Association of the dopamine receptor D4 (DRD4) gene 7-repeat allele with children with attention-deficit/hyperactivity disorder (ADHD): an update.

Child Psychiatry Branch, NIMH, NIH, Bethesda, Maryland 20892-1600, USA.
American Journal of Medical Genetics Part B Neuropsychiatric Genetics (Impact Factor: 3.23). 05/2007; 144B(3):379-82. DOI: 10.1002/ajmg.b.30460
Source: PubMed

ABSTRACT Polymorphisms of the dopamine receptor D4 gene DRD4, 11p15.5, have previously been associated with attention-deficit/hyperactivity disorder (ADHD) [Bobb et al., 2005; Am J Med Genet B Neuropsychiatr Genet 132:109-125; Faraone et al., 2005; Biol Psychiatry 57:1313-1323; Thapar et al., 2005; Hum Mol Genet 14 Spec No. 2:R275-R282]. As a follow up to a pilot study [see Castellanos et al., 1998; Mol Psychiatry 3:431-434] consisting of 41 probands and 56 controls which found no significant association between the DRD4 7-repeat allele in exon 3 and ADHD, a greatly expanded study sample (cases n = 166 and controls n = 282) and long term follow-up (n = 107, baseline mean age n = 9, follow-up mean age of n = 15) prompted reexamination of this gene. The DRD4 7-repeat allele was significantly more frequent in ADHD cases than controls (OR = 1.2; P = 0.028). Further, within the ADHD group, the 7-repeat allele was associated with better cognitive performance (measured by the WISC-III) (P = 0.013-0.07) as well as a trend for association with better long-term outcome. This provides further evidence of the role of the DRD4 7-repeat allele in the etiology of ADHD and suggests that this allele may be associated with a more benign form of the disorder.

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    ABSTRACT: The purpose of this meta-analysis was to examine whether association studies between attention deficit/hyperactivity disorder (AD/HD) and the dopamine receptor 4 gene 7-repeat (DRD4 7R) allele vary systematically based on study characteristics. A total of 27 empirical studies with 28 distinct samples using either case-control or family-based association analyses were included. Consistent with previous meta-analytic work [Gizer et al. (2009), Hum Genet 126:51-90], the DRD4 7R allele was associated with AD/HD across studies (OR = 1.33; 95% CI = 1.16-1.53, z = 4.04, P = 0.00005) and there was significant systematic variability among studies (Q = 54.24; P = 0.001; I(2) = 50.22). To account for the variability among studies, sample and study level covariates were examined. No differences in overall effect size emerged between family-based and case-control studies. However, the risk allele frequency in the control population accounted for a significant portion of the variance in overall effect size within case-control studies. In addition, evidence for the association between the DRD4 7R allele and distinct AD/HD subtypes emerged across family-based and case-control studies. The proportion of AD/HD, combined type individuals within the AD/HD sample was associated with a significant increase in the magnitude of association between the DRD4 7R allele and AD/HD. Conversely, an increase in the proportion of AD/HD, predominantly inattentive type individuals within the AD/HD sample was associated with a decrease in study effect size. Implications regarding AD/HD etiological and phenotypic heterogeneity are discussed.
    American Journal of Medical Genetics Part B Neuropsychiatric Genetics 04/2010; 153B(6):1189-99. · 3.23 Impact Factor
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    ABSTRACT: Evidence suggests the involvement of the dopamine D4 receptor gene (DRD4) in the pathogenesis of ADHD, but the exact mechanism is not well understood. Earlier reports on the effects of DRD4 polymorphisms on neurocognitive and neuroimaging measures are inconsistent. This study investigated the functional consequences of the 7-repeat allele of DRD4 on neurocognitive endophenotypes of ADHD in the Dutch subsample of the International Multicenter ADHD Genetics study. Participants were 350 children (5-11.5 years) and adolescents (11.6-19 years) with ADHD and their 195 non-affected siblings. An overall measure of neuropsychological functioning was derived by principal component analysis from five neurocognitive and five motor tasks. The effects of DRD4 and age were examined using Linear Mixed Model analyses. The analyses were stratified for affected and non-affected participants after finding a significant three-way interaction between ADHD status, age and the 7-repeat allele. Apart from a main effect of age, a significant interaction effect of age and DRD4 was found in non-affected but not in affected participants, with non-affected adolescent carriers of the 7-repeat allele showing worse neuropsychological performance. In addition, carrying the 7-repeat allele of DRD4 was related to a significantly worse performance on verbal working memory in non-affected siblings, independent of age. These results might indicate that the effect of the DRD4 7-repeat allele on neuropsychological functioning is dependent on age and ADHD status.
    The World Journal of Biological Psychiatry 11/2011; 13(4):293-305. · 3.57 Impact Factor
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