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.
"In addition, the 7R allele is associated with problematic behaviors including: alcoholism (MacKillop et al., 2007), financial risk-taking (Dreber et al., 2009), disinhibition (Congdon et al., 2008), increased sexual behavior, and infidelity (Zion et al., 2006; Eisenberg et al., 2007; Garcia et al., 2010). However, 7R carriers have an advantage in some tests of reaction time (Swanson et al., 2000a; Langley et al., 2004) and executive function (Swanson et al., 2000b; Gornick et al., 2007; Johnson et al., 2008), though these results have not been consistently replicated (Barkley et al., 2006; Konrad et al., 2010). Intriguingly, a study by Grady et al. (2013) has shown that the 7R allele contributes to longevity by moderating the beneficial effects of an enriched environment in increasing lifespan. "
[Show abstract][Hide abstract] ABSTRACT: The aim of the study was to examine functional brain activity in response to unpleasant images in individuals with the 7-repeat (7R) allele compared to individuals with the 4-repeat (4R) allele of the dopamine receptor D4 (DRD4) gene (VNTR in exon 3). Based on the response ready hypothesis, individuals with the DRD4-4R/7R genotype were expected to show greater functional brain activity in response to unpleasant compared to neutral stimuli in specific regions of the frontal, temporal, parietal and limbic lobes, which form the networks involved in attentional, emotional, and preparatory responses. Functional Magnetic Resonance Imaging activity was studied in 26 young adults (13 with the DRD4-4R/7R genotype and 13 with the DRD4-4R/4R genotype). Participants were asked to look at and subjectively rate unpleasant and neutral images. Results showed increased brain activity in response to unpleasant images compared to neutral images in the right temporal lobe in participants with the DRD4-4R/7R genotype versus participants with the DRD4-4R/4R genotype. The increase in right temporal lobe activity in individuals with DRD4-4R/7R suggests greater involvement in processing negative emotional stimuli. Intriguingly, no differences were found between the two genotypes in the subjective ratings of the images. The findings corroborate the response ready hypothesis, which suggests that individuals with the 7R allele are more responsive to negative emotional stimuli compared to individuals with the 4R allele of the DRD4 gene.
"A review of the linkage results in the region concluded that they show a lack of replication but suggested that modest interest was maintained by possible signals scattered across a 30cM interval . Some more recent studies found evidence for a role of chromosome 11p15.4 in bipolar disorder  autism  and attention deficit hyperactivity disorder . "
[Show abstract][Hide abstract] ABSTRACT: We report analyses of a Brazilian study of early onset schizophrenia (BEOS) families. We genotyped 22 members of 4 families on a linkage SNP array and report here non-parametric linkage analyses using MERLIN® software. We found suggestive evidence for linkage on two chromosomal regions, 13q32 and 11p15.4. A LOD score of 2.71 was observed at 13q32 with a one LOD interval extending from 60.63-92.35 cM. From simulations, this LOD score gave a genome-wide empirical corrected p = 0.33, after accounting for all markers tested. Similarly 11p15.4 showed the same maximum LOD of 2.71 and a narrower one LOD interval of 4-14 cM. Of these, 13q32 has been reported to be linked to schizophrenia by multiple different studies. Thus, our study provides additional supporting evidence for an aetiological role of variants at 13q32 in schizophrenia.
PLoS ONE 12/2012; 7(12):e52262. DOI:10.1371/journal.pone.0052262 · 3.23 Impact Factor
"The presence of the DRD4 7-repeat allele was associated with defi cits on a range of these measures in some studies (Auerbach et al. 2001; Fossella et al. 2002; Langley et al. 2004; Kieling et al. 2006; Mill et al. 2006; Shaw et al. 2007; Froehlich et al. 2007; Herrmann et al. 2007; Boonstra et al. 2008; Loo et al. 2008) whereas others found no relationship (Langley et al. 2004; Szobot et al. 2005; Barkley et al. 2006; Genro et al. 2006; Demiralp et al. 2007; Herrmann et al. 2007; Sonuga-Barke et al. 2008; Monuteaux et al. 2008). In contrast to expectations, carriers of at least one 7-repeat allele performed even better than non-carriers on a verbal working memory task (Boonstra et al. 2008), inhibitory control (Kramer et al. 2009) and IQ test (Gornick et al. 2007). In a case – control design, ADHD 7-repeat non-carriers rather than ADHD 7-repeat carriers performed worse on attention and inhibition tests and measures of speed and variability (Swanson et al. 2000). "
[Show abstract][Hide abstract] 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. DOI:10.3109/15622975.2011.595822 · 4.18 Impact Factor
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