Association between the Catechol O-methyltransferase (COMT) Val158met polymorphism and different dimensions of impulsivity.
ABSTRACT: BACKGROUND: Impulsivity is a multidimensional construct which has been associated with dopaminergic neurotransmission. Nonetheless, until this moment, few studies addressed the relationship between different types of impulsivity and the single nucleotide polymorphism caused by a substitution of valine (val) with methionine (met) in the 158 codon of the Catechol-o-Methyltransferase gene (COMT-val158met). The present study aimed to investigate the association between val158met COMT polymorphism and impulsive behavior measured by two neuropsychological tests. METHODOLOGY/PRINCIPAL FINDINGS: We administered two neuropsychological tests, a Continuous Performance Task and the Iowa Gambling Task were applied to 195 healthy participants to characterize their levels of motor, attentional and non-planning impulsivity. Then, subjects were grouped by genotype, and their scores on impulsivity measures were compared. There were no significant differences between group scores on attentional and motor impulsivity. Those participants who were homozygous for the met allele performed worse in the Iowa Gambling Task than val/val and val/met subjects. CONCLUSIONS/SIGNIFICANCE: Our results suggest that met allele of val158met COMT polymorphism is associated with poor performance in decision-making/cognitive impulsivity task. The results reinforce the hypothesis that val and met alleles of the val158met polymorphism show functional dissociation and are related to different prefrontal processes.
Project description:The adverse effects of cannabis use on executive functions are still controversial, fostering the need for novel biomarkers able to unveil individual differences in the cognitive impact of cannabis consumption. Two common genetic polymorphisms have been linked to the neuroadaptive impact of ?9-tetrahydrocannabinol (THC) exposure and to executive functions in animals: the catechol-O-methyltransferase (COMT) gene val158met polymorphism and the SLC6A4 gene 5-HTTLPR polymorphism. We aimed to test if these polymorphisms moderate the harmful effects of cannabis use on executive function in young cannabis users. We recruited 144 participants: 86 cannabis users and 58 non-drug user controls. Both groups were genotyped and matched for genetic makeup, sex, age, education, and IQ. We used a computerized neuropsychological battery to assess different aspects of executive functions: sustained attention (CANTAB Rapid Visual Information Processing Test, RVIP), working memory (N-back), monitoring/shifting (CANTAB ID/ED set shifting), planning (CANTAB Stockings of Cambridge, SOC), and decision-making (Iowa Gambling Task, IGT). We used general linear model-based analyses to test performance differences between cannabis users and controls as a function of genotypes. We found that: (i) daily cannabis use is not associated with executive function deficits; and (ii) COMT val158met and 5-HTTLPR polymorphisms moderate the link between cannabis use and executive performance. Cannabis users carrying the COMT val/val genotype exhibited lower accuracy of sustained attention, associated with a more strict response bias, than val/val non-users. Cannabis users carrying the COMT val allele also committed more monitoring/shifting errors than cannabis users carrying the met/met genotype. Finally, cannabis users carrying the 5-HTTLPR s/s genotype had worse IGT performance than s/s non-users. COMT and SLC6A4 genes moderate the impact of cannabis use on executive functions.
Project description:BACKGROUND:Impulsivity and compulsivity are central to understanding a range of psychiatric disorders but also to understanding the spectrum of normative human behavior. It was recently shown that separable latent phenotypes of impulsivity and compulsivity could be fractionated. The possible genetic contributions to these latent phenotypes have yet to be elicited. The catechol-o-methyl transferase (COMT) Val158Met polymorphism (rs4680) regulates cortical dopamine degradation and is a key area of interest in this context. METHODS:COMT Val158Met polymorphism status was obtained from a random subset (n = 258) of young adults from an established cohort, for whom latent phenotype scores were previously reported. Differences in latent phenotype scores were explored between COMT groups using analysis of variance (ANOVA) and post-hoc t tests. RESULTS:The Val-Val subgroup exhibited significantly elevated compulsivity scores compared to both other groups. Impulsivity scores did not differ significantly as a function of COMT Val158Met polymorphism status. CONCLUSIONS:These results suggest that the COMT polymorphism, and by implication cortical dopamine degradation, influences the expression of a trans-diagnostic compulsivity phenotype, even accounting for possible confounding effects of impulsivity.
Project description:Studies have revealed that catechol-O-methyltransferase (COMT) and dopaminegic receptor2 (DRD2) modulate human attention bias for palatable food or tobacco. However, the existing evidence about the modulations of COMT and DRD2 on attentional bias for facial expressions was still limited. In the study, 650 college students were genotyped with regard to COMT Val158Met and DRD2 TaqI A polymorphisms, and the attentional bias for facial expressions was assessed using the spatial cueing task. The results indicated that COMT Val158Met underpinned the individual difference in attentional bias for negative emotional expressions (P = 0.03) and the Met carriers showed more engagement bias for negative expressions than the Val/Val homozygote. On the contrary, DRD2 TaqIA underpinned the individual difference in attentional bias for positive expressions (P = 0.003) and individuals with TT genotype showed much more engagement bias for positive expressions than the individuals with CC genotype. Moreover, the two genes exerted significant interactions on the engagements for negative and positive expressions (P = 0.046, P = 0.005). These findings suggest that the individual differences in the attentional bias for emotional expressions are partially underpinned by the genetic polymorphisms in COMT and DRD2.
Project description:The catechol-O-methyltransferase (COMT) Val158Met polymorphism may be a risk factor for nicotine addiction. This study examined the influence of the COMT Val158Met polymorphism on subjective, physiological and cognitive effects of intravenous (IV) nicotine use in African Americans (AAs; n=56) and European Americans (EAs; n=68) smokers. Overnight abstinent smokers received saline followed by 0.5 and 1.0?mg per 70?kg doses of nicotine, administered 30?min apart. Smokers with valine (Val)/Val genotype, compared with methionine (Met) carriers, had greater negative subjective effects from IV nicotine and had more severe withdrawal severity following overnight abstinence from smoking. Women with Val/Val genotype reported greater difficulty concentrating and irritability than men with Val/Val or Met carrier genotypes. The Val/Val genotype was associated with better performance on the math task and in AA smokers it was associated with greater systolic blood pressure. These results support the rationale of pharmacologically inhibiting COMT to aid with smoking cessation among Val/Val genotype smokers.
Project description:Math anxiety (MA) is a phobic reaction to math activities, potentially impairing math achievement. Higher frequency of MA in females is explainable by the interaction between genetic and environmental factors. The molecular-genetic basis of MA has not been investigated. The COMT Val158Met polymorphism, which affects dopamine levels in the prefrontal cortex, has been associated with anxiety manifestations. The valine allele is associated with lower, and the methionine allele with higher, dopamine availability. In the present study, the effects of sex and COMT Val158Met genotypes on MA were investigated: 389 school children aged 7-12 years were assessed for intelligence, numerical estimation, arithmetic achievement and MA and genotyped for COMT Val158Met polymorphism. The Math Anxiety Questionnaire (MAQ) was used to assess the cognitive and affective components of MA. All genotype groups of boys and girls were comparable regarding genotype frequency, age, school grade, numerical estimation, and arithmetic abilities. We compared the results of all possible genetic models: codominance (Val/Val vs. Val/Met vs. Met/Met), heterosis (Val/Met vs. Val/Val plus Met/Met), valine dominance (Val/Val plus Val/Met vs. Met/Met), and methionine dominance (Met/Met plus Val/Met vs. Val/Val). Models were compared using AIC and AIC weights. No significant differences between girls and boys and no effects of the COMT Val158Met polymorphism on numerical estimation and arithmetic achievement were observed. Sex by genotype effects were significant for intelligence and MA. Intelligence scores were higher in Met/Met girls than in girls with at least one valine allele (valine dominance model). The best fitting model for MA was heterosis. In Anxiety Toward Mathematics, heterozygous individuals presented MA levels close to the grand average regardless of sex. Homozygous boys were significantly less and homozygous girls significantly more math anxious. Heterosis has been seldom explored, but in recent years has emerged as the best genetic model for some phenotypes associated with the COMT Val158Met polymorphism. This is the first study to investigate the genetic-molecular basis of MA.
Project description:The Val158Met polymorphism of human catechol-o-methyltransferase (COMT) is one of the most well-studied single-nucleotide polymorphisms in neuropsychiatry; however, findings are inconsistent due to human genetic heterogeneity. We created the first 'humanized' COMTVal158Met mouse lines, which carry either human COMT Val or Met alleles via gene targeting. The 'humanized' mouse model enables strict comparison of the physiological functions of the two alleles. Consistent with human observation, Met/Met mice exhibited a 30% reduction in enzymatic activity compared with Val/Val mice. On the basis of the reported differences in human Met and Val carriers across working memory, fear processes and sensorimotor gating, we examined these functions between sibling Met/Met and Val/Val mice. Val/Val mice exhibited robust reductions in spatial working memory compared with Met/Met mice in both sexes, with tolcapone treatment significantly reversing the Val/Val alternation deficits. Sex effects were observed in other behaviors, with male Val/Val mice exhibited lower prepulse inhibition compared with Met/Met mice, whereas female mice exhibited the opposite phenotype. Female but not male Met/Met mice exhibited reduced contextual fear, increased cued fear, and reduced extinction recall. Thus, these mice (1) support the argument that human COMT Val158Met polymorphism modulates behavioral functions and most importantly (2) exhibit the expected treatment effects supporting the 'inverted U shaped' dose response of catecholamine signaling on cognitive function. This model will be invaluable for understanding the effects of human COMT Val158Met polymorphism on cortical development and behavioral functions, and how this polymorphism modulates treatment response.
Project description:The catechol-O-methyltranferase (COMT) is one of the main enzymes that metabolise dopamine in the brain. The Val158Met polymorphism in the COMT gene (rs4680) causes a trimodal distribution of high (Val/Val), intermediate (Val/Met) and low (Met/Met) enzyme activity. We tested whether the Val158Met polymorphism is a modifier of the age at onset (AAO) in Parkinson's disease (PD). The rs4680 was genotyped in a total of 16 609 subjects from five independent cohorts of European and North American origin (5886 patients with PD and 10 723 healthy controls). The multivariate analysis for comparing PD and control groups was based on a stepwise logistic regression, with gender, age and cohort origin included in the initial model. The multivariate analysis of the AAO was a mixed linear model, with COMT genotype and gender considered as fixed effects and cohort and cohort-gender interaction as random effects. COMT genotype was coded as a quantitative variable, assuming a codominant genetic effect. The distribution of the COMT polymorphism was not significantly different in patients and controls (p=0.22). The Val allele had a significant effect on the AAO with a younger AAO in patients with the Val/Val (57.1±13.9, p=0.03) than the Val/Met (57.4±13.9) and the Met/Met genotypes (58.3±13.5). The difference was greater in men (1.9 years between Val/Val and Met/Met, p=0.007) than in women (0.2 years, p=0.81). Thus, the Val158Met COMT polymorphism is not associated with PD in the Caucasian population but acts as a modifier of the AAO in PD with a sexual dimorphism: the Val allele is associated with a younger AAO in men with idiopathic PD.
Project description:Both genetic and environmental factors have been shown to influence decision making, but their relative contributions and interactions are not well understood. The present study aimed to reveal possible gene-environment interactions on decision making in a large healthy sample. Specifically, we examined how the frequently studied COMT Val(158)Met polymorphism interacted with an environmental risk factor (i.e., stressful life events) and a protective factor (i.e., parental warmth) to influence affective decision making as measured by the Iowa Gambling Task. We found that stressful life events acted as a risk factor for poor IGT performance (i.e., high reward sensitivity) among Met carriers, whereas parental warmth acted as a protective factor for good IGT performance (i.e., higher IGT score) among Val/Val homozygotes. These results shed some new light on gene-environment interactions in decision making, which could potentially help us understand the underlying etiology of several psychiatric disorders associated with decision making impairment.
Project description:Basic investigations link a Val158Met polymorphism (rs4680) in the catechol-O-methyltransferase (COMT) gene to not only its enzymatic activity, but also to its dopaminergic tone in the prefrontal cortex. Previous PET studies have documented the relationship between COMT Val158Met polymorphism and D1 and D2/3 receptor binding potential (BP), and interpreted them in terms of dopaminergic tone. The use of baseline dopamine D1 and D2/3 receptor binding potential (BPND) as a proxy for dopaminergic tone is problematic because they reflect both endogenous dopamine levels (a change in radiotracer's apparent affinity) and receptor density. In this analysis of 31 healthy controls genotyped for the Val158Met polymorphism (Val/Val, Val/Met, and Met/Met), we used amphetamine-induced displacement of [11C]FLB 457 as a direct measure of dopamine release. Our analysis failed to show a relationship between COMT genotype status and prefrontal cortical dopamine release. COMT genotype was also not predictive of baseline dopamine D2/3 receptor BPND.