Catechol-O-methyltransferase polymorphism modulates cognitive control in children with chromosome 22q11.2 deletion syndrome

Abstract

). The q11.2 region of chromosome 22 includes the catechol-O-methyltransferase (COMT) gene, which is critical in metabolizing dopamine by methylation. A common polymorphism involving a valine (VAL) to methionine (MET) substitution at codon 158 in the aminoacid sequence changes the stability of enzyme activity. As a result, the VAL variant produces 40% more enzyme activity than does the MET variant at normal body temperature (Chen et al., 2004). Because the dopamine transporter is much less abundant in prefrontal cortex (PFC) than in the striatum, the synaptic deactivation of dopamine in PFC depends to a much greater degree on COMT. For example, methylation accounts for more than 60% of metabolic degradation of dopamine in frontal cortex in comparison with 15% in the striatum and nucleus accumbens (Karoum, Chrapusta, & Egan, 1994).The observation that variation in a single gene could explain a large amount of variance in dopamine metabolism in PFC is particularly interesting in light of previous reports of a mediating role for dopamine in higher cognitive functions (Kimberg & D'Esposito, 2003). Although it is difficult to accurately measure dopamine levels in the human brain, genotypes for COMT could be used as an indicator of dopamine metabolism. The efficiency of PFC-mediated cognition in typically developing (TD) adults has already been shown to vary by the COMT genotype. A large-sample study by Egan et al. (2001) demonstrated that TD adults with homozygous VAL alleles made more perseverative errors than did those with homozygous MET alleles during the Wisconsin Card Sort Task, and this effect was deemed reliable in a more recent meta-analysis based on 17 published studies (Barnett, Jones, Robbins, & Müller, 2007). Egan et al. also conducted a functional imaging study using an N-back task in which participants were asked to indicate whether the current stimulus was the same as the one presented N trials before. They found that those with homozygous VAL alleles produced greater activation in PFC and in the anterior cingulate-which also receives rich dopaminergic innervation-than did those with homozygous MET alleles. The observed difference in brain activation when the performance level of the two groups was similar suggests less efficient processing in the relevant PFC circuitry in the VAL group. Similar findings were found with different cognitive paradigms that required high demands for cognitive control and attention regulation (Blasi et al., 2005;Winterer et al., 2006).It has been shown that the effect of dopamine levels on cognition follows an inverse U function in which a relatively small range of dopamine optimizes cognitive performance (Williams & Goldman-Rakic, 1995 Dopamine plays a critical role in regulating neural activity in prefrontal cortex (PFC) and modulates cognition via a hypothesized inverse U function. We investigated PFC function in children with chromosome 22q11.2 deletion syndrome (22q11.2DS) in which one copy of catechol-O-methyltransferase (COMT) is deleted, thereby shifting them towa...

A second look: No effect of the COMT Val158Met polymorphism on conflict adaptation in youth with chromosome 22q11.2 deletion syndrome

“…We tested 53participants with 22q11.2DS, 49 of whom participated in a prior study (Stoddard et al, 2011) and 27 of whom participated in our previous report (Takarae et al, 2009). We used the same selection criteria and tasks as described in that report.…”

“…However, in 22q11.2DS, neither allele of the codominant, functional COMT Val108/158Met polymorphism (rs4680) has been reliably associated with clinical psychosis (Murphy et al, 1999; Gothelf et al, 2005; Bassett et al, 2007; Boot et al, 2011) or executive function (Bearden et al, 2004; Glaser et al, 2006; Shashi et al, 2010). We have previously reported an association between the rs4680 Met allele and conflict adaptation (Takarae et al, 2009) but not to flanker interference (Stoddard et al, 2011) within the same task. To resolve this discrepancy, we re-examined the association between rs4860 and impairment in conflict adaptation in the larger sample (Stoddard et al, 2011) using the same method as before (Takarae et al, 2009).…”

“…We have previously reported an association between the rs4680 Met allele and conflict adaptation (Takarae et al, 2009) but not to flanker interference (Stoddard et al, 2011) within the same task. To resolve this discrepancy, we re-examined the association between rs4860 and impairment in conflict adaptation in the larger sample (Stoddard et al, 2011) using the same method as before (Takarae et al, 2009). …”

Comprehensive neurocognitive endophenotyping strategies for mouse models of genetic disorders

“…Full Scale IQ (FSIQ) is usually around 75, but discrepancies between a typically average to high VIQ and typically low PIQ have led to the hypothesis that individuals with the 22q11.2DS have a nonverbal learning disability (similar to that reported in fragile X-associated disorders). Behavioral and psychiatric disorders are common in children with 22q11.2DS and include emotional instability, social withdrawal, attention-deficit/hyperactivity disorder, anxiety disorders, and depression (Bearden et al , 2001, 2004a, 2005; Bish et al , 2005, 2007; Gothelf et al , 2010a; Karayiorgou et al , 2010; Kiehl et al , 2009; Simon, 2008; Simon et al , 2005a, 2005b, 2008a, 2008b; Stoddard et al , 2010; Takarae et al , 2009; Xu et al , 2010; Yamagishi and Srivastava, 2003). …”

Executive attention impairment in adolescents with schizophrenia who have used cannabis

“…By contrast, cortical thickness changes dynamically across the lifespan, influenced by development and disease (Frye et al, 2010). Third, deficits in executive attention have been associated with increased risk for several neuropsychiatric disorders including schizophrenia, such as 22q11 deletion syndrome (which confers a genetic high risk for schizophrenia) (Takarae et al, 2009), post-traumatic stress disorder (Aupperle et al, 2012), and attention-deficit disorder (Mullane et al, 2011). In contrast, a previous study comparing ANT performance in heavy cannabis users, heavy cannabis + inhalant users, and healthy controls found no differences in alerting, orienting, or executive attention across the three groups (Vilar-Lopez et al, 2013).…”