The current study provides evidence (a) that children's bullying victimization leads to their developing emotional problems and (b) that genetic variation in the 5-HTTLPR is a moderator of the link between bullying victimization and children's risk of developing these problems. Specifically, frequently bullied children with the SS genotype are at greater risk of developing emotional problems at age 12 than children with the SL or LL genotype. This genetic moderation persists after controlling (a) for children's pre-victimization emotional problems and (b) other risk factors shared by children growing up within the same family environment.
These findings confirm and add to the body of evidence that victims of bullying are at risk of developing emotional problems. 14-26
However, not every bullied child develops emotional problems, and the present findings offer new clues as to why this might be. First, genetic differences (in the 5-HTT
LPR) interact with bullying victimization to exacerbate emotional problems. Second, the strength of this genetically-influenced response is related to the frequency of the bullying experience (i.e., the G×E was strongest for frequently bullied children). The present findings are consistent with the recent report that SS genotype victims of relational aggression are prone to depression.27
Because early-onset emotional problems constitute a risk for developing later mental-health problems,28
strategies to reduce bully victimization in school-age children, especially those with specific genetic vulnerabilities, could help to reduce both childhood emotional problems and subsequent psychiatric difficulties.
Since the original report of an interaction between life stress and the 5-HTT
there have been multiple positive replications of this G×E in prospective-cohort (e.g.30
), cross-sectional (e.g.31
), and case-only (e.g.32
) designs. Additional G×E studies have documented that variation in the 5-HTT
LPR is related to other stress-reactive phenotypes, including PTSD33
and anxious mood.34
There have also been failures to replicate.35
This body of research has been difficult to summarize because of cross-study inconsistency in measurement; in particular, practically every study has measured stress exposure differently. Unfortunately, this has not stopped some meta-analysts from failing to take differences in exposure measurement seriously, and from generating un-interpretable summary statistics by averaging findings across different studies of uneven quality.36-37
Some reviewers have cautioned that many of these different studies cannot be treated as replications, positive or negative, because of their ad hoc
approaches to measuring life stress.38
For example, whereas some researchers have studied maltreated children,39
others have treated large family size as a chronic stressor.40
As an analogy, would two independent genetic association studies be considered replications if the positive finding was with different markers of the same gene? Superficially, both markers measure the same thing (the gene in question), but each could be representative of two completely different pieces of information (for example, different haplotypes that have diverse biological consequences). In this example, the claim of valid replication would be met with some caution. If one considers different methods of measuring and defining stress analogous to the two different markers in the previous example, then we should consider claims of replicating 5-HTT
LPR × stress interactions with equal prudence.
As such, we do not claim the present study to be a replication of earlier study designs. Instead, we focused on a specific childhood stressor (bullying victimization) and tested the hypothesis that its effects on children's emotional problems are modified by variation in the 5-HTT
LPR. Following the lead of experimental research,41
we think that focusing on a specific, developmentally-relevant, and clearly-operationalized stressor (rather than on ad hoc
measures of stress) offers a valuable opportunity to study the genetics of stress reactivity and stress resistance.38
Furthermore, utilizing a precise, well-operationalized stressful experience decreases between-subject heterogeneity in the stressful event and thereby increases the internal validity of the study design. In turn, understanding genetic sensitivity to a particular stressor may offer insights about G×E more generally, although it must be understood that generalization to other stressors must be demonstrated rather than assumed.
With a focus on bullying victimization, we employed a number of strategies to ensure the robustness of the observed G×E. First, we used independent assessments of stress exposure and outcome (i.e., we obtained reports about victimization experiences from the children themselves and reports about emotional problems from adults who knew the children). In most previous studies of G×E, the same person who has been the source for acquiring stress data has also been the source for acquiring outcome data.38
In the present study, we used independent sources of measurement in order to control for subjective bias and reduce shared method variance which inflates associations between measures of stress exposure and emotional problems.
Second, we established a temporal relationship between the stressor (bullying victimization) and the outcome (emotional problems) and evaluated the G×E in relation to within-individual change in emotional problems between ages 5 and 12 years. Specifically, we documented that frequent bullying is associated with increases in emotional problems between ages 5 to 12 years among children with the SS genotype independently of pre-victimization emotional problems among these genetically at-risk children. Temporal precision coupled with analysis of developmental change helped to rule out the possibility of reverse causation (i.e., that emotional problems led children to be victimized by bullies42
) and the potential confounding of G×E by gene-environment correlation.24
Third, we used within-family comparisons to assess whether the genetic moderation of bullying victimization was independent of other environmental risk factors shared by children growing up in the same family. We correlated twin-pair discordance in bullying experience (the difference in the amount of bullying each twin experiences) with twin-pair discordance in emotional problems. We found that the bullied twin had more emotional problems, but only among those twin pairs where both twins carried the SS genotype. These results suggest that variation in 5-HTTLPR moderates the association between bully victimization and emotional problems independent of other risk factors shared by twins.
The present study also has limitations. First, although we carried out within-family comparisons of twins discordant for bullying victimization in order to control for family-wide factors that might influence the observed G×E, we are not able to rule out the residual influence of child-specific environmental experiences. That is, we established that the G×E persists irrespective of experiences shared by children in the same family but it remains possible that the interaction may depend on experiences unique to the bullied versus non-bullied child in the family. Furthermore, the influence of shared environmental factors may not be stable throughout childhood and early adolescence. 43-44
Second, the interaction between 5-HTT
LPR and bullying victimization observed here may be modified by other unmeasured genetic characteristics.45-46
One way to test this possibility is to conduct within-family tests using exposure-discordant but genetically-identical (MZ) twin pairs; however, we did not have sufficient power or variation to carry out analyses on MZ twin pairs alone. Third, we cannot entirely rule out the possibility that children with emotional problems over-reported victimization experiences. However, we attempted to control for this by utilizing independent assessments of exposure and outcome, as recommended in stress research.38
In conclusion, this study adds to an accumulating body of observational studies showing that emotional disturbance is jointly influenced by stressful events and 5-HTT
LPR genotype, and that this G×E is observable in childhood. This observational evidence is buttressed by a wide range of emerging experimental G×E studies of stress reactivity (highlighted in the introduction) and G×E animal models of stress exposure (e.g.47-50
), all of which underscore the need for studies that can elucidate the mechanism of the contribution of 5-HTT
LPR variation to stress reactivity in development.