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1.  Catechol-O-methyltransferase (COMT) influences the connectivity of the prefrontal cortex at rest 
Neuroimage  2013;68(C):49-54.
Catechol-O-methyltransferase (COMT) modulates dopamine in the prefrontal cortex (PFC) and influences PFC dopamine-dependent cognitive task performance. A human COMT polymorphism (Val158Met) alters enzyme activity and is associated with both the activation and functional connectivity of the PFC during task performance, particularly working memory. Here, we used functional magnetic resonance imaging and a data-driven, independent components analysis (ICA) approach to compare resting state functional connectivity within the executive control network (ECN) between young, male COMT Val158 (n = 27) and Met158 (n = 28) homozygotes. COMT genotype effects on grey matter were assessed using voxel-based morphometry. COMT genotype significantly modulated functional connectivity within the ECN, which included the head of the caudate, and anterior cingulate and frontal cortical regions. Val158 homozygotes showed greater functional connectivity between a cluster within the left ventrolateral PFC and the rest of the ECN (using a threshold of Z > 2.3 and a family-wise error cluster significance level of p < 0.05). This difference occurred in the absence of any alterations in grey matter. Our data show that COMT Val158Met affects the functional connectivity of the PFC at rest, complementing its prominent role in the activation and functional connectivity of this region during cognitive task performance. The results suggest that genotype-related differences in prefrontal dopaminergic tone result in neuroadaptive changes in basal functional connectivity, potentially including subtle COMT genotype-dependent differences in the relative coupling of task-positive and task-negative regions, which could in turn contribute to its effects on brain activation, connectivity, and behaviour.
Highlights
► We studied the impact of COMT Val158Met genotype on resting state connectivity. ► We compared resting state functional connectivity in Val/Val vs. Met/Met men. ► We focussed on the predominantly prefrontal (PFC) executive control network (ECN). ► The ECN was identified using a group ICA approach. ► We found greater resting PFC functional connectivity in Val/Val vs. Met/Met men.
doi:10.1016/j.neuroimage.2012.11.059
PMCID: PMC3566589  PMID: 23228511
Resting state network; Dopamine; Working memory; Prefrontal cortex; Polymorphism; fMRI
2.  Executive Attention in Schizophrenic Males and the Impact of COMT Val108/158Met Genotype on Performance on the Attention Network Test 
Schizophrenia Bulletin  2008;34(6):1231-1239.
Background: Executive control of attention in schizophrenia has recently been assessed by means of the Attention Network Test (ANT). In the past, for tasks assessing executive attention, findings in schizophrenia have been contradictory, among others suggesting a lack of increased stimulus interference effects. Attention and executive functioning are substantially influenced by candidate genes of schizophrenia, including the functional single-nucleotide polymorphism catechol-o-methyltransferase (COMT) Val108/158Met, with task-dependent, specific effects of Met allele load on cognitive function. Therefore, we aimed at investigating executive attention in schizophrenic patients (SZP) as compared with healthy controls (HC), and to assess the specific impact of COMT Val108/158Met on executive attention, using ANT. Methods: We applied ANT to 63 SZP and 40 HC. We calculated a general linear model to investigate the influence of affection status and the COMT Val108/158Met genotype on executive attention as assessed by the ANT. Results: Multivariate analysis of variance revealed a significant effect of group on executive attention. SZP exhibited smaller conflict effects in the ANT. Met allele load significantly modulated executive attention efficiency, with homozygous Met individuals showing low overall reaction time but increased effects conflicting stimulus information in executive attention. Conclusions: Our data suggest a disease-related dissociation of executive attention with reduced conflict effects in SZP. Furthermore, they support the hypothesis of differential tonic-phasic dopamine activation and specific dopamine level effects in different cognitive tasks, which helps interpreting contradictory findings of Met allele load on cognitive performance. Disease status seems to modulate the impact of COMT Val108/158Met on cognitive performance.
doi:10.1093/schbul/sbm155
PMCID: PMC2632487  PMID: 18199630
schizophrenia; endophenotype; genetics; attention; dopamine
3.  COMT Val108/158Met polymorphism modulates task-oriented behaviour in children with ADHD 
Context
It has been suggested that the symptoms of ADHD (inattention and/or hyperactivity/impulsivity), translate into deficits in task-oriented behaviour or problem-focussed activity. The fronto-subcortical dopamine and norepinephrine pathways have been implicated in ADHD, and one of the key modulators of these neurotransmitters in the prefrontal cortex is catechol-O-methyltransferase (COMT).
Objective
To examine the association of the COMT Val108/158Met polymorphism with (1) task-oriented behaviour in children with ADHD, and (2) response of this phenotype to methylphenidate treatment.
Design, Setting, Participants
Children diagnosed with ADHD (n=212), were assessed using the Restricted Academic Situation Scale (RASS). The RASS uses a simulated academic environment within the research clinic, to assess the child's ability for independent, sustained orientation to a task of math problems.
Interventions
Each child was administered placebo and methylphenidate (0.5 mg/kg in a divided b.i.d. dose), each for a one-week period, in a double-blind, crossover trial. On day 3 of the respective treatment week, the child was administered placebo/ methylphenidate in the clinic, and the acute change in behaviour (before and 1 hour after treatment) was evaluated on the RASS.
Main Outcome Measure
The main outcome measure was the RASS score (number of behavioural events measured during a 15-minute time period), measured at four time points: before and after placebo/methylphenidate treatment. Analysis was carried out using mixed model analysis of variance.
Results
Significant main effects of COMT genotype [F2,206 = 4.78, p = 0.009] and treatment [F1,206 = 45.22, p < 0.0001] on task-oriented behaviour were observed. The Met-Met and Val-Met genotype groups had fewer behavioural events, and were more engaged in the math task, compared to the Val-Val group. No genotype by treatment interaction was observed.
Conclusion
These results suggest that the COMT Val108/158Met polymorphism modulates task-oriented behaviour, but it does not modulate the response of this behaviour to MPH treatment.
doi:10.1038/npp.2008.85
PMCID: PMC2885152  PMID: 18580877
COMT; task-oriented behaviour; methylphenidate; ADHD
4.  Association between the Catechol O-Methyltransferase (COMT) Val158met Polymorphism and Different Dimensions of Impulsivity 
PLoS ONE  2013;8(9):e73509.
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.
doi:10.1371/journal.pone.0073509
PMCID: PMC3769314  PMID: 24039968
5.  Differential Effects of the Catechol-O-Methyltransferase Val158Met Genotype on the Cognitive Function of Schizophrenia Patients and Healthy Japanese Individuals 
PLoS ONE  2013;8(11):e76763.
Background
The functional polymorphism Val158Met in the catechol-O-methyltransferase (COMT) gene has been associated with differences in prefrontal cognitive functions in patients with schizophrenia and healthy individuals. Several studies have indicated that the Met allele is associated with better performance on measures of cognitive function. We investigated whether the COMT Val158Met genotype was associated with cognitive function in 149 healthy controls and 118 patients with schizophrenia.
Methods
Cognitive function, including verbal memory, working memory, motor speed, attention, executive function and verbal fluency, was assessed by the Brief Assessment of Cognition in Schizophrenia (BACS-J). We employed a one-way analysis of variance (ANOVA) and a multiple regression analysis to determine the associations between the COMT Val158Met genotype and the BACS-J measurements.
Results
The one-way ANOVA revealed a significant difference in the scores on the Tower of London, a measure of executive function, between the different Val158Met genotypes in the healthy controls (p = 0.023), and a post-hoc analysis showed significant differences between the scores on the Tower of London in the val/val genotype group (18.6 ± 2.4) compared to the other two groups (17.6 ± 2.7 for val/met and 17.1 ± 3.2 for met/met; p = 0.027 and p = 0.024, respectively). Multiple regression analyses revealed that executive function was significantly correlated with the Val158Met genotype (p = 0.003). However, no evidence was found for an effect of the COMT on any cognitive domains of the BACS-J in the patients with schizophrenia.
Conclusion
These data support the hypothesis that the COMT Val158Met genotype maintains an optimal level of dopamine activity. Further studies should be performed that include a larger sample size and include patients on and off medication, as these patients would help to confirm our findings.
doi:10.1371/journal.pone.0076763
PMCID: PMC3839926  PMID: 24282499
6.  COMT Val158Met Genotype Determines the Direction of Cognitive Effects Produced by Catechol-O-Methyltransferase Inhibition 
Biological Psychiatry  2012;71(6):538-544.
Background
Catechol-O-methyltransferase (COMT) metabolizes dopamine. The COMT Val158Met polymorphism influences its activity, and multiple neural correlates of this genotype on dopaminergic phenotypes, especially working memory, have been reported. COMT activity can also be regulated pharmacologically by COMT inhibitors. The inverted-U relationship between cortical dopamine signaling and working memory predicts that the effects of COMT inhibition will differ according to COMT genotype.
Methods
Thirty-four COMT Met158Met (Met-COMT) and 33 COMT Val158Val (Val-COMT) men were given a single 200-mg dose of the brain-penetrant COMT inhibitor tolcapone or placebo in a randomized, double-blind, between-subjects design. They completed the N-back task of working memory and a gambling task.
Results
In the placebo group, Met-COMT subjects outperformed Val-COMT subjects on the 2- back, and they were more risk averse. Tolcapone had opposite effects in the two genotype groups: it worsened N-back performance in Met-COMT subjects but enhanced it in Val-COMT subjects. Tolcapone made Met-COMT subjects less risk averse but Val-COMT subjects more so. In both tasks, tolcapone reversed the baseline genotype differences.
Conclusions
Depending on genotype, COMT inhibition can enhance or impair working memory and increase or decrease risky decision making. To our knowledge, the data are the clearest demonstration to date that the direction of effect of a drug can be influenced by a polymorphism in its target gene. The results support the inverted-U model of dopamine function. The findings are of translational relevance, because COMT inhibitors are used in the adjunctive treatment of Parkinson's disease and are under evaluation in schizophrenia and other disorders.
doi:10.1016/j.biopsych.2011.12.023
PMCID: PMC3314969  PMID: 22364739
Catechol-o-methyltransferase; decision making; pharmacogenetics; polymorphism; tolcapone; working memory
7.  COMT val158met and 5-HTTLPR Genetic Polymorphisms Moderate Executive Control in Cannabis Users 
Neuropsychopharmacology  2013;38(8):1598-1606.
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 Δ9-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.
doi:10.1038/npp.2013.59
PMCID: PMC3682154  PMID: 23449176
Addiction & Substance Abuse; Cannabinoids; cannabis; Cognition; executive functions; genes; Neurogenetics; cannabis; COMT; decision making; serotonin; shifting; sustained attention
8.  Executive functions and selective attention are favored in middle-aged healthy women carriers of the Val/Val genotype of the catechol-o-methyltransferase gene: a behavioral genetic study 
Background
Cognitive deficits such as poor memory, the inability to concentrate, deficits in abstract reasoning, attention and set-shifting flexibility have been reported in middle-aged women. It has been suggested that cognitive decline may be due to several factors which include hormonal changes, individual differences, normal processes of aging and age-related changes in dopaminergic neurotransmission. Catechol-O-methyltransferase (COMT), a common functional polymorphism, has been related to executive performance in young healthy volunteers, old subjects and schizophrenia patients. The effect of this polymorphism on cognitive function in middle-aged healthy women is not well known. The aim of the current study was to investigate whether measures of executive function, sustained attention, selective attention and verbal fluency would be different depending on the COMT genotype and task demand.
Method
We genotyped 74 middle-aged healthy women (48 to 65 years old) for the COMT Val158Met polymorphism. We analyzed the effects of this polymorphism on executive functions (Wisconsin Card Sorting Test), selective attention (Stroop test), sustained attention (Continuous Performance Test) and word generation (Verbal Fluency test), which are cognitive functions that involve the frontal lobe.
Results
There were 27 women with the Val/Val COMT genotype, 15 with the Met/Met genotype, and 32 with the Val/Met genotype. Women carriers of the Val/Val genotype performed better in executive functions, as indicated by a lower number of errors committed in comparison with the Met/Met or Val/Met groups. The correct responses on selective attention were higher in the Val/Val group, and the number of errors committed was higher in the Met/Met group during the incongruence trial in comparison with the Val/Val group. Performance on sustained attention and the number of words generated did not show significant differences between the three genotypes.
Conclusion
These findings indicate that middle-aged women carriers of the Val158 allele, associated with high-activity COMT, showed significant advantage over Met allele in executive processes and cognitive flexibility. These results may help to explain, at least in part, individual differences in cognitive decline in middle-aged women with dopamine-related genes.
doi:10.1186/1744-9081-6-67
PMCID: PMC2987980  PMID: 21029471
9.  No evidence of association between Catechol-O-Methyltransferase (COMT) Val158Met genotype and performance on neuropsychological tasks in children with ADHD: A case-control study 
BMC Psychiatry  2004;4:15.
Background
Several studies have suggested an association between the functional Val158Met polymorphism in the Catechol-O-Methyltransferase (COMT) gene and neurocognitive performance. Two studies showed that subjects with the low activity Met allele performed better on the Wisconsin Card Sorting Test (WCST) and another study found an effect on processing speed and attention.
Methods
We set out to examine the association between the Val158Met polymorphism and performance on neurocognitive tasks including those tapping working memory, attention and speed, impulsiveness and response inhibition in a sample of 124 children with ADHD. Task performance for each genotypic group was compared using analysis of variance.
Results
There was no evidence of association with performance on any of the neurocognitive tasks.
Conclusions
We conclude that Val158Met COMT genotype is not associated with neurocognitive performance in our sample.
doi:10.1186/1471-244X-4-15
PMCID: PMC425584  PMID: 15182372
10.  Does COMT genotype influence the effects of d-amphetamine on executive functioning? 
Genes, brain, and behavior  2012;12(1):13-20.
In a widely cited study, Mattay et al. (2003) reported that amphetamine (0.25 mg/kg oral, or 17mg for a 68kg individual) impaired behavioral and brain indices of executive functioning, measured using the Wisconsin Card Sorting Task (WCST) and N-Back working memory task, in 6 individuals homozygous for the met allele of the val158met polymorphism in the catechol-O-methyltransferase (COMT) gene, whereas it improved executive functioning in 10 individuals homozygous for the more active val allele. We attempted to replicate their behavioral findings in a larger sample, using similar executive functioning tasks and a broader range of amphetamine doses. Over four sessions, n = 200 healthy normal adults received oral placebo, d-amphetamine 5mg, 10mg, and 20mg (average of 0.07, 0.15 and 0.29 mg/kg), under counterbalanced double-blind conditions, and completed WCST and N-back tests of executive functioning. Amphetamine had typical effects on blood pressure and processing speed but did not affect executive functioning. COMT genotype (val158met) was not related to executive functioning under placebo or amphetamine conditions, even when we compared only the homozygous val/val and met/met genotypes at the highest dose of amphetamine (20 mg). Thus, we were not able to replicate the behavioral interaction between COMT and amphetamine seen in Mattay et al. (Mattay et al., 2003). We discuss possible differences between the studies and the implications of our findings for the use of COMT genotyping to predict clinical responses to dopaminergic drugs, and the use of intermediate phenotypes in genetic research.
doi:10.1111/gbb.12012
PMCID: PMC3553317  PMID: 23231539
COMT genotype; executive functioning; working memory; d-amphetamine; genetics; stimulant response
11.  Association of abstinence-induced alterations in working memory function and COMT genotype in smokers 
Psychopharmacology  2013;230(4):10.1007/s00213-013-3197-3.
Rationale
The common val158met polymorphism in the catechol-O-methyltransferase (COMT) gene has been associated with nicotine dependence, alterations in executive cognitive function, and abstinence-induced working memory deficits in smokers.
Objectives
We sought to replicate the association of the COMT val allele with abstinence-induced alterations in working memory-related activity in task-positive (executive control) and task-negative (default mode network) regions.
Methods
Forty smokers (20 val/val and 20 met/met) performed an N-back task while undergoing blood oxygen level-dependent (BOLD) fMRI on two separate occasions: following 72 hours of confirmed abstinence and during smoking as usual. An independent sample of 48 smokers who completed the identical N-back task during fMRI in smoking versus abstinence for another study was used as a validation sample.
Results
Contrary to expectations, genotype by session interactions on BOLD signal in executive control regions (dorsolateral prefrontal cortex (DLPFC) and dorsal cingulate/medial prefrontal cortex (MF/CG)) revealed significant abstinence-induced reductions in the met/met group, but not the val/val group. Results also revealed that val/val smokers may exhibit less suppression of activation in task-negative regions such as the posterior cingulate cortex during abstinence (versus smoking). These patterns were confirmed in the validation sample and in the whole-brain analysis, though the regions differed from the apriori ROIs (e.g., precuneus, insula).
Conclusions
The COMT val158met polymorphism was associated with abstinence-related working memory deficits in two independent samples of smokers. However, inconsistencies compared to prior findings and across methods (ROI vs. whole-brain analysis) highlight the challenges inherent in reproducing results of imaging genetic studies in addiction.
doi:10.1007/s00213-013-3197-3
PMCID: PMC3840089  PMID: 23828159
Smoking; nicotine; COMT; genetic; fMRI; cognition; working memory
12.  Genetic Contributions to Age-Related Decline in Executive Function: A 10-Year Longitudinal Study of COMT and BDNF Polymorphisms 
Genetic variability in the dopaminergic and neurotrophic systems could contribute to age-related impairments in executive control and memory function. In this study we examined whether genetic polymorphisms for catechol-O-methyltransferase (COMT) and brain-derived neurotrophic factor (BDNF) were related to the trajectory of cognitive decline occurring over a 10-year period in older adults. A single nucleotide polymorphism in the COMT (Val158/108Met) gene affects the concentration of dopamine in the prefrontal cortex. In addition, a Val/Met substitution in the pro-domain for BDNF (Val66Met) affects the regulated secretion and trafficking of BDNF with Met carriers showing reduced secretion and poorer cognitive function. We found that impairments over the 10-year span on a task-switching paradigm did not vary as a function of the COMT polymorphism. However, for the BDNF polymorphism the Met carriers performed worse than Val homozygotes at the first testing session but only the Val homozygotes demonstrated a significant reduction in performance over the 10-year span. Our results argue that the COMT polymorphism does not affect the trajectory of age-related executive control decline, whereas the Val/Val polymorphism for BDNF may promote faster rates of cognitive decay in old age. These results are discussed in relation to the role of BDNF in senescence and the transforming impact of the Met allele on cognitive function in old age.
doi:10.3389/neuro.09.011.2008
PMCID: PMC2572207  PMID: 18958211
BDNF; COMT; aging; task-switching; cognition; executive control; longitudinal
13.  Association between Catechol-O-Methyltrasferase Val108/158Met Genotype and Prefrontal Hemodynamic Response in Schizophrenia 
PLoS ONE  2009;4(5):e5495.
Background
“Imaging genetics” studies have shown that brain function by neuroimaging is a sensitive intermediate phenotype that bridges the gap between genes and psychiatric conditions. Although the evidence of association between functional val108/158met polymorphism of the catechol-O-methyltransferase gene (COMT) and increasing risk for developing schizophrenia from genetic association studies remains to be elucidated, one of the most topical findings from imaging genetics studies is the association between COMT genotype and prefrontal function in schizophrenia. The next important step in the translational approach is to establish a useful neuroimaging tool in clinical settings that is sensitive to COMT variation, so that the clinician could use the index to predict clinical response such as improvement in cognitive dysfunction by medication. Here, we investigated spatiotemporal characteristics of the association between prefrontal hemodynamic activation and the COMT genotype using a noninvasive neuroimaging technique, near-infrared spectroscopy (NIRS).
Methodology/Principal Findings
Study participants included 45 patients with schizophrenia and 60 healthy controls matched for age and gender. Signals that are assumed to reflect regional cerebral blood volume were monitored over prefrontal regions from 52-channel NIRS and compared between two COMT genotype subgroups (Met carriers and Val/Val individuals) matched for age, gender, premorbid IQ, and task performance. The [oxy-Hb] increase in the Met carriers during the verbal fluency task was significantly greater than that in the Val/Val individuals in the frontopolar prefrontal cortex of patients with schizophrenia, although neither medication nor clinical symptoms differed significantly between the two subgroups. These differences were not found to be significant in healthy controls.
Conclusions/Significance
These data suggest that the prefrontal NIRS signals can noninvasively detect the impact of COMT variation in patients with schizophrenia. NIRS may be a promising candidate translational approach in psychiatric neuroimaging.
doi:10.1371/journal.pone.0005495
PMCID: PMC2675059  PMID: 19424500
14.  Perinatal Risk Factors Interacting With Catechol O-Methyltransferase and the Serotonin Transporter Gene Predict ASD symptoms in Children With ADHD 
Background
Symptoms of Autism Spectrum Disorder (ASD) and Attention-Deficit/Hyperactivity Disorder (ADHD) often co-occur. Given the previously found familiality of ASD symptoms in children with ADHD, addressing these symptoms may be useful for genetic association studies, especially for candidate gene findings that have not been consistently replicated for ADHD.
Methods
We studied the association of the catechol o-methyltransferase (COMT) Val158Met polymorphism and the serotonin transporter (SLC6A4/SERT/5-HTT) 5-HTTLPR insertion/deletion polymorphism with ASD symptoms in children with ADHD, and whether these polymorphisms would interact with pre- and perinatal risk factors, i.e., maternal smoking during pregnancy and low birth weight. Analyses were performed using linear regression in 207 Dutch participants with combined type ADHD of the International Multicenter ADHD Genetics (IMAGE) study, and repeated in an independent ADHD sample (n = 439) selected from the TRracking Adolescents' Individual Lives Survey (TRAILS). Dependent variables were the total and subscale scores of the Children's Social Behavior Questionnaire (CSBQ).
Results
No significant main effects of COMT Val158Met, 5-HTTLPR, maternal smoking during pregnancy and low birth weight on ASD symptoms were found. However, the COMT Val/Val genotype interacted with maternal smoking during pregnancy in increasing stereotyped behavior in the IMAGE sample (p = 0.008); this interaction reached significance in the TRAILS sample after correction for confounders (p = 0.02). In the IMAGE sample, the 5-HTTLPR S/S genotype interacted with maternal smoking during pregnancy, increasing problems in social interaction (p = 0.02), and also interacted with low birth weight, increasing rigid behavior (p = 0.03). Findings for 5-HTTLPR in the TRAILS sample were similar, albeit for related CSBQ subscales.
Conclusions
These findings suggest gene-environment interaction effects on ASD symptoms in children with ADHD.
doi:10.1111/j.1469-7610.2010.02277.x
PMCID: PMC2970704  PMID: 20868372
Attention-deficit/Hyperactivity Disorder; Autism Spectrum Disorder; gene environment; 5-HTT; COMT
15.  The COMT Val108/158Met Polymorphism and Medial Temporal Lobe Volumetry in Patients with Schizophrenia and Healthy Adults 
NeuroImage  2009;53(3):992-1000.
Abnormalities of the medial temporal lobe have been consistently demonstrated in schizophrenia. A common functional polymorphism, Val108/158Met, in the putative schizophrenia susceptibility gene, catechol-O-methyltransferase (COMT) has been shown to influence medial temporal lobe function. However, the effects of this polymorphism on volumes of medial temporal lobe structures, particularly in patients with schizophrenia, are less clear. Here we measured the effects of COMT Val108/158Met genotype on the volume of two regions within the medial temporal lobe, the amygdala and hippocampus, in patients with schizophrenia and healthy control subjects.
We obtained MRI and genotype data for 98 schizophrenic patients and 114 matched controls. An automated atlas-based segmentation algorithm was used to generate volumetric measures of the amygdala and hippocampus. Regression analyses included COMT met allele load as an additive effect, and also controlled for age, intracranial volume, gender and acquisition site.
Across patients and controls, each copy of the COMT met allele was associated on average with a 2.6% increase in right amygdala volume, a 3.8% increase in left amygdala volume and a 2.2% increase in right hippocampus volume. There were no effects of COMT genotype on volumes of the whole brain and prefrontal regions.
Therefore, the COMT Val108/158Met polymorphism was shown to influence medial temporal lobe volumes in a linear-additive manner, mirroring its effect on dopamine catabolism. Taken together with previous work, our data support a model in which lower COMT activity, and a resulting elevation in extracellular dopamine levels, stimulates growth of medial temporal lobe structures.
doi:10.1016/j.neuroimage.2009.12.046
PMCID: PMC2888809  PMID: 20026221
COMT Val108/158Met Polymorphism; Amygdala; Hippocampus; structural MRI; Schizophrenia; Dopamine
16.  The Roles of COMT val158met Status and Aviation Expertise in Flight Simulator Performance and Cognitive Ability 
Behavior genetics  2010;41(5):700-708.
The polymorphic variation in the val158met position of the catechol-O-methyltransferase (COMT) gene is associated with differences in executive performance, processing speed, and attention. The purpose of this study is: (1) replicate previous COMT val158met findings on cognitive performance; (2) determine whether COMT val158met effects extend to a real-world task, aircraft navigation performance in a flight simulator; and (3) determine if aviation expertise moderates any effect of COMT val158met status on flight simulator performance. One hundred seventy two pilots aged 41–69 years, who varied in level of aviation training and experience, completed flight simulator, cognitive, and genetic assessments. Results indicate that although no COMT effect was found for an overall measure of flight performance, a positive effect of the met allele was detected for two aspects of cognitive ability: executive functioning and working memory performance. Pilots with the met/met genotype benefited more from increased levels of expertise than other participants on a traffic avoidance measure, which is a component of flight simulator performance. These preliminary results indicate that COMT val158met polymorphic variation can affect a real-world task.
doi:10.1007/s10519-010-9436-z
PMCID: PMC3163820  PMID: 21193954
COMT; Flight simulator performance; Cognitive performance; Aviation expertise; Age
17.  COMT val158met Genotype Affects Recruitment of Neural Mechanisms Supporting Fluid Intelligence 
Cerebral Cortex (New York, NY)  2008;18(9):2132-2140.
Fluid intelligence (gf) influences performance across many cognitive domains. It is affected by both genetic and environmental factors. Tasks tapping gf activate a network of brain regions including the lateral prefrontal cortex (LPFC), the presupplementary motor area/anterior cingulate cortex (pre-SMA/ACC), and the intraparietal sulcus (IPS). In line with the “intermediate phenotype” approach, we assessed effects of a polymorphism (val158met) in the catechol-O-methyltransferase (COMT) gene on activity within this network and on actual task performance during spatial and verbal gf tasks. COMT regulates catecholaminergic signaling in prefrontal cortex. The val158 allele is associated with higher COMT activity than the met158 allele. Twenty-two volunteers genotyped for the COMT val158met polymorphism completed high and low gf versions of spatial and verbal problem-solving tasks. Our results showed a positive effect of COMT val allele load upon the blood oxygen level–dependent response in LPFC, pre-SMA/ACC, and IPS during high gf versus low gf task performance in both spatial and verbal domains. These results indicate an influence of the COMT val158met polymorphism upon the neural circuitry supporting gf. The behavioral effects of val allele load differed inside and outside the scanner, consistent with contextual modulation of the relation between COMT val158met genotype and gf task performance.
doi:10.1093/cercor/bhm240
PMCID: PMC2517101  PMID: 18252743
COMT; fMRI; g; genotype; intelligence; prefrontal cortex
18.  COMT Val158Met polymorphism, cognitive stability and cognitive flexibility: an experimental examination 
Background
Dopamine in prefrontal cortex (PFC) modulates core cognitive processes, notably working memory and executive control. Dopamine regulating genes and polymorphisms affecting PFC - including Catechol-O-Methyltransferase (COMT) Val158Met - are crucial to understanding the molecular genetics of cognitive function and dysfunction. A mechanistic account of the COMT Val158Met effect associates the Met allele with increased tonic dopamine transmission underlying maintenance of relevant information, and the Val allele with increased phasic dopamine transmission underlying the flexibility of updating new information. Thus, consistent with some earlier work, we predicted that Val carriers would display poorer performance when the maintenance component was taxed, while Met carriers would be less efficient when rapid updating was required.
Methods
Using a Stroop task that manipulated level of required cognitive stability and flexibility, we examined reaction time performance of patients with schizophrenia (n = 67) and healthy controls (n = 186) genotyped for the Val/Met variation.
Results
In both groups we found a Met advantage for tasks requiring cognitive stability, but no COMT effect when a moderate level of cognitive flexibility was required, or when a conflict cost measure was calculated.
Conclusions
Our results do not support a simple stability/flexibility model of dopamine COMT Val/Met effects and suggest a somewhat different conceptualization and experimental operationalization of these cognitive components.
doi:10.1186/1744-9081-6-53
PMCID: PMC2945991  PMID: 20836853
19.  Associations of Cigarette Smoking and Polymorphisms in Brain-Derived Neurotrophic Factor and Catechol-O-Methyltransferase with Neurocognition in Alcohol Dependent Individuals during Early Abstinence 
Chronic cigarette smoking and polymorphisms in brain-derived neurotrophic factor (BDNF) and catechol-O-methyltransferase (COMT) are associated with neurocognition in normal controls and those with various neuropsychiatric conditions. The influence of BDNF and COMT on neurocognition in alcohol dependence is unclear. The primary goal of this report was to investigate the associations of single nucleotide polymorphisms (SNPs) in BDNF Val66Met (rs6265) and COMT Val158Met (rs4680) with neurocognition in a treatment-seeking alcohol dependent cohort and determine if neurocognitive differences between non-smokers and smokers previously observed in this cohort persist when controlled for these functional SNPs. Genotyping was conducted on 70 primarily male treatment-seeking alcohol dependent participants (ALC) who completed a comprehensive neuropsychological battery after 33 ± 9 days of monitored abstinence. After controlling for COMT and BDNF genotypes, smoking ALC performed significantly worse than non-smoking ALC on the domains of auditory-verbal and visuospatial learning and memory, cognitive efficiency, general intelligence, processing speed, and global neurocognition. In smoking ALC, greater number of years of smoking over lifetime was related to poorer performance on multiple domains after controlling for genotypes and alcohol consumption. In addition, COMT Met homozygotes were superior to Val homozygotes on measures of executive skills and showed trends for higher general intelligence and visuospatial skills, while COMT Val/Met heterozygotes showed significantly better general intelligence than Val homozygotes. COMT Val homozygotes performed better than heterozygotes on auditory-verbal memory. BDNF genotype was not related to any neurocognitive domain. The findings are consistent with studies in normal controls and neuropsychiatric cohorts that reported COMT Met carriers demonstrated better performance on measures of executive skills and general intelligence. Results also indicated that the poorer performance of smoking compared to non-smoking ALC across multiple neurocognitive domains was not mediated by COMT or BDNF genotype. Overall, the findings lend support to the expanding clinical movement to make smoking cessation programs available to smokers at the inception of treatment for alcohol/substance use disorders.
doi:10.3389/fphar.2012.00178
PMCID: PMC3469037  PMID: 23087644
cigarette smoking; brain-derived neurotrophic factor; catechol-O-methyltransferase; neurocognition; alcohol dependence
20.  Attention Deficit Hyperactivity Disorder comorbid oppositional defiant disorder and its predominately inattentive type: evidence for an association with COMT but not MAOA in a Chinese sample 
Background
There are three childhood disruptive behavior disorders (DBDs), attention deficit hyperactivity disorder (ADHD), oppositional defiant disorder (ODD), and conduct disorder (CD). The most common comorbid disorder in ADHD is ODD. DSM-IV describes three ADHD subtypes: predominantly inattentive type (ADHD-IA), predominantly hyperactive-impulsive type (ADHD-HI), and combined type (ADHD-C). Prior work suggests that specific candidate genes are associated with specific subtypes of ADHD in China. Our previous association studies between ADHD and functional polymorphisms of COMT and MAOA, consistently showed the low transcriptional activity alleles were preferentially transmitted to ADHD-IA boys. Thus, the goal of the present study is to test the hypothesis that COMT Val158Met and MAOA-uVNTR jointly contribute to the ODD phenotype among Chinese ADHD boys.
Methods
171 Chinese boys between 6 and 17.5 years old (mean = 10.3, SD = 2.6) with complete COMT val158met and MAOA-uVNTR genotyping information were studied. We used logistic regression with genotypes as independent variables and the binary phenotype as the dependent variable. We used p < 0.05 as the level of nominal statistical significance. Bonferroni correction procedures were used to adjust for multiple comparisons.
Results
Our results highlight the potential etiologic role of COMT in the ADHD with comorbid ODD and its predominately inattentive type in male Chinese subjects. ADHD with comorbid ODD was associated with homozygosity of the high-activity Val allele, while the predominantly inattentive ADHD subtype was associated with the low-activity Met allele. We found no evidence of association between the MAOA-uVNTR variant and ADHD with comorbid ODD or the ADHD-IA subtype.
Conclusion
Our study of attention deficit hyperactivity disorder comorbid oppositional defiant disorder and its predominately inattentive type highlights the potential etiologic role of COMT for ADHD children in China. But we failed to observe an interaction between COMT and MAOA, which suggests that epistasis between COMT and MAOA genes does not influence the phenotype of ADHD-IA with comorbid ODD in a clinical sample of Chinese male subjects. To confirm our findings further studies with a larger number of subjects and healthy controls are needed.
doi:10.1186/1744-9081-5-8
PMCID: PMC2661318  PMID: 19228412
21.  COMT Val158Met Genotype and Individual Differences in Executive Function in Healthy Adults 
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 APOE, BDNF and 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.
doi:10.1017/S1355617710001402
PMCID: PMC3114452  PMID: 21144101
cognition; neuropsychological tests; executive control; catechol-O-methyltransferase; polymorphism; epistasis
22.  Association between the Catechol-O-Methyltransferase (COMT) Val158Met Polymorphism and Manual Aiming Control in Healthy Subjects 
PLoS ONE  2014;9(6):e99698.
Background
Prefrontal 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 Findings
We 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/Significance
This 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.
doi:10.1371/journal.pone.0099698
PMCID: PMC4067272  PMID: 24956262
23.  Catechol-O-Methyltransferase Val158Met Polymorphism Associates with Individual Differences in Sleep Physiologic Responses to Chronic Sleep Loss 
PLoS ONE  2011;6(12):e29283.
Background
The COMT Val158Met polymorphism modulates cortical dopaminergic catabolism, and predicts individual differences in prefrontal executive functioning in healthy adults and schizophrenic patients, and associates with EEG differences during sleep loss. We assessed whether the COMT Val158Met polymorphism was a novel marker in healthy adults of differential vulnerability to chronic partial sleep deprivation (PSD), a condition distinct from total sleep loss and one experienced by millions on a daily and persistent basis.
Methodology/Principal Findings
20 Met/Met, 64 Val/Met, and 45 Val/Val subjects participated in a protocol of two baseline 10h time in bed (TIB) nights followed by five consecutive 4 h TIB nights. Met/Met subjects showed differentially steeper declines in non-REM EEG slow-wave energy (SWE)—the putative homeostatic marker of sleep drive—during PSD, despite comparable baseline SWE declines. Val/Val subjects showed differentially smaller increases in slow-wave sleep and smaller reductions in stage 2 sleep during PSD, and had more stage 1 sleep across nights and a shorter baseline REM sleep latency. The genotypes, however, did not differ in performance across various executive function and cognitive tasks and showed comparable increases in subjective and physiological sleepiness in response to chronic sleep loss. Met/Met genotypic and Met allelic frequencies were higher in whites than African Americans.
Conclusions/Significance
The COMT Val158Met polymorphism may be a genetic biomarker for predicting individual differences in sleep physiology—but not in cognitive and executive functioning—resulting from sleep loss in a healthy, racially-diverse adult population of men and women. Beyond healthy sleepers, our results may also provide insight for predicting sleep loss responses in patients with schizophrenia and other psychiatric disorders, since these groups repeatedly experience chronically-curtailed sleep and demonstrate COMT-related treatment responses and risk factors for symptom exacerbation.
doi:10.1371/journal.pone.0029283
PMCID: PMC3246458  PMID: 22216231
24.  The Effects of The COMT val108/158met Polymorphism on BOLD Activation During Working Memory, Planning, and Response Inhibition: A Role for The Posterior Cingulate Cortex? 
Neuropsychopharmacology  2010;36(4):763-771.
Catechol-O-methyl transferase (COMT) val108/158met polymorphism impacts on cortical dopamine levels and may influence functional magnetic resonance (fMRI) measures of task-related neuronal activity. Here, we investigate whether COMT genotype influences cortical activations, particularly prefrontal activations, by interrogating its effect across three tasks that have been associated with the dopaminergic system in a large cohort of healthy volunteers. A total of 50 participants (13 met/met, 23 val/met, and 14 val/val) successfully completed N-Back, Go-NoGo, and Tower of London fMRI tasks. Image analysis was performed using statistical parametric mapping. No significant relationships between COMT genotype groups and frontal lobe activations were observed for any contrast of the three tasks studied. However, the val/val group produced significantly greater deactivation of the right posterior cingulate cortex in two tasks: the Go-NoGo (NoGo vs Go deactivation contrast) and N-Back (2-back vs rest deactivation contrast). For the N-Back task, the modulated deactivation cluster was functionally connected to the precuneus, left middle occipital lobe, and cerebellum. These results do not support findings of prefrontal cortical modulation of activity with COMT genotype, but instead suggest that COMT val/val genotype can modulate the activity of the posterior cingulate and may indicate the potential network effects of COMT genotype on the default mode network.
doi:10.1038/npp.2010.210
PMCID: PMC3055733  PMID: 21150912
cognition; COMT; default mode network; dopamine; fMRI; frontal; dopamine; imaging; clinical or preclinical; neurogenetics; learning and memory; COMT; cingulated; frontal; fMRI; default mode network
25.  COMT Val158Met Polymorphism Modulates Cognitive Effects of Dietary Intervention 
A common single nucleotide polymorphism (SNP) in the gene encoding catechol-O-methyltransferase (COMT), Val158Met, is thought to influence cognitive performance due to differences in prefrontal dopaminergic neurotransmission. Previous studies lend support for the hypothesis that the “at risk” genotype comprising two Val-alleles (low dopamine) might benefit more from plasticity-enhancing interventions than carriers of one or two Met-alleles. This study aimed to determine whether the response to dietary interventions, known to modulate cognition, is dependent on COMT genotype. Blood samples of 35 healthy elderly subjects (61.3 years ±8 SD; 19 women, 16 men, BMI: 28.2 kg/m2 ±4 SD) were genotyped for COMT Val158Met by standard procedures (Val/Val = 6; Val/Met = 20; Met/Met = 9). Subjects had previously completed a randomized controlled trial investigating the effects of caloric restriction (CR) or enhancement of unsaturated fatty acids (UFA) on immediate and delayed verbal recognition memory. Homozygous Val/Val-carriers had significantly lower memory scores than Met-carriers at baseline (p < 0.001). Significant interactions of genotype and dietary intervention with regard to cognition were found: CR- and UFA enhancement-induced memory improvements of Val/Val-carriers were considerably greater than those of Met-carriers (ANOVA p's < 0.02). The current study shows for the first time that cognitive effects of dietary interventions are dependent on COMT Val158Met genotype. Our findings lend further support to the hypothesis that an “at risk” genotype might benefit more from plasticity-enhancing interventions than the “not at risk” genotype. This might help to develop individualized therapies in future research based on genetic background.
doi:10.3389/fnagi.2010.00146
PMCID: PMC2990456  PMID: 21119769
COMT; diet; aging; genetic variation; cognition; memory

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