The validity of the 5-HTTLPR stress sensitivity hypothesis has been challenged by inconsistent results in the literature on life stress, the 5-HTTLPR genotype, and depression. To address this issue, we examined stress exposure and emotional reactivity in ‘high resolution’ using a daily diary methodology. We also evaluated the specificity of 5-HTTLPR G × E effects to depressive symptoms with the use of a novel measure of transdiagnostic emotional phenotypes. Consistent with hypotheses and prior research, we found that daily stress levels were associated with severity of internalizing symptoms, but only for 5-HTTLPR S allele carriers. Going beyond existing work on this topic, however, we also found that this interaction effect extended to both the fear and distress subdomains of internalizing symptoms, suggesting that 5-HTTLPR G × E effects are not unique to depression. Yet, there was only weak support for the hypothesis that stress-induced externalizing behaviors are more common among S allele carriers. These data are in accord with the general hypothesis that variation at 5-HTTLPR plays a role in regulating emotional reactivity to daily life stress.
In line with new dimensional approaches to psychiatric classification, such as the National Institute of Mental Health Research Domain Criteria initiative , these results suggest that genetic variation at 5-HTTLPR may influence transdiagnostic stress reactivity mechanisms that contribute to the onset or development of a variety of anxiety and depressive disorders, not just unipolar depression (cross-reference [1, 8]). One implication of this transdiagnostic formulation is that studies on 5-HTTLPR could be more efficiently designed by selecting outcomes that are theorized to be common to several categorically defined internalizing syndromes. For instance, in longitudinal G × E studies, 5-HTTLPR may be more closely linked to intermediate phenotypes, such as a latent distress trait, than to the unipolar depression syndrome. We speculate that such an approach may be appropriate for other candidate genes in psychopathology research as well .
The present findings also suggest that internalizing risk associated with the S allele can be detected by observing emotional responses to everyday stressors. Through the use of genetically informed daily process studies, it may be possible - even in nonclinical populations - to identify genotypes that confer risk for clinically significant emotional disorders that are provoked by negative life events. Fear and distress responses to daily negative life events may therefore represent useful intermediate phenotypes on the causal pathway from genes to full-blown internalizing disorder.
The present results are consistent with other data showing that the interactive effects of 5-HTTLPR and stress on emotional outcomes are most robust when sophisticated stress assessment methods are used . Indeed, a major strength of the present study was that stress was measured daily, on a within-person basis. Put another way, the degree of stress exposure on a given day was compared to each participant’s average level of stress over the 14-day study period and not to the average level of stress exposure in the full sample. As a result, participants served as their own control when determining the magnitude of day-to-day fluctuations in stress reporting, thereby limiting the potentially confounding effects of state affect or personality traits on self-reported stress exposure.
The relatively modest sample size of the present study (n = 104) must be taken into account when evaluating the present results. We reasoned that a test of our hypotheses based on a smaller sample was justified because our theory was based on an existing nomological net of relations between 5-HTTLPR and stress reactivity phenotypes . In other words, the established construct validity of the phenomenon under study was assumed to reduce the danger of false positive findings . Nevertheless, conclusions regarding genetic reactivity to everyday stressors should be considered tentative until large-scale replication projects are available.
Several other limitations should also be noted. First, daily stress exposure, emotions and behaviors were reported at the same time by the same informant; therefore, it was not possible to confirm that the occurrence of stressors preceded the development of symptoms each day. Second, given that fear, distress and externalizing phenotypes have not been investigated previously in within-subjects research, the questionnaires in this study were novel and would benefit from validation in future work. Related, the validity of daily stress assessments for determining genetic differences in stress reactivity has yet to be established in the G × E literature. Future studies should examine whether the same genotype confers risk to both short- and long-term stress reactions in the same sample. Third, our analyses were focused on transitory changes in mood and behavior as a potential intermediate phenotype for emotional disorders; additional research is needed to determine the social and neurobiological processes involved in the activation of more severe and sustained symptomatology. Fourth, we did not correct for multiple testing given strong a priori hypotheses and limited sample size, and this analytic decision should be kept in mind when interpreting significance values. Fifth, the prevalence of individual stressor types was relatively low and did not permit analyses to determine whether the magnitude of G × E varied across types of stress. Determining the features of life stress that are most relevant to 5-HTTLPR G × E may ultimately lead to more effective prevention and intervention efforts. Finally, although the 5-HTTLPR G × E effects in our sample were equivalent across the two main ethnic groups, we did not use genetic controls for ethnic heterogeneity (see  for potential dangers of ethnic heterogeneity in genetic research).