In the present study the effects of chronic stress, but not severe acute stress, on depression were moderated by the 5HTTLPR polymorphisms consistent with several studies showing that those with at least one S allele were most susceptible to the depressogenic effects of stress (e.g., Caspi et al., 2003
; Kendler et al., 2005
; Wilhelm et al., 2006
). The effects were obtained controlling for maternal depression and acute stress, based on the reclassification of Lg
as S. Also consistent with several studies, the effects were significant for females but not males (Eley et al., 2004
; Grabe et al., 2005
; Sjöberg et al., 2006
). Increasingly, research has shown that females are generally more reactive to the depressive effects of stress than males are (Shih et al., 2006
), and such effects appear to be amplified or partly accounted for, at least for chronic stress, by genetic factors—a finding with implications for understanding the well-known higher rates of depression in women than men.
The results based on chronic family stress are notably consistent with studies showing elevated rates of depression among those exposed to adverse family conditions in childhood and at least one S allele (e.g., Caspi et al., 2003
; Taylor et al., 2006
; Gibb, McGeary, Beevers, & Miller, 2006
). However, several conceptual issues remain to be explored: whether the G × E effects are particularly specific to family discord, or to the feature of exposure early in life implying critical developmental processes, or to continuing, chronic exposure to stress. The issue of whether content of stress is crucial (e.g., interpersonal vs. noninterpersonal) is also an unresolved issue. Furthermore, because adverse childhood experiences are commonly chronic and predictive of acute events (Hazel et al., 2008
), what may appear to be effects of acute events in G × E interactions might actually in part reflect chronic stress exposure (Brown & Harris, 2008
). Although it is potentially difficult to entirely separate acute from chronic stress, fuller understanding of the mechanisms by which genes and stressful experiences trigger depression likely depends on efforts to distinguish the effects of each. Although the two types may overlap, they are also likely to involve somewhat different neuroendocrine, neurobiological, and psychosocial mechanisms. Thus, differentiating between chronic and acute stress exposure may help to further clarify the processes by which stress eventuates in depression.
It is noted that chronic family discord differed by genotype, possibly reflecting gene-environment correlations of some kind. The S/S group had the lowest and the S/L group the highest levels of chronic family stress exposure overall. Nevertheless, the S/S females at high levels of discord were at greatest risk for depressive symptoms. At this point we cannot offer explanations for the association of S/L with high family discord, and if replicated, further study of this pattern would be warranted.
Several limitations of the study are acknowledged. The actual genotyped sample was relatively small, and a larger sample might have yielded different results. The limited sample size also prohibited direct comparisons of acute versus chronic stress and their interactions with gender and genotype. A large sample size would be ideal for testing interactions among chronic and acute stress and genotype. It is also possible that a larger sample would yield greater power to detect potentially significant but small effect sizes associated with acute stress by genotype interactions. By chance the genotyped sample under-represented males, and the relatively smaller sample of males compared to females might have limited the ability to detect gene by stress interactions among men. On the other hand, as suggests, males’ patterns of depressive responses to chronic stress do not appear to reveal trends suggestive of a robust two-way interaction. The sample was limited to depression outcomes at age 20, and samples of different ages might yield dissimilar findings owing to likely developmental variations in gene-environment effects. Some of the youth were at increased risk for depression owing to maternal depression. However, distributions of maternal depression history were not different across the genotypes, although mothers’ history of depression was associated with higher levels of chronic family discord. The reported results were obtained when maternal depression status was statistically controlled, but results did not differ if maternal depression was omitted from the models. The evaluation of acute severe stressors included a 4-year period prior to assessment of depression outcomes, generally similar to the work of Caspi et al. (2003)
. This time period may be too lengthy to capture effects of acute stressors on depression (unless as argued by Brown and Harris (2008)
, multiple events might actually reflect chronically stressful conditions). Further, as acknowledged, acute and chronic stress may overlap, and that the boundaries between them may be far from exact. The analyses examined effects of each controlling for the other, but further work is needed to refine and distinguish acute and chronic stress.
Results were based on depressive symptoms rather than diagnoses, because only a small number of youth met diagnostic criteria for major depression at age 20, and continuous outcome variables may be less susceptible to artifactually significant interactions, compared to dichotomous outcomes like diagnostic status (Eaves, 2006
). BDI scores do not lack clinical relevance (e.g., Gotlib, Lewinsohn, & Seeley, 1995
) particularly if persistently elevated. However, such scores may be transitory, suggesting the need for further studies using clinical diagnoses.
The measure of chronic family discord had the advantage of a multivariable, multi-informant method, and indicated modest but significant stability over the life course of the youth in relation to conceptually similar but different indicators. As noted, further work is needed to discern what features of chronic family discord are relevant to the mechanisms of the genetic consequences of stress on depression.
Additionally, it is important to acknowledge increasing questions about the potential role of the 5HTTLPR gene in depression and the meaningfulness of findings with this genotype (e.g., Munafó, Durrant, Lewis, & Flint, 2009
; Risch et al., 2009
). We expect that as the field develops, other genes that modify how individuals respond to stressful experiences will doubtless invite close attention in gene-environment studies.
The current results argue for greater refinement in the measurement of stressful conditions when studied in association with genetic factors to predict depressive reactions. The results imply that the influence of chronically adverse family conditions on depressive symptoms among young adult females may be especially affected by serotonin transporter functions, but also indicate that further studies of the patterns and mechanisms of stress reactivity dependent on acute and chronic stress are needed.
- Prior studies indicate that the effects of stress on depression may be modified by the serotonin transporter gene (5HTTLPR), but inconsistencies require further clarification.
- The study explored the roles of psychometrically sound measures of severe acute life events and chronic family discord as moderators of the association between genotype and depressive symptoms, and also examined gender differences in a sample of youth with depressed or never-depressed mothers.
- Results indicated that young women with one or two s-alleles were more depressed in the face of chronic family discord. Chronic stress by genotype interactions were not found for males, and the interaction of genotype and acute stress was not significant.
- The combination of chronic family discord and s-alleles of the 5HTTLP genotype put females at risk for depressive symptoms. Further study is needed to explore whether such stress has its effects because it concerns family relations, is chronic rather than acute, or may create vulnerability associated with stress exposure from early childhood.