Association of catechol-O-methyltransferase (COMT) polymorphism and academic achievement in a Chinese cohort

Catechol-O-methyltransferase (COMT) is a methylation enzyme that catalyzes the degradation pathway and inactivation of dopamine. It is accepted widely as being involved in the modulation of dopaminergic physiology and prefrontal cortex (PFC) function. The COMT Val158Met polymorphism is associated with variation in COMT activity. COMT 158Met allele may be advantageous for PFC-related cognitive abilities; however, it is also associated with increased anxiety, depression, and emotional vulnerability in response to stress or educational adversity. We hypothesized that the COMT polymorphism might be associated with academic performance. In this study, 779 Taiwanese tenth-grade volunteers were recruited. Scores from the Basic Competency Test (BCT), an annual national competitive entrance examination, were used to evaluate academic performance. The results indicated that students bearing homozygous for the Met allele tended to perform more poorly in all BCT subtests as compared to the other groups. In particular, the former performed significantly more poorly in the science and social science subtests. These findings provide evidence that affective factors might overwhelm cognitive abilities in high-stake tests like the BCT.     

COMT多态性与连续3-back任务相关ERP的关联研究

不同COMT基因型被试者,进行连续3-back任务测试,以探讨被试者工作记忆能力的变化情况。抽取21名不同COMT基因型被试者,观测被试者在连续工作记忆任务中记忆能力和脑电生理的差异。结果表明,Val/Met基因型被试者P300波幅显著低于Val/Val型,Met/Met型被试者的P300波幅居中。Val/Met型被试者显示了最差记忆任务成绩,被试者的P300波幅和记忆能力相关。COMT基因多态性和3-back任务事件相关电位相关联,工作记忆任务的灵活性和稳定性及其交互作用受到遗传因素的调控。     

COMT基因Val158Met多态性与抑郁的关系

抑郁的发生具有重要的遗传学基础。COMT基因Val158Met多态性是抑郁的重要候选基因位点。目前有关COMT基因Val158Met多态性与抑郁关系的研究主要采用单基因设计、单基因-环境设计以及多基因-环境设计。有资料显示负性情绪偏向及其相关脑区可能在COMT基因Val158Met多态性与抑郁间起中介作用, 但具体机制仍有待探究。未来研究可以进一步考察被试的种族、年龄和性别等因素对COMT基因Val158Met多态性与抑郁关系的调节作用, 并通过采用多基因-环境设计, 综合运用积极与消极环境指标等措施深入考察负性情绪偏向和相关脑区在COMT基因Val158Met多态性与抑郁间的作用及其机制。     

Warriors versus worriers: the role of COMT gene variants

Behavioral phenotypes are generally complex, reflecting the action of multiple different genes. Nevertheless, there is growing evidence that key gene variants can alter activity within specific neuronal circuits and, therefore, influence particular cognitive-affective phenomena. One example is the catechol-O-methyltransferase (COMT) gene, which has a common variant at codon 158. Those with valine (Val158) alleles have increased greater COMT activity and lower prefrontal extracellular dopamine compared with those with the methionine (Met158) substitution. Val158 alleles may be associated with an advantage in the processing of aversive stimuli (warrior strategy), while Met158 alleles may be associated with an advantage in memory and attention tasks (worrier strategy). Under conditions of increased dopamine release (eg, stress), individuals with Val158 alleles may have improved dopaminergic transmission and better performance, while individuals with Met158 alleles may have less efficient neurotransmission and worse performance. Some evidence suggests that Val158 alleles are associated with schizophrenia, while Met158 alleles are associated with anxiety.     

How to consistently link extraversion and intelligence to the catechol-O-methyltransferase (COMT) gene: on defining and measuring psychological phenotypes in neurogenetic research

The evidence for associations between genetic polymorphisms and complex behavioral/psychological phenotypes (traits) has thus far been weak and inconsistent. Using the well-studied Val158Met polymorphism of the catechol-O-methyltransferase (COMT) gene as an example, we demonstrate that using theoretical models to guide phenotype definition and measuring the phenotypes of interest with a high degree of specificity reveals strong gene-behavior associations that are consistent with prior work and that would have otherwise gone unnoticed. Only after statistically controlling for irrelevant portions of phenotype variance did we observe strong (Cohen's d = 0.33-0.70) and significant associations between COMT Val158Met and both cognitive and affective traits in a healthy male sample (N = 201) in Study 1: Carriers of the Met allele scored higher in fluid intelligence (reasoning) but lower in both crystallized intelligence (general knowledge) and the agency facet of extraversion. In Study 2, we conceptually replicated the association of COMT Val158Met with the agency facet of extraversion after partialing irrelevant phenotype variance in a female sample (N = 565). Finally, through reanalysis of a large published data set we showed that Met allele carriers also scored higher in indicators of fluid intelligence after partialing verbal fluency. Because the Met allele codes for a less efficient variant of the enzyme COMT, resulting in higher levels of extrasynaptic prefrontal dopamine, these observations provide further support for a role for dopamine in both intelligence and extraversion. More importantly, the present findings have important implications for the definition of psychological phenotypes in neurogenetic research.     

Effect of the COMT Val158Met genotype on lateral prefrontal activations in young children

Low executive function (EF) during early childhood is a major risk factor for developmental delay, academic failure, and social withdrawal. Susceptible genes may affect the molecular and biological mechanisms underpinning EF. More specifically, genes associated with the regulation of prefrontal dopamine may modulate the response of prefrontal neurons during executive control. Several studies with adults and older children have shown that variants of the catechol‐O‐methyltransferase (COMT) gene are associated with behavioral performance and prefrontal activations in EF tasks. However, the effect of the COMT genotype on prefrontal activations during EF tasks on young children is still unknown. The present study examined whether a common functional polymorphism (Val158Met) in the COMT gene was associated with prefrontal activations and cognitive shifting in 3‐ to 6‐year‐old children. The study revealed that, compared with children with at least one Met allele (Met/Met and Met/Val), children who were Val homozygous (i) were more able to flexibly switch rules in cognitive shifting tasks and (ii) exhibited increased activations in lateral prefrontal regions during these tasks. This is the first evidence that demonstrates the relationship between a gene polymorphism and prefrontal activations in young children. It also indicates that COMT Val homozygosity may be advantageous for cognitive shifting and prefrontal functions, at least during early childhood, and children who possess this variant may have a lower risk of developing future cognitive and social development issues.     

Cognitive control and the COMT Val158Met polymorphism: genetic modulation of videogame training and transfer to task-switching efficiency

The study investigated whether successful transfer of game-based cognitive improvements to untrained tasks might be modulated by preexisting neuro-developmental factors, such as genetic variability related to the catechol-O-methyltransferase (COMT)—an enzyme responsible for the degradation of dopamine. The COMT Val¹⁵⁸Met genotype may differentially affect cognitive stability and flexibility, and we hypothesized that Val/Val homozygous individuals (who possess low prefrontal dopamine levels) show more pronounced cognitive flexibility than Met/-carriers (who possess high prefrontal dopamine levels). We trained participants, genotyped for the COMT Val¹⁵⁸Met polymorphism on playing “Half-Life 2”, a first-person shooter game which has been shown to improve cognitive flexibility. Pre-training (baseline) and post-training measures of cognitive flexibility were acquired by means of a task-switching paradigm. As expected, Val/Val homozygous individuals showed larger beneficial transfer effects than Met/-carriers. Our findings support the idea that genetic predisposition modulates transfer effects and that playing first-person shooter games promotes cognitive flexibility in individuals with a suitable genetic predisposition.     

Association of Catechol-O-Methyltransferase Polymorphism (Val108/158Met) With Parkinson's Disease: A Meta-Analysis

Parkinson's disease (PD) is a common neurodegenerative disease, the risk factors of which are gaining more attentions. Among all these risk factors, catechol-o-methyltransferase (COMT) has been widely studied, and believed to be associated with PD. However, the relationship between COMT polymorphism and PD has not been confirmed hitherto. Therefore, a meta-analysis was performed to evaluate the effect of COMT polymorphism on PD patients. A total of 24 study subjects comprising 3,807 patients with PD and 3,942 unrelated healthy controls were recruited in this meta-analysis. Heterogeneity testing and sensitivity analysis were conducted with Review Manager 5.0 software (The Nordic Cochrane Centre, The Cochrane Collaboration, Copenhagen, Denmark) and Stata software (StataCorp, College Station, TX), together with publication bias by funnel plot method and modified Egger's linear regression test. No evidences of publication bias and heterogeneity were detected. In the 24 studies, the estimated odds ratios (OR) in PD patients are 0.98 for the Met allele (95% confidence interval [0.92, 1.05]) under a fixed-effects model. The authors also conducted a stratified analysis according to geographic region among Europe, Asia, and North America, the ORs for the Met allele are 0.92, 1.02, and 1.10, respectively. According to the results of the meta-analysis, a conclusion could be drawn that polymorphism of Val108/158Met are not associated with the risk of PD. However, more convincing studies are warranted to have a solid conclusion supported.     

MAOA基因T941G多态性与同伴侵害对男青少年早期抑郁的交互作用:COMT基因Val158Met多态性的调节效应

抑郁具有复杂的多基因遗传基础,然而既有研究大多采用单基因以及单基因-环境交互设计(G×E)考察抑郁的遗传机制。以757名男青少年为被试(初次测评时Mage=11.32岁,SD=0.49岁),采用多基因-环境交互(G×G×E)设计,本研究考察了MAOA(monoamine oxidase A,单胺氧化酶A)基因T941G多态性、COMT(catechol-O-methyltransferase,儿茶酚胺氧位甲基转移酶)基因Val158Met多态性与同伴侵害对青少年早期抑郁的影响。结果显示,MAOA基因T941G多态性与同伴侵害交互作用于青少年抑郁,同伴侵害仅显著正向预测G等位基因(而非T等位基因)青少年抑郁。而且,MAOA基因T941G多态性与同伴侵害的交互作用受到COMT基因Val158Met多态性的调节,上述交互作用仅存在于COMT Met等位基因而非Val/Val基因型携带者中。研究结果显示,抑郁的产生与个体差异存在多基因与环境间的复杂交互机制。     

Effects of Comt Genotype on Behavioral Symptomatology in the 22q11.2 Deletion Syndrome

The 22q11.2 Deletion Syndrome (DiGeorge/velocardiofacial syndrome) is associated with elevated rates of psychosis, and is also characterized by severe attentional difficulties and executive dysfunction. Behavioral manifestations of this syndrome could result from haploinsufficiency of the catechol-O-methyltransferase (COMT) gene, located within the 22q11 region. The goal of the present study was to examine COMT genotype in relation to behavioral symptomatology in this syndrome. Val^158/108Met was genotyped in 38 patients (16 Met/-, 22 Val/-) with confirmed 22q11.2 deletions who had received the Child Behavior Checklist (CBCL) as part of a comprehensive evaluation. Results indicated that the Val genotype was associated with significantly greater internalizing and externalizing behavioral symptomatology in children with 22q11.2 deletions. Val allele status was associated with a greater-than-four-fold increase in risk for clinically significant behavior problems in children with this syndrome. These data are consistent with previous findings of increased psychopathology associated with the Val genotype in normal individuals and suggest that a functional genetic polymorphism in the 22q11 region may influence behavior in individuals with COMT haploinsufficiency.     

Effects of COMT genotype on behavioral symptomatology in the 22q11.2 Deletion Syndrome.

The 22q11.2 Deletion Syndrome (DiGeorge/velocardiofacial syndrome) is associated with elevated rates of psychosis, and is also characterized by severe attentional difficulties and executive dysfunction. Behavioral manifestations of this syndrome could result from haploinsufficiency of the catechol-O-methyltransferase (COMT) gene, located within the 22q11 region. The goal of the present study was to examine COMT genotype in relation to behavioral symptomatology in this syndrome. Val158/108Met was genotyped in 38 patients (16 Met/-, 22 Val/-) with confirmed 22q11.2 deletions who had received the Child Behavior Checklist (CBCL) as part of a comprehensive evaluation. Results indicated that the Val genotype was associated with significantly greater internalizing and externalizing behavioral symptomatology in children with 22q11.2 deletions. Val allele status was associated with a greater-than-four-fold increase in risk for clinically significant behavior problems in children with this syndrome. These data are consistent with previous findings of increased psychopathology associated with the Val genotype in normal individuals and suggest that a functional genetic polymorphism in the 22q11 region may influence behavior in individuals with COMT haploinsufficiency.     

Schoolchildren’s autobiographical memory: COMT gene Val158Met polymorphism effects on emotional content and quality of first memories

Cognitive Processing - Autobiographical memory is a cognitive function strongly related to emotional processing as autobiographical memory often includes emotional content. The COMT gene Val158Met...     

Influence of brain-derived neurotrophic factor and catechol O-methyl transferase polymorphisms on effects of meditation on plasma catecholamines and stress

Meditation may show differential effects on stress and plasma catecholamines based on genetic polymorphisms in brain-derived neurotrophic factor (BDNF) and catechol O-methyl transferase (COMT). Eighty adults (40 men, 40 women; mean age 26 years) who practiced meditation regularly and 57 healthy control adults (35 men, 22 women; mean age 26 years) participated. Plasma catecholamines (norepinephrine (NE), epinephrine (E), and dopamine (DA)) concentrations were measured, and a modified form of the Stress Response Inventory was administered. The results were analyzed using two-way analysis of covariance (ANCOVA) with control and meditation subjects, gene polymorphism as factors, and meditation duration as the covariate. Two-way ANCOVA showed a significant interaction between control and meditation subjects, and BDNF Val66Met polymorphism on DA/NE+DA/E (p = 0.042) and NE/E+NE/DA (p = 0.046) ratios. A significant interaction was found for control and meditation subjects with COMT Val158Met polymorphism and plasma NE concentrations (p = 0.009). Post hoc ANCOVA in the meditation group, adjusted for meditation duration, showed significantly higher plasma NE concentrations for COMT Met carriers than COMT Val/Val subjects (p = 0.025). Significant differences of stress levels were found between the control and meditation subjects in BDNF Val/Met (p < 0.001) and BDNF Met/Met (p = 0.003), whereas stress levels in the BDNF Val/Val genotype did not differ between the control and meditation groups. This is the first evidence that meditation produces different effects on plasma catecholamines according to BDNF or COMT polymorphisms.     

负性生活事件与青少年早期抑郁的关系：COMT基因Val158Met多态性与父母教养行为的调节作用

采用环境×基因×环境(E×G×E)研究设计, 以637名青少年为被试, 考察了负性生活事件、COMT基因Val158Met多态性和父母教养行为对青少年早期抑郁的影响。结果发现：负性生活事件对青少年早期抑郁具有显著正向预测作用, 且COMT基因Val158Met多态性和父亲积极教养行为在其中起调节作用, 但该调节作用仅存在于男青少年群体中：在携带Val/Val基因型的男青少年中, 当父亲积极教养行为水平较低时, 青少年的抑郁水平随负性生活事件的增多而显著上升, 当父亲积极教养行为水平较高时, 负性生活事件对抑郁无显著预测作用; 在携带Met等位基因的男青少年中, 上述交互作用不显著。     

COMT基因对注意控制神经基础的调控效应：影像遗传学研究的元分析

为探索注意控制能力个体差异的遗传来源, 当前研究主要关注儿茶酚胺氧位甲基转移酶(catechol-O-Methyltransferase, COMT)基因对参与注意控制加工的前额叶脑区的调控作用。为进一步回答COMT基因是否也对全脑范围的注意脑区具有调控作用, 本文对17篇遗传影像学研究进行元分析。结果发现, COMT基因Val/Val (vv)基因型的被试在注意控制任务下, 不仅前额叶脑区的激活水平高于Met/Met(mm)基因型的被试, 在前扣带回和后扣带回等前额叶之外的脑区激活水平也高于mm基因型的被试, 而且在这些脑区的效应值(vv>mm)都较大(Cohen’s d > 0.8)。由此, 元分析结果表明：COMT基因不仅调控前额叶脑区, 而且对形成注意控制网络的多个脑区都有调控效应。此结果提示注意控制能力的个体差异可能部分的来自于COMT基因对注意控制网络的调控作用。     

Development of dopaminergic genetic associations with visuospatial,verbal and social working memory

Dopamine transmission in the prefrontal cortex (PFC) supports working memory (WM), the temporary holding, processing and manipulation of information in one's mind. The gene coding the catechol‐O‐methyltransferase (COMT) enzyme, which degrades dopamine, in particular in the PFC, has a common single nucleotide polymorphism leading to two versions of the COMT enzyme which vary in their enzymatic activity. The methionine (Met) allele has been associated with higher WM performance and lower activation of the PFC in executive function tasks than the valine (Val) allele. In a previous study, COMT genotype was associated with performance on verbal and visuospatial WM tasks in adults, as well as with performance on a novel social WM paradigm that requires participants to maintain and manipulate information about the traits of their friends or family over a delay. Here, data collected in children and adolescents (N = 202) were compared to data from the adult sample (N = 131) to investigate possible age differences in genetic associations. Our results replicate and extend previous work showing that the pattern of superior WM performance observed in Met/Met adults emerges during development. These findings are consistent with a decrease in prefrontal dopamine levels during adolescence. Developmentally moderated genetic effects were observed for both visuospatial and social WM, even when controlling for non‐social WM performance, suggesting that the maintenance and manipulation of social information may also recruit the dopamine neurotransmitter system. These findings show that development should be considered when trying to understand the impact of genetic polymorphisms on cognitive function.     

COMT genotype influences prefrontal response to emotional distraction

Early studies of genetic effects on brain activity have been conducted to investigate primarily either the influence of polymorphisms in dopaminergic genes, especially the catechol-O-methyltransferase (COMT) gene, on prefrontal cognitive processes such as working memory, or that of polymorphisms in the serotonin transporter gene on the amygdala response to threatening stimuli. Here, we address genetic influences on the neural systems underlying cognitive-affective interactions. Specifically, we assess the effect of the COMT val¹⁵⁸met polymorphism on frontal regulation of attention under emotional distraction. Healthy volunteers were scanned while performing a house-matching task with affectively negative versus neutral distractors. Effects of val allele load were examined on frontal regions associated with attentional control and emotion regulation, and on parahippocampal regions associated with perception of houses. As we predicted, val load correlated positively with activity in control- and task-related regions during performance under emotional distraction. These findings provide an initial step toward identifying genetic contributions to interindividual variability in recruitment of mechanisms that regulate affective processing.     

Stressful life events, perceived stress, and 12-month course of geriatric depression: direct effects and moderation by the 5-HTTLPR and COMT Val158Met polymorphisms

Although the relation between stressful life events (SLEs) and risk of major depressive disorder is well established, important questions remain about the effects of stress on the course of geriatric depression. Our objectives were (1) to examine how baseline stress and change in stress is associated with course of geriatric depression and (2) to test whether polymorphisms of serotonin transporter (5-HTTLPR) and catechol-O-methyltransferase (COMT Val158Met) genes moderate this relation. Two-hundred and sixteen depressed subjects aged 60 years or older were categorized by remission status (Montgomery-Asberg depression rating scale≤6) at 6 and 12 months. At 6 months, greater baseline numbers of self-reported negative and total SLEs and greater baseline perceived stress severity were associated with lower odds of remission. At 12 months, only baseline perceived stress predicted remission. When we examined change in stress, 12-month decrease in negative SLEs and level of perceived stress were associated with improved odds of 12-month remission. When genotype data were included, COMT Val158Met genotype did not influence these relations. However, when compared with 5-HTTLPR L/L homozygotes, S allele carriers with greater baseline numbers of negative SLEs and with greater decrease in negative SLEs were more likely to remit at 12 months. This study demonstrates that baseline SLEs and perceived stress severity may influence the 12-month course of geriatric depression. Moreover, changes in these stress measures over time correlate with depression outcomes. 5-HTTLPR S carriers appear to be more susceptible to both the effects of enduring stress and the benefit of interval stress reduction.     

Examining Preschool Cognitive Abilities Using a CHC Framework

Although there has been a substantial growth in the number of published studies examining tests of cognitive abilities and using contemporary theories of cognitive abilities, to date none have done so with preschool cognitive tests. In this study the relation between cognitive ability measures for young children and Cattell-Horn-Carroll (CHC) theory is examined. Tests and subtests from the Differential Ability Scales: Upper Preschool Level and the Woodcock-Johnson Tests of Cognitive Ability-Revised with a sample of 158 children between 4 and 5 years of age were used in a series of joint factor analyses. Although a series of models were explored, the model representative of the CHC theory of cognitive abilities was best supported by the data. This provides evidence for a greater differentiation of young children's cognitive abilities than are typically interpreted. Results are discussed with regard to understanding the link between contemporary theories of intelligence and young children's cognitive abilities, as well as implications for intellectual assessment practices with young children.     

COMT val158Met and executive control: a test of the benefit of specific deficits to translational research

The role of catechol-O-methyltransferase (COMT) val158met in prefrontal cortical deficits associated with the liability to schizophrenia remains controversial. This study evaluated 464 healthy adult participants using three measures of executive functions in working memory: a 3-back version of the N-back continuous performance task (CPT) and two variants of the AX-CPT. The interpretability of N-back performance was confounded by possible generalized deficits, whereas the AX variants included internal controls for uncovering specific deficits. There was no relationship between the COMT genotype and N-back performance, whereas val/val individuals had a specific deficit on a dot-pattern version of the AX-CPT. In this case, a specific executive function known as context processing appeared to be compromised. These data suggest that the interpretability gained by including task manipulations to uncover specific deficits can enhance associations between cognitive and genetic levels of analysis.