Association of the dopamine transporter (DAT1) 10/10-repeat genotype with ADHD symptoms and response inhibition in a general population sample

Cornish, Kim; Manly, Tom; Savage, Robert; Swanson, James M.; Morisano, Dominique; Butler, Neville; Grant, Colin A.; Cross, Gareth; Bentley, L. Gordon; Hollis, Chris

doi:10.1038/sj.mp.4001641

Cited by 196 publications

(187 citation statements)

References 81 publications

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“…availability) in 10R (vs. 9R) allele carriers (Jacobsen et al, 2000;Fuke et al, 2001;Mill et al, 2002; Heinz et al, 2000) who, presumably, would evidence relatively decreased striatal dopamine tone. The SLC6A3/DAT1 genotype has been related to a range of mental processes, including cognitive control/attentional functions (Cornish et al, 2005;Cools, 2008;Cools and D'Esposito, 2006) and reward related processes (Dreher et al, 2009;Colzato et al, 2010), as well as the early sensory and higher order processing of acoustic novelty, as reflected in the N1 and nP3 ERPs, respectively (Garcia-Garcia et al, 2010a,b). Although the majority of data have demonstrated no differences in striatal DAT expression or DAT1 polymorphisms in schizophrenia (vs. controls), striatal DAT availability has been inversely correlated with auditory hallucinations in the acute illness (Schmitt et al, 2006), and DAT1 gene polymorphisms have been shown to play a significant role in response to clozapine (Xu et al, 2010).…”

Section: Cihr Author Manuscriptmentioning

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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Section: Cihr Author Manuscriptmentioning

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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“…In contrast, association with these gene variants for ADHD trait measures have either not been consistently detected or have been very much weaker, 20 or researchers have imposed cut-points on their quantitative measure to generate extreme categories (e.g. Payton et al 21 and Cornish et al 22 ). However, there are some exceptions 23 and the weakness of evidence may be because there have been fewer QTL studies.…”

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confidence: 99%

Refining the attention deficit hyperactivity disorder phenotype for molecular genetic studies

et al. 2006

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It is well established that attention deficit hyperactivity disorder (ADHD) is a familial and highly heritable disorder. Consequently, much effort is being directed towards searching for specific susceptibility genes. There is a growing trend, across the field of complex disease genetics, towards undertaking secondary analyses based on refined phenotypic definitions and in testing whether specific susceptibility genes modify the phenotypic presentation of the disorder in question. It is crucial that good, empirically derived arguments are made before undertaking multiple analyses on different phenotype refinements. In this review article, we consider the evidence from genetic epidemiological studies as well as key clinical studies that provide guidance on examining the ADHD phenotype for the purpose of molecular genetic studies. Specifically, findings on categorical versus dimensional conceptualisations of ADHD, reporter effects, comorbidity, ADHD subtypes and persistence are reviewed. Current evidence suggests that for the purpose of identifying susceptibility genes for ADHD, parent and teachers should be used as informants and that focusing on the clinical diagnosis of ADHD is useful. There is also good empirical support in favour of examining antisocial behaviour in ADHD. Genetic studies of dimensional ADHD are useful for other complementary purposes.

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“…25,27,29,34 This approach, originally suggested by Lander and Botstein 35 in the context of linkage studies, has been recommended as an efficient and effective means of detecting association with quantitative traits in large groups of subjects. [25][26][27][28][29] The power of this method depends on a number of factors, including the size of the original group, the cutoff points for selecting from the upper and lower ends of the phenotype distribution, the allele frequencies, the mode of inheritance, and the proportion of phenotypic variance explained by the polymorphism.…”

Section: Discussionmentioning

confidence: 99%

Selective Genotyping Reveals Association Between the Epithelial Sodium Channel γ-Subunit and Systolic Blood Pressure

et al. 2007

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Abstract-Systolic blood pressure is determined in large part by genes. Six independent studies have reported evidence of linkage between systolic pressure and chromosome 16p12 that incorporates SCNN1G, the gene encoding the ␥-subunit of the epithelial sodium channel. We undertook the first comprehensive association analysis of SCNN1G and systolic pressure. To achieve genetic contrast, we sampled unrelated subjects within the upper (mean: 166 mm Hg; nϭ96) and lower (mean: 98 mm Hg; nϭ94) 10% of the systolic pressure distribution of 2911 subjects from the Victorian Family Heart Study. We examined genotypes and haplotypes related to 26 single nucleotide polymorphisms across SCNN1G and its promoter. Each of 3 single nucleotide polymorphisms (rs13331086, rs11074553, and rs4299163) in introns 5 and 6 showed evidence of association with systolic pressure in logistic regression analyses adjusted for age, sex, and body mass index. Considered as a haplotype block, these single nucleotide polymorphisms were significantly associated with systolic pressure (haplo.score global: Pϭ0.0001). In permutation analyses to account for multiple testing, a result such as this was observed only once in 10 000 permutations. The estimated frequency of 1 haplotype (TGC) was substantially greater in high (13.3%) than low (0.6%) systolic pressure subjects (Pϭ0.0001). Three other haplotypes (TGG, TAC, and GGC) showed associations with high or low systolic pressure consistent with the observed associations of their composite alleles. These findings identify relatively common polymorphisms in the SCNN1G gene that are associated with high systolic blood pressure in the general Australian white population. (Hypertension. 2007;50:672-678.)

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Association of the dopamine transporter (DAT1) 10/10-repeat genotype with ADHD symptoms and response inhibition in a general population sample

Cited by 196 publications

References 81 publications

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

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

Refining the attention deficit hyperactivity disorder phenotype for molecular genetic studies

Selective Genotyping Reveals Association Between the Epithelial Sodium Channel γ-Subunit and Systolic Blood Pressure

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