A robust literature demonstrates that working memory ability is impaired in individuals with ADHD [7
]. Working memory is known to be reliant upon prefrontal catecholamine levels [14
], with COMT being an important regulator of this system [15
]. Here, for the first time in children with ADHD, we explored the relationship between allelic variation in a broad set of catecholamine genes, including COMT, and measures of working memory.
In children with ADHD there was a significant relationship between COMT genotype and performance on the DMTS task. Val/val homozygotes had lower percent correct scores compared to those who carried at least one met allele. There was no relationship between COMT genotype and any of the other working memory measures investigated. Performance on a working memory task requires the co-ordination of a number of abilities: information must be accurately encoded into working memory, maintained and/or manipulated depending on task demands, and finally retrieved. COMT genotype may be related to one or more of these sub-processes in children with ADHD.
Bruder et al. [43
] investigated the relationship between COMT genotype and performance on a number of working memory tasks in a healthy adult population. They found that COMT genotype was related to performance on a Letter-Number Sequencing Task, but not to performance on a Spatial Delayed Response task, n-back task, or Wisconsin Card Sorting Task. The authors argued that the Letter-Number Sequencing task was more taxing of executive processes and thus, that COMT genotype is more closely related to the manipulation of items in working memory than to maintenance.
The present results suggest an alternative interpretation; here there was an association between COMT and performance on the DMTS task, which relies on successful working memory maintenance, but not with the SP or SWM tasks, which place greater executive demands on the updating and manipulation of items. Within the DMTS task there was no interaction between COMT genotype and increasing working memory delay, suggesting that COMT genotype was not related to task difficulty. Similarly, there was no relationship between COMT genotype and performance on the simultaneous matching condition of the DMTS task, which provides a measure of perceptual accuracy. Therefore, it may be concluded that the relationship between COMT genotype and DMTS performance may be most sensitive to either impairments in the encoding of a stable representation into working memory or in retrieval stages.
One potential explanation for our pattern of results may be found in the tonic-phasic hypothesis of dopamine regulation [44
]. According to this hypothesis dopamine action is orchestrated through the co-ordination of tonic and phasic states. The COMT met
allele increases tonic dopamine transmission, which regulates the stability of cortical activation states. Tonic dopamine stimulation has thus been hypothesized to be important for maintaining stable representations in working memory. In contrast, phasic dopamine stimulation regulates the plasticity of activation states and is believed to be important for updating and manipulating working memory representations. Our findings are consistent with the role of the met
allele in enhancing the stability and maintenance of representations required for performance on the DMTS task. These findings suggest that the determining factor in observing associations between neurocognitive measures and COMT genotype may depend more on the nature of the representation required to perform the task, rather than, as suggested by Bruder et al. [43
], the executive load of the task per se
Interestingly, both chronic and acute administration of methylphenidate, a stimulant drug that alters extracellular catecholamine levels [45
] has been shown to improve performance on the CANTAB DMTS task, but not on the spatial working memory task in children with ADHD [33
]. It has been proposed that the therapeutic effect of methylphenidate is mediated through the enhancement of tonic rather than phasic dopamine release [45
]. Therefore the DMTS task in ADHD may show sensitivity both to treatments that alter tonic prefrontal dopamine levels and to variation in COMT genotype. Further work is needed to fully characterize the specific aspects of DMTS task performance that are related to COMT genotype. Many of the commonly used measures of working memory, such as the n-back task and the Wisconsin Card Sorting Task, confound in time both the requirement for stable and flexible representations, and the working memory sub-process (be it encoding, maintenance, or retrieval) being engaged. Selection of tasks that allow for the compartmentalization of these processes will help in disentangling the relationship between COMT genotype and neurocognitive functioning in ADHD.
The finding that impaired performance on the DMTS was associated with the val
rather than the met
allele in children with ADHD supports previous research showing an association between poorer performance on executive tasks and the val
allele in both healthy adults [18
] and children [20
]. Only a few previous studies have specifically explored the relationship between COMT genotype and cognitive abilities in ADHD populations, with results conflicting. Two studies found no relationship between COMT genotype and executive function in children with ADHD [22
], while Bellgrove et al. [24
] found that the met
rather than the val
variant was associated with impaired sustained attention performance in children with ADHD. There are a number of participant-factors that may influence the finding of a relationship between COMT genotype and executive function in children with ADHD, including history of medication and participant age. Perhaps more importantly, given the nature of the findings of the present study, it may be that cognitive task selection is also critically important.
The current study imposed a stringent correction for multiple comparisons that accounted both for the number of tasks studied and the number of SNPs and genetic models tested. The observation that the recessive model of the val
allele survived this correction is interesting in light of other studies that have also reported recessive effects. For example, among children with ADHD val/val
homozygotes have impaired task oriented performance [48
] and increased antisocial behaviour [49
] relative to carriers of at least one met
allele. Nevertheless, we note that a nominally significant effect of the additive model (p
= 0.039) was also found that might survive multiple comparison testing in larger samples. We repeated our analysis in just the sub-sample of participants who were medication free on the day of test (co-varying for gender, age, and IQ). Although this analysis did not survive correction for multiple comparisons it was nonetheless nominally significant (p
Since we failed to observe a relationship between COMT genotype and performance on either the SP or SWM tasks, one may conclude that performance on these tasks is perhaps influenced by other catecholamine gene variants. Nevertheless, we also failed to find evidence of association between performance on the working memory tasks and allelic variation in any of the other catecholamine genes (NET1, DRD2, DBH, DRD4) under study. There are however, a number of methodological considerations that should be considered. First, it should be noted that the low minor allele frequency associated with a number of the catecholamine SNPs may have reduced our power to detect significant associations in the relatively small sample size under study. Second, the three working memory tests used in this study were not matched for psychometric characteristics or task difficulty. In addition, although all our analyses co-varied for the medication status of the participants, it is possible that medication-related factors may have obscured associations between the catecholamine gene variants and working memory measures. The sample of children with ADHD presented here was recruited from a hospital service that specialized in assessment of children with severe behavioural disturbances and as such they presented with a high rate of conduct disorder co-morbidity. Previous research has demonstrated that the association between COMT val/val
genotype and ADHD is modified by coexisting extreme anti-social behaviour and conduct disturbances [49
]. However, Langley et al. [50
] investigated whether impaired social functioning or executive control mediated the relationship between COMT and anti-social behaviour in the context of children with ADHD. Their analysis revealed a mediating effect of social but not executive functioning, suggesting that the association between COMT genotype and working memory ability reported herein is unlikely to be mediated by co-morbid conduct disturbance.