The current study examined the joint effect of 5-HTTLPR and COMT val158met on depressive reactions to chronic stress in a sample of young adults. COMT genotype previously linked to stress sensitivity [30
] and depressive disorders [34
] was found to alter the strength of 5-HTTLPR G × E. Specifically, 5-HTTLPR G × E was observed only among val158 homozygotes. In the context of val158 homozygosity, the 5-HTTLPR LL genotype was associated with resilience to stress, relative to the SL and SS genotypes. However, in the presence at least one met158 allele, both 5-HTTLPR genotype groups were vulnerable to depressogenic stressors.
These results are consistent with past investigations that have linked the 5-HTTLPR S and COMT met158 variants to emotional reactivity to environmental stress [see 7
]. The presence of at least one of these susceptibility alleles was sufficient to increase risk for depression in response to stress. On the other hand, the current findings do not support the view that 5-HTTLPR L homozygotes are immune to pathogenic environments. When paired with a met158 allele, L homozygosity provided no protective effect against chronic stressors. This pattern of results may be attributable to heightened affective arousal experienced by carriers of the S or met158 allele when confronted with stressful conditions [40
]. The presence of either one of these variants has been shown to be sufficient to increase neural and psychophysiological reactivity to aversive cues [40
Contrary to hypotheses, the met158 allele did not potentiate the effect of the S allele on depressive reactivity. Biological mechanisms underlying the lack of additivity between met158 and S are unclear, but may be elucidated by future research into the interaction of serotonergic and dopaminergic neurotransmitter systems [e.g., 61
The current G × G × E findings may be relevant to some discrepancies among existing reports of 5-HTTLPR G × E. Some studies have failed to replicate the G × E observed by Caspi et al. [6
], and recent null meta-analytic findings [16
] have called attention to this inconsistency [cf. 18
]. Indeed, in the current analyses the moderating effect of 5-HTTLPR was detected only when COMT and 5-HTTLPR were analyzed simultaneously. Thus, one of several possible explanations for conflicting results in the literature is that the nature of 5-HTTLPR G × E is dependent on the background of other genes, including COMT, regulating sensitivity to stress.
The present results should be considered preliminary in light of the limited sample size available for the genetic analyses. The group homozygous for the L and val158 alleles, in particular, was relatively small (n = 29). Thus, it is possible that this study was underpowered to detect a significant effect of family stress in this group, although there was no evidence of a trend in this direction. This is potentially important given that the null stress-depression association in the LV group, relative to the strong depressogenic effect of stress obtained in all other genotype combinations, appeared to account for the observed G × G × E. It is possible that results could differ in larger samples, and conclusions should be considered tentative until replications from large-scale studies, with more representative samples of all genotype combinations, are available.
Several other limitations of the present study should be noted. First, depression outcomes were assessed over a limited age range (i.e., late adolescence). This may be an important qualification of the results in light of apparent fluctuations in G × E across developmental stages [14
]. Second, the current study controlled for gender, but future studies with sufficiently large samples should explore whether complex gene-gene interactions may apply differently for males and females [64
]. Third, sample size limitations prevented a thorough investigation of the role of heterozygosity at 5-HTTLPR and COMT. Further research is necessary to determine whether additive, dominant, or recessive models for these loci are most appropriate for G × E designs. Finally, rGE presents potential complications in the interpretation of G × E in studies of measured genes and measured environments [32
]. In the present sample, tests for rGE indicated that exposure to chronic family stress was not associated with genotype. However, it is implausible that the family context is entirely independent of genetic contributions, so the possibility remains that some portion of the observed interactions reflects unmeasured G × G.
Future research is necessary to explore the mechanisms, timing, and continuity of stressors in 5-HTTLPR G × E. In the current study, chronic stress was assessed 5 years prior to the self-reported depressive symptoms. The plausibility of G × E operating over this interval is supported by evidence suggesting relatively high stability of chronic stress exposure over time [66
]. However, given the association of chronic stress in adolescence with early childhood adversity as well as acute stressors proximal to the age 20 assessment [66
], it remains to be seen whether chronic family stress exerts a unique influence in 5-HTTLPR G × E [see 63
]. Future studies using psychometrically-sound measures of acute stress and early adversity are needed to explore the range of G × E effects involving 5-HTTLPR and COMT.
In sum, these preliminary results raise the possibility that the effect of 5-HTTLPR on depressive reactivity to life stress may be more reliably detected by simultaneously accounting for variation in other monoaminergic genes that underlie stress reactivity. The current findings of complex gene-environment interplay await replication in future research involving large samples. By identifying the biological and psychological moderators of 5-HTTLPR G × E, the conditions in which G × E is most likely to operate can be better understood.