Molecular Genetics of Attention-Deficit/Hyperactivity Disorder

Research on attention-deficit/hyperactivity disorder (ADHD), a highly prevalent and controversial condition, has, for the most part, been descriptive and atheoretical. The imperative to discover the genetic and environmental risk factors for ADHD is motivating the search for quantifiable intermediate constructs, termed endophenotypes. In this selective review, we conclude that such endophenotypes should be solidly grounded in the neurosciences. We propose that three such endophenotypes — a specific abnormality in reward-related circuitry that leads to shortened delay gradients, deficits in temporal processing that result in high intrasubject intertrial variability, and deficits in working memory — are most amenable to integrative collaborative approaches that aim to uncover the causes of ADHD.

Neuroscience of attention-deficit/hyperactivity disorder: the search for endophenotypes.

Molecular genetics of attention deficit hyperactivity disorder.

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.

Candidate gene studies of ADHD: a meta-analytic review.

The catechol-O-methyltransferase polymorphism: relations to the tonic-phasic dopamine hypothesis and neuropsychiatric phenotypes.

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Dopaminergic System Genes in ADHD: Toward a Biological Hypothesis

Pharmacological and biochemical studies have indicated that imbalances in dopaminergic transmission may contribute to the aetiology of attention deficit hyperactivity disorder (ADHD) The enzyme catechol-O-methyltransferase (COMT) plays a key role in the degradation of catecholamines such as dopamine, L-DOPA, adrenaline, and noradrenaline and therefore could be considered as a candidate locus for ADHD susceptibility We hypothesised that a proportion of the genetic susceptibility to ADHD may be a consequence of dopamine depletion in the synapses due to high-level activity of the COMT gene (allele 1) Using the haplotype-based haplotype relative risk method and 94 affected children and their parents genotyped for COMT alleles, we found no significant differences in the frequency of the transmitted and nontransmitted alleles to ADHD cases from their parents The absence of association between COMT alleles and ADHD indicated that this locus does not play a significant role or at least a role independent of other genes, in predisposing to ADHD in the Irish population Am J Med Genet (Neuropsychiatr Genet) 96:282–284, 2000 © 2000 Wiley-Liss, Inc

No association between catechol-O-methyltransferase (COMT) gene polymorphism and attention deficit hyperactivity disorder (ADHD) in an Irish sample.

Pharmacological and biochemical studies have indicated that imbalances in dopaminergic transmission may contribute to the aetiology of attention deficit hyperactivity disorder (ADHD). The enzyme catechol-Omethyltransferase (COMT) plays a key role in the degradation of catecholamines such as dopamine, L-DOPA, adrenaline, and noradrenaline and therefore could be considered as a candidate locus for ADHD susceptibility. We hypothesised that a proportion of the genetic susceptibility to ADHD may be a consequence of dopamine depletion in the synapses due to high-level activity of the COMT gene (allele 1). Using the haplotypebased haplotype relative risk method and 94 affected children and their parents genotyped for COMT alleles, we found no significant differences in the frequency of the transmitted and nontransmitted alleles to ADHD cases from their parents. The absence of association between COMT alleles and ADHD indicated that this locus does not play a significant role or at least a role independent of other genes, in predisposing to ADHD in the Irish population. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 96:282‐284, 2000. © 2000 Wiley-Liss, Inc.

Niamh Millar

Papers

Dopaminergic System Genes in ADHD: Toward a Biological Hypothesis

No association between catechol-O-methyltransferase (COMT) gene polymorphism and attention deficit hyperactivity disorder (ADHD) in an Irish sample.

Catechol-O-Methyltransferase (COMT) Gene Polymorphism and Attention Deficit Hyperactivity Disorder (ADHD) in an Irish Sample