Abstract
Catechol-O-methyltransferase (COMT) is a gene involved in the degradation of dopamine and may both increase susceptibility to develop schizophrenia and affect neuronal functions involved in working memory. A common variant of the COMT gene (val108/158met) has been widely reported to affect prefrontally mediated working memory function, with the high-activity val allele associated with poorest performance across a number of tests sensitive to updating and target detection. Pharmacological manipulations of COMT val108/158met also have reliably produced alterations in cognitive function, in line with an inverted U function of prefrontal dopamine signaling. Furthermore, there is accumulating evidence that COMT val108/158met genotype may influence the cognitive response to antipsychotic treatment in schizophrenia patients, with met allele load predicting the greatest improvement with medication. Recently, other single-nucleotide polymorphisms (SNPs) across the COMT gene have emerged as possible risk alleles for schizophrenia, although little is known about whether they affect prefrontal cognition in a manner similar to COMT val108/158met. Preliminary evidence suggests a modest role for a SNP in the 5′ region of the gene on select tests of attention and target detection. Haplotype effects also may account for a modest percentage of the variance in test performance, and are an important area for future study.
Article PDF
Similar content being viewed by others
References
Goldberg TE, Green MF. Neurocognitive functioning in patients with schizophrenia: an overview. In: Psychopharmacology: the fifth generation of progress (Davis KL, ed). New York: Raven Press, 2002.
Weickert TW, Goldberg TE, Gold JM, Bigelow LB, Egan MF, Weinberger DR. Cognitive impairments in patients with schizophrenia displaying preserved and compromised intellect. Arch Gen Psychiatry 57: 907–913, 2000.
Franke P, Maier W, Hain C, Klingler T. Wisconsin Card Sorting Test: an indicator of vulnerability to schizophrenia? Schizophr Res 6: 243–249, 1992.
Yurgelun-Todd D, Kinney DK. Patterns of neuropsychological deficits that discriminate schizophrenic individuals from siblings and control subjects. J Neuropsychiatry Clin Neurosci 5: 294–300, 1993.
Faraone S, Seidman LJ, Kremen WS, Pepple JR, Lyons MJ, Tsuang MT. Neuropsychological functioning among the nonpsychotic relatives of schizophrenic patients: a diagnostic efficiency analysis. J Abnormal Psychol 104: 286–304, 1995.
Goldberg TE, Torrey EF, Gold JM, Bigelow LB, Ragland RD, Taylor E, et al. Genetic risk of neuro psychological impairment in schizophrenia: a study of monozygotic twins discordant and concordant for the disorder. Schizophr Res 17: 77–84, 1995.
Cannon TD, Huttunen MO, Lonnqvist J, Tuulio-Henriksson A, Pirkola T, Glahn D, et al. The inheritance of neuro psychological dysfunction in twins discordant for schizophrenia. Am J Hum Genet 67: 369–382, 2000.
Egan MF, Goldberg TE, Kolachana BS, Callicott JH, Mazzanti CM, Straub RE, et al. Effect of COMT Val108/158Met genotype on frontal lobe function and risk for schizophrenia. Proc Natl Acad Sci USA 98: 6917–6922, 2001.
Harrison PJ, Weinberger DR. Schizophrenia genes, gene expression, and neuropathology: on the matter of their convergence. Mol Psychiatry 10: 40–68, 2004.
Weinberger DR, Egan MF, Bertolino A, Callicott JH, Mattay VS, Lipska BK, et al. Prefrontal neurons and the genetics of schizophrenia. Biol Psychiatry 50: 825–844, 2001.
Tenhunen J, Salminen M, Lundstr“m K, Kiviluoto T, Savolainen R, Ulmanen I. Genomic organization of the human catechol-O-methyltransferase gene and its expression from two distinct promoters. Eur J Biochem 223: 1049–1059, 1994.
Matsumoto M, Weickert CS, Akil M, Lipska BK, Hyde TM, Herman MM, et al. Catechol O-methyltransferase mRNA expression in human and rat brain: evidence for a role in cortical neuronal function. Neuroscience 116: 127–137, 2003.
Karoum F, Chrapusta S, Egan MF. 3-Methoxytryptamine is the major metabolite of released dopamine in the rat frontal cortex: reassessment of the effects of antipsychotics on the dynamics of dopamine release and metabolism in the frontal cortex, nucleus accumbens, and striatum by a simple two pool model. J Neurochem 63: 972–979, 1994.
Sesack SR, Hawrylak VA, Matus C, Guido MA, Levey AI. Dopamine axon varicosities in the prelimbic division of the rat prefrontal cortex exhibit sparse immunoreactivity for the dopamine transporter. J Neurosci 18: 2697–2708, 1998.
Gogos JA, Morgan M, Luine V, Santha M, Ogawa S, Pfaff D, et al. Catechol-O-methyltransferase-deficient mice exhibit sexually dimorphic changes in catecholamine levels and behavior. Proc Natl Acad Sci USA 95: 9991–9996, 1998.
Huotari M, Gogos JA, Karayiorgou M, Koponen I, Forsberg M, Raasmaja A, et al. Brain catecholamine metabolism in catechol-O-methyltransferase (COMT)-deficient mice. Eur J Neurosci 15: 246–256, 2002.
Kneavel M, Gogos J, Karayiorgou K, Luine V. Interaction of COMT gene deletion and environment on cognition. Soc Neurosci Abstract 26: 1–2, 2000.
Chen J, Lipska BK, Halim N, Ma QD, Matsumoto M, Melhem S, et al. Functional analysis of genetic variation in catechol-O-methyltransferase (COMT): Effects on mRNA, protein, and enzyme activity in postmortem human brain. Am J Hum Genet 75: 807–821, 2004.
Weinshilboum RM, Otterness DM, Szumlanski CL. Methylation pharmacogenetics: catechol O-methyltransferase, thiopurine methyltransferase, and histamine N-methyltransferase. Annu Rev Pharmacol Tox 39: 19–52, 1999.
Fan JB, Zhang CS, Gu NF, Li XW, Sun WW, Wang HY, et al. Catechol-O-methyltransferase gene Val/Met functional polymorphism and risk of schizophrenia: a large-scale association study plus meta-analysis. Biol Psychiatry 57: 139–144, 2005.
Glatt SJ, Faraone SV, Tsuang MT. Association between a functional catechol-O-methyltransferase gene polymorphism and schizophrenia: meta-analyses of case-control and family-based studies. Am J Psychiatry 160: 469–476, 2003.
Munafo MR, Bowes L, Clark TG, Flint J. Lack of association of the COMT (Val(158/108) Met) gene and schizophrenia: a meta-analysis of case-control studies. Mol Psychiatry 10: 765–770, 2005.
Chen X, Wang X, O’Neill AF, Walsh D, Kendler KS. Variants on the catechol-O-methyltransferase (COMT) gene are associated with schizophrenia in Irish high-density families. Mol Psychiatry 9: 962–967, 2004.
Kunugi H, Vallada HP, Sham PC, Hoda F, Arranz MJ, Li T, et al. Catechol-O-methyltransferase polymorphisms and schizophrenia: a transmission disequilibrium study in multiply affected families. Psychiatr Genet 7: 97–101, 1997.
Li T, Sham PC, Vallada H, Xie T, Tang X, Murray RM, et al. Preferential transmission of the high activity allele of COMT in schizophrenia. Psychiatr Genet 6: 131–133, 1996.
Bilder RM, Volavka J, Czobor P, Malhotra AK, Kennedy JL, Ni XQ, et al. Neurocognitive correlates of the COMT Val158Met polymorphism in chronic schizophrenia. Biol Psychiatry 52: 701–707, 2002.
Gallinat J, Bajbouj M, Sander T, Schlattmann P, Xu K, Ferro EF, et al. Association of the G1947A COMT (Val108/158Met) gene polymorphism with prefrontal P300 during information processing. Biol Psychiatry 54: 40–48, 2003.
Goldberg TE, Egan MF, Gscheidle T, Coppola R, Weickert T, Kolachana BS, et al. Executive subprocesses in working memory: relationship to catechol-O-methyltransferase Val158Met genotype and schizophrenia. Arch Gen Psychiatry 60: 889–896, 2003.
Joober R, Gauthier J, Lal S, Bloom D, Lalonde P, Rouleau G, et al. Catechol-O-methyltransferase val158met gene variants associated with performance on the Wisconsin Card Sorting Test. Arch Gen Psychiatry 59: 662–663, 2002.
Malhotra AK, Kestler LJ, Mazzanti C, Bates JA, Goldberg T, Goldman D. A functional polymorphism in the COMT gene and performance on a test of prefrontal cognition. Am J Psychiatry 159: 652–654, 2002.
Mattay VS, Goldberg TE, Fera F, Hariri AR, Tessitore A, Egan MF, et al. Catechol-O-methyltransferase val158met genotype and individual variation in the brain response to amphetamine. Proc Natl Acad Sci USA 100: 6186–6191, 2003.
Rosa A, Peralta V, Cuesta MJ, Zarzuela A, Serrano F, Martinez-Larrea A, et al. New evidence of association between COMT gene and prefrontal neurocognitive function in healthy individuals and from sibling pairs discordant for psychosis. Am J Psychiatry 161: 1110–1112, 2004.
Winterer G, Coppola R, Goldberg TE, Egan MF, Jones DW, Sanchez CE, Weinberger DR. Prefrontal broadband noise, working memory, and genetic risk for schizophrenia. Am J Psychiatry 161: 490–500, 2004.
Diamond A, Briand L, Fossella J, Gehlbach L. Genetic and neurochemical modulation of prefrontal cognitive functions in children. Am J Psychiatry 161: 125–132, 2004.
Diaz-Asper CM, Goldberg TE, Kolachana BS, Straub RE, Egan MF, Weinberger DR. Genetic variation in catechol-O-methyltransferase (COMT): effects on working memory function in schizophrenic patients and healthy controls. In preparation.
Blasi G, Mattay VS, Bertolino A, Elvevaag B, Callicott JH, Das S, et al. Effect of catechol-O-methyltransferase val158met genotype on attentional control. J Neurosci 25: 5038–5045, 2005.
Crofts HS, Dalley JW, Collins P, Van Denderen JCM, Everitt BJ, Robbins TW, et al. Differential effects of 6-OHDA lesions of the frontal cortex and caudate nucleus on the ability to acquire an attentional set. Cereb Cortex 11: 1015–1026, 2001.
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 88: 497–502, 1999.
Nieoullon A. Dopamine and the regulation of cognition and attention. Prog Neurobiol 67: 53–83, 2002.
Jazbec S, Pantelis C, Weickert T, Robbins T, Weinberger D, Goldberg T. IDED performance in schizophrenia: impact of distraction and perseveration. In preparation.
Tsai SJ, Yu YW, Chen TJ, Chen JY, Liou YJ, Chen MC, et al. Association study of a functional catechol-O-methyltransferasegene polymorphism and cognitive function in healthy females. Neurosci Lett 338: 123–126, 2003.
Stefanis NC, Van Os J, Avramopoulos D, Smyrnis N, Evdokimidis I, Hantoumi I, et al. Variation in catechol-O-methyltransferase val158met genotype associated with schizotypy but not cognition: a population study in 543 young men. Biol Psychiatry 56: 510–515, 2004.
Ho BC, Wassink TH, O’Leary DS, Sheffield VC, Andreasen NC. Catechol-O-methyltransferase val(158)met gene polymorphism in schizophrenia: working memory, frontal lobe MRI morphology and frontal cerebral blood flow. Mol Psychiatry 10: 287–298, 2005.
Nolan KA, Bilder RM, Lachman HM, Volavka J. Catecholo-O-methyltransferase val158met polymorphism in schizophrenia: differential effects of val and met alleles on cognitive stability and flexibility. Am J Psychiatry 161: 359–361, 2004.
Stefanis NC, van Os J, Avramopoulos D, Smyrnis N, Evdokimidis I, Stefanis CN. Effect of COMT val158met polymorphism on the Continuous Performance Test, Identical Pairs version: tuning rather than improving performance. Am J Psychiatry 162: 1752–1754, 2005.
Goldman-Rakic PS. The cortical dopamine system: role in memory and cognition. Adv Pharmacol 42: 707–711, 1998.
Lidow MS, Koh PO, Arnsten AF. D1 dopamine receptor in the mouse prefrontal cortex: immunocytochemical and cognitive neuropharmacological analyses. Synapse 47: 101–108, 2003.
Stahl SM. Finding what you are not looking for: strategies for developing novel treatments in psychiatry. NeuroRx 3: 7–9, 2006.
Gasparini M, Fabrizio E, Bonifati V, Meco G. Cognitive improvement during Tolcapone treatment in Parkinson’s disease. J Neural Trans 104: 887–894, 1997.
Khromova I, Rauhala P, Zolotov N, Mannisto PT. Tolcapone, an inhibitor of catechol O-methyltransferase, counteracts memory deficits caused by bilateral cholinotoxin lesions of the basal nuclei of Meynert. Neuroreport 6: 1219–1222, 1995.
Liljequist R, Haapalinna A, Ahlander M, Li YH, Mannisto PT. Catechol O-methyltransferase inhibitor tolcapone has minor influence on performance in experimental memory models in rats. Behav Brain Res 82: 195–202, 1997.
Ceravolo R, Piccini P, Bailey DL, Jorga KM, Bryson H, Brooks DJ. 18F-dopa PET evidence that tolcapone acts as a central COMT inhibitor in Parkinson’s disease. Synapse 43: 201–207, 2002.
Da Prada M, Zurcher G, Kettler R, Colzi A. New therapeutic strategies in Parkinson’s disease: inhibition of MAO-B by Ro19-6327 and of COMT by Ro40-7592. New York: Plenum Press, 1991.
Zurcher G, Dingemanse J, Da Prada M. Ro-40-7592, a potent inhibitor of extracerebral and brain catechol-O-methyltransferase: preclinical and clinical findings. Rome: John Libbey S. R. L., 1991.
Apud JA, Mattay V, Chen J, Kolachana BS, Callicott JH, Rasetti R, et al. Tolcapone improves cognition and cortical information processing in normal human subjects. In preparation.
Blasi G, Bertolino A. Imaging genomics and response to treatment with antipsychotics in schizophrenia. NeuroRx 3: 117–130, 2006.
Bertolino A, Caforio G, Blasi G, De Candia M, Latorre V, Petruzzella V, et al. Interaction of COMT (Val(108/158)Met) genotype and olanzapine treatment on prefrontal cortical function in patients with schizophrenia. Am J Psychiatry 161: 1798–1805, 2004.
Weickert TW, Goldberg TE, Mishara A, Apud JA, Kolachana BS, Egan MF, et al. COMT val108/158met genotype predicts working memory response to antipsychotic medications. Biol Psychiatry 56: 677–682, 2004.
Kapurt S, Agid O, Mizrahi R, Li M. How antipsychotics work—from receptors to reality. NeuroRx 3: 000–000, 2006.
Bray NJ, Buckland PR, Williams NM, Williams HJ, Norton N, Owen MJ, et al. A haplotype implicated in schizophrenia susceptibility is associated with reduced COMT expression in human brain. Am J Hum Genet 73: 152–161, 2003.
DeMille MMC, Kidd JR, Ruggeri V, Palmatier MA, Goldman D, Odunsi A, et al. Population variation in linkage disequilibrium across the COMT gene considering promoter region and coding region variation. Hum Genet 111: 521–537, 2002.
Palmatier MA, Pakstis AJ, Speed W, Paschou P, Goldman D, Odunsi A, et al. COMT haplotypes suggest P2 promoter region relevance for schizophrenia. Mol Psychiatry 9: 859–870, 2004.
Shifman S, Bronstein M, Sternfeld M, Pisante-Shalom A, Lev-Lehman E, Weizman A, et al. A highly significant association between a COMT haplotype and schizophrenia. Am J Hum Genet 71: 1296–1302, 2002.
Li T, Ball D, Zhao J, Murray RM, Liu X, Sham PC, et al. Family-based linkage disequilibrium mapping using SNP marker haplotypes: application to a potential locus for schizophrenia at chromosome 22q11. Mol Psychiatry 5: 77–84, 2000.
Chan RCK, Chen RYL, Chen EYH, Hui TCK, Cheung EFC, Cheung HK, et al. The differential clinical and neurocognitive profiles of COMT SNP rs165599 genotypes in schizophrenia. J Int Neuropsychol Soc 11: 202–204, 2005.
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Diaz-Asper, C.M., Weinberger, D.R. & Goldberg, T.E. Catechol-O-methyltransferase polymorphisms and some implications for cognitive therapeutics. NeuroRX 3, 97–105 (2006). https://doi.org/10.1016/j.nurx.2005.12.010
Published:
Issue Date:
DOI: https://doi.org/10.1016/j.nurx.2005.12.010