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.
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.
There was no evidence of association with performance on any of the neurocognitive tasks.
We conclude that Val158Met COMT genotype is not associated with neurocognitive performance in our sample.
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.
► 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.
Resting state network; Dopamine; Working memory; Prefrontal cortex; Polymorphism; fMRI
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.
cognition; COMT; default mode network; dopamine; fMRI; frontal; dopamine; imaging; clinical or preclinical; neurogenetics; learning and memory; COMT; cingulated; frontal; fMRI; default mode network
We demonstrate that common genetic polymorphisms contribute to the increasing heterogeneity of cognitive functioning in old age. We assess two common Val/Met polymorphisms, one affecting the Catechol-O-Methyltransferase (COMT) enzyme, which degrades dopamine (DA) in prefrontal cortex (PFC), and the other influencing the brain-derived neurotrophic factor (BDNF) protein. In two tasks (Wisconsin Card Sorting and spatial working memory), we find that effects of COMT genotype on cognitive performance are magnified in old age and modulated by BDNF genotype. Older COMT Val homozygotes showed particularly low levels of performance if they were also BDNF Met carriers. The age-associated magnification of COMT gene effects provides novel information on the inverted U-shaped relation linking dopaminergic neuromodulation in PFC to cognitive performance. The modulation of COMT effects by BDNF extends recent evidence of close interactions between frontal and medial-temporal circuitries in executive functioning and working memory.
genes; dopamine; executive functions; prefrontal cortex; aging
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.
BDNF; COMT; aging; task-switching; cognition; executive control; longitudinal
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).
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.
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.
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.
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.
COMT; task-oriented behaviour; methylphenidate; ADHD
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.
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.
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.
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.
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.
cognition; neuropsychological tests; executive control; catechol-O-methyltransferase; polymorphism; epistasis
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.
COMT; fMRI; g; genotype; intelligence; prefrontal cortex
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.
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.
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.
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.
Catechol-o-methyltransferase; decision making; pharmacogenetics; polymorphism; tolcapone; working memory
The catechol-O-methyltransferase (COMT) enzyme catabolizes dopamine. The val158met single nucleotide polymorphism (rs4680) in the COMT gene has received considerable attention as a candidate gene for schizophrenia as well as for frontally mediated cognitive functions. Antisaccade performance is a good measure of frontal lobe integrity. Deficits on the task are considered a trait marker for schizophrenia. The aim of this study was to investigate the association of COMT val158met polymorphism with antisaccade eye movements in schizophrenia patients and healthy controls. Schizophrenia patients (N = 105) and healthy controls (N = 95) underwent infrared oculographic assessment of antisaccades. Subjects were genotyped for COMT val158met and divided into 3 groups according to genotype (val/val, val/met, and met/met). Patients displayed significantly more reflexive errors, longer and more variable latency, and lower amplitude gain than controls (all P < 0.02). A greater number of val158 alleles was associated with shorter (P = 0.045) and less variable (P = 0.028) antisaccade latency and, nonsignificantly, with lower reflexive error rate (P = 0.056). None of these variables showed a group-by-genotype interaction (P > 0.1). There were no significant associations of genotype with measures of amplitude gain or spatial error (P > 0.2). The results suggest that COMT val158 carrier status is associated with better performance on the antisaccade task. Possible explanations of this finding are discussed.
COMT val158met polymorphism; dopamine; oculomotor; antisaccade; schizophrenia; endophenotype
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.
schizophrenia; endophenotype; genetics; attention; dopamine
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.
COMT; Flight simulator performance; Cognitive performance; Aviation expertise; Age
A functional polymorphism of the gene coding for Catechol-O-methyltrasferase (COMT), an enzyme responsible for the degradation of the catecholamine dopamine (DA), epinephrine, and norepinephrine, is associated with cognitive deficits. However, previous studies have not examined the effects of COMT on context processing, as measured by the AX-CPT, a task hypothesized to be maximally relevant to DA function. 32 individuals who were either healthy, with schizotypal personality disorder, or non-cluster A, personality disorder (OPD) were genotyped at the COMT Val158Met locus. Met/Met (n = 6), Val/Met (n = 10), Val/Val (n = 16) individuals were administered a neuropsychological battery, including the AX-CPT and the N-back working memory test. For the AX-CPT, Met/Met demonstrated more AY errors (reflecting good maintenance of context) than the other genotypes, who showed equivalent error rates. Val/Val demonstrated disproportionately greater deterioration with increased task difficulty from 0-back to 1-back working memory demands as compared to Met/Met, while Val/Met did not differ from either genotypes. No differences were found on processing speed or verbal working memory. Both context processing and working memory appear related to COMT genotype and the AX-CPT and N-back may be most sensitive to the effects of COMT variation.
COMT; dopamine; context processing; working memory; schizotypal personality disorder
A valine158methionine polymorphism in Catechol-O-methyltransferase (COMT) modulates cortical dopaminergic catabolism and has been associated with schizophrenia. Consistent with schizophrenia itself, during cognitive tasks, the risk (val) allele predicts less efficient prefrontal cortex (PFC) physiology and worse performance, while during aversive stimuli viewing, this allele predicts less limbic activation. Task-independent effects of this polymorphism in schizophrenia have not yet been characterized.
Twenty-five medication-free patients (28±6 years; 19 male) and forty-seven healthy individuals (29±8 years; 33 male) were genotyped for the COMT val158met polymorphism and underwent two 60-second [15O]H2O regional cerebral blood flow (rCBF) positron emission tomography (PET) scans (10 mCi/scan) during rest. Data were analyzed with a random-effects general linear model using COMT genotype as a covariate.
In patients, but not healthy individuals, val (risk) allele load predicted less regional cerebral blood flow (rCBF) in the right dorsolateral PFC (DLPFC), right superior temporal gyrus, and left precuneus, but greater rCBF in the amygdala and parahippocampal gyrus.
In schizophrenia, brain structures important for executive and affective processing show activity that is differentially predicted by COMT allelic variation in an opposing manner even at rest, providing evidence for the salience of prefrontal dopaminergic tone in task-independent, basal-level neural activity.
schizophrenia; COMT; PET; rest; prefrontal; limbic
Variation in the catechol-O-methyltransferase gene (COMT) has been associated with antisocial behavior in ADHD populations. The present study examined whether COMT would predict antisocial behavior in a sample with high levels of behavior problems, not necessarily ADHD. Additionally, because previous research suggests that COMT may be associated with ADHD in males, association between COMT and ADHD symptoms was examined.
The current study tested whether variation in three polymorphisms of the COMT gene was predictive of symptoms of conduct disorder and ADHD, in a sample of 174 incarcerated Russian adolescent male delinquents.
The Val allele of the Val158Met polymorphism was significantly associated with conduct disorder diagnosis and symptoms, whereas the Met allele was associated with ADHD symptoms.
The Val158Met polymorphism of the COMT gene shows a complex relation to behavior problems, influencing conduct disorder and ADHD symptoms in opposite directions in a high-risk population.
Conduct Disorder; ADD/ADHD; antisocial behavior; genetics; catechol-O-methyltransferase
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.
cigarette smoking; brain-derived neurotrophic factor; catechol-O-methyltransferase; neurocognition; alcohol dependence
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.
COMT Val108/158Met Polymorphism; Amygdala; Hippocampus; structural MRI; Schizophrenia; Dopamine
Various genes are known to modulate the delicate balance of dopamine in prefrontal cortex and influence cortical information processing. Catechol-O-methyltransferase (COMT) on chromosome 22q11 is the most widely studied of these genes. Val158Met, a common, functional variant in the coding sequence that increases or decreases the enzymatic activity of the gene has been shown to impact the efficiency of prefrontally-mediated cognition, specifically executive functioning, working memory, fluid intelligence and attentional control.
We review the fast-paced evolving literature exploring the association between COMT genotype and cognitive performance, and illustrate how this polymorphism has served a pivotal role in characterizing various interacting dimensions of complexity in the relationship between genes and cognition. We review how Val158Met has been used to help develop and validate behavioural and neurophysiological phenotypes, as a critical tool in dissecting overlapping neural functional systems and exploring interactions within and between genes, and in exploring how gene effects on cognition are modulated by environmental, demographic and developmental factors. Despite the impressive range of findings, the COMT story is also a bracing reminder of how much work remains to translate this knowledge into practical clinical applications.
prefrontal cortex; executive function; working memory
“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).
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.
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.
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.
COMT; diet; aging; genetic variation; cognition; memory
It has been recently shown that Catechol O-methyltransferase (COMT) Val158Met polymorphism strongly influences prepulse inhibition (PPI) of the acoustic startle response (ASR) in healthy human volunteers. Given that schizophrenia patients exhibit impairment in PPI and that COMT is a putative susceptibility gene for schizophrenia, we investigated the impact of the COMT Val158Met polymorphisms on PPI in schizophrenic inpatients. We analyzed COMT Val158Met polymorphisms and assessed startle reactivity, habituation, and PPI of ASR in 68 Caucasian schizophrenia inpatients. Clinical symptoms were measured with the Positive and Negative Syndrome Scale (PANSS). Patients carrying the Val158Met Met/Met allele showed elevated PPI levels whereas startle reactivity and habituation did not differ from the other two genotypes. These preliminary results imply that PPI is influenced by COMT Val158Met genotype in schizophrenia as well. In concert with other findings, our data suggest that PPI is a polygenic trait.
prepulse inhibition; acoustic startle response; sensorimotor gating; catechol O-methyltransferase; Val158Met; COMT; schizophrenia; polymorphism
Knowledge about the functional status of the frontal cortex in infancy is limited. This study investigated the effects of polymorphisms in four dopamine system genes on performance in a task developed to assess such functioning, the Freeze-Frame task, at 9 months of age. Polymorphisms in the catechol-O-methyltransferase (COMT) and the dopamine D4 receptor (DRD4) genes are likely to impact directly on the functioning of the frontal cortex, whereas polymorphisms in the dopamine D2 receptor (DRD2) and dopamine transporter (DAT1) genes might influence frontal cortex functioning indirectly via strong frontostriatal connections. A significant effect of the COMT valine158methionine (Val158Met) polymorphism was found. Infants with the Met/Met genotype were significantly less distractible than infants with the Val/Val genotype in Freeze-Frame trials presenting an engaging central stimulus. In addition, there was an interaction with the DAT1 3′ variable number of tandem repeats polymorphism; the COMT effect was present only in infants who did not have two copies of the DAT1 10-repeat allele. These findings indicate that dopaminergic polymorphisms affect selective aspects of attention as early as infancy and further validate the Freeze-Frame task as a frontal cortex task.
frontal cortex; infancy; dopamine genes; attention; frontal-subcortical circuits
Caused by a microdeletion at the q11.2 locus of chromosome 22, velo-cardio-facial syndrome (also known as VCFS, 22q11 deletion syndrome, DiGeorge sequence, and conotruncal anomalies face syndrome) is associated with a distinctive physical, neurocognitive and psychiatric phenotype. Increasing interest has centered on identifying the candidate genes within the deleted region that may contribute to this phenotype. One attractive candidate gene is catechol-O-methyltransferase (COMT) because it encodes for a protein that degrades dopamine. COMT activity is variable related to a Val158Met polymorphism that has been implicated in prefrontal lobe cognitive and neuropsychiatric function. We examined the effect of this polymorphism on prefrontal anatomy and frontally-mediated neuropsychological function in 58 children with VCFS, 26 who were hemizygous for the Met allele and 32 for the Val allele. We found an allele by gender interaction effect on the volumes of the dorsal prefrontal and orbital prefrontal cortices. We did not find significant allele or gender by allele effects on neuropsychological tasks, although girls with the Met allele tended to perform better on the Wisconsin Card Sorting Task. These data suggest that this functional COMT polymorphism may play a gender-moderated role in determining the neuroanatomic phenotype of individuals with VCFS. Longitudinal evaluation of these children is essential in order to identify potential clinical implications of this allele by gender interaction.
velocardiofacial syndrome (VCFS); 22q11 deletion; COMT polymorphism; prefrontal cortex; executive function
Levels of extra-synaptic dopamine in the brain vary as a function of polymorphisms at the Val158Met locus of the catechol-O-methyltransferase (COMT) gene. In vivo studies of this polymorphism in the human brain have typically measured patterns of neural activation during dopamine-mediated tasks in adults. This study is the first to investigate the effects of COMT on brain physiology during rest and in children. We used flow-sensitive arterial spin labeling (ASL) magnetic resonance imaging to examine brain blood flow (CBF) in 42 children. Compared with val-allele carriers, met-allele homozygotes exhibited greater CBF in mesolimbic, mesocortical, and nigrostriatal dopamine (DA) pathways. Higher CBF in DA-rich brain structures reflects COMT-related baseline differences that (1) underlie the selective behavioral advantages associated with each genotype; (2) affect interpretations of previously reported genotype differences in BOLD signal changes; and (3) serve as a foundation for future studies on the effects of COMT on brain development.