Genotype Influences In Vivo Dopamine Transporter Availability in Human Striatum

Heinz, Andreas

doi:10.1016/s0893-133x(99)00099-8

Cited by 510 publications

(409 citation statements)

References 45 publications

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“…For instance, subjects homozygous for the 10-repeat (10R) allele of a polymorphism of the dopamine transporter gene (DAT1) show significantly lower dopamine transporter binding in striatum than carriers of the 9-repeat (9R) allele. 26,27 This is consistent with suggestions that this polymorphism may affect the translational efficiency and thus the amount of protein expressed, resulting in less in vivo availability of the transporter. 28 In addition, the DAT1 10R has been associated with poor response to methylphenidate (MPH) in ADHD.…”

supporting

confidence: 91%

“…On Differential effects of genotype on gray matter volumes S Durston et al average, subjects homozygous for the 10R allele have smaller caudate nucleus volumes (see Figure 2). The more common 10R allele has been associated with reduced dopamine transporter activity, 26,27 suggesting that smaller caudate volumes may be related to a reduction in gene expression in these individuals. It appears therefore that the effect of the 10R allele may be to bias caudate volume towards the lower end of the distribution, possibly related to reduced expression of the dopamine transporter gene in these individuals (see Figure 1).…”

Section: Discussionmentioning

confidence: 99%

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Differential effects of DRD4 and DAT1 genotype on fronto-striatal gray matter volumes in a sample of subjects with attention deficit hyperactivity disorder, their unaffected siblings, and controls

et al. 2005

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Genetic influences on behavior are complex and, as such, the effect of any single gene is likely to be modest. Neuroimaging measures may serve as a biological intermediate phenotype to investigate the effect of genes on human behavior. In particular, it is possible to constrain investigations by prior knowledge of gene characteristics and by including samples of subjects where the distribution of phenotypic variance is both wide and under heritable influences. Here, we use this approach to show a dissociation between the effects of two dopamine genes that are differentially expressed in the brain. We show that the DAT1 gene, a gene expressed predominantly in the basal ganglia, preferentially influences caudate volume, whereas the DRD4 gene, a gene expressed predominantly in the prefrontal cortex, preferentially influences prefrontal gray matter volume in a sample of subjects including subjects with ADHD, their unaffected siblings, and healthy controls. This demonstrates that, by constraining our investigations by prior knowledge of gene expression, including samples in which the distribution of phenotypic variance is wide and under heritable influences, and by using intermediate phenotypes, such as neuroimaging, we may begin to map out the pathways by which genes influence behavior. Investigators interested in the effect of genes on behavior face a challenge in that behavior is complex, and is likely affected by multiple genes, as well as gene-gene and gene-environment interactions. As such, the effect of any single gene on behavior is probably only small. Indeed, studies investigating the effect of genotype on behavior have reported modest associations. For example, Fossella et al 1 described the influence of four genes related to dopamine function on measures of executive attention and report small effect sizes. Furthermore, their effects were subtle in that not all aspects of executive attention were affected and that genes had differential effects. 1

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supporting

confidence: 91%

Section: Discussionmentioning

confidence: 99%

Differential effects of DRD4 and DAT1 genotype on fronto-striatal gray matter volumes in a sample of subjects with attention deficit hyperactivity disorder, their unaffected siblings, and controls

et al. 2005

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“…The DAT1 3 0 -UTR VNTR may be functional, or may be in high linkage disequilibrium with a functional variant, and consequently predict stimulant response. Heinz et al (2000) reported that individuals with the 9-/10-repeat genotype had a 22% reduction of DAT protein availability in putamen compared to 10/10 homozygous individuals, and speculated that stimulant effects would be most pronounced in the 10/10 homozygous individuals for whom DAT protein appears to be more abundant. These findings were not replicated in two other studies (Jacobsen et al, 2000;Martinez et al, 2001).…”

Section: Discussionmentioning

confidence: 99%

Dopamine Transporter Genotype and Methylphenidate Dose Response in Children with ADHD

Stein

Waldman

Sarampote

et al. 2005

Neuropsychopharmacol

130

117

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Stimulant medications, such as methylphenidate (MPH), are the most commonly used, effective treatment for ADHD. MPH acts primarily by inhibiting the dopamine transporter (DAT), a protein responsible for the reuptake of dopamine from the synapse into presynaptic terminals. We sought to evaluate the relationship between DAT1 3 0 -untranslated region (3 0 -UTR) variable number tandem repeats (VNTR) genotypes and dose response to MPH. Children with ADHD (n ¼ 47), ages 5-16 years (mean ¼ 9.02 years), underwent a 4-week, double-blinded, crossover trial with forced weekly dosage changes. Children were genotyped for the DAT1 VNTR and evaluated on placebo and three dosage levels of OROS s MPH. Parents and clinicians who were blind to genotype and medication status rated ADHD symptoms, impairment, and stimulant side effects each week. Children who were homozygous for the less common, 9-repeat DAT1 3 0 -UTR genotype displayed a distinct dose-response curve from that of the other genotype groups, with an absence of typical linear improvement when the dose was increased from 18 mg to 36 and 54 mg. Further research is needed to determine the mechanisms related to poor response in patients with the 9/9-repeat genotype, and to determine if this group responds differentially to alternative treatments.

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“…It has been recently suggested that the 480bp DAT1 (10 repeat allele) allele may be associated with a hyperactive dopamine transporter . A functional brain imaging study (Heinz et al 2000) demonstrated that abstinent alcoholics heterozygous for the 10 repeat DAT1 allele had less (22%) putamen dopamine transporter availability compared with those who were homozygous. As the 10 repeat allele is considered to be the high-risk allele in ADHD, it is possible that individuals with this allele have increased transporter density, which may lead to a depletion of dopamine from critical synaptic regions.…”

Section: The Contribution Of Molecular Genetic Studies To a Dopamine mentioning

confidence: 99%

“…The evidence we have presented for DAT1 supports a theory of decreased dopamine neurotransmission in ADHD. In particular, findings from a number of neuroimaging and animal studies (Heinz et al 2000;Krause et al 2000;Jaber et al 1999;Tannock et al 1998) suggest that hypodopaminergic function in the striatum may be involved in mediating the symptoms and neurocognitive abnormalities displayed in ADHD. There are fewer studies examining the role of the other genes, and their contribution to the neurobiology of ADHD is unclear.…”

Section: The Contribution Of Molecular Genetic Studies To a Dopamine mentioning

confidence: 99%

Dopaminergic System Genes in ADHD Toward a Biological Hypothesis

Kirley

Hawi

Daly

et al. 2002

Neuropsychopharmacology

107

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Converging evidence has implicated abnormalities of dopamine neurotransmission to the pathology of attention deficit hyperactivity disorder (ADHD).Attention Deficit Hyperactivity Disorder (ADHD) is a common condition of childhood affecting 3-6% of school age children worldwide (Barkley 1990), with males being affected three times more than females (Anderson et al. 1987; Baumgartel et al. 1995). Its core clinical features include excessive motor activity, impaired attention, and impulsivity. ADHD causes marked educational, social, and family difficulties for sufferers and their relatives. The condition is of early onset (usually before age 7) and tends to persist throughout childhood. Moreover, approximately 30-60% of children with ADHD have persisting psychopathology in adulthood (Gittelman et al. 1985;Weiss and Hechtman 1986; Barkley 1990;Swanson et al. 1998a). The exact etiology of ADHD is Received March 8, 2001; revised February 12, 2002; accepted February 20, 2002. Online publication: 2/28/02 at www.acnp.org/citations/ Npp022802254. 608 A. Kirley et al. N EUROPSYCHOPHARMACOLOGY 2002 -VOL . 27 , NO . 4 unknown, but a substantial genetic element exists. This has been demonstrated by family (Biederman et al. 1990(Biederman et al. , 1992Faraone et al., 1992Faraone et al., , 1994, twin (Thapar et al. 1995;Silberg et al. 1996;Levy et al. 1997), and adoption studies (Alberts-Corush et al. 1986; Cadoret and Stewart 1991). The heritability (h 2 ) of ADHD has been estimated to be .50-.98 (Gjone et al. 1996;Levy et al. 1997). The exact mode of transmission remains unknown. Segregation analyses (Morrison and Steward 1974;Deutsch et al. 1990, Faraone et al. 1992, Hess et al. 1995 have proposed models of inheritance from major gene effects through oligogenic to polygenic and multifactorial models, but the differences in statistical "fit" between multifactorial genetic models and single gene inheritance is modest. The multifactorial concept is consistent with ADHD's high population prevalence (2-7%), high concordance in monozygotic twins (68-81%), but modest recurrence risks to first-degree relatives.Dysregulation in catecholamine neurotransmission is implicated in the pathophysiology of ADHD (Faraone and Biederman 2002). The dopaminergic neurotransmitter system has been most extensively studied. This article will focus mainly on its role in the etiology of ADHD. Evidence to support dopaminergic dysfunction in ADHD derives from three research areas: the neuropharmacology of stimulant medication (Zametkin and Rapoport 1987; Amara and Kuhar 1993), the behavior and biochemistry of animal models (Giros et al. 1996;Gainetdinov et al. 1999, Russell 2000, and neuroimaging studies in ADHD adults (Dougherty et al. 1999, Krause et al. 2000, and Faraone and Biederman 2002. For this reason, many molecular genetic studies have focused on dopamine system genes.The gene encoding the dopamine transporter, DAT1, was the initial candidate gene studied. This gene is of particular interest, as the transporter is the principal target...

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Genotype Influences In Vivo Dopamine Transporter Availability in Human Striatum

Cited by 510 publications

References 45 publications

Differential effects of DRD4 and DAT1 genotype on fronto-striatal gray matter volumes in a sample of subjects with attention deficit hyperactivity disorder, their unaffected siblings, and controls

Differential effects of DRD4 and DAT1 genotype on fronto-striatal gray matter volumes in a sample of subjects with attention deficit hyperactivity disorder, their unaffected siblings, and controls

Dopamine Transporter Genotype and Methylphenidate Dose Response in Children with ADHD

Dopaminergic System Genes in ADHD Toward a Biological Hypothesis

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