Genetics of Attention Deficit Hyperactivity Disorder

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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). Family, twin, and adoption studies provide compelling evidence that genes play a strong role in mediating susceptibility to ADHD. In contrast to a handful of genome-wide scans conducted thus far, many candidate gene studies of ADHD have produced substantial evidence implicating several genes in the etiology of the disorder. Yet, even these associations are small and consistent with the idea that the genetic vulnerability to ADHD is mediated by many genes of small effects. These small effects emphasize the need for future candidate gene studies to implement strategies that will provide enough statistical power to detect such small effects.

Section snippets

The dopamine D4 receptor

Both noradrenaline and dopamine are potent agonists of DRD4 [19], and the D4 receptor is prevalent in frontal-subcortical networks implicated in the pathophysiology of ADHD by neuroimaging and neuropsychologic studies [20]. Researchers have predominantly focused on a tandem repeat polymorphism in exon III of DRD4 because in vitro studies have shown that one variant (the 7-repeat allele) produces a blunted response to dopamine [21], [22]. Faraone and colleagues [4] conducted a meta-analysis of

Noradrenergic receptors: alpha-2A adrenergic receptor, 2C, and 1C

Three adrenergic receptors have been examined in ADHD. The alpha-2A adrenergic receptor (ADRA2A) has a promoter-region SNP (-1291 C > G) that has been examined in both case-control and family-based studies. Comings and colleagues [91] reported an association between genotypes at this SNP and ADHD symptom scores and that the G-1291C allele was associated with ADHD and oppositional defiant or conduct disorder symptoms, whereas the C-1291G allele was associated with a spectrum of other conditions,

Serotonin receptors: HTR1B and HTR2A

Of the family-based association studies of a silent SNP (861G > C) in the gene coding for the serotonin HTR1B receptor [108], [110], [111], [112], [113], [114], only the multisite study by Hawi and colleagues [110] reached statistical significance, suggesting overtransmission of the G861C allele. Smoller and colleagues pooled data from [110], [111], [112] and identified statistically significant overtransmission of this allele (OR = 1.35; CI, 1.13–1.62, P = .009) that strongly suggested

Synaptasomal-associated protein of 25kD

SNAP25 is a 206 amino acid protein found on chromosome 20p12. The gene product is a presynaptic plasma membrane protein involved in the regulation of neurotransmitter release. Its relevance to ADHD was motivated by the coloboma mouse, which has a hemizygous two centimorgan deletion of a segment on chromosome 2q, including the gene-encoding SNAP25. The coloboma mutation leads to spontaneous hyperactivity, delays in achieving complex neonatal motor abilities, deficits in hippocampal physiology

Summary

Although twin studies demonstrate that ADHD is a highly heritable condition, molecular genetic studies suggest that the genetic architecture of ADHD is complex. The handful of genome-wide scans that have been conducted thus far show divergent findings and are, therefore, not conclusive. Similarly, many of the candidate genes reviewed here (ie, DBH, MAO-A, SLC6A2, TPH-2, SLC6A4, CHRNA4, GRIN2A) are theoretically compelling from a neurobiologic systems perspective, but available data are sparse

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    Dr. Eric Mick receives or has received grant support from, is or has been a speaker for, or is or has been on the advisory board for the following sources: McNeil Pediatrics and Janssen Pharmaceuticals, Pfizer, Shire, and the National Institute of Mental Health (NIMH). Dr. Stephen V. Faraone receives or has received grant support from, is or has been a speaker for, or is or has been on the advisory board for the following sources: McNeil Pediatrics, Eli Lilly & Company, the NIMH, the National Institute of Child Health and Development, and the National Institute of Neurological Diseases and Stroke.

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