Showing papers on "Catechol-O-methyl transferase published in 2011"
TL;DR: These findings show that although estrogen, considered in isolation, may have unpredictable effects on cognitive performance, its influence is clarified when considered within a larger neuromodulatory framework.
Abstract: The prefrontal cortex (PFC) is exquisitely sensitive to its neurochemical environment. Minor fluctuations in cortical dopamine (DA) can profoundly alter working memory, a PFC-dependent cognitive function that supports an array of essential human behaviors. Dopamine's action in the PFC follows an inverted U-shaped curve, where an optimal DA level results in maximal function and insufficient or excessive DA impairs PFC function. In animals, 17β-estradiol (the major estrogen in most mammals, referred to henceforth as estradiol) has been shown to enhance DA activity, yet no human study has adequately addressed whether estradiol's impact on cognition occurs by way of modulating specific neurochemical systems. Here we examined the effects of endogenous fluctuations in estradiol on working memory in healthy young women as a function of baseline PFC DA [indexed by catechol-O-methyltransferase (COMT) Val(158)Met genotype and, at a finer scale, COMT enzyme activity]. The results demonstrate that estradiol status impacts working memory function and, crucially, the direction of the effect depends on indices of baseline DA. Moreover, consistent with a DA cortical efficiency hypothesis, functional MRI revealed that inferred optimal DA was associated with reduced PFC activity sustained across task blocks and selectively enhanced PFC activity on trials with the greatest demand for cognitive control. The magnitude of PFC activity during high control trials was predictive of an individual's performance. These findings show that although estrogen, considered in isolation, may have unpredictable effects on cognitive performance, its influence is clarified when considered within a larger neuromodulatory framework. Given the clinical prevalence of dopaminergic drugs, understanding the relationship between estrogen and DA is essential for advancing women's health.
320 citations
TL;DR: The relationship of methylation of the COMT Val158 allele with stress, gene expression, WM performance, and related brain activity suggests that stress-related methylation is associated with silencing of the gene, which partially compensates the physiological role of the high-activity Val allele in prefrontal cognition and activity.
Abstract: DNA methylation at CpG dinucleotides is associated with gene silencing, stress, and memory. The catechol- O -methyltransferase ( COMT ) Val 158 allele in rs4680 is associated with differential enzyme activity, stress responsivity, and prefrontal activity during working memory (WM), and it creates a CpG dinucleotide. We report that methylation of the Val 158 allele measured from peripheral blood mononuclear cells (PBMCs) of Val/Val humans is associated negatively with lifetime stress and positively with WM performance; it interacts with stress to modulate prefrontal activity during WM, such that greater stress and lower methylation are related to reduced cortical efficiency; and it is inversely related to mRNA expression and protein levels, potentially explaining the in vivo effects. Finally, methylation of COMT in prefrontal cortex and that in PBMCs of rats are correlated. The relationship of methylation of the COMT Val 158 allele with stress, gene expression, WM performance, and related brain activity suggests that stress-related methylation is associated with silencing of the gene, which partially compensates the physiological role of the high-activity Val allele in prefrontal cognition and activity. Moreover, these results demonstrate how stress-related DNA methylation of specific functional alleles impacts directly on human brain physiology beyond sequence variation.
185 citations
TL;DR: The results suggest that COMT genotype effects on WM brain activity and behavior are not static during development, and the full developmental picture should be considered when trying to understand the impact of genetic polymorphisms on the mature cognition of healthy adult or psychiatric populations.
151 citations
TL;DR: Vitamin D inhibits growth of Hu LM cells through the down-regulation of PCNA, CDK1, and BCL-2 and suppresses COMT expression and activity in HuLM cells, and hypovitaminosis D appears to be a risk factor for uterine fibroids.
151 citations
TL;DR: Evidence of a COMT role in the modulation of personality traits has been found, suggested that COMT variants may not be directly implicated in suicidal behavior, however evidence of an association between rs4633 and Reward Dependence and rs737865 and Angry Reaction is found.
128 citations
TL;DR: Studies published so far indicate that an association with the monoamine oxidase A, B, or tryptophan hydroxylase 1 genes is unlikely and data for the brain-derived neurotrophic factor gene are conflicting and limited.
Abstract: There is much evidence that schizophrenia patients have an increased risk for aggression and violent behavior, including homicide. The neurobiological basis and correlates of this risk have not been much studied. While genome-wide association studies are lacking, a number of candidate genes have been investigated. By far, the most intensively studied is the catechol-O-methyltransferase (COMT) gene on chromosome 22. COMT is involved in the metabolism of dopamine, a key neurotransmitter in schizophrenia pathophysiology. Several studies suggest that the Val158Met polymorphism of this gene affects COMT activity. Methionine (Met)/Met homozygote schizophrenia patients show 4- to 5-fold lower COMT activity than valine (Val)/Val homozygotes, and some but not all studies have found an association with aggression and violence. Recently, a new functional single-nucleotide polymorphism in the COMT gene, Ala72Ser, was found to be associated with homicidal behavior in schizophrenia, but this finding warrants further replication. Studies published so far indicate that an association with the monoamine oxidase A, B, or tryptophan hydroxylase 1 genes is unlikely. Data for the brain-derived neurotrophic factor gene are conflicting and limited. Data from the limited number of neuroimaging studies performed to date are interesting. Frontal and temporal lobe abnormalities are found consistently in aggressive schizophrenia patients. Positron emission tomography and single photon-emission computed tomography (SPECT) data indicate deficits also in the orbitofrontal and temporal cortex. Some functional magnetic resonance imaging studies found a negative association of violent behavior with frontal and right-sided inferior parietal activity. Neuroimaging studies may well help further elucidate the interrelationship between neurocognitive functioning, personality traits, and antisocial and violent behavior.
124 citations
TL;DR: Differential sensitivity to environmental stress occasioned by COMT Val158Met may be contingent on higher order interactions with genetic variation underlying psychotic disorder, which may depend on background risk for psychotic disorder.
Abstract: SUMMARY
Background: The interplay between the catechol-O-methyltransferase (COMT) Val158Met polymorphism and environmental stress may have etiological relevance for psychosis, but differential effects have been reported in healthy control and patient groups, suggesting that COMT Val158Met interactions with stress may be conditional on background genetic risk for psychotic disorder. Methods: Patients with a nonaffective psychotic disorder (n = 86) and control participants (n = 109) were studied with the experience sampling method (a structured diary technique) in order to assess stress, negative affect and momentary psychotic symptoms in the flow of daily life. Results: Multilevel analyses revealed significant three-way interactions between group status (patient or control), COMT genotype and stress in the model of negative affect (χ2(2) = 13.26, P < 0.01) as well as in the model of momentary psychotic symptoms (χ2(2) = 6.92, P < 0.05). Exploration of the three-way interaction revealed that in patients, COMT genotype moderated the association between stress and negative affect (χ2(4) = 11.50, P < 0.005), as well as the association between stress and momentary psychosis (χ2(4) = 12.79, P < 0.005). Met/Met genotype patients showed significantly increased psychotic and affective reactivity to stress in comparison to the Val/Met and Val/Val genotypes. In contrast, healthy controls did not display large or significant COMT Val158Met X stress interactions. Conclusions: Important differences exist in the effect of COMT Val158Met on stress reactivity, which may depend on background risk for psychotic disorder. Differential sensitivity to environmental stress occasioned by COMT Val158Met may be contingent on higher order interactions with genetic variation underlying psychotic disorder.
83 citations
TL;DR: This study suggests the heterogeneity in COMT effects reported in the literature may be due in part to gene–gene interactions that influence central dopaminergic systems.
Abstract: The Val158Met polymorphism of the catechol-O-methyltransferase (COMT) gene may be related to individual differences in cognition, likely via modulation of prefrontal dopamine catabolism. However, the available studies have yielded mixed results, possibly in part because they do not consistently account for other genes that affect cognition. We hypothesized that COMT Met allele homozygosity, which is associated with higher levels of prefrontal dopamine, would predict better executive function as measured using standard neuropsychological testing, and that other candidate genes might interact with COMT to modulate this effect. Participants were 95 healthy, right-handed adults who underwent genotyping and cognitive testing. COMT genotype predicted executive ability as measured by the Trail-Making Test, even after covarying for demographics and Apolipoprotein E (APOE), brain-derived neurotrophic factor (BDNF), and ankyrin repeat and kinase domain containing 1 (ANKK1) genotype. There was a COMT-ANKK1 interaction in which individuals having both the COMT Val allele and the ANKK1 T allele showed the poorest performance. This study suggests the heterogeneity in COMT effects reported in the literature may be due in part to gene–gene interactions that influence central dopaminergic systems. (JINS, 2011, 17, 1–7)
75 citations
TL;DR: It is demonstrated that MB-COMT is located in the cell body and in axons and dendrites of rat cortical neurons and that the COMT inhibitor tolcapone induces cell death via the mechanism of apoptosis, and its cytotoxicity is dependent on dosage and correlated with COMT Val/Met genotypes in human lymphoblastoid cells.
73 citations
TL;DR: It is suggested that COMT val/val genotype can modulate the activity of the posterior cingulate and may indicate the potential network effects of COMT genotype on the default mode network.
70 citations
TL;DR: The COMT functional polymorphism rs4680 contributes to schizophrenia genetic susceptibility under an overdominant model, indicating that both too high and too low levels of dopamine signalling may be risk factors.
TL;DR: Lower levels of CYP1B1 detected in cancerous endometrium suggest its important role in control, precancerous tissue, and for the first time higher protein levels of soluble COMT in Cancerous Endometrium, and higher levels of membrane-bound COMT as well as the changed ratio between soluble and membrane- bound COMT at real-time PCR are shown.
TL;DR: A role for both maternal and fetal COMT in preeclampsia is demonstrated and the importance of including allelic variation in MTHFR is highlighted, which is linked to enzyme activity and four single nucleotide polymorphisms that characterize COMT activity.
Abstract: Preeclampsia is a leading cause of perinatal morbidity and mortality This disorder is thought to be multifactorial in origin, with multiple genes, environmental and social factors, contributing to disease One proposed mechanism is placental hypoxia-driven imbalances in angiogenic and anti-angiogenic factors, causing endothelial cell dysfunction Catechol-O-methyltransferase (Comt)-deficient pregnant mice have a preeclampsia phenotype that is reversed by exogenous 2-methoxyestradiol (2-ME), an estrogen metabolite generated by COMT 2-ME inhibits Hypoxia Inducible Factor 1α, a transcription factor mediating hypoxic responses COMT has been shown to interact with methylenetetrahydrofolate reductase (MTHFR), which modulates the availability of S-adenosylmethionine (SAM), a COMT cofactor Variations in MTHFR have been associated with preeclampsia By accounting for allelic variation in both genes, the role of COMT has been clarified COMT allelic variation is linked to enzyme activity and four single nucleotide polymorphisms (SNPs) (rs6269, rs4633, rs4680, and rs4818) form haplotypes that characterize COMT activity We tested for association between COMT haplotypes and the MTHFR 677 C→T polymorphism and preeclampsia risk in 1103 Chilean maternal-fetal dyads The maternal ACCG COMT haplotype was associated with reduced risk for preeclampsia (P = 0004), and that risk increased linearly from low to high activity haplotypes (P = 0003) In fetal samples, we found that the fetal ATCA COMT haplotype and the fetal MTHFR minor “T” allele interact to increase preeclampsia risk (p = 0022) We found a higher than expected number of patients with preeclampsia with both the fetal risk alleles alone (P = 0052) and the fetal risk alleles in combination with a maternal balancing allele (P<0001) This non-random distribution was not observed in controls (P = 0341 and P = 0219, respectively) Our findings demonstrate a role for both maternal and fetal COMT in preeclampsia and highlight the importance of including allelic variation in MTHFR
TL;DR: A novel structural mechanism whereby functional synonymous variations near the translation initiation codon affect the translation efficiency via entropy-driven changes in mRNA dynamics is suggested and another example of stable compensatory genetic variations in the human population is presented.
Abstract: Catechol-O-methyltransferase (COMT) is a major enzyme controlling catecholamine levels that plays a central role in cognition, affective mood and pain perception. There are three common COMT haplotypes in the human population reported to have functional effects, divergent in two synonymous and one nonsynonymous position. We demonstrate that one of the haplotypes, carrying the non-synonymous variation known to code for a less stable protein, exhibits increased protein expression in vitro. This increased protein expression, which would compensate for lower protein stability, is solely produced by a synonymous variation (C(166)T) situated within the haplotype and located in the 5' region of the RNA transcript. Based on mRNA secondary structure predictions, we suggest that structural destabilization near the start codon caused by the T allele could be related to the observed increase in COMT expression. Our folding simulations of the tertiary mRNA structures demonstrate that destabilization by the T allele lowers the folding transition barrier, thus decreasing the probability of occupying its native state. These data suggest a novel structural mechanism whereby functional synonymous variations near the translation initiation codon affect the translation efficiency via entropy-driven changes in mRNA dynamics and present another example of stable compensatory genetic variations in the human population.
TL;DR: The hypothesis that high and low DA predicts increased error-specific transitions of PFC activity is supported, and the COMT × Substance interaction supports the hypothesis that low (Val, placebo) and high (Met, sulpiride) DA levels elevate reactivity to errors.
Abstract: Brain dopamine (DA) has been linked to error processing. Because high and low (vs medium) prefrontal cortex (PFC) DA levels may facilitate D2-receptor-related modulations of PFC neural activation patterns, we hypothesized that high and low DA predicts increased error-specific transitions of PFC activity. Male human participants (n = 169) were genotyped for the catechol-O-methyltransferase (COMT) Val158Met polymorphism, associated with low (Val) and medium (Met) PFC DA levels. In addition, DRD2TaqIa and 5-HTTLPR, associated with striatal D(2) receptor density and serotonin uptake, respectively, were assessed. Participants received placebo or a selective DA-D(2) receptor blocker (sulpiride, 200 mg) and performed a Flanker task. EEG was recorded and decomposed into independent brain components (ICs) using independent component analysis. After errors, participants displayed (1) a negative deflection in ICs source-localized to the proximity of the anterior midcingulate cortex [IC-error-related negativity (IC-ERN)], (2) increased midcingulate cortex IC power in the delta/theta frequency range, and (3) slowing in the subsequent trial [posterror slowing (PES)]. Importantly, all, IC-ERN, delta/theta power, and PES were modulated by COMT × Substance interactions such that the Val allele predicted elevated IC-ERN, delta/theta power, and PES after placebo; this association was reversed under sulpiride. Because low doses of sulpiride presumably increase PFC DA levels, the COMT × Substance interaction supports the hypothesis that low (Val, placebo) and high (Met, sulpiride) versus medium (Val, sulpiride; Met, placebo) DA levels elevate reactivity to errors. Consistent with an influence of serotonin on PFC DA, the COMT × Substance interaction was modulated by 5-HTTLPR.
TL;DR: The data demonstrate that the effect of COMT on pain processing can be detected in presence of a sufficiently robust challenge to the pain system to detect a genotype effect, and/or the recruitment of pain-dampening compensatory mechanisms by the putatively more pain sensitive met homozygotes.
Abstract: Despite the explosion of interest in the genetic underpinnings of individual differences in pain sensitivity, conflicting findings have emerged for most of the identified ‘‘pain genes’’. Perhaps the prime example of this inconsistency is represented by catechol-O-methyltransferase (COMT), as its substantial association to pain sensitivity has been reported in various studies, but rejected in several others. In line with findings from behavioral studies, we hypothesized that the effect of COMT on pain processing would become apparent only when the pain system was adequately challenged (i.e., after repeated pain stimulation). In the present study, we used functional Magnetic Resonance Imaging (fMRI) to investigate the brain response to heat pain stimuli in 54 subjects genotyped for the common COMT val158met polymorphism (val/val=n 22, val/met=n 20, met/met=n 12). Met/met subjects exhibited stronger pain-related fMRI signals than val/val in several brain structures, including the periaqueductal gray matter, lingual gyrus, cerebellum, hippocampal formation and precuneus. These effects were observed only for high intensity pain stimuli after repeated administration. In spite of our relatively small sample size, our results suggest that COMT appears to affect pain processing. Our data demonstrate that the effect of COMT on pain processing can be detected in presence of 1) a sufficiently robust challenge to the pain system to detect a genotype effect, and/or 2) the recruitment of pain-dampening compensatory mechanisms by the putatively more pain sensitive met homozygotes. These findings may help explain the inconsistencies in reported findings of the impact of COMT in pain regulation.
TL;DR: The results indicated that the methylation pathway in rats was significantly reduced when luteolin was coadministered with a specific COMT inhibitor, and COMT-associated drug-drug interactions need be considered in the future in lutingolin clinical trials because the plasma concentrations and related therapeutic effects may be altered in vivo in the presence of a COMT inhibitors.
Abstract: Luteolin is mainly metabolized by phase II enzymes in animals and humans with glucuronidation and sulfation as the two known metabolic pathways. Although methylation of luteolin was reported previously, the structure of the methylated metabolites and the enzymes involved in the process have not been clarified. In our study, two methylated metabolites, M1 (chrysoeriol) and M2 (diosmetin), were identified in the urine after intravenous administration of luteolin to rats, and the data suggested that the methylation was mediated by catechol-O-methyltransferase (COMT). When luteolin was coadministered with a specific COMT inhibitor, entacapone, the formation of M1 and M2 was significantly reduced, whereas the plasma concentration of luteolin increased. Methylation of luteolin was also studied in vitro using rat tissue homogenates. The apparent kinetic parameters associated with the formation of M1 and M2 in vitro were estimated, and regioselectivity of methylation of luteolin was observed. In the in vitro experiment, there was a preference for the formation of M2 over M1. In contrast, accumulation of M1 was preferred in vivo in both rat plasma and urine after an intravenous dose of luteolin. In conclusion, COMT played a crucial role in the disposition of luteolin in rats. Our results indicated that the methylation pathway in rats was significantly reduced when luteolin was coadministered with a specific COMT inhibitor. Therefore, COMT-associated drug-drug interactions need be considered in the future in luteolin clinical trials because the plasma concentrations and related therapeutic effects may be altered in vivo in the presence of a COMT inhibitor.
TL;DR: There was a modest but statistically significant interaction between MAOA and COMT genotypes such that increased prefrontal catecholamine availability was associated with better working memory and suggest that assessment of multiple genes within functionally related systems may improve the understanding of the genetic basis of cognition.
Abstract: Individual differences in cognitive function are highly heritable and most likely driven by multiple genes of small effect. Well-characterized common functional polymorphisms in the genes MAOA, COMT, and 5HTTLPR each have predictable effects on the availability of the monoamine neurotransmitters dopamine, noradrenaline, and serotonin. We hypothesized that 5HTTLPR genotype would show little association with prefrontal cognitive performance, but that COMT and MAOA would have interacting effects on cognition through their shared influence on prefrontal catecholamine availability. We assessed the individual and epistatic effects of functional polymorphisms in COMT, MAOA, and 5HTTLPR on children's prefrontal cognitive function in nearly 6,000 children from the population-based Avon Longitudinal Study of Parents and Children (ALSPAC). Neither MAOA nor 5HTTLPR polymorphisms showed significant effects on cognitive function. In boys but not girls, there was a modest but statistically significant interaction between MAOA and COMT genotypes such that increased prefrontal catecholamine availability was associated with better working memory. These results suggest that assessment of multiple genes within functionally related systems may improve our understanding of the genetic basis of cognition. © 2010 Wiley-Liss, Inc.
TL;DR: Cortical abnormalities in pedigrees affected by schizophrenia may be contributed to by a disruption of dopaminergic infleunces on cortical maturation, according to a functional Val→Met polymorphism within the gene encoding catechol-o-methyltransferase (COMT).
TL;DR: The results confirmed the associations between Met allele and aggressive behaviour or violent suicide attempts in various psychiatric diagnoses, and suggested that Met allele of the COMT Val108/158 Met might be used as an independent biomarker of suicidal behaviour across different psychopathologies.
Abstract: Alcohol dependence is frequently associated with aggressive and suicidal behaviour. Genetic factors contribute to both behaviours. Candidate genes, related to suicide and aggression, include genes involved in serotonin, norepinephrine and dopamine pathways. The enzyme catechol-O-methyl transferase (COMT) degrades dopamine, epinephrine and norepinephrine. The functional polymorphism (COMT Val108/158Met) affects COMT activity, with the valine (Val) variant associated with higher and the methionine (Met) variant with lower COMT activity. This polymorphism is associated with aggressive and suicidal behaviour, but the literature data on this relationship is contradictory and inconsistent. The hypothesis of this study was that Met allele carriers with alcohol dependence will have a higher frequency of suicide attempts compared to other genotypes. Participants were 312 male and 81 female medication-free patients with alcohol dependence and 487 male and 122 female unrelated, non-suicidal medication-free Caucasian healthy subjects. Our results showed significant (χ2 test with standardized residuals) differences in the frequencies of COMT variants in all alcoholics, alcoholics with different comorbid diagnoses, and in male but not in female alcoholics, with or without suicide attempts. Male alcoholic suicide attempters, compared to male non-attempters, had the higher frequency of Met/Met genotype or Met allele, and significantly (Kruskal-Wallis ANOVA on ranks and Mann-Whitney test) higher aggression and depression scores. These results confirmed the associations between Met allele and aggressive behaviour or violent suicide attempts in various psychiatric diagnoses, and suggested that Met allele of the COMT Val108/158 Met might be used as an independent biomarker of suicidal behaviour across different psychopathologies. Language: en
TL;DR: The results indicate a crucial role of functional genetic variants within the dopaminergic system in the modulation of HPA-axis response patterns and highlight the need to investigate combined effects of specific candidate genes on stress-related endophenotypes.
TL;DR: In healthy adults, the effects of genetic risk factors significantly modulate the course of cognitive aging, and two polymorphisms, comt val158met and ace insertion/deletion, are identified.
TL;DR: Although P50 deficits were present in patients and their unaffected relatives, there was no evidence for an association between NRG1, COMT Val158Met or BDNF Val66Met genotypes and the P50 endophenotype.
Abstract: BACKGROUND: Auditory P50 sensory gating deficits correlate with genetic risk for schizophrenia and constitute a plausible endophenotype for the disease. The well-supported role of catechol-O-methyltransferase (COMT), brain-derived neurotrophic factor (BDNF) and neuregulin 1 (NRG1) genes in neurodevelopment and cognition make a strong theoretical case for their influence on the P50 endophenotype. METHOD: The possible role of NRG1, COMT Val158Met and BDNF Val66Met gene polymorphisms on the P50 endophenotype was examined in a large sample consisting of psychotic patients, their unaffected relatives and unrelated healthy controls using linear regression analyses. RESULTS: Although P50 deficits were present in patients and their unaffected relatives, there was no evidence for an association between NRG1, COMT Val158Met or BDNF Val66Met genotypes and the P50 endophenotype. CONCLUSIONS: The evidence from our large study suggests that any such association between P50 indices and NRG1, COMT Val158Met or BDNF Val66Met genotypes, if present, must be very subtle.
TL;DR: The COMT rs4680 and MAOB rs1799836 polymorphisms may increase susceptibility to PD risk among Japanese and future studies involving larger control and case populations and better pesticide exposure histories will undoubtedly lead to a more thorough understanding of the role of the polymorphisms involved in the dopamine pathway in PD.
Abstract: Parkinson's disease (PD) is characterized by alterations in dopaminergic neurotransmission. Genetic polymorphisms involved in dopaminergic neurotransmission may influence susceptibility to PD. We investigated the relationship of catechol-O-methyltransferase (COMT), monoamine oxidase B (MAOB), dopamine receptor (DR) D2 and DRD4 polymorphisms and PD risk with special attention to the interaction with cigarette smoking among 238 patients with PD and 369 controls in a Japanese population. Subjects with the AA genotype of MAOB rs1799836 showed a significantly increased risk of PD (odds ratio (OR) = 1.70, 95% confidence interval (CI) = 1.12 - 2.58) compared with the AG and GG genotypes combined. The AA genotype of COMT rs4680 was marginally associated with an increased risk of PD (OR = 1.86, 95% CI = 0.98 - 3.50) compared with the GG genotype. The DRD2 rs1800497 and DRD4 rs1800955 polymorphisms showed no association with PD. A COMT -smoking interaction was suggested, with the combined GA and AA genotypes of rs4680 and non-smoking conferring significantly higher risk (OR = 3.97, 95% CI = 2.13 - 7.41) than the AA genotype and a history of smoking (P for interaction = 0.061). No interactions of smoking with other polymorphisms were observed. The COMT rs4680 and MAOB rs1799836 polymorphisms may increase susceptibility to PD risk among Japanese. Future studies involving larger control and case populations and better pesticide exposure histories will undoubtedly lead to a more thorough understanding of the role of the polymorphisms involved in the dopamine pathway in PD.
TL;DR: An association between the val/val genotype of the val158met COMT gene and IBS as well as to specific IBS related bowel pattern in IBS patients is found.
Abstract: Background
The catechol-O-methyltransferase (COMT) enzyme has a key function in the degradation of catecholamines and a functional polymorphism is val158met. The val/val genotype results in a three ...
TL;DR: In this paper, a functional gene × gene interaction between D-amino acid oxidase activator (DAOA) and COMT was detected in the dorsolateral prefrontal cortex (DLPFC) in schizophrenia patients.
TL;DR: A possible role for COMT variants and related haplotypes in BN and its subphenotypes is suggested and may have implications for the prevention and treatment of BN that emerges in the context of childhood ADHD.
Abstract: Up to one third of patients with bulimia nervosa (BN) report a history of ADHD symptoms, and both disorders may also be associated with dopaminergic abnormalities. COMT gene, coding for an enzyme responsible for the degradation of dopamine, may play a part in the etiology of ADHD and BN. This study aimed to (1) examine if certain variants of the COMT genetic markers (rs6269, rs4633, rs4818 and rs4680) are more common in BN versus controls; (2) assess transmission of COMT alleles in BN families; and (3) explore the role of COMT genotypes and haplotypes in bulimic women with childhood ADHD history. 72 BN probands and unaffected relatives were genotyped for COMT rs4680 (Val158Met) and three adjacent markers. The remaining 165 probands were matched with nonpsychiatric controls. We also investigated if COMT variants and haplotypes were associated with childhood ADHD history in a subgroup of 86 BN probands who completed the Wender Utah Rating Scale (WURS). Our results showed that cases and controls did not differ in COMT allele and haplotype frequencies. In contrast, specific alleles of all four COMT markers and the medium-activity haplotype were preferentially transmitted to the offspring with BN. COMT Val158 allele was overrepresented and the medium-activity haplotype was underrepresented in BN with childhood ADHD history (p=0.010). These findings suggest a possible role for COMT variants and related haplotypes in BN and its subphenotypes. If replicated, these preliminary findings may have implications for the prevention and treatment of BN that emerges in the context of childhood ADHD.
Journal Article•
TL;DR: Although the effect of estrogen on COMT activity in vivo in rats was explored, its effects were sex and tissue dependent and the estrogen down-regulation and tamoxifen up-regulation of COMT were best substantiated in the prefrontal cortex and kidneys where COMT is physiologically important for dopamine metabolism.
Abstract: Catechol-O-methyltransferase (COMT) activity depends on gender, age and physiological status suggesting that estrogen may regulate COMT activity. In fact, estrogens down-regulate the function of COMT promoters in cell cultures. On the other hand, COMT may play an important role in estrogen-induced cancers due to its ability to inactivate estrogen metabolites and thereby lowering the levels of these potential carcinogens. In this study, we explored the effect of estrogen on COMT activity in vivo in rats. Male and female Wistar rats received 14-day treatments with either estradiol (100 μg/kg/day; s.c.) or tamoxifen (500 μg/kg/day; s.c.), respectively; in addition ovariectomized rats were studied. COMT activity and COMT protein expression were measured from various brain- and peripheral tissues. Although we found a regulatory function of estrogen, its effects were sex and tissue dependent. Antagonizing the effects of estrogen via tamoxifen increased COMT protein expression in several central and peripheral tissues. However, amounts of COMT protein and COMT activities did not always match. Generally, COMT activities were quite resistant to the effects of tamoxifen and estradiol. Estradiol, unexpectedly, doubled the amount of COMT protein in the prostate but exhibited down-regulatory function in the prefrontal cortex and kidneys. Ovariectomy by itself, however, had only minor effects on COMT activity and expression. It is noteworthy that the estrogen down-regulation and tamoxifen up-regulation of COMT were best substantiated in the prefrontal cortex and kidneys where COMT is physiologically important for dopamine metabolism.
TL;DR: It is suggested that rs4680 could be an inheritable aspect of the mechanisms of dopamine regulation that influence the individual susceptibility of patients with bipolar disorder to develop manic episodes of illness.
TL;DR: In SCZ+ subjects there was a negative correlation between prolactin levels and scores on the general psychopathology subscale of the PANSS scores, suggesting intriguing, but complex, interactions of the COMT Val108/158 Met polymorphism, gender and additional factors on DA metabolism, and its relationship with schizophrenia.
Abstract: 22q11 Deletion syndrome (22q11DS) is a major risk factor for schizophrenia. In addition, both conditions are associated with alterations of the dopaminergic system. The catechol-O-methyltransferase (COMT) gene, located within the deleted region, encodes for the enzyme COMT that is important for degradation of catecholamines, including dopamine (DA). COMT activity is sexually dimorphic and its gene contains a functional polymorphism, Val¹⁰⁸/¹⁵⁸ Met; the Met allele is associated with lower enzyme activity. We report the first controlled catecholamine study in 22q11DS-related schizophrenia. Twelve adults with 22q11DS with schizophrenia (SCZ+) and 22 adults with 22q11DS without schizophrenia (SCZ-) were genotyped for the COMT Val¹⁰⁸/¹⁵⁸ Met genotype. We assessed dopaminergic markers in urine and plasma. We also correlated these markers with scores on the Positive and Negative Symptom Scale (PANSS). Contrary to our expectations, we found SCZ+ subjects to be more often Val hemizygous and SCZ- subjects more often Met hemizygous. Significant COMT cross gender interactions were found on dopaminergic markers. In SCZ+ subjects there was a negative correlation between prolactin levels and scores on the general psychopathology subscale of the PANSS scores. These findings suggest intriguing, but complex, interactions of the COMT Val¹⁰⁸/¹⁵⁸ Met polymorphism, gender and additional factors on DA metabolism, and its relationship with schizophrenia.