COMMENTARY

The Genetics of Attention-Deficit/Hyperactivity Disorder: Current Status and Clinical Implications

Stephen V. Faraone, PhD

Disclosures

November 02, 2006

In This Article

Which Gene Variants Increase Susceptibility to ADHD?

Although the high heritability of ADHD suggests that it is a "genetic" disorder, to assert that any single gene causes the disorder would be inaccurate. Rather, many genes combine to increase the risk for ADHD. Thus, instead of declaring that genes "cause" ADHD, it is better to understand that, as with environmental risk factors, some gene variants boost one's susceptibility to the disorder. With the exception of very rare conditions, no single gene is either necessary or sufficient to cause ADHD.

Two molecular genetic methods have been used in the search for ADHD susceptibility genes: linkage and candidate gene studies. By collecting DNA and clinical diagnoses from ADHD families, the linkage method has the remarkable ability to screen the entire human genome to discover segments that contain ADHD genes. To date, 4 linkage studies have been completed.[8,9,10,11,12] These have implicated broad areas of chromosomes 5, 10, 12, 16, and 17. Currently, researchers are studying these chromosomal regions in more detail to determine which of the many genes in these regions are involved in ADHD.

In contrast to linkage studies, which scan the entire genome in search of ADHD genes, candidate gene studies focus on 1 or more genes believed, a priori, to be involved in the disorder. These analyses choose genes based on neurobiological studies or theoretical considerations suggesting that the gene product is relevant to the etiology of ADHD. The logic of these studies is straightforward. If a gene variant increases the risk for ADHD, that variant should be more common among ADHD patients compared with non-ADHD controls. From candidate gene studies, we can compute an odds ratio (OR), which assesses the magnitude of the association between ADHD and the putative risk variant (an OR of 1.0 indicates no association; those greater than 1.0 indicate that the variant increases risk for ADHD; and those less than 1.0 indicate that the variant decreases the risk for ADHD).

Faraone and colleagues[5] reviewed the candidate gene literature and examined pooled odds ratios for candidate genes that had been examined in at least 3 studies. This review implicated 7 genes. Because the stimulants that are given to treat ADHD work by raising levels of synaptic dopamine, many studies have examined the association between ADHD and several genes involved in dopamine transmission. Perhaps the most frequently studied of these genes is the dopamine D4 receptor (DRD4) gene. Both noradrenaline and dopamine are potent agonists of DRD4.[13] Moreover, the D4 receptor is prevalent in frontal-subcortical networks implicated in the pathophysiology of ADHD.[14] Researchers have focused on a variant of DRD4 known as the 7-repeat variant. Despite some differences across studies, when data from analyses of this variant are pooled, the association of the DRD4 7-repeat variant and ADHD remains statistically significant with an odds ratio of about 1.3.[5]

Many researchers have also studied the gene that codes for the dopamine 5 receptor (DRD5). The most widely studied variant for DRD5 is known as the 148bp variant. An analysis that combined 14 independent studies[15] identified a significant association of the 148bp variant and ADHD, with an odds ratio of 1.2. The dopamine transporter gene (DAT1) is an important gene for ADHD because the stimulant medications that are efficacious in ADHD block the dopamine transporter.[14,16] In mice, eliminating DAT1 function leads to hyperactivity and deficits in inhibition. As with ADHD children, treating these "knockout" mice with stimulants reduces hyperactivity.[17,18] Using single photon emission computed tomography (SPECT), Dougherty and associates[19] found striatal dopamine transporter activity to be elevated by about 70% in adults with ADHD, which is consistent with the idea that one cause of ADHD is too much activity of the dopamine transporter, leading to hypoactivity of dopamine synapses. When studies of a dopamine transporter gene variant known as the 10-repeat allele were pooled, the odds ratio was small but significant (1.13).[5]

Dopamine beta-hydroxylase (DBH) is the primary enzyme responsible for converting dopamine to norepinephrine. When studies of this gene are pooled, they jointly suggest a significant association between ADHD and DBH (OR=1.33).[5] The norepinephrine transporter (NET) has been examined in ADHD because drugs that block the norepinephrine transporter ameliorate symptoms of ADHD.[20] In a study involving patients with Tourette's syndrome, Comings and colleagues[21] found an association between ADHD symptoms and a single nucleotide polymorphism (SNP) in SLC6A2 . Subsequently, Barr and colleagues[22] examined SNPs in exon 9, intron 9, and intron 13 in 122 ADHD families and found no evidence of association for these loci or the haplotypes comprising them. Likewise, a study of Irish families found no association with intron 7 and intron 9 SNPs,[23] or with a restriction fragment length polymorphism in offspring of adults with ADHD.[24]

The serotonin transporter gene (HTT) is perhaps the best-studied gene in psychiatric genetics, with associations reported for a broad range of diagnoses and traits.[25,26] When the studies of this gene are combined, the pooled odds ratio for the variant implicated in other psychiatric disorders is 1.31.[5] Several studies examined the G861 variant of the gene encoding the serotonin HTR1B receptor. When results of these studies are combined, the pooled odds ratio is 1.44.[5]

Several investigators have used the coloboma mouse model to investigate the genetics of ADHD. These mice are missing part of chromosome 2q. This mutation leads to spontaneous hyperactivity, delays in achieving complex neonatal motor abilities, deficits in hippocampal physiology (which may contribute to learning deficiencies), and deficits in Ca2+-dependent dopamine release in dorsal striatum.[27] When these mice were given a normal SNAP-25 gene, their hyperactivity diminished.[28] Treatment with amphetamine (but not methylphenidate) reverses the mouse hyperactivity.[27] This latter finding is consistent with the mechanism of action of these 2 stimulant drugs. Both treat ADHD symptoms by blocking the dopamine transporter, but only amphetamine cases reverse transport of dopamine through the dopamine transporter, an effect that could compensate for the reduced exocytotic dopamine release that may be a consequence of the SNAP25 mutation. Several human studies of SNAP25 suggested the gene might be associated with ADHD in humans. Faraone and colleagues[5] pooled these data and found significant evidence for an association with ADHD (OR = 1.19).

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