However, controversy over the robustness of this G×E interaction continues. Although it is likely that G×E interactions play an important role in disease, gene-by-environment studies are challenged by the fact that statistical power to detect interactions is typically less than for main effects.19 Furthermore, many candidate gene main-effect association reports appear to be false positives.20, 21 As Duncan and Keller22 illustrate, this indicates a need for caution regarding similar gene-by-environment hypotheses. Several meta-analyses have examined the 5-HTTLPR-by-stress hypothesis, some providing support for the interaction and others finding no evidence for it,23–26 with various reasons proposed for the differences.22, 25, 27–29 Munafò et al.24 performed a literature-based meta-analysis, finding that only 5 of the previously published studies (N = 2 999) used phenotypes and statistical models suitably comparable to the original study to be included in the meta-analysis. This meta-analysis did not support replication of the original finding. Risch et al.23 obtained individual level data from 10 previously published studies (N= 14 250) that met inclusion criteria and analyzed the data using a common model based on number of stressful life
