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.

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Available from: Irwin Waldman, Nov 09, 2015
    • "Future large-scale original studies and further metaanalyses are required to more firmly support or falsify our current conclusion. In relation to statistical power, however, it should be pointed out that the observation of meta-analytic associations of the SLC6A3 VNTR with striatal DAT availability (Costa et al., 2011; Faraone et al., 2014), ADHD (Gizer et al., 2009) and MPH response in naturalistic studies of ADHD treatment (Kambeitz et al., 2014) suggests that such single-gene effects do indeed occur, in analyses with smaller numbers of studies, and with sufficient power to be detected statistically. It thus appears that any associations of this polymorphism with cognition may be of considerably smaller magnitude than those with striatal DAT, ADHD or MPH response. "
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    ABSTRACT: The gene coding for the dopamine transporter (DAT), SLC6A3, contains a 40-base pair variable number of tandem repeats (VNTR) polymorphism (rs28363170) in its 3' untranslated region. This VNTR has been associated with attention deficit hyperactivity disorder (ADHD) and has been investigated in relation to cognition and brain function. Here, we report the results of a comprehensive meta-analysis with meta-regression examining the association of the VNTR with different domains of cognition in healthy adults. We extracted data from 28 independent studies and carried out meta-analyses for associations with working memory (k=10 samples, N=1193 subjects), inhibition (k=8 samples, N=829 subjects), executive functions including inhibition (k=10 samples, N=984 subjects), attention (k=6 samples, N=742 subjects) and declarative long-term memory (k=5 samples, N=251 subjects). None of the investigated dimensions showed significant associations with the VNTR (all p>0.26). Meta-regression including year of publication, gender, age, ethnicity and percentage of 10R-homozygotes similarly did not attain significance. We conclude that there is no evidence that rs28363170 may be a significant predictor of cognitive function in healthy adults.
    No preview · Article · Nov 2015 · Neuroscience & Biobehavioral Reviews
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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.
    Full-text · Article · Sep 2015 · Journal of child and adolescent psychopharmacology
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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.
    Full-text · Article · Sep 2015 · Journal of Criminal Justice
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