Showing papers on "Catechol-O-methyl transferase published in 2010"

Neural substrates of pleiotropic action of genetic variation in COMT: a meta-analysis

Abstract: Genetic variation in catechol-O-methyltransferase (COMT), encoding an enzyme critical for prefrontal dopamine flux, has been studied extensively using both behavioral and neuroimaging methods. In behavior, pleiotropic action of a functional Val(158)Met (rs4680) polymorphism on executive cognition and emotional stability has been described and proposed to be of evolutionary significance (the 'warrior/worrier' hypothesis). We conducted a meta-analysis of all available neuroimaging studies of rs4680 to investigate the evidence for a neural substrate of this behavioral pleiotropy. We show significant association between the COMT genotype and prefrontal activation, with large (d=0.73) effect size without evidence for publication bias. Strong and opposing effects were found for executive cognition paradigms (favoring Met allele carriers) and emotional paradigms (favoring Val), providing meta-analytical evidence for a neural substrate for the pleiotropic behavioral effects of COMT genetic variation and validating the use of intermediate phenotypes as a method to bridge between genes and behavior.

Quantitative role of COMT in dopamine clearance in the prefrontal cortex of freely moving mice

Abstract: Catechol-O-methyltransferase (COMT) plays an active role in the metabolism of dopamine (DA) in the prefrontal cortex (PFC). Because of low levels of dopamine transporter (DAT), it is proposed that the majority of released DA is taken up by either norepinephrine transporter (NET) and subsequently metabolized by monoamine oxidize (MAO) or by uptake(2) (to glial cells and post-synaptic neurons) and metabolized by COMT. However, a comprehensive in vivo study of rating the mechanisms involved in DA clearance in the PFC has not been done. Here, we employ two types of microdialysis to study these pathways using DAT, NET and MAO blockers in conscious mice, with or without Comt gene disruption. In quantitative no-net-flux microdialysis, DA levels were increased by 60% in the PFC of COMT-knockout (ko) mice, but not in the striatum and nucleus accumbens. In conventional microdialysis studies, we showed that selective NET and MAO inhibition increased DA levels in the PFC of wild-type mice by two- to fourfold, an effect that was still doubled in COMT-ko mice. Inhibition of DAT had no effect on DA levels in either genotype. Therefore, we conclude that in the mouse, PFC COMT contributes about one half of the total DA clearance.

Discovery of a Long-Acting, Peripherally Selective Inhibitor of Catechol-O-methyltransferase

Abstract: Novel nitrocatechol-substituted heterocycles were designed and evaluated for their ability to inhibit catechol-O-methyltransferase (COMT). Replacement of the pyrazole core of the initial hit 4 with a 1,2,4-oxadiazole ring resulted in a series of compounds endowed with longer duration of COMT inhibition. Incorporation of a pyridine N-oxide residue at position 3 of the 1,2,4-oxadiazole ring led to analogue 37f, which was found to possess activity comparable to entacapone and lower toxicity in comparison to tolcapone. Lead structure 37f was systematically modified in order to improve selectivity and duration of COMT inhibition as well as to minimize toxicity. Oxadiazole 37d (2,5-dichloro-3-(5-(3,4-dihydroxy-5-nitrophenyl)-1,2,4-oxadiazol-3-yl)-4,6-dimethylpyridine 1-oxide (BIA 9-1067)) was identified as a long-acting, purely peripheral inhibitor, which is currently under clinical evaluation as an adjunct to l-Dopa therapy of Parkinson's disease.

Effect of catechol-O-methyltransferase polymorphism on response to propranolol therapy in chronic musculoskeletal pain: a randomized, double-blind, placebo-controlled, crossover pilot study.

Abstract: Introduction Three common haplotypes in the gene encoding catechol-O-methyltransferase (COMT) have been associated with pain modulation and the risk of developing chronic musculoskeletal pain, namely temporomandibular disorder (TMD). Haplotypes coding for higher enzymatic activity were correlated with lower pain perception. Rodent studies showed that COMT inhibition increases pain sensitivity through beta2/3-adrenergic receptors. We hypothesized that the nonselective beta-adrenergic antagonist propranolol will reduce clinical and experimental pain in TMD patients in a manner dependent on the individuals' COMT diplotype. Methods Forty Caucasian female participants meeting the Research Diagnostic Criteria for TMD were genotyped for COMT polymorphisms and completed a randomized, double-blind, placebo-controlled, two-period crossover pilot study. Each period consisted of a baseline assessment week followed by an intervention week (propranolol or placebo). Changes in clinical pain ratings, psychological status, and responses to heat and pressure stimuli between baseline and intervention weeks were compared across periods. Results The number of patients reporting a reduction in pain intensity rating was greater during propranolol treatment (P=0.014) compared with placebo. Propranolol significantly reduced a composite pain index (P=0.02) but did not decrease other clinical and experimental pain ratings. When stratified by the COMT high activity haplotype, a beneficial effect of propranolol on pain perception was noted in patients not carrying this haplotype, a diminished benefit was observed in the heterozygotes, and no benefit was noted in the homozygotes. Conclusion COMT haplotypes may serve as genetic predictors of propranolol treatment outcome, identifying a subgroup of TMD patients who will benefit from propranolol therapy.

Distribution of catechol-O-methyltransferase (COMT) proteins and enzymatic activities in wild-type and soluble COMT deficient mice

Abstract: Catechol-O-methyltransferase (COMT) has both soluble (S-COMT) and membrane-bound (MB-COMT) isoforms. A specific COMT antibody was used in immunohistochemical and confocal co-localization studies to explore the distribution of COMT in general in normal mice and MB-COMT in particular, in an S-COMT deficient mouse line. In the peripheral tissues, high COMT protein and activity levels were observed in liver and kidney, whereas in the brain, COMT expression and activity were much lower. MB-COMT was widely distributed throughout all tissues, and overall, the MB-COMT distribution mimicked the distribution of S-COMT. MB-COMT displayed some preference for brain tissue, notably in the hippocampus. MB-COMT related enzymatic activity was also pronounced in the cerebral cortical areas and hypothalamus. MB-COMT, like S-COMT, was found to be an intracellular enzyme but it was not associated with plasma membranes in the brain. Both COMT forms were abundantly found in microglial cells and intestinal macrophages, but also in astroglial cells. COMT was also present in some neuronal cells, like pyramidal neurons, cerebellar Purkinje and granular cells and striatal spiny neurons, but not in major long projection neurons. Finally, it seemed that nuclear COMT is not visible in S-COMT deficient mice.

Prefrontal-Related Functional Connectivities within the Default Network Are Modulated by COMT val158met in Healthy Young Adults

Abstract: Previous studies have supported the concept that the default network is an intrinsic brain system that participates in internal modes of cognition. Neural activity and connectivity within the default network, which are correlated with cognitive ability even at rest, may be plausible intermediate phenotypes that will enable us to understand the genetic mechanisms of individuals' cognitive function or the risk for genetic brain diseases. Using resting functional magnetic resonance imaging and imaging genetic paradigms, we investigated whether individual default network connectivity was modulated by COMT val(158)met in 57 healthy young subjects. Compared with COMT heterozygous individuals, homozygous val individuals showed significantly decreased prefrontal-related connectivities, which primarily occurred between prefrontal regions and the posterior cingulate/restrosplenial cortices. Further analyses of the topological characteristics of the default network showed homozygous val individuals had significantly fewer node degrees in the prefrontal regions. This finding may partially elucidate previous reports that the COMT val variant is associated with inefficient prefrontal information processing and poor cognitive performance. Our findings suggest that default network connectivity that involves the prefrontal cortex is modulated by COMT val(158)met through differential effects on prefrontal dopamine levels.

The Effects of COMT (Val108/158Met) and DRD4 (SNP −521) Dopamine Genotypes on Brain Activations Related to Valence and Magnitude of Rewards

Abstract: People’s sensitivity to reinforcing stimuli such as monetary gains and losses shows a wide interindividual variation that might in part be determined by genetic differences. Because of the established role of the dopaminergic system in the neural encoding of rewards and negative events, we investigated young healthy volunteers being homozygous for either the Valine or Methionine variant of the catechol-O-methyltransferase (COMT) codon 158 polymorphism as well as homozygous for the C or T variant of the SNP 2521 polymorphism of the dopamine D4 receptor. Participants took part in a gambling paradigm featuring unexpectedly high monetary gains and losses in addition to standard gains/losses of expected magnitude while undergoing functional magnetic resonance imaging at 3 T. Valence-related brain activations were seen in the ventral striatum, the anterior cingulate cortex, and the inferior parietal cortex. These activations were modulated by the COMT polymorphism with greater effects for valine/valine participants but not by the D4 receptor polymorphism. By contrast, magnituderelated effects in the anterior insula and the cingulate cortex were modulated by the D4 receptor polymorphism with larger responses for the CC variant. These findings emphasize the differential contribution of genetic variants in the dopaminergic system to various aspects of reward processing.

Executive functions and memory abilities in children with 22q11.2 deletion syndrome

Abstract: Objective: Velo-cardio-facial syndrome or 22q11.2 deletion syndrome (22q11DS) is the most common known microdeletion syndrome. One of the genes in the deleted region is the catechol-O-methyltransferase (COMT) gene, which is thought to have significant effects on cognition through its influence on dopamine metabolism. The aim of the present study was to better characterize the cognitive phenotype in a large cohort children with 22q11DS compared with sibling controls and to investigate if the cognitive deficits in 22q11DS were modulated by COMT expression.Method: The memory, executive function and attentional abilities of children with 22q11DS (n = 50) compared to sibling controls (n = 31), were measured. Also, within children with 22q11DS, a preliminary exploration was carried out of the relationship between cognitive ability and COMT genotype.Results: Overall, the 22q11DS group had significantly reduced scores on tests of memory (especially in visual memory) and executive function (particularly in plannin...

Polymorphisms in Dopamine System Genes Are Associated With Individual Differences in Attention in Infancy

Abstract: Knowledge about the functional status of the frontal cortex in infancy is limited. This study investigated the effects of polymorphisms in four dopamine system genes on performance in a task developed to assess such functioning, the Freeze-Frame task, at 9 months of age. Polymorphisms in the catechol-O-methyltransferase (COMT) and the dopamine D4 receptor (DRD4) genes are likely to impact directly on the functioning of the frontal cortex, whereas polymorphisms in the dopamine D2 receptor (DRD2) and dopamine transporter (DAT1) genes might influence frontal cortex functioning indirectly via strong frontostriatal connections. A significant effect of the COMT valine158methionine (Val158Met) polymorphism was found. Infants with the Met/Met genotype were significantly less distractible than infants with the Val/Val genotype in Freeze-Frame trials presenting an engaging central stimulus. In addition, there was an interaction with the DAT1 3′ variable number of tandem repeats polymorphism; the COMT effect was present only in infants who did not have two copies of the DAT1 10-repeat allele. These findings indicate that dopaminergic polymorphisms affect selective aspects of attention as early as infancy and further validate the Freeze-Frame task as a frontal cortex task.

Sensorimotor Gating of Schizophrenia Patients Depends on Catechol O-Methyltransferase Val158Met Polymorphism

Abstract: It has been recently shown that Catechol O-methyltransferase (COMT) Val 158 Met polymorphism strongly influences prepulse inhibition (PPI) of the acoustic startle response (ASR) in healthy human volunteers. Given that schizophrenia patients exhibit impairment in PPI and that COMT is a putative susceptibility gene for schizophrenia, we investigated the impact of the COMT Val 158 Met polymorphisms on PPI in schizophrenic inpatients. We analyzed COMT Val 158 Met polymorphisms and assessed startle reactivity, habituation, and PPI of ASR in 68 Caucasian schizophrenia inpatients. Clinical symptoms were measured with the Positive and Negative Syndrome Scale (PANSS). Patients carrying the Val 158 Met Met/Met allele showed elevated PPI levels whereas startle reactivity and habituation did not differ from the other two genotypes. These preliminary results imply that PPI is influenced by COMT Val 158 Met genotype in schizophrenia as well. In concert with other findings, our data suggest that PPI is a polygenic trait.

Catechol-O-methyl transferase and schizophrenia

Abstract: SUMMARY Catechol-O-methyl transferase (COMT) is an enzyme involved in the degradation of dopamine. The most commonly examined polymorphism within the COMT gene is Val108/158Met polymorphism, which results in three to fourfold difference in COMT enzyme activity. It is particularely important in prefrontal cortex, since COMT activity is the most important regulator of the prefrontal dopamine function. Given the association between schizophrenia and decreased dopamine activity in the prefrontal cortex, it is not surprising that Val108/158Met polymorphism is among the most extensively investigated polymorphisms in schizophrenia. According to different studies, Val allele may be a small risk factor for schizophrenia. There is also some evidence that Val108/158Met polymorphism influences the age of onset of schizophrenia, cognitive function, severity of psychotic symptoms, as well as efficacy and adverse events of antipsychotics. Heterogenity of patient population has undoubtedly influenced the results of these studies. Interaction of Val108/158Met polymorphism with other genes and environmental factors is an important avenue for future research.

COMT Val108/158 Met Genotype Affects Neural but not Cognitive Processing in Healthy Individuals

Abstract: The relationship between cognition and a functional polymorphism in the catechol-O-methlytransferase (COMT) gene, val108/158met, is one of debate in the literature. Furthermore, based on the dopaminergic differences associated with the COMT val108/158met genotype, neural differences during cognition may be present, regardless of genotypic differences in cognitive performance. To investigate these issues the current study aimed to 1) examine the effects of COMT genotype using a large sample of healthy individuals (n = 496–1218) and multiple cognitive measures, and using a subset of the sample (n = 22), 2) examine whether COMT genotype effects medial temporal lobe (MTL) and frontal activity during successful relational memory processing, and 3) investigate group differences in functional connectivity associated with successful relational memory processing. Results revealed no significant group difference in cognitive performance between COMT genotypes in any of the 19 cognitive measures. However, in the subset sample, COMT val homozygotes exhibited significantly decreased MTL and increased prefrontal activity during both successful relational encoding and retrieval, and reduced connectivity between these regions compared with met homozygotes. Taken together, the results suggest that although the COMT val108/158met genotype has no effect on cognitive behavioral measures in healthy individuals, it is associated with differences in neural process underlying cognitive output.

Catechol-O-methyltransferase and pain.

Abstract: In animals, different types of COMT inhibitors, irrespective of their brain penetration, are pro-nociceptive in several models of acute and inflammatory pain. Similarly, COMT knock-out mice are more sensitive to nociceptive stimuli, whereas in mice over-expressing a high activity COMT variant nociceptive sensitivity is decreased. COMT knock-out mice also show altered response to opioids and stress-induced analgesia. In different rat models of neuropathic pain, the action of nitecapone is opposite: it is antinociceptive and antiallodynic. Complex actions of low COMT activity may be caused by enhanced adrenergic and dopaminergic activities that play different and even contrasting roles at different parts of the nociceptive system. Also compensatory changes in other neurotransmitters may occur. Pro-nociceptive effects seem to be caused by increased activation of peripheral adrenergic β(2)- and β(3) -receptors. Other properties of COMT inhibitors, like scavenging of oxygen and nitrogen radicals, may be important in antiallodynic effects found in neuropathic pain models. Increased number of µ-opioid receptors in certain brain areas may be responsible of enhanced opioid effects associated with a low COMT activity. In human pain studies, a low COMT activity is often associated with increased pain sensitivity in experimental pain models and with increased pre- and postoperative pain in acute clinical situations. As a rule, a simultaneous occurrence of several SNPs within the haplotype, causing low COMT activity, is more often associated with pain than any single SNP alone. In experimental pain studies, all negative findings resulted from concentrating solely on SNP rs4680 (Val158Met). Virtually all studies assessing haplotypes were able to confirm an association of a low COMT and increased pain. In chronic clinical pain, the effect of COMT polymorphisms depends on the pain conditions. Hence, in neuropathic and cancer pains, COMT activity is meaningless but in some chronic musculoskeletal pain conditions and migraine or headache low COMT activity appears to increase incidence and symptoms. A low COMT activity also increases availability of opioid receptors and may enhance opioid analgesia and adverse effects at least in cancer pains.

Inhibition of catechol-O-methyltransferase activity in human breast cancer cells enhances the biological effect of the green tea polyphenol (-)-EGCG

Abstract: Tea is one of the most popular beverages in the world and has been studied extensively as a health-promoting beverage that may act to prevent a number of chronic diseases and cancers. (-)-Epigallocatechin gallate [(-)-EGCG], a major component in green tea, is unstable under physiological conditions and methylation of (-)-EGCG by catechol-Omicron-methyltransferase (COMT) is a modification that reduces the biological activity of (-)-EGCG. In the current study, we hypothesized that suppression of COMT activity in human breast cancer cells could increase the proteasome-inhibitory potency of (-)-EGCG and therefore enhance its tumor cell growth-inhibitory activity. We first determined the COMT genotype and basal levels of COMT activity in various human breast cancer cell lines. Furthermore, when breast cancer MDA-MB-231 cells containing high COMT activity were tested, the diminished COMT activity apparently increased the effectiveness of (-)-EGCG via augmented proteasome inhibition and apoptosis induction. This study supplements the previous findings that methylated (-)-EGCG is less bioactive and supports the notion that COMT inhibition may increase the anti-cancer properties of tea polyphenols and the combination may serve as a novel approach or supplemental treatment for breast cancer chemotherapy.

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

Abstract: 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.

Catechol-O-Methyltransferase (COMT) Val158Met variations and cannabis use in first-episode non-affective psychosis: clinical-onset implications.

Abstract: New models of interaction between genetic and environmental factors have been proposed to explain the pathogenesis of schizophrenia. The Val158Met polymorphism of the COMT (Catechol-O-Methyltransferase) gene, involved in dopamine regulation and related to negative symptoms, has been previously thought to interact with cannabis use in the modulation of risk of psychosis. The aim of the study was to explore the existence of an interaction between COMT genotype and cannabis use in early stages of psychosis and its effects on the age of onset in a representative group of first-episode psychosis patients. Age of onset, DUP (Duration of Untreated Psychosis) and cannabis use (regular user versus sporadic or non-user) were assessed in 169 Caucasian patients with a first-episode schizophrenia spectrum disorder. COMT polymorphism was typed using PCR of the relevant region followed by digestion with NlaIII and electrophoresis. A multivariate ANCOVA was performed with DUP and age of onset as dependent variables, cannabis and the COMT genotype as fixed factors, and gender as a covariate. The MANCOVA was significant for age of onset and DUP. Cannabis users had a significant earlier age of onset. Age of onset was later in the Met homozygote group (non-significant). The cannabis-COMT interaction showed a significant effect on both DUP and age of onset. Post hoc analyses showed that differences between genotypes were only present in the non-users' group. Based on these results, the use of cannabis could exert a modulator effect on the genotype, suppressing the delay effect for the age of onset in the case of the Met allele patients.

Interaction of chronic stress with serotonin transporter and catechol-O-methyltransferase polymorphisms in predicting youth depression.

Abstract: Background: Investigations of gene environment interaction (G x E) in depression have implicated a polymorphism in the promoter region of the serotonin transporter gene (5-HTTLPR) as a moderator of the stress depression relationship. However, recent evidence for 5-HTTLPR G x E in depression has been inconsistent. This study examined the moderating effect of the val158met polymorphism in the catechol-O-methyltransferase (COMT) gene on the strength of 5-HTTLPR G x E. Methods: A community sample of youth (n = 384) was genotyped for 5-HTTLPR and COMT. A multi-method, multi-informant index of chronic family stress was derived from interviews and questionnaires administered at youth age 15. G x G x E was examined in relation to depression diagnoses between ages 15 and 20 and depressive symptoms at age 20. Results: Significant three-way interactions were observed for both depressive symptoms and diagnoses, such that 5-HTTLPR G x E occurred only in the context of COMT val158 allele homozygosity. For val158 homozygotes, the 5-HTTLPR LL genotype exerted a protective effect in the face of stress. No genetic main effect or two-way G x E was found for 5-HTTLPR. Conclusions: Inconsistent 5-HTTLPR G x E findings to date may be partly attributable to unmeasured epistatic effects between 5-HTTLPR and COMT val158met. Identifying the conditions under which 5-HTTLPR G x E is most likely to operate may allow depression prevention and treatment efforts to target youth at highest risk. Depression and Anxiety 27:737-745, 2010. (C) 2010 Wiley-Liss, Inc.

Catechol-O-methyltransferase val158met genotype modulates sustained attention in both the drug-free state and in response to amphetamine.

Abstract: Catechol-O-methyltransferase (COMT) is an enzyme which metabolizes catecholamines and catechol-estrogens in both the CNS and periphery. The discovery of a common functional genetic variant at codon 158 (val158met) (Lachman et al.,1996; Lotta et al.,1995) led to the observation that individuals who were homozygous for the val allele performed more poorly than other genotypic groups on tasks of executive function (Egan et al., 2001). The differences in performance have been attributed to localized function of COMT in the prefrontal system. Further these differences appear to contribute to individual differences in responses to stimulant drugs, such as d-amphetamine (Mattay et al, 2003). However, given the complex modulation and functional heterogeneity of frontal lobe systems, further evaluation of COMT val158met-related phenotypes is needed. Here, we examined additional measures of cognition, including lapses in attention and general measures of visuo-spatial-motor speed of processing, as well as self-reports of mood, both without a drug and in response to acute administration of d-amphetamine. Dopamine (DA) is removed from the synapse in most parts of the brain by the dopamine transporter, but in the frontal cortex, the DA is cleared mainly by the catabolic enzyme COMT (Karoum et al., 1994). The substitution of methionine (met) for valine (val) at codon 158 in the COMT gene (COMT) leads to a lower enzymatic activity so that met/met carriers have higher synaptic levels of DA in the frontal cortex, which appears to improve their performance on measures of executive function and working memory (Mattay et al., 2003; Egan et al., 2001; Turnbridge et al., 2006). Both environmental factors and pharmacologic manipulations modify the effects of COMT val158met genotype on cognition. For example, years of education – one possible marker of socioeconomic status – interacts with the COMT val158met genotype such that met/met carriers' cognitive scores improve markedly with increasing years of education, whereas the scores of val/val individuals are only marginally influenced by years of education (Enoch et al., 2009). Interestingly, in one study (Mattay et al., 2003) the psychostimulant d-amphetamine, which increases synaptic DA levels, worsened executive function and working memory of met/met carriers, whereas it improved performance among val/val carriers. This was explained as an inverted “U” functional response curve so that performance is improved by modest increases in synaptic DA levels, but impaired when levels exceed a certain optimal level. The goal of the present study was to further characterize the function of COMT val158met by analyzing 1. Whether genotypic groups differ in drug free condition on measures of motor processing and attention, and 2. Whether genotypic groups differ on their responses to these measures following administration of d-amphetamine. We used two measures of cognition - the Digit Symbol Substitution Test (DSST; Wechsler, 1958), which provides a non-specific measure of visuo-spatial and motor speed-of-processing, and Deviation from the Mode (DevMod), a new measure of lapses in attention (de Wit 2009), derived from a simple reaction time task. We used a task measuring lapses in attention to obtain important information about moment-to-moment fluctuations in task performance. In addition to these measures of cognitive function, we also evaluated mood states using Profile of Mood States (McNair et al., 1971) and personality, using Multidimensional Personality Questionnaire (Tellegen, 1982). We hypothesized that the val/val carriers would perform more poorly than met/met carriers on lapses in attention and visuo-spatial-motor speed of processing tasks in the absence of pharmacologic manipulation, consistent with what has been reported on other measures of cognition. In addition, we hypothesized that val/val carriers would exhibit a greater improvement in performance after d-amphetamine than met/met carriers. We did not expect that these genotypic groups would differ in the mood-altering effects of d-amphetamine because these effects are not believed to be mediated in brain regions where COMT plays a major role (Volkow, 1997). Studies of this kind, investigating the relationships between genotype and responses to drugs, will help to explain inter-individual variability in responses to drugs, including drugs such as stimulants that are used in clinical settings. These studies will also help to identify the separate brain processes that mediate the cognitive and mood-altering effects of drugs.

A Transposon in Comt Generates mRNA Variants and Causes Widespread Expression and Behavioral Differences among Mice

Abstract: Background Catechol-O-methyltransferase (COMT) is a key enzyme responsible for the degradation of dopamine and norepinephrine. COMT activity influences cognitive and emotional states in humans and aggression and drug responses in mice. This study identifies the key sequence variant that leads to differences in Comt mRNA and protein levels among mice, and that modulates synaptic function and pharmacological and behavioral traits. Methodology/Principal Findings We examined Comt expression in multiple tissues in over 100 diverse strains and several genetic crosses. Differences in expression map back to Comt and are generated by a 230 nt insertion of a B2 short interspersed element (B2 SINE) in the proximal 3′ UTR of Comt in C57BL/6J. This transposon introduces a premature polyadenylation signal and creates a short 3′ UTR isoform. The B2 SINE is shared by a subset of strains, including C57BL/6J, A/J, BALB/cByJ, and AKR/J, but is absent in others, including DBA/2J, FVB/NJ, SJL/J, and wild subspecies. The short isoform is associated with increased protein expression in prefrontal cortex and hippocampus relative to the longer ancestral isoform. The Comt variant causes downstream differences in the expression of genes involved in synaptic function, and also modulates phenotypes such as dopamine D1 and D2 receptor binding and pharmacological responses to haloperidol. Conclusions/Significance We have precisely defined the B2 SINE as the source of variation in Comt and demonstrated that a transposon in a 3′ UTR can alter mRNA isoform use and modulate behavior. The recent fixation of the variant in a subset of strains may have contributed to the rapid divergence of inbred strains.

Association between hypnotizability and the catechol-O-methyltransferase (COMT) polymorphism.

Abstract: Previous studies implicate involvement of dopaminergic systems in hypnotizability and report association with the COMT Val158Met single nucleotide polymorphism (SNP, rs4680) demonstrating the Val/Met heterozygotes as the most hypnotizable group using the Stanford Hypnotic Susceptibility Scale. This study replicates that association using an independent sample of 127 healthy Hungarian young adults and the Waterloo-Stanford Group C Scale of Hypnotic Susceptibility. Significant association (p = .016) was found between the COMT genotypes and hypnotizability, with a clear additive effect of the Val allele: Hypnotizability scores were highest in Val/Val (5.9), intermediate in Val/Met (4.7), and lowest in Met/Met (4.1). Differences between these results and those of previous studies support recent findings suggesting an inverted-U-shaped relation between dopamine level in the prefrontal cortex and cognitive functioning. The present study replicates association of COMT Val158Met SNP and hypnotizability a...

Catechol-O-methyltransferase val158met and cognitive function in Parkinson's disease

Abstract: Cognitive dysfunction is one of the most incapacitating non-motor symptoms of Parkinson's disease (PD). Some cognitive deficits are thought to be related to abnormal dopamine homeostasis. The latter is influenced by catechol-O-methyltransferase (COMT), an enzyme that degrades dopamine. Previous research suggests a relationship between the COMT val158met functional polymorphism (SNP) and measures of executive function. We evaluated this hypothesis in a cohort of PD patients with an extensive neuropsychological test battery. Cognitive assessment and COMT genotyping were performed in 153 early PD patients from outpatient clinics general hospitals in the Netherlands. Our results do not support a direct effect of COMT val158met genotype on performance on neuropsychological measures of attention and executive function, but they suggest that genotype may interact with dopaminergic medication use to influence cognitive ability.