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Detecting Epistasis with the Marginal Epistasis Test in Genetic Mapping Studies of Quantitative Traits

View ORCID ProfileLorin Crawford, Ping Zeng, View ORCID ProfileSayan Mukherjee, Xiang Zhou
doi: https://doi.org/10.1101/066985
Lorin Crawford
1Department of Statistical Science, Duke University, Durham, NC, USA
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  • For correspondence: lac55@stat.duke.edu xzhousph@umich.edu
Ping Zeng
2Department of Biostatistics, University of Michigan, Ann Arbor, MI, USA
3Center for Statistical Genetics, University of Michigan, Ann Arbor, MI, USA
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Sayan Mukherjee
1Department of Statistical Science, Duke University, Durham, NC, USA
4Department of Computer Science, Duke University, Durham, NC, USA
5Department of Mathematics, Duke University, Durham, NC, USA
6Department of Bioinformatics & Biostatistics, Duke University, Durham, NC, USA
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Xiang Zhou
2Department of Biostatistics, University of Michigan, Ann Arbor, MI, USA
3Center for Statistical Genetics, University of Michigan, Ann Arbor, MI, USA
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  • For correspondence: lac55@stat.duke.edu xzhousph@umich.edu
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Abstract

Epistasis, commonly defined as the interaction between multiple genes, is an important genetic component underlying phenotypic variation. Many statistical methods have been developed to model and identify epistatic interactions between genetic variants. However, because of the large combinatorial search space of interactions, most epistasis mapping methods face enormous computational challenges and often suffer from low statistical power due to multiple test correction. Here, we present a novel, alternative strategy for mapping epistasis: instead of directly identifying individual pairwise or higher-order interactions, we focus on mapping variants that have non-zero marginal epistatic effects — the combined pairwise interaction effects between a given variant and all other variants. By testing marginal epistatic effects, we can identify candidate variants that are involved in epistasis without the need to identify the exact partners with which the variants interact, thus potentially alleviating much of the statistical and computational burden associated with standard epistatic mapping procedures. Our method is based on a variance component model, and relies on a recently developed variance component estimation method for efficient parameter inference and p-value computation. We refer to our method as the “MArginal ePIstasis Test”, or MAPIT. With simulations, we show how MAPIT can be used to estimate and test marginal epistatic effects, produce calibrated test statistics under the null, and facilitate the detection of pairwise epistatic interactions. We further illustrate the benefits of MAPIT in a QTL mapping study by analyzing the gene expression data of over 400 individuals from the GEUVADIS consortium.

Author Summary Epistasis is an important genetic component that underlies phenotypic variation and is also a key mechanism that accounts for missing heritability. Identifying epistatic interactions in genetic association studies can help us better understand the genetic architecture of complex traits and diseases. However, the ability to identify epistatic interactions in practice faces important statistical and computational challenges. Standard statistical methods scan through all-pairs (or all high-orders) of interactions, and the large number of interaction combinations results in slow computation time and low statistical power. We propose an alternative mapping strategy and a new variance component method for identifying epistasis. Our method examines one variant at a time, and estimates and tests its marginal epistatic effect — the combined pairwise interaction effects between a given variant and all other variants. By testing for marginal epistatic effects, we can identify variants that are involved in epistasis without the need of explicitly searching for interactions. Our method also relies on a recently developed variance component estimation method for efficient and robust parameter inference, and accurate p-value computation. We illustrate the benefits of our method using simulations and real data applications.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted March 06, 2017.
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Detecting Epistasis with the Marginal Epistasis Test in Genetic Mapping Studies of Quantitative Traits
Lorin Crawford, Ping Zeng, Sayan Mukherjee, Xiang Zhou
bioRxiv 066985; doi: https://doi.org/10.1101/066985
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Detecting Epistasis with the Marginal Epistasis Test in Genetic Mapping Studies of Quantitative Traits
Lorin Crawford, Ping Zeng, Sayan Mukherjee, Xiang Zhou
bioRxiv 066985; doi: https://doi.org/10.1101/066985

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