Affinage

COMT

Catechol O-methyltransferase · UniProt P21964

Round 2 corrected
Length
271 aa
Mass
30.0 kDa
Annotated
2026-04-28
130 papers in source corpus 20 papers cited in narrative 20 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

COMT is a magnesium- and S-adenosylmethionine-dependent O-methyltransferase that inactivates catecholamines (dopamine, norepinephrine) and catechol estrogens via O-methylation, expressed as soluble (S-COMT) and membrane-bound (MB-COMT) isoforms with MB-COMT predominating in human brain catecholamine metabolism at physiological substrate concentrations (PMID:11735324, PMID:11559542). The common Val158Met polymorphism produces a 3–4-fold difference in catalytic activity and thermostability, and common synonymous haplotype variants further modulate enzyme output by altering mRNA stem-loop structure and translational efficiency, thereby governing prefrontal dopamine tone, pain sensitivity via the mu-opioid system, and homocysteine production through S-adenosylhomocysteine generation (PMID:8807664, PMID:17185601, PMID:12595695, PMID:18189241). In the olfactory bulb, COMT rather than the dopamine transporter serves as the primary synaptic dopamine clearance mechanism, and cell-type-specific COMT overexpression in dopaminergic neurons produces catalepsy and motor impairment, while COMT-deficient mice exhibit altered stress-hormone responses, anxiety, and a preeclampsia-like phenotype rescued by the COMT product 2-methoxyestradiol (PMID:27445153, PMID:31135049, PMID:22192380, PMID:21304959). COMT hemizygosity in 22q11.2 deletion syndrome halves mRNA, protein, and enzyme activity, and epistatic interactions with DTNBP1 genotype non-linearly modulate prefrontal working memory efficiency (PMID:23992923, PMID:24145376).

Mechanistic history

Synthesis pass · year-by-year structured walk · 11 steps
  1. 1996 High

    Establishing how a single coding variant controls COMT catalytic output: the Val158Met polymorphism was shown to cause a 3–4-fold difference in enzyme activity and thermostability, providing the first mechanistic basis for inter-individual variation in catecholamine metabolism.

    Evidence PCR-RFLP genotyping with enzyme activity assays in human erythrocytes and lymphocytes

    PMID:8807664

    Open questions at the time
    • Crystal-structure basis for thermolability not defined in this study
    • Effect on MB-COMT isoform not directly measured
  2. 2001 High

    Defining substrate scope and isoform partitioning: recombinant enzyme assays demonstrated that Val158Met modulates catechol estrogen methylation with regioselectivity, while kinetic modeling showed that MB-COMT predominates in human brain dopamine O-methylation at physiological concentrations.

    Evidence Purified recombinant S-COMT and MB-COMT kinetic assays (GC/MS quantitation); kinetic modeling from published Km/Vmax values; validation in breast cancer cell lines

    PMID:11559542 PMID:11735324

    Open questions at the time
    • Kinetic model not validated by direct isoform-selective measurement in intact brain tissue
    • Relative contribution of each isoform to catechol estrogen metabolism in vivo unknown
  3. 2001 High

    Linking COMT genotype to prefrontal cognition: Val158Met was shown to predict executive function performance and prefrontal cortical efficiency in an allele-dosage manner, establishing that dopamine catabolism by COMT is rate-limiting for prefrontal cortical function.

    Evidence Neuropsychological testing (WCST) and fMRI during working memory in patients, siblings, and controls stratified by genotype; transmission disequilibrium test in schizophrenia trios

    PMID:11381111

    Open questions at the time
    • Causal directionality (dopamine level vs. downstream signaling) not resolved
    • Contribution of other prefrontal catecholamine-metabolizing pathways not excluded
  4. 2003 High

    Extending COMT's functional reach beyond dopamine cognition: PET imaging revealed that Val158Met genotype modulates endogenous mu-opioid system responses to sustained pain, connecting catecholamine metabolism to opioid neurotransmission and pain processing.

    Evidence PET with [11C]carfentanil during experimental sustained pain, stratified by COMT genotype

    PMID:12595695

    Open questions at the time
    • Molecular pathway linking catechol metabolism to mu-opioid receptor activation not identified
    • Whether the effect is dopamine- or norepinephrine-mediated is unresolved
  5. 2006 High

    Revealing that synonymous haplotype variants, not Val158Met alone, are the dominant determinant of COMT enzyme output: synonymous SNPs alter mRNA local stem-loop structure, reducing translational efficiency and protein abundance, providing a post-transcriptional regulatory mechanism.

    Evidence Luciferase reporter assays with haplotype constructs; quantitative Western blotting; RNA structure prediction; site-directed mutagenesis rescue

    PMID:17185601

    Open questions at the time
    • In vivo validation of stem-loop-mediated translational control in brain tissue not performed
    • Whether ribosome profiling data support the model is unknown
  6. 2008 Medium

    Connecting COMT catalysis to one-carbon metabolism: high-activity COMT Val158 carriers showed elevated plasma homocysteine (via SAH production), with an epistatic interaction with MTHFR C677T, establishing that COMT activity feeds into methionine cycle intermediates.

    Evidence Plasma homocysteine measurement in 780 elderly subjects stratified by COMT and MTHFR genotypes

    PMID:18189241

    Open questions at the time
    • Direct measurement of SAH flux attributable to COMT not performed
    • Replication in younger cohorts or different populations not reported
  7. 2011 Medium

    Identifying a non-catecholamine pathway for COMT in reproduction: COMT-deficient pregnant mice developed preeclampsia-like features reversed by the COMT product 2-methoxyestradiol, linking COMT to placental angiogenesis via 2-ME/HIF-1α inhibition.

    Evidence COMT KO pregnant mouse phenotyping with 2-ME rescue; human COMT/MTHFR haplotype association in preeclampsia cohort

    PMID:21304959

    Open questions at the time
    • Human causal evidence limited to genetic association
    • Quantitative contribution of COMT vs. other methyltransferases to 2-ME production in human placenta not defined
  8. 2013 High

    Quantifying the functional consequence of COMT hemizygosity: in 22q11.2 deletion syndrome, COMT mRNA, protein, and enzyme activity are halved, and haplotype-specific effects on S-COMT vs. MB-COMT were resolved, including a rare variant ablating S-COMT expression.

    Evidence Concurrent mRNA, Western blot, and enzyme activity assays in 22q11.2DS patient lymphoblasts with full haplotype characterization

    PMID:23992923

    Open questions at the time
    • Consequences for brain dopamine levels in 22q11.2DS patients not directly measured
    • Functional impact of rare S-COMT-null variant not tested in neuronal cells
  9. 2013 High

    Demonstrating non-linear epistasis in dopamine signaling: combined reduction of COMT and DTNBP1 reverses the working memory advantage seen with either reduction alone, in both mouse models and human fMRI, establishing that prefrontal dopamine function follows an inverted-U relationship dependent on multiple genetic inputs.

    Evidence COMT KO × DTNBP1 KO double-mutant mice behavioral testing; fMRI in 176 subjects stratified by both genotypes

    PMID:24145376

    Open questions at the time
    • Molecular mechanism of COMT–DTNBP1 interaction at the synaptic level not defined
    • Whether the epistasis extends to pain or other COMT-dependent phenotypes unknown
  10. 2016 High

    Establishing COMT as the dominant dopamine clearance mechanism in the olfactory bulb: optogenetic dopamine release combined with pharmacological inhibition showed that tolcapone (COMT inhibitor) but not a DAT inhibitor prolonged dopamine signals, challenging the assumption that DAT is universally the primary clearance route.

    Evidence Fast-scan cyclic voltammetry with optogenetic stimulation in TH-Cre mice; tolcapone vs. GBR12909; COMT/DAT protein quantification across brain regions

    PMID:27445153

    Open questions at the time
    • Whether other brain regions with low DAT similarly depend on COMT clearance is unexplored
    • Contribution of extracellular vs. intracellular COMT not dissected
  11. 2019 High

    Linking COMT dysregulation to Parkinson's disease pathology: PARK2-mutant iPSC-derived dopaminergic neurons show COMT upregulation via DNA hypomethylation, and cell-type-specific COMT overexpression in dopaminergic neurons produces motor impairment, providing a gain-of-function disease-relevant mechanism.

    Evidence iPSC-derived dopaminergic neurons and isogenic CRISPR PARK2 KO lines (RNA-seq, bisulfite sequencing); AAV-mediated COMT overexpression in DAT-Cre mice with motor behavioral testing

    PMID:31135049

    Open questions at the time
    • Whether COMT upregulation is causal to neurodegeneration or a compensatory response is unresolved
    • Human in vivo confirmation of elevated COMT in PARK2 patient brains not shown

Open questions

Synthesis pass · forward-looking unresolved questions
  • The structural basis for how MB-COMT membrane tethering alters substrate selectivity and regioselectivity remains undefined, and whether COMT inhibition can be leveraged therapeutically for prefrontal cognitive deficits or preeclampsia in humans lacks clinical evidence.
  • No high-resolution structure of full-length MB-COMT in a membrane environment
  • Clinical trial data for COMT modulation in cognition or preeclampsia absent from the timeline
  • Cell-type-resolved COMT activity mapping across the full human brain not performed

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016740 transferase activity 5 GO:0140096 catalytic activity, acting on a protein 2
Localization
GO:0005829 cytosol 3 GO:0005886 plasma membrane 3
Pathway
R-HSA-1430728 Metabolism 6 R-HSA-112316 Neuronal System 4 R-HSA-162582 Signal Transduction 2
Partners
DTNBP1MTHFRZNF804A

Evidence

Reading pass · 20 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1996 A G→A transition at codon 158 of the COMT gene (Val158Met) causes a 3- to 4-fold variation in COMT enzyme activity; the Met158 allele encodes a thermolabile, low-activity enzyme, while Val158 encodes a high-activity, thermostable form. PCR-RFLP genotyping combined with enzyme activity assays in human red blood cells and lymphocytes Pharmacogenetics High 8807664
2001 Recombinant wild-type COMT (108Val) and variant COMT (108Met) differ in catechol estrogen methylation: the Met variant is thermolabile and shows 2-3-fold lower catalytic activity toward 2-OHE2, 4-OHE2, 2-OHE1, and 4-OHE1. Methylation of 4-OH catechol estrogens occurs only at the 4-OH group, while 2-OH catechol estrogens are methylated at both 2-OH and 3-OH positions. Recombinant His-tagged COMT isoforms purified by nickel chromatography; GC/MS quantitation of methoxy products; comparison with MCF-7 and ZR-75 breast cancer cell lines with matched genotypes Cancer research High 11559542
2001 A kinetic model using published Km/Vmax values of recombinant MB-COMT and S-COMT indicates that in human brain, where MB-COMT constitutes ~70% of total COMT protein, MB-COMT predominates in the O-methylation of dopamine and noradrenaline at low (physiological) concentrations; in rat brain (MB-COMT ~30%), S-COMT predominates for L-DOPA and 3,4-dihydroxybenzoic acid. The meta/para product ratio is higher for MB-COMT than S-COMT. Enzyme kinetic modeling using published in vitro Km/Vmax values for recombinant isoforms combined with published tissue composition data Medical hypotheses Medium 11735324
2001 COMT Val158Met genotype predicts prefrontal cognitive performance (Wisconsin Card Sorting Test perseverative errors) in an allele-dosage fashion, with Met allele load associated with better executive function; COMT Val158Met also predicts efficiency of prefrontal cortical physiological response during working memory measured by fMRI; Val allele transmission was increased in schizophrenia trios. Neuropsychological testing + fMRI during working memory task in patients, siblings and controls stratified by COMT genotype; family-based transmission disequilibrium test Proceedings of the National Academy of Sciences of the United States of America High 11381111
2003 COMT Val158Met genotype modulates mu-opioid neurotransmitter responses to sustained pain: Met158 homozygotes show diminished regional mu-opioid system activation (measured by PET with [11C]carfentanil), higher sensory and affective pain ratings, and more negative affect; Val158 homozygotes show opposite effects. PET neuroimaging with mu-opioid receptor radioligand [11C]carfentanil during sustained experimental pain, stratified by COMT Val158Met genotype Science High 12595695
2004 Three common COMT haplotypes (LPS, APS, HPS), defined by combinations of synonymous and one nonsynonymous SNP, determine COMT enzymatic activity inversely correlating with pain sensitivity. The LPS haplotype produces the highest enzymatic activity and is associated with reduced risk of temporomandibular disorder. Pharmacological inhibition of COMT in rats produces a profound increase in pain sensitivity. Haplotype analysis in human cohorts; COMT enzyme activity assays; rat model with COMT inhibitor administration and behavioral pain testing Human molecular genetics High 15537663
2005 The Ala72Ser substitution in COMT (rs6267; codon 22/72 in soluble/membrane-bound form respectively) reduces COMT enzyme activity and is associated with increased schizophrenia risk in Koreans, while the Val158Met polymorphism was not associated in this population. Enzyme activity assays in lymphocyte samples stratified by Ala72Ser genotype; case-control association study (320 patients, 379 controls) Human genetics Medium 15645182
2006 Three common COMT haplotypes that differ at two synonymous positions (in addition to Val158Met) produce the largest differences in enzymatic activity primarily due to differences in the amount of translated protein. These synonymous variants alter mRNA local stem-loop secondary structure; more stable stem-loops correlate with lower protein levels and lower enzymatic activity. Site-directed mutagenesis eliminating the stable stem-loop structure restores translated protein levels. Luciferase reporter assays with COMT haplotype constructs; quantitative Western blotting; computational RNA secondary structure prediction; site-directed mutagenesis Science High 17185601
2007 Multiple COMT variant mRNAs are expressed in human frontal cortex, resulting from insertions and deletions within the known brain transcript; several alter the predicted coding sequence. These variants are differentially distributed across brain regions. RT-PCR with intron-spanning primers across all exon-to-exon combinations; sequencing confirmation; regional RT-PCR characterization American journal of medical genetics. Part B, Neuropsychiatric genetics Medium 17477346
2008 High-activity COMT Val158 carriers have significantly higher plasma total homocysteine levels than Met158 homozygotes, an effect limited to individuals homozygous for the MTHFR T677 allele. This demonstrates that COMT activity influences homocysteine metabolism via generation of S-adenosylhomocysteine (SAH), a homocysteine precursor, and shows interaction with the SAM-regenerating enzyme MTHFR. Plasma total homocysteine measurement in 780 elderly individuals stratified by COMT Val158Met and MTHFR C677T genotypes; interaction analysis American journal of medical genetics. Part B, Neuropsychiatric genetics Medium 18189241
2011 Estrogen regulates COMT activity in a sex- and tissue-dependent manner in rats: estradiol down-regulates COMT protein in prefrontal cortex and kidneys but doubles COMT protein in prostate; tamoxifen (estrogen antagonist) increases COMT protein in multiple central and peripheral tissues. COMT activity does not always parallel COMT protein levels. In vivo estradiol and tamoxifen treatment of male/female/ovariectomized Wistar rats; COMT enzyme activity assays and COMT protein quantification in multiple tissues Journal of physiology and pharmacology Medium 22100850
2011 COMT-deficient (knockout) mice show increased corticosterone response to acute but not chronic restraint stress, and a modified cytokine profile after chronic but not acute stress. Female COMT KO mice display increased anxiety behavior and altered benzodiazepine sensitivity, indicating COMT modulates stress-related hormonal and immune parameters in a stressor-chronicity-dependent manner. COMT KO mice (heterozygous and homozygous); serum corticosterone and cytokine measurement after acute vs. chronic restraint; light-dark anxiety test with benzodiazepine administration Behavioural brain research Medium 22192380
2012 ZNF804a, a C2H2 zinc-finger transcription factor, directly binds chromatin proximal to the COMT promoter region and upregulates COMT transcript levels. Chromatin immunoprecipitation (ChIP) demonstrated both epitope-tagged and endogenous ZNF804a interaction with COMT promoter sequences. ZNF804a overexpression with quantitative RT-PCR for COMT mRNA; chromatin immunoprecipitation (ChIP) with both tagged and endogenous ZNF804a; immunocytochemistry confirming nuclear localization in rat neural progenitors PloS one Medium 22384243
2013 COMT hemizygosity in 22q11.2 deletion syndrome results in approximately 50% reduction in COMT mRNA, protein, and enzyme activity. Haplotype analysis reveals that different Val-containing haplotypes differ in their effects on soluble COMT (S-COMT) and membrane-bound COMT (MB-COMT) protein levels and enzyme activity. The 3'UTR SNP rs165599 G variant is associated with low COMT expression. A rare COMT mutation (rs74745580 'T') is associated with absent S-COMT expression and near-absent enzyme activity. COMT mRNA quantification, protein expression (Western blot), and enzyme activity assays in lymphoblast samples from 22q11.2DS patients and controls; haplotype analysis Biological psychiatry High 23992923
2013 Genetic reduction of either COMT or DTNBP1 (dysbindin) alone produces working memory advantages in mice, but combined reduction of both produces working memory deficits — a non-linear epistatic interaction. This same non-linear interaction is observed in human fMRI: COMT Met158 homozygotes (reduced COMT activity) show more efficient prefrontal engagement, but this advantage is reversed on the background of a DTNBP1 haplotype associated with decreased expression. COMT KO × DTNBP1 KO double-mutant mouse working memory behavioral testing; fMRI during working memory in 176 healthy volunteers stratified by COMT and DTNBP1 genotypes Molecular psychiatry High 24145376
2016 In the olfactory bulb (OB), COMT is the predominant mechanism for dopamine clearance rather than the dopamine transporter (DAT). The OB contains ~50% more COMT per unit tissue than the dopamine-rich striatum and far less DAT. Optical activation of short axon cells (SACs) expressing ChR2 in TH-containing neurons evokes dopamine release measured by fast-scan cyclic voltammetry; the COMT inhibitor tolcapone increases the DA signal ~2-fold, whereas the DAT inhibitor GBR12909 has no effect. Fast-scan cyclic voltammetry; optogenetic stimulation (ChR2 in TH-Cre mice); pharmacological COMT inhibition with tolcapone; Western blot quantification of COMT and DAT protein across brain regions The Journal of neuroscience High 27445153
2017 Transgenic mice overexpressing human COMT have lower basal striatal dopamine levels and, after 6-OHDA lesion and chronic L-DOPA treatment, exhibit exacerbated L-DOPA-induced dyskinesia with potentiated induction of FosB and phospho-acetylated histone 3 (molecular markers of dyskinesia) in the lesioned striatum. L-DOPA produces a greater increase in the dopamine metabolite 3-methoxytyramine in dyskinetic COMT-overexpressing mice, confirming enhanced COMT-mediated dopamine catabolism. Human COMT transgenic mouse model; 6-OHDA lesion; chronic L-DOPA treatment; dyskinesia scoring; striatal dopamine/metabolite HPLC; FosB and histone immunohistochemistry Neurobiology of disease High 28315782
2018 In human prefrontal cortex (postmortem), COMT SNPs rs4680 (Val158Met) and rs4818 are associated with varying levels of soluble COMT (S-COMT) protein but not membrane-bound COMT (MB-COMT), indicating that genotype influences S-COMT abundance independently of MB-COMT. SNPs rs737865 and rs165599 showed no association with either isoform. Western blotting for S-COMT and MB-COMT protein in postmortem prefrontal cortex from 199 subjects with defined COMT genotypes at four SNPs; statistical association analysis stratified by diagnosis Journal of human genetics Medium 30218069
2019 In iPSC-derived dopaminergic neurons from Parkinson's disease patients with PARK2 mutations, COMT expression is dramatically increased relative to healthy controls, associated with lower DNA methylation at the COMT locus. Isogenic PARK2 knockout lines (by CRISPR-Cas9) show the same COMT upregulation. Cell-type-specific overexpression of COMT in dopaminergic neurons of DAT-Cre mice produces cataleptic behavior and impaired motor coordination. iPSC differentiation to dopaminergic neurons; CRISPR-Cas9 isogenic PARK2 KO; RNA-seq and bisulfite sequencing for methylation; viral vector cell-type-specific COMT overexpression in DAT-Cre mice with behavioral phenotyping Brain High 31135049
2011 COMT-deficient pregnant mice develop a preeclampsia-like phenotype that is reversed by exogenous 2-methoxyestradiol (2-ME), an estrogen metabolite generated by COMT. 2-ME inhibits Hypoxia Inducible Factor 1α (HIF-1α), a transcription factor mediating hypoxic responses, linking COMT enzymatic activity to placental angiogenesis via the 2-ME/HIF-1α pathway. COMT KO pregnant mouse phenotyping; 2-ME supplementation rescue experiment; human genetic study of COMT and MTHFR haplotypes in preeclampsia cohort PloS one Medium 21304959

Source papers

Stage 0 corpus · 130 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2020 A SARS-CoV-2 protein interaction map reveals targets for drug repurposing. Nature 3411 32353859
2005 Towards a proteome-scale map of the human protein-protein interaction network. Nature 2090 16189514
2001 Effect of COMT Val108/158 Met genotype on frontal lobe function and risk for schizophrenia. Proceedings of the National Academy of Sciences of the United States of America 1868 11381111
2005 A human protein-protein interaction network: a resource for annotating the proteome. Cell 1704 16169070
2002 Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. Proceedings of the National Academy of Sciences of the United States of America 1479 12477932
1996 Human catechol-O-methyltransferase pharmacogenetics: description of a functional polymorphism and its potential application to neuropsychiatric disorders. Pharmacogenetics 1447 8807664
1999 Characterization of single-nucleotide polymorphisms in coding regions of human genes. Nature genetics 1381 10391209
2014 An atlas of genetic influences on human blood metabolites. Nature genetics 1209 24816252
2015 A human interactome in three quantitative dimensions organized by stoichiometries and abundances. Cell 1015 26496610
2014 A proteome-scale map of the human interactome network. Cell 977 25416956
2004 Genetic basis for individual variations in pain perception and the development of a chronic pain condition. Human molecular genetics 911 15537663
2003 COMT val158met genotype affects mu-opioid neurotransmitter responses to a pain stressor. Science (New York, N.Y.) 852 12595695
2020 A reference map of the human binary protein interactome. Nature 849 32296183
2008 Systematic meta-analyses and field synopsis of genetic association studies in schizophrenia: the SzGene database. Nature genetics 817 18583979
2005 Moderation of the effect of adolescent-onset cannabis use on adult psychosis by a functional polymorphism in the catechol-O-methyltransferase gene: longitudinal evidence of a gene X environment interaction. Biological psychiatry 804 15866551
2009 The distinct cognitive syndromes of Parkinson's disease: 5 year follow-up of the CamPaIGN cohort. Brain : a journal of neurology 724 19812213
2009 Candidate gene studies of ADHD: a meta-analytic review. Human genetics 713 19506906
2021 Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. Cell 705 33961781
2006 Human catechol-O-methyltransferase haplotypes modulate protein expression by altering mRNA secondary structure. Science (New York, N.Y.) 686 17185601
2011 Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium. Briefings in bioinformatics 656 21873635
2008 An empirical framework for binary interactome mapping. Nature methods 652 19060904
2008 Large-scale proteomics and phosphoproteomics of urinary exosomes. Journal of the American Society of Nephrology : JASN 607 19056867
2011 Global landscape of HIV-human protein complexes. Nature 593 22190034
2020 Comparative host-coronavirus protein interaction networks reveal pan-viral disease mechanisms. Science (New York, N.Y.) 564 33060197
2002 A highly significant association between a COMT haplotype and schizophrenia. American journal of human genetics 553 12402217
2006 Catechol-o-methyltransferase, cognition, and psychosis: Val158Met and beyond. Biological psychiatry 550 16476412
2021 Multilevel proteomics reveals host perturbations by SARS-CoV-2 and SARS-CoV. Nature 532 33845483
2003 Executive subprocesses in working memory: relationship to catechol-O-methyltransferase Val158Met genotype and schizophrenia. Archives of general psychiatry 488 12963670
2002 A functional polymorphism in the COMT gene and performance on a test of prefrontal cognition. The American journal of psychiatry 463 11925305
2004 The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). Genome research 438 15489334
2022 OpenCell: Endogenous tagging for the cartography of human cellular organization. Science (New York, N.Y.) 432 35271311
2007 Catechol-O-methyltransferase (COMT): a gene contributing to sex differences in brain function, and to sexual dimorphism in the predisposition to psychiatric disorders. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 250 17805313
2006 The molecular genetics of cognition: dopamine, COMT and BDNF. Genes, brain, and behavior 235 16716201
2001 Catechol-O-methyltransferase (COMT)-mediated metabolism of catechol estrogens: comparison of wild-type and variant COMT isoforms. Cancer research 221 11559542
2006 The catechol-O-methyl transferase (COMT) gene as a candidate for psychiatric phenotypes: evidence and lessons. Molecular psychiatry 164 16505837
1999 Association between the functional variant of the catechol-O-methyltransferase (COMT) gene and type 1 alcoholism. Molecular psychiatry 144 10395222
2009 Genes, cognition and brain through a COMT lens. Neuroscience 138 19446012
2007 Genotype effects of CHRNA7, CNR1 and COMT in schizophrenia: interactions with tobacco and cannabis use. The British journal of psychiatry : the journal of mental science 124 17978319
2004 COMT: a common susceptibility gene in bipolar disorder and schizophrenia. American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics 124 15211633
2007 Is COMT a susceptibility gene for schizophrenia? Schizophrenia bulletin 120 17412710
2004 COMT gene polymorphism is associated with declarative memory in adulthood and old age. Behavior genetics 119 15319576
2011 Effects of COMT polymorphisms on brain function and behavior in health and disease. Brain research bulletin 118 22138198
2008 Genetic variation in the catechol-O-methyltransferase (COMT) gene and morphine requirements in cancer patients with pain. Molecular pain 118 19094200
2007 Meta-analysis of COMT val158met in panic disorder: ethnic heterogeneity and gender specificity. American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics 113 17357147
2003 Catechol O-methyltransferase (COMT) mRNA expression in the dorsolateral prefrontal cortex of patients with schizophrenia. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 113 12799619
2012 Pain sensitivity in fibromyalgia is associated with catechol-O-methyltransferase (COMT) gene. European journal of pain (London, England) 103 22528689
2009 Meta-analysis of association between genetic variants in COMT and schizophrenia: an update. Schizophrenia research 102 19329282
2009 Variation in the COMT gene: implications for pain perception and pain treatment. Pharmacogenomics 102 19374521
2004 Catecholamines and aggression: the role of COMT and MAO polymorphisms. Annals of the New York Academy of Sciences 102 15817751
2003 Association analysis of MAOA and COMT with neuroticism assessed by peers. American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics 94 12815746
2006 The quantification of COMT mRNA in post mortem cerebellum tissue: diagnosis, genotype, methylation and expression. BMC medical genetics 93 16483362
2011 Cannabis, COMT and psychotic experiences. The British journal of psychiatry : the journal of mental science 91 21947654
2013 The role of COMT gene variants in depression: Bridging neuropsychological, behavioral and clinical phenotypes. Neuroscience and biobehavioral reviews 90 23792050
2012 ZNF804a regulates expression of the schizophrenia-associated genes PRSS16, COMT, PDE4B, and DRD2. PloS one 85 22384243
2014 Medicinal chemistry of catechol O-methyltransferase (COMT) inhibitors and their therapeutic utility. Journal of medicinal chemistry 82 25080080
2014 COMT haplotypes modulate associations of antenatal maternal anxiety and neonatal cortical morphology. The American journal of psychiatry 72 25320962
2018 Simultaneous regulation of F5H in COMT-RNAi transgenic switchgrass alters effects of COMT suppression on syringyl lignin biosynthesis. Plant biotechnology journal 64 30267599
2005 Association of Ala72Ser polymorphism with COMT enzyme activity and the risk of schizophrenia in Koreans. Human genetics 64 15645182
2009 Association studies of catechol-O-methyltransferase (COMT) gene with schizophrenia and response to antipsychotic treatment. Pharmacogenomics 63 19290789
2006 The COMT val158met polymorphism and brain morphometry in healthy young adults. Neuroscience letters 61 16857316
2013 Epistatic interaction between COMT and DTNBP1 modulates prefrontal function in mice and in humans. Molecular psychiatry 55 24145376
2007 Meta-analyses suggest association between COMT, but not HTR1B, alleles, and suicidal behavior. American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics 55 17525973
2013 Biological effects of COMT haplotypes and psychosis risk in 22q11.2 deletion syndrome. Biological psychiatry 52 23992923
2011 COMT genetic variants and pain. Drugs of today (Barcelona, Spain : 1998) 50 21695287
2013 Effect of catechol-o-methyltransferase-gene (COMT) variants on experimental and acute postoperative pain in 1,000 women undergoing surgery for breast cancer. Anesthesiology 47 24343288
2011 Sex modulates the associations between the COMT gene and personality traits. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 47 21471954
2022 Identification and Functional Analysis of the Caffeic Acid O-Methyltransferase (COMT) Gene Family in Rice (Oryza sativa L.). International journal of molecular sciences 46 35955626
2017 Pharmacophore-based virtual screening of catechol-o-methyltransferase (COMT) inhibitors to combat Alzheimer's disease. Journal of biomolecular structure & dynamics 46 29281938
2012 The role of the catechol-O-methyltransferase (COMT) gene in personality and related psychopathological disorders. CNS & neurological disorders drug targets 46 22483293
2010 Analysis of association between the catechol-O-methyltransferase (COMT) gene and negative symptoms in chronic schizophrenia. Psychiatry research 46 20483479
2001 Catechol-O-Methyltransferase (COMT) gene polymorphism and breast cancer risk in young women. British journal of cancer 46 11556837
2013 Role of COMT in ADHD: a systematic meta-analysis. Molecular neurobiology 45 23907791
2011 Epistasis between COMT and MTHFR in maternal-fetal dyads increases risk for preeclampsia. PloS one 45 21304959
2015 The Role of the Catechol-o-Methyltransferase (COMT) GeneVal158Met in Aggressive Behavior, a Review of Genetic Studies. Current neuropharmacology 44 26630958
2000 No association between catechol-O-methyltransferase (COMT) gene polymorphism and attention deficit hyperactivity disorder (ADHD) in an Irish sample. American journal of medical genetics 44 10898900
2000 Association between homozygosity at the COMT gene locus and obsessive compulsive disorder. American journal of medical genetics 44 11121168
2010 Toxicology and safety of COMT inhibitors. International review of neurobiology 43 21095462
2017 Catechol-O-Methyltransferase (COMT): An Update on Its Role in Cancer, Neurological and Cardiovascular Diseases. Reviews of physiology, biochemistry and pharmacology 42 28456872
2012 COMT as a drug target for cognitive functions and dysfunctions. CNS & neurological disorders drug targets 41 22483296
2016 Modification of COMT-dependent pain sensitivity by psychological stress and sex. Pain 40 26675825
2010 Are genetic variants of COMT associated with addiction? Pharmacogenetics and genomics 40 20975619
2008 Polymorphisms in the catechol-O-methyltransferase (COMT) gene influence plasma total homocysteine levels. American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics 40 18189241
2000 The relationship between COMT genotype and the clinical effectiveness of tolcapone, a COMT inhibitor, in patients with Parkinson's disease. Clinical neuropharmacology 40 10895397
2019 OPRM1 rs1799971, COMT rs4680, and FAAH rs324420 genes interact with placebo procedures to induce hypoalgesia. Pain 39 31335650
2012 The COMT Met158 allele and violence in schizophrenia: a meta-analysis. Schizophrenia research 38 22784685
2006 Is there an association between the COMT gene and P300 endophenotypes? European psychiatry : the journal of the Association of European Psychiatrists 36 16414251
1999 Linkage disequilibrium on the COMT gene in French schizophrenics and controls. American journal of medical genetics 36 10490696
2011 Complex estrogenic regulation of catechol-O-methyltransferase (COMT) in rats. Journal of physiology and pharmacology : an official journal of the Polish Physiological Society 35 22100850
2008 [Relationship between COMT gene genotypes and severity of fibromyalgia]. Reumatologia clinica 35 21794324
2000 Exploratory association study between catechol-O-methyltransferase (COMT) high/low enzyme activity polymorphism and hypnotizability. American journal of medical genetics 35 11121178
2007 Expression of multiple catechol-o-methyltransferase (COMT) mRNA variants in human brain. American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics 33 17477346
2007 Exploratory and habituation phenotype of heterozygous and homozygous COMT knockout mice. Behavioural brain research 33 17707921
2006 The association between high-activity COMT allele and alcoholism. Neuro endocrinology letters 33 16648777
2016 Monoamine Oxidase A (MAOA) and Catechol-O-Methyltransferase (COMT) Gene Polymorphisms Interact with Maternal Parenting in Association with Adolescent Reactive Aggression but not Proactive Aggression: Evidence of Differential Susceptibility. Journal of youth and adolescence 32 26932718
2015 Genetics and functional imaging: effects of APOE, BDNF, COMT, and KIBRA in aging. Neuropsychology review 30 25666727
2017 Stressful life events and catechol-O-methyl-transferase (COMT) gene in bipolar disorder. Depression and anxiety 28 28102561
2011 Physiological and behavioural responsivity to stress and anxiogenic stimuli in COMT-deficient mice. Behavioural brain research 27 22192380
2003 Tissue histopathology, clinical chemistry and behaviour of adult Comt-gene-disrupted mice. Journal of applied toxicology : JAT 26 12884403
2013 Genetic influence of COMT and BDNF gene polymorphisms on resilience in healthy college students. Neuropsychobiology 25 24107543
2011 Association of MAOA and COMT gene polymorphisms with palatable food intake in children. The Journal of nutritional biochemistry 25 21530215
2007 Breast density and polymorphisms in genes coding for CYP1A2 and COMT: the Multiethnic Cohort. BMC cancer 25 17295924
2001 Catecholamine metabolism in the brain by membrane-bound and soluble catechol-o-methyltransferase (COMT) estimated by enzyme kinetic values. Medical hypotheses 25 11735324
2017 Impact of DRD2/ANKK1 and COMT Polymorphisms on Attention and Cognitive Functions in Schizophrenia. PloS one 24 28085950
2014 Association of COMT and COMT-DRD2 interaction with creative potential. Frontiers in human neuroscience 24 24782743
2003 Structure of the tobacco caffeic acid O-methyltransferase (COMT) II gene: identification of promoter sequences involved in gene inducibility by various stimuli. Plant molecular biology 24 12956522
1996 Identification of a BglI polymorphism of catechol-O-methyltransferase (COMT) gene, and association study with schizophrenia. American journal of medical genetics 24 8950414
2018 The opioid receptor mu 1 (OPRM1) rs1799971 and catechol-O-methyltransferase (COMT) rs4680 as genetic markers for placebo analgesia. Pain 23 30130297
2017 Catechol-O-methyltransferase (COMT) genotype affects cognitive control during total sleep deprivation. Cortex; a journal devoted to the study of the nervous system and behavior 22 29248857
2009 Association between COMT gene and Chinese male schizophrenic patients with violent behavior. Medical science monitor : international medical journal of experimental and clinical research 22 19721400
2007 Association of DRD4 and COMT polymorphisms with anger and forgiveness traits in healthy volunteers. Neuroscience letters 22 18063308
2018 Catechol-O-methyltransferase (COMT) genotypes are associated with varying soluble, but not membrane-bound COMT protein in the human prefrontal cortex. Journal of human genetics 20 30218069
2017 Human COMT over-expression confers a heightened susceptibility to dyskinesia in mice. Neurobiology of disease 20 28315782
2014 Hypnotizability and Catechol-O-Methyltransferase (COMT) polymorphysms in Italians. Frontiers in human neuroscience 20 24431998
2011 Association between polymorphisms in catechol-O-methyltransferase (COMT) and cocaine-induced paranoia in European-American and African-American populations. American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics 20 21656904
2011 A COMT gene haplotype associated with methamphetamine abuse. Pharmacogenetics and genomics 20 21934638
2017 Variations in COMT and NTRK2 Influence Symptom Burden in Women Undergoing Breast Cancer Treatment. Biological research for nursing 19 28205449
1998 Extending levodopa action: COMT inhibition. Neurology 19 9633684
2019 Cell-specific overexpression of COMT in dopaminergic neurons of Parkinson's disease. Brain : a journal of neurology 18 31135049
2016 Subsecond Regulation of Synaptically Released Dopamine by COMT in the Olfactory Bulb. The Journal of neuroscience : the official journal of the Society for Neuroscience 18 27445153
2013 Genetic polymorphisms in CYP1A1, CYP1B1 and COMT genes in Greenlandic Inuit and Europeans. International journal of circumpolar health 18 23785672
2012 Association analysis of dopaminergic gene variants (Comt, Drd4 And Dat1) with Alzheimer s disease. Journal of biological regulators and homeostatic agents 18 23034259
2021 Brain predictive coding processes are associated to COMT gene Val158Met polymorphism. NeuroImage 17 33716157
2019 Systems pharmacogenomics - gene, disease, drug and placebo interactions: a case study in COMT. Pharmacogenomics 17 31124409
2019 Evaluation of genetic risk related to catechol-O-methyltransferase (COMT) and β2-adrenergic receptor (ADRB2) activity in different diagnostic subgroups of temporomandibular disorder in Brazilian patients. International journal of oral and maxillofacial surgery 17 31285095
2018 Catechol-O-methyltransferase (COMT) genetic variants are associated with cognitive decline in patients with Parkinson's disease. Parkinsonism & related disorders 17 29439855
2017 Nonlinear modulation of interacting between COMT and depression on brain function. European psychiatry : the journal of the Association of European Psychiatrists 17 28728097
2012 The catechol-O-methyltransferase gene (COMT) and cognitive function from childhood through adolescence. Biological psychology 17 23178897
2006 Lack of association between COMT gene and deficit/nondeficit schizophrenia. Behavioral and brain functions : BBF 17 17173666
2010 No Association Between Functional Polymorphisms in COMT and MTHFR and Schizophrenia Risk in Korean Population. Epidemiology and health 16 21217836
2008 The catechol-O-methyltransferase (COMT) gene polymorphism and prevalence of uterine fibroids. Maturitas 16 18752908