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Interactive Effects of DAOA (G72) and Catechol-O-Methyltransferase on Neurophysiology in Prefrontal Cortex

  • Devon C. Nixon
    Affiliations
    Unit on Dynamic Imaging Genetics, 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

    Genes, Cognition and Psychosis Program, 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
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  • Morgan J. Prust
    Affiliations
    Unit on Dynamic Imaging Genetics, 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

    Genes, Cognition and Psychosis Program, 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
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  • Fabio Sambataro
    Affiliations
    Neuroimaging Core Facility, 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

    Genes, Cognition and Psychosis Program, 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
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  • Hao-Yang Tan
    Affiliations
    Unit on Dynamic Imaging Genetics, 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

    Genes, Cognition and Psychosis Program, 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
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  • Venkata S. Mattay
    Affiliations
    Neuroimaging Core Facility, 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

    Genes, Cognition and Psychosis Program, 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
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  • Daniel R. Weinberger
    Affiliations
    Genes, Cognition and Psychosis Program, 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
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  • Joseph H. Callicott
    Correspondence
    Address correspondence to Joseph H. Callicott, M.D., National Institute of Mental Health, National Institutes of Health, Department of Health and Human Services, 10 Center Drive, Room 3C-117, MSC 1379, Bethesda, Maryland 20892-1379
    Affiliations
    Unit on Dynamic Imaging Genetics, 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

    Genes, Cognition and Psychosis Program, 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
    Search for articles by this author

      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.

      Key Words

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      Linked Article

      • Dopamine-Glutamate Interactions: A Neural Convergence Mechanism of Common Schizophrenia Risk Variants
        Biological PsychiatryVol. 69Issue 10
        • Preview
          Schizophrenia research has been dominated by two, seemingly competitive neurotransmitter concepts. The historically older dopamine hypothesis (1) posits that exaggerated subcortical dopamine release, a phenomenon linked to prefrontal cortex dysfunction, is central to pathogenesis. The relatively younger glutamate hypothesis postulates a disruption of excitatory neural pathways through N-methyl-D-aspartate receptor hypofunction, which evokes a neural state that promotes psychosis and prefrontal cognitive deficits (2).
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