Skip to main content
SpringerLink
Log in

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

  • Original Investigation
  • Published:
Human Genetics Aims and scope Submit manuscript

Abstract

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  • Electronic database information, Online Mendelian Inheritance in Man: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db = OMIM

  • 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 20:70–73

    Article  PubMed  CAS  Google Scholar 

  • 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 73:152–161

    Article  PubMed  CAS  Google Scholar 

  • Brown BW, Lovato J, Russell K (1999) Asymptotic power calculations: description, examples, computer code. Stat Med 18:3137–3151

    Article  PubMed  CAS  Google Scholar 

  • 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 58:901–907

    Article  PubMed  CAS  Google Scholar 

  • 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)

  • 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 102:8627–8632

    Article  PubMed  CAS  Google Scholar 

  • 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 62:1205–1213

    Article  PubMed  CAS  Google Scholar 

  • 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 62:473–481

    Article  PubMed  Google Scholar 

  • 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 75:807–821

    Article  PubMed  CAS  Google Scholar 

  • 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:23–26

    Article  Google Scholar 

  • 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 73:21–26

    Article  PubMed  Google Scholar 

  • 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 7:658–664

    Article  PubMed  CAS  Google Scholar 

  • 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 51:3–9

    Article  Google Scholar 

  • 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 11:1373–1380

    Article  PubMed  CAS  Google Scholar 

  • 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 99:13675–13680

    Article  PubMed  CAS  Google Scholar 

  • 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 4:45–50

    Article  PubMed  CAS  Google Scholar 

  • 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 26:167–185

    Article  PubMed  Google Scholar 

  • 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]

  • 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 111:521–537

    Article  PubMed  CAS  Google Scholar 

  • 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)

  • 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 157:1309–1316

    Article  PubMed  CAS  Google Scholar 

  • 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 98:6917–6922

    Article  PubMed  CAS  Google Scholar 

  • 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 101:12604–12609

    Article  PubMed  CAS  Google Scholar 

  • 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 57:139–144

    Article  PubMed  CAS  Google Scholar 

  • 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 York

    Google Scholar 

  • 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 York

    Google Scholar 

  • 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 13:71–76

    Article  PubMed  Google Scholar 

  • 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 163:469–476

    Article  Google Scholar 

  • 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 60:889–896

    Article  PubMed  CAS  Google Scholar 

  • 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]

  • 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):15–2

    Google Scholar 

  • 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 10:589–597

    Article  PubMed  CAS  Google Scholar 

  • Harrison PJ, Weinberger DR (2005) Schizophrenia genes, gene expression, and neuropathology: on the matter of their convergence. Mol Psychiatry 10:40–68

    Article  PubMed  CAS  Google Scholar 

  • 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 23:3151–3159

    Article  Google Scholar 

  • 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 75:862–872

    Article  PubMed  CAS  Google Scholar 

  • Horvath S, Xu X, Laird NM (2001) The family based association test method: strategies for studying general genotype–phenotype associations. Eur J Hum Genet 9:301–306

    Article  PubMed  CAS  Google Scholar 

  • 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 56:169–176

    Article  PubMed  CAS  Google Scholar 

  • 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 7:97–101

    Article  PubMed  CAS  Google Scholar 

  • Li SS, Khalid N, Carlson C, Zhao LP (2003) Estimating haplotype frequencies and standard errors for multiple single nucleotide polymorphisms. Biostatistics 4:513–522

    Article  PubMed  Google Scholar 

  • 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 5:77–84

    Article  PubMed  CAS  Google Scholar 

  • 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. 11

  • 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 33:177–182

    Article  PubMed  CAS  Google Scholar 

  • Longmate JA (2001) Complexity and power in case-control association studies. Am J Hum Genet 68:1229–1237

    Article  PubMed  CAS  Google Scholar 

  • 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 34:4202–4210

    Article  PubMed  CAS  Google Scholar 

  • 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 114:46–50

    Article  Google Scholar 

  • 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 100:6186–6191

    Article  PubMed  CAS  Google Scholar 

  • McGuigan FE, Ralston SH (2002) Single nucleotide polymorphism detection: allelic discrimination using TaqMan. Psychiatr Genet 12:133–136

    Article  PubMed  Google Scholar 

  • 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 8:594–596

    Article  PubMed  CAS  Google Scholar 

  • 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]

  • 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 125:50–53

    Article  PubMed  Google Scholar 

  • 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 10:431–433

    Article  PubMed  CAS  Google Scholar 

  • 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 5:5–23

    Article  Google Scholar 

  • 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:96–101

    Article  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  • 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 10:213–219

    Article  PubMed  CAS  Google Scholar 

  • Risch N, Baron M (1984) Segregation analysis of schizophrenia and related disorders. Am J Hum Genet 36:1039–1059

    PubMed  CAS  Google Scholar 

  • Risch N (1990) Genetic linkage and complex diseases, with special reference to psychiatric disorders. Genet Epidemiol 7:3–16

    Article  PubMed  CAS  Google Scholar 

  • 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 9:203–207

    Article  PubMed  CAS  Google Scholar 

  • Self SG, Mauritsen RH, O’Hara J (1992) Power calculations for likelihood ratio tests in generalized linear models. Biometrics 48:31–39

    Article  Google Scholar 

  • 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 71:1296–1302

    Article  PubMed  CAS  Google Scholar 

  • 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 128:61–64

    Article  PubMed  Google Scholar 

  • Shprintzen RJ, Goldberg RB, Young D, Wolford L (1981) The velo-cardio-facial syndrome: a clinical and genetic analysis. Pediatrics 67:167–172

    PubMed  CAS  Google Scholar 

  • 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 25:836–842

    Article  PubMed  CAS  Google Scholar 

  • 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:23–27

    Article  Google Scholar 

  • 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 71:877–892

    Article  PubMed  Google Scholar 

  • Stephens M, Smith NJ, Donnelly P (2001) A new statistical method for haplotype reconstruction from population data. Am J Human Genet 68:978–989

    Article  CAS  Google Scholar 

  • Stephens M, Donnelly P (2003) A comparison of bayesian methods for haplotype reconstruction. Am J Human Genet 73:1162–1169

    Article  CAS  Google Scholar 

  • 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)

  • 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) 67:179–190

    Article  Google Scholar 

  • 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)

  • 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)

  • 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 10:657–668

    Article  Google Scholar 

  • Tunbridge EM, Harrison PJ, Weinberger DR (2006) Catechol-o-methyltransferase, cognition and psychosis: Val158Met and beyond. Biol Psychiatry Feb 11 [Epub ahead of print]

  • 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 319:1281–1286

    Article  PubMed  CAS  Google Scholar 

  • 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 50:825–844

    Article  PubMed  CAS  Google Scholar 

  • Williams GV, Goldman-Rakic PS (1995) Modulation of memory fields by dopamine D1 receptors in prefrontal cortex. Nature 376:572–575

    Article  PubMed  CAS  Google Scholar 

  • 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 55:195–195

    Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  • 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 4:444–448

    Article  PubMed  CAS  Google Scholar 

  • 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 79:175–180

    Article  PubMed  Google Scholar 

  • 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 72:1231–1250

    Article  PubMed  CAS  Google Scholar 

  • 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 73:257–261

    Article  PubMed  Google Scholar 

Download references

Acknowledgments

GlaxoSmithKline supported the recruitment of the German patients.

Author information

Authors and Affiliations

  1. Clinical Brain Disorders Branch, National Institute of Mental Health, National Institute of Health, Bethesda, MD, USA

    Kristin K. Nicodemus, Bhaskar S. Kolachana, Radhakrishna Vakkalanka, Richard E. Straub, Michael F. Egan & Daniel R. Weinberger

  2. Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA

    Kristin K. Nicodemus

  3. Molecular and Clinical Neurobiology, Department of Psychiatry, Ludwig Maximilians University, Munich, Germany

    Ina Giegling & Dan Rujescu

  4. Genes, Cognition and Psychosis Program, IRP, NIMH, NIH, Rm. 4S-235, 10 Center Drive, Bethesda, MD, 20892, USA

    Daniel R. Weinberger

Authors
  1. Kristin K. Nicodemus
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Bhaskar S. Kolachana
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Radhakrishna Vakkalanka
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Richard E. Straub
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Ina Giegling
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Michael F. Egan
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Dan Rujescu
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Daniel R. Weinberger
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Daniel R. Weinberger.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Nicodemus, K.K., Kolachana, B.S., Vakkalanka, R. et al. Evidence for statistical epistasis between catechol-O-methyltransferase (COMT) and polymorphisms in RGS4, G72 (DAOA), GRM3, and DISC1: influence on risk of schizophrenia. Hum Genet 120, 889–906 (2007). https://doi.org/10.1007/s00439-006-0257-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00439-006-0257-3

Keywords

Search

Navigation