title: Epistasis between COMT Val158Met and DRD3 Ser9Gly polymorphisms and cognitive function in schizophrenia: genetic influence on dopamine transmission.
abstract: OBJECTIVE
  To assess the relationship between cognitive function, a proposed schizophrenia endophenotype, and two genetic polymorphisms related to dopamine function, catechol-O-methyl transferase (COMT) Val158Met and dopamine receptor 3 (DRD3) Ser9Gly.
  
  
  METHODS
  Fifty-eight outpatients with schizophrenia/schizoaffective disorder and 88 healthy controls underwent neurocognitive testing and genotyping. Analyses of covariance (ANCOVAs) using age, sex, and years of education as covariates compared cognitive performance for the proposed genotypes in patients and controls. ANCOVAs also tested for the epistatic effect of COMT and DRD3 genotype combinations on cognitive performance.
  
  
  RESULTS
  For executive functioning, COMT Val/Val patients performed in a similar range as controls (30.70-33.26 vs. 35.53-35.67), but as COMT Met allele frequency increased, executive functioning worsened. COMT Met/Met patients carrying the DRD3 Ser/Ser genotype performed poorest (16.184 vs. 27.388-31.824). Scores of carriers of this COMT/DRD3 combination significantly differed from all DRD3 Gly/Gly combinations (p < 0.05), from COMT Val/Met DRD3 Ser/Gly (p = 0.02), and from COMT Val/Val DRD3 Ser/Ser (p = 0.01) in patients. It also differed significantly from all control scores (p < 0.001).
  
  
  CONCLUSIONS
  Combined genetic polymorphisms related to dopamine neurotransmission might influence executive function in schizophrenia. Looking at the effects of multiple genes on a single disease trait (epistasis) provides a comprehensive and more reliable way to determine genetic effects on endophenotypes.
authors.affiliation: Laboratory of Neuroscience, Department and Institute of Psychiatry, Faculty of Medicine, Universidade de São Paulo, São Paulo, SP, BR.
authors.forename: Alexandre A
authors.initials: AA
authors.lastname: Loch
authors.affiliation: Laboratory of Neuroscience, Department and Institute of Psychiatry, Faculty of Medicine, Universidade de São Paulo, São Paulo, SP, BR.
authors.forename: Martinus T
authors.initials: MT
authors.lastname: van de Bilt
authors.affiliation: Laboratory of Neuroscience, Department and Institute of Psychiatry, Faculty of Medicine, Universidade de São Paulo, São Paulo, SP, BR.
authors.forename: Danielle S
authors.initials: DS
authors.lastname: Bio
authors.affiliation: Laboratory of Neuroscience, Department and Institute of Psychiatry, Faculty of Medicine, Universidade de São Paulo, São Paulo, SP, BR.
authors.forename: Carolina M do
authors.initials: CM
authors.lastname: Prado
authors.affiliation: Laboratory of Neuroscience, Department and Institute of Psychiatry, Faculty of Medicine, Universidade de São Paulo, São Paulo, SP, BR.
authors.forename: Rafael T
authors.initials: RT
authors.lastname: de Sousa
authors.affiliation: Laboratory of Neuroscience, Department and Institute of Psychiatry, Faculty of Medicine, Universidade de São Paulo, São Paulo, SP, BR.
authors.forename: Leandro L
authors.initials: LL
authors.lastname: Valiengo
authors.affiliation: Mood Disorders Unit, Department and Institute of Psychiatry, Faculty of Medicine, USP, São Paulo, SP, BR.
authors.forename: Ricardo A
authors.initials: RA
authors.lastname: Moreno
authors.affiliation: Laboratory of Neuroscience, Department and Institute of Psychiatry, Faculty of Medicine, Universidade de São Paulo, São Paulo, SP, BR.
authors.forename: Marcus V
authors.initials: MV
authors.lastname: Zanetti
authors.affiliation: Laboratory of Neuroscience, Department and Institute of Psychiatry, Faculty of Medicine, Universidade de São Paulo, São Paulo, SP, BR.
authors.forename: Wagner F
authors.initials: WF
authors.lastname: Gattaz
mesh_terms: D000328:Adult; D000704:Analysis of Variance; D016022:Case-Control Studies; D002394:Catechol O-Methyltransferase / Q000235:genetics*; D003071:Cognition / Q000502:physiology*; D004522:Educational Status; D004843:Epistasis, Genetic; D056344:Executive Function / Q000502:physiology; D005260:Female; D005787:Gene Frequency; D056726:Genetic Association Studies; D006801:Humans; D008297:Male; D008875:Middle Aged; D009483:Neuropsychological Tests; D020641:Polymorphism, Single Nucleotide; D060888:Real-Time Polymerase Chain Reaction; D050637:Receptors, Dopamine D3 / Q000235:genetics*; D012559:Schizophrenia / Q000235:genetics* / Q000503:physiopathology; D055815:Young Adult
chemical_list: D050637:Receptors, Dopamine D3; D002394:Catechol O-Methyltransferase