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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    • "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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    • "Among them, the dopamine transporter gene (DAT1) has been consistently reported to be associated with ADHD across studies (Gizer et al., 2009; Shang et al., 2011), supporting the relevance of this gene for the pathophysiology of ADHD. Although Durston et al. (2008) have suggested that DAT1 effects in the striatum may be involved in translating the genetic risk of ADHD into a neurobiological substrate, the exact mechanisms of the effect of DAT1 on ADHD pathophysiology remain unclear (Rommelse et al., 2008). An endophenotypic approach has been proposed to improve the detection of genetic effects in ADHD (Castellanos and Tannock, 2002). "
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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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