Chunk #13 — 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?
In a sample of 803 Caucasian individuals, Caspi et al. (22) found that adolescent-onset cannabis use interacted with a SNP in the Catechol-O-Methyltransferase (COMT) gene to significantly predict several related adult psychotic symptoms. The investigators attempted to rule out the hypothesis that early cannabis use was a gateway to using amphetamines and hallucinogens, which in turn were the true moderators of the COMT polymorphism. They did this by including amphetamine/hallucinogen usage as a covariate in the model, which unsurprisingly (see Equation 3) had little effect on the COMT-by-cannabis use interaction. However, given that there is a relationship between early cannabis use and later usage of ‘harder’ drugs (23), it is possible that the observed interaction had little to do with cannabis use, but rather was driven by or was partially mediated by a COMT-by-hallucinogen/amphetamine interaction. Similarly, Caspi et al. (22) 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
