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Prioritizing tests of epistasis through hierarchical representation of genomic redundancies.

ABSTRACT: Epistasis is defined as a statistical interaction between two or more genomic loci in terms of their association with a phenotype of interest. Epistatic loci that are identified using data from Genome-Wide Association Studies (GWAS) provide insights into the interplay among multiple genetic factors, with applications including assessment of susceptibility to complex diseases, decision making in precision medicine, and gaining insights into disease mechanisms. Since the number of genomic loci assayed by GWAS is extremely large (usually in the order of millions), identification of epistatic loci is a statistically difficult and computationally intensive problem. Even when only pairwise interactions are considered, the size of the search space ranges from hundreds of millions to billions of locus pairs. The large number of statistical tests performed also makes sufficient type one error correction imperative. Consequently, efficient algorithms are required to filter the tests that are performed and evaluate large GWAS data sets in a reasonable amount of computation time. It has been observed that many pairwise tests are redundant due to correlations in their genotype values across samples, known as linkage disequilibrium. However, algorithms that have been developed for efficient identification of epistatic loci do not systematically exploit linkage disequilibrium. Here, we propose a new algorithm for fast epistasis detection based on hierarchical representation of linkage disequilibrium (LinDen). We utilize redundancies in genotype patterns between neighboring loci to generate a hierarchical structure and execute a branch-and-bound search to prioritize loci testing based on approximations of a test statistic for pairs of locus groups. The hierarchical organization of tests performed by LinDen allows for efficient scaling based on the screened loci. We test LinDen comprehensively on three data sets obtained from the Wellcome Trust Case Control Consortium: type two diabetes, psoriasis, and hypertension. Our results show that, as compared other state-of-the-art tools for fast epistasis detection, LinDen drastically reduces the number of tests performed while discovering statistically significant locus pairs. LinDen is implemented in C++ and is available as open source at http://compbio.

Case

edu/linden/.

SUBMITTER: Cowman T

PROVIDER: S-EPMC5737499 | biostudies-literature | 2017 Aug

REPOSITORIES: biostudies-literature

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Prioritizing tests of epistasis through hierarchical representation of genomic redundancies.

Cowman Tyler T Koyutürk Mehmet M

Nucleic acids research 20170801 14

Epistasis is defined as a statistical interaction between two or more genomic loci in terms of their association with a phenotype of interest. Epistatic loci that are identified using data from Genome-Wide Association Studies (GWAS) provide insights into the interplay among multiple genetic factors, with applications including assessment of susceptibility to complex diseases, decision making in precision medicine, and gaining insights into disease mechanisms. Since the number of genomic loci ass ...[more]

PMID: 28605458

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Project description:Humans have the ability to craft abstract, temporally extended and hierarchically organized plans. For instance, when considering how to make spaghetti for dinner, we typically concern ourselves with useful "subgoals" in the task, such as cutting onions, boiling pasta, and cooking a sauce, rather than particulars such as how many cuts to make to the onion, or exactly which muscles to contract. A core question is how such decomposition of a more abstract task into logical subtasks happens in the first place. Previous research has shown that humans are sensitive to a form of higher-order statistical learning named "community structure". Community structure is a common feature of abstract tasks characterized by a logical ordering of subtasks. This structure can be captured by a model where humans learn predictions of upcoming events multiple steps into the future, discounting predictions of events further away in time. One such model is the "successor representation", which has been argued to be useful for hierarchical abstraction. As of yet, no study has convincingly shown that this hierarchical abstraction can be put to use for goal-directed behavior. Here, we investigate whether participants utilize learned community structure to craft hierarchically informed action plans for goal-directed behavior. Participants were asked to search for paintings in a virtual museum, where the paintings were grouped together in "wings" representing community structure in the museum. We find that participants' choices accord with the hierarchical structure of the museum and that their response times are best predicted by a successor representation. The degree to which the response times reflect the community structure of the museum correlates with several measures of performance, including the ability to craft temporally abstract action plans. These results suggest that successor representation learning subserves hierarchical abstractions relevant for goal-directed behavior.

Dataset Information

Prioritizing tests of epistasis through hierarchical representation of genomic redundancies.

Case

Publications

Prioritizing tests of epistasis through hierarchical representation of genomic redundancies.

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