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Nat Genet DOI:10.1038/ng.2804

Evaluating empirical bounds on complex disease genetic architecture.

Publication TypeJournal Article
Year of Publication2013
AuthorsAgarwala, V, Flannick, J, Sunyaev, S, Altshuler, D
Corporate AuthorsGoT2D Consortium
JournalNat Genet
Volume45
Issue12
Pages1418-27
Date Published2013 Dec
ISSN1546-1718
KeywordsComputer Simulation, Diabetes Mellitus, Type 2, Disease, Empirical Research, Genetic Linkage, Genetic Predisposition to Disease, Genetic Variation, Genome-Wide Association Study, Humans, Models, Genetic, Multifactorial Inheritance
Abstract

The genetic architecture of human diseases governs the success of genetic mapping and the future of personalized medicine. Although numerous studies have queried the genetic basis of common disease, contradictory hypotheses have been advocated about features of genetic architecture (for example, the contribution of rare versus common variants). We developed an integrated simulation framework, calibrated to empirical data, to enable the systematic evaluation of such hypotheses. For type 2 diabetes (T2D), two simple parameters--(i) the target size for causal mutation and (ii) the coupling between selection and phenotypic effect--define a broad space of architectures. Whereas extreme models are excluded by the combination of epidemiology, linkage and genome-wide association studies, many models remain consistent, including those where rare variants explain either little (80%) of T2D heritability. Ongoing sequencing and genotyping studies will further constrain the space of possible architectures, but very large samples (for example, >250,000 unselected individuals) will be required to localize most of the heritability underlying T2D and other traits characterized by these models.

URLhttp://dx.doi.org/10.1038/ng.2804
DOI10.1038/ng.2804
Pubmed

http://www.ncbi.nlm.nih.gov/pubmed/24141362?dopt=Abstract

Alternate JournalNat. Genet.
PubMed ID24141362
PubMed Central IDPMC4158716
Grant ListR01 GM078598 / GM / NIGMS NIH HHS / United States
R01MH084676 / MH / NIMH NIH HHS / United States
T32 GM007753 / GM / NIGMS NIH HHS / United States
RC2 DK088389 / DK / NIDDK NIH HHS / United States
T32GM008313 / GM / NIGMS NIH HHS / United States
T32GM007748-33 / GM / NIGMS NIH HHS / United States
T32 GM008313 / GM / NIGMS NIH HHS / United States
T32GM007753 / GM / NIGMS NIH HHS / United States
R01 MH084676 / MH / NIMH NIH HHS / United States
R01GM078598 / GM / NIGMS NIH HHS / United States
T32 GM007748 / GM / NIGMS NIH HHS / United States
1RC2DK088389-01 / DK / NIDDK NIH HHS / United States