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Attention Deficit Hyperactivity Disorder - The Molecular Genetics Of Adhd

dopamine studies faraone study

Molecular genetic studies have already implicated several genes as mediating the susceptibility to ADHD. Researchers have examined candidate genes in dopamine pathways because animal models, theoretical considerations, and the effectiveness of stimulant treatment implicate dopaminergic dysfunction in the pathophysiology of this disorder. Dopamine is a neural trans-Dopamine is a neurotransmitter in the brain and is used in neural pathways involved in both movement control and pleasure/reward systems. Dopamine released by one neuron crosses the synapse to stimulate the adjacent neuron. It is broken down by glial cells. mitter in the brain used in both movement control and pleasure/reward systems. In its simplest form, the dopamine hypothesis holds that excess clearance of dopamine between neurons may contribute to ADHD.

Many studies have focused on the D4 dopamine receptor gene (DRD4) which encodes a protein receptor that mediates the post-synaptic action of dopamine. A meta-analysis of these studies showed a small but statistically significant association, which could not be accounted for by any single study or by publication biases. Although the nature of the mutations in DRD4 have not been conclusively described, a version of the gene known as the 7repeat allele has generated much interest because this allele causes a blunted response to dopamine and has been implicated in novelty seeking, a personality trait of many ADHD patients.

Several authors have reported an association between ADHD and a particular allele of the dopamine transporter (DAT) gene. This finding has been replicated by some, but not all studies. The link between the DAT gene and ADHD is further supported by a study that relates this gene to poor methylphenidate response in humans, a "knockout" mouse study showing that its elimination leads to hyperactivity in mice, and two molecular neuroimaging studies that found elevated DAT density in the striatum of ADHD adults.

Molecular genetics studies of ADHD have also targeted other genes that are related to the dopamine system. Four studies have examined the Catechol-O-Methyltransferase (COMT) gene, whose protein product breaks down dopamine and norepinephrine. Although one study found ADHD was associated with the high-activity form of COMT, three others could not replicate the finding. Other candidate genes that show promising results for ADHD are the D5 dopamine receptor gene and the serotonin 1B receptor. This latter finding is intriguing because, although serotonergic medicines do not help ADHD symptoms, these systems have been implicated in animal models of the disorder.

Stephen V. Faraone

Bibliography

Faraone, S. V., D. Tsuang, and M. T. Tsuang. Genetics of Mental Disorders: A Guide for Students, Clinicians, and Researchers. New York: Guilford, 1999.

Faraone, S. V., and A. Doyle. "The Nature and Heritability of Attention Deficit Hyperactivity Disorder." Child and Adolescent Psychiatric Clinics of North America 10 (2001): 299-316.

Faraone, S. V., and J. Biederman. "Neurobiology of Attention Deficit Hyperactivity Disorder." Biological Psychiatry 44 (1998): 951-958.

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