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

ABSTRACT 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.

  • [Show abstract] [Hide abstract]
    ABSTRACT: Associations of polymorphisms from dopaminergic neurotransmitter pathway genes have mostly been reported in Caucasian ancestry schizophrenia (SZ) samples. As studies investigating single SNPs with SZ have been inconsistent, more detailed analyses utilizing multiple SNPs with the diagnostic phenotype as well as cognitive function may be more informative. Therefore, these analyses were conducted in a north Indian sample. Indian SZ case-parent trios (n = 601 families); unscreened controls (n = 468) and an independent set of 118 trio families were analyzed. Representative SNPs in the Dopamine D3 receptor (DRD3), dopamine transporter (SLC6A3), vesicular monoamine transporter 2 (SLC18A2), catechol-o-methyltransferase (COMT) and dopamine beta-hydroxylase (DBH) were genotyped using SNaPshot/SNPlex assays (n = 59 SNPs). The Trail Making Test (TMT) was administered to a subset of the sample (n = 260 cases and n = 302 parents). Eight SNPs were nominally associated with SZ in either case-control or family based analyses (p < 0.05, rs7631540 and rs2046496 in DRD3; rs363399 and rs10082463 in SLC18A2; rs4680, rs4646315 and rs9332377 in COMT). rs6271 at DBH was associated in both analyses. Haplotypes of DRD3 SNPs incorporating rs7631540-rs2134655-rs3773678-rs324030-rs6280-rs905568 showed suggestive associations in both case-parent and trio samples. At SLC18A2, rs10082463 was nominally associated with psychomotor performance and rs363285 with executive functions using the TMT but did not withstand multiple corrections. Suggestive associations with dopaminergic genes were detected in this study, but convincing links between dopaminergic polymorphisms and SZ or cognitive function were not observed.
    Journal of Psychiatric Research 08/2013; 47(11). DOI:10.1016/j.jpsychires.2013.07.007 · 4.09 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    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.
    Schizophrenia Research 09/2013; DOI:10.1016/j.schres.2013.08.009 · 4.43 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Methylphenidate (MPH) reduces hyperactive-impulsive symptoms common in children with autism spectrum disorders (ASDs), however, response and tolerability varies widely. We hypothesized monoaminergic gene variants may moderate MPH effects in ASD, as in typically developing children with attention-deficit/hyperactivity disorder. Genotype data were available for 64 children with ASD and hyperactivity who were exposed to MPH during a 1-week safety/tolerability lead-in phase and 58 who went on to be randomized to placebo and three doses of MPH during a 4-week blinded, crossover study. Outcome measures included the Clinical Global Impression-Improvement (CGI-I) scale and the Aberrant Behavior Checklist (ABC-hyperactivity index). A total of 14 subjects discontinued the study because of MPH side effects. Subjects were genotyped for variants in DRD1-DRD5, ADRA2A, SLC6A3, SLC6A4, MAOA and MAOB, and COMT. Forty-nine percent of the sample met positive responder criteria. In this modest but relatively homogeneous sample, significant differences by DRD1 (P=0.006), ADRA2A (P<0.02), COMT (P<0.04), DRD3 (P<0.05), DRD4 (P<0.05), SLC6A3 (P<0.05) and SLC6A4 (P<0.05) genotypes were found for responders versus non-responders. Variants in DRD2 (P<0.001) and DRD3 (P<0.04) were associated with tolerability in the 14 subjects who discontinued the trial. For this first MPH pharmacogenetic study in children with ASD, multiple monoaminergic gene variants may help explain individual differences in MPH's efficacy and tolerability.The Pharmacogenomics Journal advance online publication, 16 July 2013; doi:10.1038/tpj.2013.23.
    The Pharmacogenomics Journal 07/2013; DOI:10.1038/tpj.2013.23 · 5.51 Impact Factor