Dataset Information

Genome-wide detection of intervals of genetic heterogeneity associated with complex traits.

ABSTRACT:

Motivation

Genetic heterogeneity, the fact that several sequence variants give rise to the same phenotype, is a phenomenon that is of the utmost interest in the analysis of complex phenotypes. Current approaches for finding regions in the genome that exhibit genetic heterogeneity suffer from at least one of two shortcomings: (i) they require the definition of an exact interval in the genome that is to be tested for genetic heterogeneity, potentially missing intervals of high relevance, or (ii) they suffer from an enormous multiple hypothesis testing problem due to the large number of potential candidate intervals being tested, which results in either many false positives or a lack of power to detect true intervals.

Results

Here, we present an approach that overcomes both problems: it allows one to automatically find all contiguous sequences of single nucleotide polymorphisms in the genome that are jointly associated with the phenotype. It also solves both the inherent computational efficiency problem and the statistical problem of multiple hypothesis testing, which are both caused by the huge number of candidate intervals. We demonstrate on Arabidopsis thaliana genome-wide association study data that our approach can discover regions that exhibit genetic heterogeneity and would be missed by single-locus mapping.

Conclusions

Our novel approach can contribute to the genome-wide discovery of intervals that are involved in the genetic heterogeneity underlying complex phenotypes.

Availability and implementation

The code can be obtained at: http://www.bsse.ethz.ch/mlcb/research/bioinformatics-and-computational-biology/sis.html.

SUBMITTER: Llinares-Lopez F

PROVIDER: S-EPMC4559912 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Epistasis, commonly defined as the interaction between genetic loci, is known to play an important role in the phenotypic variation of complex traits. As a result, many statistical methods have been developed to identify genetic variants that are involved in epistasis, and nearly all of these approaches carry out this task by focusing on analyzing one trait at a time. Previous studies have shown that jointly modeling multiple phenotypes can often dramatically increase statistical power for association mapping. In this study, we present the "multivariate MArginal ePIstasis Test" (mvMAPIT)-a multioutcome generalization of a recently proposed epistatic detection method which seeks to detect marginal epistasis or the combined pairwise interaction effects between a given variant and all other variants. By searching for marginal epistatic effects, one can identify genetic 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 conventional explicit search-based methods. Our proposed mvMAPIT builds upon this strategy by taking advantage of correlation structure between traits to improve the identification of variants involved in epistasis. We formulate mvMAPIT as a multivariate linear mixed model and develop a multitrait variance component estimation algorithm for efficient parameter inference and P-value computation. Together with reasonable model approximations, our proposed approach is scalable to moderately sized genome-wide association studies. With simulations, we illustrate the benefits of mvMAPIT over univariate (or single-trait) epistatic mapping strategies. We also apply mvMAPIT framework to protein sequence data from two broadly neutralizing anti-influenza antibodies and approximately 2,000 heterogeneous stock of mice from the Wellcome Trust Centre for Human Genetics. The mvMAPIT R package can be downloaded at https://github.com/lcrawlab/mvMAPIT.