title: Interactive effects of DAOA (G72) and catechol-O-methyltransferase on neurophysiology in prefrontal cortex.
abstract: BACKGROUND
  Accumulating evidence indicates that genetic polymorphisms of D-amino acid oxidase activator (DAOA) (M24; rs1421292; T-allele) and catechol-O-methyltransferase (COMT) (Val¹⁵⁸Met; rs4680) likely enhance susceptibility to schizophrenia. Previously, clinical association between DAOA M24 (T-allele) and a functionally inefficient 3-marker COMT haplotype (that included COMT Val¹⁵⁸Met) uncovered epistatic effects on risk for schizophrenia. Therefore, we projected that healthy control subjects with risk genotypes for both DAOA M24 (T/T) and COMT Val¹⁵⁸Met (Val/Val) would produce prefrontal inefficiency, a critical physiological marker of the dorsolateral prefrontal cortex (DLPFC) in schizophrenic patients influenced by both familial and heritable factors.
  
  
  METHODS
  With 3T blood oxygen level dependent functional magnetic resonance imaging data, we analyzed in SPM5 the proposed interaction of DAOA and COMT in 82 healthy volunteers performing an N-back executive working memory paradigm (2-back > 0-back).
  
  
  RESULTS
  As predicted, we detected a functional gene x gene interaction between DAOA and COMT in the DLPFC.
  
  
  CONCLUSIONS
  The neuroimaging findings here of inefficient information processing in the prefrontal cortex seem to echo prior statistical epistasis between risk alleles for DAOA and COMT, albeit within a small sample. These in vivo results suggest that deleterious genotypes for DAOA and COMT might contribute to the pathophysiology of schizophrenia, perhaps through combined glutamatergic and dopaminergic dysregulation.
authors.affiliation: Clinical Brain Disorders Branch, Division of Intramural Research Programs, National Institute of Mental Health, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland 20892, USA.
authors.forename: Devon C
authors.initials: DC
authors.lastname: Nixon
authors.forename: Morgan J
authors.initials: MJ
authors.lastname: Prust
authors.forename: Fabio
authors.initials: F
authors.lastname: Sambataro
authors.forename: Hao-Yang
authors.initials: HY
authors.lastname: Tan
authors.forename: Venkata S
authors.initials: VS
authors.lastname: Mattay
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Weinberger
authors.forename: Joseph H
authors.initials: JH
authors.lastname: Callicott
mesh_terms: D000328:Adult; D000704:Analysis of Variance; D002352:Carrier Proteins / Q000235:genetics*; D002394:Catechol O-Methyltransferase / Q000235:genetics*; D005260:Female; D005838:Genotype; D006801:Humans; D007091:Image Processing, Computer-Assisted / Q000379:methods; D047908:Intracellular Signaling Peptides and Proteins; D008279:Magnetic Resonance Imaging / Q000379:methods; D008297:Male; D008570:Memory, Short-Term / Q000502:physiology*; D008715:Methionine / Q000235:genetics; D009483:Neuropsychological Tests; D010100:Oxygen / Q000097:blood; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D017397:Prefrontal Cortex / Q000098:blood supply / Q000502:physiology*; D011930:Reaction Time / Q000235:genetics; D014633:Valine / Q000235:genetics; D055815:Young Adult
chemical_list: D002352:Carrier Proteins; C475071:DAOA protein, human; D047908:Intracellular Signaling Peptides and Proteins; D008715:Methionine; D002394:Catechol O-Methyltransferase; D014633:Valine; D010100:Oxygen