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Gene Review

COMT  -  catechol-O-methyltransferase

Homo sapiens

Synonyms: Catechol O-methyltransferase

Disease relevance of COMT


Psychiatry related information on COMT


  1. COMT and the Development of Aggressive Behaviors: The val/met variant of the catechol O-methyltransferase (COMT) gene in association with low birth weight has been linked to early onset antisocial behaviors in children diagnosed with attention deficit disorder [6]. However, a posterior study has failed to replicate this[7]. Strous and colleagues have reported an association between the low activity COMT polymorphism and risk of aggression in schizophrenia [8].
  2. Other associations:



High impact information on COMT


Chemical compound and disease context of COMT


Biological context of COMT

  • Indexes of deamination, sulfoconjugation, and O-methylation, with the exception of a reduced deamination of dopamine and the activities of COMT, MAO-B, and TL-PST were not different in the two groups [20].
  • Consistent with these genotype effects, RGS4 mRNA was inversely correlated with the COMT enzyme activity in the DLPFC [21].
  • We found nominal evidence for association of illness to rs165849 (P=0.051) in ARVCF, and a stronger signal (global P=0.0019-0.0036) from three-marker haplotypes spanning the 3' portions of COMT and ARVCF, including Val(108/158)Met with Val(108/158) being the overtransmitted allele, consistent with previous studies [22].
  • No evidence of association between genotype or allele frequencies of both MAO-A or COMT gene and narcolepsy was found [10].
  • Catechol-O-methyltransferase (COMT) has been implicated in schizophrenia by its function through its roles in monoamine neurotransmitter metabolism and its impact on prefrontal cognition, and also by its position through linkage scans and a strong cytogenetic association [22].

Anatomical context of COMT


Associations of COMT with chemical compounds

  • Enzyme activity correlated positively with age in all brain areas for MAO (with both benzylamine and tryptamine substrates) but no consistent pattern of correlation was found for COMT and TH [27].
  • Further evidence for a modulation of Novelty Seeking by DRD4 exon III, 5-HTTLPR, and COMT val/met variants [28].
  • Pretreatment with entacapone (OR-611), a peripheral catechol O-methyl-transferase (COMT) inhibitor, greatly reduces the plasma 3OMFD fraction and provides an ideal situation to evaluate the contribution of the plasma 3OMFD fraction in several kinetic models of FDOPA uptake [29].
  • OR486 (COMT inhibitor) also blocked the antimitogenic effects of estradiol in both the presence and absence of the CYP450 inducers [30].
  • Other mechanisms are capable of regulating the concentrations of norepinephrine and epinephrine in circulating blood (and apparently also at receptors in the heart and vascular tissue) when both COMT and MAO-A activity are inhibited to a significant extent [3].
  • The significant increase in COMT activity from neonate to adulthood complements previous findings of protracted postnatal changes in the PFC dopamine system and may reflect an increasing importance of COMT for PFC dopamine regulation during maturation [31].
  • The biological plausibility of the association is increased by the functionality of the val(158)met polymorphism in terms of its effect on COMT enzyme activity, and by the role of COMT in cortical dopamine signalling and information processing [32].
  • This finding suggests a potentially beneficial effect of an antidepressive add-on therapy with substances increasing dopamine availability individually tailored according to COMT val158met genotype [33].
  • The doses of levodopa treatment can be influenced by specific COMT haplotypes and this may be useful in instituting individualized therapy for PD patients [34].

Physical interactions of COMT

  • DRD2 C957T polymorphism interacts with the COMT Val158Met polymorphism in human working memory ability [35].
  • PST and membrane-bound COMT were found to have the lowest Km values for both catecholamines [36].

Regulatory relationships of COMT

  • Although these results suggest the COMT gene exerts some influence on the risk for ADHD in the Han Chinese population, given the potential for Type I error, these findings require replication before drawing definitive conclusions [37].
  • Two patients with COMT inhibitor-induced hepatic dysfunction and UGT1A9 genetic polymorphism [38].
  • Transgenic maize (Zea mays) plants were generated with a construct harboring a maize caffeic acid O-methyltransferase (COMT) cDNA in the antisense (AS) orientation under the control of the maize Adh1 (alcohol dehydrogenase) promoter [39].
  • It was found that epidermal homogenates from vitiligo patients expressed higher levels of COMT activity than homogenates from healthy controls [40].
  • These results are compatible with the conclusion that the genetic polymorphism which regulates RBC COMT activity may also regulate the level of human lymphocyte COMT activity [41].

Other interactions of COMT

  • The breast cancer risk associated with individual susceptibility genotypes varied among the three genes and was highest for COMT, followed by CYP1A1 and CYP17 [1].
  • These findings support previous association signals of schizophrenia to COMT markers, and suggest that ARVCF might contribute to this signal [22].
  • Concentrations of MHPG in plasma are determined mainly by MAO-A activity because COMT inhibition did not have an additional effect on the moclobemide-induced decrease in plasma MHPG [3].
  • The COMT L allele modifies the association between MAOB polymorphism and PD in Taiwanese [42].
  • We did not observe any effect modification by BMI, PMH use and cigarette smoking for the CYP1B1 and COMT genotypes [43].
  • COMT Met-homozygous background mediated against the effect of GRM3 genotype [44].

Analytical, diagnostic and therapeutic context of COMT


  1. Breast cancer risk associated with genotype polymorphism of the estrogen-metabolizing genes CYP17, CYP1A1, and COMT: a multigenic study on cancer susceptibility. Huang, C.S., Chern, H.D., Chang, K.J., Cheng, C.W., Hsu, S.M., Shen, C.Y. Cancer Res. (1999) [Pubmed]
  2. Polymorphisms of the estrogen-metabolizing genes CYP17 and catechol-O-methyltransferase and risk of epithelial ovarian cancer. Garner, E.I., Stokes, E.E., Berkowitz, R.S., Mok, S.C., Cramer, D.W. Cancer Res. (2002) [Pubmed]
  3. Simultaneous inhibition of catechol-O-methyltransferase and monoamine oxidase A: effects on hemodynamics and catecholamine metabolism in healthy volunteers. Illi, A., Sundberg, S., Ojala-Karlsson, P., Scheinin, M., Gordin, A. Clin. Pharmacol. Ther. (1996) [Pubmed]
  4. Characterization and implications of estrogenic down-regulation of human catechol-O-methyltransferase gene transcription. Xie, T., Ho, S.L., Ramsden, D. Mol. Pharmacol. (1999) [Pubmed]
  5. Polymorphisms in estrogen bioactivation, detoxification and oxidative DNA base excision repair genes and prostate cancer risk. Nock, N.L., Cicek, M.S., Li, L., Liu, X., Rybicki, B.A., Moreira, A., Plummer, S.J., Casey, G., Witte, J.S. Carcinogenesis (2006) [Pubmed]
  6. Catechol O-methyltransferase gene variant and birth weight predict early-onset antisocial behavior in children with attention-deficit/hyperactivity disorder. Thapar, A., Langley, K., Fowler, T., Rice, F., Turic, D., Whittinger, N., Aggleton, J., Van den Bree, M., Owen, M., O'Donovan, M. Arch. Gen. Psychiatry. (2005) [Pubmed]
  7. COMT Val108/158Met gene variant, birth weight, and conduct disorder in children with ADHD. Sengupta, S.M., Grizenko, N., Schmitz, N., Schwartz, G., Ben Amor, L., Bellingham, J., de Guzman, R., Polotskaia, A., Ter Stepanian, M., Thakur, G., Joober, R. J. Am. Acad. Child. Adolesc. Psychiatry. (2006) [Pubmed]
  8. Aggressive behavior in schizophrenia is associated with the low enzyme activity COMT polymorphism: a replication study. Strous, R.D., Nolan, K.A., Lapidus, R., Diaz, L., Saito, T., Lachman, H.M. Am. J. Med. Genet. B. Neuropsychiatr. Genet. (2003) [Pubmed]
  9. Catechol o-methyltransferase, serotonin transporter, and tryptophan hydroxylase gene polymorphisms in bipolar disorder patients with and without comorbid panic disorder. Rotondo, A., Mazzanti, C., Dell'Osso, L., Rucci, P., Sullivan, P., Bouanani, S., Gonnelli, C., Goldman, D., Cassano, G.B. The American journal of psychiatry. (2002) [Pubmed]
  10. MAO-A and COMT polymorphisms and gene effects in narcolepsy. Dauvilliers, Y., Neidhart, E., Lecendreux, M., Billiard, M., Tafti, M. Mol. Psychiatry (2001) [Pubmed]
  11. Family-based association studies support a sexually dimorphic effect of COMT and MAOA on genetic susceptibility to obsessive-compulsive disorder. Karayiorgou, M., Sobin, C., Blundell, M.L., Galke, B.L., Malinova, L., Goldberg, P., Ott, J., Gogos, J.A. Biol. Psychiatry (1999) [Pubmed]
  12. Effect of schizotypy on cognitive performance and its tuning by COMT val158 met genotype variations in a large population of young men. Smyrnis, N., Avramopoulos, D., Evdokimidis, I., Stefanis, C.N., Tsekou, H., Stefanis, N.C. Biol. Psychiatry (2007) [Pubmed]
  13. Association of COMT Val108/158Met genotype with smoking cessation. Munafò, M.R., Johnstone, E.C., Guo, B., Murphy, M.F., Aveyard, P. Pharmacogenet. Genomics (2008) [Pubmed]
  14. The effect of catechol-O-methyltransferase Met/Val functional polymorphism on smoking cessation: retrospective and prospective analyses in a cohort study. Omidvar, M., Stolk, L., Uitterlinden, A.G., Hofman, A., Van Duijn, C.M., Tiemeier, H. Pharmacogenet. Genomics (2009) [Pubmed]
  15. Crystal structure of catechol O-methyltransferase. Vidgren, J., Svensson, L.A., Liljas, A. Nature (1994) [Pubmed]
  16. Catechol-O-methyltransferase (COMT): biochemistry, molecular biology, pharmacology, and clinical efficacy of the new selective COMT inhibitors. Männistö, P.T., Kaakkola, S. Pharmacol. Rev. (1999) [Pubmed]
  17. Catechol-O-methyltransferase polymorphism is not associated with ovarian cancer risk. Goodman, J.E., Lavigne, J.A., Hengstler, J.G., Tanner, B., Helzlsouer, K.J., Yager, J.D. Cancer Epidemiol. Biomarkers Prev. (2000) [Pubmed]
  18. Simultaneous MAO-B and COMT inhibition in L-Dopa-treated patients with Parkinson's disease. Lyytinen, J., Kaakkola, S., Ahtila, S., Tuomainen, P., Teräväinen, H. Mov. Disord. (1997) [Pubmed]
  19. Haplotype relative risk study of catechol-O-methyltransferase (COMT) and attention deficit hyperactivity disorder (ADHD): association of the high-enzyme activity Val allele with ADHD impulsive-hyperactive phenotype. Eisenberg, J., Mei-Tal, G., Steinberg, A., Tartakovsky, E., Zohar, A., Gritsenko, I., Nemanov, L., Ebstein, R.P. Am. J. Med. Genet. (1999) [Pubmed]
  20. Catecholamine metabolic pathways and exercise training. Plasma and urine catecholamines, metabolic enzymes, and chromogranin-A. Rogers, P.J., Tyce, G.M., Weinshilboum, R.M., O'Connor, D.T., Bailey, K.R., Bove, A.A. Circulation (1991) [Pubmed]
  21. RGS4 mRNA expression in postmortem human cortex is associated with COMT Val158Met genotype and COMT enzyme activity. Lipska, B.K., Mitkus, S., Caruso, M., Hyde, T.M., Chen, J., Vakkalanka, R., Straub, R.E., Weinberger, D.R., Kleinman, J.E. Hum. Mol. Genet. (2006) [Pubmed]
  22. Haplotypic association spanning the 22q11.21 genes COMT and ARVCF with schizophrenia. Sanders, A.R., Rusu, I., Duan, J., Vander Molen, J.E., Hou, C., Schwab, S.G., Wildenauer, D.B., Martinez, M., Gejman, P.V. Mol. Psychiatry (2005) [Pubmed]
  23. Sulfate and methyldopa metabolism: metabolite patterns and platelet phenol sulfotransferase activity. Campbell, N.R., Sundaram, R.S., Werness, P.G., Van Loon, J., Weinshilboum, R.M. Clin. Pharmacol. Ther. (1985) [Pubmed]
  24. Catecholamines block the antimitogenic effect of estradiol on human coronary artery smooth muscle cells. Dubey, R.K., Jackson, E.K., Gillespie, D.G., Zacharia, L.C., Imthurn, B. J. Clin. Endocrinol. Metab. (2004) [Pubmed]
  25. Evidence for statistical epistasis between catechol-O-methyltransferase (COMT) and polymorphisms in RGS4, G72 (DAOA), GRM3, and DISC1: influence on risk of schizophrenia. Nicodemus, K.K., Kolachana, B.S., Vakkalanka, R., Straub, R.E., Giegling, I., Egan, M.F., Rujescu, D., Weinberger, D.R. Hum. Genet. (2007) [Pubmed]
  26. Human catechol-O-methyltransferase down-regulation by estradiol. Jiang, H., Xie, T., Ramsden, D.B., Ho, S.L. Neuropharmacology (2003) [Pubmed]
  27. Monoamine metabolism in human brain. Robinson, D.S., Sourkes, T.L., Nies, A., Harris, L.S., Spector, S., Bartlett, D.L., Kaye, I.S. Arch. Gen. Psychiatry (1977) [Pubmed]
  28. Further evidence for a modulation of Novelty Seeking by DRD4 exon III, 5-HTTLPR, and COMT val/met variants. Strobel, A., Lesch, K.P., Jatzke, S., Paetzold, F., Brocke, B. Mol. Psychiatry (2003) [Pubmed]
  29. Fluorodopa positron emission tomography with an inhibitor of catechol-O-methyltransferase: effect of the plasma 3-O-methyldopa fraction on data analysis. Ishikawa, T., Dhawan, V., Chaly, T., Robeson, W., Belakhlef, A., Mandel, F., Dahl, R., Margouleff, C., Eidelberg, D. J. Cereb. Blood Flow Metab. (1996) [Pubmed]
  30. Cytochromes 1A1/1B1- and catechol-O-methyltransferase-derived metabolites mediate estradiol-induced antimitogenesis in human cardiac fibroblast. Dubey, R.K., Jackson, E.K., Gillespie, D.G., Rosselli, M., Barchiesi, F., Krust, A., Keller, H., Zacharia, L.C., Imthurn, B. J. Clin. Endocrinol. Metab. (2005) [Pubmed]
  31. Catechol-o-methyltransferase enzyme activity and protein expression in human prefrontal cortex across the postnatal lifespan. Tunbridge, E.M., Weickert, C.S., Kleinman, J.E., Herman, M.M., Chen, J., Kolachana, B.S., Harrison, P.J., Weinberger, D.R. Cereb. Cortex (2007) [Pubmed]
  32. The met(158) allele of catechol-O-methyltransferase (COMT) is associated with obsessive-compulsive disorder in men: case-control study and meta-analysis. Pooley, E.C., Fineberg, N., Harrison, P.J. Mol. Psychiatry (2007) [Pubmed]
  33. Association of the COMT val158met variant with antidepressant treatment response in major depression. Baune, B.T., Hohoff, C., Berger, K., Neumann, A., Mortensen, S., Roehrs, T., Deckert, J., Arolt, V., Domschke, K. Neuropsychopharmacology (2008) [Pubmed]
  34. The association of functional catechol-O-methyltransferase haplotypes with risk of Parkinson's disease, levodopa treatment response, and complications. Bialecka, M., Kurzawski, M., Klodowska-Duda, G., Opala, G., Tan, E.K., Drozdzik, M. Pharmacogenet. Genomics (2008) [Pubmed]
  35. DRD2 C957T polymorphism interacts with the COMT Val158Met polymorphism in human working memory ability. Xu, H., Kellendonk, C.B., Simpson, E.H., Keilp, J.G., Bruder, G.E., Polan, H.J., Kandel, E.R., Gilliam, T.C. Schizophr. Res. (2007) [Pubmed]
  36. Contribution of sulfate conjugation, deamination, and O-methylation to metabolism of dopamine and norepinephrine in human brain. Rivett, A.J., Eddy, B.J., Roth, J.A. J. Neurochem. (1982) [Pubmed]
  37. Family-based and case-control association studies of catechol-O-methyltransferase in attention deficit hyperactivity disorder suggest genetic sexual dimorphism. Qian, Q., Wang, Y., Zhou, R., Li, J., Wang, B., Glatt, S., Faraone, S.V. Am. J. Med. Genet. B Neuropsychiatr. Genet. (2003) [Pubmed]
  38. Two patients with COMT inhibitor-induced hepatic dysfunction and UGT1A9 genetic polymorphism. Martignoni, E., Cosentino, M., Ferrari, M., Porta, G., Mattarucchi, E., Marino, F., Lecchini, S., Nappi, G. Neurology (2005) [Pubmed]
  39. Down-regulation of caffeic acid o-methyltransferase in maize revisited using a transgenic approach. Piquemal, J., Chamayou, S., Nadaud, I., Beckert, M., Barrière, Y., Mila, I., Lapierre, C., Rigau, J., Puigdomenech, P., Jauneau, A., Digonnet, C., Boudet, A.M., Goffner, D., Pichon, M. Plant Physiol. (2002) [Pubmed]
  40. Catechol-O-methyltransferase in vitiligo. Le Poole, I.C., van den Wijngaard, R.M., Smit, N.P., Oosting, J., Westerhof, W., Pavel, S. Arch. Dermatol. Res. (1994) [Pubmed]
  41. Catechol-o-methyltransferase biochemical genetics: human lymphocyte enzyme. Sladek-Chelgren, S., Weinshilboum, R.M. Biochem. Genet. (1981) [Pubmed]
  42. The COMT L allele modifies the association between MAOB polymorphism and PD in Taiwanese. Wu, R.M., Cheng, C.W., Chen, K.H., Lu, S.L., Shan, D.E., Ho, Y.F., Chern, H.D. Neurology (2001) [Pubmed]
  43. Cytochrome P450 1B1 and catechol-O-methyltransferase polymorphisms and endometrial cancer susceptibility. McGrath, M., Hankinson, S.E., Arbeitman, L., Colditz, G.A., Hunter, D.J., De Vivo, I. Carcinogenesis (2004) [Pubmed]
  44. Epistasis between catechol-O-methyltransferase and type II metabotropic glutamate receptor 3 genes on working memory brain function. Tan, H.Y., Chen, Q., Sust, S., Buckholtz, J.W., Meyers, J.D., Egan, M.F., Mattay, V.S., Meyer-Lindenberg, A., Weinberger, D.R., Callicott, J.H. Proc. Natl. Acad. Sci. U.S.A. (2007) [Pubmed]
  45. An investigation of mammographic density and gene variants in healthy women. Maskarinec, G., Lurie, G., Williams, A.E., Le Marchand, L. Int. J. Cancer (2004) [Pubmed]
  46. Val158Met Polymorphism in catechol-O-methyltransferase gene associated with risk factors for breast cancer. Hong, C.C., Thompson, H.J., Jiang, C., Hammond, G.L., Tritchler, D., Yaffe, M., Boyd, N.F. Cancer Epidemiol. Biomarkers Prev. (2003) [Pubmed]
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