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  • Title: Interactive effects of DAOA (G72) and catechol-O-methyltransferase on neurophysiology in prefrontal cortex.
    Author: Nixon DC, Prust MJ, Sambataro F, Tan HY, Mattay VS, Weinberger DR, Callicott JH.
    Journal: Biol Psychiatry; 2011 May 15; 69(10):1006-8. PubMed ID: 21215384.
    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.
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