Showing papers on "Catechol-O-methyl transferase published in 2008"
TL;DR: Despite initially promising results, the COMT Val158/108Met polymorphism appears to have little if any association with cognitive function and publication bias may hamper attempts to understand the genetic basis of psychological functions and psychiatric disorders.
397 citations
TL;DR: The studies identify a genetic mouse model for pre-eclampsia and suggest that 2-ME may have utility as a plasma and urine diagnostic marker for this disease, and may also serve as a therapeutic supplement to prevent or treat this disorder.
Abstract: Despite intense investigation, mechanisms that facilitate the emergence of the pre-eclampsia phenotype in women are still unknown. Placental hypoxia, hypertension, proteinuria and oedema are the principal clinical features of this disease. It is speculated that hypoxia-driven disruption of the angiogenic balance involving vascular endothelial growth factor (VEGF)/placenta-derived growth factor (PLGF) and soluble Fms-like tyrosine kinase-1 (sFLT-1, the soluble form of VEGF receptor 1) might contribute to some of the maternal symptoms of pre-eclampsia. However, pre-eclampsia does not develop in all women with high sFLT-1 or low PLGF levels, and it also occurs in some women with low sFLT-1 and high PLGF levels. Moreover, recent experiments strongly suggest that several soluble factors affecting the vasculature are probably elevated because of placental hypoxia in the pre-eclamptic women, indicating that upstream molecular defect(s) may contribute to pre-eclampsia. Here we show that pregnant mice deficient in catechol-O-methyltransferase (COMT) show a pre-eclampsia-like phenotype resulting from an absence of 2-methoxyoestradiol (2-ME), a natural metabolite of oestradiol that is elevated during the third trimester of normal human pregnancy. 2-ME ameliorates all pre-eclampsia-like features without toxicity in the Comt(-/-) pregnant mice and suppresses placental hypoxia, hypoxia-inducible factor-1alpha expression and sFLT-1 elevation. The levels of COMT and 2-ME are significantly lower in women with severe pre-eclampsia. Our studies identify a genetic mouse model for pre-eclampsia and suggest that 2-ME may have utility as a plasma and urine diagnostic marker for this disease, and may also serve as a therapeutic supplement to prevent or treat this disorder.
363 citations
TL;DR: A critical role for the COMT gene is indicated in an apparent evolutionary trade-off between cognitive and affective functions and in the involvement of PFC CaMK pathways in COMT-regulated cognitive function and adaptive stress responses.
Abstract: The COMT (catechol-O-methyltransferase) gene has been linked to a spectrum of human phenotypes, including cognition, anxiety, pain sensitivity and psychosis. Doubts about its clinical impact exist, however, because of the complexity of human COMT polymorphism and clinical variability. We generated transgenic mice overexpressing a human COMT-Val polymorphism (Val-tg), and compared them with mice containing a null COMT mutation. Increased COMT enzyme activity in Val-tg mice resulted in disrupted attentional set-shifting abilities, and impaired working and recognition memory, but blunted stress responses and pain sensitivity. Conversely, COMT disruption improved working memory, but increased stress responses and pain sensitivity. Amphetamine ameliorated recognition memory deficits in COMT-Val-tg mice but disrupted it in wild types, illustrating COMT modulation of the inverted-U relationship between cognition and dopamine. COMT-Val-tg mice showed increased prefrontal cortex (PFC) calcium/calmodulin-dependent protein kinase II (CaMKII) levels, whereas COMT deficiency decreased PFC CaMKII but increased PFC CaMKKβ and CaMKIV levels, suggesting the involvement of PFC CaMK pathways in COMT-regulated cognitive function and adaptive stress responses. Our data indicate a critical role for the COMT gene in an apparent evolutionary trade-off between cognitive and affective functions.
300 citations
TL;DR: There are accumulating and in places compelling data showing that COMT differentially impacts on brain function and dysfunction in men and women, and it is anticipated that additional evidence will emerge for sexual dimorphisms not only in COMT but also in many other autosomal genes.
292 citations
TL;DR: The results confirm the prominent role of COMT in regulating DA transmission in cortex but not striatum, and the reliability of [11C]NNC 112 as a marker for low DA tone as previously suggested by studies in patients with schizophrenia.
Abstract: A common polymorphism (val158met) in the gene encoding catechol-O-methyltransferase (COMT) has been shown to affect dopamine (DA) tone in cortex and cortical functioning. D1 receptors are the main DA receptors in the cortex, and studies have shown that decreased levels of cortical DA are associated with upregulation of D1 receptor availability, as measured with the positron-emission tomography (PET) radiotracer [11C]NNC112. We compared [11C]NNC 112 binding in healthy volunteers homozygous for the Val allele compared with Met carriers. Subjects were otherwise matched for parameters known to affect [11C]NNC 112 binding. Subjects with Val/Val alleles had significantly higher cortical [11C]NNC 112 binding compared with Met carriers, but did not differ in striatal binding. These results confirm the prominent role of COMT in regulating DA transmission in cortex but not striatum, and the reliability of [11C]NNC 112 as a marker for low DA tone as previously suggested by studies in patients with schizophrenia.
198 citations
TL;DR: It is shown for the first time that attentional control in PD is critically determined by genetic and pharmacological influences on dopaminergic activity in frontoparietal networks.
Abstract: impact of the COMT val 158 met genotype and dopaminergic medication on both patterns of behaviour and associated brain activation in 29 medicated patients with early PD Genotype had a critical impact on task strategy: whilst patients with high activity COMT genotypes (val/val) adopted a typical approach of preferentially shifting attention within rather than between dimensions, those with low activity genotypes (met/met) failed to adopt such a strategy, suggesting an inability to form an attentional ‘set’ Moreover, this behaviour was associated with significant underactivation across the frontoparietal attentional network Furthermore, we demonstrated an interactive effect of COMT genotype and dopaminergic medication on task performance and BOLD response Hence we have shown for the first time that attentional control in PD is critically determined by genetic and pharmacological influences on dopaminergic activity in frontoparietal networks This has important implications for understanding the neurobiological basis of attentional control, and highlights the risk of medication-induced cognitive dysfunction in certain genotypic groups of PD patients, which may ultimately impact on clinical practice
159 citations
TL;DR: This study suggests that genetic variability in the COMT gene influence the efficacy of morphine in cancer patients with pain, and that increased understanding of this variability is reached by expanding from analyses of single SNPs to haplotype construction and analyses.
Abstract: Background: Genetic variation contributes to differences in pain sensitivity and response to different analgesics. Catecholamines are involved in the modulation of pain and are partly metabolized by the catechol-O-methyltransferase (COMT) enzyme. Genetic variability in the COMT gene may therefore contribute to differences in pain sensitivity and response to analgesics. It is shown that a polymorphism in the COMT gene, Rs4680 (Val158Met), influence pain sensitivity in human experimental pain and the efficacy for morphine in cancer pain treatment. In this study we wanted to investigate if variability in other regions in the COMT gene also contributes to interindividual variability in morphine efficacy. Results: We genotyped 11 single nucleotide polymorphisms (SNPs) throughout the COMT gene, and constructed haplotypes from these 11 SNPs, which were in Hardy-Weinberg equilibrium. We compared both genotypes and haplotypes against pharmacological, demographical and patient symptoms measurements in a Caucasian cancer patient cohort (n = 197) receiving oral morphine treatment for cancer pain. There were two frequent haplotypes (34.5% and 17.8%) in our cohort. Multivariate analyses showed that patients carrying the most frequent haplotype (34.5%) needed lower morphine doses than patients not carrying the haplotype, with a reduction factor of 0.71 (p = 0.005). On the allele level, carriers of alleles for six of the SNPs show weak associations in respect to morphine dose and the alleles associated with the lowest morphine doses constitute part of the most frequent haplotype. Conclusion: This study suggests that genetic variability in the COMT gene influence the efficacy of morphine in cancer patients with pain, and that increased understanding of this variability is reached by expanding from analyses of single SNPs to haplotype construction and analyses.
153 citations
TL;DR: The present results strongly point toward a negative influence of the higher activity COMT 158val/val genotype on antidepressant treatment response during the first 6 weeks of pharmacological treatment in major depression, possibly conferred by consecutively decreased dopamine availability.
138 citations
TL;DR: The results suggest that early information processing and working memory may both depend on PFC DA signaling, and that they may both relate to PFCDA levels according to an inverted U-shaped curve function.
130 citations
TL;DR: The findings support prior genetic and neuroimaging associations of the COMT 158Met allele to affective psychopathology and alterations in neural systems for emotional arousal and regulation.
Abstract: Emotional dysregulation is a core characteristic of many psychiatric diseases, including the anxiety disorders. Although heritable influences account for a significant degree of variation in risk for such disorders, relatively few candidate susceptibility factors have been identified. A coding variant in one such gene, encoding the dopamine catabolic enzyme catechol-O-methyltransferase (COMT Val158Met), has previously been associated with anxiety and with anxiety-related temperament and altered neural responses to affective stimuli in healthy individuals. In 96 healthy women recruited from a sample of 800 participants according to genotype, the authors tested for an association between the DRD2/ANKK1 Taq Ia, the COMT Val158Met, and a psychophysiological measure of emotion processing, the acoustic affective startle reflex modulation (ASRM) paradigm, and found that COMT genotype significantly affected startle reflex modulation by aversive stimuli, with Met158 homozygotes exhibiting a markedly potentiated startle reflex compared with Val158 carriers. A trait measure of anxiety (Gray’s Behavioral Inhibition System; J. A. Gray & N. McNaughton, 2000) was also associated with ASRM. The functional polymorphism in the dopamine D2 receptor (DRD2/ANKK1 Taq Ia) had no effect on startle modulation. The findings support prior genetic and neuroimaging associations of the COMT 158Met allele to affective psychopathology and alterations in neural systems for emotional arousal and regulation.
124 citations
TL;DR: An overview of the strategies available for dealing with motor complications associated with chronic levodopa treatment for Parkinson's disease patients is provided and the importance of initiating therapy with a treatment strategy that reduces the risk that a patient will develop motor complications in the first place is highlighted.
Abstract: Chronic levodopa treatment for Parkinson's disease patients is frequently associated with the development of motor complications such as end-of-dose wearing-off and dyskinesias. In this review, we provide an overview of the strategies available for dealing with these problems. Medical management includes manipulation of levodopa dosing to establish the optimum treatment schedule, improving levodopa absorption, catechol-O-methyl transferase-inhibition (COMT), Monoamine oxidase-B (MAO-B) inhibition, dopaminergic agonists, amantadine, and continuous dopaminergic infusions. Surgical procedures and particularly deep brain stimulation are also reviewed. It should be noted that none of these treatments has been shown to provide anti-parkinsonian efficacy that is greater than what can be achieved with levodopa. We highlight the importance of initiating therapy with a treatment strategy that reduces the risk that a Parkinson's disease patient will develop motor complications in the first place. Key Words: Advanced PD, dyskinesias, motor fluctuations, levodopa, dopamine agonists, COMT inhibitors, MAO-B inhibitors.
TL;DR: The crystal structures of the 108V and 108M variants of the soluble form of human COMT bound with S-adenosylmethionine (SAM) and a substrate analog, 3,5-dinitrocatechol, are described.
TL;DR: Variations in the COMT gene contribute to genetic risk shared across a range of anxiety-related phenotypes, and these findings are female-specific.
TL;DR: Preliminary evidence for a role of the functional val158met COMT polymorphism in amygdala and prefrontal activation in response to emotional faces in panic disorder is provided.
Abstract: Panic disorder is an anxiety disorder with an estimated heritability of up to 48%. The functional val158met polymorphism in the catechol-O-methyltransferase (COMT) gene has been found to be associated with panic disorder and to influence limbic and prefrontal brain activation in response to unpleasant stimuli. In the present study, neuronal activation following emotional stimulation was used as an endophenotype and investigated for association with the COMT val158met polymorphism in panic disorder. Twenty patients with panic disorder were scanned by means of functional magnetic resonance imaging at 3 Tesla under visual presentation of emotional faces and genotyped for the COMT val158met polymorphism. In response to fearful faces, increased activation in the right amygdala was observed in patients carrying at least one 158val allele. Increased activation or less deactivation associated with the 158val allele was seen upon presentation of fearful, angry and happy faces in the orbitofrontal and ventromedial prefrontal cortex, respectively. Our data provide preliminary evidence for a role of the functional val158met COMT polymorphism in amygdala and prefrontal activation in response to emotional faces in panic disorder. This COMT variant might increase the vulnerability to panic disorder by modulating dopaminergic tonus in relevant brain regions and thus altering neuronal processing of anxiety-related emotional cues.
TL;DR: It is found that the hypofunctional 677T variant was associated with decreased working memory load-dependent activation in the prefrontal and insular cortices in 79 schizophrenia patients, but not in 75 demographically matched healthy controls, and the importance of weighing COMT effects on prefrontal function within the context of MTHFR genotype is suggested.
Abstract: Understanding how risk genes cumulatively impair brain function in schizophrenia could provide critical insights into its pathophysiology. Working memory impairment in schizophrenia has been associated with abnormal dopamine signaling in the prefrontal cortex, which is likely under complex genetic control. The catechol-O-methyltransferase (COMT) 158Val → Met polymorphism (rs4680), which affects the availability of prefrontal dopamine signaling, consistently stratifies prefrontal activation during working memory performance. However, the low-dopamine COMT 158Val allele does not confer increased risk for schizophrenia, and its effects on prefrontal function are not specific to the disorder. In the setting of other genetic variants influencing prefrontal dopamine signaling, COMT 158Val → Met genotype may exert disease-specific effects. A second polymorphism, methylenetetrahydrofolate reductase (MTHFR) 677C → T (rs1801133), has been associated with overall schizophrenia risk and executive function impairment in patients, and may influence dopamine signaling through mechanisms upstream of COMT effects. We found that the hypofunctional 677T variant was associated with decreased working memory load-dependent activation in the prefrontal and insular cortices in 79 schizophrenia patients, but not in 75 demographically matched healthy controls. Further, significant MTHFR × COMT genotype interactions were observed, which differed by diagnostic group: Reduced prefrontal activation was associated with the 677T and 158Val alleles in patients, but with 677C/C and 158Met/Met genotype in controls. These findings are consistent with epistatic effects of the COMT and MTHFR polymorphisms on prefrontal dopamine signaling, and suggest that in schizophrenia patients, the MTHFR 677T allele exacerbates prefrontal dopamine deficiency. The findings also suggest the importance of weighing COMT effects on prefrontal function within the context of MTHFR genotype.
TL;DR: All measured variables were significantly correlated; however, the associations between COMT val158-met and cardiovascular variables, and the association between COMCatechol O-methyltransferase and anthropometry, respectively, were partly independent of each other, as revealed by multiple linear regression.
Abstract: Catechol O-methyltransferase (COMT) degrades catecholamines and estrogens, both of which are of known importance for cardiovascular risk factors such as obesity and hypertension. The gene coding for COMT contains a val158-met polymorphism that exerts a considerable influence on enzymatic activity. We hypothesized that this polymorphism might influence risk factors for cardiovascular disease. Deoxyribonucleic acid samples and data regarding blood pressure and anthropometry were collected from 240 Swedish men, all 51 years old. Subjects homozygous for the low-activity allele (met) displayed higher blood pressure, heart rate, waist-to-hip ratio, and abdominal sagittal diameter as compared with heterozygous subjects, who in turn displayed higher blood pressure, heart rate, waist-to-hip ratio, and abdominal sagittal diameter than subjects homozygous for the high-activity allele (val). All measured variables were significantly correlated; however, the associations between COMT val158-met and cardiovascular variables, and the association between COMT val158-met and anthropometry, respectively, were partly independent of each other, as revealed by multiple linear regression.
TL;DR: This study provides the first indication that dopamine availability (as opposed to other effects of MAOA) is involved in human obesity, and it is a priority to assess the associations in replication datasets.
Abstract: Human and animal studies have implicated dopamine in appetite regulation, and family studies have shown that BMI has a strong genetic component. Dopamine availability is controlled largely by three enzymes: COMT, MAOA and MAOB, and by the dopamine transporter SLC6A3, and each gene has a well-characterized functional variant. Here we look at these four functional polymorphisms together, to investigate how heritable variation in dopamine levels influences the risk of obesity in a cohort of 1150, including 240 defined as obese (BMI > or = 30). The COMT and SLC6A3 polymorphisms showed no association with either weight, BMI or obesity risk. We found, however, that both MAOA and MAOB show an excess of the low-activity genotypes in obese individuals (MAOA:chi2= 15.45, p = 0.004; MAOB:chi2= 8.05, p = 0.018). Additionally, the MAOA genotype was significantly associated with both weight (p = 0.0005) and BMI (p = 0.001). When considered together, the 'at risk genotype'--low activity genotypes at both the MAOA and MAOB loci--shows a relative risk for obesity of 5.01. These results have not been replicated and, given the experience of complex trait genetics, warrant caution in interpretation. In implicating both the MAOA and MOAB variants, however, this study provides the first indication that dopamine availability (as opposed to other effects of MAOA) is involved in human obesity. It is therefore a priority to assess the associations in replication datasets.
TL;DR: Both nonsynonymous and synonymous SNPs within functional COMT haplotype blocks may be more relevant than individual SNPs in conferring PD susceptibility and this may be useful in instituting individualized therapy for PD patients.
Abstract: IntroductionDifferences in catechol-O-methyltransferase (COMT) activity and genotype may determine individual variations in the therapeutic response to levodopa or Parkinson's disease (PD) susceptibility. The role of functional COMT haplotypes in PD susceptibility and treatment response has not been
TL;DR: Findings suggest that genetically determined dopamine signaling during memory processing maps to a nonlinear relationship also in the hippocampus, and in human brain epistasis of two genes implicated in dopamine signaling on brain activity during different memory conditions.
TL;DR: A case‐control study and pharmacogenetic association analyses in ADHD investigating three dopaminergic polymorphisms showed significant role of the high activity Val‐allele of cathecol‐O‐methyltransferase (COMT) Val158Met polymorphism in the ADHD population.
Abstract: Methylphenidate is the most frequently prescribed drug in the treatment of attention deficit hyperactivity disorder (ADHD) but it is not effective in every case. Therefore, identifying genetic and/or biological markers predicting drug-response is increasingly important. Here we present a case-control study and pharmacogenetic association analyses in ADHD investigating three dopaminergic polymorphisms. Previous studies suggested variable number of tandem repeats (VNTR) in the dopamine D4 receptor (DRD4) and the dopamine transporter (DAT1) genes as genetic risk factors for ADHD and as possible markers of methylphenidate response. Our results did not indicate substantial involvement of these two VNTRs in ADHD, however, both the case-control and the pharmacogenetic analyses showed significant role of the high activity Val-allele of cathecol-O-methyltransferase (COMT) Val158Met polymorphism in our ADHD population. The Val-allele was more frequent in the ADHD group (n = 173) compared to the healthy population (P = 0.016). The categorical analysis of 90 responders versus 32 non-responders showed an association between the Val-allele or Val/Val genotype and good methylphenidate response (P = 0.009 and P = 0.034, respectively). Analyzing symptom severity as a continuous trait, significant interaction of COMT genotype and methylphenidate was found on the Hyperactivity-Impulsivity scale (P = 0.044). Symptom severity scores of all three genotype groups decreased following methylphenidate administration (P < 0.001), however Val/Val homozygote children had significantly less severe symptoms than those with Met/Met genotype after treatment (P = 0.015). This interaction might reflect the regulatory effect of COMT dominated prefrontal dopamine transmission on subcortical dopamine systems, which are the actual site of methylphenidate action. © 2008 Wiley-Liss, Inc.
TL;DR: The results suggest that PPI is regulated by DA neurotransmission in the PFC and its levels depend on the COMT Val158Met gene polymorphism, the main catabolic pathway of released DA in the prefrontal cortex.
Abstract: Background Recent evidence suggests that dopamine (DA) agonist-induced disruption of prepulse inhibition (PPI) depends on basal PPI values, in a manner that suggests an inverted U-shaped relationship between PPI and prefrontal DA levels. This is the first study to examine possible genetic determinants of PPI and the catechol O-methyltransferase (COMT) Val158Met polymorphism, the main catabolic pathway of released DA in the prefrontal cortex (PFC). Method PPI was measured in 93 healthy males presented with 75-dB and 85-dB prepulses at 60-ms and 120-ms prepulse-pulse intervals. Subjects were grouped according to their COMT status into a Val/Val, a Val/Met and a Met/Met group. Results ANOVAs showed that at all prepulse and interval conditions, Val/Val individuals had the lowest PPI, Met/Met the highest, and Val/Met were intermediate. Conclusions These results suggest that PPI is regulated by DA neurotransmission in the PFC and its levels depend on the COMT Val158Met gene polymorphism. These findings enhance the value of the PPI paradigm in examining individual variability of early information processing in healthy subjects and psychiatric disorders associated with changes in PFC DA activity and attentional deficits such as schizophrenia.
TL;DR: It is found that the met(158) allele, which is presumably linked to higher synaptic DA levels, was associated with higher responses in ventral striatum to loss incentives, and this effect of COMT genotype on striatal reactivity as a result of a cortico-striatal interaction is compatible with an interpretation that construes this effect.
TL;DR: Evidence is provided that the Val108/158Met polymorphism of the COMT gene might be responsible for individual variation in the human brain morphology.
Abstract: A variation in catechol-O-methyltransferase (COMT) gene (Val(108/158)Met) affects the physiological response of hippocampal-prefrontal circuits, predicts variation in human memory and is associated with increased risk for psychiatric disorders. Using optimized voxel-based morphometry we studied the effect of this functional polymorphism on the anatomy of the hippocampus, and the prefrontal cortex. Fifty-seven healthy participants were investigated (nine had Met/Met, 30 Val/Met, and 14 Val/Val). Voxel-based morphometry showed that individuals who are homozygous for the Val-COMT allele had greater gray matter volume of the prefrontal cortex bilaterally, whereas Met-COMT carriers were associated with increased tissue volume of the hippocampus bilaterally. This study provides evidence that the Val(108/158)Met polymorphism of the COMT gene might be responsible for individual variation in the human brain morphology.
TL;DR: In this paper, the authors examined the relationship between the val 158 met polymorphism and cognitive function as well as personality traits in 522 healthy individuals (mean age: 24.75 years, SD=5.84, mean years of education: 15.59 and SD=2.65).
TL;DR: A positive effect of COMT val allele load upon the blood oxygen level–dependent response in LPFC, pre-SMA/ACC, and IPS during high gf versus low gf task performance in both spatial and verbal domains is shown.
Abstract: Fluid intelligence (g f ) influences performance across many cognitive domains. It is affected by both genetic and environmental factors. Tasks tapping g f activate a network of brain regions including the lateral prefrontal cortex (LPFC), the presupplementary motor area/anterior cingulate cortex (pre-SMA/ACC), and the intraparietal sulcus (IPS). In line with the “intermediate phenotype” approach, we assessed effects of a polymorphism (val 158 met) in the catechol-O-methyltransferase (COMT) gene on activity within this network and on actual task performance during spatial and verbal g f tasks. COMT regulates catecholaminergic signaling in prefrontal cortex. The val 158 allele is associated with higher COMT activity than the met 158 allele. Twenty-two volunteers genotyped for the COMT val 158 met polymorphism completed high and low g f versions of spatial and verbal problem-solving tasks. Our results showed a positive effect of COMT val allele load upon the blood oxygen level-dependent response in LPFC, pre-SMA/ACC, and IPS during high g f versus low g f task performance in both spatial and verbal domains. These results indicate an influence of the COMT val 158 met polymorphism upon the neural circuitry supporting g f . The behavioral effects of val allele load differed inside and outside the scanner, consistent with contextual modulation of the relation between COMT val 158 met genotype and g f task performance.
TL;DR: The Letter‐Number Sequencing task, which requires not only maintenance but also active manipulation of information seemed to be more sensitive to the disadvantageous Val/Val genotype in a large non‐clinical sample, confirming the hypothesis that Val158Met polymorphism (COMT gene) might account for individual differences on dopamine‐dependent prefrontally related neurocognitive functions.
Abstract: Working memory has been described as a neurocognitive probe of prefrontal brain functioning. Genetic variability related with catechol-O-methyltransferase (COMT) gene (Val158Met polymorphism) has received increasing attention as a possible modulator of working memory tasks in both schizophrenic patients and healthy subjects, although inconsistencies across studies have been found. This may be related to the existence of different working memory components, processes and modalities, which may have different sensitivities to subtle changes in dopamine levels and, therefore, the effect of the underlying COMT Val158Met genetic variability. To test this out a large sample of 521 healthy individuals from the general population were tested on the WCST and three working memory tasks that cover the assessment of verbal and spatial working modalities as well as different components and processes (Letter and Number Sequencing, CPT-IP, Backwards Visual Span). All individuals were genotyped for the rs4680 (Val158Met) polymorphism at the COMT gene. Met carriers showed near-significant better performance in the LNS compared with Val/Val individuals (F = 3.9, df = 1, P = 0.046). Moreover, the analysis for linear trend found that Met allele carriers showed significantly better performance than Val/Val individuals (B = 0.58 P = 0.031), although evidence for a linear trend was not found. None of the WCST indices differed among genotypes. Consistent with the hypothesis that Val158Met polymorphism (COMT gene) might account for individual differences on dopamine-dependent prefrontally related neurocognitive functions, the Letter-Number Sequencing task, which requires not only maintenance but also active manipulation of information seemed to be more sensitive to the disadvantageous Val/Val genotype in a large non-clinical sample.
TL;DR: Findings support the COMT Val158Met polymorphism conferring vulnerability for different clinical phenotypes in schizophrenia and bipolar disorder.
TL;DR: An unexpected role for catecholamines in the function of auditory and vestibular sense organs is indicated and screened DNA from human families is identified and identified a nonsense mutation in the human ortholog of the murine Comt2 gene that causes nonsyndromic deafness.
Abstract: We have identified a previously unannotated catechol-O-methyltranferase (COMT), here designated COMT2, through positional cloning of a chemically induced mutation responsible for a neurobehavioral phenotype. Mice homozygous for a missense mutation in Comt2 show vestibular impairment, profound sensorineuronal deafness, and progressive degeneration of the organ of Corti. Consistent with this phenotype, COMT2 is highly expressed in sensory hair cells of the inner ear. COMT2 enzymatic activity is significantly reduced by the missense mutation, suggesting that a defect in catecholamine catabolism underlies the auditory and vestibular phenotypes. Based on the studies in mice, we have screened DNA from human families and identified a nonsense mutation in the human ortholog of the murine Comt2 gene that causes nonsyndromic deafness. Defects in catecholamine modification by COMT have been previously implicated in the development of schizophrenia. Our studies identify a previously undescribed COMT gene and indicate an unexpected role for catecholamines in the function of auditory and vestibular sense organs.
TL;DR: Erythrocyte catechol‐O‐methyltransferase (COMT) activity has been analyzed in 185 individuals and the activities showed a trimodal frequency distribution, which suggests an autosomal codominant inheritance of the human erythrocytes COMT activity.
Abstract: Erythrocyte catechol-O-methyltransferase (COMT) activity has been analyzed in 185 individuals. The activities showed a trimodal frequency distribution. This suggests an autosomal codominant inheritance of the human erythrocyte COMT activity. The mean male COMT activity was 18.9 +/- 7.0 (S.D.) nmol/ml RBC/h. The mean female activity was 16.1 +/- 6.3 nmol/ml RBC/h and the frequency distribution pattern for women was shifted towards lower values.
TL;DR: The purpose of the present study was to determine whether the tyrosine hydroxylase (TH) val81met and catechol‐O‐methyltransferase (COMT) val158met polymorphisms are associated with the antidepressant effect of milnacipran, a serotonin/noradrenaline reuptake inhibitor.
Abstract: Objective
Genetic polymorphisms of the noradrenergic pathway can be factors to predict the effect of antidepressants when their pharmacological mechanisms of action include the noradrenergic system. The purpose of the present study was to determine whether the tyrosine hydroxylase (TH) val81met and catechol-O-methyltransferase (COMT) val158met polymorphisms are associated with the antidepressant effect of milnacipran, a serotonin/noradrenaline reuptake inhibitor.
Method
Eighty-one Japanese patients with major depressive disorder were treated with milnacipran for 6 weeks. Severity of depression was assessed with the Montgomery and Asberg Depression Rating Scale (MADRS). Assessments were carried out at baseline and at 1, 2, 4 and 6 weeks of treatment. The method of polymerase chain reaction was used to determine allelic variants.
Results
The met/met genotype of the COMT val158met polymorphism was associated with a significantly faster therapeutic effect of milnacipran in the MADRS score during this study. No influence of the TH val81met polymorphism on the antidepressant effect of milnacipran was detected.
Conclusion
These results suggest that the COMT val158met polymorphism in part determines the antidepressant effect of milnacipran. Copyright © 2007 John Wiley & Sons, Ltd.