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Agarwala, V.* ; Flannick, J.* ; Sunyaev, S.R.* ; GoT2D Consortium (Gieger, C. ; Grallert, H. ; Hrabě de Angelis, M. ; Huth, C. ; Kriebel, J. ; Meisinger, C. ; Meitinger, T. ; Müller-Nurasyid, M. ; Peters, A. ; Rathmann, W. ; Ried, J.S. ; Strauch, K. ; Strom, T.M.) ; Altshuler, D.*

Evaluating empirical bounds on complex disease genetic architecture.

Nat. Genet. 45, 1418-1427 (2013)
DOI PMC
Open Access Green as soon as Postprint is submitted to ZB.
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 (<25%) or most (>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.
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Publication type Article: Journal article
Document type Scientific Article
Corresponding Author
ISSN (print) / ISBN 1061-4036
e-ISSN 1546-1718
Journal Nature Genetics
Quellenangaben Volume: 45, Issue: 12, Pages: 1418-1427 Article Number: , Supplement: ,
Publisher Nature Publishing Group
Publishing Place New York, NY
Non-patent literature Publications
Reviewing status Peer reviewed
Institute(s) Institute of Genetic Epidemiology (IGE)
Institute of Experimental Genetics (IEG)
Institute of Human Genetics (IHG)
Institute of Epidemiology II (EPI2)