It is our contention that the purely statistical approach is not sufficient, or necessary, for evaluating research into G×E hypotheses involving candidate genes. In such G×E research, the prior probability of association is far from nil, thus mitigating the risk of false positives. For example, the 5-HTTLPR stress-sensitivity hypothesis was informed by knowledge about the serotonin system’s role in depression and the transporter gene’s function (1), by inconsistent associations between the 5-HTTLPR and depression suggesting environmental moderation might be operating (146), by evidence that stress causes depression (147), and by initial reports that 5-HTT variation influenced stress reactivity (2, 148, 149). In G×E research, replication attempts’ elements need not match those of the original report. G×E research involves not only polymorphism and phenotype, but another element: the environment. Whereas genetic measurements are standard and unchanging across time and across studies and phenotypic measurements can also be standardized to a high degree, environmental exposure measurements vary markedly across studies (150). Two kinds of heterogeneity should be distinguished: heterogeneity in the types of stress exposure versus heterogeneity in the quality of exposure
