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: 2.96). 01/2011; 17(1):174-80. DOI: 10.1017/S1355617710001402
Source: PubMed


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
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    • "Second, the COMT G variant (including Val-Val and Val-Met) has been identified as a risk factor for cognitive deficits with normal aging, given the association with the degradation of catecholamine neurotransmitters (such as dopamine) (Savitz et al., 2006). However, previous results of candidate gene studies have revealed promising but inconsistent association patterns (Barnett et al., 2008; Wishart et al., 2011; Sapkota et al., 2014) and MCI status (Martinez et al., 2009; Yarnell et al., 2014). Had we only examined concurrent data we would have reported no MCI-related associations. "
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    ABSTRACT: Objective: Research has reported associations among selected genetic susceptibility biomarkers and risk of (a) normal cognitive aging decrements, (b) established mild cognitive impairment (MCI), and (c) sporadic Alzheimer's disease (AD). In focusing on the transitional normal-to-early MCI phase, we examine associations among three theoretically relevant polymorphisms (APOE [rs429358, rs7412], BDNF [rs6265], COMT [rs4680]) and both baseline cognitive status (MCI vs. normal aging) and two-wave (four-year) longitudinal stability or change profiles. The latter included three profiles: (a) stable as normal aging, (b) stable or chronic impairment (MCI-to-MCI), and (c) emergence of impairment (normal-to-MCI). Method: Genotyped older adults (n = 237 at baseline; age range = 64–91; 62% women) from the Victoria Longitudinal Study were examined for (a) independent and interactive associations of three genetic polymorphisms with (b) two objectively classified cognitive status groups (not-impaired controls (NIC) and MCI) at (c) both baseline and across a two-wave (four-year) longitudinal interval. Results: First, logistic regression revealed that the presence of at least one APOE ε4 allele (the risk factor for AD) was linked to greater baseline risk of objective MCI. Second, multinomial logistic regression revealed that (a) the presence of an APOE ε4 allele was associated with an increased risk of 4-year MCI status stability (chronicity), and (b) the COMT homozygous risk genotype (G/G or Val/Val) was associated with an increased risk of both MCI-to-MCI stability (chronicity) and emerging NIC-to-MCI conversion. Discussion: Both chronicity and emergence of objectively classified early cognitive impairment may be genetically heterogeneous phenomena, with influences from a panel of both normal cognitive aging (COMT) and AD-related (APOE) polymorphisms.
    Full-text · Article · Sep 2014 · Frontiers in Aging Neuroscience
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    • "Recent evidence suggests that improved performance in executive function evaluations is associated with longer survival in AD cohorts [32]. The influence of COMT variants on executive function performance, as reported in schizophrenia and bipolar disorder, has been consistently replicated in middle-aged and elderly individuals without mental disorders [33,34]. "
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    ABSTRACT: Alzheimer's disease (AD) is the leading cause of dementia worldwide and is associated with individual, familial and social burdens. Catechol-O-methyltransferase (COMT) may have a prominent role in AD pathophysiology by affecting the metabolism of catecholamine neurotransmitters and estrogen. Although the COMT rs4680 gene polymorphism has been investigated as a susceptibility factor for AD, the results are inconsistent. The aim of this study was to examine the influence of the COMT rs4680 gene polymorphism as a risk factor for AD in the Han Chinese population and its synergistic effect with the apolipoprotein E (APOE)gene. A total of 137 AD patients and 194 healthy controls were analyzed. Clinical criteria and neuropsychological tests were used to establish diagnostic groups. All subjects were analyzed for the COMTrs4680 polymorphism and APOEgenotype. No significant differences were observed between AD and control subjects regarding the COMT genotype frequencies of Val/Val, Val/Met and Met/Met, but Met alleles were higher in AD than in control subjects (35.4 and 28.1%, p = 0.045). A minor synergistic effect between the genotypes GG and APOEε4 was observed in AD patients (OR: 5.707, 95% CI: 2.505-13.002, p < 0.001). This synergistic effect was greater in women, who showed higher OR of AD (16.007, 95% CI: 4.606-56.118, p < 0.001) versus the AD group with APOE ε4 (11.972, 95% CI: 5.534-25.902, p < 0.001). Furthermore, the COMT Met allele was an independent risk factor for AD without APOE ε4 allele carriers (OR: 1.806, 95% CI: 1.160-2.810, p = 0.009), especially in men (OR: 4.904, 95% CI: 2.381-10.099, p < 0.001). The COMT(Val158Met) polymorphism is not an independent risk factor for AD but shows a synergistic effect between the genotypes GG and APOEε4 that proves greater in women with AD. The COMT Met allele represents a risk factor in AD without APOE ε4 allele carriers, which is notable in men with AD.
    Full-text · Article · Jan 2014
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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 disorders in those with a family history of Alcohol Dependence (AD) may be related to structural differences in brain circuits 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: Adolescent/young adult high and low-risk for AD offspring (N = 130) were studied using magnetic resonance imaging. Volumes of the caudate nucleus were obtained using manual tracing with BRAINS2 software and neuropsychological functioning 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-methyltransferase (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 performance 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.
    Full-text · Article · Oct 2013 · Advances in Molecular Imaging
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