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The Molecular Genetics of ADHD: A View From the IMAGE Project

The Molecular Genetics of ADHD: A View From the IMAGE Project


Psychiatric Times August 2005
Vol. XXII
Issue 9


Although attention-deficit/hyperactivity disorder is frequently misunderstood as caused by normal childhood energy, boring classrooms, or overstressed parents and teachers, several decades of research show ADHD to be a valid disorder with a neurobiological basis (Faraone, in press). Genetic studies have played a leading role in clarifying the biological basis of the disorder. Family studies have documented familial transmission; adoption studies show this transmission occurs through biological, not adoptive relationships; and twin studies show that ADHD is highly heritable such that genes account for about 75% of the disorder's variability in the population (Faraone et al., in press). With a prevalence of 8% to 12% (Faraone et al., 2003), it is among the most common of psychiatric disorders.

Given this strong evidence from epidemiologic studies, molecular genetic studies have begun the search for genes that increase susceptibility to ADHD. Two general approaches have been used. Genome scan linkage studies scan the entire genome in search of regions that might harbor susceptibility genes. They do not require a prior hypothesis about which genes cause the disorder. In contrast, candidate gene studies nominate specific genes based on a biological theory about their putative role. They use the method of association to test these prior hypotheses.

To date, there have been three research groups performing genome linkage scans of ADHD (Arcos-Burgos et al., 2004; Bakker et al., 2003; Fisher et al., 2002; Ogdie et al., 2004, 2003). Table 1 summarizes their main results and gives their highest LOD scores (a statistic that measures the evidence for linkage). With the exception of chromosome 17p11, genomic regions implicated by these studies do not overlap. Because three of the implicated regions (17p11, 16p13 and 15q15) have also been implicated in studies of autism, these findings may suggest a shared genetic susceptibility for these disorders.

For ADHD, the modest replication across studies completed so far suggests that genes of moderately large effect are unlikely to exist. For this reason, further studies are needed to increase the power of available linkage data. Difficulties in replication may also be due to genetic heterogeneity (i.e., there are different forms of ADHD influenced by different genes).

In contrast to the small number of linkage studies, numerous candidate gene studies have used association to determine if biologically relevant genes influence the susceptibility to ADHD. Much of this work has focused on genes in catecholaminergic systems because the drugs that effectively treat ADHD are either dopamine reuptake inhibitors (e.g., stimulants) or norepinephrine reuptake inhibitors (e.g., tricyclic antidepressants, atomoxetine [Strattera]).

Compared with dopaminergic and noradrenergic systems, serotonergic systems have received relatively little attention in ADHD research. This is because measures of serotonin metabolism are minimally related to the clinical efficacy of the medicines that treat ADHD. Nevertheless, molecular genetic studies have examined serotonergic genes due to the well-known role of serotonin in impulsivity, one of the core symptoms of ADHD (Brunner and Hen, 1997).

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