Dopamine 2 receptor C957T and catechol-o-methyltransferase Val158Met polymorphisms are associated with treatment response in electroconvulsive therapy

Alterations in dopamine levels and dopamine receptors in brain are suggested to be associated with treatment response in electroconvulsive therapy (ECT). Dopamine 2 receptor gene (DRD2) polymorphism C957T (rs6277) and cathechol-o-methyltransferase (COMT) polymorphism Val158Met (rs4680) interaction was studied in 118 patients suffering from major depressive disorder (MDD) treated with ECT and 383 healthy controls. It was found that the combination of COMT Met allele and DRD2 T allele predicted more severe depression in those already affected but did not predict the risk of depression when compared to normal population. The genotype modified the response to ECT. The patients with TT genotype of D2 receptor gene C957T polymorphism combined with COMT gene polymorphism Met/Met genotype did not achieve remission as often as those with CC genotype of DRD2 C957T combined with COMT Val/Val genotype. Thus the interaction of these polymorphisms may be associated with response to ECT.     

Association study of a functional catechol-O-methyltransferase polymorphism and executive function in elderly males without dementia

Cognitive function in older people is a major factor influencing quality of life. The catechol-O-methyltransferase (COMT) gene, which is essential in the metabolic degradation of prefrontal dopamine, has been considered as a leading candidate gene in the variation in cognitive performance. The aim of this study was to investigate the effect of a functional COMT (Val158Met) polymorphism on several cognition domains in a relatively homogeneous population consisting of elderly Chinese males without dementia. Six neuropsychological measurements, including Spatial Span Forward and Backward, Digit Span Forward and Backward, and Trail Making Test-A and -B, were assessed in 161 aged males. It was found that the Met/Met carriers showed a better performance than the Val/Met and Val/Val subjects on the Digit Span Forward (a measure of general attention; p=0.017, after correction for education level) test, but not on the other cognitive tests. These findings suggest that the COMT Val158Met genotype may contribute to differences in normal cognitive aging, particularly in the area of general attention.     

COMT genotype and cognitive ability: a longitudinal aging study

Dopaminergic neurotransmission in the pre-frontal cortex (PFC) contributes to individual cognitive differences in animals and humans. Catechol-O-methyltransferase (COMT) influences dopamine concentration in the PFC. Functional variation in the human COMT gene occurs at a single nucleotide polymorphism (SNP)--472G>A--that results in a valine (Val) to methionine (Met) amino acid substitution (Val158Met). The Met/Met form is less active resulting in higher dopamine concentrations and thus may enhance cognitive function. We applied repeated measures mixed general linear modelling over three waves between ages 64 and 68 years to optimise cognitive phenotype characterisation in a cohort of 473 community volunteers who had validated childhood IQ data. After adjusting for childhood IQ, wave of testing and specific test type, COMT Val158Met genotype polymorphism had a significant overall effect on cognition (F(2,935.7)=7.92, p<.001) with adjusted means of all cognitive test scores taken together being: Val/Val 33.0 (95% C.I. 32.2-33.8), Val/Met 34.9 (95% C.I. 34.3-35.5), and Met/Met 34.9 (95% C.I. 34.1-35.8). This study adds to the evidence that the Val/Val polymorphism has a detrimental effect on cognition, extending upwards the age range in which such an effect has been detected.     

Relationship between dopamine system genes and extraversion and novelty seeking

Dopamine transmission is known to play an important role in the reinforcement system of the brain. Studies have identified dopamine system genes whose polymorphic variants have been linked with the intensity of psychological traits reflecting the tendency to form behaviors characterized by impulsivity and the need for additional stimulation. The aim of the present work was to seek associations between polymorphisms in the catechol-O-methyltransferase (COMT) and D4 dopamine receptor (DRD4) genes and personality traits in the Russian population. Studies of 130 subjects showed that carriers of the Met/Met genotype of the COMT gene had a greater intensity of the novelty-seeking trait than carriers of the Val/Val and Val/Met genotypes, though this association was seen only in women. In addition, the presence of the C allele of the DRD4 gene in carriers of the Met/Met genotype showed high levels of extraversion and hypomania. These results are consistent with current theoretical concepts of the regulation of dopamine transmission in the brain. __________ Translated from Zhurnal Vysshei Nervnoi Deyatel’nosti imeni I. P. Pavlova, Vol. 56, No. 4, pp. 457–463, July–August, 2006.     

Differential effects of COMT on gait and executive control in aging

Walking speed is associated with attention and executive control processes subserved by the prefrontal cortex. Because polymorphisms in catechol-O-methyltransferase (COMT) influence these cognitive processes we hypothesized that the same polymorphisms may influence gait velocity. We examined the associations between the Val(158)Met polymorphism in COMT and gait velocity as well as attention and executive function. Participants were 278 non-demented older adults. The results revealed that methionine (Met)/valine (Val) was associated with faster gait velocity. This association can be explained by the putative role of the Val allele in regulating tonic dopamine release in the striatum. In contrast, Met/Met was associated with better attention and executive function. Stratification by gender revealed that the association between COMT genotype and gait was significant only in men. Conversely, the association between COMT genotype and attention and executive function was significant only in women. These findings suggest a differential effect in relating the Val(158)Met polymorphism to gait and to cognitive function while supporting the previously described sexual dimorphism in the phenotypic expressions of COMT.     

Catechol O-methyl transferase and dopamine D2 receptor gene polymorphisms: evidence of positive heterosis and gene-gene interaction on working memory functioning

The COMT Val(108/158)Met polymorphism has been extensively studied in relation to individual differences in working memory (WM) performance. The present study tested the association of the COMT Val(108/158)Met polymorphism with WM performance in two independent family-based Dutch samples: 371 children (mean age 12.4 years) and 391 adults (mean age 36.2 years). A significant association was found between the COMT polymorphism and WM scores in the combined adult and young cohorts. The association reflected positive heterosis such that the Met/Met and Val/Val homozygotes did not perform as well as the Met/Val heterozygotes on the WM tasks. A secondary analysis was conducted in which a DRD2-tagging SNP (rs2075654) was tested for an interactive effect with the COMT polymorphism on WM performance. A significant interactive effect of the DRD2 and COMT genes was found such that heterosis was present only in the DRD2 genotype that has been linked to lower receptor density. Our results support previous findings that WM performance needs an optimal level of dopamine signaling within the PFC. This optimum level depends on enzymatic activity controlling dopamine level as well as dopamine receptor sensitivity, both of which may differ as a function of age and genotype. We conclude that the effects of a single polymorphism in a dopaminergic gene on a well-defined cognitive trait may easily remain hidden if the interaction with age and other genes in the pathway are not taken into account.     

Irritable assault and variation in the COMT gene

Aggression is associated with the 'low' activity allele (Met) of the functional Val158Met polymorphism among people with schizophrenia spectrum disorders relative to the 'high' activity (Val) allele. We examined this polymorphism in a sample of 112 people with axis II personality disorders. Participants completed the Buss Durkee Hostility Inventory. Two single nucleotide polymorphisms in the COMT gene were genotyped in these participants classified as 'white' according to US Census Bureau definitions. We failed to observe an association between the Val158Met allele and aggression but observed an association between self-reported aggression and the G allele of a biallelic polymorphism located in the 3' UTR (rs16559). This allele is less prevalent among schizophrenics and is associated with lower COMT expression in the brain. These findings provide limited support for a role of COMT in modulating aggressive behavior, and are extended to people with personality disorders.     

Effects of serotonin transporter promoter and BDNF Val66Met genotype on personality traits in a population representative sample of adolescents

The purpose of this study was to investigate the effects of the 5-HTTLPR and brain-derived neurotrophic factor (BDNF) Val66Met polymorphisms on self-reported Big Five personality traits and their facets in a population representative sample of adolescents. The sample consisted of both cohorts of the Estonian Children Personality Behaviour and Health Study, and personality data were collected during its second waves. The 5-HTTLPR and BDNF Val66Met polymorphisms were genotyped. The BDNF Val66Met had a significant effect on conscientiousness [F(1,807)=4.32, P=0.038]. We did not find effects of the 5-HTTLPR polymorphism on the main domains of personality, however, a gene×gene interaction on conscientiousness emerged -BDNF Val66Met Met-allele carriers with the 5-HTTLPR s/s genotype had by far the lowest scores in conscientiousness [F(2,803)=4.38, P=0.012]. In addition, we found genotype effects on some facet scales. In conclusion, the BDNF Val66Met genotype Met-allele carriers have lower conscientiousness, and this effect is increased in the 5-HTTLPR s/s individuals.     

No association between the Catechol-O-Methyltransferase (COMT) val158met polymorphism and cognitive improvement following cognitive remediation therapy (CRT) in schizophrenia

Cognitive deficits are rate limiters on recovery in schizophrenia that respond poorly to pharmacotherapy. Cognitive remediation therapy (CRT), a novel psychological therapy, has produced promising outcomes for cognition. However, little is known about the biological mechanisms that might underlie individual differences in CRT response. Catechol-O-Methyltransferase (COMT) is associated specifically with prefrontal cognition. The COMT Val158Met polymorphism is known to have a functional effect on the rate of dopamine degradation, which may be related to cognitive treatment response. This study aimed to determine whether COMT genotype influences cognitive improvement following CRT in schizophrenia. Participants with schizophrenia were recruited from three randomised controlled trials of CRT compared to treatment as usual, and one CRT treatment only trial, each providing 40 CRT sessions. Eighty-seven participants (40%) agreed to participate in the genetic study, and provided DNA for COMT genotyping. Cognitive function and psychopathology were assessed at baseline, post-treatment and 3-6-month follow-up. People with the COMT Val/Met genotype performed more poorly on categories achieved at baseline on the Wisconsin Card Sorting Test (WCST) than those homozygous for the Val or Met allele. Cognitive function improved with CRT but there was no association between this cognitive improvement and COMT genotype, either in the CRT group or in the total sample. The COMT val158Met polymorphism does not appear to be a clinically useful biomarker of cognitive improvement following CRT in schizophrenia. A complex set of factors may influence cognitive change, however, such that the COMT genotype might still have a subtle effect on response to CRT or similar interventions.     

Catechol-O-methyltransferase Val158Met genotype variation is associated with prefrontal-dependent task performance in schizotypal personality disorder patients and comparison groups

OBJECTIVE: A single-nucleotide polymorphism of the gene coding for catechol-O-methyltransferase (COMT Val(158)Met) is associated with prefrontal-dependent task performance in schizophrenia. We evaluated the relationship of the COMT genotype with diagnostic status and cognitive performance in schizotypal personality disorder. METHODS: Unmedicated outpatients with schizotypal personality disorder (SPD; n = 67) and non-schizotypal personality disorder (NSPD; n = 154) by DSM-III-R, and normal control (NC; n = 60) participants were genotyped at the COMT Val(158)Met locus. Of these, 98 Caucasians (23 SPD, 52 NSPD and 23 NC) performed a brief neurocognitive battery: Wisconsin Card Sorting Test (WCST), Paced Auditory Serial Addition Test (PASAT), California Verbal Learning Test (CVLT), Visuospatial Working Memory (DOT) and Visual Delayed Recall (Wechsler Memory Scale Visual Reproduction, WMS-VR). RESULTS: Allele distribution was not significantly different in the full sample (by chi(2)) for the SPD group compared with either the NC or combined NC/NSPD groups. In analyses of variance of Caucasian individuals, the SPD group performance met or approached significantly worse performance than NC, NSPD or both groups, on the PASAT, CVLT and WMS-VR. In regression analyses of cognitive performance, the COMT genotype was significantly associated with performance on WCST and PASAT, independent of diagnosis, with the Val/Val genotype associated with the worse performance. CONCLUSIONS: (1) Allelic variation in COMT activity is unrelated to the diagnosis of SPD in this sample. (2) Individuals with SPD exhibit multiple deficits in prefrontal and temporal lobe-dependent tasks. (3) The COMT genotype is related to performance on prefrontal cortex-dependent tasks and may contribute to the deficit in prefrontal-dependent memory processes in SPD as it does in schizophrenia.     

Influence of catechol-O-methyltransferase Val158Met polymorphism on neuropsychological and functional outcomes of classical rehabilitation and cognitive remediation in schizophrenia

Neurocognitive deficits are recognized as core features of schizophrenia and have a great impact on functional outcome. Recent reports have suggested that a functional polymorphism, Val158Met, of the catechol-O-methyltransferase (COMT) gene, partially influences cognitive performances (mainly cognitive flexibility and working memory) both in schizophrenic patients and in healthy controls, probably by modulating prefrontal dopamine function. While previous studies focused on single evaluation of cognitive functioning, we aimed to analyse the additive effect of COMT genotype and cognitive exercise on dynamic modulation of cognitive performances. We analysed the COMT Val158Met polymorphism in 50 patients with chronic schizophrenia randomly allocated to two treatment conditions for 3 months: standard rehabilitation treatment (SRT) alone and SRT plus specific cognitive exercise of impaired functions. We then divided our sample in four subgroups on the basis of genotype (Val/Val versus Met carriers) and treatment (placebo versus active). We assessed patients with a neuropsychological battery, the Positive and Negative Symptoms Scale (PANSS) and the Quality of Life Scale (QLS) at enrolment, after 3 months of therapy and after further 3 months of follow-up. We found significantly greater improvement of cognitive flexibility performance and QLS total score for Met carriers on active treatment in comparison to Val/Val on placebo. The findings support the hypothesis that COMT polymorphism influences individual capacity to recover from cognitive deficit through rehabilitation therapy after a wider intervention also including deficit-specific cognitive exercise as a potentiating tool.     

TIM-4基因多态性与湖北地区汉族人群支气管哮喘易感性的研究

目的 探讨T细胞免疫球蛋白域及黏蛋白域蛋白-4(T cells immunoglobulindomain andmucindomain protein-4,TIM-4)基因外显子2区Lys65Lys(G/A)、外显子9区Val1365Met(G/A)的单核昔酸多态性(SNP)与湖北地区汉族人群支气管哮喘易感性的关系.方法 采用聚合酶链反应-限制性片段长度多态性(PCR-RFLP)的方法对湖北地区185例哮喘患者和162例健康者TIM-4基因外显子2区Lys65Lys(G/A)、外显子9区Vai365Met(G/A)的多态性进行分析,计算基因型和等位基因频率.结果 (1)湖北地区汉族人群健康者TIM-4基因外显子2区Lys65Lys(G/A)位G/G、G/A、A/A基因型频率分别为0.840、0.160、0,而哮喘人群其频率分别为0.859、0.141、0,其基因型和等位基因型频率与对照组相比差异均无统计学意义(P=0.603,P=0.618);(2)本试验未检测到TIM-4外显子9区Va1365Met(G/A)的多态性.结论 湖北地区汉族人群TIM-4基因外显子2区Lys65Lys(G/A)存在单核苷酸多态性变异,但该位点的变异与湖北地区汉族人群支气管哮喘易感性无关;TIM-4基因外显子9区Va1365Met(G/A)在湖北地区汉族人群中未发现单核苷酸多态性.     

Schizotypal dimensions: an intermediate phenotype associated with the COMT high activity allele.

BACKGROUND: Although catechol-O-methyltransferase (COMT) has long been suggested to be implicated in the pathogenesis of schizophrenia, association studies have generated discrepant results concerning the involvement of the COMT gene in schizophrenia. As several studies have suggested that schizotypal traits might be genetically related to schizophrenia, increased statistical power to detect gene effects could be obtained by using dimensional personality traits in unaffected relatives. METHODS: We tested the hypothesis that the functional Val158Met COMT polymorphism might contribute to the variance of self-reported schizotypal scores in a sample of 106 unaffected subjects, composed of controls (N = 57), first-degree relatives of schizophrenic (N = 27) and of bipolar (N = 22) probands. We also looked for specific associations between COMT polymorphisms and the three dimensions of schizotypy (positive, negative, disorganized) assessed by the Schizotypal Personality Questionnaire (SPQ). RESULTS: We found that self-reported SPQ scores are related to COMT genotype (P = 0.01), with individuals homozygous for the high activity allele having the highest scores. This association is primarily due to specific associations with the positive (P = 0.001) and negative (P = 0.04) dimensions. CONCLUSIONS: Our data support the hypothesis that the functional COMT polymorphism could be involved in different psychotic dimensions. This confirms that studying specific schizotypal dimensions can help to identify the genes involved in the pathogenesis of psychosis.     

Association study of a functional catechol-o-methyltransferase polymorphism and smoking in healthy Caucasian subjects

Tobacco smoking is a global health problem. The association of a functional common polymorphism in the catechol-o-methyltransferase gene (COMT Val158Met) with smoking behavior has been extensively studied, but with divergent findings. In the present study the frequency of COMT genotypes and alleles was evaluated in 578 male and a smaller group of 79 female unrelated, medication-free Caucasian healthy subjects of Croatian origin. Smokers were classified as subjects smoking ≤10 cigarettes per day, while subjects who never smoked in their life were regarded as nonsmokers. A χ²-test with standardized residuals and Bonferroni correction revealed significant (P = 0.017) differences in Met/Met, Met/Val or Val/Val genotype frequency between male smokers and nonsmokers. This significant association between COMT Val158Met polymorphism and smoking was not detected in female subjects, due to the small number of women, which represents a limitation of the study. Our results confirmed the significant association between COMT variants and smoking, which was due to the higher frequency of Val/Val homozygotes in male smokers compared to male nonsmokers. These results suggest that carriers of the high activity COMT variant are more prone to develop a higher level of nicotine dependence, or that they release more dopamine than carriers of Met/Met or Met/Val genotypes.     

No associations exist between five functional polymorphisms in the catechol-O-methyltransferase gene and schizophrenia in a Japanese population

Catechol-O-methyltransferase (COMT) is one of the enzymes that degrade catecholamine neurotransmitters including dopamine. The COMT gene is located on 22q11.2, a common susceptibility locus for schizophrenia. Therefore, COMT is a strong functional and positional candidate gene for schizophrenia. A common functional polymorphism (rs4680, Val158Met) has been extensively tested for an association with schizophrenia, but with conflicting results. Recent studies indicate that if COMT is implicated in susceptibility to schizophrenia, this cannot be wholly accounted for by the Val158Met polymorphism. To assess this view, the authors conducted a case-control association study (399 patients with schizophrenia and 440 control subjects) for five functional polymorphisms (rs2075507, rs737865, rs6267, rs4680 and rs165599) in Japanese subjects. There were no significant associations found between the polymorphisms or haplotypes of COMT and schizophrenia. The present study shows that these five functional COMT polymorphisms do not play a major role in conferring susceptibility to schizophrenia in Japanese.     

注意缺陷多动障碍与儿茶酚-O-甲基转移酶基因的关联分析

目的：分析COMT基因多态性与ADHD的关联;寻找ADHD的易感基因。方法：采用PCR-RFLP技术,检测54名ADHD患者及其父母（n=82）和正常对照者（n=30）COMT基因Val158Met多态性的基因型和等位基因频率,运用病例对照研究和核心家系的关联分析（HRR和TDT）方法分别进行分析。结果：Val158Met多态性的各基因型和等位基因频率在ADHD组与对照组以及核心家系中的分布差异均无显著性（均P〉0．05）。注意缺陷为主型患儿COMT基因的G／G型频率和G等位基因频率明显高于混合型的（P〈0．05）,A等位基因与ADHD的某些临床症状如注意问题、违纪行为、攻击行为等相关。结论：（1）COMT基因可能与ADHD缺乏关联。仅起微效基因的作用：（2）COMT可能与ADHD临床亚型或临床症状有关。     

Association study of a functional catechol-O-methyltransferase-gene polymorphism and cognitive function in healthy females

Using the Wisconsin Card Sorting Test, it has been determined, that the catechol-O-methyltransferase (COMT) Val158Met genetic polymorphism, a functional polymorphism that may affect dopamine metabolism, is associated with prefrontal cognitive function. This study of a cohort of 120 healthy young Chinese females attempted to utilize P300 event-related potentials to replicate this finding and to test the relationship between this COMT polymorphism and cortical physiology. The results demonstrate that subjects bearing the Met/Met homozygote have significantly lower mean P300 latencies than do analogs bearing the Val allele. A significant association between this COMT polymorphism and perseverative errors was not demonstrated in the Wisconsin Card Sorting Test, however. We suggest that, although the COMT Val158Met genetic polymorphism may play a role in cognitive function, ethnicity and testing method may affect the association. Since statistical relationships between P300 components and both the COMT genetic polymorphism and schizophrenic disorders have been demonstrated, it seems reasonable to suggest that this COMT genetic variant may affect the P300 abnormality in schizophrenia.     

The high-activity Val allele of the catechol-O-methyltransferase gene predicts greater cognitive deterioration in patients with psychosis

The objective of this study was to examine whether the functional genetic polymorphism Val158Met in the catechol-O-methyltransferase (COMT) gene influences cognitive deterioration in a sample of patients with psychosis under treatment with atypical antipsychotics. Eighty-seven patients with psychosis were genotyped for this polymorphism and were assessed with three Wechsler Adult Intelligence Scale (WAIS)-III subtests (Vocabulary, Information, and Digit Symbol-Coding). Performance on these three subtests was used to compute a 'cognitive deterioration index', and the effect of COMT genotype on this cognitive deterioration index was examined. A linear relationship between the number of Val alleles and the score on the cognitive deterioration index (i.e. the more Val alleles, the more cognitive deterioration) was observed. These results confirm the role of COMT genotype in the cognition of patients under treatment for psychosis, suggesting that it influences the extent of their cognitive deterioration.     

Association between Low-Activity Allele of Cathecolamine-O-Methyl-Transferase (COMT) and Borderline Personality Disorder in an Italian Population

The objective of the present study was to test the association between Borderline Personality Disorder (BPD) and the cathecolamine-O-methyl-transferase (COMT) low-activity (Met158) single nucleotide polymorphism (SNP). In this case-control study, DNA was obtained from venous blood of 19 BPD patients and 36 healthy subjects. COMT-Val158Met single-nucleotide polymorphism was genotyped by predesigned SNP assay. The COMT Met158 allele was over-represented in patients with BPD in comparison to normal subjects (68.4% vs 44.4%, respectively; Fisher exact test, p = .02). In terms of genotype, the Met158Met subjects were more frequent in patients versus controls (47.4% vs 22.2%, respectively), whereas the high-activity genotype Val158Val was under-represented (10.5% vs 33.3%, respectively). The allele encoding for the COMT with low enzymatic efficiency was found to be over-represented in BPD, possibly resulting in excessive synaptic dopaminergic activity and ultimately affecting externalizing behaviours, such as impulsivity and aggressiveness.     

COMT Val158Met moderation of stress-induced psychosis

BACKGROUND: Exposure to stressful life events increases the risk of developing a psychotic disorder. Moreover, increased reactivity to stress seems to represent part of the vulnerability for psychosis. This study aimed to investigate whether a functional polymorphism in the catechol-O-methyltransferase (COMT Val(158)Met) gene moderates the psychosis-inducing effects of stress. METHOD: A semi-experimental stress exposure paradigm was used in a sample of 306 genotyped young men (aged 19-24 years), in whom measures of psychotic symptoms were obtained at recruitment in the Greek army (exposed condition) and again after 18 months of military training (unexposed condition). RESULTS: Stress exposure at army induction was associated with an increased level of psychotic symptoms. In addition, carriers of the COMT Val(158)Met Val allele were more susceptible to the effect of stress on the psychosis outcome than those with the Met/Met genotype (test for interaction: chi2 = 5.02, df = 1, p = 0.025). CONCLUSION: The COMT Val(158)Met genotype may moderate the effect of stress on psychotic symptoms.