Finally, it should be noted that even if a G×E result ‘disappears’ after properly controlling for covariates, this does not necessarily mean that the original G×E hypothesis was wrong. For example, the genetic polymorphism might cause changes in the covariate which in turn moderates the environmental variable, in which case the covariate is a mediating mechanism by which the gene moderates the environmental variable (19). That said, this possibility applies to all models that statistically control for covariates in regression, and the traditional interpretation of ‘disappearing’ effects after controlling for a covariate is that the true causal pathway is ambiguous and alternative (confounding) explanations cannot be ruled out. That said, in some cases, a particular causal pathway can be discarded as impossible or unlikely. In such cases, investigators can be more definitive about ruling out certain hypotheses. For example, changes at a genetic polymorphism will not lead to changes in ethnicity, and so a G×E hypothesis can be safely discarded if it is mediated by an ethnicity-by-environment interaction.
