The robustness of the observed associations to the environmental effect raises the issue of whether genotype-by-environment interactions influence the peripheral blood transcriptome at all. Genome-wide significant interaction effects are generally unlikely to occur in the absence of significant main genotype effects36. The only circumstances in which they will are if the genotype effect is in the opposite direction in two locations, and if the genetic effect in these locations is at least the same magnitude as the main effects detected in this GWAS, namely explaining over 30% of the variance of a particular transcript. While a few such interactions may exist, it would take a study comparing several thousand individuals from each location to reveal weaker genotype-by-environment interactions. If the genetic architecture of transcription is generally similar to that of visible phenotypes like height and body mass37,38, even such a study will be underpowered to explain the vast majority of transcriptional variance.
