We have demonstrated that the COMT
Val158Met polymorphism affects prefrontal tissue volumes in a gender-specific manner in children with VCFS. We did not find a genotype effect or a genotype by gender effect on total frontal lobe or whole brain volume, suggesting that this polymorphism affects prefrontal tissue differentially. This is consistent with previous studies that have demonstrated that the COMT
gene is expressed preferentially in the prefrontal cortex (Chen et al., 2004
; Matsumoto et al., 2003
Since we did not find allele by gender variation in age, psychiatric comorbidity or medication use, it is unlikely that these factors account for our findings. Nonetheless, the mechanism by which this polymorphism affects brain morphology in VCFS is not clear. Due to the role that COMT
plays in neurotransmission, most previous studies of non-VCFS individuals have focused on the effect of the Val158Met polymorphism on prefrontal function rather than anatomy (Diamond et al., 2004
; Egan et al., 2001
; Goldberg et al., 2003
). These studies have found that individuals who are homozygous for the Met allele perform better on functional MRI – mediated tasks of working memory and executive function, which depend primarily on prefrontal function, suggesting that higher levels of available dopamine in the prefrontal cortex permit more efficient neurocognitive function.
A recent study focusing on the effect of this polymorphism on prefrontal anatomy in individuals with schizophrenia did not find an effect of genotype on anatomy (Ho et al., 2005
). However, we do not know the effect of hemizygosity in individuals with VCFS. Interestingly, in their longitudinal study of children with VCFS, Gothelf and colleagues (2005)
did not find COMT-related differences in prefrontal volume at their Time 1 assessment, but did find reduced prefrontal volumes in individuals hemizygous for the Met allele at Time 2. This supports the notion that the dopaminergic environment in the brains of patients with VCFS influences prefrontal morphology as well as function; however this influence may be moderated by a complex interplay between other genes (Karayiorgou & Gogos, 2004
) and environmental factors (Grossman et al., 2003
Our finding of differential effects of this polymorphism on subregions of the prefrontal cortex was unexpected. Since dorsal PFC and orbital PFC differ in function and in connectivity (Kaufer & Lewis, 1999
), it is possible that each subregion requires different levels of dopamine for optimal development. Insofar as the evidence for the expression of COMT in the orbital PFC is less robust than that of the dorsal PFC, alterations in the orbitofrontal cortex may also be due to an interaction between COMT and other genes that are expressed in that subregion, or to a compensatory mechanism in response to COMT-related changes in the dorsal PFC.
The precise mechanism that underlies our findings of region-specific sexual dimorphism is also not clear. Women have been shown to have lower COMT
activity than men (Boudikova et al., 1990
; Floderus et al., 1981
), presumably due to the downregulation of COMT
by estradiol (Jiang et al., 2003
). Moreover, the COMT
Val158Met polymorphism has been reported to differentially affect gender in individuals with schizophrenia (Shifman et al., 2002
), anxiety (Enoch et al., 2002
) and obsessive compulsive disorder (Alsobrook et al., 2002
; Karayiorgou et al., 1999
). Gogos and colleagues (1998)
further demonstrated sexually dimorphic effects on dopamine levels and behaviors in COMT-deficient mice. Interestingly, sexual dimorphism has also been reported in the volumes of the orbitofrontal cortex in typical individuals and those with schizophrenia (Gur et al., 2002
; Gur et al., 2004
). In general, these findings, taken together, support but do not explain our findings of gender by allele differences in prefrontal volumes. It is likely that the COMT
gene is either in interaction or linkage disequilibrium with other genes to produce this effect. In addition, gender differences in compensatory capacity (Gogos et al., 1998
) may be contributing to our findings as well.
Although these findings suggest that COMT
and gender affect the morphology of the network of brain regions that are involved in executive function, working memory and response inhibition, we did not find that either allelic variation alone, or an allele by gender interaction, affected performance on our tasks of working memory or sustained attention. We did find that individuals with the Met allele, particularly girls, tended to achieve higher scores on a test of executive function. This finding is somewhat consistent with those of Bearden and colleagues (Bearden et al., 2004
), who found that individuals with VCFS who were hemizygous for the Val allele exhibited poorer performance on tests of prefrontal function, although Bearden et al.'s findings were more robust than ours. However, Bearden and coworkers did not find a gender effect. The partial discrepancy in findings could be explained by the differences in study instruments, as well as potential differences in sample homogeneity and demographics (e.g. age). To the extent that our sample was more heterogeneous than Bearden's sample, either according to age or cognitive function, it may have been more difficult to detect a more robust effect of the COMT
polymorphism on neuropsychological function.
It is possible (but unlikely) that the absence of a gender by allele effect on most tests of neuropsychological function could have been due to the fact that these tests of executive function have not been normed specifically on children with intellectual disabilities. However, they have been used meaningfully and successfully in studies of individuals with a wide range of disabilities, including fragile X syndrome (Loesch et al., 2003
) and autism (Joseph et al., 2005). Moreover, previous studies indicate that IQ accounts for a very modest proportion of the variance in executive function skills (Crinella & Yu, 2000
). It is more likely that our findings result from the indirect association between genes and behavior. Whereas brain morphology is an endophenotype (Almasy and Blangero, 2001
) that may be affected relatively directly by genotype, it is likely that specific behavioral phenotypes result, instead, from a confluence of multiple genetic and environmental factors. Accordingly, the effect of a specific gene on behavior is likely to be smaller and less direct than its effect on brain morphology.
Despite the indirect effect of genotype on behavioral phenotype, a relationship between COMT
and gender has been demonstrated in several disorders, as noted above. COMT
continues to be expressed throughout adolescence and adulthood (Maynard et al., 2003
), suggesting that this gene may mediate an abnormal neurodevelopmental process that unfolds with age. Since our sample was relatively young (ranging in age from 6 to 15 years), it is possible that the full effect of variation in the COMT gene may not have manifested itself. Accordingly, we may not be able to discern potential clinical implications of this gender by allele interaction until the children in our sample move into late adolescence or early adulthood. This notion is consistent with the study cited above by Gothelf and colleagues (2005)
, who found that COMT-related differences in cognition and psychiatric symptoms as well as prefrontal volumes changed with age. Accordingly, we will be reassessing these children in three years and may be able to identify at that time whether this interaction confers susceptibility to psychiatric disorder.