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The catechol-O-methyl transferase (COMT) gene as a candidate for psychiatric phenotypes: evidence and lessons

Molecular Psychiatry volume 11, pages 446–458 (2006)Cite this article

Abstract

The enzyme catechol-O-methyl transferase (COMT), identified in the 1950s, is involved in catabolism of monoamines that are influenced by psychotropic medications, including neuroleptics and antidepressants. The COMT gene lies in a chromosomal region of interest for psychosis and bipolar spectrum disorder and a common polymorphism within the gene alters the activity of the enzyme. As a consequence, COMT has been one of the most studied genes for psychosis. On the basis of prior probabilities it would seem surprising if functional variation at COMT did not have some influence either on susceptibility to psychiatric phenotypes, modification of the course of illness or moderation of response to treatment. There is now robust evidence that variation at COMT influences frontal lobe function. However, despite considerable research effort, it has not proved straightforward to demonstrate and characterise a clear relationship between genetic variation at COMT and psychiatric phenotypes. It is of course, possible that COMT will turn out to be an unusually intractable case but it seems more likely that the experiences with this gene will provide a foretaste of the complexity of genotype–phenotype relationships that will be found for psychiatric traits. In this review, we consider the current state of evidence and the implications both for further studies of COMT and more generally for studies of other genes.

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References

  1. Axelrod J, Tomchick R . Enzymatic O-methylation of epinephrine and other catechols. J Biol Chem 1958; 233: 702–705.

    CAS  PubMed  Google Scholar 

  2. Jeffery DR, Roth JA . Characterization of membrane-bound and soluble catechol-O-methyltransferase from human frontal cortex. J Neurochem 1984; 42: 826–832.

    Article  CAS  PubMed  Google Scholar 

  3. Tenhunen J, Salminen M, Lundstrom 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 1994; 223: 1049–1059.

    Article  CAS  PubMed  Google Scholar 

  4. Huotari M, Santha M, Lucas LR, Karayiorgou M, Gogos JA, Mannisto PT et al. Effect of dopamine uptake inhibition on brain catecholamine levels and locomotion in catechol-O-methyltransferase-disrupted mice. J Pharmacol Exp Ther 2002; 303: 1309–1316.

    Article  CAS  PubMed  Google Scholar 

  5. 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 1998; 18: 2697–2708.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. 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 1998; 95: 9991–9996.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Tunbridge EM, Bannerman DM, Sharp T, Harrison PJ . Catechol-O-methyltransferase inhibition improves set-shifting performance and elevates stimulated dopamine release in the rat prefrontal cortex. J Neurosci 2004; 24: 5331–5335.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Lachman HM, Papolos DF, Saito T, Yu YM, Szumlanski CL, Weinshilboum RM . Human catechol-O-methyltransferase pharmacogenetics: description of a functional polymorphism and its potential application to neuropsychiatric disorders. Pharmacogenetics 1996; 6: 243–250.

    Article  CAS  PubMed  Google Scholar 

  9. Floderus Y, Wetterberg L . The inheritance of human erythrocyte catechol-O-methyltransferase activity. Clin Genet 1981; 19: 392–395.

    Article  CAS  PubMed  Google Scholar 

  10. 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 2004; 75: 807–821.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Xie T, Ho SL, Ramsden D . Characterization and implications of estrogenic down-regulation of human catechol-O-methyltransferase gene transcription. Mol Pharmacol 1999; 56: 31–38.

    Article  CAS  PubMed  Google Scholar 

  12. Jiang H, Xie T, Ramsden DB, Ho SL . Human catechol-O-methyltransferase down-regulation by estradiol. Neuropharmacology 2003; 45: 1011–1018.

    Article  CAS  PubMed  Google Scholar 

  13. Tunbridge EM, Weinberger DR, Harrison PJ . A novel protein isoform of catechol-O-methyltransferase (COMT): brain expression analysis in schizophrenia and bipolar disorder and effect of Val(158)Met genotype. Mol Psychiatry 2006; 11: 116–117.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  15. 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 2004; 9: 1359–4184.

    Article  CAS  Google Scholar 

  16. Lee SG, Joo Y, Kim B, Chung S, Kim HL, Lee I et al. Association of Ala72Ser polymorphism with COMT enzyme activity and the risk of schizophrenia in Koreans. Hum Genet 2005; 116: 319–328.

    Article  CAS  PubMed  Google Scholar 

  17. Swillen A, Devriendt K, Legius E, Eyskens B, Dumoulin M, Gewillig M et al. Intelligence and psychosocial adjustment in velocardiofacial syndrome: a study of 37 children and adolescents with VCFS. J Med Genet 1997; 34: 453–458.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Gerdes M, Solot C, Wang PP, Moss E, LaRossa D, Randall P et al. Cognitive and behavior profile of preschool children with chromosome 22q11.2 deletion. Am J Med Genet 1999; 85: 127–133.

    Article  CAS  PubMed  Google Scholar 

  19. Golding-Kushner KJ, Weller G, Shprintzen RJ . Velo-cardio-facial syndrome: language and psychological profiles. J Craniofac Genet Dev Biol 1985; 5: 259–266.

    CAS  PubMed  Google Scholar 

  20. Papolos DF, Faedda GL, Veit S, Goldberg R, Morrow B, Kucherlapati R et al. Bipolar spectrum disorders in patients diagnosed with velo-cardio-facial syndrome: does a hemizygous deletion of chromosome 22q11 result in bipolar affective disorder? Am J Psychiatry 1996; 153: 1541–1547.

    Article  CAS  PubMed  Google Scholar 

  21. Feinstein C, Eliez S, Blasey C, Reiss AL . Psychiatric disorders and behavioral problems in children with velocardiofacial syndrome: usefulness as phenotypic indicators of schizophrenia risk. Biol Psychiatry 2002; 51: 312–318.

    Article  PubMed  Google Scholar 

  22. Shprintzen RJ, Goldberg R, Golding-Kushner KJ, Marion RW . Late-onset psychosis in the velo-cardio-facial syndrome. Am J Med Genet 1992; 42: 141–142.

    Article  CAS  PubMed  Google Scholar 

  23. Pulver AE, Nestadt G, Goldberg R, Shprintzen RJ, Lamacz M, Wolyniec PS et al. Psychotic illness in patients diagnosed with velo-cardio-facial syndrome and their relatives. J Nerv Ment Dis 1994; 182: 476–478.

    Article  CAS  PubMed  Google Scholar 

  24. Bassett AS, Hodgkinson K, Chow EW, Correia S, Scutt LE, Weksberg R . 22q11 deletion syndrome in adults with schizophrenia. Am J Med Genet 1998; 81: 328–337.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  27. Lewis CM, Levinson DF, Wise LH, DeLisi LE, Straub RE, Hovatta I et al. Genome scan meta-analysis of schizophrenia and bipolar disorder, part II: Schizophrenia. Am J Hum Genet 2003; 73: 34–48.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Hamshere ML, Bennett P, Williams N, Segurado R, Cardno A, Norton N et al. Genome-wide linkage scan in schizoaffective disorder: significant evidence for linkage (LOD=3.54) at 1q42 close to DISC1, and suggestive evidence at 22q11 and 19q13. Archives of General Psychiatry 2005; 62: 1081–1088.

    Article  CAS  PubMed  Google Scholar 

  29. Craddock N, Forty E . Genetics of mood disorders. Eur J Hum Genet, in press.

  30. Hamilton SP, Slager SL, Heiman GA, Deng Z, Haghighi F, Klein DF et al. Evidence for a susceptibility locus for panic disorder near the catechol-O-methyltransferase gene on chromosome 22. Biol Psychiatry 2002; 51: 591–601.

    Article  CAS  PubMed  Google Scholar 

  31. MacKinnon DF, Zandi PP, Cooper J, Potash JB, Simpson SG, Gershon E et al. Comorbid bipolar disorder and panic disorder in families with a high prevalence of bipolar disorder. Am J Psychiatry 2002; 159: 30–35.

    Article  PubMed  Google Scholar 

  32. Egan MF, Goldberg TE, Kolachana BS, Callicott JH, Mazzanti CM, Straub RE et al. Effect of Comt Val(108/158) Met genotype on frontal lobe function and risk for schizophrenia. Proc Natl Acad Sci USA 2001; 98: 6917–6922.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Malhotra AK, Kestler LJ, Mazzanti C, Bates JA, Goldberg T, Goldman D et al. A functional polymorphism in the COMT gene and performance on a test of prefrontal cognition. Am J Psychiatry 2002; 59: 652–654.

    Article  Google Scholar 

  34. 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.

    Article  CAS  PubMed  Google Scholar 

  35. Diamond A, Briand L, Fossella J, Gehlbach L . Genetic and neurochemical modulation of prefrontal cognitive functions in children. Am J Psychiatry 2004; 161: 125–132.

    Article  PubMed  Google Scholar 

  36. 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.

    Article  CAS  PubMed  Google Scholar 

  37. 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.

    Article  PubMed  Google Scholar 

  38. Rosa A, Peralta V, Cuesta M, Zarzuela A, Serrano F, Martinez-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.

    Article  PubMed  Google Scholar 

  39. Bearden CE, Jawad AF, Lynch DR, Sokol S, Kanes SJ, McDonald-McGinn DM . Effects of a functional COMT polymorphism on prefrontal cognitive function in patients with 22q11.2 deletion syndrome. Am J Psychiatry 2004; 161: 1700–1702.

    Article  PubMed  Google Scholar 

  40. 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; 8: 123–126.

    Article  CAS  Google Scholar 

  41. Ho BC, Wassink TH, O'leary DS, Sheffield VC, Andreasen NC . Catechol-O-methyl transferase Val(158)Met gene polymorphism in schizophrenia: working memory, frontal lobe MRI morphology and frontal cerebral blood flow. Mol Psychiatry 2005; 10: 287–298.

    Article  CAS  Google Scholar 

  42. Stefanis NC, Van Os J, Avramopoulos D, Smyrnis N, Evdokimidis I, Hantoumi I et al. Variation in catechol-O-methyltransferase val158 met genotype associated with schizotypy but not cognition: a population study in 543 young men. Biol Psychiatry 2004; 56: 510–515.

    Article  CAS  PubMed  Google Scholar 

  43. Gothelf D, Eliez S, Thompson T, Hinard C, Penniman L, Feinstein C et al. COMT genotype predicts longitudinal cognitive decline and psychosis in 22q11.2 deletion syndrome. Nat Neurosci 2005; 8: 1500–1502.

    Article  CAS  PubMed  Google Scholar 

  44. 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 2003; 73: 152–161.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Zhu G, Lipsky RH, Xu K, Ali S, Hyde T, Kleinman J et al. Differential expression of human COMT alleles in brain and lymphoblasts detected by RT-coupled 5′ nuclease assay. Psychopharmacology (Berl) 2004; 177: 178–184.

    Article  CAS  Google Scholar 

  46. Winterer G, Weinberger DR . Genes, dopamine and cortical signal-to-noise ratio in schizophrenia. Trends Neurosci 2004; 27: 683–690.

    Article  CAS  PubMed  Google Scholar 

  47. Thierry AM, Tassin JP, Blanc G, Glowinski J . Selective activation of mesocortical DA system by stress. Nature 1976; 263: 242–244.

    Article  CAS  PubMed  Google Scholar 

  48. Baker K, Baldeweg T, Sivagnanasundaram S, Scambler P, Skuse D . COMT Val108/158 Met modifies mismatch negativity and cognitive function in 22q11 deletion syndrome. Biol Psychiatry 2005; 58: 23–31.

    Article  CAS  PubMed  Google Scholar 

  49. Glatt SJ, Faraone SV, Tsung 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.

    Article  PubMed  Google Scholar 

  50. 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.

    Article  CAS  PubMed  Google Scholar 

  51. 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.

    Article  CAS  PubMed  Google Scholar 

  52. 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 2005; 57: 139–144.

    Article  CAS  PubMed  Google Scholar 

  53. Munafo MR, Bowes L, Clark TG, Flint J . Lack of association of the COMT (Val158/108 Met) gene and schizophrenia: a meta-analysis of case–control studies. Mol Psychiatry 2005; 10: 765–770.

    Article  CAS  PubMed  Google Scholar 

  54. Williams HJ, Glaser B, Williams NM, Norton N, Zammit S, MacGregor S et al. No association between schizophrenia and polymorphisms in COMT in two large samples. Am J Psychiatry 2005; 162: 1736–1738.

    Article  PubMed  Google Scholar 

  55. 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. Brain Res Mol Brain Res 2004; 132: 51–56.

    Article  CAS  PubMed  Google Scholar 

  56. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Chen X, Wang X, O'Neill AF, Walsh D, Kendler KS . Variants in the catechol-O-methyltransferase (COMT) gene are associated with schizophrenia in Irish high-density families. Mol Psychiatry 2004; 9: 962–967.

    Article  CAS  PubMed  Google Scholar 

  58. Sanders AR, Rusu I, Duan J, Molen JE, Hou C, Schwab SG et al. Haplotypic association spanning the 22q11.21 genes COMT and ARVCF with schizophrenia. Mol Psychiatry 2005; 10: 353–365.

    Article  CAS  PubMed  Google Scholar 

  59. Handoko HY, Nyholt DR, Haywood NK, Nertney DA, Hannah DE, Windus LC et al. Separate and interacting effects within the catechol-O-methyltransferase (COMT) are associated with schizophrenia. Mol Psychiatry 2005; 10: 589–597.

    Article  CAS  PubMed  Google Scholar 

  60. Neale BM, Sham PC . The future of association studies: gene-based analysis and replication. Am J Hum Genet 2004; 75: 353–362.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Craddock N, Dave S, Greening J . Association studies of bipolar disorder. Bipolar Disord 2001; 3: 284–298.

    Article  CAS  PubMed  Google Scholar 

  62. Mynett-Johnson LA, Murphy VE, Claffey E, Shields DC, McKeon P . Preliminary evidence of an association between bipolar disorder in females and the catechol-O-methyltransferase gene. Psychiatr Genet 1998; 8: 221–225.

    Article  CAS  PubMed  Google Scholar 

  63. Kirov G, Jones I, McCandless F, Craddock N, Owen MJ . Family-based association studies of bipolar disorder with candidate genes involved in dopamine neurotransmission: DBH, DAT1, COMT, DRD2, DRD3 and DRD5. Mol Psychiatry 1999; 4: 558–565.

    Article  CAS  PubMed  Google Scholar 

  64. Serretti A, Cusin C, Cristina S, Lorenzi C, Lilli R, Lattuada E et al. Multicentre Italian family-based association study on tyrosine hydroxylase, catechol-O-methyl transferase and Wolfram syndrome 1 polymorphisms in mood disorders. Psychiatr Genet 2003; 13: 121–126.

    PubMed  Google Scholar 

  65. Lachman HM, Morrow B, Shprintzen R, Veit S, Parsia SS, 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 1996; 67: 468–472.

    Article  CAS  PubMed  Google Scholar 

  66. Kirov G, Murphy KC, Arranz MJ, 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.

    Article  CAS  PubMed  Google Scholar 

  67. Papolos DF, Veit S, Faedda GL, Saito T, Lachman HM . Ultra-ultra rapid cycling bipolar disorder is associated with the low activity catecholamine-O-methyltransferase allele. Mol Psychiatry 1998; 3: 346–349.

    Article  CAS  PubMed  Google Scholar 

  68. Shifman S, Bronstein M, Sternfeld M, Pisante A, Weizman A, Reznik I et al. COMT: a common susceptibility gene in bipolar disorder and schizophrenia. Am J Med Genet B Neuropsychiatr Genet 2004; 128: 61–64.

    Article  Google Scholar 

  69. Karayiorgou M, Altemus M, Galke BL, Goldman D, Murphy DL, 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Azzam A, Mathews CA . Meta-analysis of the association between the catecholamine-O-methyl-transferase gene and obsessive-compulsive disorder. Am J Med Genet B Neuropsychiatr Genet 2003; 123: 64–69.

    Article  Google Scholar 

  71. Meira-Lima I, Shavitt RG, Miguita K, Ikenaga E, Miguel EC, 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. Genes Brain Behav 2004; 3: 75–79.

    Article  CAS  PubMed  Google Scholar 

  72. Poyurovsky M, Michaelovsky E, Frisch A, Knoll G, Amir I, Finkel B et al. COMT Val158Met polymorphism in schizophrenia with obsessive-compulsive disorder: a case–control study. Neurosci Lett 2005; 389: 21–24.

    Article  CAS  PubMed  Google Scholar 

  73. Massat I, Souery D, Del-Favero J, Nothen M, Blackwood D, Muir W et al. Association between COMT (Val158Met) functional polymorphism and early onset in patients with major depressive disorder in a European multicenter genetic association study. Mol Psychiatry 2005; 10: 598–605.

    Article  CAS  PubMed  Google Scholar 

  74. Ohara K, Nagai M, Suzuki Y, Ohara K . Low activity allele of catechol-O-methyltransferase gene and Japanese unipolar depression. Neuroreport 1998; 11: 1305–1308.

    Article  Google Scholar 

  75. Turic D, Williams H, Langley K, Owen M, Thapar A, O'Donovan MC . A family based study of catechol-O-methyltransferase (COMT) and attention deficit hyperactivity disorder (ADHD). Am J Med Genet B Neuropsychiatr Genet 2005; 133: 64–67.

    Article  Google Scholar 

  76. 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 B Neuropsychiatr Genet 2003; 118: 103–109.

    Article  Google Scholar 

  77. Bellgrove MA, Domschke K, Hawi Z, Kirley A, Mullins C, Robertson IH et al. The methionine allele of the COMT polymorphism impairs prefrontal cognition in children and adolescents with ADHD. Exp Brain Res 2005; 163: 352–360.

    Article  CAS  PubMed  Google Scholar 

  78. Jiang SD, Wu XD, Zhang Y, Tang GM, Qian YP, Wang DX . No association between attention-deficit hyperactivity disorder and catechol-O-methyltransferase gene in Chinese. Yi Chuan Xue Bao 2005; 32: 784–788.

    CAS  PubMed  Google Scholar 

  79. Woo JM, Yoon KS, Choi YH, Oh KS, Lee YS, Yu BH . The association between panic disorder and the L/L genotype of catechol-O-methyltransferase. J Psychiatr Res 2004; 38: 365–370.

    Article  PubMed  Google Scholar 

  80. Domschke K, Freitag CM, Kuhlenbaumer G, Schirmacher A, Sand P, Nyhuis P et al. Association of the functional V158M catechol-O-methyl-transferase polymorphism with panic disorder in women. Int J Neuropsychopharmacol 2004; 7: 183–188.

    Article  CAS  PubMed  Google Scholar 

  81. Rotondo A, Mazzanti C, Dell'Osso L, Rucci P, Sullivan P, Bouanani S et al. Catechol-O-methyltransferase, serotonin transporter, and tryptophan hydroxylase gene polymorphisms in bipolar disorder patients with and without comorbid panic disorder. Am J Psychiatry 2002; 159: 23–29.

    Article  PubMed  Google Scholar 

  82. McGrath M, Kawachi I, Ascherio A, Colditz GA, Hunter DJ, De Vivo I . Association between catechol-O-methyltransferase and phobic anxiety. Am J Psychiatry 2004; 161: 1703–1705.

    Article  PubMed  Google Scholar 

  83. Olsson CA, Anney RJ, Lotfi-Miri M, Byrnes GB, Williamson R, Patton GC . Association between the COMT Val158Met polymorphism and propensity to anxiety in an Australian population-based longitudinal study of adolescent health. Psychiatr Genet 2005; 15: 109–115.

    Article  PubMed  Google Scholar 

  84. Redden DT, Shields PG, Epstein L, Wileyto EP, Zakharkin SO, Allison DB et al. Catechol-O-methyl-transferase functional polymorphism and nicotine dependence: an evaluation of nonreplicated results. Cancer Epidemiol Biomarkers Prev 2005; 14: 1384–1389.

    Article  CAS  PubMed  Google Scholar 

  85. Michaelovsky E, Frisch A, Leor S, Stein D, Danziger Y, Carel C et al. Haplotype analysis of the COMT-ARVCF gene region in Israeli anorexia nervosa family trios. Am J Med Genet B Neuropsychiatr Genet 2005; 139: 45–50.

    Article  CAS  Google Scholar 

  86. Moffitt TE, Caspi A, Rutter M . Strategy for investigating interactions between measured genes and measured environments. Arch Gen Psychiatry 2005; 62: 473–481.

    Article  CAS  PubMed  Google Scholar 

  87. Zammit S, Owen MJ . Stressful life events, 5-HTT genotype, and risk of depression. Br J Psychiatry, in press.

  88. Caspi A, Moffitt TE, Cannon M, McClay J, Murray R, Harrington H et al. 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. Biol Psychiatry 2005; 57: 1117–1127.

    Article  CAS  PubMed  Google Scholar 

  89. Thapar A, Langley K, Fowler T, Rice F, Turic D, Whittinger N et al. Catechol-O-methyltransferase gene variant and birth weight predict early-onset antisocial behavior in children with attention-deficit/hyperactivity disorder. Arch Gen Psychiatry 2005; 62: 1275–1278.

    Article  CAS  PubMed  Google Scholar 

  90. van Rossum JM . The significance of dopamine receptor blockade for the mechanism of action of neuroleptic drugs. Archives Internationales de Pharmacodynamic et de Therapie 1966; 160: 492–494.

    CAS  Google Scholar 

  91. Carlsson A . Mechanism of action of neuroleptic drugs. In: Lipton MA, DiMascio A, Killam KF (eds). Psychopharmacology. A Generation of Progress. Raven Press: New York, 1978, pp 1057–1070.

    Google Scholar 

  92. Daniel DG, Berman KF, Weinberger DR . The effect of apomorphine on regional cerebral blood flow in schizophrenia. J Neuropsychiatry Clin Neurosci 1989; 1: 377–384.

    Article  CAS  PubMed  Google Scholar 

  93. Davis KL, Kahn RS, Ko G, Davidson M . Dopamine in schizophrenia: a review and reconceptualization. Am J Psychiatry 1991; 148: 1474–1486.

    Article  CAS  PubMed  Google Scholar 

  94. Weinshilboum R, Dunnette J . Thermal stability and the biochemical genetics of erythrocyte catechol-O-methyl-transferase and plasma dopamine-beta-hydroxylase. Clin Genet 1981; 19: 426–437.

    Article  CAS  PubMed  Google Scholar 

  95. 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 2000; 5: 77–84. Erratum in: Mol Psychiatry 2000; 5(4):452.

    Article  CAS  PubMed  Google Scholar 

  96. Craddock N, O'Donovan MC, Owen MJ . The genetics of schizophrenia and bipolar disorder: dissecting psychosis. J Med Genet 2005; 42: 193–204.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Craddock N, O'donovan MC, Owen MJ . Genes for schizophrenia and bipolar disorder? Implications for psychiatric nosology. Schizophr Bull 2006; 32: 9–16.

    Article  PubMed  Google Scholar 

  98. 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 2004; 161: 1798–1805.

    Article  PubMed  Google Scholar 

  99. Weickert TW, Goldberg TE, Mishara A, Apud JA, Kolachana BS, Egan MF et al. Catechol-O-methyltransferase val108/158met genotype predicts working memory response to antipsychotic medications. Biol Psychiatry 2004; 56: 677–682.

    Article  CAS  PubMed  Google Scholar 

  100. Potash JB, Zandi PP, Willour VL, Lan TH, Huo Y, Avramopoulos D et al. Suggestive linkage to chromosomal regions 13q31 and 22q12 in families with psychotic bipolar disorder. Am J Psychiatry 2003; 160: 680–686.

    Article  PubMed  Google Scholar 

  101. Funke B, Malhotra AK, Finn CT, Plocik AM, Lake SL, Lencz T et al. COMT genetic variation confers risk for psychotic and affective disorders: a case control study. Behav Brain Funct 2005; 18: 1:19.

    Google Scholar 

  102. Craddock N, Raybould R, Green E, Macgregor S, Grozeva D, Williams H et al. Genetic variation at or near COMT influences susceptibility to a phenotype characterized by the co-existence of marked features of mania and psychosis. Am J Med Genet B Neuropsychiatr Genet 2005; 138B: 23–24, (abstract).

    Google Scholar 

  103. Green E, Craddock N . Brain-derived neurotrophic factor as a potential risk locus for bipolar disorder: evidence, limitations, and implications. Curr Psychiatry Rep 2003; 5: 469–476.

    Article  PubMed  Google Scholar 

  104. Wang WY, Barratt BJ, Clayton DG, Todd JA . Genome-wide association studies: theoretical and practical concerns. Nat Rev Genet 2005; 6: 109–118.

    Article  CAS  PubMed  Google Scholar 

  105. Suarez BK, Hampe CL, Van Eerdewegh P . Problems of replicating linkage claims in psychiatry. In: Gerson ES, Cloninger CR (eds). Genetic Approaches to Mental Disorders. American Psychiatric Press, Inc.: Washington, DC, 1994, pp 23–46.

    Google Scholar 

  106. Altshuler D, Hirschhorn JN, Klannemark M, Lindgren CM, Vohl MC, Nemesh J . The common PPARgamma Pro12Ala polymorphism is associated with decreased risk of type 2 diabetes. Nat Genet 2000; 26: 76–80.

    Article  CAS  PubMed  Google Scholar 

  107. Berrettini W . Evidence for shared susceptibility in bipolar disorder and schizophrenia. Am J Med Genet C Semin Med Genet 2003; 123: 59–64.

    Article  Google Scholar 

  108. Craddock N, Owen MJ . The beginning of the end for the Kraepelinian dichotomy. Br J Psychiatry 2005; 186: 364–366.

    Article  PubMed  Google Scholar 

  109. Gordon D, Finch SJ, Nothnagel M, Ott J . Power and sample size calculations for case–control genetic association tests when errors are present: application to single nucleotide polymorphisms. Hum Hered 2002; 54: 22–33.

    Article  PubMed  Google Scholar 

  110. Kang SJ, Finch SJ, Haynes C, Gordon D . Quantifying the percent increase in minimum sample size for SNP genotyping errors in genetic model-based association studies. Hum Hered 2004; 58: 139–144.

    Article  PubMed  Google Scholar 

  111. Kang SJ, Gordon D, Finch SJ . What SNP genotyping errors are most costly for genetic association studies? Genet Epidemiol 2004; 26: 132–141.

    Article  PubMed  Google Scholar 

  112. Rice KM, Holmans P . Allowing for genotyping error in analysis of unmatched case–control studies. Ann Hum Genet 2003; 67: 165–174.

    Article  CAS  PubMed  Google Scholar 

  113. Knapp M, Becker T . Impact of genotyping errors on type I error rate of the haplotype-sharing Transmission/Disequilibrium test (HS-TDT). American Journal of Human Genetics 2004; 74: 589–591.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Kirk KM, Cardon LR . The impact of genotyping error on haplotype reconstruction and frequency estimation. Eur J Hum Genet 2002; 10: 616–622.

    Article  CAS  PubMed  Google Scholar 

  115. Clayton D, Walker NM, Smyth DJ, Pask R, Cooper JD, Maier LM . Population structure, differential bias and genomic control in a large-scale, case–control association study. Nat Genet 2005; 37: 1243–1246.

    Article  CAS  PubMed  Google Scholar 

  116. Moskvina V, Craddock N, Holmans P, Owen M, O'Donovan M . Minor genotyping error can result in substantial elevation in type I error rate in haplotype based case control studies. Am J Med Genet (Neuropsychiatric Genetics) 2005; 138B: 19, (abstract).

    Google Scholar 

  117. Cucherat M, Boissel JP, Leizorovicz A, Haugh MC . EasyMA: a program for the meta-analysis of clinical trials. Comput Methods Programs Biomed 1997; 53: 187–190.

    Article  CAS  PubMed  Google Scholar 

  118. BIOMED. [No authors listed]. No association between bipolar disorder and alleles at a functional polymorphism in the COMT gene. Biomed European Bipolar Collaborative Group. Br J Psychiatry 1997; 170: 526–528.

  119. Gutierrez B, Bertranpetit J, Guillamat R, Valles V, Arranz MJ, Kerwin R et al. Association analysis of the catechol-O-methyltransferase gene and bipolar affective disorder. Am J Psychiatry 1997; 154: 113–115.

    Article  CAS  PubMed  Google Scholar 

  120. Lachman HM, Kelsoe J, Moreno L, Katz S, Papolos DF . Lack of association of catechol-O-methyltransferase (COMT) functional polymorphism in bipolar affective disorder. Psychiatr Genet 1997; 7: 13–17.

    Article  CAS  PubMed  Google Scholar 

  121. Kunugi H, Vallada HP, Hoda F, Kirov G, Gill M, Aitchison KJ 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.

    Article  CAS  PubMed  Google Scholar 

  122. Li T, Vallada H, Curtis D, Arranz M, Xu K, Cai G . Catechol-O-methyltransferase Val158Met polymorphism: frequency analysis in Han Chinese subjects and allelic association of the low activity allele with bipolar affective disorder. Pharmacogenetics 1997; 7: 349–353.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We are grateful to the Medical Research Council (UK) who support our work on schizophrenia, and to the Wellcome Trust who fund our studies on bipolar spectrum disorders and our psychosis work on chromosome 22.

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  1. Department of Psychological Medicine, The Henry Wellcome Building for Biomedical Research in Wales, Cardiff University, School of Medicine, Heath Park, Cardiff, UK

    N Craddock, M J Owen & M C O'Donovan

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  1. N Craddock
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  2. M J Owen
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  3. M C O'Donovan
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Correspondence to N Craddock.

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Craddock, N., Owen, M. & O'Donovan, M. The catechol-O-methyl transferase (COMT) gene as a candidate for psychiatric phenotypes: evidence and lessons. Mol Psychiatry 11, 446–458 (2006). https://doi.org/10.1038/sj.mp.4001808

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  • DOI: https://doi.org/10.1038/sj.mp.4001808

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