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Confounding of linkage disequilibrium patterns in large scale DNA based gene-gene interaction studies.


ABSTRACT: Background:In Genome-Wide Association Studies (GWAS), the concept of linkage disequilibrium is important as it allows identifying genetic markers that tag the actual causal variants. In Genome-Wide Association Interaction Studies (GWAIS), similar principles hold for pairs of causal variants. However, Linkage Disequilibrium (LD) may also interfere with the detection of genuine epistasis signals in that there may be complete confounding between Gametic Phase Disequilibrium (GPD) and interaction. GPD may involve unlinked genetic markers, even residing on different chromosomes. Often GPD is eliminated in GWAIS, via feature selection schemes or so-called pruning algorithms, to obtain unconfounded epistasis results. However, little is known about the optimal degree of GPD/LD-pruning that gives a balance between false positive control and sufficient power of epistasis detection statistics. Here, we focus on Model-Based Multifactor Dimensionality Reduction as one large-scale epistasis detection tool. Its performance has been thoroughly investigated in terms of false positive control and power, under a variety of scenarios involving different trait types and study designs, as well as error-free and noisy data, but never with respect to multicollinear SNPs. Results:Using real-life human LD patterns from a homogeneous subpopulation of British ancestry, we investigated the impact of LD-pruning on the statistical sensitivity of MB-MDR. We considered three different non-fully penetrant epistasis models with varying effect sizes. There is a clear advantage in pre-analysis pruning using sliding windows at r 2 of 0.75 or lower, but using a threshold of 0.20 has a detrimental effect on the power to detect a functional interactive SNP pair (power

SUBMITTER: Joiret M 

PROVIDER: S-EPMC6558841 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Confounding of linkage disequilibrium patterns in large scale DNA based gene-gene interaction studies.

Joiret Marc M   Mahachie John Jestinah M JM   Gusareva Elena S ES   Van Steen Kristel K  

BioData mining 20190610


<h4>Background</h4>In Genome-Wide Association Studies (GWAS), the concept of linkage disequilibrium is important as it allows identifying genetic markers that tag the actual causal variants. In Genome-Wide Association Interaction Studies (GWAIS), similar principles hold for pairs of causal variants. However, Linkage Disequilibrium (LD) may also interfere with the detection of genuine epistasis signals in that there may be complete confounding between Gametic Phase Disequilibrium (GPD) and intera  ...[more]

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