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Efficient gene-environment interaction tests for large biobank-scale sequencing studies.

ABSTRACT: Complex human diseases are affected by genetic and environmental risk factors and their interactions. Gene-environment interaction (GEI) tests for aggregate genetic variant sets have been developed in recent years. However, existing statistical methods become rate limiting for large biobank-scale sequencing studies with correlated samples. We propose efficient Mixed-model Association tests for GEne-Environment interactions (MAGEE), for testing GEI between an aggregate variant set and environmental exposures on quantitative and binary traits in large-scale sequencing studies with related individuals. Joint tests for the aggregate genetic main effects and GEI effects are also developed. A null generalized linear mixed model adjusting for covariates but without any genetic effects is fit only once in a whole genome GEI analysis, thereby vastly reducing the overall computational burden. Score tests for variant sets are performed as a combination of genetic burden and variance component tests by accounting for the genetic main effects using matrix projections. The computational complexity is dramatically reduced in a whole genome GEI analysis, which makes MAGEE scalable to hundreds of thousands of individuals. We applied MAGEE to the exome sequencing data of 41,144 related individuals from the UK Biobank, and the analysis of 18,970 protein coding genes finished within 10.4 CPU hours.

SUBMITTER: Wang X

PROVIDER: S-EPMC7754763 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description: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 <?25%). Signal sensitivity, directly using LD-block information to determine whether an epistasis signal is present or not, benefits from LD-pruning as well (average power across scenarios: 87%), but is largely hampered by functional loci residing at the boundaries of an LD-block. Conclusions:Our results confirm that LD patterns and the position of causal variants in LD blocks do have an impact on epistasis detection, and that pruning strategies and LD-blocks definitions combined need careful attention, if we wish to maximize the power of large-scale epistasis screenings.

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Efficient gene-environment interaction tests for large biobank-scale sequencing studies.

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