The primary aim of the present study was to test the association between Val158Met genotype and two behavioral phenotypes commonly linked with child psychopathology: attention problems and aggressive behavior. Following from previous work by Grace, and Bilder et al., we predicted that the Val and Met alleles would be differentially associated with attention problems and aggressive behavior in youth. Given that allelic variation in this polymorphism is believed to result in countervailing patterns of dopaminergic signaling, we hypothesized that Met-carrying youth would be rated as more aggressive relative to Val-homozygotes. In contrast, we hypothesized that Val-homozygotes would possess higher ratings of attention problems relative to Met-carriers. These hypotheses were partially supported. Youth Met-carriers were found to possess significantly higher CBCL AGG scores when compared to Val-homozygotes. In order to better characterize this association between Met-carrier status and aggressive behavior, we investigated the extent to which the Met allele was differentially associated with two subtypes of aggressive behavior measured by the CBCL AGG scale: Direct Aggression and Relational Aggression. Although Met-carrier status was significantly associated with both subtypes of aggressive behavior, our findings suggest that Met-carrier status may be more closely associated with Direct Aggression compared to Relational Aggression. In regards to the hypothesized association between Val158Met genotype and attention problems, a trend was revealed suggesting that Val-homozygote youth possess higher CBCL AP scores relative to Met-carriers.
Our finding that Met-carrying youth possess higher CBCL AGG scores relative to Val-homozygotes is consistent with Bilder et al.'s proposed role of the Val158Met polymorphism in the context of dopamine tonic-phasic firing. This model postulates that elevated dopamine levels in the prefrontal cortex leads to cognitive inflexibility and increased risk for exhibiting aggressive behaviors. Interestingly, evidence from a number of recent functional neuroimaging studies suggests that the Met allele is positively associated with neural activity in prefrontal and amygdala regions during the processing of emotional stimuli.38–41
Moreover, this heightened activity in prefrontal and limbic regions exhibited by Met-carriers appears to be specific to the processing of negative as opposed to positive emotional stimuli. These imaging findings are particularly intriguing given that the brain regions influenced by the Met allele during the processing of unpleasant stimuli (e.g., orbital frontal cortex, ventromedial prefrontal cortex, amygdala) overlap with areas implicated in the exhibition of direct aggression.42
Davidson and colleagues have argued that the proclivity to engage in impulsive aggression is closely associated with a “low threshold for activating negative affect.”42
Williams and colleagues recently reported that brain regions found to exhibit Met allele dose effects during the processing of negative emotional stimuli were also associated with self-reported bias toward both anticipating and attending to negative information and events.41
Thus, it is plausible that the Met allele confers risk for aggressive behavior by facilitating the activation of negative affect.
Our results indicate that Met-carrier status is associated with both Direct and Relational subtypes of CBCL Aggressive Behavior. The results of the present study further suggest that the association between Direct Aggression and Val158Met genotype may be more robust when compared to the association between Relational Aggression and Val158Met genotype. We have previously reported that the genetic factors associated with these two subtypes of aggression, contained in the CBCL AGG scale, only partially overlap and possess a genetic correlation of .54 for boys and .43 for girls.32
Thus, it is possible that the Val158Met polymorphism may constitute a specific genetic factor that is differentially associated with these two subtypes of aggressive behavior.
Several recent studies have reported an association between the Val allele and symptoms of conduct disorder in youth. Although the present study did not specifically look at symptoms of conduct disorder, we have previously noted that the CBCL items comprising the Direct Aggression factor more closely correspond to symptoms of conduct disorder, whereas items comprising the Relational Aggression factor are more consistent with symptoms of oppositional defiant disorder.32
Caspi et al.14
found that Val-homozygotes were more aggressive and exhibited more symptoms of conduct disorder, but only for those children diagnosed with ADHD. Monuteaux et al.15
found that the Val allele was associated with overtly aggressive symptoms of conduct disorder in children diagnosed with ADHD, but this finding was non-significant after correcting for multiple comparisons. In the present study, quantitative, empirically-derived phenotypic measures were utilized to more fully capture variation in youth attention problems and aggression. This difference in methodology may account, in part, for the apparent inconsistency between these past reports and our current findings.
Our hypothesized association between CBCL AP and Val-homozygosity was significant only at the trend level but in the predicted direction. This result is also in accordance with the COMT dopamine tonic-phasic hypothesis which contends that low dopamine levels in the prefrontal cortex, conferred by the Val allele, result in an increase in phasic dopaminergic signaling. This increase in phasic dopaminergic signaling is believed to facilitate cognitive flexibility and set-shifting. Interestingly, our finding parallels reports by other groups suggesting that the Val allele is associated with `off-task' behaviors and, more specifically, distractibility.16
Exclusion of the parenting variables from the regression of AP on COMT genotype revealed that the parenting variables acted as negative confounders; the unadjusted estimate moved closer to the null hypothesis.43
Therefore, other studies that fail to control for the hypothesized confounding effect of maternal parental qualities may under-estimate the association between the Val allele and average AP raw score.
It is important to discuss our limitations as well as some offsetting strengths. First, in testing the above associations, we rely solely on maternal reports of child psychopathology. Thus, it is possible that the associations revealed in this study are confounded by maternal psychopathology as well as maternal genotype. Future studies testing similar hypotheses would benefit from including data from multiple raters and also accounting for the contribution of parental genotype and psychopathology. Second, the cohort used in the present study includes a wide range of ages. Given that particular parenting qualities may be associated with certain psychopathologies at specific age ranges, future studies should utilize more developmentally homogenous samples, and/or larger cohorts to conduct age-specific sub-analyses. Third, although parenting quality is treated as an independent environmental factor that child participants are passively exposed to during their upbringing, this assumption belies the degree to which child behavior may serve to shape maternal parenting. Thus, the environmental factor of maternal parenting used in our analyses is undoubtedly influenced by children's biology and behavior. Fourth, other genes are likely to play significant roles in influencing the physiological underpinnings of aggressive behavior and attention problems. One of the strengths of the present study is our use of empirically-derived, quantitative phenotypic measures as opposed to DSM diagnoses, or symptom counts. By using continuous measures of aggressive behavior and attention problems, we were able to more effectively control for the co-occurrence of these behaviors in our analyses, while also increasing statistical power.
In conclusion, the results of the present study indicate that variation in the Val158Met polymorphism influences problem behaviors associated with psychopathology in youth. More specifically, our findings suggest that the Val and Met alleles of this polymorphism are associated with attention problems and aggressive behavior, respectively. Furthermore, our results indicate that the Met allele is associated with both Direct Aggression and Relational Aggression. The results of the present study may help future efforts to identify unique classes of externalizing disorders with distinct biological substrates.