Interactive effects of DAOA (G72) and catechol-O-methyltransferase on neurophysiology in prefrontal cortex

Devon C. Nixon, Morgan J. Prust, Fabio Sambataro, Hao Yang Tan, Venkata S. Mattay, Daniel R. Weinberger, Joseph H. Callicott

Research output: Contribution to journalArticlepeer-review

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 × 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.

Original languageEnglish (US)
Pages (from-to)1006-1008
Number of pages3
JournalBiological psychiatry
Volume69
Issue number10
DOIs
StatePublished - May 15 2011
Externally publishedYes

Keywords

  • Dopamine
  • efficiency
  • fMRI
  • glutamate
  • prefrontal
  • working memory

ASJC Scopus subject areas

  • Biological Psychiatry

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