Interaction of dopamine system genes and cognitive functions in patients with schizophrenia and their relatives and in healthy subjects from the general population

Scientific Center for Mental Health, Russian Academy of Medical Sciences, Moscow.
Neuroscience and Behavioral Physiology 10/2007; 37(7):643-50. DOI: 10.1007/s11055-007-0064-x
Source: PubMed


Linkage between the DRD4 and COMT genes and cognitive measures characterizing verbal memory, executive functions, and associative processes was studied in 150 patients with schizophrenia, 83 of their relatives, and 118 mentally healthy subjects without any family history of psychoses, with the aim of detecting the main effects of the polymorphic markers -809G/A and -521C/T (DRD4) and Val158Met (COMT) when present individually and together. The group of patients showed a main effect for polymorphism -521C/T on verbal fluency and an effect of the interaction of this polymorphism and the COMT gene on this cognitive trait. The highest level of verbal fluency was seen among carriers of the Val/Val+CC and Met/Met+TT genotypes. In the combined group of unaffected individuals, the interaction of the COMT and DRD4 -521C/TT genotypes had an effect on the standardness of speech associations due to a decrease in the standardness of associations in carriers of the Met/Met+CC genotype. Finally, both patients and unaffected individuals showed an effect for the interaction between the COMT and DRD4 -809G/A genotypes on working memory. Patients and healthy subjects showed similar features: the highest values were seen in subjects homozygous for the Val and G alleles, while the lowest values were seen in homozygotes for the Met and A alleles. These data provide evidence for a relationship between the DRD4 and COMT genes and different aspects of executive functions and the absence of such a relationship in relation to verbal memory.

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    • "Aberrant functional and structural connectivity between corticostriatal structures are increasingly implicated in psychiatric phenomena (Quan et al., 2013; Shepherd, 2013), and have recently been associated with executive dysfunctions in working memory (WM; Fornito et al., 2012). Impaired WM is a promising endophenotypic candidate for schizophrenia, having filled a number of requirements for endophenotypic status (Gottesman and Gould, 2003): that is, the WM deficit is associated with illness, evident in unaffected relatives (Snitz et al., 2006; Gur et al., 2007), associated with an identifiable brain network (Bertolino et al., 2006; Ceaser et al., 2012), and there have been many replications of genetic association of the catechol-O-methyltransferase (COMT) Val158Met polymorphism with WM performance (Alfimova et al., 2007; Lopez-Garcia et al., 2012). However, there remains ambiguity with respect to the precise neurophysiological substrate of WM dysfunction , partly owing to mixed findings of hypo-and hyper-activation of frontal brain networks during WM performance in schizophrenia that have now accumulated in the literature (Eisenberg and Berman, 2010), and partly owing to the emergence of recent studies highlighting the importance of cortico-striatal connectivity for WM dysfunction (Meda et al., 2009; Satterthwaite et al., 2012). "
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    ABSTRACT: Working memory (WM) deficits and associated brain dysfunction are among the most well replicated candidate endophenotypic processes in schizophrenia. However, previous studies demonstrate inconsistent over- and under-activation of dorsolateral and ventrolateral prefrontal cortices (DLPFC; VLPFC), inferior parietal lobule (IPL) during WM performance, as well as subcortical structures including the striatum, and dysfunctional connectivity among fronto-striatal regions in schizophrenia. However, no previous study has investigated task-related functional connectivity (FC) of DLPFC and striatal regions using a seed-based method; here we employed this method to assess patterns of cortical and subcortical functional connectivity among WM structures during a standard 2-back WM task performed by 28 schizophrenia (SZ) and 28 healthy controls (HC). Initial group comparisons of blood oxygenation level dependent (BOLD) responses during the WM task revealed significantly greater bilateral activity in the striatum in SZ relative to HC, but there was no significant group difference in WM cortical activity (right DLPFC, VLPFC or IPL). Analyses of FC within the cortico-subcortical WM network in the HC group revealed positive performance-related FC between the right DLPFC and the right caudate, and between the right VLPFC and the right IPL; this pattern was absent in SZ. In contrast, SZ patients showed negative performance-related functional connectivity between the left putamen and the right VLPFC. Direct group comparisons in functional connectivity showed significantly greater performance-related FC between the VLPFC and bilateral putamen, as well as unilaterally between the VLPFC and the right IPL, in HC. Results suggest a critical dysfunction of cortico-striatal connectivity underpinning information retrieval for SZ patients during WM performance.
    Full-text · Article · Sep 2013 · Schizophrenia Research
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    • "Sambataro and coworkers (2009) demonstrated that the effect of Val108(158)Met polymorphism on activity and functional connectivity of brain regions involved in working memory network increases with age. There is also an evidence for a sexually dimorphic influence of COMT (Sazci et al. 2004, Harrison and Turnbridge 2008).The other polymorphisms of COMT are also postulated to have an influence on prefrontal cognitive functions (Meyer- Lindenberg et al. 2006, Diaz-Asper et al. 2008), as well as interaction between COMT and DRD4 (Alfimova et al. 2007) or DRD2 polymorphisms (Xu et al. 2007). "
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    ABSTRACT: Working memory is an ability to keep information in short-term memory and manipulate them 'on line'. Working memory is also involved in complex frontal executive functions. The role of dopaminergic system in modulating working memory processes in prefrontal cortex is well established. Also the role of serotoninergic receptors is postulated. The purpose of this study was to assess the association between the polymorphisms of dopaminergic (DRD1, DRD3, DRD4, COMT) and serotoninergic (SERT--serotonin transporter, 5HT2A, 5HT2C) genes' polymorphisms and performance on WCST in 200 volunteers from the Polish population. We found the association between DRD1, DRD4, COMT and SERT genes polymorphisms and the performance on WCST. The results obtained in the study indicate that dopaminergic and serotoninergic genes may play a role in modulating the executive function and working memory processes in healthy subjects. The pattern of this influence may be different in males and females. Moreover, the relationship between the efficacy of prefrontal cognitive function and genes polymorphisms may differ between healthy subjects and schizophrenic patients.
    Full-text · Article · Jan 2010 · Acta neurobiologiae experimentalis
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    • "Frontal lobe function composite score. Past studies have demonstrated that performance on certain tests thought to depend on frontal lobe function, such as working memory (Mehta et al., 2001; Erixon-Lindroth et al., 2005; Alfimova et al., 2007), verbal fluency (Erixon-Lindroth et al., 2005; Alfimova et al., 2007), and executive function (Vernaleken et al., 2007b; Lane et al., 2008), may be modulated by the dopamine system in healthy adults. Our neuropsychological battery contained seven tests of frontal lobe function: Listening Span (Daneman and Carpenter, 1980) and Digit Span (Wechsler, 1981), which measure working memory; Controlled "

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