A review and analysis of the relationship between neuropsychological measures and DAT1 in ADHD

Department of Clinical Neuropsychology, VU University Amsterdam, Amsterdam, The Netherlands.
American Journal of Medical Genetics Part B Neuropsychiatric Genetics (Impact Factor: 3.42). 12/2008; 147B(8):1536-46. DOI: 10.1002/ajmg.b.30848
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Meta-analyses indicate that the gene coding for the dopamine transporter (DAT1 or SLC6A3) is associated with an increased risk for ADHD. The mechanisms of this gene for ADHD are unclear. We systematically reviewed studies linking the VNTR in the 3' UTR of the DAT1 to neurophysiological and neuropsychological measures. In addition, a broad set of executive/cognitive and motor tests was administered to 350 children (5-11 years) and adolescents (11-19 years) with ADHD and 195 non-affected siblings. Two VNTRs (in intron 8 and the 3' UTR) and four SNPs (two 5' and two 3') in DAT1 were genotyped. The effect of the polymorphisms on neuropsychological functioning was studied. The review indicated that the majority of studies did not find a relation between DAT1 and neurophysiological or neuropsychological measures. In our sample, several of the polymorphisms of DAT1 were associated with ADHD and ADHD was associated with impaired neuropsychological functioning. However, none of the DAT1 polymorphisms was convincingly associated with neuropsychological dysfunctioning. This suggests that the effect of DAT1 on ADHD was not mediated by neuropsychological performance. However, since DAT1 is mainly expressed in the striatum and not the prefrontal cortex, it may influence striatum-related functions (such as delay aversion) more heavily than prefrontal related functions (such as executive functions). Associations of DAT1 with ADHD were only found in adolescents, which may suggest that DAT1 mainly exerts its effect in adolescence, and/or that having a more persistent form of ADHD may mark a more severe or homogeneous genetic form of the disorder.

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Available from: Alejandro Arias-Vásquez, Sep 30, 2015
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    • "This decreased availability of DAT likely leads to increased availability of striatal dopamine in the synaptic cleft. In line with these findings, evidence from behavioral genetic studies shows that the DAT VNTR 9-repeat allele is associated with better working memory (Brehmer et al., 2009) and episodic memory (Li, Papenberg, et al., 2013; Schott et al., 2006), although some studies did not replicate such an association (Boonstra et al., 2008; Rommelse et al., 2008). Of particular interest, Simon and collaborators (Simon et al., 2011) reported an association between implicit learning and the DAT VNTR genotype, with 9-repeat carriers learning more than 10/10 homozygotes in an sequential triplet learning task. "
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    ABSTRACT: The striatum and medial temporal lobe play important roles in implicit and explicit memory, respectively. Furthermore, recent studies have linked striatal dopamine modulation to both implicit as well as explicit sequence learning and suggested a potential role of the striatum in the emergence of explicit memory during sequence learning. With respect to aging, previous findings indicated that implicit memory is less impaired than explicit memory in older adults and that genetic effects on cognition are magnified by aging. To understand the links between these findings, we investigated effects of aging and genotypes relevant for striatal dopamine on the implicit and explicit components of sequence learning. Reaction time (RT) and error data from 80 younger (20-30 years) and 70 older adults (60-71 years) during a serial reaction time task showed that age differences in learning-related reduction of RTs emerged gradually over the course of learning. Verbal recall and measures derived from the process-dissociation procedure revealed that younger adults acquired more explicit memory about the sequence than older adults, potentially causing age differences in RT gains in later stages of learning. Of specific interest, polymorphisms of the dopamine- and cAMP-regulated neuronal phosphoprotein (DARPP-32, rs907094) and dopamine transporter (DAT, VNTR) genes showed interactive effects on overall RTs and verbal recall of the sequence in older but not in younger adults. Together our findings show that variations in genotypes relevant for dopamine functions are associated more with aging-related impairments in the explicit than the implicit component of sequence learning, providing support for theories emphasizing the role of dopaminergic modulation in cognitive aging and the magnification of genetic effect in human aging.
    Neuropsychologia 09/2013; 51(13). DOI:10.1016/j.neuropsychologia.2013.09.009 · 3.30 Impact Factor
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    • "Guided by research indicating that the 10-repeat (10-R) allele of the DAT 3 " UTR VNTR is associated with higher dopamine transporter expression and dopamine reduction in the synaptic cleft (Rommelse et al., 2008), we subsequently classified children into three groups: (0) two copies of 10-R, (1) one copy of 10-R, and (2) no copies of 10-R. Based on studies linking the C allele of the remaining two DAT genes with greater impulsivity, hyperactivity, and inattention (Gizer, Ficks, & Waldman, 2009; Soderqvist et al., in press), genotypes for rs27072 and rs40184 were quantified as (0) two copies of the C allele, (1) one copy of the C allele (C/T), and (2) no copies of the C allele (T/T). "
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    ABSTRACT: Guided by evolutionary game theory (Korte, Koolhaas, Wingfield, & McEwen, 2005), this study aimed to identify the genetic precursors and the psychosocial sequelae of inhibited temperament in a sociodemographically disadvantaged and racially diverse sample (N = 201) of 2-year-old children who experienced elevated levels of domestic violence. Using a multimethod, prospective design across 3 annual measurement occasions, the authors conducted structural equation modeling analyses indicating that trained observer ratings of inhibited temperament at age 2 were uniquely predicted by polymorphisms in dopamine and serotonin transporter genes. Children's inhibited temperament, in turn, indirectly predicted decreases in their externalizing problems at age 4 through its association with greater behavioral flexibility at age 3. Results highlight the value of integrating evolutionary and developmental conceptualizations in more comprehensively charting the developmental cascades of inhibited temperament. (PsycINFO Database Record (c) 2013 APA, all rights reserved).
    Developmental Psychology 03/2013; 49(12). DOI:10.1037/a0032312 · 3.21 Impact Factor
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    • "The higher availability of DAT in 10-repeat homozygotes might result in increased clearance of synaptic DA, and thus lower striatal synaptic DA levels. Consistent with the DA-cognition link, an advantage of 9-repeat carriers in executive functions (Loo et al., 2003), working memory (Brehmer et al., 2009), episodic memory (Schott et al., 2006), and sequential learning (Simon et al., 2011) has been reported, although some studies have failed to demonstrate such an association (Boonstra et al., 2008; Rommelse et al., 2008). The C957T (rs6277) single nucleotide polymorphism (SNP) of D2 receptor gene (DRD2) affects messenger RNA (mRNA) stability. "
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    ABSTRACT: Aging compromises dopamine transporter (DAT) and receptor mechanisms in the frontostriatal circuitry. In a sample of 1288 younger and older adults, we investigated (i) whether individual differences in genotypes of the DAT gene (i.e., SLC6A3, the DAT variable number of tandem repeat 9/9, 9/10, and 10/10) and in the D2 receptor (DRD2) gene (i.e., the C957T [rs6277] CC and any T) interactively contribute to phenotype variations in episodic memory performance; and (ii) whether these genetic effects are magnified in older adults, because of considerable declines in the dopamine functions. Our results showed that carrying genotypes associated with higher levels of striatal synaptic dopamine (DAT 9/9) and higher density of extrastriatal D2 receptors (C957T CC) were associated with better backward serial recall, an episodic memory task with high encoding and retrieval demands. Critically, the gene-gene interaction effect was reliably stronger in older than in younger adults. In line with the resource modulation hypothesis, our findings suggest that aging-related decline in brain phenotypes (e.g., dopamine functions) could alter the relations between genotypes and behavioral phenotypes (e.g., episodic memory).
    Neurobiology of aging 01/2013; DOI:10.1016/j.neurobiolaging.2012.08.001 · 5.01 Impact Factor
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