catechol-O-methyltransferase Gene Research Articles

Genes of the dopaminergic system selectively modulate top-down but not bottom-up attention.

Cognitive performance is modulated by the neurotransmitter dopamine (DA). Recently, it has been proposed that DA has a strong impact on top-down but not on bottom-up selective visual attention. We tested this assumption by analyzing the influence of two gene variants of the dopaminergic system. Both the catechol O-methyltransferase (COMT) protein and the dopamine transporter (DAT) protein are crucial for the degradation and inactivation of DA. These metabolizing proteins modulate the availability of DA, especially in the prefrontal cortex and basal ganglia. The functional COMT Val158Met polymorphism of the COMT gene represents two coding variants, valine and methionine. In Met allele carriers, the COMT activity is reduced three- to fourfold. A variable number of tandem repeats (VNTR) polymorphism exists in the DAT1 gene, which encodes DAT. The DAT density was reported to be about 50% higher for the DAT1 10-repeat than the DAT1 9-repeat allele. We assessed attention via two experimental tasks that predominantly measure either top-down processing (the Stroop task) or bottom-up processing (the Posner-Cuing task). Carriers of the Met allele of the COMT Val158Met polymorphism displayed better performance in the Stroop task, but did not outperform the other participants in the Posner-Cuing task. The same result was noted for carriers of the DAT1 10-repeat allele. From these findings, we suggest that normal variations of the dopaminergic system impact more strongly on top-down than on bottom-up attention.

COMT met allele differentially predicts risk versus severity of aberrant eating in a large community sample

Prefrontal dopamine (DA) transmission participates in the reinforcement of reward-driven behaviors like eating. Because catechol-O-methyltransferase (COMT) degrades DA and is expressed in the prefrontal cortex, variation in the COMT gene may modulate eating behavior. Previous studies have shown that the met allele of the COMT val158met single nucleotide polymorphism (SNP) is associated with Bulimia Nervosa (BN). The specific aim of this study was to test whether the met allele increased risk for, and severity of, eating disorder symptomatology in community volunteers. Caucasian adults (N=1003; 51.2% female) from the University of Pittsburgh Adult Health and Behavior Project (AHAB) were genotyped and completed the Eating Disorders Inventory (EDI). Logistic and Poisson regression analyses assessed genotype-dependent presence and severity of eating disorder symptomatology. The met allele was significantly associated with the presence of symptoms on the Bulimia subscale and the severity of Body Dissatisfaction scores. All EDI subscales significantly predicted BMI. To our knowledge, these are the first data indicating that the COMT met allele increases risk for some symptoms of disordered eating, while increasing severity of others, in a community sample. These novel findings may have important implications for understanding the etiology of heterogeneous disordered eating phenotypes.

Effects of COMT genotype on cognitive ability and functional capacity in individuals with schizophrenia

Cognitive and functional impairments are core features of schizophrenia. This study examined the catechol-O-methyltransferase (COMT) genotype and its relationship to cognition and functional capacity in 188 individuals with schizophrenia or schizoaffective disorder. We found that in a dose–response fashion, individuals with more Met alleles performed significantly better on tests of learning/memory and abstraction. The effects of COMT genotype on cognition were modest, explaining about 3% of the variance in learning/memory and abstraction. Larger studies will be needed to examine the relationships between COMT and other genes and cognitive performance and everyday functioning.

The Interplay Between Parenting Practices with Dopamine D2 Receptor and Catechol-O-Methyltransferase Genotype on Alcohol Drinking in Early Adolescence

The Interplay Between Parenting Practices with Dopamine D2 Receptor and Catechol-O-Methyltransferase Genotype on Alcohol Drinking in Early Adolescence

Association of catechol-O-methyltransferase Val 108/158 Met polymorphism with essential hypertension

To explore the association of catechol-O-methyltransferase (COMT) Val 108/158 Met polymorphism with essential hypertension in Chinese population. COMT Val 108/158 Met polymorphism was detected by polymerase chain reaction- restriction fragment length polymorphism (PCR-RFLP) in a case-control study, including 215 hypertensive patients (hypertensive group, n=215) and 227 controls (control group, n=227). 1)There was no significant difference in the frequency distribution of genotypic (Val/Val, Val/Met, and Met/Met) and the allelic of COMT gene Val 108/158 Met polymorphism between the 2 groups (P>0.05). 2) After gender stratification, there was no significant difference in the genotypic and allelic frequency distribution in men or women between the 2 groups (P>0.05). 3) After risk stratification of hypertension, there was no significant difference in the genotypic and allelic frequency distribution between the low risk, middle risk, high risk and very high risk grades (P>0.05). 4) Raised body mass index, blood glucose and low-density lipoprotein, and hypertension family history were risk factors for hypertension by logistic regression analysis, while genotype had no effect on the occurrence of hypertension. No relationship between COMT Val 108/158 Met polymorphism and essential hypertension has been found.

Catechol-O-methyltransferase Val158Met polymorphism: modulation of wearing-off susceptibility in a Chinese cohort of Parkinson's disease.

Catechol-O-methyltransferase (COMT) is one of the cardinal enzymes that metabolize dopamine and other catecholamine neurotransmitters in the central and peripheral nervous system. Recent studies have shown that the impact of COMT haplotypes on the development of wearing-off phenomenon is in dispute, while the relationship between COMT haplotypes and wearing-off phenomenon in ethnic Chinese population is lacking. The purpose of this study was to characterize the correlation between the Val158Met polymorphism in the COMT gene and the motor complication "wearing-off" in Chinese PD patients. We have sequenced the COMT gene in 259 PD patients and 257 healthy controls. Our results demonstrated that Met/Met homozygosity of the COMT Val158Met polymorphism was related to a decreased risk of developing wearing-off. This finding suggests that COMT Val158Met may affect susceptibility to wearing-off in PD.

Val158Met polymorphism of COMT gene and Parkinson's disease risk in Asians.

In previous study, we have found the catechol-O-methyltransferase (COMT) Val158Met polymorphism as an associated risk factor for Parkinson's disease (PD) in Asian rather than Caucasian populations. The aim of this study was to further evaluate the associations of PD risk with COMT polymorphisms in different Asian populations. We carried out a retrieval of studies that investigated associations between COMT Val158Met polymorphism and PD risk in Asians, and included the study if it met the eligibility criteria. Stata version 12.0 was used to analyze the data. A total of 13 studies including 1,834 patients and 2,298 controls were included. The overall result indicated that COMT Val158Met polymorphism was significantly associated with the risk of PD in Asians (AA vs others: OR=1.58, 95% CI 1.26-1.97, p<0.001; GG vs AA: OR=0.63, 95% CI 0.47-0.85, p=0.002; AA vs GA: OR=1.58, 95% CI 1.24-2.00, p<0.001). In Japanese population, the homozygote AA tends to increase the risk of PD (AA vs others: OR=1.54, 95% CI 1.10-2.15, p=0.012; AA vs GA: OR=1.61, 95% CI 1.14-2.29, p=0.008). This study showed that the Val158Met polymorphism of COMT gene may be associated with PD in Japanese rather than Chinese population. Further studies are needed to confirm this association in more ethnicities.

Magnified effects of the COMT gene on white-matter microstructure in very old age.

Genetic factors may partly account for between-person differences in brain integrity in old age. Evidence from human and animal studies suggests that the dopaminergic system is implicated in the modulation of white-matter integrity. We investigated whether a genetic variation in the Catechol-O-Methyltransferase (COMT) Val158Met polymorphism, which influences dopamine availability in prefrontal cortex, contributes to interindividual differences in white-matter microstructure, as measured with diffusion-tensor imaging. In a sample of older adults from a population-based study (60-87 years; n = 238), we found that the COMT polymorphism affects white-matter microstructure, indexed by fractional anisotropy and mean diffusivity, of several white-matter tracts in the oldest age group (81-87 years), although there were no reliable associations between COMT and white-matter microstructure in the two younger age groups (60-66 and 72-78 years). These findings extend previous observations of magnified genetic effects on cognition in old age to white-matter integrity.

Variants in maternal COMT and MTHFR genes and risk of neural tube defects in offspring

Methylenetetrahydrofolate reductase (MTHFR) C677T and catechol-O-Methyltransferase (COMT) G158A are associated with a risk of neural tube defects (NTDs) in offspring. This study examined the effect of a MTHFR × COMT interaction on the risk of NTDs in a Chinese population with a high prevalence of NTDs. A total of 576 fetuses or newborns with NTDs and 594 controls were genotyped for MTHFRrs1801133, MTHFRrs1801131, and COMTrs4680 and COMTrs737865. Information on maternal sociodemographic characteristics, reproductive history, and related behavior was collected through face-to-face interviews. Possible interactions between genetic variants of MTHFR and COMT were examined. MTHFR C677T homozygous TT was associated with an elevated risk of total NTDs (odds ratio [OR] = 1.37, 95 % confidence interval [CI] = 0.93-2.03) and of anencephaly (OR = 1.67, 95 % CI = 0.98-2.84) compared with the CC genotype. There was a COMT rs737865 CC × MTHFR rs1801133 TT interaction for total NTDs (OR = 3.02, 95 % CI = 1.00-9.14) and for anencephaly (OR = 3.39, 95 % CI = 0.94-12.18). No interaction was found between COMT rs4680 AA/AG and MTHFR CT/TT genotypes for total NTDs or any subtype of NTD. The interaction of COMT rs737865 and MTHFR C677T was associated with an increased risk of NTDs, especially anencephaly, in a Chinese population with a high prevalence of NTDs.

Association of Catechol-O-Methyltransferase and monoamine oxidase B gene polymorphisms with motor complications in parkinson's disease in a Chinese population.

Catechol-O-Methyltransferase (COMT) and Monoamine oxidase B (MAO-B) are the main enzymes that metabolize dopamine in the brain. The polymorphisms of the COMT gene and MAO-B gene are associated with high, intermediate and low levels of activity. This may influence the prevalence of motor complications in Parkinson's Disease (PD). The study enrolled 1087 Chinese PD patients throughout the country. Sanger dideoxynucleotide chain termination methods were used for COMT and MAO-B genotyping. The researchers compared the association between presence of motor complications and COMT and MAO-B gene polymorphisms, both separately and in combination. Comparison of the allele frequencies revealed that COMT (GG) was significantly more common among PD patients who exhibited wearing-off compared to PD patients without wearing-off (P < 0.05). A statistically higher frequency of the MAO-B (AG) genotype in PD patients with dyskinesias was found (P < 0.05). Although these differences were not significant after Bonferroni's correction. The combined haplotype of the MAO-B and COMT showed no increase (p < 0.05) in the risk of wearing-off and dyskinesias. Our findings suggest that polymorphisms in COMT and MAO-B may increase the risk of wearing-off and dyskinesias. COMT (GG) genotype may be the risk factor of wearing-off. While MAO-B (AG) genotype may be the risk factor of dyskinesias.

COMT gene and risk for Parkinson's disease: a systematic review and meta-analysis.

Several single-nucleotide polymorphisms (SNPs) in the catechol-O-methyltransferase (COMT) gene have been associated with the risk of developing Parkinson's disease (PD). We conducted a systematic review and a meta-analysis including all the studies published on PD risk related with COMT SNPs (mainly rs4680). We also reviewed the possible relationship of COMT SNPs with clinical, neuropharmacological, neurochemical, and neuroimaging features of PD. The systematic review was conducted using several databases. Meta-analysis of the eligible studies was carried out using the software Meta-Disc 1.1.1. Heterogeneity between studies was tested using the Q-statistic. The meta-analysis included 24 association studies for the COMT rs4680 SNP (9719 PD patients, 14 634 controls) and the risk for PD. The frequency of allele positivity showed a significant association between rs4680 and the risk for PD in the total series, as well as homozygosity for the low-activity allele in the Asiatic population (these associations were marginal or disappeared when studies on Hardy-Weinberg disequilibrium were not considered). Global diagnostic odds ratios (95% confidence intervals) for rs4680 were 0.99 (0.94-1.04) for the total group, 0.99 (0.93-1.05) for White, and 1.05 (0.90-1.22) for Asiatic individuals. COMT genotypes could be related with a modest modification in the age at onset of PD, but its possible genotypes in excessive daytime somnolence, impulse control disorders, cognitive impairment, and neuropharmacological or neurochemical variables are unclear. The results of the meta-analysis suggest that the COMT rs4680 polymorphism is not a major determinant of either the risk for PD or clinical, neuropharmacological and neurochemical features of PD. Data on other COMT polymorphisms are scarce but do not suggest association with PD.

Catechol‐O‐methyltransferase gene methylation and substance use in adolescents: the TRAILS study

Substance use often starts in adolescence and poses a major problem for society and individual health. The dopamine system plays a role in substance use, and catechol-O-methyltransferase (COMT) is an important enzyme that degrades dopamine. The Val(108/158) Met polymorphism modulates COMT activity and thus dopamine levels, and has been linked to substance use. COMT gene methylation, on the other hand, may affect expression and thus indirectly COMT activity. We investigated whether methylation of the COMT gene was associated with adolescents' substance use. Furthermore, we explored whether the COMT Val(108/158) Met polymorphism interacts with COMT gene methylation in association with substance use. In 463 adolescents (mean age=16, 50.8% girls), substance use (cigarette smoking, alcohol and cannabis use) was assessed with self-report questionnaires. From blood samples, COMT Val(108/158) Met genotype and methylation rates of membrane bound (MB) and soluble (S) COMT promoters were assessed. MB-COMT promoter methylation was associated with non-daily smoking [odds ratio (OR)=1.82, P=0.03], but not with daily smoking (OR=1.20, P=0.34), MB-COMT promoter methylation was not associated with alcohol use. Adolescents with the Met/Met genotype and high rates of MB-COMT promoter methylation were less likely to be high-frequent cannabis users than adolescents with the Val/Val or Val/Met genotype. S-COMT promoter methylation was not associated with substance use. These results indicate that there is an association between substance use and COMT gene methylation. Although this association is complex, combining genetic and epigenetic variation of the COMT gene may be helpful in further elucidating the influence of the dopamine system on substance use in adolescence.

Association between the catechol-O-methyltransferase (COMT) Val158Met polymorphism and manual aiming control in healthy subjects.

BackgroundPrefrontal dopamine is catabolized by the catechol-O-methyltransferase (COMT) enzyme. Current evidence suggests that the val/met single nucleotide polymorphism in the COMT gene can predict the efficiency of executive cognition in humans. Individuals carrying the val allele perform more poorly because less synaptic dopamine is available.Methodology/Principal FindingsWe investigated the influence of the COMT polymorphism on motor performance in a task that requires different executive functions. We administered a manual aiming motor task that was performed under four different conditions of execution by 111 healthy participants. Participants were grouped according to genotype (met/met, met/val, val/val), and the motor performance among groups was compared. Overall, the results indicate that met/met carriers presented lower levels of peak velocity during the movement trajectory than the val carriers, but met/met carriers displayed higher accuracy than the val carriers.Conclusions/SignificanceThis study found a significant association between the COMT polymorphism and manual aiming control. Few studies have investigated the genetics of motor control, and these findings indicate that individual differences in motor control require further investigation using genetic studies.

Perceived stress during pregnancy and the catechol-O-methyltransferase (COMT) rs165599 polymorphism impacts on childhood IQ

Maternal stress during pregnancy has been associated with a range of adverse outcomes in offspring and the catechol-O-methyltransferase (COMT) gene has been linked to differential susceptibility to the consequences of antenatal stress. This study examined two functional polymorphisms of the COMT gene (rs4680 and rs165599) in relation to maternal perceived stress and childhood cognitive performance. Data from the longitudinal Auckland Birthweight Collaborative (ABC) study was used. Maternal perceived stress over the prior month was measured at birth, 3.5 and 7years. Full-Scale IQ (FSIQ) was measured at ages 7 and 11. At age 11, a total of 546 DNA samples were collected from the child participants. Data were subjected to a series of split-plot ANCOVAs with birthweight for gestational age and maternal school leaving age as covariates. There were direct effects of maternal stress during the last month of pregnancy on offspring FSIQ at ages 7 and 11years. A significant interaction revealed that children exposed to high maternal antenatal stress had significantly lower FSIQ scores at both 7 and 11years of age than those exposed to low stress, only when they were carriers of the rs165599 G allele. At each age, this difference was of approximately 5 IQ points. The G allele of the rs165599 polymorphism may confer genetic susceptibility to negative cognitive outcomes arising from exposure to antenatal stress. This finding highlights the need to consider gene-environment interactions when investigating the outcomes of antenatal stress exposure.

COMT Val158Met, but not BDNF Val66Met, is associated with white matter abnormalities of the temporal lobe in patients with first-episode, treatment-naïve major depressive disorder: a diffusion tensor imaging study.

We investigated the association between the Val158Met polymorphism of the catechol-O-methyltransferase (COMT) gene, the Val66Met polymorphism of the brain-derived neurotrophic factor (BDNF) gene, and white matter changes in patients with major depressive disorder (MDD) and healthy subjects using diffusion tensor imaging (DTI). We studied 30 patients with MDD (17 males and 13 females, with mean age ± standard deviation [SD] =44±12 years) and 30 sex- and age-matched healthy controls (17 males and 13 females, aged 44±13 years). Using DTI analysis with a tract-based spatial statistics (TBSS) approach, we investigated the differences in fractional anisotropy, radial diffusivity, and axial diffusivity distribution among the three groups (patients with the COMT gene Val158Met, those with the BDNF gene Val66Met, and the healthy subjects). In a voxel-wise-based group comparison, we found significant decreases in fractional anisotropy and axial diffusivity within the temporal lobe white matter in the Met-carriers with MDD compared with the controls (P<0.05). No correlations in fractional anisotropy, axial diffusivity, or radial diffusivity were observed between the MDD patients and the controls, either among those with the BDNF Val/Val genotype or among the BDNF Met-carriers. These results suggest an association between the COMT gene Val158Met and the white matter abnormalities found in the temporal lobe of patients with MDD.

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Catechol-O-methyltransferase (COMT) metabolizes catecholamines in the prefrontal cortex (PFC). A common polymorphism in the COMT gene (COMT val158met) has pleiotropic effects on cognitive and emotional processing. The met allele has been associated with enhanced cognitive processing but impaired emotional processing relative to the val allele. We genotyped healthy, white men in relation to the COMT val158met polymorphism. They were given a single 4 mg dose of the selective noradrenaline reuptake inhibitor (NRI) reboxetine or placebo in a randomized, double-blind between-subjects model and then completed an emotional memory task 2 hours later. We included 75 men in the study; 41 received reboxetine and 34 received placebo. In the placebo group, met/met carriers did not demonstrate the usual memory advantage for emotional stimuli that was observed in val carriers. Reboxetine restored this emotional enhancement of memory in met/met carriers, but had no significant effect in val carriers. We studied only men, thus limiting the generalizability of our findings. We also relied on self-reported responses to screening questions to establish healthy volunteer status, and in spite of the double-blind design, participants were significantly better than chance at identifying their intervention allocation. Emotional memory is impaired in healthy met homozygotes and selectively improved in this group by reboxetine. This has potential translational implications for the use of reboxetine, which is currently licensed as an antidepressant in several countries, and edivoxetine, a new selective NRI currently in development.

Promoter variation in the catechol-O-methyltransferase gene is associated with remission of symptoms during fluvoxamine treatment for major depression

We investigated the association between remission of depressive symptoms in fluvoxamine treatment and catechol-O-methyltransferase (COMT) gene. Sixteen SNPs in the COMT gene were investigated in 123 outpatients with major depression. Three single nucleotide polymorphisms located in the 5′ region were associated with remission in fluvoxamine-treated outpatients with moderate to severe depression.

Clinical symptoms in fibromyalgia are associated to catechol-O-methyltransferase (COMT) gene Val158Met polymorphism

1. Fibromyalgia syndrome (FMS) is a common chronic widespread pain syndrome mainly affecting women. The aim of this study was to explore the frequency and clinical significance of catechol-O-methyltransferase (COMT) gene Val158Met polymorphism in a large cohort of Turkish patients with FMS.2. The study included 379 FMS patients and 290 controls. Genomic DNA was isolated and genotyped using polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) analyses.3. The genotype frequencies of Val158Met polymorphism showed a small difference between FMS patients and healthy controls (p = 0.047), however, the Met/Met genotype was significantly higher in FMS patients than healthy controls (p = 0.016). No difference was observed for allele frequencies between two groups. Stratification analysis according to clinical features for this disease reveals that weight, FMS Impact Questionnaire score, algometry and Raynaud’s syndrome, were detected to have statistically significant associations with Val158Met polymorphism (p = 0.037, p = 0.042, p = 0.039 and p = 0.033, respectively). Pain sensitivity, measured by algometry, was statistically higher in patients with Met/Met genotype than the patients with Val/Val and Val/Met genotypes (p = 0.017).4. The results of this study suggested that COMT gene Val158Met polymorphism is positively associated with FMS and play a relevant role in the clinical symptoms of the disease.

Association between genes, stressful childhood events and processing bias in depression vulnerable individuals

The brain-derived neurotrophic factor (BDNF) and catechol-O-methyltransferase (COMT) genes are relevant candidates for depression. Variation in these genes is associated with stress sensitivity and depressotypic cognitive biases. The interaction between genes and stressful events is considered as an important mechanism in the development of depression. This study examined the effects of the BDNF and COMT genes on biased processing and the interaction with childhood stress in vulnerable individuals. A total of 198 remitted depressed individuals performed an n-back task with emotional facial stimuli (happy and sad). Childhood events were measured with a questionnaire. Genotype by childhood events interactions were analyzed for happy and sad expressions for BDNF (Val66Met; rs6265) and COMT (Val158Met; rs4680), individually and combined. BDNF and COMT both interacted significantly (P = 0.006 and P = 0.014, respectively) with childhood trauma on reaction time for happy faces. For both genes, Met-carriers with childhood trauma showed less positive bias for happy faces than those without childhood trauma. Val-carriers did not show a differential bias. Individuals with childhood trauma and 3 or 4 risk alleles (BDNF and COMT combined) showed less positive bias than those without childhood trauma (P = 0.011). The BDNF × COMT × childhood trauma interaction yielded a P = 0.055, but had limited power. A potential weakness is the measurement method of the childhood events, as negative bias might have affected participants' recall. Our findings endorse the association of BDNF and COMT with stress and depression and provide a possible intermediate, i.e. biased processing of positive information. Tailoring treatment to specific risk profiles based on genetic susceptibility and childhood stress could be promising.

Association study between COMT 158Met and creativity scores in bipolar disorder and healthy controls

Background Bipolar disorder (BD) patients have been reported to be associated higher creativity abilities, and recent data tend to support the hypothesis that dopaminergic system that could be associated with creativity. Catechol-O-methyltransferase (COMT) is one of the major enzymes involved in the metabolic degradation of dopamine. The COMT gene polymorphism (rs4680 or Val158Met) Met allele is reported to cause decreased activity of this enzyme in prefrontal cortex and improve performance in several cognitive domains. Objective The objective of this study was to evaluate the influence of Val158Met on creativity in BD type I and healthy controls. Methods Ninety-seven healthy volunteers and 120 BD type I were genotyped for COMT rs4680 and tested for creativity (Barrow Welsh Art Scale – BWAS) and intelligence Wechsler Abbreviated Scale of Intelligence (WASI). Results COMT Met allele positively influenced creativity scores in healthy controls but not in BD subjects during mood episodes and euthymia. The presence of allele Met did not influence IQ scores. No influence of IQ total score on creativity was observed. Limitations control group presented higher IQ scores and euthymic group was under medication use. Discussion Our research suggests positive effect of COMT rs4680 (allele Met) on creativity scores in healthy controls. One possible interpretation is that creativity is more likely to be associated with lesser degrees of bipolarity. The fact that the same results were not observed in BD may be associated to dysfunctions in the dopaminergic system that characterizes this disorder. Further studies with larger samples and other types of BD should explore the role of the dopaminergic system in creativity.