Candidate gene studies of ADHD: A meta-analytic review

Department of Genetics, University of North Carolina at Chapel Hill, 120 Mason Farm Road, Room 5015 Genetic Medicine Building CB 7264, Chapel Hill, NC 27599-7264, USA.
Human Genetics (Impact Factor: 4.82). 07/2009; 126(1):51-90. DOI: 10.1007/s00439-009-0694-x
Source: PubMed


Quantitative genetic studies (i.e., twin and adoption studies) suggest that genetic influences contribute substantially to the development of attention deficit hyperactivity disorder (ADHD). Over the past 15 years, considerable efforts have been made to identify genes involved in the etiology of this disorder resulting in a large and often conflicting literature of candidate gene associations for ADHD. The first aim of the present study was to conduct a comprehensive meta-analytic review of this literature to determine which candidate genes show consistent evidence of association with childhood ADHD across studies. The second aim was to test for heterogeneity across studies in the effect sizes for each candidate gene as its presence might suggest moderating variables that could explain inconsistent results. Significant associations were identified for several candidate genes including DAT1, DRD4, DRD5, 5HTT, HTR1B, and SNAP25. Further, significant heterogeneity was observed for the associations between ADHD and DAT1, DRD4, DRD5, DBH, ADRA2A, 5HTT, TPH2, MAOA, and SNAP25, suggesting that future studies should explore potential moderators of these associations (e.g., ADHD subtype diagnoses, gender, exposure to environmental risk factors). We conclude with a discussion of these findings in relation to emerging themes relevant to future studies of the genetics of ADHD.


Available from: Irwin Waldman, Nov 09, 2015
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    • "However, these findings only explained a small portion of ADHD heritability, because their effect sizes were small. In addition, each susceptibility gene is likely to have low penetrance (Gizer et al. 2009; Akutagava-Martins et al. 2013). Methylphenidate (MPH) has been reported to improve core symptoms of ADHD. "
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    ABSTRACT: Objectives: The purpose of this study is to examine the relationship between 5-HTTLPR polymorphism (44-bp insertion/deletion polymorphism of serotonin transporter gene) and methylphenidate (MPH) treatment response, as well as the association between the adverse events of MPH treatment and 5-HTTLPR polymorphism in children with attention-deficit/hyperactivity disorder (ADHD). Methods: A total of 114 children with ADHD (mean age 9.08 ± 1.94 years) were recruited from the child psychiatric clinic in a hospital in South Korea. We have extracted the genomic DNA of the subjects from their blood lymphocytes and analyzed 5-HTTLPR polymorphism of the SLC6A4 gene. All children were treated with MPH for 8 weeks, with clinicians monitoring both the improvement of ADHD symptoms and the side effects. We compared the response to MPH treatment and adverse events among those with the genotype of 5-HRRLPR polymorphism. Results: There was no significant association between the 5-HTTLPR genotype and the response to MPH treatment in children with ADHD. Subjects with the S/L+L/L genotype tended to have tics and nail biting (respectively, p < 0.001, p = 0.017). Conclusions: The results of this study do not support the association between the 5-HTTLPR polymorphism and treatment response with MPH in ADHD. However, our findings suggest the association between 5-HTTLPR polymorphism and the occurrence of tics and nail-biting as an adverse event of methylphenidate. This may aid in our understanding of the genetic contribution and genetic susceptibility of a particular allele in those ADHD patients with tics or nail biting.
    Journal of child and adolescent psychopharmacology 09/2015; DOI:10.1089/cap.2014.0168 · 2.93 Impact Factor
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    • "One possibility suggested by molecular genetic research is that the 5-HTTLPR polymorphism in the serotonin transporter gene (SLC6A4) plays a role in the development of self-control. Studies have shown that the 5-HTTLPR polymorphism is associated with both ADHD (Gizer, Ficks, & Waldman, 2009) and impulsivity (Paaver et al., 2007; Walderhaug et al., 2007). Beaver, Ratchford, and Ferguson (2009), using Add Health data, found direct evidence for a link between 5-HTTLPR and self-control wherein 5-HTTLPR interacted with delinquent peer association to explain levels of self-control. "
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    ABSTRACT: Purpose: Several studies now show that self-control, as proposed by Gottfredson and Hirschi (1990), is at least moderately heritable. Studies of molecular genetic variation related to serotonergic function suggest that the heritability of self-control may be explained, in part, by the 5-HTTLPR polymorphism. Methods: The current research tests the association between the 5-HTTLPR polymorphism and self-control as measured by the Grasmick et al. (1993) scale. Analyses were based on a sample of incarcerated males and considered the effect of the 5-HTTLPR polymorphism on the full self-control scale as well as the specific dimensions of self-control. Results: The s/s genotype interacted with abuse to predict increases in overall self-control, preference for simple tasks and physical activity. Relative to the s/l genotype, the l/l genotype, which has been linked to psychopathy, was directly associated with more self-centeredness. Conclusions: Results show that molecular genetic variation related to serotonergic function plays a role in the heritability of self-control. Variation in the association between 5-HTTLPR genotype and the distinct dimensions of self-control, while consistent with recent literature (see Yildirim & Derksen, 2013), indicates that self-control as originally presented by Gottfredson and Hirschi (1990) is not a unitary construct.
    Journal of Criminal Justice 09/2015; 43(5):386. DOI:10.1016/j.jcrimjus.2015.07.004 · 1.24 Impact Factor
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    • "Multiple neural pathways have been implicated in the development of ADHD and the most studied is the dopaminergic neurotransmission based on the observed dopamine (DA) deficiency in children with ADHD and on the therapeutic benefits provided by methylpheni‐ date (MPH), a DA agonist. A meta-analysis of commonly studied candidate genes has revealed associations between ADHD and variants of the dopamine transporter (DAT1) gene (SLC6A3) and the dopamine D4 and D5 receptor genes (DRD4, DRD5) [11]. Moreover, significant peripheral alterations in norepinephrine (NE) levels and its main metabolites have been observed in ADHD patients [12]. "
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    ABSTRACT: This chapter aims to identify, among the dopaminergic and noradrenergic molecules strongly associated to aetiopathogenesis of the disorder, potential genetic and bio‐ chemical markers linked to ADHD diagnosis and to assess whether treatments can change peripheral levels of a biomarker, to be then useful, if tested, as a response pre‐ dictor. The results, based on literature research, evidenced a role of some molecules such as SLC6A3, DRD4, MHPG, MAOA, NE, SLC6A2, DBH, COMT that could represent, in this order, a hypothetical signature of genetic and biochemical markers useful for ADHD diagnosis. From this hypothetical signature, the NE metabolite MHPG result‐ ed, after a meta-analytic approach, the main molecule whose urinary levels were in‐ fluenced by the dAMP treatment. Urinary MHPG levels were decreased after stimulants administration only in the responder patients, indicating that MHPG could be a useful predictor of the response to these drugs. This, along with the well-report‐ ed correlation between decrease in MHPG and behavioral improvements after dAMP treatment, focuses attention on MHPG as a potential mediator of stimulant drug re‐ sponse, in addition to a potential useful biological marker for diagnostic assessment. Future studies on specificity, sensitivity and replication of these findings are needed.
    ADHD - New Directions in Diagnosis and Treatment, Edited by Jill M. Norvilitis, 09/2015: chapter 4: pages 55-83; InTech., ISBN: 978-953-51-2166-4
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