Some researchers claim that G×E studies should only be carried out if there exists a genotype-to-phenotype main effect, but this claim is statistically unwarranted (112). Such a strategy also precludes identification of environmentally dependent genetic effects that are small in absolute size or are contingent on relatively uncommon environmental factors (Figure 4). Moreover, genotype-phenotype association studies may not replicate if G×E interactions are operating and research samples differ on environmental risk exposure. Waiting for genomewide association studies (GWAS) to throw up candidate genes may be ill-advised because G×E interactions may conceal good candidates from GWAS. Inconsistent genotype-phenotype associations have inspired successful searches for G×E interactions in different fields of medicine, from asthma (113) to cardiovascular disease (114). Inconsistent associations between the 5-HTTLPR S allele and depression (115–117) prompted us to consider a G×E interaction in our initial studies of the 5-HTTLPR and depression.
