Executive attention in schizophrenic males and the impact of COMT Val108/158Met genotype on performance on the attention network test

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) Val^108/158Met, 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 Val^108/158Met 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 Val^108/158Met 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 Val^108/158Met on cognitive performance.     

Prefrontal dopamine and the dynamic control of human long-term memory

Dopaminergic projections to the prefrontal cortex support higher-order cognitive functions, and are critically involved in many psychiatric disorders that involve memory deficits, including schizophrenia. The role of prefrontal dopamine in long-term memory, however, is still unclear. We used an imaging genetics approach to examine the hypothesis that dopamine availability in the prefrontal cortex selectively affects the ability to suppress interfering memories. Human participants were scanned via functional magnetic resonance imaging while practicing retrieval of previously studied target information in the face of interference from previously studied non-target information. This retrieval practice (RP) rendered the non-target information less retrievable on a later final test—a phenomenon known as retrieval-induced forgetting (RIF). In total, 54 participants were genotyped for the catechol-O-methyltransferase (COMT) Val^108/158Met polymorphism. The COMT Val^108/158Met genotype showed a selective and linear gene-dose effect on RIF, with the Met allele, which leads to higher prefrontal dopamine availability, being associated with greater RIF. Mirroring the behavioral pattern, the functional magnetic resonance imaging data revealed that Met allele carriers, compared with Val allele carriers, showed a greater response reduction in inhibitory control areas of the right inferior frontal cortex during RP, suggesting that they more efficiently reduced interference. These data support the hypothesis that the cortical dopaminergic system is centrally involved in the dynamic control of human long-term memory, supporting efficient remembering via the adaptive suppression of interfering memories.     

COMT Val158Met polymorphism is related with interpersonal problem solving in schizophrenia

ObjectiveThe aim of this study was to investigate associations between COMT Val¹⁵⁸Met polymorphism, and interpersonal problem solving capacity and cognitive functions in schizophrenia.MethodsCOMT Val¹⁵⁸Met polymorphism was studied with ARMS-PCR method in 99 outpatients with schizophrenia. Brief Psychiatric Rating Scale was used to assess symptom severity. The Assessment of Interpersonal Problem Solving Skills (AIPSS) was used to evaluate problem solving capacity. Continuous Performance Test (CPT) and Wisconsin Card Sorting Test (WCST), were used to measure cognition.ResultsPatients with Met/Met genotype had higher AIPSS subscores for detecting the problem, than those with Val/Val at baseline (p = 0.02). Met allele was also found to be related with higher AIPSS-receiving skills (p = 0.04). Val allele was found to be related with more commission errors in CPT (p = 0.03). There was no relation between Val¹⁵⁸Met polymorphism and WCST and clinical measurements.ConclusionOur findings suggest that Val allele might be related to poor performance on detecting the interpersonal problems, and attention in schizophrenia.     

Impact of COMT Val158Met‐polymorphism on appetitive conditioning and amygdala/prefrontal effective connectivity

Appetitive conditioning is an important mechanism for the development, maintenance, and treatment of psychiatric disorders like substance abuse. Therefore, it is important to identify genetic variations, which impact appetitive conditioning. It has been suggested that the Val¹⁵⁸Met‐polymorphism in the Catechol‐O‐Methyl‐Transferase (COMT) is associated with the alteration of neural processes of appetitive conditioning due to the central role of the dopaminergic system in reward processing. However, no study has so far investigated the relationship between variations in the COMT Val¹⁵⁸Met‐polymorphism and appetitive conditioning. In this fMRI study, an appetitive conditioning paradigm was applied, in which one neutral stimulus (CS+) predicted appetitive stimuli (UCS) while a second neutral stimulus (CS?) was never paired with the UCS. As a main result, we observed a significant association between the COMT Val¹⁵⁸Met‐genotype and appetitive conditioning: skin conductance responses (SCRs) revealed a significant difference between CS+ and CS? in Val/Val‐allele carriers but not in the other genotype groups. Val/Val‐allele carriers showed increased hemodynamic responses in the amygdala compared with the Met/Met‐allele group in the contrast CS+ > CS?. In addition, psychophysiological‐interaction analysis revealed increased effective amygdala/ventromedial prefrontal cortex connectivity in Met/Met‐allele carriers. The increased amygdala activity points to facilitated appetitive conditioning in Val/Val‐allele carriers while the amygdala/prefrontal connectivity results could be regarded as a marker for altered emotion regulation during conditioning, which potentially impacts appetitive learning sensitivity. The SCRs finding indicates a stronger conditioned response in the Val/Val‐allele group and dovetails with the neural differences between the groups. These findings contribute to the current research on COMT in emotional processing. Hum Brain Mapp 36:1093–1101, 2015. © 2014 Wiley Periodicals, Inc.     

Association between Novelty Seeking of opiate-dependent patients and the catechol-O-methyltransferase ValMet polymorphism

Background

Candidate genes of the dopaminergic system have been reported as key elements in shaping human temperament. Catechol-O-methyltransferase (COMT) plays a vital role in dopamine inactivation, and the Val¹⁵⁸Met single nucleotide polymorphism (rs4680) in its gene has been recently associated with the Novelty Seeking (NS) temperament scale of the Temperament and Character Inventory in studies of healthy adults, as well as methamphetamine abusers.

Method

Our goal was to examine the association between temperament dimensions of the Temperament and Character Inventory and the COMT Val¹⁵⁸Met variation in a Hungarian sample of 117 heroin-dependent patients and 124 nondependent controls.

Results

Case-control analysis did not show any significant difference in allele or genotype distributions. However, dimensional approach revealed an association between the COMT Val¹⁵⁸Met and NS (P = .01): both controls and opiate users with Met/Met genotypes showed higher NS scores compared to those with the Val allele. The NS scores are also significantly higher among opiate users; however, no interaction was found between group status and COMT genotype.

Conclusion

Association of the COMT polymorphism and NS temperament scale has been shown for heroin-dependent patients and controls regardless of group status.     

COMT Val158Met polymorphism,cognitive stability and cognitive flexibility: an experimental examination

Background  

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.     

Interaction between catechol-O-methyltransferase (COMT) Val108/158Met and brain-derived neurotrophic factor (BDNF) Val66Met polymorphisms in age at onset and clinical symptoms in schizophrenia

Summary. Catechol-O-methyltransferase (COMT) gene is one of the candidate genes for schizophrenia because it codes an enzyme that participates in the metabolic inactivation of dopamine and noradrenaline and a limiting factor of dopamine metabolism in the prefrontal cortex. COMT gene lies on chromosome 22q11.2, which has been associated with schizophrenia susceptibility. A single-nucleotide polymorphism of COMT gene at position 108/158 results in an amino acid substitution from valine (val) to methionine (met), which modifies its enzymatic activity and may change the brain morphology and expressional behaviors. On the other hand, brain-derived neurotrophic factor (BDNF) plays a critical role in the development of mesolimbic dopaminergic- related systems. BDNF also contains a functional single-nucleotide polymorphism at codon 66 (Val66Met) of its prodomain and this polymorphism is responsible for schizophrenia susceptibility. In this study, we first investigated the relationship between COMT Val108/158Met polymorphism and age at onset as well as levels of clinical symptoms in 158 of chronic schizophrenia inpatients and then we investigated the gene-by-gene interaction between COMT Val108/158Met polymorphism and BDNF Val66Met polymorphism with age- and sex-matched control subjects (n = 318). We concluded that the COMT Val108/158Met polymorphism was not related to either the onset at age or the levels of clinical symptoms after long-term antipsychotic treatment in schizophrenia.     

The catechol o‐methyltransferase (COMT) val158met polymorphism modulates the association of serious life events (SLE) and impulsive aggression in female patients with borderline personality disorder (BPD)

Wagner S, Baskaya Ö, Anicker NJ, Dahmen N, Lieb K, Tadi? A. The catechol o‐methyltransferase (COMT) val¹⁵⁸met polymorphism modulates the association of serious life events (SLE) and impulsive aggression in female patients with borderline personality disorder (BPD). Objective: We analyzed i) the effects of serious life events (SLE) on impulsive aggression, and ii) modulating effects of the COMT Val¹⁵⁸Met polymorphism on the association between SLEs and impulsive aggression in borderline personality disorder (BPD). Method: One hundred and twelve female BPD patients from Germany were included in this study. Impulsive aggression was assessed by the Buss‐Durkee‐Hostility Inventory (BDHI). Results: Childhood sexual abuse was associated with lower BDHI sum score (P = 0.003). In COMT Val¹⁵⁸Val carriers, but not in Val/Met and Met/Met carriers, childhood sexual abuse and the cumulative number of SLEs were associated with lower BDHI sum scores (P < 0.05). Conclusion: This study analyzing a specific gene × environment interaction in female BPD patients suggests an association between SLEs and impulsive aggression, as well as a modulating effect of the COMT Val¹⁵⁸Val genotype on the relation between SLEs and impulsive aggression.     

The COMT Val158Met polymorphism does not modulate the after‐effect of tDCS on working memory

Transcranial direct current stimulation (tDCS) can alter cortical excitability, neural plasticity, and cognitive‐behavioral performance; however, its effects are known to vary across studies. A partial account of this variability relates to individual differences in dopamine function. Indeed, dopaminergic manipulations alter the physiological and cognitive‐behavioral effects of tDCS, and gene polymorphisms related to dopamine have predicted individual response to online tDCS (i.e., stimulation overlapping with the critical task). Notably, the role of individual differences in dopamine has not yet been properly assessed in the effect of offline tDCS (i.e., stimulation prior to the critical task). We investigated if and how the COMT Val¹⁵⁸Met polymorphism (rs4680) modulates the after‐effect of prefrontal tDCS on verbal working memory (WM). One hundred and thirty‐nine participants were genotyped for the COMT Val¹⁵⁸Met polymorphism and received anodal‐over‐left, cathodal‐over‐right (AL‐CR), cathodal‐over‐left, anodal‐over‐right (CL‐AR), or sham stimulation over the dorsolateral prefrontal cortex in a between‐subjects, pretest–posttest study design. WM was assessed using the N‐back task. The results provide no evidence that the COMT polymorphism impacts the after‐effect of prefrontal tDCS on WM. Taken together with previous findings on dopamine and tDCS interactions, the results of the present study suggest that (a) indirect markers of dopamine (such as COMT) are differently related to online and offline effects of tDCS, and (b) findings from studies involving pharmacological manipulation should be generalized with caution to findings of inter‐individual differences. In sum, we argue that state (i.e., a manipulation of) and trait (i.e., baseline) differences in dopamine may exert different effects on online and offline tDCS.     

Lack of association between COMT gene and deficit/nondeficit schizophrenia

Background  

The dopamine dysregulation hypothesis of schizophrenia posits that positive, negative and cognitive symptoms correlate with cortical/subcortical imbalances in dopaminergic transmission. A functional polymorphism (Val¹⁵⁸Met) in the catechol-O-methyltransferase (COMT) gene is implicated in the pathophysiology of schizophrenia by its effect on prefrontal dopamine transmission, and its unique impact on prefrontal cognitive and behavioral phenotypes. Cognitive impairments and negative symptoms in schizophrenia have been hypothesized to be associated with hypodopaminergic states. Schizophrenia patients with the deficit syndrome are characterized by primary enduring negative symptoms, impairment on neurocognitive tasks sensitive to frontal and parietal cortical functioning, and poorer functional outcome compared to non-deficit patients.     

Catechol-O-methyltransferase gene and obsessive-compulsive symptoms in patients with recent-onset schizophrenia: preliminary results

The catechol-O-methyltransferase (COMT) gene is a candidate gene for schizophrenia because of its role in the breakdown of dopamine in the prefrontal cortex. The COMT gene contains a functional polymorphism changing enzyme activity that has been associated with some neuropsychiatric (endo)phenotypes, e.g. cognitive performance and anxiety. In this study we investigated the association between the COMT Val(158)Met polymorphism and obsessive-compulsive symptoms in patients with schizophrenia. Severity of obsessive-compulsive symptoms in 77 male patients with recent-onset schizophrenia was assessed using the Yale-Brown Obsessive-Compulsive Scale (Y-BOCS), and the COMT Val(158)Met polymorphism was genotyped for these patients. We found a significant effect of the COMT genotype on Y-BOCS scores: the Val/Val genotype was associated with the highest Y-BOCS scores, whereas patients with the Met/Met genotype had the lowest Y-BOCS scores. Our data suggest that the COMT high-activity Val allele is associated with more obsessive-compulsive symptoms in young patients with schizophrenia. These results support the hypothesis that the COMT Val(158)Met polymorphism may be a modifier gene for the symptomatology of schizophrenia.     

Catechol-o-methyl transferase modulates cognition in late life: evidence and implications for cognitive enhancement

Aging is associated with deficits in several cognitive domains as well as a decline in brain dopamine activity. Catechol-O-methyl transferase (COMT), an enzyme involved in the degradation of dopamine, is a critical determinant of the availability of this neurotransmitter in the prefrontal cortex. A functional single nucleotide polymorphism in the COMT gene, Val158Met, modulates the activity of this enzyme and affects cognition and the brain regions underlying this function. The effects of COMT Val158Met polymorphism are magnified in the aging brain. Here, we review the evidence supporting a role of COMT genetic variation in cognitive as well as structural and functional brain changes associated with senescence. We will address the potential modulatory role of genetic and non-genetic factors on the neural and cognitive effects of COMT Val158Met in late life. Furthermore, we will discuss the viability of a COMT-targeted treatment for improving cognitive efficiency in aging.     

COMT ValMet moderation of cannabis-induced psychosis: a momentary assessment study of 'switching on' hallucinations in the flow of daily life

Objective: A functional polymorphism in the catechol‐o‐methyltransferase gene (COMT Val¹⁵⁸Met) may moderate the psychosis‐inducing effects of cannabis. In order to extend this finding to dynamic effects in the flow of daily life, a momentary assessment study of psychotic symptoms in response to cannabis use was conducted. Method: The experience sampling technique was used to collect data on cannabis use and occurrence of symptoms in daily life in patients with a psychotic disorder (n = 31) and healthy controls (n = 25). Results: Carriers of the COMT Val¹⁵⁸Met Val allele, but not subjects with the Met/Met genotype, showed an increase in hallucinations after cannabis exposure, conditional on prior evidence of psychometric psychosis liability. Conclusion: The findings confirm that in people with psychometric evidence of psychosis liability, COMT Val¹⁵⁸Met genotype moderates the association between cannabis and psychotic phenomena in the flow of daily life.     

Influence of COMT genotype and affective distractors on the processing of self-generated thought

The catechol-O-methyltransferase (COMT) enzyme is a major determinant of prefrontal dopamine levels. The Val¹⁵⁸Met polymorphism affects COMT enzymatic activity and has been associated with variation in executive function and affective processing. This study investigated the effect of COMT genotype on the flexible modulation of the balance between processing self-generated and processing stimulus-oriented information, in the presence or absence of affective distractors. Analyses included 124 healthy adult participants, who were also assessed on standard working memory (WM) tasks. Relative to Val carriers, Met homozygotes made fewer errors when selecting and manipulating self-generated thoughts. This effect was partly accounted for by an association between COMT genotype and visuospatial WM performance. We also observed a complex interaction between the influence of affective distractors, COMT genotype and sex on task accuracy: male, but not female, participants showed a sensitivity to the affective distractors that was dependent on COMT genotype. This was not accounted for by WM performance. This study provides novel evidence of the role of dopaminergic genetic variation on the ability to select and manipulate self-generated thoughts. The results also suggest sexually dimorphic effects of COMT genotype on the influence of affective distractors on executive function.     

A functional polymorphism in the COMT gene and performance on a test of prefrontal cognition

OBJECTIVE: In the prefrontal cortex, the enzyme catechol O-methyltransferase (COMT) is critical in the metabolic degradation of dopamine, a neurotransmitter hypothesized to influence human cognitive function. The COMT gene contains a functional polymorphism, Val158Met, that exerts a fourfold effect on enzyme activity. The current study investigated whether prefrontal cognition varies with COMT genotype. METHOD: Val158Met was genotyped in 73 healthy volunteers. A task of prefrontal cognition, the Wisconsin Card Sorting Test, was also administered. RESULTS: Subjects with only the low-activity met allele made significantly fewer perseverative errors on the Wisconsin Card Sorting Test than did subjects with the val allele. CONCLUSIONS: These data are consistent with those of previous studies, suggesting that a functional genetic polymorphism may influence prefrontal cognition.     

Catechol-O-methyltransferase Val158Met polymorphism and hyperactivity symptoms in Egyptian children with autism spectrum disorder

Catechol-O-methyltransferase (COMT) plays an important role in the catabolism of brain dopamine and norepinephrine, which have been implicated in the pathogenesis of Autism spectrum disorder (ASD) as well as in other neuropsychatric disorders. We aimed to investigate the association of COMT Val158Met gene polymorphism with ASD and to examine the influence of such genotypes on hyperactivity symptoms in ASD patients. Eighty ASD patients (mean age 9 ± 1.9 years) and 100 control children (mean age 8.9 ± 1.9 years) were examined. COMT Val58Met polymorphism was genotyped using Tetra-primer ARMS-PCR method. The clinical diagnosis of ASD and ADHD were confirmed according to the DSM-IV criteria for research. We found no significant difference in genotypes or alleles’ frequencies of COMT Val158Met polymorphism between ASD patients and control group. There was a significant association between COMT (Val/Val) genotype and both increasing CARS (p = 0.001) and hyperactivity scores (p = 0.006). Regarding Conner's Score, the DSM-IV hyperactive impulsive were significantly higher in Val/Val genotype than both Met/Val and Met/Met genotypes (p = 0.03). Our data suggested an association between COMT Val58Met polymorphism and hyperactivity symptoms in Egyptian children with ASD.     

Impact of catechol-O-methyltransferase Val(108/158) Met genotype on hippocampal and prefrontal gray matter volume

A variation in catechol-O-methyltransferase (COMT) gene (Val(108/158)Met) affects the physiological response of hippocampal-prefrontal circuits, predicts variation in human memory and is associated with increased risk for psychiatric disorders. Using optimized voxel-based morphometry we studied the effect of this functional polymorphism on the anatomy of the hippocampus, and the prefrontal cortex. Fifty-seven healthy participants were investigated (nine had Met/Met, 30 Val/Met, and 14 Val/Val). Voxel-based morphometry showed that individuals who are homozygous for the Val-COMT allele had greater gray matter volume of the prefrontal cortex bilaterally, whereas Met-COMT carriers were associated with increased tissue volume of the hippocampus bilaterally. This study provides evidence that the Val(108/158)Met polymorphism of the COMT gene might be responsible for individual variation in the human brain morphology.     

Effect of COMT Val108/158Met Genotype on Risk for Polydipsia in Chronic Patients with Schizophrenia

Polydipsia is a serious condition often seen among patients with schizophrenia (SCZ). The cause of polydipsia is unknown; hence, it is hard to treat or manage. Animal studies showed that the drinking behavior is regulated by central dopaminergic neurotransmission at the hypothalamus. Meanwhile, the existence of a genetic predisposition to polydipsia in patients with SCZ has been suggested. The purpose of this study was to assess whether a functional polymorphism, Val^108/158Met in the gene for catechol-O-methyltransferase (COMT), is associated with susceptibility to polydipsia using a Japanese sample of SCZ. Our sample includes 330 chronic patients with SCZ (83 polydipsic patients and 247 non-polydipsic controls). The common COMT Val^108/158Met polymorphism was genotyped, and the differences in genotype distribution and allele frequency between cases and controls were evaluated using the χ ² test. A significant association between the COMT Val^108/158Met polymorphism and polydipsia was found (genotype distribution: χ ² = 13.0, df = 2, p = 0.001; allele frequency: χ ² = 7.50, df = 1, p = 0.006). The high-COMT activity group (Val/Val) was more frequent among patients with polydipsia compared with the low-COMT activity group (Val/Met + Met/Met) [odds ratio (OR) = 2.46]. The association survived after controlling for other possible confounding factors, including gender, age, age of onset, current antipsychotic dose, and smoking status. Our results suggest that the COMT Val^108/158Met genotype may confer susceptibility to polydipsia in SCZ. To our knowledge, this is the first association study between the COMT gene and polydipsia in SCZ. Further studies with larger sample sizes are warranted to confirm present findings.     

Association study of a functional catechol-O-methyltransferase genetic polymorphism with age of onset, cognitive function, symptomatology and prognosis in chronic schizophrenia

The gene coding for catechol-O-methyltransferase (COMT), which is involved in the metabolism of catecholamines, has long been implicated as a candidate gene for schizophrenia. This study aimed to assess the relationship between a functional polymorphism (Val158Met) of the COMT gene and age of onset (AOO), symptomatology, global cognitive function and prognosis in patients with schizophrenia. The study enrolled 154 patients with schizophrenia from chronic wards. Results failed to show a significant association between the Val158Met polymorphism and the Brief Psychiatric Rating Scale scores, Mini-Mental State Examination scores, and Social and Occupational Functioning Assessment Scale scores, but COMT Val158Met heterozygotes had a later AOO than homozygous patients. However, by further expanding the number of patients to 228 patients, the differences in AOO among the three COMT genotypic groups was not significant. The COMT Val158Met polymorphism did not appear to significantly affect susceptibility, symptomatology, global cognitive function and prognosis in Chinese patients with schizophrenia, but the possible association with AOO merits further investigation.     

Catechol O-methyltransferase Val158Met polymorphism in schizophrenia: differential effects of Val and Met alleles on cognitive stability and flexibility

OBJECTIVE: The catechol O-methyltransferase (COMT) Val158Met polymorphism has been associated with cognitive and behavioral phenotypes in schizophrenia. Whether COMT genotype is beneficial may depend on phenotype definition. The authors examined the effects of COMT genotype on a task that distinguishes imitation from reversal learning. They hypothesized that the Val and Met alleles would be associated with deficits in imitation learning and reversal learning, respectively. METHOD: Twenty-six patients with schizophrenia and schizoaffective disorder completed a task requiring alternation between imitation and reversal rules. RESULTS: Met homozygotes showed better acquisition of the imitation rule but greater deficit shifting from imitation to reversal. Val homozygotes had poorer imitation performance and slower reaction times. CONCLUSIONS: The Met allele, by increasing tonic dopamine, may promote cognitive stability but limit cognitive flexibility.