In the present study, we also considered likely scenarios for an interactive influence between 5-HTTLPR genotype with stressful life events on depression in the absence of evidence for a main effect between this genotype and depression in prior studies.13,56 The most likely explanation for an interaction without a main effect would require a reversal in the direction of the life events-by-genotype association, with the risk of depression increasing with the number of S alleles in the presence of stressful life events and decreasing with the number of S alleles in the absence of life events. Our analysis showed there was no such decrease. Therefore, attempts to rescue an unsuccessful candidate gene disease association, no matter how strong the candidate, by invoking an interaction with a common environmental exposure (such as life events) may be fraught with similar rates of false-positive associations as the original marginal gene association studies themselves.57-59
