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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Article info
Publication history
Published online: January 10, 2011
Accepted:
October 29,
2010
Received in revised form:
October 28,
2010
Received:
March 26,
2010
Identification
Copyright
© 2011 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.
ScienceDirect
Access this article on ScienceDirectLinked Article
- Dopamine-Glutamate Interactions: A Neural Convergence Mechanism of Common Schizophrenia Risk VariantsBiological PsychiatryVol. 69Issue 10
- PreviewSchizophrenia 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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