Abstract
The switch to a modern lifestyle in recent decades has coincided with a rapid increase in prevalence of obesity and other diseases. These shifts in prevalence could be explained by the release of genetic susceptibility for disease in the form of gene-by-environment (GxE) interactions. Yet, the detection of interaction effects requires large sample sizes, little replication has been reported, and a few studies have demonstrated environmental effects only after summing the risk of GWAS alleles into genetic risk scores (GRSxE). We performed extensive simulations of a quantitative trait controlled by 2500 causal variants to inspect the feasibility to detect gene-by-environment interactions in the context of GWAS. The simulated individuals were assigned either to an ancestral or a modern setting that alters the phenotype by increasing the effect size by 1.05–2-fold at a varying fraction of perturbed SNPs (from 1 to 20%). We report two main results. First, for a wide range of realistic scenarios, highly significant GRSxE is detected despite the absence of individual genotype GxE evidence at the contributing loci. Second, an increase in phenotypic variance after environmental perturbation reduces the power to discover susceptibility variants by GWAS in mixed cohorts with individuals from both ancestral and modern environments. We conclude that a pervasive presence of gene-by-environment effects can remain hidden even though it contributes to the genetic architecture of complex traits.
Highlights
Diseases such as diabetes, cardiovascular disease, and obesity have become highly prevalent in the developed world in a period of just a few generations
We aimed to evaluate the performance of two different approaches, namely (i) power of detection through the examination of individual SNPs and (ii) by means of unweighted genetic risk scores (GRS) that sum up the number of causal alleles for each individual
We simulated an environmental perturbation in genetic effect sizes to explore the feasibility of detecting gene-by-environment interactions
Summary
Cardiovascular disease, and obesity have become highly prevalent in the developed world in a period of just a few generations. A further study of Danish twins showed that one percentage point increase in the prevalence of obesity accompanies a ∼3.3% increase in the genetic variance for the trait (Rokholm et al, 2011a). The increased influence of the current “obesogenic” environment exerts its effects through a large alteration in the overall contribution of genetic factors to the susceptibility for obesity. The two most likely explanations for this phenomenon consist of (i) uncovering of new cryptic susceptibility variants that did not previously participate in the genetic architecture of the trait (Gibson and Dworkin, 2004), or (ii) an increase in the effect size of variants already associated with obesity before the emergence of the current “obesogenic” environment (Hermisson and Wagner, 2004)
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