Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Research Article
  • Published:

Catechol-O-methyl transferase Val158Met gene polymorphism in schizophrenia: working memory, frontal lobe MRI morphology and frontal cerebral blood flow

Abstract

The catechol-O-methyl transferase (COMT) gene is considered a leading schizophrenia candidate gene. Although its role in increasing schizophrenia susceptibility has been conflicting, recent studies suggest the valine allele may contribute to poor cognitive function in schizophrenia. V158M COMT genotype was obtained on 159 schizophrenia patients and 84 healthy controls. The effects of COMT genotype on four measures of working memory/executive functions (Wisconsin Card Sorting, digit span backward, Trail Making and N-back tests) and on MRI frontal brain volumes were examined. Genotype distributions were not significantly different between patients and controls. There were no significant genotype or genotype-by-group effects on any working memory/executive function measures. No genotype or genotype-by-diagnosis interaction effects were found with MRI frontal lobe volumes. Randomization analyses using [15O]H2O positron emission tomography (PET) cerebral blood flow data found Val/Val patients had higher frontal lobe activation than Met/Met patients while performing the one-back task. Overall, these findings do not support a major role for COMT in increasing susceptibility for schizophrenia or in mediating frontal lobe function. Age-related changes and phenotypic heterogeneity of schizophrenia may influence the complex relationships between COMT genotype and cognition.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3

Similar content being viewed by others

References

  1. Andreasen NC . Schizophrenia: the fundamental questions. Brain Res Brain Res Rev 2000; 31: 106–112.

    PubMed  CAS  Google Scholar 

  2. Kennedy JL, Farrer LA, Andreasen NC, Mayeux R, St George-Hyslop P . The genetics of adult-onset neuropsychiatric disease: complexities and conundra? Science 2003; 302: 822–826.

    PubMed  CAS  Google Scholar 

  3. Moldin SO . Indicators of liability to schizophrenia: perspectives from genetic epidemiology. Schizophr Bull 1994; 20: 169–184.

    PubMed  CAS  Google Scholar 

  4. Thaker GK . Current progress in schizophrenia research. Search for genes of schizophrenia: back to defining valid phenes. J Nerv Ment Dis 2002; 190: 411–412.

    PubMed  Google Scholar 

  5. Almasy L, Blangero J . Endophenotypes as quantitative risk factors for psychiatric disease: rationale and study design. Am J Med Genet 2001; 105: 42–44.

    PubMed  CAS  Google Scholar 

  6. Tsuang MT, Faraone SV . The frustrating search for schizophrenia genes. Am J Med Genet (Semin Med Genet) 2000; 97: 1–3.

    CAS  Google Scholar 

  7. Gottesman II, Gould TD . The endophenotype concept in psychiatry: etymology and strategic intentions. Am J Psychiatry 2003; 160: 636–645.

    PubMed  Google Scholar 

  8. Arolt V, Lencer R, Nolte A, Muller-Myhsok B, Purmann S, Schurmann M et al. Eye tracking dysfunction is a putative phenotypic susceptibility marker of schizophrenia and maps to a locus on chromosome 6p in families with multiple occurrence of the disease. Am J Med Genet 1996; 67: 564–579.

    PubMed  CAS  Google Scholar 

  9. Freedman R, Coon H, Myles-Worsley M, Orr-Urtreger A, Olincy A, Davis A et al. Linkage of a neurophysiological deficit in schizophrenia to a chromosome 15 locus. Proc Natl Acad Sci USA 1997; 94: 587–592.

    PubMed  CAS  PubMed Central  Google Scholar 

  10. Liu H, Heath SC, Sobin C, Roos JL, Galke BL, Blundell ML et al. Genetic variation at the 22q11 PRODH2/DGCR6 locus presents an unusual pattern and increases susceptibility to schizophrenia. Proc Natl Acad Sci USA 2002; 99: 3717–3722.

    PubMed  CAS  PubMed Central  Google Scholar 

  11. Leal SM . Phenotypes and genetic analysis of psychiatric and neuropsychiatric traits. Am J Med Genet 2001; 105: 4–7.

    PubMed  CAS  Google Scholar 

  12. Baddeley A . Working memory. Science 1992; 255: 556–559.

    PubMed  CAS  Google Scholar 

  13. Cohen JD, Braver TS, O'Reilly RC . A computational approach to prefrontal cortex, cognitive control and schizophrenia: recent developments and current challenges. Philos Trans R Soc Lond Ser B 1996; 351: 1515–1527.

    CAS  Google Scholar 

  14. Goldman-Rakic PS . Prefrontal cortical dysfunction in schizophrenia: the relevance of working memory. In: Carroll BJ, Barrett JE (eds). Psychopathology and the Brain. Raven Press: New York, NY, 1990 pp 1–23.

    Google Scholar 

  15. Park S, Holzman PS . Schizophrenics show spatial working memory deficits. Arch Gen Psychiatry 1992; 49: 975–982.

    PubMed  CAS  Google Scholar 

  16. Park S, Holzman PS, Goldman-Rakic PS . Spatial working memory deficits in the relatives of schizophrenic patients. Arch Gen Psychiatry 1995; 52: 821–828.

    PubMed  CAS  Google Scholar 

  17. Goldberg TE, Torrey EF, Gold JM, Ragland JD, Bigelow LB, Weinberger DR . Learning and memory in monozygotic twins discordant for schizophrenia. Psychol Med 1993; 23: 71–85.

    PubMed  CAS  Google Scholar 

  18. Cannon TD, Bearden CE, Hollister JM, Rosso IM, Sanchez LE, Hadley T . Childhood cognitive functioning in schizophrenia patients and their unaffected siblings: a prospective cohort study. Schizophr Bull 2000; 26: 379–393.

    PubMed  CAS  Google Scholar 

  19. Myles-Worsley M, Park S . Spatial working memory deficits in schizophrenia patients and their first degree relatives from Palau, Micronesia. Am J Med Genet 2002; 114: 609–615.

    PubMed  Google Scholar 

  20. Tuulio-Henriksson A, Arajarvi R, Partonen T, Haukka J, Varilo T, Schreck M et al. Familial loading associates with impairment in visual span among healthy siblings of schizophrenia patients. Biol Psychiatry 2003; 54: 623–628.

    PubMed  Google Scholar 

  21. Tuulio-Henriksson A, Haukka J, Partonen T, Varilo T, Paunio T, Ekelund J et al. Heritability and number of quantitative trait loci of neurocognitive functions in families with schizophrenia. Am J Med Genet 2002; 114: 483–490.

    PubMed  Google Scholar 

  22. Conklin HM, Curtis CE, Katsanis J, Iacono WG . Verbal working memory impairment in schizophrenia patients and their first-degree relatives: evidence from the digit span task. Am J Psychiatry 2000; 157: 275–277.

    PubMed  CAS  Google Scholar 

  23. Farmer CM, O'Donnell BF, Niznikiewicz MA, Voglmaier MM, McCarley RW, Shenton ME . Visual perception and working memory in schizotypal personality disorder. Am J Psychiatry 2000; 157: 781–788.

    PubMed  PubMed Central  CAS  Google Scholar 

  24. Ando J, Ono Y, Wright MJ . Genetic structure of spatial and verbal working memory. Behav Genet 2001; 31: 615–624.

    PubMed  CAS  Google Scholar 

  25. Cannon TD, Huttunen MO, Lonnqvist J, Tuulio-Henriksson A, Pirkola T, Glahn D et al. The inheritance of neuropsychological dysfunction in twins discordant for schizophrenia. Am J Hum Genet 2000; 67: 369–382.

    PubMed  PubMed Central  CAS  Google Scholar 

  26. Gold S, Arndt S, Nopoulos P, O'Leary DS, Andreasen NC . Longitudinal study of cognitive function in first-episode and recent-onset schizophrenia. Am J Psychiatry 1999; 156: 1342–1348.

    PubMed  CAS  Google Scholar 

  27. Goldberg TE, Weinberger DR . Effects of neuroleptic medications on the cognition of patients with schizophrenia: a review of recent studies. J Clin Psychiatry 1996; 57: 62–65.

    PubMed  CAS  Google Scholar 

  28. Carter C, Robertson L, Nordahl T, Chaderjian M, Kraft L, O'Shora-Celaya L . Spatial working memory deficits and their relationship to negative symptoms in unmedicated schizophrenia patients. Biol Psychiatry 1996; 40: 930–932.

    PubMed  CAS  Google Scholar 

  29. Barch DM, Carter CS, Braver TS, Sabb FW, MacDonald III A, Noll DC et al. Selective deficits in prefrontal cortex function in medication-naive patients with schizophrenia. Arch Gen Psychiatry 2001; 58: 280–288.

    PubMed  CAS  Google Scholar 

  30. Keefe RS, Silva SG, Perkins DO, Lieberman JA . The effects of atypical antipsychotic drugs on neurocognitive impairment in schizophrenia: a review and meta-analysis. Schizophr Bull 1999; 25: 201–222.

    PubMed  CAS  Google Scholar 

  31. Friedman HR, Goldman-Rakic PS . Coactivation of prefrontal cortex and inferior parietal cortex in working memory tasks revealed by 2DG functional mapping in the rhesus monkey. J Neurosci 1994; 14(Part 1): 2775–2788.

    PubMed  CAS  PubMed Central  Google Scholar 

  32. Petrides M, Alivisatos B, Meyer E, Evans AC . Functional activation of the human frontal cortex during the performance of verbal working memory tasks. Proc Natl Acad Sci USA 1993; 90: 878–882.

    PubMed  CAS  PubMed Central  Google Scholar 

  33. Lewis DA, Campbell MJ, Foote SL, Goldstein M, Morrison JH . The distribution of tyrosine hydroxylase-immunoreactive fibers in primate neocortex is widespread but regionally specific. J Neurosci 1987; 7: 279–290.

    PubMed  CAS  PubMed Central  Google Scholar 

  34. Levitt P, Rakic P, Goldman-Rakic P . Region-specific distribution of catecholamine afferents in primate cerebral cortex: a fluorescence histochemical analysis. J Comp Neurol 1984; 227: 23–36.

    PubMed  CAS  Google Scholar 

  35. Lidow MS, Goldman-Rakic PS, Gallager DW, Rakic P . Distribution of dopaminergic receptors in the primate cerebral cortex: quantitative autoradiographic analysis using [3H]raclopride, [3H]spiperone and [3H]SCH23390. Neuroscience 1991; 40: 657–671.

    PubMed  CAS  Google Scholar 

  36. Hurd YL, Suzuki M, Sedvall GC . D1 and D2 dopamine receptor mRNA expression in whole hemisphere sections of the human brain. J Chem Neuroanat 2001; 22: 127–137.

    PubMed  CAS  Google Scholar 

  37. Brozoski TJ, Brown RM, Rosvold HE, Goldman PS . Cognitive deficit caused by regional depletion of dopamine in prefrontal cortex of rhesus monkey. Science 1979; 205: 929–932.

    PubMed  CAS  Google Scholar 

  38. Sawaguchi T, Goldman-Rakic PS . The role of D1-dopamine receptor in working memory: local injections of dopamine antagonists into the prefrontal cortex of rhesus monkeys performing an oculomotor delayed-response task. J Neurophysiol 1994; 71: 515–528.

    PubMed  CAS  Google Scholar 

  39. Callicott JH, Bertolino A, Mattay VS, Langheim FJ, Duyn J, Coppola R et al. Physiological dysfunction of the dorsolateral prefrontal cortex in schizophrenia revisited. Cereb Cortex 2000; 10: 1078–1092.

    PubMed  CAS  Google Scholar 

  40. Stevens AA, Goldman-Rakic PS, Gore JC, Fulbright RK, Wexler BE . Cortical dysfunction in schizophrenia during auditory word and tone working memory demonstrated by functional magnetic resonance imaging. Arch Gen Psychiatry 1998; 55: 1097–1103.

    PubMed  CAS  Google Scholar 

  41. Honey GD, Bullmore ET, Soni W, Varatheesan M, Williams SC, Sharma T . Differences in frontal cortical activation by a working memory task after substitution of risperidone for typical antipsychotic drugs in patients with schizophrenia. Proc Natl Acad Sci USA 1999; 96: 13432–13437.

    PubMed  CAS  PubMed Central  Google Scholar 

  42. Manoach DS, Press DZ, Thangaraj V, Searl MM, Goff DC, Halpern E et al. Schizophrenic subjects activate dorsolateral prefrontal cortex during a working memory task, as measured by fMRI. Biol Psychiatry 1999; 45: 1128–1137.

    PubMed  CAS  Google Scholar 

  43. Manoach DS, Gollub RL, Benson ES, Searl MM, Goff DC, Halpern E et al. Schizophrenic subjects show aberrant fMRI activation of dorsolateral prefrontal cortex and basal ganglia during working memory performance. Biol Psychiatry 2000; 48: 99–109.

    PubMed  CAS  Google Scholar 

  44. Karoum F, Chrapusta SJ, Egan MF . 3-Methoxytyramine 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 1994; 63: 972–979.

    PubMed  CAS  Google Scholar 

  45. Huotari M, Gogos JA, Karayiorgou M, Koponen O, Forsberg M, Raasmaja A et al. Brain catecholamine metabolism in catechol-O-methyltransferase (COMT)-deficient mice. Eur J Neurosci 2002; 15: 246–256.

    PubMed  Google Scholar 

  46. Wayment HK, Schenk JO, Sorg BA . Characterization of extracellular dopamine clearance in the medial prefrontal cortex: role of monoamine uptake and monoamine oxidase inhibition. J Neurosci 2001; 21: 35–44.

    PubMed  CAS  PubMed Central  Google Scholar 

  47. Moron JA, Brockington A, Wise RA, Rocha BA, Hope BT . Dopamine uptake through the norepinephrine transporter in brain regions with low levels of the dopamine transporter: evidence from knock-out mouse lines. J Neurosci 2002; 22: 389–395.

    PubMed  CAS  PubMed Central  Google Scholar 

  48. Palmatier MA, Kang AM, Kidd KK . Global variation in the frequencies of functionally different catechol-O-methyltransferase alleles. Biol Psychiatry 1999; 46: 557–567.

    PubMed  CAS  Google Scholar 

  49. Lotta T, Vidgren J, Tilgmann C, Ulmanen I, Melen K, Julkunen I et al. Kinetics of human soluble and membrane-bound catechol O-methyltransferase: a revised mechanism and description of the thermolabile variant of the enzyme. Biochemistry 1995; 34: 4202–4210.

    PubMed  CAS  Google Scholar 

  50. Badner JA, Gershon ES . Meta-analysis of whole-genome linkage scans of bipolar disorder and schizophrenia. Mol Psychiatry 2002; 7: 405–411.

    PubMed  CAS  Google Scholar 

  51. Murphy KC, Jones LA, Owen MJ . High rates of schizophrenia in adults with velo-cardio-facial syndrome. Arch Gen Psychiatry 1999; 56: 940–945.

    PubMed  CAS  Google Scholar 

  52. Egan MF, Goldberg TE, Kolachana BS, Callicott JH, Mazzanti CM, Straub RE 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.

    PubMed  PubMed Central  CAS  Google Scholar 

  53. Weinberger DR, Egan MF, Bertolino A, Callicott JH, Mattay VS, Lipska BK et al. Prefrontal neurons and the genetics of schizophrenia. Biol Psychiatry 2001; 50: 825–844.

    PubMed  CAS  Google Scholar 

  54. Daniels JK, Williams NM, Williams J, Jones LA, Cardno AG, Murphy KC 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.

    PubMed  CAS  Google Scholar 

  55. Karayiorgou M, Gogos JA, Galke BL, Wolyniec PS, Nestadt G, Antonarakis SE 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.

    PubMed  CAS  Google Scholar 

  56. 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 1996; 6: 131–133.

    PubMed  CAS  Google Scholar 

  57. 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 multiplying affected families. Psychiatr Genet 1997; 7: 97–101.

    PubMed  CAS  Google Scholar 

  58. de Chaldee M, Laurent C, Thibaut F, Martinez M, Samolyk D, Petit M et al. Linkage disequilibrium on the COMT gene in French schizophrenics and controls. Am J Med Genet 1999; 88: 452–457.

    PubMed  CAS  Google Scholar 

  59. 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.

    PubMed  Google Scholar 

  60. Park TW, Yoon KS, Kim JH, Park WY, Hirvonen A, Kang D . Functional catechol-O-methyltransferase gene polymorphism and susceptibility to schizophrenia. Eur Neuropsychopharmacol 2002; 12: 299–303.

    PubMed  CAS  Google Scholar 

  61. Norton N, Kirov G, Zammit S, Jones G, Jones S, Owen R et al. Schizophrenia and functional polymorphisms in the MAOA and COMT genes: no evidence for association or epistasis. Am J Med Genet 2002; 114: 491–496.

    PubMed  Google Scholar 

  62. Glatt SJ, Faraone SV, Tsuang MT . Association between a functional catechol O-methyltransferase gene polymorphism and schizophrenia: meta-analysis of case–control and family-based studies. Am J Psychiatry 2003; 160: 469–476.

    PubMed  Google Scholar 

  63. Wonodi I, Stine OC, Mitchell BD, Buchanan RW, Thaker GK . Association between Val108/158 Met polymorphism of the COMT gene and schizophrenia. Am J Med Genet 2003; 120B: 47–50.

    PubMed  Google Scholar 

  64. Andreasen NC, Flaum M, Arndt S . The Comprehensive Assessment of Symptoms and History (CASH). An instrument for assessing diagnosis and psychopathology. Arch Gen Psychiatry 1992; 49: 615–623.

    PubMed  CAS  Google Scholar 

  65. Lahiri DK, Nurnberger Jr JI . A rapid non-enzymatic method for the preparation of HMW DNA from blood for RFLP studies. Nucleic Acids Res 1991; 19: 5444.

    PubMed  PubMed Central  CAS  Google Scholar 

  66. Perry W, Heaton RK, Potterat E, Roebuck T, Minassian A, Braff DL . Working memory in schizophrenia: transient ‘online’ storage versus executive functioning. Schizophr Bull 2001; 27: 157–176.

    PubMed  CAS  Google Scholar 

  67. Pukrop R, Matuschek E, Ruhrmann S, Brockhaus-Dumke A, Tendolkar I, Bertsch A et al. Dimensions of working memory dysfunction in schizophrenia. Schizophr Res 2003; 62: 259–268.

    PubMed  Google Scholar 

  68. Heaton RK, Chelune GK, Talley JL, Kay GG, Curtiss G . Wisconsin Card Sorting Test Manual. Psychological Assessment Resources Inc.: Odessa, FL, 1993.

    Google Scholar 

  69. Reitan RM . Validity of the Trail Making Test as an indicator of organic brain damage. Percept Motor Skills 1958; 8: 271–276.

    Google Scholar 

  70. Jarvis PE, Barth JT . Halstead-Reitan Test Battery: An Interpretative Guide. Psychological Assessment Resources: Odessa, FL, 1986.

    Google Scholar 

  71. Andreasen NC, Cohen G, Harris G, Cizadlo T, Parkkinen J, Rezai K et al. Image processing for the study of brain structure and function: problems and programs. J Neuropsychiatry Clin Neurosci 1992; 4: 125–133.

    PubMed  CAS  Google Scholar 

  72. Andreasen NC, Cizadlo T, Harris G, Swayze V, O'Leary DS, Cohen G et al. Voxel processing techniques for the antemortem study of neuroanatomy and neuropathology using magnetic resonance imaging. J Neuropsychiatry Clin Neurosci 1993; 5: 121–130.

    PubMed  CAS  Google Scholar 

  73. Andreasen NC, Harris G, Cizadlo T, Arndt S, O'Leary DS, Swayze V et al. Techniques for measuring sulcal/gyral patterns in the brain as visualized through magnetic resonance scanning: BRAINPLOT and BRAINMAP. Proc Natl Acad Sci USA 1994; 91: 93–97.

    PubMed  CAS  PubMed Central  Google Scholar 

  74. Magnotta VA, Heckel D, Andreasen NC, Cizadlo T, Corson PW, Ehrhardt JC et al. Measurement of brain structures with artificial neural networks: two- and three-dimensional applications. Radiology 1999; 211: 781–790.

    PubMed  CAS  Google Scholar 

  75. Woods RP, Cherry SR, Mazziotta JC . Rapid automated algorithm for aligning and reslicing PET images. J Comput Assist Tomogr 1992; 16: 620–633.

    PubMed  CAS  Google Scholar 

  76. Talairach J, Tournoux P . Co-Planar Stereotaxic Atlas of the Human Brain. Thieme Medical Publishers: New York, 1988.

    Google Scholar 

  77. Andreasen NC, Rajarethinam R, Cizadlo T, Arndt S, Swayze II VW, Flashman LA et al. Automatic atlas-based volume estimation of human brain regions from MR images. J Comput Assist Tomogr 1996; 20: 98–106.

    PubMed  CAS  Google Scholar 

  78. Harris G, Andreasen NC, Cizadlo T, Bailey JM, Bockholt HJ, Magnotta VA et al. Improving tissue classification in MRI: a three-dimensional multispectral discriminant analysis method with automated training class selection. J Comput Assist Tomogr 1999; 23: 144–154.

    PubMed  CAS  Google Scholar 

  79. Herscovitch P, Markham J, Raichle ME . Brain blood flow measured with intravenous H2(15)O. I. Theory and error analysis. J Nucl Med 1983; 24: 782–789.

    PubMed  CAS  Google Scholar 

  80. Hichwa RD, Boles Ponto LL, Watkins GL . Clinical blood flow measurement with [15O]water and positron emission tomography (PET). In: Emran AM (ed). Chemists' Views of Imaging Centers. Plenum Press: New York, 1995 pp 401–417.

    Google Scholar 

  81. Arndt S, Cizadlo T, Andreasen NC, Heckel D, Gold S, O'Leary DS . Tests for comparing images based on randomization and permutation methods. J Cereb Blood Flow Metab 1996; 16: 1271–1279.

    PubMed  CAS  Google Scholar 

  82. Strous RD, Bark N, Woerner M, Lachman HM . Lack of association of a functional catechol-O-methyltransferase gene polymorphism in schizophrenia. Biol Psychiatry 1997; 41: 493–495.

    PubMed  CAS  Google Scholar 

  83. Chen CH, Lee YR, Wei FC, Koong FJ, Hwu HG, Hsiao KJ . Association study of NlaIII and MspI genetic polymorphisms of catechol-O-methyltransferase gene and susceptibility to schizophrenia. Biol Psychiatry 1997; 41: 985–987.

    PubMed  CAS  Google Scholar 

  84. Chen CH, Lee YR, Chung MY, Wei FC, Koong FJ, Shaw CK et al. Systematic mutation analysis of the catechol O-methyltransferase gene as a candidate gene for schizophrenia. Am J Psychiatry 1999; 156: 1273–1275.

    PubMed  CAS  Google Scholar 

  85. Arinami T, Ohtsuki T, Takase K, Shimizu H, Yoshikawa T, Horigome H et al. Screening for 22q11 deletions in a schizophrenia population. Schizophr Res 2001; 52: 167–170.

    PubMed  CAS  Google Scholar 

  86. Herken H, Erdal ME . Catechol-O-methyltransferase gene polymorphism in schizophrenia: evidence for association between symptomatology and prognosis. Psychiatr Genet 2001; 11: 105–109.

    PubMed  CAS  Google Scholar 

  87. Liou YJ, Tsai SJ, Hong CJ, Wang YC, Lai IC . Association analysis of a functional catechol-o-methyltransferase gene polymorphism in schizophrenic patients in Taiwan. Neuropsychobiology 2001; 43: 11–14.

    PubMed  CAS  Google Scholar 

  88. Inada T, Nakamura A, Iijima Y . Relationship between catechol-O-methyltransferase polymorphism and treatment-resistant schizophrenia. Am J Med Genet 2003; 120B: 35–39.

    PubMed  Google Scholar 

  89. 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 2002; 71: 1296–1302.

    PubMed  PubMed Central  CAS  Google Scholar 

  90. 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.

    PubMed  CAS  Google Scholar 

  91. Kotler M, Barak P, Cohen H, Averbuch IE, 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 1999; 88: 628–633.

    PubMed  CAS  Google Scholar 

  92. Wei J, Hemmings GP . Lack of evidence for association between the COMT locus and schizophrenia. Psychiatr Genet 1999; 9: 183–186.

    PubMed  CAS  Google Scholar 

  93. de Chaldee M, Corbex M, Campion D, Jay M, Samolyk D, Petit M et al. No evidence for linkage between COMT and schizophrenia in a French population. Psychiatry Res 2001; 102: 87–90.

    PubMed  CAS  Google Scholar 

  94. Semwal P, Prasad S, Bhatia T, Deshpande SN, Wood J, Nimgaonkar VL et al. Family-based association studies of monoaminergic gene polymorphisms among North Indians with schizophrenia. Mol Psychiatry 2001; 6: 220–224.

    PubMed  CAS  Google Scholar 

  95. Lohmueller KE, Pearce CL, Pike M, Lander ES, Hirschhorn JN . Meta-analysis of genetic association studies supports a contribution of common variants to susceptibility to common disease. Nat Genet 2003; 33: 177–182.

    PubMed  CAS  Google Scholar 

  96. Strous RD, Bark N, Parsia SS, Volavka J, Lachman HM . 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.

    PubMed  CAS  Google Scholar 

  97. Lachman HM, Nolan KA, Mohr P, Saito T, Volavka J . Association between catechol O-methyltransferase genotype and violence in schizophrenia and schizoaffective disorder. Am J Psychiatry 1998; 155: 835–837.

    PubMed  CAS  Google Scholar 

  98. Nolan KA, Volavka J, Czobor P, Cseh A, Lachman H, Saito T et al. Suicidal behavior in patients with schizophrenia is related to COMT polymorphism. Psychiatr Genet 2000; 10: 117–124.

    PubMed  CAS  Google Scholar 

  99. Jones G, Zammit S, Norton N, Hamshere ML, Jones SJ, Milham C et al. Aggressive behaviour in patients with schizophrenia is associated with catechol-O-methyltransferase genotype. Br J Psychiatry 2001; 179: 351–355.

    PubMed  CAS  Google Scholar 

  100. Illi A, Kampman O, Anttila S, Roivas M, Mattila KM, Lehtimaki T et al. Interaction between angiotensin-converting enzyme and catechol-O-methyltransferase genotypes in schizophrenics with poor response to conventional neuroleptics. Eur Neuropsychopharmacol 2003; 13: 147–151.

    PubMed  CAS  Google Scholar 

  101. 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 2002; 159: 652–654.

    PubMed  Google Scholar 

  102. 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 2003; 60: 889–896.

    PubMed  CAS  Google Scholar 

  103. Gallinat J, Bajbouj M, Sander T, Schlattmann P, Xu K, Ferro EF et al. Association of the G1947A COMT (Val(108/158)Met) gene polymorphism with prefrontal P300 during information processing. Biol Psychiatry 2003; 54: 40–48.

    PubMed  CAS  Google Scholar 

  104. Tsai SJ, Yu YW, Chen TJ, Chen JY, Liou YJ, Chen MC et al. Association study of a functional catechol-O-methyltransferase-gene polymorphism and cognitive function in healthy females. Neurosci Lett 2003; 338: 123–126.

    PubMed  CAS  Google Scholar 

  105. Bilder RM, Volavka J, Czobor P, Malhotra AK, Kennedy JL, Ni X et al. Neurocognitive correlates of the COMT Val(158)Met polymorphism in chronic schizophrenia. Biol Psychiatry 2002; 52: 701–707.

    PubMed  CAS  Google Scholar 

  106. Nolan KA, Bilder RM, Lachman HM, Volavka J . Catechol O-methyltransferase Val158Met polymorphism in schizophrenia: differential effects of Val and Met alleles on cognitive stability and flexibility. Am J Psychiatry 2004; 161: 359–361.

    PubMed  Google Scholar 

  107. Fossella J, Sommer T, Fan J, Wu Y, Swanson JM, Pfaff DW et al. Assessing the molecular genetics of attention networks. BMC Neurosci 2002; 3: 14.

    PubMed  PubMed Central  Google Scholar 

  108. Joober R, Rouleau GA, Lal S, Dixon M, O'Driscoll G, Palmour R et al. Neuropsychological impairments in neuroleptic-responder vs nonresponder schizophrenic patients and healthy volunteers. Schizophr Res 2002; 53: 229–238.

    PubMed  Google Scholar 

  109. Rinne JO . Muscarinic and dopaminergic receptors in the aging human brain. Brain Res 1987; 404: 162–168.

    PubMed  CAS  Google Scholar 

  110. de Keyser J, De Backer JP, Vauquelin G, Ebinger G . The effect of aging on the D1 dopamine receptors in human frontal cortex. Brain Res 1990; 528: 308–310.

    PubMed  CAS  Google Scholar 

  111. Suhara T, Fukuda H, Inoue O, Itoh T, Suzuki K, Yamasaki T et al. Age-related changes in human D1 dopamine receptors measured by positron emission tomography. Psychopharmacology (Berl) 1991; 103: 41–45.

    CAS  Google Scholar 

  112. Kaasinen V, Vilkman H, Hietala J, Nagren K, Helenius H, Olsson H et al. Age-related dopamine D2/D3 receptor loss in extrastriatal regions of the human brain. Neuobiol Aging 2000; 21: 683–688.

    CAS  Google Scholar 

  113. Volkow ND, Logan J, Fowler JS, Wang GJ, Gur RC, Wong C et al. Association between age-related decline in brain dopamine activity and impairment in frontal and cingulate metabolism. Am J Psychiatry 2000; 157: 75–80.

    PubMed  CAS  Google Scholar 

  114. Goldman-Rakic PS, Brown RM . Regional changes of monoamines in cerebral cortex and subcortical structures of aging rhesus monkeys. Neuroscience 1981; 6: 177–187.

    PubMed  CAS  Google Scholar 

  115. Wassink TH, Crowe RR, Andreasen NC . Tumor necrosis factor receptor—II: heritability and effect on brain morphology in schizophrenia. Mol Psychiatry 2000; 5: 678–682.

    PubMed  CAS  Google Scholar 

  116. Wassink TH, Nopoulos P, Pietila J, Crowe RR, Andreasen NC . NOTCH4 and the frontal lobe in schizophrenia. Am J Med Genet 2003; 118B: 1–7.

    PubMed  Google Scholar 

  117. Manoach DS . Prefrontal cortex dysfunction during working memory performance in schizophrenia: reconciling discrepant findings. Schizophr Res 2003; 60: 285–298.

    PubMed  Google Scholar 

Download references

Acknowledgements

This research was supported in part by NIMH Grants MH31593, MH40856 and MH43271. Parts of this research were presented at the IXth International Congress on Schizophrenia Research, Colorado Springs, CO, March 28–April 2, 2003.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to B -C Ho.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Ho, BC., Wassink, T., O'Leary, D. et al. Catechol-O-methyl transferase Val158Met gene polymorphism in schizophrenia: working memory, frontal lobe MRI morphology and frontal cerebral blood flow. Mol Psychiatry 10, 287–298 (2005). https://doi.org/10.1038/sj.mp.4001616

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.mp.4001616

Keywords

This article is cited by

Search

Quick links