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Showing papers on "Catechol-O-methyl transferase published in 2004"


Journal ArticleDOI
TL;DR: Val is a predominant factor that determines higher COMT activity in the prefrontal cortex, which presumably leads to lower synaptic dopamine levels and relatively deleterious prefrontal function.
Abstract: Catechol-O-methyltransferase (COMT) is a key enzyme in the elimination of dopamine in the prefrontal cortex of the human brain. Genetic variation in the COMT gene (MIM 116790) has been associated with altered prefrontal cortex function and higher risk for schizophrenia, but the specific alleles and their functional implications have been controversial. We analyzed the effects of several single-nucleotide polymorphisms (SNPs) within COMT on mRNA expression levels (using reverse-transcriptase polymerase chain reaction analysis), protein levels (using Western blot analysis), and enzyme activity (using catechol methylation) in a large sample (n = 108) of postmortem human prefrontal cortex tissue, which predominantly expresses the -membrane-bound isoform. A common coding SNP, Val158Met (rs4680), significantly affected protein abundance and enzyme activity but not mRNA expression levels, suggesting that differences in protein integrity account for the difference in enzyme activity between alleles. A SNP in intron 1 (rs737865) and a SNP in the 3′ flanking region (rs165599)—both of which have been reported to contribute to allelic expression differences and to be associated with schizophrenia as part of a haplotype with Val—had no effect on mRNA expression levels, protein immunoreactivity, or enzyme activity. In lymphocytes from 47 subjects, we confirmed a similar effect on enzyme activity in samples with the Val/Met genotype but no effect in samples with the intron 1 or 3′ SNPs. Separate analyses revealed that the subject's sex, as well as the presence of a SNP in the P2 promoter region (rs2097603), had small effects on COMT enzyme activity. Using site-directed mutagenesis of mouse COMT cDNA, followed by in vitro translation, we found that the conversion of Leu at the homologous position into Met or Val progressively and significantly diminished enzyme activity. Thus, although we cannot exclude a more complex genetic basis for functional effects of COMT, Val is a predominant factor that determines higher COMT activity in the prefrontal cortex, which presumably leads to lower synaptic dopamine levels and relatively deleterious prefrontal function.

1,596 citations


Journal ArticleDOI
TL;DR: It is hypothesized that the COMT Met allele (associated with low enzyme activity) results in increased levels of tonic DA and reciprocal reductions in phasic DA in subcortical regions and increased D1 transmission cortically.

759 citations


Journal ArticleDOI
TL;DR: It is concluded that COMT activity specifically affects ED set shifting and is a significant modulator of mPFC DA but not NE under conditions of increased catecholaminergic transmission, suggesting that the links between COMTActivity and PFC function can be modeled in rats and may be specifically mediated by DA.
Abstract: The Val158Met polymorphism of the human catechol-O-methyltransferase (COMT) gene affects activity of the enzyme and influences performance and efficiency of the prefrontal cortex (PFC); however, although catecholaminergic neurotransmission is implicated, the underlying mechanisms remain elusive because studies of the role of COMT in PFC function are sparse. This study investigated the effect of tolcapone, a brain-penetrant COMT inhibitor, on a rat model of attentional set shifting, which is dependent on catecholamines and the medial PFC (mPFC). Additionally, we investigated the effect of tolcapone on extracellular catecholamines in the mPFC using microdialysis in awake rats. Tolcapone significantly and specifically improved extradimensional (ED) set shifting. Tolcapone did not affect basal extracellular catecholamines, but significantly potentiated the increase in extracellular dopamine (DA) elicited by either local administration of the depolarizing agent potassium chloride or systemic administration of the antipsychotic agent clozapine. Although extracellular norepinephrine (NE) was also elevated by local depolarization and clozapine, the increase was not enhanced by tolcapone. We conclude that COMT activity specifically affects ED set shifting and is a significant modulator of mPFC DA but not NE under conditions of increased catecholaminergic transmission. These data suggest that the links between COMT activity and PFC function can be modeled in rats and may be specifically mediated by DA. The interaction between clozapine and tolcapone may have implications for the treatment of schizophrenia.

414 citations


Journal ArticleDOI
TL;DR: The authors achieved a level of specificity never previously attempted; the COMT polymorphism was found to be differentially related to performance on tasks linked to the same prefrontal region by whether cognitive requirements of the tasks were sensitive to the level of dopamine found.
Abstract: OBJECTIVE: The catechol O-methyltransferase (COMT) gene affects how long dopamine acts in the prefrontal cortex. The Methionine polymorphism, which results in a slower breakdown of prefrontal dopamine, is associated with better adult prefrontal cortex function. The authors investigated the relation between the COMT gene polymorphism and cognitive performance in children. METHOD: Children were tested on cognitive tasks that depend on the dorsolateral prefrontal cortex and seem to be sensitive to the level of dopamine there (dots-mixed task), depend on that neural region but appear insensitive to its dopamine content (self-ordered pointing), and depend on other neural systems (recall memory and mental rotation). After data collection, cheek swabs were obtained from all children. DNA was extracted and genotyped for the COMT gene with polymerase chain reaction. RESULTS: Children who were homozygous for the Methionine polymorphism performed significantly better on the dots-mixed task but not on others. CONCLUS...

371 citations


Journal ArticleDOI
TL;DR: In this article, the effect of the COMT genotype on symptom variation, working memory performance, and prefrontal cortical physiology in response to treatment with an atypical antipsychotic drug was evaluated in patients with schizophrenia.
Abstract: OBJECTIVE: Deficits in working memory and in prefrontal cortical physiology are important outcome measures in schizophrenia, and both have been associated with dopamine dysregulation and with a functional polymorphism (Val108/158Met) in the catechol O-methyltransferase (COMT) gene that affects dopamine inactivation in the prefrontal cortex. The purpose of the present study was to evaluate in patients with schizophrenia the effect of COMT genotype on symptom variation, working memory performance, and prefrontal cortical physiology in response to treatment with an atypical antipsychotic drug. METHOD: Thirty patients with acute untreated schizophrenia were clinically evaluated with the Positive and Negative Syndrome Scale, underwent COMT Val/Met genotyping, and entered an 8-week prospective study of olanzapine treatment. Twenty patients completed two 3-T functional magnetic resonance imaging scans at 4 and 8 weeks during performance of N-back working memory tasks. RESULTS: There was a significant interaction...

290 citations


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

232 citations


Journal ArticleDOI
TL;DR: The results seem to confirm the role of COMT genotype in the modulation of executive functions related to frontal lobe function in healthy individuals but not in schizophrenia patients.
Abstract: OBJECTIVE: Using a sample of sibling pairs discordant for psychosis, the authors attempted to replicate the findings of previous studies suggesting that the functional genetic polymorphism Val158Met in the catechol O-methyltransferase (COMT) gene influences prefrontal cognitive function and increases the risk for schizophrenia. METHOD: Eighty-nine sibling pairs discordant for psychosis were genotyped for this polymorphism and were assessed with the Wisconsin Card Sorting Test, a measure of prefrontal function. Additionally, the preferential transmission of alleles for this polymorphism was analyzed in a sample of 89 nuclear families in order to examine the genetic association. RESULTS: In the healthy siblings, a linear relationship was seen in which performance on the Wisconsin Card Sorting Test was associated in an allele dosage fashion with COMT genotype (i.e., fewer perseverative errors with higher number of methionine alleles). However, this association was not observed in patients. Furthermore, no ev...

175 citations


Journal ArticleDOI
TL;DR: The association between COMT and bipolar disorder was tested by examining the allele and haplotype found to be associated with schizophrenia and a significant association between bipolar disorder and COMT polymorphisms was found.
Abstract: A variety of psychiatric illnesses, including schizophrenia and bipolar disorder, have been reported in patients with microdeletion on chromosome 22q11-a region which includes the catechol-O-methyltransferase (COMT) gene. The variety of psychiatric manifestations in patients with the 22q11 microdeletion and the role of COMT in the degradation of catecholamine neurotransmitters may thus suggest a general involvement of the COMT gene in psychiatric diseases. We have previously reported on a significant association between a COMT haplotype and schizophrenia. In this study, we attempt to test for association between bipolar disorder and the polymorphisms implicated in schizophrenia. The association between COMT and bipolar disorder was tested by examining the allele and haplotype found to be associated with schizophrenia. A significant association between bipolar disorder and COMT polymorphisms was found. The estimated relative risk is greater in women, a result consistent with our previous findings in schizophrenia. We suggest that polymorphisms in the COMT gene may influence susceptibility to both diseases--and probably also a wider range of behavioral traits.

170 citations


Journal ArticleDOI
TL;DR: Observations represent steps toward an understanding of molecular genetic mechanisms responsible for variation in COMT level and/or properties, variation that may contribute to the pathophysiology of neuropsychiatric disease.
Abstract: Catechol O-methyltransferase (COMT) plays an important role in the metabolism of catecholamines, catecholestrogens and catechol drugs. A common COMT G472A genetic polymorphism (Val108/158Met) that was identified previously is associated with decreased levels of enzyme activity and has been implicated as a possible risk factor for neuropsychiatric disease. We set out to 'resequence' the human COMT gene using DNA samples from 60 African-American and 60 Caucasian-American subjects. A total of 23 single nucleotide polymorphisms (SNPs), including a novel nonsynonymous cSNP present only in DNA from African-American subjects, and one insertion/deletion were observed. The wild type (WT) and two variant allozymes, Thr52 and Met108, were transiently expressed in COS-1 and HEK293 cells. There was no significant change in level of COMT activity for the Thr52 variant allozyme, but there was a 40% decrease in the level of activity in cells transfected with the Met108 construct. Apparent K(m) values of the WT and variant allozymes for the two reaction cosubstrates differed slightly, but significantly, for 3,4-dihydroxybenzoic acid but not for S-adenosyl-L-methionine. The Met108 allozyme displayed a 70-90% decrease in immunoreactive protein when compared with WT, but there was no significant change in the level of immunoreactive protein for Thr52. A significant decrease in the level of immunoreactive protein was also observed in hepatic biopsy samples from patients homozygous for the allele encoding Met108. These observations represent steps toward an understanding of molecular genetic mechanisms responsible for variation in COMT level and/or properties, variation that may contribute to the pathophysiology of neuropsychiatric disease.

154 citations


Journal ArticleDOI
TL;DR: Division of episodic memory into its recall and recognition components showed that the difference was specific to episodic recall, not recognition tasks; an effect that was observed across three age groups (middle-age, young-old, and old-old adults) and over a 5-year period.
Abstract: Variation in memory performance is to a large extent explained by genes. In the prefrontal cortex, the catechol O-methyltransferase (COMT) gene is essential in the metabolic degradation of dopamine, a neurotransmitter implicated in cognitive functions. The present study examined the effect of a polymorphism in the COMT gene on individual differences and changes in memory in adulthood and old age. Tests assessing episodic and semantic memory were administered to 286 men (initially aged 35-85 years) from a random sample of the population (i.e., the Betula prospective cohort study) at two occasions followed over a 5-year period. Carriers of the Met/Met genotype (with low enzyme activity) performed better on episodic and semantic memory, as compared to carriers of the Val allele (with higher enzyme activity). Division of episodic memory into its recall and recognition components showed that the difference was specific to episodic recall, not recognition tasks; an effect that was observed across three age groups (middle-age, young-old, and old-old adults) and over a 5-year period. The COMT gene is a plausible candidate gene for memory functioning in adulthood and old age.

151 citations


Journal ArticleDOI
TL;DR: The genotyping of a single nucleotide polymorphism in the coding region of the catechol-O-methyl-transferase (COMT) gene supports a role of the 472G/A (V158M) COMT polymorphism or a nearby locus in the pathogenesis of panic disorder in women.
Abstract: Panic disorder is an anxiety disorder with an estimated heritability of up to 48%. Pharmacological and genetic studies suggest that genes coding for proteins involved in the catecholaminergic system might be relevant for the pathogenesis of the disease. In the present study, we genotyped a single nucleotide polymorphism (472G/A=V158M) in the coding region of the catechol- O -methyl-transferase (COMT) gene in 115 patients with panic disorder and age- and sex-matched controls. Association analysis revealed a significant excess of the more active COMT allele (472G=V158) in patients with panic disorder ( p =0.04), particularly in female patients ( p =0.01), but not in male patients ( p =1.0). The assessment of a possible interaction of the COMT polymorphism with a previously reported functional 30-bp VNTR in the monoamine oxidase A promoter (MAOA–LPR) in female patients did not yield significant results. Our data support a role of the 472G/A (V158M) COMT polymorphism or a nearby locus in the pathogenesis of panic disorder in women.

Journal ArticleDOI
TL;DR: Reports of inconsistencies in the relationship between catechol-O-methyltransferase valine158 methionine genotypes and cognition were not resolved, however, catecholl-o-methyl transferase genotype may affect expression of negative schizotypy by direct or indirect effects on central dopamine neurotransmitter signaling.

Journal ArticleDOI
TL;DR: The results of this study support other data suggesting that the COMT val(108/158)met polymorphism might be an important factor in the cognitive response to antipsychotic medication.

Journal ArticleDOI
TL;DR: Elevated SAH in Alzheimer brain inhibits methyltransferases and is related to markers of disease progression and cognitive impairment in Alzheimer’s disease.
Abstract: Hyperhomocysteinemia is common in Alzheimer’s disease and is negatively correlated with cognitive function. Hyperhomocysteinemia can increase S-adenosylhomocysteine (SAH), a potent methyltransferase inhibitor. This study investigates the role of brain SAH in the cognitive and neurological disruption in Alzheimer’s disease. SAH was significantly (26%) higher in prefrontal cortex of Alzheimer patients than normals. Brain homogenates from Alzheimer patients inhibited an exogenous methyltransferase 15% more than normal homogenates (P < .001). Brain SAH levels correlated (r=.508) with methyltransferase inhibition by brain homogenates. Methyltransferase inhibition by Alzheimer brain homogenates correlated inversely with cognitive function as determined by MMSE (r=−0.36). Phenylethanolamine N-methyltransferase (PNMT) and catechol O-methyltransferase (COMT) activities were more than 30% lower (P<0.001) in Alzheimer than normal brains. Brain PNMT activity correlated significantly with cognitive function (r=0.243), age of Alzheimer’s onset (r=0.272), and choline acetyltransferase activity (r=0.333), but negatively with neurofibrillary tangles (r=−0.332). COMT activity also correlated significantly with cognitive function (r=0.324), age of disease onset (r=0.209), choline acetyltransferase activity (r=0.326), levels of synaptophysin (r=0.506), and negatively with tangles (r=−0.216 P=0.039). Elevated SAH in Alzheimer brain inhibits methyltransferases and is related to markers of disease progression and cognitive impairment.

Journal ArticleDOI
TL;DR: The study of association of COMT with schizophrenia in Irish families with a high density of schizophrenia concluded that COMT gene is associated with schizophrenia and carries a small but significant risk to the susceptibility in the Irish subjects.
Abstract: The enzyme catechol-o-methyltransferase (COMT) transfers a methyl group from adenosylmethionine to catecholamines including the neurotransmitters dopamine, epinephrine and norepinephrine This methylation results in the degradation of catecholamines The involvement of the COMT gene in the metabolic pathway of these neurotransmitters has made it an attractive candidate gene for many psychiatric disorders In this article, we reported our study of association of COMT with schizophrenia in Irish families with a high density of schizophrenia Three single nucleotide polymorphisms (SNPs) were genotyped for the 274 such families and within-family transmission disequilibrium tests were performed SNP rs4680, which is the functional Val/Met polymorphism, showed modest association with the disease by the TRANSMIT, FBAT and PDT programs, while the other two SNPs were negative These SNPs showed lower level of LDs with each other in the Irish subjects than in Ashkenazi Jews Haplotype analysis indicated that a haplotype, haplotype A-G-A for SNPs rs737865-rs4680-rs165599, was preferentially transmitted to the affected subjects This was different from the reported G-G-G haplotype found in Ashkenazi Jews, but both haplotypes shared the Val allele We concluded that COMT gene is associated with schizophrenia and carries a small but significant risk to the susceptibility in the Irish subjects

Journal ArticleDOI
TL;DR: The results suggest that the COMT L/L genotype is associated with PD and the genetic variant of theCOMT enzyme may be related to the clinical severity and treatment response to paroxetine in PD.

Journal ArticleDOI
TL;DR: Data from this study are consistent with those of previous studies in normal individuals, suggesting that a functional genetic polymorphism in the 22q11 region may influence prefrontal cognition in individuals with COMT haploinsufficiency.
Abstract: OBJECTIVE: The 22q11.2 deletion syndrome (DiGeorge/velocardiofacial syndrome) is associated with attentional problems and executive dysfunction, and is one of the highest known risk factors for schizophrenia. These behavioral manifestations of 22q11.2 deletion syndrome could result from haploinsufficiency of the catechol O-methyltransferase (COMT) gene, located within the 22q11 region. The goal of the present study was to examine COMT genotype as a predictor of prefrontal cognitive function in patients with 22q11.2 deletion syndrome. METHOD: Patients with confirmed 22q11.2 deletions (N=44) underwent neurocognitive testing following Val158Met genotyping (Met hemizygous: N=16; Val hemizygous: N=28). RESULTS: Analyses of covariance revealed that Met-hemizygous patients performed significantly better on a composite measure of executive function (comprising set-shifting, verbal fluency, attention, and working memory) than did Val-hemizygous patients. CONCLUSIONS: These data are consistent with those of previou...

Journal ArticleDOI
TL;DR: The present study suggests that the functional COMT Val158Met genetic polymorphism contributes to individual differences in the personality traits novelty seeking and reward dependence.
Abstract: Human personality traits, which are substantially heritable, may be modulated by monoamine neurotransmitters. It has been demonstrated that the catechol-O-methyltransferase (COMT) V

Journal ArticleDOI
TL;DR: The results suggest that the C516T variant of the 5HT2A gene may be one of the genetic risk factors for OCD in the sample, however, further studies using larger samples and family based methods are recommended to confirm these findings.
Abstract: Family and twin studies have supported a strong genetic factor in the etiology of obsessive-compulsive disorder (OCD), although the precise mechanism of inheritance is unclear. Clinical and pharmacological studies have implicated the serotonergic and dopaminergic systems in disease pathogenesis. In this cross-sectional study, we have examined the allelic and genotypic frequencies of a Val-158-Met substitution in the COMT gene, a 44-base pair (bp) length variation in the regulatory region of the serotonin transporter gene (5-HTTLPR) and the T102C and C516T variants in the serotonin receptor type 2A (5HT2A) gene in 79 OCD patients and 202 control subjects. There were no observed differences in the frequencies of allele and genotype between patients and control groups for the COMT, the 5HTTLPR and the T102C 5HT2A gene polymorphisms. In contrast, a statistically significant difference between OCD patients and controls was observed on the genotypic distribution (χ2 = 16.7, 2df, P = 0.0002) and on the allelic frequencies (χ2 = 15.8, 1df, P = 0.00007) for the C516T 5HT2A gene polymorphism. The results suggest that the C516T variant of the 5HT2A gene may be one of the genetic risk factors for OCD in our sample. However, further studies using larger samples and family based methods are recommended to confirm these findings.

Journal ArticleDOI
TL;DR: It is concluded that genetic variation in the dopamine system may encode an additive effect on risk of becoming a methamphetamine abuser.
Abstract: We analyzed two polymorphisms in genes encoding proteins of the dopamine system, the Val158Met polymorphism in the catechol-O-methyltransferase gene and the 120-bp VNTR polymorphism in the promoter of the dopamine D4 receptor gene for association with methamphetamine abuse. We used a case/control design with 416 methamphetamine abusing subjects and 435 normal controls. All subjects were Han Chinese from Taiwan. We found an excess of the high activity Val158 allele in the methamphetamine abuser group, consistent with several previous reports of association of this allele with drug abuse. The 120-bp VNTR polymorphism in the promoter of the dopamine D4 receptor gene itself did not show significant association with methamphetamine abuse. However, analysis of the 120-bp VNTR polymorphism and the exon 3 VNTR in the dopamine D4 receptor as a haplotype showed significant association with methamphetamine abuse, which gave an empirical P value 0.0034 for a heterogeneity model. Moreover, there were significant interactive effects between polymorphisms in the catechol-O-methyltransferase and dopamine D4 genes. The evidence of interaction between COMT 158 Val/Met and DRD4 48-bp VNTR polymorphisms (P = 0.0003, OR = 1.45, 95% CI: 1.148-1.77), and between COMT 158 Val/Met and DRD4 120 bp promoter polymorphisms (P = 0.01, OR = 1.10, 95% CI: 1.10-1.18) were significant but the latter was weak. We conclude that genetic variation in the dopamine system may encode an additive effect on risk of becoming a methamphetamine abuser.

Journal ArticleDOI
TL;DR: The results suggest that the functional COMT polymorphism is associated with the development of phobic anxiety.
Abstract: OBJECTIVE: The authors assessed the association between the catechol-O-methyltransferase (COMT) Val158Met polymorphism and scores on the phobic anxiety scale of the Crown-Crisp Experimental Index. METHOD: A total of 1,234 women completed the Crown-Crisp Experimental Index phobic anxiety scale and were genotyped for the COMT polymorphism. The authors used unconditional logistic regression to compute odds ratios and 95% confidence intervals (CIs) to evaluate the association between the COMT genotype and phobic anxiety. RESULTS: The mean scores for the three genotypes were statistically significantly different. Compared to the COMT Met/Met genotype, the age-adjusted odds ratio for scoring ≥6 compared to scoring 0 or 1 were 1.15 (95% CI=0.71–1.85) and 1.99 (95% CI=1.17–3.40) for the COMT Val/Met and COMT Val/Val genotypes, respectively; a significant gene dosage effect was observed. CONCLUSIONS: Our results suggest that the functional COMT polymorphism is associated with the development of phobic anxiety.

Journal ArticleDOI
01 Feb 2004-Synapse
TL;DR: It is concluded that any involvement of COMT and PRODH genes in schizophrenia is not accompanied by significant alterations in their overall mRNA expression, at least in dorsolateral prefrontal cortex.
Abstract: Catechol-o-methyltransferase (COMT) and proline dehydrogenase (PRODH) may both be susceptibility genes for schizophrenia. As part of the evaluation of their roles in psychosis, we used reverse transcription-polymerase chain reaction to measure COMT and PRODH mRNAs in the dorsolateral prefrontal cortex in schizo- phrenia, bipolar disorder, major depression, and normal controls (n 15 subjects in each group). We also genotyped two common COMT polymorphisms (-287A/G and 158Val/ Met) which might affect its expression. Neither COMT nor PRODH mRNA abundance differed between diagnostic groups, nor when controls were compared with all psychotic patients. COMT mRNA levels were unrelated to COMT genotypes. We conclude that any involvement of COMT and PRODH genes in schizophrenia is not accompanied by significant alterations in their overall mRNA expression, at least in dorsolateral pre- frontal cortex. As COMT and PRODH are both located on chromosome 22q11, the results also argue against the hypothesis that schizophrenia is associated with a decrease in expression of all 22q11 genes, as had been suggested by the high prevalence of psychosis in people with hemizygous 22q11 deletions. Synapse 51:112-118, 2004. © 2003 Wiley-Liss, Inc.

Journal ArticleDOI
TL;DR: These results fail to support the theory that functional polymorphisms within the MAOA, MAOB, or COMT genes, as determinants of catecholamine enzymatic activity, are risk factors for aggressive behavior.
Abstract: Some studies have reported associations between COMT and MAO genotypes and aggression, though results have been inconsistent. We examined the relationship between Overt aggression scale (OAS) scores, and both MAOA and MAOB polymorphisms in a well-powered sample of 346 subjects with schizophrenia. We also examined COMT in a Stage II replication sample of 150 individuals, and combined these results with our previously reported (Stage I) findings for COMT. We found no evidence of any associations between OAS ratings and any of the polymorphisms investigated under different genetic models. There was no evidence of epistatic interaction between MAOA and COMT on OAS scores. These results fail to support the theory that functional polymorphisms within the MAOA, MAOB, or COMT genes, as determinants of catecholamine enzymatic activity, are risk factors for aggressive behavior.

Journal ArticleDOI
TL;DR: Contrary to the observed association between WCST performance and the Val108/158Met polymorphism of the COMT gene in both healthy and schizophrenic adults, this polymorphism does not appear to modulate executive functions in children with ADHD.
Abstract: Background An association has been observed between the catechol-O-methyltransferase (COMT) gene, the predominant means of catecholamine catabolism within the prefrontal cortex (PFC), and neuropsychological task performance in healthy and schizophrenic adults Since several of the cognitive functions typically deficient in children with Attention Deficit Hyperactivity Disorder (ADHD) are mediated by prefrontal dopamine (DA) mechanisms, we investigated the relationship between a functional polymorphism of the COMT gene and neuropsychological task performance in these children

Journal ArticleDOI
TL;DR: Changes in COMT activity modulates dopamine metabolism but the behavioral effects of d-amphetamine in male mice only to a small extent, and this action does not seem to depend on the actual extracellular dopamine concentration.
Abstract: We have earlier found that 1) COMT inhibitors did not enhance amphetamine-induced dopamine efflux into striatal extracellular, that 2) they did not increase dopamine levels in striatal tissue and that 3) they did not potentiate amphetamine-induced turning behavior of hemiparkinsonian rats. Further, when COMT knockout mice were challenged with l-dopa or a dopamine transporter (DAT) inhibitor, an accumulation of dopamine occurred and the neurochemical and locomotor effects of l-dopa and GBR 12909 were modified accordingly. Since DAT inhibitors and amphetamine apparently have different mechanisms of action, we were interested to see how COMT knockout mice would react to d-amphetamine treatment. We measured the effects of d-amphetamine on locomotor activity and on the levels of catecholamines and their metabolites in striatal microdialysis fluid and in striatal, hypothalamic and cortical brain regions of COMT gene disrupted mice. Striatal dopamine receptor binding was also determined. After d-amphetamine administration, the DOPAC content in homozygous mice was 3-fold in the striatum, 17- to 18-fold in the cortex and 7- to 8-fold in the hypothalamus higher than in wild-type control mice, and there were no indications of genotype×sex interactions. However, the lack of COMT did not potentiate d-amphetamine-induced dopamine levels in brain tissue or in striatal extracellular fluid. d-Amphetamine-induced (10 mg/kg) hyperlocomotion was less suppressed in male COMT knockout mice than in their wild-type counterparts. Striatal dopamine D1 and D2 receptor levels in male mice were not altered by COMT gene disruption. Changes in COMT activity modulates dopamine metabolism but the behavioral effects of d-amphetamine in male mice only to a small extent, and this action does not seem to depend on the actual extracellular dopamine concentration. Nor is it mediated through compensatory changes in dopamine D1 and D2 receptor levels. In dopaminergic neurons, the contribution of intracellular COMT remains secondary in conditions when dopamine is released by d-amphetamine.

Journal ArticleDOI
Hisae Ono1, Osamu Shirakawa1, Hideyuki Nushida1, Yasuhiro Ueno1, Kiyoshi Maeda1 
TL;DR: The results suggest that the Val/Val genotype is a protective factor against suicide in males, and this was not the case in females.

Journal ArticleDOI
TL;DR: It is suggested that phytochemicals with a catechol structure have the potential to reduce COMT activity in mammary tissues and may consequently reduce the inactivation of potentially mutagenic estradiol metabolites and increase the chance of DNA damage.

Journal ArticleDOI
TL;DR: The RT-coupled 5′ nuclease assay is a reliable method for the quantitative evaluation of cis-acting regulatory effects of catechol-O-methyltransferase (COMT) enzyme activity and predicts higher mRNA expression in both brain and lymphoblasts.
Abstract: A common polymorphism, Val158Met, alters catechol-O-methyltransferase (COMT) enzyme activity and has been linked to psychiatric phenotypes. Bray et al. (2003) reported that COMT is subject to differential allele expression in brain, finding modest (13–22%) underexpression of a haplotype containing Val158. However, disparate findings by another group who used the same method, but in lymphoblasts, raise the issues of tissue specificity, magnitude of differential expression, and identity of loci altering expression. We measured COMT allele expression ratios in heterozygous human lymphoblast cell lines and brains. Using transcribed single nucleotide polymorphisms as endogenous reporters, we developed an RT-coupled 5′ nuclease assay for allele expression ratios and applied it to 63 COMT rs4818(C>G) heterozygotes and 68 Val158Met [rs4680(G>A)] heterozygotes. For rs4818(C>G), the C allele was overexpressed relative to the G allele in 18 of 27 lymphoblast lines and 23 of 36 brains. For Val158Met, Met158 was overexpressed relative to Val158 in all (29 of 29) lymphoblast lines and all (39 of 39) brains. Each of the 22 rs4818 heterozygotes without differential allele expression was a Val158/Val158 homozygote. The Met158 allele was overexpressed by 65–77% when compared with Val158 in lymphoblasts and brain. Haplotype augmented ability to predict expression in brain only. However, the expression of the Val158 allele on the high-expressing haplotype was only 19% higher than Val158 alleles on the other haplotype background. COMT alleles are differentially expressed. The Met158 allele predicts higher mRNA expression in both brain and lymphoblasts. As exemplified here, the RT-coupled 5′ nuclease assay is a reliable method for the quantitative evaluation of cis-acting regulatory effects.

Journal ArticleDOI
TL;DR: The aim of the study was to find out if a relationship exists between MAOB and COMT haplotypes and motor disturbances onset in PD patients treated with levodopa preparations.
Abstract: Objectives – The etiology of sporadic idiopathic Parkinson's disease (PD) is considered multifactorial with both genetic and environmental factors modifying the disease expression. Recent studies suggest that polymorphism in monoamine oxidase B (MAOB) and catechol-O-methyltransferase (COMT) might influence the risk and treatment of PD. The aim of the study was to evaluate the effect of MAOB and COMT genetic polymorphism on effective daily dose of levodopa applied during the first 5 years of treatment, and to find out if a relationship exists between MAOB and COMT haplotypes and motor disturbances onset in PD patients treated with levodopa preparations. Materials and methods – A total of 95 patients (40 females and 55 males) of Polish origin diagnosed with sporadic PD were enrolled into the study, and were divided into two groups. Group 1 – patients treated with doses of levodopa below 500 mg/day during the first 5 years of treatment. Group 2 – patients requiring levodopa doses exceeding 500 mg/24 h during the first 5 years of treatment. Low activity alleles of MAOB and COMT, i.e. MAOB allele A and COMTL as well as high activity ones, i.e. MAOB allele G and COMTH, were determined using PCR-RFLP method. Results – No statistically significant differences were found in MAOB and COMT allele distribution in the two groups. However, the frequency of COMTL/L homozygotes was higher in the group treated with low doses of levodopa when compared with the second group. MAOB and COMT AG-HH haplotype predominated in the group of females treated with high daily doses of levodopa when compared with AG-LL haplotype in the group of females treated with low daily doses of levodopa (<500 mg/24 h). Conclusion – The results of the study suggest that patients with COMTL/L genotype and possibly MAOB genotype A may benefit from more efficient and safer levodopa therapy.

Journal ArticleDOI
TL;DR: It is suggested that COMT polymorphism influences on the risk of psychosis since the early stages, and claims for the possibility to identify distinct phenotypes on genetic basis among AD patients are made.