Most observational G×E research on 5-HTT in humans has focused on depression. However, additional evidence links the 5-HTTLPR to a broader range of stress-reactive phenotypes, including PTSD (18), posttrauma suicide attempt (19), aggressive reactions to a cold-pressor test (20), stress-linked alcohol consumption (21, 22) and substance use (23, 24), stress-related sleep disturbance (25), and even premature ejaculation (26). Research on quantitative endophenotypes shows that S-carriers with high levels of childhood maltreatment and adversity exhibit enhanced anxiety sensitivity (27) and a bias toward perceiving and expecting negative outcomes (28). Moreover, S-carrying children who are raised by unresponsive or nonsupportive mothers exhibit poor self-regulation of negative affect (29–32), which predicts a variety of adult psychiatric disorders (33). Finally, research that monitors affective experiences on a daily basis shows that S-carriers experience anxious mood on days with more intense stressors (34) and larger increases in negative affect while trying to quit smoking (35). To claim that these diverse outcomes are heterotypic manifestations of a unifying genetic vulnerability to stress reflected in the 5-HTTLPR S allele requires a theory that specifies the unifying mechanism.
