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Tests for compositional epistasis under single interaction-parameter models.

ABSTRACT: Compositional epistasis is said to be present when the effect of a genetic factor at one locus is masked by a variant at another locus. Although such compositional epistasis is not equivalent to the presence of an interaction in a statistical model, non-standard tests can sometimes be used to detect compositional epistasis. In this paper we consider empirical tests for compositional epistasis under models for the joint effect of two genetic factors which place no restrictions on the main effects of each factor but constrain the interactive effects of the two factors so as to be captured by a single parameter in the model. We describe the implications of these tests for cohort, case-control, case-only and family-based study designs and we illustrate the methods using an example of gene-gene interaction already reported in the literature.

SUBMITTER: VanderWeele TJ

PROVIDER: S-EPMC3413635 | biostudies-literature | 2011 Jan

REPOSITORIES: biostudies-literature

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Tests for compositional epistasis under single interaction-parameter models.

VanderWeele Tyler J TJ Laird Nan M NM

Annals of human genetics 20100820 1

Compositional epistasis is said to be present when the effect of a genetic factor at one locus is masked by a variant at another locus. Although such compositional epistasis is not equivalent to the presence of an interaction in a statistical model, non-standard tests can sometimes be used to detect compositional epistasis. In this paper we consider empirical tests for compositional epistasis under models for the joint effect of two genetic factors which place no restrictions on the main effects ...[more]

PMID: 20726965

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Project description:PurposeEpistasis, the interaction between two or more genes, is integral to the study of genetics and is present throughout nature. Yet, it is seldom fully explored as most approaches primarily focus on single-locus effects, partly because analyzing all pairwise and higher-order interactions requires significant computational resources. Furthermore, existing methods for epistasis detection only consider a Cartesian (multiplicative) model for interaction terms. This is likely limiting as epistatic interactions can evolve to produce varied relationships between genetic loci, some complex and not linearly separable.MethodsWe present new algorithms for the interaction coefficients for standard regression models for epistasis that permit many varied models for the interaction terms for loci and efficient memory usage. The algorithms are given for two-way and three-way epistasis and may be generalized to higher order epistasis. Statistical tests for the interaction coefficients are also provided. We also present an efficient matrix based algorithm for permutation testing for two-way epistasis. We offer a proof and experimental evidence that methods that look for epistasis only at loci that have main effects may not be justified. Given the computational efficiency of the algorithm, we applied the method to a rat data set and mouse data set, with at least 10,000 loci and 1,000 samples each, using the standard Cartesian model and the XOR model to explore body mass index.ResultsThis study reveals that although many of the loci found to exhibit significant statistical epistasis overlap between models in rats, the pairs are mostly distinct. Further, the XOR model found greater evidence for statistical epistasis in many more pairs of loci in both data sets with almost all significant epistasis in mice identified using XOR. In the rat data set, loci involved in epistasis under the XOR model are enriched for biologically relevant pathways.ConclusionOur results in both species show that many biologically relevant epistatic relationships would have been undetected if only one interaction model was applied, providing evidence that varied interaction models should be implemented to explore epistatic interactions that occur in living systems.

Dataset Information

Tests for compositional epistasis under single interaction-parameter models.

Publications

Tests for compositional epistasis under single interaction-parameter models.

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