Is it possible to detect G×E interactions in GWAS when causal exposure is unobserved?

Abstract

Background: It is generally acknowledged that most complex diseases are affected in part by interactions between genes andgenes and/or between genes and environmental factors. Taking into account environmental exposures and their interactionswith genetic factors in genome-wide association studies (GWAS) can help to identify high-risk subgroups in the population andprovide a better understanding of the disease. For this reason, many methods have been developed to detect gene-environment (G×E) interactions. Despite this, few loci that interact with environmental exposures have been identified so far. Indeed, themodest effect of G×E interactions as well as confounding factors entail low statistical power to detect such interactions. Anotherpotential obstacle to detect G×E interaction is the fact that true exposure is seldom observed: Indeed, only proxy effects aremeasured in general. Furthermore, power studies used to evaluate a new method often are done through simulations that give anadvantage to the new approach over the other methods.Methods: In this work, we compare the relative performance of popular methods such as PLINK, random forests and linearmixed models to detect G×E interactions in the particular scenario where the causal exposure (E) is unknown and only proxycovariates are observed. For this purpose, we provide an adapted simulated dataset and apply a recently introduced method for H1simulations called waffect.Results: When the causal environmental exposure is unobserved but only a proxy of this exposure is observed, all the methodsconsidered fail to detect G×E interaction.Conclusions: The hidden causal exposure is an obstacle to detect G×E interaction in GWAS and the approaches considered inour power study all have insufficient power to detect the strong simulated interaction.