Lachman HM, Papolos DF, Saito T, Yu YM, Szymlanksi C, Weinshilboum RM. Human catechol-O-methyl-transferase polymorphism and its potential application to neuropsychiatric disorders. Pharmacogenetics 6: 243-250

Department of Medicine, Albert Einstein College of Medicine, Bronx, New York 10461, USA.
Pharmacogenetics 06/1996; 6(3):243-50. DOI: 10.1097/00008571-199606000-00007
Source: PubMed


Catechol-O-methyltransferase (COMT) inactivates catecholamines and catechol drugs such as L-DOPA. A common genetic polymorphism in humans is associated with a three-to-four-fold variation in COMT enzyme activity and is also associated with individual variation in COMT thermal instability. We now show that this is due to G-->A transition at codon 158 of the COMT gene that results in a valine to methionine substitution. The two alleles can be identified with a PCR-based restriction fragment length polymorphism analysis using the restriction enzyme Nla III. The identification of a gentic marker associated with significant alterations in enzyme activity will facilitate the analysis of a possible role for the COMT gene in neuropsychiatric conditions in which abnormalities in catecholamine neurotransmission are believed to occur, including mood disorders, schizophrenia, obsessive compulsive disorder, alcohol and substance abuse, and attention deficit hyperactivity disorder. In addition, this polymorphism may have pharmacogenetic significance in that it will help make it possible to identify patients who display altered metabolism of catechol drugs.

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    • "This SNP (reference sequence identification code rs4680) results in a valine-to-methionine substitution at codon 158 (val 158 met) of the membrane-bound isoform of the protein. This allelic variation (also known as the val 158 met polymorphism) is functional, as the met 158 allele has about one third to one fourth of the activity of the val 158 allele, resulting in less efficient catecholamine catabolism (Lachman et al., 1996; Lotta et al., 1995; Weinshilboum, Otterness, & Szumlanski, 1999). This COMT polymorphism plays a modulating role in dopamine transmission in prefrontal cortex, but not in subcortical regions (Slifstein et al., 2008). "
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    ABSTRACT: Evidence of the genetic correlates of inhibitory control is scant. Two previously studied dopamine-related polymorphisms, COMT rs4680 and the SLC6A3 3' UTR 40-base-pair VNTR (rs28363170), have been associated with response inhibition, however with inconsistent findings. Here, we investigated the influence of these two polymorphisms in a large healthy adult sample (N = 515) on a response inhibition battery including the antisaccade, stop-signal, go/no-go and Stroop tasks as well as a psychometric measure of impulsivity (Barratt Impulsiveness Scale) (Experiment 1). Additionally, a subsample (N = 144) was studied while performing the go/no-go, stop-signal and antisaccade tasks in 3T fMRI (Experiment 2). In Experiment 1, we did not find any significant associations of COMT or SLC6A3 with inhibitory performance or impulsivity. In Experiment 2, no association of COMT with BOLD was found. However, there were consistent main effects of SLC6A3 genotype in all inhibitory contrasts: Homozygosity of the 10R allele was associated with greater fronto-striatal BOLD response than genotypes with at least one 9R allele. These findings are consistent with meta-analyses showing that the 10R allele is associated with reduced striatal dopamine transporter expression, which in animal studies has been found to lead to increased extracellular dopamine levels. Our study thus supports the involvement of striatal dopamine in the neural mechanisms of cognitive control, in particular response inhibition. Copyright © 2015 Elsevier Ltd. All rights reserved.
    Full-text · Article · Oct 2015 · Cortex
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    • "Catabolic flux of synaptic dopamine in the cortex is controlled primarily by the enzyme catechol-O-methyltransferase (COMT) (Huotari et al. 2002). The COMT gene contains a single nucleotide polymorphism that produces a valine-to-methionine (Val/Met) substitution at position 158 (Val158Met), producing a trimodal distribution of enzyme activity (Floderus et al. 1981; Lachman et al. 1996). Met158 homozygotes biotransform dopamine less than Val carriers, showing one third less COMT enzymatic activity in brain. "
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    ABSTRACT: Performance improvements in cognitive tasks requiring executive functions are evident with nicotinic acetylcholine receptor (nAChR) agonists and activation of the underlying neural circuitry supporting these cognitive effects is thought to involve dopamine neurotransmission. As individual difference in response to nicotine may be related to a functional polymorphism in the gene encoding catechol-O-methyltransferase (COMT), an enzyme that strongly influences cortical dopamine metabolism, this study examined the modulatory effects of the COMT Val158Met polymorphism on the neural response to acute nicotine as measured with resting state electroencephalographic (EEG) oscillations. In a sample of 62 healthy nonsmoking adult males, a single dose (6 mg) of nicotine gum administered in a randomized, double-blind, placebo controlled design was shown to affect α oscillatory activity, increasing power of upper α oscillations in fronto-central regions of Met/Met homozygotes and in parietal/occipital regions of Val/Met heterozygotes. Peak α frequency was also found to be faster with nicotine (vs. placebo) treatment in Val/Met heterozygotes, who exhibited a slower α frequency compared to Val/Val homozygotes. The data tentatively suggest that interindividual differences in brain α oscillations and their response to nicotinic agonist treatment are influenced by genetic mechanisms involving COMT. This article is protected by copyright. All rights reserved.
    Full-text · Article · Jun 2015 · Genes Brain and Behavior
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    • "The human COMT gene codes for the major enzyme involved in the metabolic degradation of released DA. This gene, located on the long arm of chromosome 22q11 (Mannisto & Kaakkola, 1999), contains a single-nucleotide polymorphism (SNP) in codon 158 (Val 158 Met) that affects the enzyme's activity (Chen et al., 2004; Lachman et al., 1996) in the frontal cortices (Karoum et al., 1994). A transition of guanine to adenine in this SNP (rs4680) results in a valine-to-methionine substitution. "
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    ABSTRACT: Genetic variability related to the catechol-O-methyltransferase (COMT) gene has received increasing attention in the last 15 years, in particular as a potential modulator of the neural substrates underlying inhibitory processes and updating in working memory (WM). In an event-related functional magnetic resonance imaging (fMRI) study, we administered a modified version of the Sternberg probe recency task (Sternberg, 1966) to 43 young healthy volunteers, varying the level of interference across successive items. The task was divided into two parts (high vs. low interference) to induce either proactive or reactive control processes. The participants were separated into three groups according to their COMT Val158Met genotype [Val/Val (VV); Val/Met (VM); Met/Met (MM)]. The general aim of the study was to determine whether COMT polymorphism has a modulating effect on the neural substrates of interference resolution during WM processing. Results indicate that interfering trials were associated with greater involvement of frontal cortices (bilateral medial frontal gyrus, left precentral and superior frontal gyri, right inferior frontal gyrus) in VV homozygous subjects (by comparison to Met allele carriers) only in the proactive condition of the task. In addition, analysis of peristimulus haemodynamic responses (PSTH) revealed that the genotype-related difference observed in the left SFG was specifically driven by a larger increase in activity from the storage to the recognition phase of the interfering trials in VV homozygous subjects. These results confirm the impact of COMT genotype on inhibitory processes during a WM task, with an advantage for Met allele carriers. Interestingly, this impact on frontal areas is present only when the level of interference is high, and especially during the transition from storage to recognition in the left superior frontal gyrus.
    Full-text · Article · Apr 2015 · Brain and Cognition
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