Li D, Sham PC, Owen MJ, He L. Meta-analysis shows significant association between dopamine system genes and attention deficit hyperactivity disorder (ADHD). Hum Mol Genet 15: 2276-2284

ArticleinHuman Molecular Genetics 15(14):2276-84 · August 2006with14 Reads
DOI: 10.1093/hmg/ddl152 · Source: PubMed
Molecular genetic investigations of attention deficit hyperactivity disorder (ADHD) have found associations with a variable number of tandem repeat (VNTR) situated in the 3'-untranslated region of dopamine transporter gene (DAT1), a VNTR in exon 3 of dopamine receptor 4 gene (DRD4) and a microsatellite polymorphism located at 18.5 kb from the 5' end of dopamine receptor 5 gene (DRD5). A number of independent studies have attempted to replicate these findings but the results have been mixed, possibly reflecting inadequate statistical power and the use of different populations and methodologies. In an attempt to clarify this inconsistency, we have combined all the published studies of European and Asian populations up to October 2005 in a meta-analysis to give a comprehensive picture of the role of the three dopamine-related genes using multiple research methods and models. The DRD4 7-repeat (OR=1.34, 95% CI 1.23-1.45, P= 2 x 10(-12)) and 5-repeat (OR=1.68, 95% CI 1.17-2.41, P=0.005) alleles as well as the DRD5 148-bp allele (OR=1.34, 95% CI 1.21-1.49, P= 8 x 10(-8)) confer increased risk of ADHD, whereas the DRD4 4-repeat (OR=0.90, 95% CI 0.84-0.97, P=0.004) and DRD5 136-bp (OR=0.57, 95% CI 0.34-0.96, P=0.022) alleles have protective effects. In contrast, we found no compelling evidence for association with the 480-bp allele of DAT (OR=1.04, 95% CI 0.98-1.11, P=0.20). No significant publication bias was detected in current studies. In conclusion, there is a statistically significant association between ADHD and dopamine system genes, especially DRD4 and DRD5. These findings strongly implicate the involvement of brain dopamine systems in the pathogenesis of ADHD.
    • "Moreover, this receptor possesses a remarkable VNTR (variable number of tandem repeats) polymorphism in its third intracellular loop (IC3) where a 16 amino acid sequence is repeated two to eleven times [4, 5]. The precise role of this polymorphism is not clear, but the seven repeat allele (D 4.7 R), which has been subject to positive selection during recent evolution, is associated with a predisposition to develop ADHD [6]. "
    [Show abstract] [Hide abstract] ABSTRACT: Dopamine receptors are G protein-coupled receptors involved in regulation of cognition, learning, movement and endocrine signaling. The action of G protein-coupled receptors is highly regulated by multifunctional proteins, such as β-arrestins which can control receptor desensitization, ubiquitination and signaling. Previously, we have reported that β-arrestin 2 interacts with KLHL12, a BTB-Kelch protein which functions as an adaptor in a Cullin3-based E3 ligase complex and promotes ubiquitination of the dopamine D4 receptor.
    Article · May 2016
    • "The goal of the current study was to conduct a meta-analysis to examine a) the magnitude of the associations between ADHD status and emotion dysregulation, b) determine any differences in the magnitude of these associations according to the domain of emotion dysregulation (ERU, ERNL, EREG, and ECUT), and c) determine the extent to which demographic variables (i.e., sex, age), comorbid CP, and individual differences in cognitive functioning impact the association between ADHD and emotion dysregulation. While there have been several metaanalyses conducted as it relates to ADHD and treatment (DuPaul & Eckert, 1997; Faraone, Biederman, & Mick, 2006; Van Der Oord, Prins, Oosterlaan, & Emmelkamp, 2008), genes (Gizer, Ficks, & Waldman, 2009; Li, Sham, Owen, & He, 2006; Nikolas & Burt, 2010), executive functioning (Frazier, Demaree, & Youngstrom, 2004; Martinussen, Hayden, Hogg-Johnson, & Tannock, 2005; Willcutt et al., 2005), neural correlates (Cortese, 2012; Dickstein, Bannon, Castellanos, & Milham, 2006 ), we are not aware of any meta-analysis that has specifically focused on emotion dysregulation. However, there has been some theoretical and review papers on aspects of emotion dysregulation in general psychopathology (Gerow & Kendall, 2002 ) and specifically to ADHD (Barkley, 2010; Bunford, Evans, & Wymbs, 2015; Shaw et al., 2014; Skirrow et al., 2009). "
    [Show abstract] [Hide abstract] ABSTRACT: While executive functioning deficits have been central to cognitive theories of Attention-Deficit Hyperactivity Disorder (ADHD), recent work has suggested that emotion dysregulation may also play a key role in understanding the impairments suffered by youth with ADHD. However, given the multiple processes involved in emotion dysregulation, the extent to which youth with ADHD are impaired across multiple domains of emotion dysregulation including: emotion recognition/understanding (ERU), emotion reactivity/negativity/lability (ERNL), emotion regulation (EREG), and empathy/callous–unemotional traits (ECUT) remains unclear. A meta-analysis of 77 studies (n = 32,044 youths) revealed that youth with ADHD have the greatest impairment on ERNL (weighted ES d = .95) followed by EREG (weighted ES d = .80). Significantly smaller effects were observed for ECUT (weighted ES d = .68) and ERU (weighted ES d = .64). Moderation analyses indicated that the association between ADHD and ERNL was stronger among studies that had a sample containing older youth (no other demographic factors were significant). Additionally, the association between ADHD and ECUT was significantly weaker among studies that controlled for co-occurring conduct problems. Co-occurring conduct problems did not moderate the link between ADHD and any other emotion dysregulation domain. Lastly, the association between ADHD and ERNL was significantly weaker when controlling for youth's cognitive functioning. Cognitive functioning did not moderate the link between ADHD and ERU, EREG, or ECUT, respectively. Theoretical/practical implications for the study of emotional dysregulation in youth with ADHD are discussed.
    Full-text · Article · Apr 2016
    • "Currently one of the main theories on genetic risk factors for ADHD involves aberrant dopaminergic neurotransmission [4, 5]. Dopamine receptor and transporter genes play a significant role in ADHD [6, 7], which may explain decreased dopamine levels in ADHD [8]. Other genetic studies provide evidence for an association between the serotonergic system and ADHD91011, in line with aberrant postsynaptic serotonin levels found in some individuals with ADHD [12]. "
    [Show abstract] [Hide abstract] ABSTRACT: Background The aim of the current study was to explore the role of aromatic amino acids (AAAs) in blood in relation to attention-deficit/hyperactivity disorder (ADHD). Given their impact on the synthesis of serotonin and dopamine, decreased concentrations of the AAAs tryptophan, tyrosine and phenylalanine in blood may contribute to the expression of ADHD symptoms. Decreased AAA blood concentrations, in turn, may be related to lowered dietary protein intake or to abnormal AAA catabolism, as evidenced by increased urinary AAA concentrations. Methods Eighty-three children with ADHD (75% males) and 72 typically developing (TD) children (51% males), aged 6 to 13 years, participated in the study. AAA concentrations were assessed in blood spots and an 18-hour urinary sample. A nutritional diary was filled out by parents to calculate dietary protein intake. Parent and teacher questionnaires assessed symptoms of ADHD, oppositional defiant disorder, conduct disorder, and autism spectrum disorder. Results Children with ADHD showed normal AAA concentrations in blood spots and urine, as well as normal protein intake compared to controls. No associations between AAA concentrations and symptoms of ADHD or comorbid psychiatric disorders were found. Conclusions This study is the first to explore AAA metabolism in children with ADHD using a well-defined and relatively large sample. We found that AAA deficiencies are not related to ADHD. The results do not support treatment with AAA supplements in children with ADHD. Future studies regarding the cause of serotonin and dopamine alterations in ADHD should focus on other explanations, such as effects of altered transport of AAAs.
    Full-text · Article · Mar 2016
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