Chunk #14 — Three examples of misspecified models in the G×E literature — Caspi et al., 2005: The effect of COMT on psychosis risk depends on adolescent cannabis use, but is cannabis the true moderator?
attempted to eliminate the counter-explanation that the COMT-by-cannabis interaction was driven by conduct disorder by including conduct disorder as a covariate, which again had little effect on the interaction result. However, given the relationship between cannabis use and conduct disorder reported by the investigators, it is also possible that the observed interaction was caused by COMT effects differing by level of conduct disorder. In other words, despite attempts to show the specificity of the interaction by controlling for covariates, their findings do not provide convincing evidence that adolescent cannabis use per se moderated the effect of COMT. Finally, if COMT itself is related either to hallucinogen/amphetamine usage or to conduct disorder (due to a passive or evocative gene-environment correlation or to subtle stratification effects), then it is possible that there is no G×E interaction here at all. Rather, the effect of conduct disorder (or hallucinogen/amphetamine usage, SES, IQ, etc.) on psychosis might depend on cannabis usage, and the apparent G×E interaction may have actually been caused by a covariate-by-cannabis interaction.
