It is evident from research conducted with multiple species and from research using both observational and experimental methods that variation in 5-HTT modifies organisms’ stress responses to their environments (Figure 1). Complementary experimental and observational research designs are integral to testing not only the 5-HTT stress-sensitivity hypothesis, but all G×E hypotheses (4, 5). Experiments with humans, nonhuman primates, and rodents elucidate biological mechanisms behind the hypothesis and also validate findings from human observational studies by using designs with stronger internal validity (e.g., by random assignment to stress conditions). Observational studies use designs with stronger external validity (e.g., by studying real-world stressors), estimate the effect size of the 5-HTTLPR G×E interaction in the human population, and allow researchers to study clinical depression as the outcome.
