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
Source: PubMed


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
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    • "The dopamine transporter clears the synapse of dopamine via dopamine reuptake into the presynaptic neuron. The first variant is rs40184; the C/C genotype is thought to confer risk for ADHD-like symptoms, including impulsivity (Caylak, 2012; Rommelse, 2008). This SNP was one of two DAT1 variants used in a similar design by Davies et al. (2014), wherein this variant and rs27072 moderated the mediation of maternal unresponsiveness on problem behaviors though increased uninhibited temperament. "
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    ABSTRACT: A model examining the effects of an increasing number of maltreatment subtypes experienced on antisocial behavior, as mediated by impulsivity and moderated by a polygenic index of dopaminergic genotypes, was investigated. An African American sample of children (N = 1,012, M age = 10.07) with and without maltreatment histories participated. Indicators of aggression, delinquency, and disruptive peer behavior were obtained from peer- and counselor-rated measures to form a latent variable of antisocial behavior; impulsivity was assessed by counselor report. Five genotypes in four dopaminergic genes (dopamine receptors D4, D2, known as DRD4, DRD2; dopamine active transporter 1, known as DAT1; and catechol-O-methyltransferase, known as COMT) conferring heightened environmental sensitivity were combined into one polygenic index. Using structural equation modeling, a first-stage, moderated-mediation model was evaluated. Age and sex were entered as covariates, both as main effects and in interaction with maltreatment and the gene index. The model had excellent fit: χ2 (32, N = 1,012) = 86.51, p < .001; comparative fit index = 0.982, Tucker-Lewis index = 0.977, root mean square error of approximation = 0.041, and standardized root mean square residual = 0.022. The effect of maltreatment subtypes on antisocial behavior was partially mediated by impulsivity (β = 0.173, p < .001), and these relations were moderated by the number of differentiating dopaminergic genotypes. Specifically, a significant Gene × Environment interaction (β = 0.016, p = .013) indicated that the relation between maltreatment and impulsivity was stronger as children evinced more differentiating genotypes, thereby strengthening the mediational effect of impulsivity on antisocial behavior. These findings elucidate the manner by which maltreated children develop early signs of antisocial behavior, and the genetic mechanisms involved in greater vulnerability for maladaptation in impulse control within the context of child maltreatment.
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    • "To conclude, we failed to observe a significant association of the SLC6A3 VNTR with cognitive function in healthy adults. This result is in agreement with a previous overview of such studies in patients with ADHD (Rommelse et al., 2008 ). Together, these negative findings , whilst of course not proving a lack of effect, are compatible with the interpretations that the VNTR may have (i) effects on cognition of only very small magnitude that were not detected in either analysis, (ii) effects on domains of cognitive function that were not measured here, (iii) effects on behaviour and cognition that emerge only when the system is challenged by interventions that act on the dopamine system (Kambeitz et al., 2014; Kasparbauer et al., 2015b) or (iv) effects on BOLD during cognitive task performance (Kasparbauer et al., 2015a). "
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    ABSTRACT: The gene coding for the dopamine transporter (DAT), SLC6A3, contains a 40-base pair variable number of tandem repeats (VNTR) polymorphism (rs28363170) in its 3' untranslated region. This VNTR has been associated with attention deficit hyperactivity disorder (ADHD) and has been investigated in relation to cognition and brain function. Here, we report the results of a comprehensive meta-analysis with meta-regression examining the association of the VNTR with different domains of cognition in healthy adults. We extracted data from 28 independent studies and carried out meta-analyses for associations with working memory (k=10 samples, N=1193 subjects), inhibition (k=8 samples, N=829 subjects), executive functions including inhibition (k=10 samples, N=984 subjects), attention (k=6 samples, N=742 subjects) and declarative long-term memory (k=5 samples, N=251 subjects). None of the investigated dimensions showed significant associations with the VNTR (all p>0.26). Meta-regression including year of publication, gender, age, ethnicity and percentage of 10R-homozygotes similarly did not attain significance. We conclude that there is no evidence that rs28363170 may be a significant predictor of cognitive function in healthy adults.
    No preview · Article · Nov 2015 · Neuroscience & Biobehavioral Reviews
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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.
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