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。     

父母教养行为与青少年早期抑郁的关系：多基因与负性生活事件的调节作用

以745名青少年为被试,采用多基因×多环境设计,考察COMT Val158Met、5-HTR1A C-1019G和BDNF Val66Met基因多态性的多基因累加得分与负性生活事件在父母教养行为与青少年早期抑郁之间的调节作用及其性别差异。结果发现,多基因累加得分与负性生活事件仅能显著调节父亲积极教养行为对青少年抑郁的预测作用,且该调节作用只存在于男青少年群体中。研究结果丰富了抑郁的多基因遗传机制研究,为制定青少年早期抑郁的干预措施提供了理论依据。     

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。     

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。     

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。     

发展行为遗传学简介

发展行为遗传学是发展心理学与行为遗传学的交叉学科, 旨在探明遗传与环境对人类心理与行为发展是否存在影响, 如何产生影响, 以及该影响及其作用机制是否随年龄增长而发展变化的问题。该学科与行为遗传学在研究对象、设计和内容等方面存在不同; 开展发展行为遗传学研究需要综合运用心理测量法和行为遗传学研究方法; 未来研究应拓宽和深化候选基因与行为关联性的考察, 并着力探析基因与环境的相互作用机制。     

抑郁症的影像遗传学研究:探索基因与环境的交互作用

抑郁症具有中等的遗传度。通过影像遗传学方法探讨抑郁相关基因的多态性对神经活动的影响,发现编码五羟色胺、促肾上腺素释放激素受体、多巴胺等神经递质或受体的基因多态性会影响杏仁核、前扣带等情绪加工脑区的功能或结构,且多数基因与压力生活经历发生交互作用。表明基因与环境的交互作用在抑郁症发病机理中扮演重要角色。未来的研究应拓展遗传和神经影像分析方法,重视环境因素的测量,通过整合遗传、神经影像及环境变量构建抑郁病理模型。     

亲子关系、感觉加工敏感性与COMT Val158Met多态性对学前儿童亲社会行为的交互影响

基于个体多重敏感性因素与环境交互的视角,本研究探讨了亲子关系、感觉加工敏感性(Sensory Processing Sensitivity, SPS)与COMT Val158Met多态性的交互作用对学前儿童亲社会行为的影响。研究以507名学前儿童为被试(M年龄=4.83岁, SD=0.90岁),分别采用父母报告的亲子关系量表、高敏感儿童量表、长处与困难问卷中的亲社会分问卷测量了亲子关系、儿童的SPS和亲社会行为,采集唾液样本进行基因位点的分型。研究结果发现,亲子冲突、SPS与COMTVal158Met多态性的三重交互作用对儿童亲社会行为影响显著。在携带Val/Val基因型的儿童中,高SPS儿童比低SPS儿童在低亲子冲突条件下表现更多的亲社会行为,但在高亲子冲突条件下表现更少的亲社会行为;在携带Met等位基因的儿童中,亲子冲突与SPS的交互作用对儿童亲社会行为的影响不显著。研究结果表明同时具有高气质敏感性和高基因敏感性儿童的亲社会行为更容易受到亲子冲突的影响,这为深入理解个体多重敏感性因素与家庭环境交互影响儿童发展提供了证据。     

人类行为遗传学的伦理问题

行为遗传学是试图定位与行为特性有关的特殊基因或基因组及了解基因与环境之间复杂关系的一种研究.行为遗传学是研究正常范围内的非病理变化,与人类疾病遗传学存在差异.行为遗传学研究面临许多伦理学问题,诸如,智力的遗传性,基因能否决定一切,生物社会学与人类文化评估,生命伦理学与行为遗传学的关系等,因此,对行为遗传学研究结果的阐述必须十分谨慎.     

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。     

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.     

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.     

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.     

The BDNF Val66Met polymorphism impacts victim's moral emotions following interpersonal transgression

Immoral behaviors make individuals abominate and punish transgressors. Inspired by the associations between the Val66Met polymorphism of brain‐derived neurotropic factor (BDNF) gene and emotional responses following negative events, we investigated whether this polymorphism was also associated moral emotions such as punishment and forgiveness following interpersonal transgression. To do so, we categorized 340 individuals according to the BDNF Val66Met and assessed moral emotions by using 12 hypothetic scenarios in different conditions of intention and interpersonal consequence. The results indicated that this polymorphism was significantly associated with moral aversion and punishment towards transgressors. Victims with the Val/Val genotype expressed less aversion and punishment than the Met carriers, regardless of intention and interpersonal consequence. Moreover, this polymorphism was associated with forgiveness. Victims with the Val/Val genotype expressed more forgiveness than the Met carriers. Taken together, these findings highlight the importance of the BDNF Val66Met to moral emotions.     

Serum levels of brain-derived neurotrophic factor (BDNF), BDNF gene Val66Met polymorphism, or plasma catecholamine metabolites, and response to mirtazapine in Japanese patients with major depressive disorder (MDD)

Object We investigated an association between the polymorphism of brain-derived neurotrophic factor (BDNF) gene Val66Met and the response to mirtazapine in Japanese patients with major depressive disorder (MDD). We also examined mirtazapine's effects on the serum BDNF and plasma levels of catecholamine metabolites in these patients. METHODS: Eighty-four patients who met the DSM-IV-TR criteria for MDD were treated with only mirtazapine for 4 weeks. The BDNF Val66Met polymorphism was detected by direct sequencing in the region, and serum BDNF levels and plasma levels of catecholamine metabolites were measured by ELISA and HPLC-ECD, respectively. RESULTS: Mirtazapine treatment for 4 weeks significantly increased serum BDNF levels in the responders, whereas nonresponders showed significant decreases. No association was found between either of the two genotypes (Val/Val vs. Met-carriers) and the response to mirtazapine at T4 or the serum BDNF levels at T0. Mirtazapine did not alter the plasma levels of homovanillic acid (HVA) or 3-methoxy-4-hydroxyphenylglycol (MHPG). Discussion The dynamics of serum BDNF levels, but not plasma levels of HVA and MHPG, reflect the response to mirtazapine treatment; the BDNF Val66Met polymorphism in patients with depression is, however, associated with neither a particular response to mirtazapine treatment nor baseline serum BDNF levels. Conclusion Serum BDNF levels, but not plasma levels of HVA or MHPG, and BDNF Val66Met polymorphism are related to the mirtazapine response in MDD.     

Catechol-O-methyltransferase Val158Met genotype affects neural correlates of aversive stimuli processing

It was previously shown that variation of the catechol-O-methyltransferase (COMT) gene modulates brain activity during the processing of stimuli with negative valence, but not for pleasant stimuli. Here, we tested whether the COMT genotype also modulates the electrophysiological correlates of emotional processing and explored whether the environmental factor of life stress influences this effect. Using the early posterior negativity (EPN) paradigm, event-related brain potentials were measured in 81 healthy individuals during the processing of pictures that evoked emotions of positive and negative valence. As was hypothesized, the COMT genotype affected the EPN amplitudes for unpleasant stimuli, but not for pleasant ones. Specifically, Met/Met carriers respond more sensitively to unpleasant stimuli, as compared with Val/Val carriers. We did not find evidence that life stress moderates the effect of the COMT genotype on emotional stimuli processing.     

Variant BDNF (Val66Met) impact on brain structure and function

Neurotrophins, such as brain-derived neurotrophic factor (BDNF), are a unique family of polypeptide growth factors that influence differentiation and survival of neurons in the developing nervous system. In adults, BDNF is important in regulating synaptic plasticity and connectivity in the brain. Recently, a common single-nucleotide polymorphism in the human BDNF gene, resulting in a valine to methionine substitution in the prodomain (Val66Met), has been shown to lead to memory impairment and susceptibility to neuropsychiatric disorders. An understanding of how this naturally occurring polymorphism affects behavior, anatomy, and cognition in adults is an important first step in linking genetic alterations in the neurotrophin system to definable biological outcomes in humans. We review the recent literature linking this BDNF polymorphism to cognitive impairment in the context of in vitro and transgenic animal studies that have established BDNF’s central role in neuronal functioning in the adult brain.     

The Influence of the BDNF Val66Met Polymorphism on Mechanisms of Semantic Priming: Analyses with Drift-Diffusion Models of Masked and Unmasked Priming

Automatic and strategic processes in semantic priming can be investigated with masked and unmasked priming tasks. Unmasked priming is thought to enable strategic processes due to the conscious processing of primes, while masked priming exclusively depends on automatic processes due to the invisibility of the prime. Besides task properties, interindividual differences may alter priming effects. In a recent study, masked and unmasked priming based on mean response time (RT) and error rate (ER) differed as a function of the BDNF Val66Met polymorphism (Sanwald et al., 2020). The BDNF Val66Met polymorphism is related to the integrity of several cognitive executive functions and might thus influence the magnitude of priming. In the present study, we reanalyzed this data with drift-diffusion models. Drift-diffusion models conjointly analyze single trial RT and ER data and serve as a framework to elucidate cognitive processes underlying priming. Masked and unmasked priming effects were observed for the drift rates ν, presumably reflecting semantic preactivation. Priming effects on nondecision time t0 were especially pronounced in unmasked priming, suggesting additional conscious processes to be involved in the t0 modulation. Priming effects on the decision thresholds a may reflect a speed-accuracy tradeoff. Considering the BDNF Val66Met polymorphism, we found lowered drift rates and decision thresholds for Met allele carriers, possibly reflecting a superficial processing style in Met allele carriers. The present study shows that differences in cognitive tasks between genetic groups can be elucidated using drift-diffusion modeling.     

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.     

Association of polymorphisms in BDNF, MTHFR, and genes involved in the dopaminergic pathway with memory in a healthy Chinese population

The contribution of genetic factors to the memory is widely acknowledged. Research suggests that these factors include genes involved in the dopaminergic pathway, as well as the genes for brain-derived neurotrophic factor (BDNF) and methylenetetrahydrofolate reductase (MTHFR). The activity of the products of these genes is affected by single nucleotide polymorphisms (SNPs) within the genes. This study investigates the association between memory and SNPs in genes involved in the dopaminergic pathway, as well as in the BDNF and MTHFR genes, in a sample of healthy individuals. The sample includes 134 Taiwanese undergraduate volunteers of similar cognitive ability. The Chinese versions of the Wechsler Memory Scale (WMS-III) and Wechsler Adult Intelligence Scale (WAIS-III) were employed. Our findings indicate that the BDNF Met66Val polymorphism and dopamine receptor D3 (DRD3) Ser9Gly polymorphism are associated significantly with long-term auditory memory. Further analysis detects no significant associations in the other polymorphisms and indices. Future replicated studies with larger sample sizes, and studies that consider different ethnic groups, are encouraged.