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Pac Symp Biocomput. 2010:327-36.

Enabling personal genomics with an explicit test of epistasis.

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  • 1Department of Genetics, Dartmouth Medical School, Lebanon, NH 03756, USA.

Abstract

One goal of personal genomics is to use information about genomic variation to predict who is at risk for various common diseases. Technological advances in genotyping have spawned several personal genetic testing services that market genotyping services directly to the consumer. An important goal of consumer genetic testing is to provide health information along with the genotyping results. This has the potential to integrate detailed personal genetic and genomic information into healthcare decision making. Despite the potential importance of these advances, there are some important limitations. One concern is that much of the literature that is used to formulate personal genetics reports is based on genetic association studies that consider each genetic variant independently of the others. It is our working hypothesis that the true value of personal genomics will only be realized when the complexity of the genotype-to-phenotype mapping relationship is embraced, rather than ignored. We focus here on complexity in genetic architecture due to epistasis or nonlinear gene-gene interaction. We have previously developed a multifactor dimensionality reduction (MDR) algorithm and software package for detecting nonlinear interactions in genetic association studies. In most prior MDR analyses, the permutation testing strategy used to assess statistical significance was unable to differentiate MDR models that captured only interaction effects from those that also detected independent main effects. Statistical interpretation of MDR models required post-hoc analysis using entropy-based measures of interaction information. We introduce here a novel permutation test that allows the effects of nonlinear interactions between multiple genetic variants to be specifically tested in a manner that is not confounded by linear additive effects. We show using simulated nonlinear interactions that the power using the explicit test of epistasis is no different than a standard permutation test. We also show that the test has the appropriate size or type I error rate of approximately 0.05. We then apply MDR with the new explicit test of epistasis to a large genetic study of bladder cancer and show that a previously reported nonlinear interaction between is indeed significant, even after considering the strong additive effect of smoking in the model. Finally, we evaluated the power of the explicit test of epistasis to detect the nonlinear interaction between two XPD gene polymorphisms by simulating data from the MDR model of bladder cancer susceptibility. The results of this study provide for the first time a simple method for explicitly testing epistasis or gene-gene interaction effects in genetic association studies. Although we demonstrated the method with MDR, an important advantage is that it can be combined with any modeling approach. The explicit test of epistasis brings us a step closer to the type of routine gene-gene interaction analysis that is needed if we are to enable personal genomics.

PMID:
19908385
[PubMed - indexed for MEDLINE]
PMCID:
PMC2916690
Free PMC Article

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