The genetic architecture of type 2 diabetes

The genetic architecture of common traits, including the number, frequency, and effect sizes of inherited variants that contribute to individual risk, has been long debated. Genome-wide association studies have identified scores of common variants associated with type 2 diabetes, but in aggregate, these explain only a fraction of the heritability of this disease. Here, to test the hypothesis that lower-frequency variants explain much of the remainder, the GoT2D and T2D-GENES consortia performed whole-genome sequencing in 2,657 European individuals with and without diabetes, and exome sequencing in 12,940 individuals from five ancestry groups. To increase statistical power, we expanded the sample size via genotyping and imputation in a further 111,548 subjects. Variants associated with type 2 diabetes after sequencing were overwhelmingly common and most fell within regions previously identified by genome-wide association studies. Comprehensive enumeration of sequence variation is necessary to identify functional alleles that provide important clues to disease pathophysiology, but large-scale sequencing does not support the idea that lower-frequency variants have a major role in predisposition to type 2 diabetes. Sequencing data from two large-scale studies show that most of the genetic variation influencing the risk of type 2 diabetes involves common alleles and is found in regions previously identified by genome-wide association studies, clarifying the genetic architecture of this disease. Common variants at more than 80 genomic loci have been associated with susceptibility to type 2 diabetes, but together explain only a small fraction of the estimated heritability. Studies have hypothesized that rare or low-frequency genetic variation may explain a large proportion of the remaining disease risk. These authors now provide a test of this hypothesis in a large-scale sequencing study for type 2 diabetes conducted as part of the GoT2D and T2D-GENES projects. This work provides the most comprehensive view to date of the overall genomic architecture for disease risk, with the ability to examine the role for rare and low-frequency genetic variation. They find that most of the identified genetic risk variants were common and found in regions previously identified by genome-wide association studies.