School of Medicine Publications and Presentations
Document Type
Article
Publication Date
8-4-2016
Abstract
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 heritability. 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 Europeans with and without diabetes, and exome sequencing in a total of 12,940 subjects from five ancestral groups. To increase statistical power, we expanded 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 a major role for lower-frequency variants in predisposition to type 2 diabetes.
Recommended Citation
Fuchsberger, C., Flannick, J., Teslovich, T. M., Mahajan, A., Agarwala, V., Gaulton, K. J., Ma, C., Fontanillas, P., Moutsianas, L., McCarthy, D. J., Rivas, M. A., Perry, J., Sim, X., Blackwell, T. W., Robertson, N. R., Rayner, N. W., Cingolani, P., Locke, A. E., Tajes, J. F., Highland, H. M., … McCarthy, M. I. (2016). The genetic architecture of type 2 diabetes. Nature, 536(7614), 41–47. https://doi.org/10.1038/nature18642
Publication Title
Nature
DOI
10.1038/nature18642
Academic Level
faculty
Mentor/PI Department
Office of Human Genetics