Human Genetics

, Volume 120, Issue 6, pp 889–906

Evidence for statistical epistasis between catechol-O-methyltransferase (COMT) and polymorphisms in RGS4, G72 (DAOA), GRM3, and DISC1: influence on risk of schizophrenia

  • Kristin K. Nicodemus
  • Bhaskar S. Kolachana
  • Radhakrishna Vakkalanka
  • Richard E. Straub
  • Ina Giegling
  • Michael F. Egan
  • Dan Rujescu
  • Daniel R. Weinberger
Original Investigation


Catechol-O-methyltransferase (COMT) regulates dopamine degradation and is located in a genomic region that is deleted in a syndrome associated with psychosis, making it a promising candidate gene for schizophrenia. COMT also has been shown to influence prefrontal cortex processing efficiency. Prefrontal processing dysfunction is a common finding in schizophrenia, and a background of inefficient processing may modulate the effect of other candidate genes. Using the NIMH sibling study (SS), a non-independent case-control set, and an independent German (G) case-control set, we performed conditional/unconditional logistic regression to test for epistasis between SNPs in COMT (rs2097603, Val158Met (rs4680), rs165599) and polymorphisms in other schizophrenia susceptibility genes. Evidence for interaction was evaluated using a likelihood ratio test (LRT) between nested models. SNPs in RGS4, G72, GRM3, and DISC1 showed evidence for significant statistical epistasis with COMT. A striking result was found in RGS4: three of five SNPs showed a significant increase in risk [LRT P-values: 90387 = 0.05 (SS); SNP4 = 0.02 (SS), 0.02 (G); SNP18 = 0.04 (SS), 0.008 (G)] in interaction with COMT; main effects for RGS4 SNPs were null. Significant results for SNP4 and SNP18 were also found in the German study. We were able to detect statistical interaction between COMT and polymorphisms in candidate genes for schizophrenia, many of which had no significant main effect. In addition, we were able to replicate other studies, including allelic directionality. The use of epistatic models may improve replication of psychiatric candidate gene studies.


  1. Electronic database information, Online Mendelian Inheritance in Man: = OMIM
  2. Blouin JL, Dombroski BA, Nath SK, Lasseter VK, Wolyniec PS, Nestadt G, Thornquist M, Ullrich G, McGrath J, Kasch L, Lamacz M, Thomas MG, Gehrig C, Radhakrishna U, Snyder SE, Balk KG, Neufeld K, Swartz KL, DeMarchi N, Papadimitriou GN, Dikeos DG, Stefanis CN, Chakravarti A, Childs B, Housman DE, Kazazian HH, Antonarakis S, Pulver AE (1998) Schizophrenia susceptibility loci on chromosomes 13q32 and 8p21. Nat Genet 20:70–73PubMedCrossRefGoogle Scholar
  3. Bray NJ, Buckland PR, Williams NM, Williams HJ, Norton N, Owen MJ, O’Donovan MC (2003) A haplotype implicated in schizophrenia susceptibility is associated with reduced COMT expression in human brain. Am J Hum Genet 73:152–161PubMedCrossRefGoogle Scholar
  4. Brown BW, Lovato J, Russell K (1999) Asymptotic power calculations: description, examples, computer code. Stat Med 18:3137–3151PubMedCrossRefGoogle Scholar
  5. Bruder GE, Keilp JG, Xu H, Shikhman M, Schori E, Gorman JM, Gilliam TC (2005) Catechol-O-methyltransferase (COMT) genotypes and working memory: associations with differing cognitive operations. Biol Psychiatry 58:901–907PubMedCrossRefGoogle Scholar
  6. Buckholtz JW, Meyer-Lindenberg A, Honea R, Egan MF, Pezawas L, Straub RE, Kolachana B, Verchinski BA, Sust S, Mattay VS, Weinberger DR, Callicott JH Allelic variation in RGS4 impacts functional and structural connectivity in the human brain (submitted)Google Scholar
  7. Callicott JH, Straub RE, Pezawas L, Egan MF, Mattay VS, Hariri AR, Verchinski BA, Meyer-Lindenberg A, Balkissoon R, Kolachana B, Goldberg TE, Weinberger DR (2005) Variation in DISC1 affects hippocampal structure and function and increases risk for schizophrenia. PNAS 102:8627–8632PubMedCrossRefGoogle Scholar
  8. Cannon TD, Hennah W, van Erp TG, Thompson PM, Lonnqvist J, Huttunen M, Gasperoni T, Tuulio-Henriksson A, Pirkola T, Toga AW, Kaprio J, Mazziotta J, Peltonen L (2005) Association of DISC1/TRAX haplotypes with schizophrenia, reduced prefrontal gray matter, and impaired short-and long-term memory. Arch Gen Psychiatry 62:1205–1213PubMedCrossRefGoogle Scholar
  9. Caspi A, Moffitt TE, Cannon M, McClay J, Murray R, Harrington H, Taylor A, Arseneault L, Williams B, Brathwaite A, Poulton R, Craig IW (2005) Moderation of the effect of adolescent-onset cannabis use on adult psychosis by functional polymorphism in the catechol-O-methyltransferase gene: longitudinal evidence of a gene X environment interaction. Arch Gen Psychiatry 62:473–481PubMedCrossRefGoogle Scholar
  10. Chen J, Lipska BK, Halim N, Ma QD, Matsumoto M, Melhem S, Kolachana BS, Hyde TM, Herman MM, Apud J, Egan MF, Kleinman JE, Weinberger DR (2004) Functional analysis of genetic variation in catechol-O-methyltranferase (COMT): effects on mRNA, protein, and enzyme activity in postmortem human brain. Am J Hum Genet 75:807–821PubMedCrossRefGoogle Scholar
  11. Chen X, Dunham C, Kendler S, Wang X, O’Neill FA, Dermot W, Kendler KS (2004) Regulator of G-protein signaling 4 (RGS4) gene is associated with schizophrenia in Irish high density families. Am J Med Genet B Neuropsychiatry Genet 129B:23–26CrossRefGoogle Scholar
  12. Chen Q, He G, Chen Q, Wu S, Xu Y, Feng G, Li Y, Wang L, He L (2005) A case-control study of the relationship between the metabotropic glutamate receptor 3 gene and schizophrenia in the Chinese population. Schizophr Res 73:21–26PubMedCrossRefGoogle Scholar
  13. Chiu YF, McGrath JA, Thornquist MH, Wolyniec PS, Nestadt G, Swartz KL, Lasseter VK, Liang KY, Pulver AE (2002) Genetic heterogeneity in schizophrenia II: conditional analyses of affected schizophrenia sibling pairs provide evidence for an interaction between markers on chromosome 8p and 14q. Mol Psychiatry 7:658–664PubMedCrossRefGoogle Scholar
  14. Chotai J, Serretti A, Lorenzi C (2004) Interaction between the trutophan hydroxylase gene and the serotonin transporter gene in schizophrenia but not in bipolar or unipolar affective disorders. Neuropsychobiology 51:3–9CrossRefGoogle Scholar
  15. Chowdari KV, Mirnics K, Semwal P, Wood J, Lawrence E, Bhatia T, Deshpande SM, Thelma BK, Ferrell RE, Middleton FA, Devlin B, Levitt P, Lewis DA, Nimgaonkar VL (2002) Association and linkage analysis of RGS4 polymorphisms and schizophrenia. Hum Molec Genet 11:1373–1380PubMedCrossRefGoogle Scholar
  16. Chumakov I, Blumenfeld M, Guerassimenko O, Cavarec L, Palicio M, Abderrahim H, Bougueleret L (2002) Genetic and physiological data implicating the new human gene G72 and the gene for d-amino acid oxidase in schizophrenia. PNAS 99:13675–13680PubMedCrossRefGoogle Scholar
  17. Cordeiro Q, Talkowski ME, Chowdari KV, Wood J, Nimgaonkar V, Vallada H (2005) Association and linkage analysis of RGS4 polymorphisms with schizophrenia and bipolar disorder in Brazil. Genes Brain Behav 4:45–50PubMedCrossRefGoogle Scholar
  18. Cordell HJ, Barratt BJ, Clayton DG (2004) Case/pseudocontrol analysis in genetic association studies: a unified framework for detection of genotype and haplotype associations, gene–gene and gene–environment interactions, and parent-of-origin effects. Genet Epidemiol 26:167–185PubMedCrossRefGoogle Scholar
  19. De Luca V, Voineskos S, Wong G, Kennedy JL (2006) Genetic interaction between α4 and β2 subunits of high affinity nicotinic receptor: analysis in schizophrenia. Exp Brain Res [Apr 25; Epub ahead of print]Google Scholar
  20. DeMille MMC, Kidd JR, Ruggeri V, Palmatier MA, Goldman D, Odunsi A, Okonofua F, Grigorenko E, Schulz LO, Bonne-Tamir B, Lu R-B, Parnas J, Pakstis AJ, Kidd KK (2002) Population variation in linkage disequilibrium across the COMT gene considering promoter region and coding region variation. Hum Genet 111:521–537PubMedCrossRefGoogle Scholar
  21. Drabant EM, Hariri AR, Meyer-Lindenberg A, Munoz KE, Mattay VS, Kolachana BS, Egan MF, Weinberger DR Catechol-O-methyltransferase Val158Met genotype and neural mechanisms related to affective arousal and regulation. Arch Gen Psychiatry (in press)Google Scholar
  22. Egan MF, Goldberg TE, Gscheidle T, Weirich M, Bigelow LB, Weinberger DR (2000) Relative risk of attention deficits in siblings of patients with schizophrenia. Am J Psychiatry 157:1309–1316PubMedCrossRefGoogle Scholar
  23. Egan MF, Goldberg TE, Kolachana BS, Callicott JH, Mazzanti CM, Straub RE, Goldman D, Weinberger DR (2001) Effect of COMT Val 108/158 Met genotype on frontal lobe function and risk for schizophrenia. PNAS 98:6917–6922PubMedCrossRefGoogle Scholar
  24. Egan MF, Straub RE, Goldberg TE, Yakub I, Callicott JH, Hariri AR, Mattay VS, Bertolino A, Hyde TM, Shannon-Weickert C, Akil M, Crook J, Vakkalanka RK, Balkissoon R, Gibbs RA, Kleinman JE, Weinberger DR (2004) Variation in GRM3 affects cognition, prefrontal glutamate, and risk for schizophrenia. PNAS 101:12604–12609PubMedCrossRefGoogle Scholar
  25. Fan JB, Zhang CS, Gu NF, Li XW, Sun WW, Wang HY, Feng GY, St Clair D, He L (2005) Catechol-O-methyltransferase gene Val/Met functional polymorphism and risk of schizophrenia: a large-scale association study plus meta-analysis. Biol Psychiatry 57:139–144PubMedCrossRefGoogle Scholar
  26. First MB, Spitzer RL, Gibbon M, Williams JBW (1996a) Structured clinical interview for DSM-IV Axis I disorders, research version (SCID-I) Biometrics research. New York State Psychiatric Inst New YorkGoogle Scholar
  27. First MB, Spitzer RL, Gibbon M, Williams JB (1996b) Structured clinical interview for DSM-IV Axis II disorders, version 2 (SCID-II) Biometrics research. New York State Psychiatric Inst New YorkGoogle Scholar
  28. Fujii Y, Shibata H, Kikuta R, Makino C, Tani A, Hirata N, Shibata A, Ninomiya H, Tashiro N, Fukumaki Y (2003) Positive associations of polymorphisms in the metabotropic glutamate receptor 3 gene (GRM3) with schizophrenia. Psychiatr Genet 13:71–76PubMedCrossRefGoogle Scholar
  29. Glatt SJ, Faraone SV, Tsuang MT (2003) Association between a functional catechol O-methyltransferase gene polymorphism and schizophrenia: meta-analysis of case-control and family-based studies. Am J Psychiatry 163:469–476CrossRefGoogle Scholar
  30. Goldberg TE, Egan MF, Gscheidle T, Coppola R, Weickert T, Kolachana BS, Goldman D, Weinberger DR (2003) Executive subprocesses in working memory: relationship to catechol-O-methyltransferase Val158Met genotype and schizophrenia. Arch Gen Psychiatry 60:889–896PubMedCrossRefGoogle Scholar
  31. Goldberg TE, Straub RE, Callicott JH, Hariri A, Mattay VS, Bigelow L, Coppola R, Egan MF, Weinberger DR (2006) The G72/G30 gene complex and cognitive abnormalities in schizophrenia. Neuropsychopharmacology Mar 22 [Epub ahead of print]Google Scholar
  32. Gothelf D, Eliez S, Thompson T, Hinard C, Penniman L, Feinstein C, Kwon H, Shuting J, Jo B, Antonarakis SE, Morris MA, Reiss AL (2005) COMT genotype predicts longitudinal cognitive decline and psychosis in 22q11.2 deletion syndrome. Nat Neurosci 8(1500):15–2Google Scholar
  33. Handoko HY, Nyholt DR, Hayward NK, Nertney DA, Hannah DE, Windus LC, McCormack CM, Smith HJ, Filippich C, James MR, Mowry BJ (2005) Separate and interacting effects within the catechol-O-methyltransferase (COMT) are associated with schizophrenia. Mol Psychiatry 10:589–597PubMedCrossRefGoogle Scholar
  34. Harrison PJ, Weinberger DR (2005) Schizophrenia genes, gene expression, and neuropathology: on the matter of their convergence. Mol Psychiatry 10:40–68PubMedCrossRefGoogle Scholar
  35. Hennah W, Varilo T, Kestilä M, Paunio T, Arajrävi R, Haukka J, Parker A, Martin R, Levitzky S, Partonen T, Meyer J, Lönnqvist J, Peltonen L, Ekelund J (2003) Haplotype transmission analysis provides evidence of association for DISC1 to schizophrenia and suggests sex-dependent effects. Hum Mol Genet 23:3151–3159CrossRefGoogle Scholar
  36. Hodgkinson CA, Goldman D, Jaeger J, Persaud S, Kane JM, Lipsky RH, Malhotra AK (2004) Disrupted in schizophrenia 1 (DISC1): association with schizophrenia, schizoaffective disorder, and bipolar disorder. Am J Hum Genet 75:862–872PubMedCrossRefGoogle Scholar
  37. Horvath S, Xu X, Laird NM (2001) The family based association test method: strategies for studying general genotype–phenotype associations. Eur J Hum Genet 9:301–306PubMedCrossRefGoogle Scholar
  38. Korostishevsky M, Kaganovich M, Cholostoy A, Ashkenazi M, Ratner Y, Dahary D, Bernstein J, Bening-Abu-Shach U, Ben-Asher E, Lancet D, Ritsner M, Navon R (2004) Is the G72/G30 locus associated with schizophrenia? Single nucleotide polymorphisms, haplotypes, and gene expression analysis. Biol Psychiatry 56:169–176PubMedCrossRefGoogle Scholar
  39. Kunugi H, Vallada HP, Sham PC, Hoda F, Arranz MJ, Li T, Nanko S, Murray RM, McGuffin P, Owen M, Gill M, Collier DA (1997) Catechol-O-methyltransferase polymorphisms and schizophrenia: a transmission disequilibrium study in multiply affected families. Psychiatr Genet 7:97–101PubMedCrossRefGoogle Scholar
  40. Li SS, Khalid N, Carlson C, Zhao LP (2003) Estimating haplotype frequencies and standard errors for multiple single nucleotide polymorphisms. Biostatistics 4:513–522PubMedCrossRefGoogle Scholar
  41. Li T, Ball D, Zhao J, Murray RM, Liu X, Sham PC, Collier DA (2000) Family-based linkage disequilibrium mapping using SNP marker haplotypes: application to a potential locus for schizophrenia at chromosome 22q11. Mol Psychiatry 5:77–84PubMedCrossRefGoogle Scholar
  42. Lipska BK, Mitkus S, Caruso M, Hyde TM, Straub R, Kolachana B, Chen J, Weinberger DR, Kleinman JE (2006) RGS4 mRNA expression in postmortem human cortex is associated with COMT Val158Met genotype and COMT enzyme activity. Hum Mol Genet Epub Aug. 11Google Scholar
  43. Lohmueller KE, Pearce CL, Pike M, Lander ES, Hirschhorn JN (2003) Meta-analysis of genetic association studies supports a contribution of common variants to susceptibility to common disease. Nat Genet 33:177–182PubMedCrossRefGoogle Scholar
  44. Longmate JA (2001) Complexity and power in case-control association studies. Am J Hum Genet 68:1229–1237PubMedCrossRefGoogle Scholar
  45. Lotta T, Vidgren J, Tilgmann C, Ulmanen I, Melen K, Julkunen I, Taskinen J (1995) Kinetics of the human soluble and membrane-bound catechol O-methyltransferase: a revised mechanism and description of the thermolabile variant of the enzyme. Biochemistry 34:4202–4210PubMedCrossRefGoogle Scholar
  46. Marti SB Cichon S, Propping P, Nöthen M (2002) Metabotropic glutamate receptor 3 (GRM3) gene variation is not associated with schizophrenia or bipolar affective disorder in the German population. Am J Med Genet B Neuropsychiatry Genet 114:46–50CrossRefGoogle Scholar
  47. Mattay VS, Goldberg TE, Fera F, Hariri AR, Tessitore A, Egan MF, Kolachana B, Callicott JH, Weinberger DR (2003) Catechol O-methyltransferase val158-met genotype and individual variation in the brain response to amphetamine. PNAS 100:6186–6191PubMedCrossRefGoogle Scholar
  48. McGuigan FE, Ralston SH (2002) Single nucleotide polymorphism detection: allelic discrimination using TaqMan. Psychiatr Genet 12:133–136PubMedCrossRefGoogle Scholar
  49. Meyer-Lindenberg A, Kohn PD, Kolachana B, Kippenhan S, McInerney-Leo A, Nussbaum R, Weinberger DR, Berman KF (2005) Midbrain dopamine and prefrontal function in humans: interaction and modulation by COMT genotype. Nat Neurosci 8:594–596PubMedCrossRefGoogle Scholar
  50. Meyer-Lindenberg A, Nichols T, Callicott J, Ding J, Kolachana B, Buckholtz J, Mattay VS, Egan M, Weinberger DR (2006) Functional neuroimaging of ambiguous haplotypes reveals impact of complex genetic variation in COMT. Mol Psychiatry Jun 20 [Epub ahead of print]Google Scholar
  51. Morris DW, Rodgers A, McGhee KA, Schwaiger S, Scully P, Quinn J, Meagher D, Waddington JL, Gill M, Corvin AP (2004) Confirming RGS4 as a susceptibility gene for schizophrenia. Am J Med Genet B Neuropsychiatr Genet 125:50–53PubMedCrossRefGoogle Scholar
  52. Mulle JG, Chowdari KV, Nimgaonkar V, Chakravarti A (2005) No evidence for association to the G72/G30 locus in an independent sample of schizophrenia families. Mol Psychiatry 10:431–433PubMedCrossRefGoogle Scholar
  53. Norton N, Williams HJ, Dwyer S, Ivanov D, Preece AC, Gerrish A, Williams NM, Yerassimou P, Zammit S, O’Donovan MC, Owen MJ (2005) No evidence for association between polymorphisms in GRM3 and schizophrenia. BMC Psychiatry 5:5–23CrossRefGoogle Scholar
  54. Norton N, Moskvina V, Morris DW, Bray NJ, Zammit S, Williams NM, Williams HJ, Preece AC, Dwyer S, Wilkinson JC, Spurlock G, Kirov G, Buckland P, Waddington JL, Gill M, Corvin AP, Owen MJ, O’Donovan MC (2006) Evidence that interaction between neuregulin 1 and its receptor erbB4 increases susceptibility to schizophrenia. Neuropsychiatr Genet 141B:96–101CrossRefGoogle Scholar
  55. Palmatier MA, Kang AM, Kidd KK (1999) Global variation in the frequencies of functionally different catechol-O-methyltransferase alleles. Biol Psychiatry 46:557–567PubMedCrossRefGoogle Scholar
  56. Prasad KM, Chowdari KV, Nimgaonkar VL, Talkowski ME, Lewis DA, Keshavan MS (2005) Genetic polymorphisms of the RGS4 and dorsolateral prefrontal cortex morphometry among first episode schizophrenia patients. Mol Psychiatry 10:213–219PubMedCrossRefGoogle Scholar
  57. Risch N, Baron M (1984) Segregation analysis of schizophrenia and related disorders. Am J Hum Genet 36:1039–1059PubMedGoogle Scholar
  58. Risch N (1990) Genetic linkage and complex diseases, with special reference to psychiatric disorders. Genet Epidemiol 7:3–16PubMedCrossRefGoogle Scholar
  59. Schumacher J, Abon Jamra R, Fruedenberg J, Becker T, Ohlraun S, Otte ACJ, Tullius M, Kovalenka S, Van Den Bogaert A, Maier W, Rietschel M, Propping P, Nöthen MM, Cichon S (2004) Examination of G72 and d-amino-acid oxidase as genetic risk factors for schizophrenia and bipolar affective disorder. Mol Psychiatry 9:203–207PubMedCrossRefGoogle Scholar
  60. Self SG, Mauritsen RH, O’Hara J (1992) Power calculations for likelihood ratio tests in generalized linear models. Biometrics 48:31–39CrossRefGoogle Scholar
  61. Shifman S, Bronstein M, Sternfeld M, Pisante-Shalom A, Lev-Lehman E, Weizman A, Reznik I, Spivak B, Grisaru N, Karp L, Schiffer R, Kotler M, Strous RD, Swartz-Vanetik M, Knobler HY, Shinar E, Beckmann JS, Yakir B, Risch N, Zak NB, Darvasi A (2002) A highly significant association between a COMT haplotype and schizophrenia. Am J Hum Genet 71:1296–1302PubMedCrossRefGoogle Scholar
  62. Shifman S, Bronstein M, Sternfeld M, Pisante A, Weizman A, Reznik I, Spivak B, Grisaru N, Karp L, Schiffer R, Kotler M, Strous RD, Swartz-Vanetik M, Knobler HY, Shinar E, Yakir B, Zak NB, Darvasi A (2004) COMT: a common susceptibility gene in bipolar disorder and schizophrenia. Am J Med Genet B Neuropsychiatr Genet 128:61–64PubMedCrossRefGoogle Scholar
  63. Shprintzen RJ, Goldberg RB, Young D, Wolford L (1981) The velo-cardio-facial syndrome: a clinical and genetic analysis. Pediatrics 67:167–172PubMedGoogle Scholar
  64. Smolka MN, Schumann G, Wrase J, Grusser SM, Flor H, Mann K, Braus DF, Goldman D, Buchel C, Heinz A (2005) Catechol-O-methyltransferase val158met genotype affects processing of emotional stimuli in the amygdala and prefrontal cortex. J Neurosci 25:836–842PubMedCrossRefGoogle Scholar
  65. Sobell JL, Richard C, Wirshing DA, Heston LL (2005) Failure to confirm association between RGS4 haplotypes and schizophrenia in Caucasians. Am J Med Genet B Neuropsychiatry Genet 139B:23–27CrossRefGoogle Scholar
  66. Stefansson H, Sigurdsson E, Steinthrosdottir V, Bjornsdottir S, Sigmundsson T, Ghosh S, Bynjolfsson J (2002) Neuregulin 1 and susceptibility to schizophrenia. Am J Hum Genet 71:877–892PubMedCrossRefGoogle Scholar
  67. Stephens M, Smith NJ, Donnelly P (2001) A new statistical method for haplotype reconstruction from population data. Am J Human Genet 68:978–989CrossRefGoogle Scholar
  68. Stephens M, Donnelly P (2003) A comparison of bayesian methods for haplotype reconstruction. Am J Human Genet 73:1162–1169CrossRefGoogle Scholar
  69. Straub RE, Lipska BK, Egan MF, Goldberg TE, Callicott JH, Mayhew MB, Kolachana B, Vakkalanka R, Kleinman JE, Weinberger DR. Allelic variation in GAD1 (GAD67) is associated with schizophrenia and influences cortical function and gene expression. Mol Psychiatry (in press)Google Scholar
  70. Sullivan PF, O’Neill FA, Walsh D, Ma Y, Kendler KS, Straub RE (1996) Analysis of epistasis in linked regions in the Irish study of high-density schizophrenia families. Am J Med Genet (Neuropsychiatr Genet) 67:179–190CrossRefGoogle Scholar
  71. Talkowski ME, Seltman H, Bassett AS, Brzustowicz LM, Chen X, Chowdari KV, Collier DA Meta-analysis of RGS4 polymorphisms with schizophrenia using genotypes of 13,807 individuals from 13 independent samples. Biol Psychiatry (in press)Google Scholar
  72. Tan H-Y, Chen Q, Sust S, Buckholtz JW, Kolachana B, Straub R, Mattay VS, Meyer-Lindenberg A, Egan MF, Weinberger DR, Callicott JH Evidence of biologic epistasis between COMT and GRM3 on human prefrontal function during working memory (submitted)Google Scholar
  73. Thompson PA, Wray NR, Millar JK, Evans KL, Le Hellard S, Condle A, Muir WJ, Blackwood DHR, Porteous DJ (2005) Association between the TRAX/DISC locus and both bipolar disorder and schizophrenia in the Scottish population. Mol Psychiatry 10:657–668CrossRefGoogle Scholar
  74. Tunbridge EM, Harrison PJ, Weinberger DR (2006) Catechol-o-methyltransferase, cognition and psychosis: Val158Met and beyond. Biol Psychiatry Feb 11 [Epub ahead of print]Google Scholar
  75. Wang X, He G, Gu N, Yang J, Tang J, Chen Q, Liu X, Shen Y, Qian X, Lin W, Duan Y, Feng G, He L (2004) Association of G72/G30 with schizophrenia in the Chinese population. Biochem Biophys Res Commun 319:1281–1286PubMedCrossRefGoogle Scholar
  76. Weinberger DR, Egan MF, Bertolino A, Callicott JH, Mattay VS, Lipska BK, Berman KF, Goldberg TE (2001) Prefrontal neurons and the genetics of schizophrenia. Biol Psychiatry 50:825–844PubMedCrossRefGoogle Scholar
  77. Williams GV, Goldman-Rakic PS (1995) Modulation of memory fields by dopamine D1 receptors in prefrontal cortex. Nature 376:572–575PubMedCrossRefGoogle Scholar
  78. Williams NM, Preece A, Spurlock G, Norton N, Williams HJ, McCreadie RG, Buckland P, Sharkey V, Chowdari KV, Zammit S, Nimgaonkar V, Kirov G, Owen MJ, O’Donovan MC (2004) Support for RGS4 as a susceptibility gene for schizophrenia. Biol Psychatry 55:195–195Google Scholar
  79. Winterer G, Weinberger DR (2004) Genes, dopamine and cortical signal-to-noise ratio in schizophrenia. Trends Neurosci 27:683–690PubMedCrossRefGoogle Scholar
  80. Zhang F, St Clair D, Liu X, Sun X, Sham PC, Crombie C, Ma X, Wang Q, Meng H, Deng W, Yates P, Hu X, Walker N, Murray RM, Collier DA, Li T (2005) Association analysis of RGS4 gene in Han Chinese and Scottish populations with schizophrenia. Genes Brain Behav 4:444–448PubMedCrossRefGoogle Scholar
  81. Zhang X, Tochigi M, Ohashi J, Maeda M, Kato T, Okazaki Y, Kato N, Tokunaga K, Sawa A, Sasaki T (2005) Association study of the DISC1/TRAX locus with schizophrenia in a Japanese population. Schizophr Res 79:175–180PubMedCrossRefGoogle Scholar
  82. Zhao LP, Li SS, Khalid N (2003) A method for the assessment of disease associations with single-nucleotide polymorphism haplotypes and environmental variables in case-control studies. Am J Hum Genet 72:1231–1250PubMedCrossRefGoogle Scholar
  83. Zou F, Li C, Duan S, Zheng Y, Gu N, Feng G, Xing Y, Shi J, He L (2005) A family-based study of the association between the G72/G30 genes and schizophrenia in the Chinese population. Schizophr Res 73:257–261PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2006

Authors and Affiliations

  • Kristin K. Nicodemus
    • 1
    • 2
  • Bhaskar S. Kolachana
    • 1
  • Radhakrishna Vakkalanka
    • 1
  • Richard E. Straub
    • 1
  • Ina Giegling
    • 3
  • Michael F. Egan
    • 1
  • Dan Rujescu
    • 3
  • Daniel R. Weinberger
    • 1
    • 4
  1. 1.Clinical Brain Disorders Branch, National Institute of Mental HealthNational Institute of HealthBethesdaUSA
  2. 2.Department of EpidemiologyJohns Hopkins Bloomberg School of Public HealthBaltimoreUSA
  3. 3.Molecular and Clinical Neurobiology, Department of PsychiatryLudwig Maximilians UniversityMunichGermany
  4. 4.Genes, Cognition and Psychosis ProgramIRP, NIMH, NIHBethesdaUSA

Personalised recommendations