modest associations between common variants in MTNR1B, the gene encoding melatonin receptor 1B, and T2D. In this report, exon resequencing in 7,632 Europeans revealed 36 very rare, nonsynonymous variants that were strongly associated with T2D. Of these, four were characterized by a complete loss of melatonin binding and signaling capabilities. Among the very rare variants, only those associated with partial or total loss of function were associated with diabetes. The magnitude of this association was large (odds ratio [OR] 5.67 [95% CI 2.17–14.82]) and much stronger than associations observed for common variants (∼1.10–1.15). The authors then genotyped the four complete loss-of-function variants in an unrelated sample of nearly 12,000 individuals and confirmed the association …