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。     

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.     

COMT基因Val158Met多态性与同伴关系对青少年抑郁的影响

以1048名汉族青少年为被试,采用问卷法和基因分型技术,综合运用传统回归分析和新兴的再参数化回归分析,考察COMT基因Val158Met多态性与同伴关系对青少年抑郁的交互作用模式及其性别差异。结果发现,COMT基因与同伴接纳和同伴拒绝交互预测青少年抑郁,具体表现为,在低同伴接纳或高同伴拒绝环境中,携带ValVal基因型的青少年抑郁水平高于Met等位基因携带者;在高同伴接纳或低同伴拒绝环境中,携带ValVal基因型的青少年抑郁水平低于Met等位基因携带者。此外,COMT基因与同伴接纳和同伴拒绝的交互作用与男生抑郁的关联更加密切。结果显示,COMT基因与同伴关系的交互效应为不同易感性模型提供了证据,而且该基因×环境交互效应存在性别差异。     

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.     

The COMT Val/Met polymorphism is associated with reading‐related skills and consistent patterns of functional neural activation

In both children and adults there is large variability in reading skill, with approximately 5–10% of individuals characterized as having reading disability; these individuals struggle to learn to read despite adequate intelligence and opportunity. Although it is well established that a substantial portion of this variability is attributed to the genetic differences between individuals, specifics of the connections between reading and the genome are not understood. This article presents data that suggest that variation in the COMT gene, which has previously been associated with variation in higher‐order cognition, is associated with reading and reading‐related skills, at the level of both brain and behavior. In particular, we found that the COMT Val/Met polymorphism at rs4680, which results in the substitution of the ancestral Valine (Val) by Methionine (Met), was associated with better performance on a number of critical reading measures and with patterns of functional neural activation that have been linked to better readers. We argue that this polymorphism, known for its broad effects on cognition, may modulate (likely through frontal lobe function) reading skill.     

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.     

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.     

Increased parasympathetic activity and ability to generate positive emotion: The influence of the BDNF Val66Met polymorphism on emotion flexibility

Cross-species behavioral research suggests that a single nucleotide polymorphism (SNP) in the brain-derived neurotrophic factor (BDNF) gene (rs6265, Val66Met), influences behavioral inflexibility. This SNP has not yet been linked to variability in emotion-related behaviors, despite broader evidence suggesting an association may be present. This investigation explored the role of the BDNF Val66Met polymorphism in emotion response behaviors measured during a lab-based emotional provocation. Specifically, the influence of BDNF Val66Met in emotion flexibility was explored in a sample of healthy adults (N?=?120), emotion responses were recorded during the emotional provocation on multiple dimensions, in response to emotionally-evocative videos of negative then positive valence. These results suggest that Met carriers exhibit decreased parasympathetic responding, and reduced ability to generate positive emotion, relative to Val homozygotes. These findings are the first to suggest an association between the Met allele and a pattern of responding indicative of emotion inflexibility that might afford greater risk for psychopathology.     

On the molecular genetics of flexibility: The case of task-switching,inhibitory control and genetic variants

The adjustment of behavior to changing goals and environmental constraints requires the flexible switching between different task sets. Cognitive flexibility is an endophenotype of executive functioning and is highly heritable, as indicated by twin studies. Individual differences in global flexibility as assessed by reaction-time measurement in a task-switching paradigm were recently related to a single nucleotide polymorphism in the vicinity of the dopamine d2 receptor gene DRD2. In the present study, we assessed whether the DRD2 gene is related to backward inhibition, a control mechanism that contributes to cognitive flexibility by reducing proactive interference by no longer relevant task sets. We found that carriers of the DRD2 A1+ variant who have a lower striatal dopamine d2 receptor density than A1– carriers show a larger backward inhibition effect. This is in line with previous results demonstrating increased behavioral flexibility in carriers of this genetic variant. The discussion relates the present finding to those of previous studies assessing the neurogenetic foundations of inhibitory control.     

Gaining control: training executive function and far transfer of the ability to resolve interference

Functional brain-imaging data document overlapping sites of activation in prefrontal cortex across memory tasks, suggesting that these tasks may share common executive components. We leveraged this evidence to develop a training regimen and a set of transfer tasks to examine the trainability of a putative executive-control process: interference resolution. Eight days of training on high-interference versions of three different working memory tasks increased the efficiency with which proactive interference was resolved on those particular tasks. Moreover, an improved ability to resolve interference was also transferred to different working memory, semantic memory, and episodic memory tasks, a demonstration of far-transfer effects from process-specific training. Participants trained with noninterference versions of the tasks did not exhibit transfer. We infer that the transfer we demonstrated resulted from increased efficiency of the interference-resolution process. Therefore, this aspect of executive control is plastic and adaptive, and can be improved by training.     

Cognitive control of language production in bilinguals involves a partly independent process within the domain-general cognitive control network: evidence from task-switching and electrical brain activity

In highly proficient, early bilinguals, behavioural studies of the cost of switching language or task suggest qualitative differences between language control and domain-general cognitive control. By contrast, several neuroimaging studies have shown an overlap of the brain areas involved in language control and domain-general cognitive control. The current study measured both behavioural responses and event-related potentials (ERPs) from bilinguals who performed picture naming in single- or mixed-language contexts, as well as an alphanumeric categorisation task in single- or mixed-task context. Analysis of switch costs during the mixed-context conditions showed qualitative differences between language control and domain-general cognitive control. A 2 × 2 ANOVA of the ERPs, with domain (linguistic, alphanumeric) and context (single, mixed) as within-participant factors, revealed a significant interaction, which also suggests a partly independent language-control mechanism. Source estimations revealed the neural basis of this mechanism to be in bilateral frontal-temporal areas.     

Changes in executive control across the life span: examination of task-switching performance

A study was conducted to examine changes in executive control processes over the life span. More specifically, changes in processes responsible for preparation and interference control that underlie the ability to flexibly alternate between two different tasks were examined. Individuals (N = 152) ranging in age from 7 to 82 years participated in the study. A U-shaped function was obtained for switch costs (i.e., the time required to switch between tasks compared with a repeated-task baseline), with larger costs found for young children and older adults. Switch costs were reduced with practice, particularly for children. All age groups benefited from increased preparation time, with larger benefits observed for children and older adults. Adults benefited to a greater extent than children when the interval between the response to one task and the cue indicating which task to perform next was lengthened, which suggested faster decay of interference from the old task set for adults than for children. A series of hierarchical analyses indicated that the age-related variance in task-switching performance is independent, at least in part, from the age-related variance in other cognitive processes such as perceptual speed and working memory. The results are discussed in terms of the development and decline of executive control processes across the life span.     

Adjustments of task-set control processes: Effect of task switch frequency on task-mixing and task-switching costs

The present study tested the hypothesis that task-switch frequency triggers adjustments of task-set control processes. A mixed-task condition where task switches are frequent should promote flexibility—thus improving task-switch performance—whereas a condition where task repetitions are more expected should favour stability—thus improving task-repeat performance. In two experiments, participants performed single-task and mixed-task blocks. In mixed-task blocks, tasks varied randomly on a trial-by-trial basis. For half of the mixed-task blocks, the frequency with which the task changed was 25%, for the other half, it was 50%. Overall, depending on the task-switch frequency, performance on both task-repeat and task-switch trials was modified. Switch cost was reduced and task-repeat performance was altered by the increase in switch probability. This study demonstrates context-sensitive adjustments of task-set control processes. These results further support the view that mixing cost reflects sustained and endogenous components of cognitive control.     

Rules and more rules: The effects of multiple tasks, extensive training, and aging on task-switching performance

Task-switching performance was assessed in young and older adults as a function of the number of task sets to be actively maintained in memory (varied from 1 to 4) over the course of extended training (5 days). Each of the four tasks required the execution of a simple computational algorithm, which was instantaneously cued by the color of the two-digit stimulus. Tasks were presented in pure (task set size 1) and mixed blocks (task set sizes 2, 3, 4), and the task sequence was unpredictable. By considering task switching beyond two tasks, we found evidence for a cognitive control system that is not overwhelmed by task set size load manipulations. Extended training eliminated age effects in task-switching performance, even when the participants had to manage the execution of up to four tasks. The results are discussed in terms of current theories of cognitive control, including task set inertia and production system postulates.     

The psychology of psychiatric genetics: evidence that positive emotions in females moderate genetic sensitivity to social stress associated with the BDNF Val-sup-6-sup-6Met polymorphism

Previous work indicated protective effects of positive emotions on genetically influenced stress sensitivity. Given the fact that expression of brain-derived-neurotrophic-factor (BDNF) is associated with stress-induced behavioral changes, it was hypothesized that the BDNF Val-sup-6-sup-6Met genotype may mediate genetic effects on stress sensitivity, conditional on the level of concurrent positive emotions. Subjects (n=446) participated in a momentary assessment study, collecting appraisals of stress and affect in the flow of daily life. Multilevel regression analyses examined moderation of daily life stress-induced negative affect (NA) by BDNF genotype, and to what degree this was conditional on concurrent positive emotions. Results showed that heterozygous BDNF "Met" carriers exhibited an increased NA response to social stress compared with "Val/Val" subjects. Positive emotions at the time of the stressor decreased BDNF genetic moderation of the NA response to social stress in a dose-response fashion. This effect was most pronounced in BDNF Met carriers. Thus, the impact of BDNF genotype on stress sensitivity is conditional on the experience of positive emotions. Interdisciplinary research in psychology and psychiatric genetics may lead to the improvement of treatment choices in stress-related disorders.