The Contribution of Low-Frequency and Rare Coding Variation to Susceptibility to Type 2 Diabetes

Soon after the first genome-wide association study (GWAS) for type 2 diabetes (T2D) was published, it was hypothesized that rare and low-frequency variants might explain a substantial proportion of disease risk. Rare coding variants in particular were emphasized given their large expected role in disease. This review summarizes the extent to which recent T2D genetic studies provide evidence for or against this hypothesis.

Following a comprehensive study of T2D genetic architecture using three sequencing and genotyping technologies, four even larger studies have provided a yet higher resolution view of the role of rare and low-frequency coding variation in T2D susceptibility. Empirical evidence strongly suggests that common regulatory variants are the dominant contributor to T2D heritability. However, rare coding variants may nonetheless be pervasive across T2D-relevant genes. A strategy using common variants to map disease genes, and rare coding variants to link molecular gene perturbations to cellular and phenotypic effects, may be an effective means to investigate T2D pathogenesis and potential new therapies.