Molecular Genetics of Attention-Deficit/Hyperactivity Disorder

Harvard University, Cambridge, Massachusetts, United States
Biological Psychiatry (Impact Factor: 10.26). 07/2005; 57(11):1313-23. DOI: 10.1016/j.biopsych.2004.11.024
Source: PubMed


Results of behavioral genetic and molecular genetic studies have converged to suggest that both genetic and nongenetic factors contribute to the development of attention-deficit/hyperactivity disorder (ADHD). We review this literature, with a particular emphasis on molecular genetic studies. Family, twin, and adoption studies provide compelling evidence that genes play a strong role in mediating susceptibility to ADHD. This fact is most clearly seen in the 20 extant twin studies, which estimate the heritability of ADHD to be .76. Molecular genetic studies suggest that the genetic architecture of ADHD is complex. The few genome-wide scans conducted thus far are not conclusive. In contrast, the many candidate gene studies of ADHD have produced substantial evidence implicating several genes in the etiology of the disorder. For the eight genes for which the same variant has been studied in three or more case-control or family-based studies, seven show statistically significant evidence of association with ADHD on the basis of the pooled odds ratio across studies: DRD4, DRD5, DAT, DBH, 5-HTT, HTR1B, and SNAP-25.

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    • "deficit hyperactivity disorder (ADHD) is the result of genetic factors (Farone et al., 2005; McLaughlin, Ronald, Kuntsi, Asherson, & Plomin, 2007; Nikolas & Burt, 2010; Rietveld, Hudziak, Bartels, van Beijsterveldt, & Boomsma, 2003). Evidence for the heritability of traits and clinical diagnoses overlapping with self-control extends also to the trait of impulsivity. "
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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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    • "The risk of ADHD among parents of children with ADHD is increased by twofold to eightfold compared with the population rate [7]. A meta-analysis of 20 pooled twin studies estimated an average hereditability of 76%, suggesting that ADHD is one of the disorders with the strongest genetic component in psychiatry [7]. Despite these high heritability estimates, identification of genes that confer susceptibility to ADHD has been a slow and difficult process and current findings from both candidate gene studies and genome-wide association studies (GWAS) suggest that ADHD is a polygenic disorder with minor contribution from each individual susceptibility gene [for reviews, see 8, 9]. "
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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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    • "Attention Deficit/Hyperactivity Disorder (ADHD) is a common and highly heritable neuropsychiatric disorder (heritability 70– 80% [Faraone et al., 2005; Burt 2009]), with prevalence rates of 5– 6% in childhood [Polanczyk et al., 2007; American Psychiatric Association 2013]. Clinically, ADHD is characterized by two core symptom domains: inattention and hyperactivity/impulsivity [American Psychiatric Association, 2013]. "
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    ABSTRACT: Attention-Deficit/Hyperactivity Disorder (ADHD) is a common neuropsychiatric disorder with a complex genetic background. The G protein-coupled receptor kinase interacting ArfGAP 1 (GIT1) gene was previously associated with ADHD. We aimed at replicating the association of GIT1 with ADHD and investigated its role in cognitive and brain phenotypes. Gene-wide and single variant association analyses for GIT1 were performed for three cohorts: (1) the ADHD meta-analysis data set of the Psychiatric Genomics Consortium (PGC, N = 19,210), (2) the Dutch cohort of the International Multicentre persistent ADHD CollaboraTion (IMpACT-NL, N = 225), and (3) the Brain Imaging Genetics cohort (BIG, N = 1,300). Furthermore, functionality of the rs550818 variant as an expression quantitative trait locus (eQTL) for GIT1 was assessed in human blood samples. By using Drosophila melanogaster as a biological model system, we manipulated Git expression according to the outcome of the expression result and studied the effect of Git knockdown on neuronal morphology and locomotor activity. Association of rs550818 with ADHD was not confirmed, nor did a combination of variants in GIT1 show association with ADHD or any related measures in either of the investigated cohorts. However, the rs550818 risk-genotype did reduce GIT1 expression level. Git knockdown in Drosophila caused abnormal synapse and dendrite morphology, but did not affect locomotor activity. In summary, we could not confirm GIT1 as an ADHD candidate gene, while rs550818 was found to be an eQTL for GIT1. Despite GIT1's regulation of neuronal morphology, alterations in gene expression do not appear to have ADHD-related behavioral consequences. © 2015 Wiley Periodicals, Inc. © 2015 Wiley Periodicals, Inc.
    American Journal of Medical Genetics Part B Neuropsychiatric Genetics 06/2015; DOI:10.1002/ajmg.b.32327 · 3.42 Impact Factor
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