COMT Va158Met Genotype and Individual Differences in Executive Function in Healthy Adults

Department of Psychiatry, Dartmouth Medical School, Lebanon, New Hampshire 03756-0001, USA.
Journal of the International Neuropsychological Society (Impact Factor: 3.01). 01/2011; 17(1):174-80. DOI: 10.1017/S1355617710001402
Source: PubMed

ABSTRACT The Val158Met polymorphism of the catechol-O-methyltransferase (COMT) gene may be related to individual differences in cognition, likely via modulation of prefrontal dopamine catabolism. However, the available studies have yielded mixed results, possibly in part because they do not consistently account for other genes that affect cognition. We hypothesized that COMT Met allele homozygosity, which is associated with higher levels of prefrontal dopamine, would predict better executive function as measured using standard neuropsychological testing, and that other candidate genes might interact with COMT to modulate this effect. Participants were 95 healthy, right-handed adults who underwent genotyping and cognitive testing. COMT genotype predicted executive ability as measured by the Trail-Making Test, even after covarying for demographics and Apolipoprotein E (APOE), brain-derived neurotrophic factor (BDNF), and ankyrin repeat and kinase domain containing 1 (ANKK1) genotype. There was a COMT-ANKK1 interaction in which individuals having both the COMT Val allele and the ANKK1 T allele showed the poorest performance. This study suggests the heterogeneity in COMT effects reported in the literature may be due in part to gene-gene interactions that influence central dopaminergic systems.

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Available from: Andrew J Saykin, Aug 10, 2015
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    • "Dopaminergic activity plays a major role in the regulation of executive functioning in the prefrontal cortex [24]. Presence of the COMT Met allele is associated with higher levels of prefrontal dopamine and appears to have a positive effect on executive functioning [37]. Also, COMT and DRD2 conjointly affect working memory performance [38] [39] [40]. "
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    ABSTRACT: Background: There is emerging evidence that the increased susceptibility to developing alcohol and substance use dis-orders in those with a family history of Alcohol Dependence (AD) may be related to structural differences in brain cir-cuits that influence the salience of rewards or modify the efficiency of information processing. Externalizing disorders of childhood including Attention Deficit Hyperactivity Disorder, Conduct and Oppositional Disorders are a prominent feature of those with a positive family history. The caudate nuclei have been implicated in both the salience of rewards and in the pathophysiology of alcohol dependence and these often antecedent childhood disorders. Methods: Adoles-cent/young adult high and low-risk for AD offspring (N = 130) were studied using magnetic resonance imaging. Vol-umes of the caudate nucleus were obtained using manual tracing with BRAINS2 software and neuropsychological func-tioning determined. Childhood disorders were assessed as part of a long-term longitudinal follow-up that includes young adult assessment. Dopaminergic variation was assessed using genotypic variation in the catechol-O-methyl-transferase (COMT) and DRD2 genes. Results: High-risk subjects showed poorer Working Memory functioning. Cau-date volume did not differ between high and low-risk subjects, but those with externalizing disorders of childhood showed reduced caudate volume. Variation in COMT and DRD2 genes was associated with Working Memory per-formance and caudate volume. Conclusions: Caudate volume is reduced in association with externalizing disorders of childhood/adolescence. Working Memory deficits appear in familial high-risk offspring and those with externalizing disorders of childhood. The dopaminergic system appears to be involved in both working memory performance and externalizing disorders of childhood.
    Advances in Molecular Imaging 10/2013; 3(04):43-54. DOI:10.4236/ami.2013.34007
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    • "They concluded that COMT effects are modulated by DRD2 / ANKK1 - Taq - Ia genotype such that they are apparent only in the A12 group . Wishart and colleagues ( 2011 ) tested performance on the Trail Making test , in which participants connect numbers ( Trails A ) or alternate numbers and letters ( Trails B ) [ 50 ] . "
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    ABSTRACT: Complex cognitive tasks such as visual working memory (WM) involve networks of interacting brain regions. Several neurotransmitters, including an appropriate dopamine concentration, are important for WM performance. A number of gene polymorphisms are associated with individual differences in cognitive task performance. COMT, for example, encodes catechol-o-methyl transferase the enzyme primarily responsible for catabolizing dopamine in the prefrontal cortex. Striatal dopamine function, linked with cognitive tasks as well as habit learning, is influenced by the Taq-Ia polymorphism of the DRD2/ANKK1 gene complex; this gene influences the density of dopamine receptors in the striatum. Here, we investigated the effects of these polymorphisms on a WM task requiring the maintenance of 4 or 6 items over delay durations of 1 or 5 seconds. We explored main effects and interactions between the COMT and DRD2/ANKK1-Taq-Ia polymorphisms on WM performance. Participants were genotyped for COMT (Val(158)Met) and DRD2/ANKK1-Taq-Ia (A1+, A1-) polymorphisms. There was a significant main effect of both polymorphisms. Participants' WM reaction times slowed with increased Val loading such that the Val/Val homozygotes made the slowest responses and the Met/Met homozygotes were the fastest. Similarly, WM reaction times were slower and more variable for the DRD2/ANKK1-Taq-Ia A1+ group than the A1- group. The main effect of COMT was only apparent in the DRD2/ANKK1-Taq-Ia A1- group. These findings link WM performance with slower dopaminergic metabolism in the prefrontal cortex as well as a greater density of dopamine receptors in the striatum.
    PLoS ONE 01/2013; 8(1):e55862. DOI:10.1371/journal.pone.0055862 · 3.53 Impact Factor
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    • "Third, it may be that COMT effects are only evident in combination with other genotypes, or against a psychiatric disease background. Several studies have suggested the importance of a COMT haplotype, or of interactions with other genes that collectively determine dopaminergic tone (Meyer-Lindenberg et al, 2006; Wishart et al, 2011). Indeed, although there was a main effect of COMT in the childhood assessment, a COMT-related haplotype also emerged as a significant predictor (Barnett et al, 2009). "
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    ABSTRACT: The Val158Met polymorphism of the catechol-O-methyltransferase (COMT) gene is an important regulator of dopamine in the prefrontal cortex, an area critical to working memory. Working memory deficits are present in several psychiatric disorders, and there is wide variation in working memory capacity in the normal population. Association studies of COMT and working memory in healthy volunteers have yielded inconsistent results, possibly because of small sample sizes. Here we examine COMT in relation to N-Back working memory task performance in a large population-based cohort of young adults. We predicted individuals with one or two copies of the Met allele would perform better, and that this relationship would be more evident in males than females. Participants (N=1857-2659) tested at 18 years of age, were enrolled in the Avon Longitudinal Study of Parents and Children (ALSPAC). We used multiple regression to examine effects of sex and COMT genotype on N-Back hits, false positives, discriminability, and reaction time while controlling for important covariates. COMT genotype did not predict hits or discriminability. There was a nominally significant interaction between COMT and sex on false positives, but this was not in the predicted direction, and was not significant after controlling for covariates. COMT genotype was not related to working memory in this large population-based cohort. It is possible COMT is not meaningfully associated with working memory in healthy young adults, or that COMT effects are detectable only in assessments reflecting neural processes underlying cognition, such as fMRI, rather than in behavioral performance.Neuropsychopharmacology accepted article preview online, 21 January 2013; doi:10.1038/npp.2013.24.
    Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 01/2013; 38(7). DOI:10.1038/npp.2013.24 · 7.83 Impact Factor
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