The genetic architecture of type 2 diabetes
By Christian Fuchsberger, Jason Flannick, T. Teslovich, A. Mahajan, Vineeta Agarwala, K. Gaulton, Clement Ma, P. Fontanillas, L. Moutsianas, Davis J. McCarthy and 291 more. 2016
1,066 citations recorded by the source corpus.
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.
Subfields: Genetics, Molecular Biology
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In Genetics
- Alkes L Price
- Peter M. Visscher
- Jian Yang
- Gonçalo R. Abecasis
- Bogdan Pasaniuc
- Matthew Stephens
- Mark J. Daly
- Naomi R. Wray
In Molecular Biology
- Gonçalo R. Abecasis
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- David Altshuler
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- Leif Groop
- Philippe Froguel
Citations in the corpus
- Environmental/lifestyle factors in the pathogenesis and prevention of type 2 diabetes (2017, background): “This may be due to the fact that these genetic polymorphisms explain only approximately 15% of T2D heritability [149, 150].”
- An Expanded Genome-Wide Association Study of Type 2 Diabetes in Europeans (2017, positive): “While low-frequency variant coverage in the current study was not complete, this observation adds to the growing evidence (2,4,9,46) that few low-frequency T2D risk variants with moderate to strong effect sizes exist in European ancestry samples and is consistent with a primary role for common varia”
- Geographic variation and bias in polygenic scores of complex diseases and traits in Finland (2018, background): “the Finnish disease heritage (The Finnish Disease Heritage), and through variation in the polygenic components of many complex diseases (Fuchsberger et al. 2016; Hartiala et al. 2017; O'Connell et al. 2018).”
- Dissecting the genetics of complex traits using summary association statistics (2016, background): “Indeed, some recent studies have created web portals where summary data can be publicly accessed and visualized 60 .”