catechol-O-methyltransferase Val158Met Polymorphism Research Articles

Reward system neurodynamics during menstrual pain modulated by COMT Val158Met polymorphisms.

Primary dysmenorrhea (PDM), characterized by cyclic pain, may involve pain modulation within the reward system (RS). The Catechol-O-methyltransferase (COMT) Val158Met polymorphism, which significantly influences dopamine activity, is linked to the regulation of both acute and chronic pain. This study examines the differential neurodynamic modulation in the RS associated with COMT Val158Met polymorphisms during menstrual pain among PDM subjects. Ninety-one PDM subjects underwent resting-state fMRI during menstruation and were genotyped for COMT Val158Met polymorphisms. The amplitude of low-frequency fluctuation (ALFF) and functional connectivity (FC) analyses were used to assess the RS response. Psychological evaluations included the McGill Pain Questionnaire, Pain Catastrophizing Scale, Beck Anxiety Inventory, and Beck Depression Inventory. Val/Val homozygotes (n = 50) and Met carriers (n = 41) showed no significant differences in McGill Pain Questionnaire, Beck Anxiety Inventory, and Beck Depression Inventory. However, Met carriers exhibited lower scores on the Pain Catastrophizing Scale. Distinct FC patterns was observed between Val/Val homozygotes and Met carriers, specifically between the nucleus accumbens (NAc) and prefrontal cortex, NAc and inferior parietal lobe, ventral tegmental area (VTA) and prefrontal cortex, VTA and precentral gyrus, and VTA and superior parietal lobe. Only Met carriers showed significant correlations between ALFF and FC values of the NAc and VTA with pain-related metrics (McGill Pain Questionnaire and Pain Catastrophizing Scale scores). NAc ALFF and NAc-prefrontal cortex FC values positively correlated with pain-related metrics, while VTA ALFF and VTA-prefrontal cortex and VTA-superior parietal lobe FC values negatively correlated with pain-related metrics. This study reveals that the COMT Val158Met polymorphism results in genotype-specific functional changes in the brain's RS during menstrual pain. In Met carriers, engagement of these regions is potentially linked to motivational reward-seeking and top-down modulation. This polymorphism likely influences the RS's responses, significantly contributing to individual differences in pain regulation.

To Each His Own Fear: Gender-Related Association of Anxiety, Substance Use, and Eating Disorders in a Representative Birth Cohort Sample of Young Adults with Either COMT Val158Met allele

Introduction: The role of catechol-O-methyltransferase (COMT) in catecholamine neurotransmitter metabolism has led to the investigation of variants of the corresponding gene in the etiology of different psychiatric disorders, but the results are inconclusive. Methods: We have examined the relationship between COMT Val158Met single nucleotide polymorphism (rs4680) and the occurrence of psychiatric disorders in a highly representative birth cohort sample of young adults in the Estonian Children Personality Behaviour and Health Study (original n = 1,238). The lifetime occurrence of psychiatric disorders at the age of 25 years was assessed with the Mini-International Neuropsychiatric Interview. Results: Both Val- and Met-alleles of the COMT Val158Met were associated with specific psychiatric disorders. Met-allele carriers had a significantly higher occurrence of agoraphobia (3.2% vs. 0.5%; χ² = 4.10; p < 0.05) compared to Val/Val homozygotes. Also, the occurrence of panic disorder was significantly higher in female Met-allele carriers than in Val/Val homozygote females (10.2% vs. 3.6%; χ² = 4.62 p = 0.03). In contrast, the occurrence of generalized anxiety disorder was higher in Val/Val females when compared to Met-allele carriers (12.7% vs. 6.8%; χ² = 4.16; p = 0.04). Also, female Val/Val homozygotes (15.5%) had a higher occurrence of eating disorders than Met-allele carriers (6.1%) of the COMT Val158Met polymorphism (χ² = 10.39; p = 0.002). In the whole sample, Met-allele homozygotes had a higher occurrence of alcohol use and substance use disorders than Val-allele carriers (χ² = 3.62 and 3.68, respectively; p < 0.05). Conclusion: In a regional highly birth cohort representative sample, either COMT rs4680 variant was observed in association with specific psychiatric disorders.

Association between Val158Met polymorphism in the COMT gene with anxiety and heart rate variability in children with irritable bowel syndrome

The aim of this study was to examine the peculiarities of trait anxiety and heart rate variability parameters as well as their relationship depending on the catechol O-methyltransferase (COMT) gene Val158Met polymorphism in children with irritable bowel syndrome. Materials and methods. A total of 26 children aged 6–12 years with a verified diagnosis of irritable bowel syndrome according to the Rome IV criteria were examined. Beforehand, all the patients underwent molecular genetic testing for the COMT Val158met single nucleotide polymorphism by using the polymerase chain reaction-restriction fragment length polymorphism method. Heart rate variability was analyzed via cardiointervalography (Neurosoft) based on short five-minute resting-state ECG recordings. The CMAS (Children’s Manifest Anxiety Scale) test was used to measure trait anxiety levels. The Pearson’s test was used to assess correlations between heart rate variability parameters and anxiety levels. Data were processed using Microsoft Excel 2016 and analyzed with GraphPad (Prism 5.0). Results. Depending on the functional COMT Val158met polymorphism, all the patients were allocated to 3 groups: 8 children with 472 GA (Val/Met) COMT genotype; 10 children with 472 AA (Met/Met) genotype; 8 children with 472 GG (Val/Val) genotype. Time and frequency domain parameters of heart rate variability were significantly different in each group. The highest level of anxiety and the largest percentage of LF component (mainly sympathetic activity) in the structure of heart rate variability was noted among Met/Met carriers. Val/Val carriers had a significantly lower anxiety level and an autonomic imbalance with a higher percentage of HF component (parasympathetic activity). Positive correlations between trait anxiety and heart rate variability parameters were found only in Val/Val and Val/Met groups. Conclusions. Our study has revealed the influence of the COMT Val158met polymorphism on the level of trait anxiety and heart rate variability parameters. It is important for a better understanding of the gut-brain axis dysregulation and impaired stress resilience in children with irritable bowel syndrome. Also, these data could be used to improve current schemes for the treatment of irritable bowel syndrome, supplementing them with activation therapy, psychotherapy, psychopharmacotherapy.

COMT Val158Met and BDNF Val66Met Single-Nucleotide Polymorphisms Are Not Associated With Emotional Distress One Year After Moderate-Severe Traumatic Brain Injury.

Emotional distress is a common, but poorly addressed, feature of moderate-severe traumatic brain injury (TBI). Previously identified sociodemographic, psychological, and injury-related factors account for only a small proportion of the variability in emotional distress post-TBI. Genetic factors may help to further understand emotional distress in this population. The catechol-O-methyltransferase (COMT) Val158 and brain-derived neurotrophic factor (BDNF) 66Met single-nucleotide polymorphisms (SNPs) have been identified as possible contributory factors to outcomes after TBI. We investigated whether the COMT Val158 and BDNF 66Met SNPs were associated with emotional distress 1 year after moderate-severe TBI, and whether these associations were moderated by age, sex, and TBI severity (as measured by the duration of post-traumatic amnesia [PTA]). Moderate-severe TBI survivors (COMT, n = 391; BDNF, n = 311) provided saliva samples after admission to a TBI rehabilitation hospital. At a follow-up interview ∼1 year after injury, participants completed a self-report measure of emotional distress (Hospital Anxiety and Depression Scale; HADS). Multiple linear regression models were constructed for each SNP to predict total scores on the HADS. Neither COMT Val158 nor BDNF 66Met carriage status (carrier vs. non-carrier) significantly predicted emotional distress (COMT, p = 0.49; BDNF, p = 0.66). Interactions of SNP × age (COMT, p = 0.90; BDNF, p = 0.93), SNP × sex (COMT, p = 0.09; BDNF, p = 0.60), SNP × injury severity (COMT, p = 0.53; BDNF, p = 0.87), and SNP × sex × age (COMT, p = 0.08; BDNF, p = 0.76) were also non-significant. Our null findings suggest that COMT Val158 and BDNF 66Met SNPs do not aid the prediction of emotional distress 1 year after moderate-severe TBI, neither in isolation nor in interaction with age, sex and injury severity. The reporting of null findings such as ours is important to avoid publication bias and prompt researchers to consider the challenges of single-gene candidate studies in understanding post-TBI outcomes. Analyses in larger samples that incorporate multiple genetic factors and their relevant moderating factors may provide a greater understanding of the role of genetics in post-TBI emotional distress.

Association of COMT Val158Met Polymorphism with Fibromyalgia in Khartoum State, Sudan.

Fibromyalgia (FM) is a disorder characterized by chronic musculoskeletal pain, fatigue, and cognitive problems. Neurotransmitters, mainly catecholamines, appear to be involved in regulating the etiology of FM. Catechol-O-methyltransferase (COMT) is involved in catabolizing catecholamines such as norepinephrine. The most common variant studied in the COMT gene is the valine (Val) to methionine (Met) substitution at codon 158. This is the first study in Sudan addressing FM cases and genetic susceptibility to the disease. We aimed in this study to investigate the frequency of COMT Val 158 Met polymorphism among patients with FM, rheumatoid arthritis, and in healthy individuals. Genomic DNA from forty female volunteers was analyzed: twenty were from primary and secondary FM patients, ten were from rheumatoid arthritis patients, and ten were from healthy control. FM patients' age was ranging from 25 years to 55 with a mean of 41.14 ± 8.90. The mean age of the rheumatoid arthritis patients and healthy individuals was 31.3 ± 7.5 and 38.6 ± 11.2, respectively. Samples were genotyped for COMT single nucleotide polymorphism rs4680 (Val158Met), using the amplification-refractory mutation system (ARMS-PCR). Genotyping data have been analyzed using the Chi-square and Fisher exact test. The most common genotype among the study participants was the heterozygous Val/Met found in all participants. It was the only genotype found in the healthy participants. The genotype Met/Met was found only in FM patients. The genotype Val/Val was found only in rheumatoid patients. Analyses have shown no association between the Met/Met genotype and FM, and this could be due to a small sample size. In a larger sample size, a significant association could be found as this genotype was shown only by FM patients. Moreover, the Val/Val genotype, which is shown only among rheumatoid patients, might protect them from developing FM symptoms.

COMT rs4680 and DRD2 rs6275 variants and their association with YMRS scores in children with early-onset bipolar disorder

Background and objectivesBipolar disorder (BD) is a clinical status with at least one manic, hypomanic or mixed attacks. Genetic factors take part significantly in early-onset BD (EOBD). Dopamine receptors (DRD) act in neurological mechanisms like motivation, learning, memory, and, control of neuroendocrine signaling. DRD2 receptor has been reported to influence the stability of DRD2 transcript. Catechol-O-Methyl transferase (COMT) inactivates catecholamines and Val158Met variation on COMT has effects on COMT activity. This study aims to explore DRD2 and COMT variants in the clinical development of EOBD. MethodsIn this case-control study, 102 EOBD patients and 168 healthy control subjects were used. DRD2 rs6275 and COMT Val158Met variations were detected by real-time polymerase chain reaction (RT-PCR). Young Mania Rating Scale (YMRS) was utilized to determine the EOBD severity. ResultsFor DRD2 rs6275 and COMT Val158Met polymorphisms, no significant relationship was observed in the genotype and allele frequencies between patient and control groups. Nevertheless, TT genotype carriers of DRD2 rs6275 polymorphism demonstrated significantly increased YMRS scores when compared with CC and CT genotype carriers (p = 0.039). Nevertheless, no significant difference was observed between COMT Val158Met genotypes and YMRS scores. ConclusionsWe suggest that the DRD2 rs6275 TT variant can be associated with symptom severity in children with EOBD and can have a clinical significance in EOBD pathogenesis. However, these results need to be confirmed with larger samples of patient and control groups.

Висока частота гомозиготного генотипу 472АА COMT (Val158) гена катехол-О-метилтрансферази (COMT) у дітей із синдромом подразненого кишечника

Following the biopsychosocial model of medicine, the pathophysiological basis of irritable bowel syndrome (IBS) is a combination of biological, psychoemotional, and psychosocial factors, the contribution of each of them to the development of this disorder remains unclear. Psychoemotinal factors, which are involved in the pathogenesis of IBS, are caused not only by the environment but also by the metabolism of catecholamines, particularly by the functional activity of catechol-O-methyltransferase (COMT). Purpose - to determine the role of Val158Met COMT polymorphism in development of IBS in children; to identify associations between genotype and clinical variant of the disorder and the nature of the provoking factor. Materials and methods. The material for the molecular genetic study were DNA samples obtained from nuclear cells of venous blood of 54 patients aged 6-12 years with diagnosed IBS. In 48 practically healthy children of the same age DNA samples were isolated from buccal epithelial cells. Molecular genetic study of single nucleotide polymorphism rs4680 of COMT gene was performed by polymerase chain reaction followed by analysis of restriction fragment length polymorphism. Microsoft Excel 2016 and GraphPad Prism 5 software were used for statistical analysis. Results. We have revealed significant differences in the distribution of Val158Met COMT genotypes in children with IBS in comparison with the control group. There was established that the 472GА COMT is more prevalent in healthy children and has a protective role in the development of IBS. In contrast, homozygous genotypes 472GG and 472AA, which are associated with changes in functional activity of enzyme COMT, may be considered as the risk factors for IBS (p≤0.0001). Conclusions. Genotype 472АА COMT was mostly detected in сhildren with stress-associated IBS, which is more related to dysnociception, disorders of cognition, and emotional disturbances. The higher prevalence of 472GA COMT heterozygotes among children with postinfectious IBS and IBS associated with antibiotic therapy indicates a less important role for the psychoemotional component and nociceptive disorders in the onset of this disorder (p=0.03). The research was carried out in accordance with the principles of the Helsinki Declaration. The study protocol was approved by the Local Ethics Committee of all participating institutions. The informed consent of the patient was obtained for conducting the studies. No conflict of interests was declared by the authors.

Adverse childhood experience referring to parental relationship is associated with the risk of alcohol dependence and with COMT Val158Met polymorphism, but out of gene-environment interactions

IntroductionGene-environment interactions (GxE) are considered to make a substantial impact on the risk of alcohol dependence (AD).ObjectivesThe aim of the study: to test the associations between the functional polymorphism Val158Met (rs6265) in the catechol-O-methyl transferase (COMT) gene, affecting dopamine neurotransmission, and adverse childhood experiences (ACE) and their GxE interactions with AD risk.MethodsThe study included 149 AD inpatients (mean age 29.9 (SD=3.91), 16.1% females) and 201 healthy volunteers (23.3 (2.48), 30.1% females). The Adverse Childhood Experiences International Questionnaire (ACE-IQ) was used for assessing ACE. COMT Val158Met polymorphism was detected by RT-PCR.ResultsFirst, COMT Val158Met polymorphism was associated only with adverse childhood experience referring o parental relationship (ACE-IQ), but differently in two groups. Healthy minor Met158 carriers have lower scores on the subscale “relationship with parents/guardians” (P) (p=0.025) and “physical neglect” (PN) (p=0.059) vs. homozygous Val158 carriers. However, AD patients - Met158carriers have a tendency to a higher score on the subscale “one or no parents, parental separation or divorce” (PSD) (p=0.078). Then logistic regression revealed associations of these ACE scores with increased AD risk: P (p=0.001, OR=1.186, 95%CI [1.069-1.315]), PN (p=0.024, OR=1.254, 95%CI [1.030-1.526]), and PSD (p=0.016, OR=1.499, 95%CI [1.080-2.082]). No associations of COMT Val158Met alone or in interactions with these ACE-IQ scores with the AD risk were found.ConclusionsAdverse childhood experience referring to parental relationship is associated with alcohol dependence risk and separately with COMT Val158Met, but no clear interactions in frame of GxE has been supported.DisclosureNo significant relationships.

Association of Catechol-O-Methyltransferase Gene rs4680 Polymorphism and Levodopa Induced Dyskinesia in Parkinson's Disease: A Meta-Analysis and Systematic Review.

Long-term levodopa therapy for Parkinson's disease (PD) can cause levodopa induced dyskinesia (LID). Genetic predisposition has a significant role to play in inter-individual heterogeneity in the clinical manifestation of LID. Despite accumulating evidence for the role of COMT gene polymorphism (rs4680) as a genetic basis for LID, to date results have been inconsistent. Early assessment of the Catechol-O-Methyltransferase (COMT) genotype might be helpful to stratify PD patients concerning their individual risk for LID. In this meta-analysis, we have used 9 studies, which were selected through online databases. Statistical analysis was performed using R (v-3.6) software. 5 genetic models have been used in the present study: Allele model (A vs. G), Dominant model (AA+AG vs. GG), Homozygote model (AA vs. GG), Co-dominant/heterozygote model (AG vs. GG), and Recessive model (AA vs. AG + GG). The results indicated a significant association between COMT rs4680 (Val158Met) polymorphism and LID risk. The genotype AA of COMT rs4680 is a risk factor for LID in PD patients under the recessive model (AA vs GG+AG) in the random-effect model. Analysis based on ethnicity showed that COMT rs4680 SNP allele A is a risk factor for LID development in Asian PD patients, while GG genotype is a risk factor for LID development in non-Asian PD patients using different genetic models. The results of the present meta-analysis support that the COMT Val158Met polymorphism is a risk factor for the development of LID in PD patients having ethnic variations.

Interaction between COMT Val158 Met polymorphism and childhood trauma predicts risk for depression in men.

Depression is a disabling illness with complex etiology. While the catechol-O-methyltransferase (COMT) gene, in particular the functional Val158 Met polymorphism, has been related to depression, the mechanisms underlying this gene-disease association are not completely understood. Therefore, we explore the association of COMT Val158 Met polymorphism with depression as well as its interaction with childhood trauma in 1136 young adults from a population-based study carried out in the city of Pelotas, Brazil. The diagnosis was performed through the Mini International Neuropsychiatric Interview 5.0 (MINI 5.0), and trauma was assessed with the Childhood Trauma Questionnaire (CTQ). Total DNA was extracted and genotyped by real-time PCR, and the QTLbase dataset was queried to perform large-scale quantitative trait locus (QTL) analysis. Our research showed no direct association between the Val158 Met polymorphism and the diagnosis of depression (women: χ2 =0.10, d= 1, p= 0.751; men: χ2 =0.003, df =1, p= 0.956). However, the Met-allele of the Val158 Met polymorphism modified the effect of childhood trauma in men (OR =2.58 [95% CI: 1.05-6.29]; p= 0.038) conferring risk for depression only on those who suffer from trauma. The conditional effect from moderation analysis showed that trauma impacts the risk of depression only in men carrying the Met-allele (effect: 0.9490, standard error [SE]: 0.2570; p= 0.0002). QTLbase and dataset for Val158 Met polymorphism were consistent for markers that influence chromatin accessibility transcription capacity including histone methylation and acetylation. The changes caused in gene regulation by childhood trauma exposure and polymorphism may serve as evidence of the mechanism whereby the interaction increases susceptibility to this disorder in men.

Catechol-O-methyltransferase activity does not influence emotional processing in men.

Background:Catechol-O-methyltransferase (COMT) regulates cortical dopaminergic transmission and prefrontal-dependent cognitive function. However, its role in other cognitive processes, including emotional processing, is relatively unexplored. We therefore investigated the separate and interactive influences of COMT inhibition and Val158Met (rs4680) genotype on performance on an emotional test battery.Methods:We recruited 74 healthy men homozygous for the functional COMT Val158Met polymorphism. Volunteers were administered either a single 200 mg dose of the brain-penetrant COMT inhibitor tolcapone or placebo in a double-blind, randomised manner. Emotional processing was assessed using the emotional test battery, and mood was rated using visual analogue scales and the Profile of Mood States (POMS) questionnaire across the test day.Results:There were no main or interactive effects of Val158Met genotype or tolcapone on any of the emotional processing measures or mood ratings.Conclusions:Our findings suggest that, at least in healthy adult men, COMT has little or no effect on emotional processing or mood. These findings contrast with several neuroimaging studies that suggest that COMT modulates neural activity during emotional processing. Thus, further studies are required to understand how COMT impacts on the relationship between behavioural output and neural activity during emotional processing. Nevertheless, our data suggest that novel COMT inhibitors under development for treating cognitive dysfunction are unlikely to have acute off target effects on emotional behaviours.

Childhood trauma and genetic variation in the DAT 40-bp VNTR contribute to HIV-associated neurocognitive disorders.

HIV/AIDS is a major public health burden in South Africa, currently affecting an estimated 13.5% of the population. Despite improved access to antiretroviral therapies, HIV-associated neurocognitive disorders (HAND), characterised by a spectrum of neurocognitive impairment, emotional disturbances and motor abnormalities, continue to persist. Gene-environment interactions contribute to HAND pathophysiology and previous research has identified childhood trauma as an environmental risk factor. Dopaminergic signalling in the prefrontal cortex plays a key role in cognitive function. Thus, variants in genes encoding the dopamine transporter (DAT) and catechol-O-methyltransferase (COMT), which are responsible for dopamine transport and metabolism, could represent genetic risk factors for HAND. This study investigated whether the DAT variable number of tandem repeats (VNTR) and COMT Val158Met (rs4680) polymorphisms are associated with longitudinal change in cognitive function in the context of childhood trauma and HIV. Participants (n = 49 HIV-negative and n = 64 HIV-positive women) completed the Childhood Trauma Questionnaire – Short Form (CTQ-SF) and provided blood for genetic analyses. Global cognitive scores were generated from baseline and one-year follow-up assessments. Following polymerase chain reaction, genotypes were determined using gel electrophoresis and confirmed by Sanger sequencing. Baseline global cognitive scores, genotype, HIV status and CTQ-SF scores were regressed on one-year global cognitive scores in regression models. Analysis of variance was used to examine the effect of including predictor variable interactions on model fit. HIV seropositivity was associated with poorer cognitive performance at one-year follow-up (p = 2.46 ×10−4). The combination of HIV and DAT 10-repeat homozygosity (DAT 10/10) was associated with reduced global cognitive scores in longitudinal models (p = 0.010). Including the interaction between DAT 10/10, childhood trauma, and HIV explained significantly more of the variance in longitudinal cognitive scores (p = 0.008). There were no significant associations with the COMT genotype. Our research indicates that childhood trauma and genetic variation in DAT contribute toward the aetiology of HAND. Future studies in larger cohorts are warranted to verify these results.

Harsh parenting and non-suicidal self-injury in adolescence: the mediating effect of depressive symptoms and the moderating effect of the COMT Val158Met polymorphism

BackgroundPrevious studies have suggested that negative parenting environments, especially harsh parenting, are a specific risk factor for non-suicidal self-injury (NSSI). However, the potential mechanism between harsh parenting and NSSI has not been explored. Based on the experiential avoidance model and empirical research, we aimed to examine whether depressive symptoms are a mediator between harsh parenting and NSSI. Moreover, the catechol-O-methyltransferase (COMT) Val158Met polymorphism related to depressive symptoms may also exert a moderating effect on NSSI; thus, the interaction between harsh parenting and COMT was also considered in our study.MethodsA total of 373 junior high school students were recruited for the study by using a longitudinal design. The adolescents answered self-report questionnaires and provided saliva samples for DNA genotyping.ResultsThe results revealed that harsh parenting was positively associated with NSSI after 24 months, and this association was mediated by depressive symptoms. Moreover, the moderating role of COMT in the direct and indirect effects of harsh parenting on NSSI was observed only among adolescents with two Val alleles and the relationship was not significant for Met carriers.ConclusionsGenetic variations of COMT Val158Met may be a critical candidate in understanding the development of depression and NSSI. We conclude that Val homozygotes of the COMT Val158Met polymorphism play a role in susceptibility to both depressive symptoms and NSSI.

Association Between the COMT Val158Met Polymorphism and Antipsychotic Efficacy in Schizophrenia: An Updated Meta-Analysis.

Background Catechol-O-methyltransferase (COMT) contributes to the control of synaptic dopamine (DA) transmission by catalyzing DA degradation in the presynaptic space. The COMT Val158Met polymorphism (rs4680) substantially alters enzymatic activity and consequently synaptic DA concentration in the prefrontal cortex and hippocampus. The COMT genotype could, therefore, exert a major influence on antipsychotic treatment response as many of these agents also target dopaminergic transmission.Objective The present meta-analysis aimed to test a putative relationship between the COMT Val158Met polymorphism and antipsychotic response across different populations and antipsychotic types.Methods Searches of PubMed, Web of Science, EMBASE, OVID, Google Scholar, and Baidu Scholar databases yielded 30 peer-reviewed studies published before January 2020 with a pooled total of 6291 participants. The Lipták-Stouffer Z score method for meta-analysis was applied to combine data. The Z score was also calculated separately for Caucasian and Asian subgroups.Results Pooled results indicated a highly significant association between COMT Val158Met and antipsychotic response (Z = 6.709, P = 9.8 × 10-12). Further, this relationship remained significant in subgroup analyses of Caucasian patients (Z = 3.180, P = 7.4 × 10-4) and Asian patients (Z = 4.487, P = 3.6 × 10-6).Conclusion Pooled evidence supports the hypothesis that the COMT Val158Met polymorphism influences the antipsychotic response in Caucasian and Asian schizophrenia patient populations. Prediction of antipsychotic response by patient genotyping may warrant closer consideration in randomized clinical trials of efficacy.

Role of COMT V158M Polymorphism in the Development of Dystonia after Administration of Antipsychotic Drugs.

Antipsychotics (APDs) represent the main pharmacological strategy in the treatment of schizophrenia; however, their administration often may result in severe adverse effects, such as extrapyramidal symptoms. Typically, dystonic movements are considered the result of impaired function and/or abnormalities of dopaminergic neurotransmission/signaling in the basal ganglia. The catechol O-methyltransferase (COMT) gene is located within the 22q11.2 region, and its product is an enzyme involved in transferring a methyl group from S-adenosylmethionine to catecholamines, including dopamine. Studies showed that COMT Val158Met polymorphism modifies enzymatic activity and, consequently, synaptic dopamine concentration in specific brain areas. We identified a patient with 22q11.2 deletion syndrome presenting with cervical and trunk dystonia after paliperidone administration, which persisted even after drug discontinuation. Given the patient’s genetic condition, we hypothesized that the dopaminergic dysfunction had been aggravated by COMT involvement, thus causing dystonia. In line with this hypothesis, we carried out a study on psychiatric patients in chronic treatment with APD to evaluate the distribution of the COMT Val158Met polymorphism and its role in the onset of adverse extrapyramidal symptoms. The study included four patients with dystonia after administration of APDs compared to 17 patients who never presented adverse drug reactions. Our data suggest that the Val/Val and Met/Met polymorphisms of the COMT gene are associated with a protective effect for the development of collateral extrapyramidal symptoms in patients treated with APDs, while the Val/Met genotype could be considered a risk factor for the development of dystonia after APDs administration.

Association of Internet gaming disorder with catechol-O-methyltransferase: Role of impulsivity and fun-seeking.

Dopamine functioning is an essential mechanism underlying addictive behaviors. This paper evaluates the association of Internet gaming disorder (IGD) with the catechol-O-methyltransferase (COMT) val158met polymorphism and examines the roles of impulsivity and reinforcement sensitivity in this association. Using diagnostic interviews, this study recruited 69 participants with IGD and 138 participants without. All participants underwent diagnostic interviews for IGD and an evaluation for the COMT val158met polymorphism, impulsivity, and reinforcement sensitivity. Among participants with the Val/Val genotype, the odds ratio (95% confidence interval) for IGD was 2.09 (1.15-3.80). The IGD-Val/Val genotype association was mediated by impulsivity and fun-seeking. The Val/Val genotype is indicative of low frontal functioning and is a predictive factor of IGD, with this effect being confounded by impulsivity and fun-seeking. Interventions targeting impulsivity and fun-seeking might attenuate the risk of IGD, particularly among individuals with the Val/Val genotype. Additional studies are necessary to elucidate the possible role of dopamine functioning.

The roles of borderline personality disorder symptoms and dispositional capability for suicide in suicidal ideation and suicide attempts: Examination of the COMT Val158Met polymorphism

There is a need to identify the subset of individuals with borderline personality disorder (BPD) symptoms at greatest risk for transitioning from suicidal ideation to a suicide attempt. Contemporary models of suicide risk propose that the capability for suicide is necessary for moving from suicidal ideation to a suicide attempt. Few studies have examined dispositional capability factors for suicide, especially among individuals with BPD symptoms. One candidate may be the catechol-o-methyltransferase (COMT) Val158Met polymorphism given its influence on pain sensitivity and fear. This study examined the interactive relation of BPD symptoms and the COMT Val158Met polymorphism to suicidal ideation and suicide attempts. Fifty-nine treatment-seeking patients were recruited. Participants were administered a series of clinical interviews to evaluate BPD symptoms and suicidal thoughts and behaviors. Saliva samples were collected for genotyping. The relation between BPD symptoms and suicidal ideation was not influenced by the Val158Met polymorphism. However, among Val/Val carriers, the probability of a lifetime suicide attempt increased as BPD symptom severity increased. Findings provide preliminary support for the Val/Val variant as a dispositional factor that may increase risk for suicide attempts in BPD; however, results must be interpreted with caution until replication of findings occurs in larger samples.

Association of polymorphic marker Val158Met of COMT gene with depression in an open population 25–44 years old (WHO international program MONICA, epidemiological study)

Objective : to investigate the association of the polymorphic marker Val158Met in the catechol-O-methyl transferase (COMT) gene with depression in an open population aged 25–44 years. Patients and methods . A representative sample of the population living in Oktjabr'skij district of Novosibirsk aged 25– 44 years (427 men, median age – 34±0.4 years, response rate – 71%; 548 women, median age 35±0.4 years, response rate – 72%) was screened in 2013–2016 (budget framework № 0324- 2018-0001, Reg. № AAAA-A17-117112850280-2). In addition to the standard epidemiological examination, screening participants underwent psychological testing, which determined the level of depression. Study participants who underwent COMT Val158Met (rs4680) polymorphism genotyping were randomly assigned to a cohort of 224 men and 217 women. Pearson's χ2 test was used to test the statistical significance of differences between these groups; p≤0.05 was considered statistically significant in all types of analysis. Results and discussion . In an open population aged 25–44 years, the prevalence of severe depression (SD) was 13.2%, moderate depression – 24.4%. SD was more prevalent in COMT G/G genotype carriers (61.8%), compared to A/A genotype carriers (38.2%; χ 2 =6.097; df=2, p=0.047); the G allele carriers also had a higher prevalence of SD (55.3%), compared to A allele carries (44.7%; χ 2 =5.408; df=1; p=0.02). SD was less prevalent among male COMT A/A genotype carriers (15.8%), compared to G/A genotype carriers (84.2%; χ 2 =4.603; df=1; p=0.032). SD was more prevalent in female G/G genotype carriers (65.5%), compared to A/A genotype carriers (34.5%; χ 2 =4.769; df=1; p=0.029). The G allele was more common among women with SD (58.2%) than the A allele (41.8%; χ 2 =6.658; df=2; p=0.01). In a logistic regression model, COMT Val/Val genotype in the studied population [Relative risk (RR) 1.594], as well as G (Val) allele in the studied population (RR=1.378) and women (RR=1.557), significantly increased the risk of depression. Conclusion. The data allows us to assume that COMT G/G polymorphism may be linked to a high depression level.

Dopaminergic modulation of regional cerebral blood flow: An arterial spin labelling study of genetic and pharmacological manipulation of COMT activity

Dopamine has direct and complex vasoactive effects on cerebral circulation. Catechol-O-methyltransferase (COMT) regulates cortical dopamine, and its activity can be influenced both genetically and pharmacologically. COMT activity influences the functional connectivity of the PFC at rest, as well as its activity during task performance, determined using blood oxygen level-dependent (BOLD) fMRI. However, its effects on cerebral perfusion have been relatively unexplored. Here, 76 healthy males, homozygous for the functional COMT Val158Met polymorphism, were administered either the COMT inhibitor tolcapone or placebo in a double-blind, randomised design. We then assessed regional cerebral blood flow at rest using pulsed arterial spin labelling. Perfusion was affected by both genotype and drug. COMT genotype affected frontal regions (Val158 > Met158), whilst tolcapone influenced parietal and temporal regions (placebo > tolcapone). There was no genotype by drug interaction. Our data demonstrate that lower COMT activity is associated with lower cerebral blood flow, although the regions affected differ between those affected by genotype compared with those altered by acute pharmacological inhibition. The results extend the evidence for dopaminergic modulation of cerebral blood flow. Our findings also highlight the importance of considering vascular effects in functional neuroimaging studies, and of exercising caution in ascribing group differences in BOLD signal solely to altered neuronal activity if information about regional perfusion is not available.

Maternal rearing styles and loneliness: The moderating role of the COMT Val158Met polymorphism

Loneliness is a common problem in adulthood, with deleterious effects on mental health. In the present study, we examined whether the effects of maternal rearing styles on loneliness are moderated by the catechol-O-methyltransferase (COMT) Val158Met polymorphism and whether loneliness can further affect mental health as a mediator in 1034 genotyped participants. The results showed that the COMT genotype significantly moderated the relationship between maternal rejection and loneliness; more specifically, Val carriers who perceived higher levels of rejection from their mothers demonstrated higher levels of loneliness. The moderated mediation model revealed that loneliness meditated the indirect effects of maternal rejection on life satisfaction. Specifically, for individuals with the Val/Val genotype, higher rejection from their mothers had a greater influence on their life satisfaction through loneliness. In addition, we found that the effect of COMT Val158Met maternal rejection on loneliness and the effect of maternal rejection on Val/Val adults’ life satisfaction via loneliness existed across different age groups. These findings provide a new understanding of the gene–parenting interaction effect on loneliness and its influence on mental health.