Meta-Analysis of the Association Between the 7-Repeat Allele of the Dopamine D<sub>4</sub> Receptor Gene and Attention Deficit Hyperactivity Disorder

Faraone, Stephen V.; Doyle, Alysa E.; Mick, Eric; Biederman, Joseph

doi:10.1176/appi.ajp.158.7.1052

Cited by 682 publications

(465 citation statements)

References 28 publications

Supporting

Mentioning

429

Contrasting

Unclassified

Order By: Relevance

“…Further studies on chronically ill schizophrenia patients, aimed at quantitative assessments of specific cognitive functions and social functioning, are needed to adequately evaluate D 4 receptor as a potentially important therapeutic target. Genetic studies have strongly implicated D 4 receptor polymorphism in ADHD (La Hoste et al, 1996;Faraone et al, 2001). Using young rats with neonatal 6-hydroxydopamine lesions as a model for ADHD, we reported that locomotor hyperactivity in this model was inhibited by several selective D 4 antagonists as by the stimulant methylphenidate, but not antagonists that bind preferentially to the D 2 or 5-HT 2A receptor Zhang et al, 2001Zhang et al, , 2002.…”

Section: Discussionmentioning

confidence: 74%

Regulation of Working Memory by Dopamine D4 Receptor in Rats

Zhang

Grady

Tsapakis

et al. 2004

Neuropsychopharmacol

View full text Add to dashboard Cite

Working memory is regulated by neurotransmitters in prefrontal cortex (PFC), including dopamine and norepinephrine. Previous studies of dopamine function in working memory have focused on the D 1 and D 2 receptors, with most evidence suggesting a dominant role for the D 1 receptor. Since the dopamine D 4 receptor is highly expressed in PFC, we hypothesize that it may also contribute to working memory. To test this hypothesis, we examined behavioral effects of L-745,870, a highly selective, centrally active, D 4 antagonist, using a delayed alternation task in rats. Task performance was dose-dependently affected by the D 4 antagonist, depending on individual baseline functional status of working memory. In rats with good baseline performance, the D 4 antagonist had no effects at low doses, whereas high doses disrupted working memory. In rats with poor baseline working memory, the D 4 antagonist significantly improved working memory at low doses, and higher doses were not distinguishable from vehicle controls. Effects of the D 4 antagonist among poor performers were most robust when task demand for working memory was high, with lesser effects at lower demand level, suggesting that such effects were selective for working memory. The present findings indicate a significant role of the D 4 receptor in working memory, and suggest innovative, D 4 -based, treatment of cognitive deficits associated with neuropsychiatric disorders.

show abstract

Section: Discussionmentioning

confidence: 74%

Regulation of Working Memory by Dopamine D4 Receptor in Rats

Zhang

Grady

Tsapakis

et al. 2004

Neuropsychopharmacol

View full text Add to dashboard Cite

show abstract

“…This strategy has proven to be informative in the case of the 7-repeat DRD4 variant. Faraone et al (2001) concluded that in a meta-analysis of 22 studies, a small but highly significant association exists at DRD4. Future directions for molecular genetic studies in ADHD include increasing sample size and power by collaboration, coordinating usage of data collection instruments to allow for comparison between research groups, the use of meta-analysis, and a move toward better characterization of the ADHD phenotype.…”

Section: Integrating Our Results With Existing Workmentioning

confidence: 99%

“…To date, there have been 16 studies examining for association between the 7 repeat DRD4 polymorphism and ADHD, with positive results in many (LaHoste et al 1996;Swanson et al 1998b;Smalley et al 1998;Rowe et al 1998;Faraone et al 1999;Muglia et al 2000;Holmes et al 2000;Sunohara et al 2000;Tahir et al 2000a;Mill et al 2001), but not all (Castellanos et al 1998; Comings et al 1999;Eisenberg et al 2000;Hawi et al 2000a;Kotler et al 2000;Todd et al 2001) studies. A recent meta-analysis of DRD4 by Faraone et al 2001 supported an overall association (albeit small) between DRD4 and ADHD. Case-control studies were more strongly significant (OR ϭ 1.9, p ϭ .00000008) than familybased studies (OR ϭ 1.4, p ϭ .02).…”

mentioning

confidence: 98%

Dopaminergic System Genes in ADHD Toward a Biological Hypothesis

Kirley

Hawi

Daly

et al. 2002

Neuropsychopharmacology

106

View full text Add to dashboard Cite

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...

show abstract

“…[4][5][6][7][8] Various genetic studies using this polymorphism have implicated a seven-repeat allele in behavioral disorders, as for example, in novelty-seeking behavior and attention deficit hyperactivity disorder (ADHD). [9][10][11] The three most common polymorphic variants of the receptor, D4.2, D4.4 and D4.7, are functionally and pharmacologically nearly indistinguishable from each other. 6,8,12,13 However, mice deficient in D4 expression display increased anxiety 14 and altered exploratory behavior.…”

Section: Introductionmentioning

confidence: 99%

“…4 This particular variant is also associated in various studies with ADHD. [9][10][11] To date, only a limited number of studies have addressed whether the different variants can differentially modulate receptor function. The different receptor variants show no major differences in pharmacology.…”

Section: Introductionmentioning

confidence: 99%

The human dopamine D4 receptor repeat sequences modulate expression

2003

View full text Add to dashboard Cite

Genetic studies have implicated a polymorphic repeat sequence in exon 3 of the human dopamine D4 receptor in various behavioral and psychiatric disorders. Functionally various repeat variants are nearly identical, but whether these have different effects on gene expression has not been studied. To study the role of the repeat sequences on expression independently from its structural and functional effects at the protein level, we introduced these sequences immediately upstream of the promoter and in the 3 0 untranslated region of a luciferase reporter vector. In this report, we demonstrate that the repeat sequence can both modulate promoter activity and alter expression post-transcriptionally. The repeat sequence can serve as a substrate for a nuclear binding factor and all the three repeat variants can suppress promoter activity. Placement of the three repeat variants downstream from the luciferase gene in the expression vector shows, however, that the D4.7 repeat sequence has significantly suppressed expression of the reporter compared to the D4.2 and D4.4 repeats, likely via mechanisms involving RNA stability or translational efficiency. These data indicate that the various D4 repeat sequences have different effects on expression, which may explain its potential role in behavioral disorders.

show abstract

Meta-Analysis of the Association Between the 7-Repeat Allele of the Dopamine D₄ Receptor Gene and Attention Deficit Hyperactivity Disorder

Abstract: Although the association between ADHD and DRD4 is small, these results suggest that it is real. Further studies are needed to clarify what variant of DRD4 (or some nearby gene) accounts for this association.

Cited by 682 publications

References 28 publications

Regulation of Working Memory by Dopamine D4 Receptor in Rats

Regulation of Working Memory by Dopamine D4 Receptor in Rats

Dopaminergic System Genes in ADHD Toward a Biological Hypothesis

The human dopamine D4 receptor repeat sequences modulate expression

Contact Info

Product

Resources

About

Meta-Analysis of the Association Between the 7-Repeat Allele of the Dopamine D4 Receptor Gene and Attention Deficit Hyperactivity Disorder

Abstract: Although the association between ADHD and DRD4 is small, these results suggest that it is real. Further studies are needed to clarify what variant of DRD4 (or some nearby gene) accounts for this association.

Cited by 682 publications

References 28 publications

Regulation of Working Memory by Dopamine D4 Receptor in Rats

Regulation of Working Memory by Dopamine D4 Receptor in Rats

Dopaminergic System Genes in ADHD Toward a Biological Hypothesis

The human dopamine D4 receptor repeat sequences modulate expression

Contact Info

Product

Resources

About

Meta-Analysis of the Association Between the 7-Repeat Allele of the Dopamine D₄ Receptor Gene and Attention Deficit Hyperactivity Disorder