Table 1 and Table 2 list all human observational studies up to summer 2009 that tested the hypothesis that the 5-HTTLPR moderates the effect of stress on depression phenotypes. Three observations emerge from the tables. First, multiple studies have reported that S-carriage moderates the influence of stress on depression. Whether or not the initial finding can be replicated has been answered in the affirmative. Second, positive findings have emerged from a variety of observational research designs used to test the hypothesis, including phenotype case-only designs, case-control designs, cross-sectional designs, longitudinal designs, and exposure designs. This suggests the finding is “sturdy,” in the sense that its signal can be detected despite noise from varying research settings, sample characteristics, and study designs (6). Third, there have also been quite a few negative findings. The degree to which negative findings call the original result into question depends on whether differences in study designs are systematically related to differences in study findings. If failures to replicate are characterized by systematically different subject populations or systematically weaker methodologies, their challenge to the original result is greatly diminished.
