Gene-gene interaction associated with neural reward sensitivity

NeuroImage Nord, Department of Systems Neuroscience, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246 Hamburg, Germany.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 06/2007; 104(19):8125-30. DOI: 10.1073/pnas.0702029104
Source: PubMed


Reward processing depends on dopaminergic neurotransmission and is modulated by factors affecting dopamine (DA) reuptake and degradation. We used fMRI and a guessing task sensitive to reward-related activation in the prefrontal cortex and ventral striatum to study how individual variation in genes contributing to DA reuptake [DA transporter (DAT)] and degradation [catechol-o-methyltransferase (COMT)] influences reward processing. Prefrontal activity, evoked by anticipation of reward irrespective of reward probability and magnitude, was COMT genotype-dependent. Volunteers homozygous for the Met allele, associated with lower enzyme activity and presumably greater DA availability, showed larger responses compared with volunteers homozygous for the Val allele. A similar COMT effect was observed in the ventral striatum. As reported previously, the ventral striatum was also found to code gain-related expected value, i.e., the product of reward magnitude and gain probability. Individual differences in ventral striatal sensitivity for value were in part explained by an epistatic gene-gene interaction between COMT and DAT. Although most genotype combinations exhibited the expected activity increase with more likely and larger rewards, two genotype combinations (COMT Met/Met DAT 10R and COMT Val/Val 9R) were associated with blunted ventral striatal responses. In view of a consistent relationship between reduced reward sensitivity and addiction, our findings point to a potential genetic basis for vulnerability to addiction.

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    • "Developmental Review (2014), models assume that the number of initial ''hits'' determines outcome, multiplicative models account for the dynamic nature of functional brain development by assuming that a few initial factors interact and amplify (or decrease) each other's effects during development. Multiplicative effects of gene–gene interaction on brain function (Yacubian et al., 2007) and behavior (Lakatos et al., 2003), have been described. One should be reminded, nonetheless, that the multivariate models we described above are based on the premise that there is a unitary autism phenotype, varying only in severity. "
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    ABSTRACT: A fast growing field, the study of infants at risk because of having an older sibling with autism (i.e. infant sibs) aims to identify the earliest signs of this disorder, which would allow for earlier diag-nosis and intervention. More importantly, we argue, these studies offer the opportunity to validate existing neuro-developmental models of autism against experimental evidence. Although autism is mainly seen as a disorder of social interaction and communica-tion, emerging early markers do not exclusively reflect impairments of the ''social brain''. Evidence for atypical development of sensory and attentional systems highlight the need to move away from localized deficits to models suggesting brain-wide involvement in autism pathology. We discuss the implications infant sibs findings have for future work into the biology of autism and the development of interventions. Ó 2014 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY license ( licenses/by/3.0/).
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    • "Further studies have shown epistatic (i.e. gene-gene) interactions between COMT and DAT during cognitive tasks [Bertolino et al., 2008; Caldu et al., 2007; Prata et al., 2009b; Yacubian et al., 2007]. G72 regulates glutamatergic transmission, by activating D-amino acid oxidase (DAAO), which modulates the metabolism of D-amino acids like D-serine, a coagonist for the NMDA glutamate receptor [Boks et al., 2007]. "
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    ABSTRACT: The genes for the dopamine transporter (DAT) and the D-Amino acid oxidase activator (DAOA or G72) have been independently implicated in the risk for schizophrenia and in bipolar disorder and/or their related intermediate phenotypes. DAT and G72 respectively modulate central dopamine and glutamate transmission, the two systems most robustly implicated in these disorders. Contemporary studies have demonstrated that elevated dopamine function is associated with glutamatergic dysfunction in psychotic disorders. Using functional magnetic resonance imaging we examined whether there was an interaction between the effects of genes that influence dopamine and glutamate transmission (DAT and G72) on regional brain activation during verbal fluency, which is known to be abnormal in psychosis, in 80 healthy volunteers. Significant interactions between the effects of G72 and DAT polymorphisms on activation were evident in the striatum, parahippocampal gyrus, and supramarginal/angular gyri bilaterally, the right insula, in the right pre-/postcentral and the left posterior cingulate/retrosplenial gyri (P < 0.05, FDR-corrected across the whole brain). This provides evidence that interactions between the dopamine and the glutamate system, thought to be altered in psychosis, have an impact in executive processing which can be modulated by common genetic variation. Hum Brain Mapp, 2012. © 2012 Wiley Periodicals, Inc.
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    • "One study showed increased activation of the dorsolateral PFC and ventral striatum (areas implicated in the anticipation of reward) and in the orbitofrontal cortex at the time of reward delivery in Met/Met homozygotes (Dreher et al., 2009 ) compared to the Val allele participants. A Similar pattern of results was previously observed in another study of reward processing (Yacubian et al., 2007). One study showed an opposite allelic effect (Camara et al., 2010), in the medial PFC (anterior cingulate) and ventral striatum, but using a slightly different paradigm involving unexpected rewards. "
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    ABSTRACT: Depression is a common and disabling psychiatric disorder with a complex etiology, which includes predisposing risk genes and environmental stressors. Variation in the Catechol-O-Methyltransferase (COMT) gene, the Val158Met polymorphism in particular, has been extensively investigated in relation to clinical phenotypes of depression and, in parallel, neurocognitive processes. In this review, we bridge evidence from neuroimaging, behavioral and clinical studies that have examined the role of COMT variants on depression-relevant phenotypes. We observed that clinical phenotypes such as depression severity and diagnosis, or behavioral endophenotypes, are less reliably associated with COMT genetic variation. On the other hand, genetic effects are more discernible on brain systems of emotional processing. Specifically, the Met allele is associated with increased activity in limbic areas and prefrontal cortex, but is also more likely to have a better response to antidepressant treatment, compared to the Val allele. Gender and stress are important modulators of COMT genetic effects. On the basis of current evidence, we propose a tentative pathway through which the COMT gene may influence cognitive vulnerability to depression.
    No preview · Article · Jun 2013 · Neuroscience & Biobehavioral Reviews
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