Altered Effect of Dopamine Transporter 3′UTR VNTR Genotype on Prefrontal and Striatal Function in Schizophrenia

Prata, Diana; Mechelli, Andrea; Picchioni, Marco; Fu, Cynthia H.Y.; Toulopoulou, Timothea; Bramon, Elvira; Walshe, Muriel; Murray, Robin M.; Collier, David; McGuire, Philip

doi:10.1001/archgenpsychiatry.2009.147

Cited by 37 publications

(34 citation statements)

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“…We have previously reported the separate effects of COMT Val158Met and DAT 3Ј UTR VNTR genotype on fronto-temporal cortical activation during verbal fluency and the main effect of task and of diagnosis in this sample (27,84). Both genes regulate brain dopaminergic transmission, and both polymorphisms are functional, in that they lead to differences in gene expression and/or protein function (13)(14)(15)(16)(17)(19)(20)(21)(22).…”

Section: Discussionmentioning

confidence: 88%

“…In respect to DAT 3Ј UTR VNTR, significant main effects of genotype were found in the activation of the left anterior insula (Ϫ30 6 16, Z ϭ 3.5 and Ϫ34 14 Ϫ6, Z ϭ 3.2) and the right caudate nucleus (22 4 20, Z ϭ 3.2) reflecting greater activation in 10/10-repeat than 9-repeat carriers. A significant diagnosis by genotype interaction was detected in the left middle frontal gyrus (Ϫ42 44 24, Z ϭ 2.8) and the nucleus accumbens (Ϫ6 6 Ϫ10, Z ϭ 3.1), with greater activation in 9-repeat than 10/10-repeat carriers in schizophrenia, but not in healthy controls (84).…”

Section: Resultsmentioning

confidence: 99%

“…This observation suggests that the impact of variation in the COMT and DAT genes on regional brain activation might differ in patients compared with healthy controls. We have recently verified this hypothesis for both COMT and DAT, with variation in each gene associated with a different pattern of activation during verbal fluency in patients and controls (27,84). Interestingly, both DAT and COMT genes are strong candidate susceptibility genes for schizophrenia given their biological role, but there is lack of consensus between genetic association studies with a similar number of positive and negative studies reported for each gene.…”

mentioning

confidence: 84%

“…Variation in the functional Val158Met polymorphism within COMT is associated with significant differences in both the performance of cognitive tasks (23)(24)(25)(26), including verbal fluency (27), and the pattern of cortical activation during their execution (24,(27)(28)(29)(30)(31)(32). Similarly, functional neuroimaging studies of the DAT 3Ј UTR VNTR in healthy subjects suggest that this gene modulates cortical activation during working memory (12) and verbal fluency (84). Also, 2 neuroimaging studies have reported additive interactions between the effects of COMT Val158Met and of DAT 3Ј UTR VNTR on activation in the prefrontal cortex during working memory tasks (12,33).…”

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confidence: 99%

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Epistasis between the DAT 3′ UTR VNTR and the COMT Val158Met SNP on cortical function in healthy subjects and patients with schizophrenia

Prata

Mechelli

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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Dopamine has a crucial role in the modulation of neurocognitive function, and synaptic dopamine activity is normally regulated by the dopamine transporter (DAT) and catechol-O-methyltransferase (COMT). Perturbed dopamine function is a key pathophysiological feature of schizophrenia. Our objectives were (i) to examine epistasis between the DAT 3 UTR variable number of tandem repeats (VNTR) and COMT Val158Met polymorphisms on brain activation during executive function, and (ii) to then determine the extent to which such interaction is altered in schizophrenia. Regional brain response was measured by using blood-oxygen-level-dependent fMRI during an overt verbal fluency task in 85 subjects (44 healthy volunteers and 41 patients with DSM-IV schizophrenia), and inferences were estimated by using an ANOVA in SPM5. There was a significant COMT ؋ DAT nonadditive interaction effect on activation in the left supramarginal gyrus, irrespective of diagnostic group (Z-score ‫؍‬ 4.3; familywise error (FWE) p ‫؍‬ 0.03), and in healthy volunteers alone (Z-score ‫؍‬ 4.7; FWEp ‫؍‬ 0.006). In this region, relatively increased activation was detected only when COMT Met-158/Met-158 subjects also carried the 9-repeat DAT allele, or when, reversely, Val-158/Val-158 subjects carried the 10/10-repeat genotype. Also, there was a significant diagnosis ؋ COMT ؋ DAT nonadditive interaction in the right orbital gyrus (Z-score ‫؍‬ 4.3; FWEp ‫؍‬ 0.04), where, only within patients, greater activation was only associated with a 9-repeat allele and Val-158 conjunction, and with a 10-repeat and Met-158 conjunction (Z-score ‫؍‬ 4.3; FWE p ‫؍‬ 0.04). These data demonstrate that COMT and DAT genes interact nonadditively to modulate cortical function during executive processing, and also, that this effect is significantly altered in schizophrenia, which may reflect abnormal dopamine function in the disorder.

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Section: Discussionmentioning

confidence: 88%

Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 84%

mentioning

confidence: 99%

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Epistasis between the DAT 3′ UTR VNTR and the COMT Val158Met SNP on cortical function in healthy subjects and patients with schizophrenia

Prata

Mechelli

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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“…Although not expressing high levels of DAT, the frontal cortex is connected to the striatum via the corticothalamostriatal loop, and activation of the prefrontal cortex in healthy controls is influenced by variation in the DAT 3′ UTR VNTR genotype (Bertolino et al, 2006;Caldú et al, 2007;Yacubian et al, 2007). In schizophrenia patients, who are characterized by elevated striatal dopamine activity, increased prefrontal activation in 9R (vs. 10R patients and 9R/10R controls) allele carriers during executive processing is believed to result from increased local dopamine levels and D 2 R stimulation, which inhibits thalamic input into the prefrontal cortex, leading to a marked reduction in S/N ratio and cortical efficiency (Prata et al, 2009). While this baseline-dependent dopaminergic mechanism may play a role in the abnormal P50 gating seen in schizophrenia, it is possible that DAT activity in our healthy control 9R allele carriers may have stimulated striatal D 2 Rs to a level that produces a thalamically-mediated optimal prefrontal S/N ratio that benefits a more efficient top-down processing (i.e.…”

Section: Discussionmentioning

confidence: 99%

The moderating role of the dopamine transporter 1 gene on P50 sensory gating and its modulation by nicotine

et al. 2011

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Although schizophrenia has been considered primarily a disease of dopaminergic neurotransmission, the role of dopamine in auditory sensory gating deficits in this disorder and their amelioration by smoking/nicotine is unclear. Hypothesizing that individual differences in striatal dopamine levels may moderate auditory gating and its modulation by nicotine, this preliminary study used the mid-latency (P50) auditory event-related potential (ERP) to examine the single dose (6 mg) effects of nicotine (vs. placebo) gum on sensory gating in 24 healthy nonsmokers varying in the genetic expression of the dopamine transporter (DAT). Consistent with an inverted-U relationship between dopamine level and the drug effects, individuals carrying the 9R (lower gene expression) allele, which is related to greater striatal dopamine levels, tended to evidence increased baseline gating compared to 10R (higher gene expression) allele carriers and showed a reduction in gating with acute nicotine. The present results may help to understand the link between excessive smoking and sensory gating deficits in schizophrenia and to explain the potential functional implications of genetic disposition on nicotinic treatment in schizophrenia. Keywords schizophrenia; P50; gating; dopamine transporter gene; nicotine; smoking Early theoretical models of information processing in schizophrenia postulated impairment in the preattentive, automatic processing of sensory input to be a contributing factor in the appearance of psychotic symptoms, perceptual disturbances, and various cognitive deficits that characterize this disorder (Venables, 1964). Meta-analyses and reviews of event-related potential (ERP) studies probing auditory sensory gating in a paired stimulus paradigm (involving the presentation two [ CIHR Author Manuscript CIHR Author Manuscript CIHR Author Manuscriptfound that ~90% of patients with schizophrenia as well as ~50% of their first-degree relatives exhibit insufficient inhibitory processing of repetitive, irrelevant acoustic stimuli (Bramon et al., 2004;De Wilde et al., 2007;Patterson et al., 2008). Typically assessed with the amplitude of the early (50 ms) positive ERP component, P50, abnormal auditory sensory gating has been evidenced by a relative inability to suppress P50 to S 2 , and is expressed by larger S 2 /S 1 ratio (rP50) and/or smaller S 1 minus S 2 difference (dP50) scores.Smoking and acute nicotine have transiently corrected deficient P50 processing in schizophrenia patients and their relatives, respectively (Adler et al., 1992(Adler et al., , 1993. In addition, in a rodent model of schizophrenia-like gating deficiency, studies assessing the P20-N40 ERP, which is an analogue of the human P50, have shown agonists and antagonists of the α7 nicotinic receptor to improve deficient S 2 inhibition and to block normal S 2 inhibition, respectively (Stevens et al., 1998(Stevens et al., , 1999Simosky et al., 2001). Other studies reporting gating improvements with nicotine in rodents and humans, however, have found increa...

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Fine‐mapping reveals novel alternative splicing of the dopamine transporter

Talkowski

McCann

Chen

et al. 2010

American J of Med Genetics Pt B

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The dopamine transporter gene (SLC6A3, DAT) has been implicated in the pathogenesis of numerous psychiatric and neurodevelopmental disorders, including schizophrenia (SZ). We previously detected association between SZ and intronic SLC6A3 variants that replicated in two independent Caucasian samples, but had no obvious function. In follow‐up analyses, we sequenced the coding and intronic regions of SLC6A3 to identify complete linkage disequilibrium patterns of common variations. We genotyped 78 polymorphisms, narrowing the potentially causal region to two correlated clusters of associated SNPs localized predominantly to introns 3 and 4. Our computational analysis of these intronic regions predicted a novel cassette exon within intron 3, designated E3b, which is conserved among primates. We confirmed alternative splicing of E3b in post‐mortem human substantia nigra (SN). As E3b introduces multiple in‐frame stop codons, the SLC6A3 open reading frame is truncated and the spliced product may undergo nonsense mediated decay. Thus, factors that increase E3b splicing could reduce the amount of unspliced product available for translation. Observations consistent with this prediction were made using cellular assays and in post‐mortem human SN. In mini‐gene constructs, the extent of splicing is also influenced by at least two common haplotypes, so the alternative splicing was evaluated in relation to SZ risk. Meta‐analyses across genome‐wide association studies did not support the initial associations and further post‐mortem studies did not suggest case‐control differences in splicing. These studies do not provide a compelling link to schizophrenia. However, the impact of the alternative splicing on other neuropsychiatric disorders should be investigated. © 2010 Wiley‐Liss, Inc.

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Altered Effect of Dopamine Transporter 3′UTR VNTR Genotype on Prefrontal and Striatal Function in Schizophrenia

Cited by 37 publications

References 104 publications

Epistasis between the DAT 3′ UTR VNTR and the COMT Val158Met SNP on cortical function in healthy subjects and patients with schizophrenia

Epistasis between the DAT 3′ UTR VNTR and the COMT Val158Met SNP on cortical function in healthy subjects and patients with schizophrenia

The moderating role of the dopamine transporter 1 gene on P50 sensory gating and its modulation by nicotine

Fine‐mapping reveals novel alternative splicing of the dopamine transporter

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