When ADHD is conceptualized as emanating from the development of emotional and behavioral regulation, specific genetic and family environmental factors are likely to jointly influence ADHD outcomes in particular ways. The present report capitalized on the potential to investigate an important genetic marker for liability to emotional and behavioral dysregulation (5HTTLPR), along with a particularly salient marker of environmental risk (children's appraisals of blame in relation to inter-parental conflict).
The current study provides evidence of G × E effects for ADHD involving 5HTTLPR and youth appraisals of self-blame. Our analytic methods allowed us to examine a hypothesis previously untested at the genetic level - namely that both high and low serotonergic activity genotypes (e.g., 5HTTLPR) exert risk for ADHD symptoms. Findings from both the functional serotonin literature as well as from molecular genetic association studies have yielded seemingly conflicting findings about whether increased or reduced serotonergic activity is related to ADHD. The present results suggest that at the genetic level, both high and low serotonergic activity genotypes exert risk and that these risk mechanisms are modulated by salient psychosocial stressors.
The results were generally consistent across informant, although results for parent ratings were shy of the significance levels seen with teacher ratings. For teacher report, the pattern of results indicated significant non-linear 5HTTLPR × self-blame interactions for hyperactivity/impulsivity but not inattention or cognitive problems. The interactions revealed that youth appraisals of self-blame were significantly related to ADHD symptoms for children with the low activity (Lg/Lg, Lg/short, short/short) and high activity (La/La) 5HTTLPR genotypes. Those with the intermediate activity genotypes (La/Lg, La/short), on the other hand, appeared to be immune to whatever effects self blame was having on hyperactivity/impulsivity. The interaction was not accounted for by age, gender, or ethnicity, by family composition, by overall levels of conflict frequency/intensity, or by main effects of 5HTTLPR genotype or youth reports of self-blame. It was also not likely to be due to measurement artifact, because another scale (conflict properties) showed no hint of interaction.
Analysis of the symptom dimensions appeared to indicate some preliminary evidence for specificity of effects. The non-linear 5HTTLPR × self-blame interactions were non-significant or marginally significant for teacher and parent report of cognitive problems. In contrast, non-linear interactions were significant for teacher report and marginally significant for parent report of hyperactivity. The interaction again revealed that for youth with the high and low serotonin activity genotypes, the relationship between self-blame and hyperactivity was positive and significant. When examined again via the ADHD Rating Scale, a similar pattern emerged, however, the effect appeared attenuated for both parent and teacher report using DSM-IV symptom counts, perhaps due to the loss of power using the less well-distributed scores on that scale. Some potential specificity in terms of G × E effects for the ADHD symptom dimensions may make sense, as hyperactivity-impulsivity and inattention have been described as being partially separable at the genetic, neural, and temperament levels [41, 73, 74] as well as in recent factor analytic work .
The effects appeared to be somewhat specific for ADHD, as the non-linear 5HTTLPR × self-blame interactions showed no hint of an effect for oppositional defiant disorder symptoms (by teacher report) or conduct problems (by parent report). In contrast, the linear 5HTTLPR × self-blame interaction showed marginal significance for oppositional defiant disorder symptoms. If that result were to prove stronger in future work, it could indicate that only individuals with the low activity 5HTTLPR genotypes are vulnerable to development of oppositional and conduct problems .
Post-hoc data checks indicated that results were not generalizable to any appraisals of inter-parental conflict, as conflict properties failed to show significant moderation in the G × E analyses. Thus, there appears to be something about self-blame that is important for ADHD specifically. This is line with current work from our own laboratory (which included a portion of this sample) that indicates that among the CPIC scales, self-blame is a significant and unique predictor of ADHD symptomatology .
In addition, while serotonin functioning and serotonin genes have also shown association with a number of conditions, including mood disorders, the current findings were not explainable by a history of comorbid depression symptoms. Furthermore, while effects were stronger in late and post-pubertal youth, non-linear 5HTTLPR × self-blame interactions continued to show marginal significance in younger children (pre- to mid-pubertal). Thus, while developmental timing and its relationship with serotonergic functioning may be accounting for some of the effects - and will be an interesting avenue for future study - the non-linear 5HTTLPR × self-blame interactions observed here could not be fully explained developmentally.
With regard to the genetic literature for ADHD, our results failed to replicate a main effect of 5HTTLPR genotype with ADHD symptoms that has been previously reported [76–78]. Unlike these prior studies, we genotyped the A>G substitution to create a more precise set of 5HTTLPR genotypes in regard to functionality. Using this triallelic configuration of 5HTTLPR genotype, our results are consistent with prior research, which also found no main effect of association between the triallelic formulation of 5HTTLPR and ADHD . Furthermore, while our results did not support a main effect of 5HTTLPR, these results add to recent evidence that serotonin genetic risk as indexed by 5HTTLPR genotype and disruptions in the family environment interact together to predict deficits in behavioral and emotional regulation [79, 80]. Overall, these results complement growing evidence suggesting that 5HTTLPR confers liability for ADHD that is activated in particular environments, rather than conferring risk for ADHD directly.
The overall results are also suggestive of a potential heterozygote advantage, which has been suggested as a potential explanation for some diseases, including mental disorders . However, a recent G × E study examining 5HTTLPR and psychosocial risk indicated effects in the opposite direction: only those with heterozygote 5HTTLPR genotypes showed increased violent behavior in adulthood within the context of an adverse rearing environment . It may be the case that any 'heterozygote advantage' in 5HTTLPR may be modulated by developmental stage. In the present study, concurrent negative outcomes (i.e., increased ADHD behaviors) were associated with interactions between low and high 5HTTLPR activity and self-blame, whereas the prior G × E study  evidenced heterozygote "disadvantage" for outcomes later in life. In line with this, the serotonin system has been shown to function differently in children and adults in regard to its association with impulsive and aggressive behavior. Further, our main outcome variables involved ADHD and oppositionality symptoms measured in childhood and adolescence, compared with aggressive and violent behavior measured in adulthood, which was examined as outcome measures in this prior G × E research . It is possible that the heterozygote genotype may differentially exert risk or protect from negative outcomes depending upon developmental stage (childhood and adolescence versus adulthood) as well as the type of behavior being assessed (inattention, hyperactivity-impulsivity versus aggression and violence).
Certain limitations are important to note. First, we did not have parent DNA available for the majority of our sample, thus the use of family-based analyses was not possible. While unlikely, we cannot rule out population stratification effects. Second, because our sample is cross-sectional, we could not examine the longitudinal relationships between appraisals of self-blame and ADHD symptoms. It may be the case that more frequent inter-parental conflict is the result of having a child with more severe ADHD symptoms and that over time, children view themselves (perhaps correctly) as being responsible for their parents' marital problems. As is always the case with single studies of genetic or environmental effects, our findings may be false-positives. Thus, replication of these results in other samples is necessary.
The influence of development on the functioning of the serotonin system, including any potential role for G × E interactions for ADHD involving serotonin system genes, remains in need of further investigation in more costly studies, which may be justified by results such as the current one. In addition, the influence of age regarding comprehension of the 48-item CPIC remains in need of further exploration. While we took several steps to assure correct comprehension and completion of the CPIC in younger children, future work extending on these results may be well-served by considering the CPIC-Y designed for younger children .
Overall, our study is among the first to examine relationships between 5HTTLPR and ADHD as well as interaction effects using the triallelic genotype configuration. Results suggest that both the low- and high-activity 5HTTLPR genotypes increase risk for ADHD symptoms within the context of higher levels of youth self-blame in relation to their parents' marital conflict.