Another widely contested issue is whether gene-environment interactions should be examined only when main effects of genotype are detected. Perhaps not surprisingly, this is the approach most commonly advocated by statistical geneticists (Risch et al. 2009) and that was recommended by the Psychiatric GWAS Consortium (Psychiatr. GWAS Consort. Steer. Comm. 2008). However, this strategy could preclude the detection of crossover interaction effects as well as gene-environment interactions that occur in the presence of relatively low-frequency environments. In addition, if genetic effects are conditional on environmental exposure, main effects of genotype could vary across samples, that is to say, a genetic effect could be detected in one sample and fail to replicate in another if the samples differ on environmental exposure.
