Hostname: page-component-cd9895bd7-p9bg8 Total loading time: 0 Render date: 2024-12-25T02:24:56.544Z Has data issue: false hasContentIssue false
  • English
  • Français

Role of the COMT gene Val158Met polymorphism in mental disorders: A review

Published online by Cambridge University Press:  16 April 2020

Ladislav Hosák
Ladislav Hosák*
Affiliation:
Department of Psychiatry, Charles University in Prague, Faculty of Medicine in Hradec Králové, Czech Republic Department of Psychiatry, University Hospital Hradec Králové, Czech Republic
*
*Department of Psychiatry, University Hospital Hradec Králové, 500 05 Hradec Králové, Czech Republic. Tel.: +420 495 832 228; fax: +420 495 511 677. E-mail address: [email protected]
Get access

Abstract

The Val158Met polymorphism of the COMT gene is functional, easily detectable, and significantly related to metabolism of catecholamines, which underlie pathogenesis of a significant number of mental disorders. Evidence for the role of this polymorphism in schizophrenia, substance dependence, bipolar disorder, obsessive-compulsive disorder, anorexia nervosa and attention deficit hyperactivity disorder is summed up in this review article. The results make it unlikely that the COMT gene plays an important role in these mental disorders, although a minor effect can not be excluded. Future studies on the COMT gene in mentally ill subjects should be stratified by clinical subtypes of the disorder, gender and ethnicity. Studies of endophenotypes instead of the complex disorder seem to be another promising research strategy. Gene-gene and gene-environment interactions should also be considered. The COMT gene is probably not “a gene for” any mental disorder, but the Val158Met polymorphism appears to have pleiotropic effects on human behavior.

Keywords

COMT geneVal158Met polymorphismMental disordersPleiotropic effect
Type
Review
Information
European Psychiatry , Volume 22 , Issue 5 , July 2007 , pp. 276 - 281
Copyright
Copyright © Elsevier Masson SAS 2007

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

Alsobrook, J.P. II, Zohar, A.H., Leboyer, M., Chabane, N., Ebstein, R., Pauls, D.L.Association between the COMT locus and obsessive-compulsive disorder in females but not males. Am J Med Genet (Neuropsychiatr Genet) 2002;114:116–120.CrossRefGoogle Scholar
Bilder, R.M., Volavka, J., Lachman, H.M., Grace, A.A.The catechol-O-methyltransferase polymorphism: relations to the tonic-phasic dopamine hypothesis and neuropsychiatric phenotypes. Neuropsychopharmacology 2004;29:1943–1961.CrossRefGoogle ScholarPubMed
Chen, C.H., Lee, Y.R., Chung, M.Y., Wei, F.C., Koong, F.J., Shaw, C.K.et al.Systematic mutation analysis of the catechol O-methyltransferase gene as a candidate gene for schizophrenia. Am J Psychiatry 1999;156:1273–1275.Google Scholar
Daniels, J.K., Williams, N.M., Williams, J., Jones, L.A., Cardno, A.G., Murphy, K.C.et al.No evidence for allelic association between schizophrenia and a polymorphism determining high or low catechol O-methyltransferase activity. Am J Psychiatry 1996;153:268–270.Google ScholarPubMed
Egan, M.F., Goldberg, T.E., Kolachana, B.S., Callicott, J.H., Mazzanti, C.M., Straub, R.E.et al.Effect of COMT Val108/158 Met genotype on frontal lobe function and risk for schizophrenia. Proc Natl Acad Sci USA 2001;98:6917–6922.CrossRefGoogle ScholarPubMed
Eisenberg, J., Mei-Tal, G., Steinberg, A., Tartakovsky, E., Zohar, A., Gritsenko, I.et al.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. Am J Med Genet (Neuropsychiatr Genet) 1999;88:497–502.3.0.CO;2-F>CrossRefGoogle ScholarPubMed
Erdal, M.E., Tot, S., Yazici, K., Yazici, A., Herken, H., Erdem, P.et al.Lack of association of catechol-o-methyltransferase gene polymorphism in obsessive-compulsive disorder. Depres Anxiety 2003;18:41–45.CrossRefGoogle ScholarPubMed
Fan, J.B., Zhang, C.S., Gu, N.F., Li, X.W., Sun, W.W., Wang, H.Y.et al.Catechol-O-methyltransferase gene Val/Met functional polymorphism and risk of schizophrenia: a large-scale association study plus meta-analysis. Biol Psychiatry 2005;57:139–144.CrossRefGoogle ScholarPubMed
Frisch, A., Laufer, N., Danziger, Y., Michaelovsky, E., Leor, S., Carel, C.et al.Association of anorexia nervosa with the high activity allele of the COMT gene: a family-based study in Israeli patients. Mol Psychiatry 2001;6:243–245.CrossRefGoogle ScholarPubMed
Gabrovsek, M., Brecelj-Anderluh, M., Bellodi, L., Cellini, E., Di Bella, D., Estivill, X.et al.Combined family trio and case-control analysis of the COMT Val158Met polymorphism in European patients with anorexia nervosa. Am J Med Genet (Neuropsychiatr Genet) 2004;124B:68–72.CrossRefGoogle ScholarPubMed
Goldberg, T.E., Egan, M.F., Gscheidle, T., Coppola, R., Weickert, T., Kolachana, B.S.et al.Executive subprocesses in working memory. Arch Gen Psychiatry 2003;60:889–896.CrossRefGoogle ScholarPubMed
Gottesman, I.I., Gould, T.D.The endophenotype concept in psychiatry: etymology and strategic intentions. Am J Psychiatry 2003;160:636–645.CrossRefGoogle ScholarPubMed
Gutiérrez, B., Bertranpetit, J., Guillamat, R., Valles, V., Arranz, M.J., Kerwin, R.et al.Association analysis of the catechol O-methyltransferase gene and bipolar affective disorder. Am J Psychiatry 1997;154:113–115.Google ScholarPubMed
Hallikainen, T., Lachman, H., Saito, T., Volavka, J., Kauhanen, J., Salonen, J.T.et al.Lack of association between the functional variant of the catechol-O-methyltransferase (COMT) gene and early-onset alcoholism associated with severe antisocial behavior. Am J Med Genet (Neuropsychiatr Genet) 2000;96:348–352.3.0.CO;2-Z>CrossRefGoogle ScholarPubMed
Handoko, H.Y., Nyholt, D.R., Hayward, N.K., Nertney, D.A., Hannah, D.E., Windus, L.C.et al.Separate and interacting effects within the catechol-O-methyltransferase (COMT) are associated with schizophrenia. Mol Psychiatry 200410.1038/sj.mp 4001606 advance online publication 26 October 2004.Google Scholar
Hawi, Z., Millar, N., Daly, G., Fitzgerald, M., Gill, M.No association between catechol-O-methyltransferase (COMT) gene polymorphism and attention deficit hyperactivity disorder (ADHD) in an Irish sample. Am J Med Genet (Neuropsychiatr Genet) 2000;96:282–284.3.0.CO;2-R>CrossRefGoogle Scholar
Horowitz, R., Kotler, M., Shufman, E., Aharoni, S., Kremer, I., Cohen, H.et al.Confirmation of an excess of the high enzyme activity COMT val allele in heroin addicts in a family-based haplotype relative risk study. Am J Med Genet (Neuropsychiatr Genet) 2000;96:599–603.3.0.CO;2-O>CrossRefGoogle Scholar
http://www4.infotrieve.com/newmedline/search.asp.Google Scholar
Inada, T., Nakamura, A., Iijima, Y.Relationship between catechol-O-methyltransferase polymorphism and treatment-resistant schizophrenia. Am J Med Genet (Neuropsychiatr Genet) 2003;120:35–39.CrossRefGoogle Scholar
Joober, R., Gauthier, J., Lal, S., Bloom, D., Lalonde, P., Rouleau, G.et al.Catechol-O-methyltransferase Val-108/158-Met gene variants associated with performance on the Wisconsin card sorting test. Arch Gen Psychiatry 2002;59:662–663.CrossRefGoogle ScholarPubMed
Kalivas, P.W.Neurotransmitter regulation of dopamine neurons in the ventral tegmental area. Brain Res Rev 1993;18:75–113.CrossRefGoogle ScholarPubMed
Karayiorgou, M., Altemus, M., Galke, B.L., Goldman, D., Murphy, D.L., Ott, J.et al.Genotype determining low catechol-O-methyltransferase activity as a risk factor for obsessive-compulsive disorder. Proc Natl Acad Sci USA 1997;94:4572–4575.CrossRefGoogle ScholarPubMed
Karayiorgou, M., Gogos, J.A., Galke, B.L., Wolyniec, P.S., Nestadt, G., Antonarakis, S.E.et al.Identification of sequence variants and analysis of the role of the catechol-O-methyl-transferase gene in schizophrenia susceptibility. Biol Psychiatry 1998;43:425–431.CrossRefGoogle ScholarPubMed
Karoum, F., Chrapusta, S.J., Egan, M.F.3-Methoxytyramine is the major metabolite of released dopamine in the rat frontal cortex. J Neurochem 1994;63:972–979.CrossRefGoogle ScholarPubMed
Kendler, K.S.“A gene for…”: the nature of gene action in psychiatric disorders. Am J Psychiatry 2005;162:1243–1252.CrossRefGoogle Scholar
Kirov, G., Murphy, K.C., Arranz, M.J., Jones, I., McCandles, F., Kunugi, H.et al.Low activity allele of catechol-O-methyltransferase gene associated with rapid cycling bipolar disorder. Mol Psychiatry 1998;3:342–345.CrossRefGoogle ScholarPubMed
Kotler, M., Barak, P., Cohen, H., Averbuch, I.E., Grinshpoon, A., Gritsenko, I.et al.Homicidal behavior in schizophrenia associated with a genetic polymorphism determining low catechol O-methyltransferase (COMT) activity. Am J Med Genet (Neuropsychiatr Genet) 1999;88:628–633.3.0.CO;2-E>CrossRefGoogle ScholarPubMed
Kunugi, H., Vallada, H.P., Hoda, F., Kirov, G., Gill, M., Aitchison, K.J.et al.No evidence for an association of affective disorders with high- or low-activity allele of catechol-O-methyltransferase gene. Biol Psychiatry 1997;42:282–285.CrossRefGoogle ScholarPubMed
Kunugi, H., Vallada, H.P., Sham, P.C., Hoda, F., Arranz, M.J., Li, T.et al.Catechol-O-methyltransferase polymorphisms and schizophrenia: a transmission disequilibrium study in multiply affected families. Psychiatr Genet 1997;7:97–101.CrossRefGoogle ScholarPubMed
Lachman, H.M., Morrow, B., Shprintzen, R., Veit, S., Parsia, S.S., Faedda, G.et al.Association of codon 108/158 catechol-O-methyltransferase gene polymorphism with the psychiatric manifestations of velo-cardio-facial syndrome. Am J Med Genet (Neuropsychiatr Genet) 1996;67:468–472.3.0.CO;2-G>CrossRefGoogle ScholarPubMed
Lachman, H.M., Papolos, D.F., Saito, T., Yu, Y.M., Szumlanski, C.L., Weinshilboum, R.M.Human catechol-O-methyltransferase pharmacogenetics: description of a functional polymorphism and its potential application to neuropsychiatric disorders. Pharmacogenetics 1996;6:243–250.CrossRefGoogle ScholarPubMed
Li, T., Chen, C.K., Hu, X., Ball, D., Lin, S.K., Chen, W.et al.Association analysis of the DRD4 and COMT genes in methamphetamine abuse. Am J Med Genet (Neuropsychiatr Genet) 2004;129B:120–124.CrossRefGoogle ScholarPubMed
Li, T., Sham, P.C., Vallada, H., Xie, T., Tang, X., Murray, R.M.et al.Preferential transmission of the high activity allele of COMT in schizophrenia. Psychiatr Genet 1996;6:131–133.CrossRefGoogle Scholar
Malhotra, A.K., Kestler, L.J., Mazzanti, C., Bates, J.A., Goldberg, T., Goldman, D.A functional polymorphism in the COMT gene and performance on a test of prefrontal cognition. Am J Psychiatry 2002;159:652–654.CrossRefGoogle ScholarPubMed
Meira-Lima, I., Shavitt, R.G., Miguita, K., Ikenaga, E., Miguel, E.C., Vallada, H.Association analysis of the catechol-o-methyltransferase (COMT), serotonin transporter (5-HTT) and serotonin 2A receptor (5HT2A) gene polymorphisms with obsessive-compulsive disorder. Gen Brain Behav 2004;3:75–79.CrossRefGoogle ScholarPubMed
Nutt, J.G.Catechol-O-methyltransferase inhibition and the treatment of Parkinson's disease. Adv Pharmacol 1998;42:331–334.CrossRefGoogle ScholarPubMed
Ohmori, O., Shinkai, T., Kojima, H., Terao, T., Suzuki, T., Mita, T.et al.Association study of a functional catechol-O-methyltransferase gene polymorphism in Japanese schizophrenics. Neurosci Lett 1998;243:109–112.CrossRefGoogle ScholarPubMed
Palmatier, M.A., Kang, A.M., Kidd, K.K.Global variation in the frequencies of functionally different catechol-O-methyltransferase alleles. Biol Psychiatry 1999;46:557–567.CrossRefGoogle ScholarPubMed
Papolos, D.F., Veit, S., Faedda, G.L., Saito, T., Lachman, H.M.Ultra-ultra rapid cycling bipolar disorder is associated with the low activity catecholamine-O-methyltransferase allele. Mol Psychiatry 1998;3:346–349.CrossRefGoogle ScholarPubMed
Payton, A., Holmes, J., Barrett, J.H., Hever, T., Fitzpatrick, H., Trumper, A.L.et al.Examining for association between candidate gene polymorphisms in the dopamine pathway and attention-deficit hyperactivity disorder: a family-based study. Am J Med Genet (Neuropsychiatr Genet) 2001;105:464–470.CrossRefGoogle ScholarPubMed
Pritchard, J.K., Rosenberg, N.A.Use of unlinked genetic markers to detect population stratification in association studies. Am J Hum Genet 1999;65:220–228.CrossRefGoogle ScholarPubMed
Qian, Q., Wang, Y., Zhou, R., Li, J., Wang, B., Glatt, S.et al.Family-based and case-control association studies of catechol-O-methyltransferase in attention deficit hyperactivity disorder suggest genetic sexual dimorphism. Am J Med Genet (Neuropsychiatr Genet) 2003;118B:103–109.CrossRefGoogle ScholarPubMed
Rosa, A., Peralta, V., Cuesta, M.J., Zarzuela, A., Serrano, F., Martínez-Larrea, A.et al.New evidence of association between COMT gene and prefrontal neurocognitive function in healthy individuals from sibling pairs discordant for psychosis. Am J Psychiatry 2004;161:1110–1112.CrossRefGoogle Scholar
Sazci, A., Ergul, E., Kucukali, I., Kilic, G., Kaya, G., Kara, I.Catechol-O-methyltransferase gene Val108/158Met polymorphism, and susceptibility to schizophrenia: association is more significant in women. Mol Brain Res 2004;132:51–56.CrossRefGoogle ScholarPubMed
Schrag, A.Entacapone in the treatment of Parkinson's disease. Lancet Neurol 2005;4:366–370.CrossRefGoogle ScholarPubMed
Shifman, S., Bronstein, M., Sternfeld, M., Pisanté, A., Weizman, A., Reznik, I.et al.COMT: A common susceptibility gene in bipolar disorder and schizophrenia. Am J Med Genet (Neuropsychiatr Genet) 2004;128B:61–64.CrossRefGoogle Scholar
Shifman, S., Bronstein, M., Sternfeld, M., Pisanté-Shalom, A., Lev-Lehman, E., Weizman, A.et al.A highly significant association between a COMT haplotype and schizophrenia. Am J Hum Genet 2002;71:1296–1302.CrossRefGoogle Scholar
Spielman, R.S., McGinnis, R.E., Ewens, W.J.Transmission test for linkage disequilibrium: the insulin gene region and insulin-dependent diabetes mellitus (IDDM). Am J Hum Genet 1993;52:506–516.Google Scholar
Strous, R.D., Bark, N., Parsia, S.S., Volavka, J., Lachman, H.M.Analysis of a functional catechol-O-methyltransferase gene polymorphism in schizophrenia: evidence for association with aggressive and antisocial behavior. Psychiatry Res 1997;69:71–77.CrossRefGoogle ScholarPubMed
Strous, R.D., Bark, N., Woerner, M., Lachman, H.M.Lack of association of a functional catechol-O-methyltransferase gene polymorphism in schizophrenia. Biol Psychiatry 1997;41:493–495.CrossRefGoogle Scholar
Strous, R.D., Nolan, K.A., Lapidus, R., Diaz, L., Saito, T., Lachman, H.M.Aggressive behavior in schizophrenia is associated with the low enzyme activity COMT polymorphism: a replication study. Am J Med Genet (Neuropsychiatr Genet) 2003;120B:29–34.CrossRefGoogle ScholarPubMed
Tiihonen, J., Hallikainen, T., Lachman, H., Saito, T., Volavka, J., Kauhanen, J.et al.Association between the functional variant of the catechol-O-methyltransferase (COMT) gene and type 1 alcoholism. Mol Psychiatry 1999;4:286–289.CrossRefGoogle ScholarPubMed
Turic, D., Williams, H., Langley, K., Owen, M., Thapar, A., O’Donovan, M.C.A family based study of catechol-O-methyltransferase (COMT) and attention deficit hyperactivity disorder (ADHD). Am J Med Genet (Neuropsychiatr Genet) 2005;133B:64–67.CrossRefGoogle Scholar
Vandenbergh, D.J., Rodriguez, L.A., Miller, I.T., Uhl, G.R., Lachman, H.M.High-activity catechol-O-methyltransferase allele is more prevalent in polysubstance abusers. Am J Med Genet (Neuropsychiatr Genet) 1997;74:439–442.3.0.CO;2-J>CrossRefGoogle ScholarPubMed
Volavka, J., Kennedy, J.L., Ni, X., Czobor, P., Nolan, K., Sheitman, B.et al.COMT158 polymorphism and hostility. Am J Med Genet (Neuropsychiatr Genet) 2004;127B:28–29.CrossRefGoogle ScholarPubMed
Wei, J., Hemmings, G.P.Lack of evidence for association between the COMT locus and schizophrenia. Psychiatr Genet 1999;9:183–186.CrossRefGoogle Scholar
Wonodi, I., Stine, O.C., Mitchell, B.D., Buchanan, R.W., Thaker, G.K.Association between Val108/158 Met polymorphism of the COMT gene and schizophrenia. Am J Med Genet (Neuropsychiatr Genet) 2003;120B:47–50.CrossRefGoogle Scholar
Xie, T., Ho, S.L., Ramsden, D.Characterization and implications of estrogenic down-regulation of human catechol-O-methyltransferase gene transcription. Mol Pharmacol 1999;56:31–38.CrossRefGoogle ScholarPubMed
Yirmiya, N., Pilowsky, T., Nemanov, L., Arbelle, S., Feinsilver, T., Fried, I.et al.Evidence for an association with the serotonin transporter promoter region polymorphism and autism. Am J Med Genet (Neuropsychiatr Genet) 2001;105:381–386.CrossRefGoogle ScholarPubMed
Submit a response

Comments

No Comments have been published for this article.