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.     

COMT Val158Met polymorphism in schizophrenia with obsessive-compulsive disorder: a case-control study

ZDHHC8 is a new and attractive candidate for a schizophrenia-susceptibility factor. First, several lines of linkage studies showed that 22q11, on which ZDHHC8 is located, is a "hot" region. Second, fine linkage disequilibrium mapping revealed a significant association around ZDHHC8. Moreover, a very recent study reported that one single nucleotide polymorphism (SNP: rs175174) in ZDHHC8 might affect the splicing process, the ZDHHC8 knock-out mice showed the gender-specific phenotype, and the transmission disequilibrium test (TDT) using this SNP also showed significant association with human female schizophrenia. Thus, we attempted a replication study of this SNP using relatively large Japanese case-control samples (561 schizophrenics and 529 controls). No association was found between schizophrenia and controls even after dividing samples by gender. Because our sample size provided quite high power, ZDHHC8 may not play a major role in Japanese schizophrenia. And our results did not support the gender-specific effect of this SNP.     

Effects of Modafinil on the Sleep EEG Depend on Val158Met Genotype of COMT

Study Objectives:

Modafinil may promote wakefulness by increasing cerebral dopaminergic neurotransmission, which importantly depends on activity of catechol-O-methyltransferase (COMT) in prefrontal cortex. The effects of modafinil on sleep homeostasis in humans are unknown. Employing a novel sleep-pharmacogenetic approach, we investigated the interaction of modafinil with sleep deprivation to study dopaminergic mechanisms of sleep homeostasis.

Design:

Placebo-controlled, double-blind, randomized crossover study.

Setting:

Sleep laboratory in temporal isolation unit.

Participants:

22 healthy young men (23.4 ± 0.5 years) prospectively enrolled based on genotype of the functional Val158Met polymorphism of COMT (10 Val/Val and 12 Met/Met homozygotes).

Interventions:

2 × 100 mg modafinil and placebo administered at 11 and 23 hours during 40 hours prolonged wakefulness.

Measurements and Results:

Subjective sleepiness and EEG markers of sleep homeostasis in wakefulness and sleep were equally affected by sleep deprivation in Val/Val and Met/Met allele carriers (placebo condition). Modafinil attenuated the evolution of sleepiness and EEG 5-8 Hz activity during sleep deprivation in both genotypes. In contrast to caffeine, modafinil did not reduce EEG slow wave activity (0.75-4.5 Hz) in recovery sleep, yet specifically increased 3.0-6.75 Hz and > 16.75 Hz activity in NREM sleep in the Val/Val genotype of COMT.

Conclusions:

The Val158Met polymorphism of COMT modulates the effects of modafinil on the NREM sleep EEG in recovery sleep after prolonged wakefulness. The sleep EEG changes induced by modafinil markedly differ from those of caffeine, showing that pharmacological interference with dopaminergic and adenosinergic neurotransmission during sleep deprivation differently affects sleep homeostasis.

Citation:

Bodenmann S; Landolt HP. Effects of modafinil on the sleep EEG depend on Val158Met genotype of COMT. SLEEP 2010;33(8):1027-1035.     

Effect of functional catechol-O-methyltransferase Val158Met polymorphism on physical aggression

Genetic and psychological analysis of the relationships between catechol-O-methyltransferase Val158Met polymorphism and various types of aggressiveness was performed in 114 women. Dispersion analysis revealed significant association of ValVal genotype with elevated physical aggression. __________ Translated from Byulleten’ Eksperimental’noi Biologii i Meditsiny, Vol. 145, No. 1, pp. 68–70, January, 2008     

RGS4 mRNA expression in postmortem human cortex is associated with COMT Val158Met genotype and COMT enzyme activity

Linkage, association and postmortem studies have implicated regulator of G-protein signaling 4 (RGS4), which negatively modulates signal transduction at G-protein-coupled receptors, as a candidate schizophrenia susceptibility gene. We compared RGS4 mRNA expression in the dorsolateral prefrontal cortex (DLPFC), between normal controls and patients with schizophrenia in two independent cohorts (>100 subjects each) (the CBDB/NIMH Collection and the Stanley Array Collection), and in the hippocampus in the CBDB/NIMH Collection. We also examined the effects of the four previously identified putative RGS4 risk SNPs (rs10917670, rs951436, rs951439, rs2661319) on RGS4 expression levels in these cohorts. As dopamine signaling is linked to RGS4 expression and there is evidence for statistical epistasis between COMT Val158Met polymorphism and RGS4 alleles, we also examined relationships between the COMT Val158Met genotype and RGS4 expression in the DLPFC. We did not detect a difference in RGS4 expression levels between schizophrenic patients (or bipolar disorder patients in the Stanley Collection) and controls and found no significant association between any of the RGS4 risk SNPs and RGS4 expression. However, COMT Val158Met genotype was associated with prefrontal and hippocampal RGS4 mRNA expression in an allele dose-dependent manner, with carriers of the COMT Val allele showing significantly lower expression than heterozygous individuals or subjects homozygous for the Met allele. Consistent with these genotype effects, RGS4 mRNA was inversely correlated with the COMT enzyme activity in the DLPFC. These data suggest that RGS4 mRNA expression is associated with cortical dopamine signaling and illustrate the importance of genetic and/or environmental background in gene expression studies in schizophrenia.     

长寿家系COMT Val158Met基因多态性及其与血压和血脂水平的相关性

目的探讨长寿家系COMT Val158Met(GA)基因多态性与血压、血脂水平的相关性,了解其在长寿中的作用。方法用PCR-RFLP方法对广西红水河流域长寿家系(HL)及非长寿家系(HNL)、外地区(平果)长寿(PL)及非长寿家系(PNL)的COMT Val158Met进行基因分型,分析该多态与血压和血脂水平的相关性。结果等位基因A及其基因型(GA/AA)频率在HL和HNL间无差异,但高于PL和PNL(P0.01)。HL和PNL的血压、血脂水平在GA/AA和GG基因型携带者之间无差异,但HNL的GA/AA携带者的收缩压、脉压差、TC、TG及LDL-C水平明显高于GG携带者(P0.05),尤以女性为甚,PL的部分结果与此类似。COMT Val158Met多态与HNL及PL的TC和LDL-C水平呈负相关(P0.05)。结论 COMT Val158Met虽然在红水河流域人群中高频出现,但其对血压及血脂的影响主要在一般家系,对长寿家系的影响较小。     

Association between the Catechol-O-Methyltransferase (COMT) Val158Met Polymorphism and Alexithymia in Patients with Obsessive-Compulsive Disorder

PurposeAlexithymia, defined as a deficit in the ability to recognize and describe one''s own feelings, may be related to the development and maintenance of obsessive-compulsive symptoms. The aim of this study was to evaluate the association between the catechol-O-methyltransferase (COMT) Val¹⁵⁸Met polymorphism and alexithymia in patients with obsessive-compulsive disorder (OCD).ResultsPatients with the COMT Val/Val genotype had significantly higher total and "difficulty identifying feelings" (DIF) subdimension scores than those with the Val/Met or Met/Met genotypes. Patients with the COMT Val/Val genotype had significantly higher "difficulty describing feelings" (DDF) subdimension scores than those with the COMT Val/Met genotype. However, there were no differences in the scores for the "externally oriented thinking" (EOT) subdimension among the three genotypes.ConclusionThese results indicate that the high-activity Val allele of the COMT Val¹⁵⁸Met polymorphism is associated with increased alexithymic traits in patients with OCD. The present finding suggests that alexithymia is an endophenotype of OCD that is mediated by the COMT Val¹⁵⁸Met polymorphism.     

Interactions between the COMT Val108/158Met polymorphism and maternal prenatal smoking predict aggressive behavior outcomes

The purpose of the current study is to examine the moderating influence of the catechol O methyltransferase gene (COMT) on the maternal prenatal smoking/offspring externalizing disorder relationship. The sample consisted of 430 young adults born between 1981 and 1984 at the Mater Misericordiae Mother's Hospital in Brisbane, Australia, as well as their mothers and peers. Mothers reported their prenatal smoking status during pregnancy, and genetic data was obtained from the youth at a later follow-up in adulthood. The outcome measures in this study were mother and teacher reports of youth attention problems and aggression at age 15, and youth, mother and peer reports of youth attention problems and aggression at age 20 (combined to create latent factors of attention problems and aggression at each age). The COMT Val108/158Met polymorphism (rs4680) significantly interacted with maternal cigarette smoking during pregnancy to predict youth aggressive behavior at ages 15 and 20. This gene-environment interaction was not significant for youth attention problems.     

Association of the Val158Met Polymorphism of the COMT Gene with Measures of Psychophysiological Status in Athletes

Neuroscience and Behavioral Physiology - Resistance to psychological stress, motivation, physical work capacity, and fatigue are genetically determined characteristics which are important for...     

Catechol-O-Methyltransferase (COMT) Val 108/158 Met polymorphism does not modulate executive function in children with ADHD

Background

Autism is a pervasive developmental disorder characterized by a triad of deficits: qualitative impairments in social interactions, communication deficits, and repetitive and stereotyped patterns of behavior. Although autism is etiologically heterogeneous, family and twin studies have established a definite genetic basis. The inheritance of idiopathic autism is presumed to be complex, with many genes involved; environmental factors are also possibly contributory. The analysis of chromosome abnormalities associated with autism contributes greatly to the identification of autism candidate genes.

Case presentation

We describe a child with autistic disorder and an interstitial deletion on chromosome 4q. This child first presented at 12 months of age with developmental delay and minor dysmorphic features. At 4 years of age a diagnosis of Pervasive Developmental Disorder was made. At 11 years of age he met diagnostic criteria for autism. Cytogenetic studies revealed a chromosome 4q deletion. The karyotype was 46, XY del 4 (q31.3-q33). Here we report the clinical phenotype of the child and the molecular characterization of the deletion using molecular cytogenetic techniques and analysis of polymorphic markers. These studies revealed a 19 megabase deletion spanning 4q32 to 4q34. Analysis of existing polymorphic markers and new markers developed in this study revealed that the deletion arose on a paternally derived chromosome. To date 33 genes of known or inferred function are deleted as a consequence of the deletion. Among these are the AMPA 2 gene that encodes the glutamate receptor GluR2 sub-unit, GLRA3 and GLRB genes that encode glycine receptor subunits and neuropeptide Y receptor genes NPY1R and NPY5R.

Conclusions

The deletion in this autistic subject serves to highlight specific autism candidate genes. He is hemizygous for AMPA 2, GLRA3, GLRB, NPY1R and NPY5R. GluR2 is the major determinant of AMPA receptor structure. Glutamate receptors maintain structural and functional plasticity of synapses. Neuropeptide Y and its receptors NPY1R and NPY5R play a role in hippocampal learning and memory. Glycine receptors are expressed in very early cortical development. Molecular cytogenetic studies and DNA sequence analysis in other patients with autism will be necessary to confirm that these genes are involved in autism.     

The COMT Val158Met polymorphism regulates the effect of a dopamine antagonist on the feedback‐related negativity

Consistent with dopamine accounts of internal and external feedback processing, prior work showed that the dopamine D2 receptor antagonist sulpiride modulates the relationship between the dopaminergic COMT Val158Met polymorphism and the error‐related negativity (ERN). Here, we tested in an independent sample whether this Gene × Substance interaction generalizes to the feedback‐related negativity (FRN), which presumably shares underlying dopaminergic mechanisms with the ERN. N = 83 female participants genotyped for COMT Val158Met received 200 mg sulpiride versus placebo and performed a virtual ball‐catching task. The FRN to positive versus negative feedback was modulated by a significant COMT × Substance interaction. Mirroring prior work on the ERN, the tendency of the FRN to be more pronounced for VAL+ versus MET/MET carriers after placebo was reversed by sulpiride. The findings thus provide new evidence for dopaminergic models of feedback processing.     

Association between the COMT Val158Met polymorphism and propensity to anxiety in an Australian population-based longitudinal study of adolescent health

OBJECTIVES: Catechol-O-methyltransferase plays a central role in the metabolism of biogenic amines such as norepinephrine, dopamine and serotonin. Functional studies have demonstrated a dose relationship between ValMet genotypes and catechol-O-methyltransferase activity. Compared with the ValVal genotype, the ValMet and MetMet genotypes result in two- and four-fold reductions in catechol-O-methyltransferase activity, respectively. Two recent reports have observed the association between the MetMet genotype and risk of anxiety in adult populations. We examined the association between the ValMet genotypes and propensity to anxiety across adolescence. METHODS: Participants were drawn from an eight-wave study of the mental and behavioural health of over 2000 young Australians followed from 14 to 24 years of age (Victorian Adolescent Health Cohort Study, 1992 to present). DNA was received from 962 participants using a cheek swab collection method. RESULTS: The odds of reporting persistent episodic anxiety (phobic avoidance, panic attacks) were doubled among carriers of the MetMet genotype (odds ratio 2.0, 95% confidence interval 1.1-3.4, P=0.014). A dose relationship between additional copies of the Met allele and persistent episodic anxiety was also observed (1.5, 1.1-1.94, P=0.007). Stratification by sex showed that the risk effect of the Met allele was among females only. No association was observed for measures of neuroticism, persistent generalized anxiety, or a composite measure of psychiatric distress. CONCLUSION: These data replicate previous findings suggesting association between the ValMet polymorphism and specific expressions of anxiety among females.     

Analysis of COMT gene (Val 158 Met polymorphism) in the clinical response to SSRIs in depressive patients of European origin

INTRODUCTION AND OBJECTIVES: There is convincing evidence of interactions between serotonergic and dopaminergic systems and it seems that an increase of dopamine concentration in the whole brain could be a limiting factor for the antidepressant like effect of antidepressants. The COMT gene might be a good candidate for explaining some aspects of the pharmacological response to SSRIs. METHODS: The aim of our study was to analyse the Val 158 Met functional polymorphism on COMT gene and clinical response (4 weeks) and clinical remission (6/8 and 12 weeks) in two samples of depressive patients (DSM-IV) treated with SSRIs of Italian and Spanish origin. Clinical outcome was measured using 21 items Hamilton scale, weekly in the Italian sample (along 6 weeks) and monthly in the Spanish one (along 12 weeks). RESULTS: No overall effect of genotype or genotypextime interaction was detected. However, we observed a genotypextime interaction on HDRS decrease for citalopram treatment (F((4.6,317.5)) = 3.38, P = 0.007) in the Spanish sample. No clear effect was observed in the Italian sample. The three samples were pooled in order to test if carrying the Met/Met genotype confers an increased risk for non-remission at 6-8 weeks. The results showed that Met/Met carriers have an odds ratio of 2.21 (95% CI [1.20-4.12]) for non-remission (chi(2) = 7.43, df = 2, P = 0.006). The Met/Met effect was not observed in response at 4th week (for all SSRI treatments) or in remission at 12th week (citalopram treatment). CONCLUSIONS: COMT gene could have a small and indirect effect of clinical response to SSRIs by slowing-down the antidepressant action along the follow-up, basically in citalopram treatment.     

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.     

Aging influence on functional connectivity of the motor network in the resting state

We used functional MRI (fMRI) to study the aging influence on functional connectivity of the motor network in the resting state. A network model based on graph theory was used to measure functional connectivity. The total connectivity degree of each region within the motor network was calculated and compared between aged and young groups. We found that the pattern of functional connectivity was changed in aged subjects, including a significant decrease in the functional connectivity degree of the right cingulate motor area and left premotor area compared to young subjects. Our study demonstrates that normal aging modulates the functional connectivity of motor network in the resting state. We postulate that this abnormal functional connectivity of motor network in the baseline state is an important reason contributing to the deteriorated motor ability in aged subjects.     

The role of maternal stress during pregnancy,maternal discipline,and child COMT Val158Met genotype in the development of compliance

Maternal discipline is an important predictor of child committed compliance. Maternal stress can affect both parenting and child development. In a large population‐based cohort study (N = 613) we examined whether maternal discipline mediated the association between maternal stress during pregnancy and child compliance, and whether COMT or DRD4 polymorphisms moderated the association between maternal discipline and child compliance. Family‐related and general stress were measured through maternal self‐report and genetic material was collected through cord blood sampling at birth. Mother–child dyads were observed at 36 months in disciplinary tasks in which the child was not allowed to touch attractive toys. Maternal discipline and child compliance were observed in two different tasks and independently coded. The association between family stress during pregnancy and child committed compliance was mediated by maternal positive discipline. Children with more COMT Met alleles seemed more susceptible to maternal positive discipline than children with more COMT Val alleles. © 2012 Wiley Periodicals, Inc. Dev Psychobiol 55: 451–464, 2013