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

Harvard University, Cambridge, Massachusetts, United States
American Journal of Psychiatry (Impact Factor: 12.3). 08/2001; 158(7):1052-7. DOI: 10.1176/appi.ajp.158.7.1052
Source: PubMed

ABSTRACT Family, twin, and adoption studies show attention deficit hyperactivity disorder (ADHD) to have a substantial genetic component. Although several studies have shown an association between ADHD and the 7-repeat allele of the dopamine D(4) receptor gene (DRD4), several studies have not. Thus, the status of the ADHD-DRD4 association is uncertain.
Meta-analysis was applied to case-control and family-based studies of the association between ADHD and DRD4 to assess the joint evidence for the association, the influence of individual studies, and evidence for publication bias.
For both the case-control and family-based studies, the authors found 1) support for the association between ADHD and DRD4, 2) no evidence that this association was accounted for by any one study, and 3) no evidence for publication bias.
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.

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    • "Thispolymorphism(DRD4-III)wasassociatedwithbehaviors andtraitsthatarerelatedtoempathy.Anexampleofthisis theassociationbetweenDRD4-IIIpolymorphismandaltruistic behavior(Bachner-Melmanetal.,2005),andthepossiblerole ofthepolymorphisminADHD(Faraoneetal.,2001),a disorderthatwasshowntoberelatedtoToMdeficitsand reducedempathy(Uekermannetal.,2010).Anotherinteresting investigationfocusedonthefunctionofDRD4-IIIpolymorphism inrepresentationalToM(RTM)–theabilitytoexplicitly understandthatother'smentalstates(beliefs,desires,knowledge) areperson-specificrepresentationsoftheworld(Lackneretal., 2012).ThisstudyhassuggestedthatvariationsintheDRD4- IIImaypredictpreschoolers'performanceinRTM,showing thatindividualswithtwoshorteralleles(4repeatsorless) outperformedthosewithoneortwolongeralleles(6repeatsor more),(Lackneretal.,2010). "
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    ABSTRACT: Affective knowledge, the ability to understand others' emotional states, is considered to be a fundamental part in efficient social interaction. Affective knowledge can be seen as related to cognitive empathy, and in the framework of theory of mind (ToM) as affective ToM. Previous studies found that cognitive empathy and ToM are heritable, yet little is known regarding the specific genes involved in individual variability in affective knowledge. Investigating the genetic basis of affective knowledge is important for understanding brain mechanisms underlying socio-cognitive abilities. The 7-repeat (7R) allele within the third exon of the dopamine D4 receptor gene (DRD4-III) has been a focus of interest, due to accumulated knowledge regarding its relevance to individual differences in social behavior. A recent study suggests that an interaction between the DRD4-III polymorphism and sex is associated with cognitive empathy among adults. We aimed to examine the same association in two childhood age groups. Children (N = 280, age 3.5 years, N = 283, age 5 years) participated as part of the Longitudinal Israel Study of Twins. Affective knowledge was assessed through children's responses to an illustrated story describing different emotional situations, told in a laboratory setting. The findings suggest a significant interaction between sex and the DRD4-III polymorphism, replicated in both age groups. Boy carriers of the 7R allele had higher affective knowledge scores than girls, whereas in the absence of the 7R there was no significant sex effect on affective knowledge. The results support the importance of DRD4-III polymorphism and sex differences to social development. Possible explanations for differences from adult findings are discussed, as are pathways for future studies.
    Frontiers in Psychology 06/2015; 6:846. DOI:10.3389/fpsyg.2015.00846 · 2.80 Impact Factor
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    • "Recently, it has been suggested that DRD4 behaves not as a " vulnerability " gene but as a " plasticity " gene (Belsky et al., 2009; Wells et al., 2013). The vulnerability gene hypothesis conceptualizes the long variant of DRD4 as a risk factor for psychiatric disorders such as ADHD (Faraone et al., 2001), and the likelihood of that disorder will increase in the face of adverse environment (Belsky and Hartman, 2014). In contrast, the plasticity gene idea contends that, rather than being more susceptible to adverse environmental influences, long allele carriers show increased susceptibility to environmental influences in general (Belsky and Hartman, 2014). "
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    ABSTRACT: Listeners vary substantially in their ability to recognize speech in noisy environments. Here we examined the role of genetic variation on individual differences in speech recognition in various noise backgrounds. Background noise typically varies in the levels of energetic masking (EM) and informational masking (IM) imposed on target speech. Relative to EM, release from IM is hypothesized to place greater demand on executive function to selectively attend to target speech while ignoring competing noises. Recent evidence suggests that the long allele variant in exon III of the DRD4 gene, primarily expressed in the prefrontal cortex, may be associated with enhanced selective attention to goal-relevant high-priority information even in the face of interference. We investigated the extent to which this polymorphism is associated with speech recognition in IM and EM conditions. In an unscreened adult sample (Experiment 1) and a larger screened replication sample (Experiment 2), we demonstrate that individuals with the DRD4 long variant show better recognition performance in noise conditions involving significant IM, but not in EM conditions. In Experiment 2, we also obtained neuropsychological measures to assess the underlying mechanisms. Mediation analysis revealed that this listening condition-specific advantage was mediated by enhanced executive attention/working memory capacity in individuals with the long allele variant. These findings suggest that DRD4 may contribute specifically to individual differences in speech recognition ability in noise conditions that place demands on executive function. Copyright © 2014. Published by Elsevier Ltd.
    Neuropsychologia 12/2014; 67. DOI:10.1016/j.neuropsychologia.2014.12.013 · 3.30 Impact Factor
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    • "All rights reserved. in the phenotype of Attention-Deficit/Hyperactivity Disorder (ADHD) (LaHoste et al., 1996; Faraone et al., 2001; Grady et al., 2003, 2005a; Li et al., 2006 "
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    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.
    Psychiatry Research: Neuroimaging 11/2014; 231(1). DOI:10.1016/j.pscychresns.2014.10.021 · 2.42 Impact Factor
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