December 8, 2006

Link between gene variant, ADHD identified

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Randy Blakely, Ph.D., and his team, including Angela Steele, left, and Maureen Hahn, Ph.D., are studying a gene associated with attention-deficit hyperactivity disorder.
Photo by Susan Urmy

Link between gene variant, ADHD identified

Researchers have identified a link between a genetic variant that influences brain chemistry and attention-deficit hyperactivity disorder (ADHD).

In the December 12 issue of the Proceedings of the National Academy of Sciences, researchers from Vanderbilt University Medical Center and McLean Hospital at Harvard Medical School report that a common gene variation that could alter levels of the brain chemicals norepinephrine and dopamine is more common in children with ADHD than children without the disorder.

ADHD, characterized by impulsive behavior, hyperactivity, and an inability to maintain attention, affects nearly 2 million children in the United States. Because ADHD often runs in families, scientists have been searching for genes that might be linked to the disorder.

Since the neurotransmitters dopamine and norepinephrine are thought to play a role in ADHD, genes involved in their regulation have been a major focus of investigation.

A recently approved drug called atomoxetine (brand name Strattera) selectively blocks the norepinephrine transporter (NET) and has shown some effectiveness in treating ADHD. This suggests that the NET, which regulates levels of the neurotransmitter norepinephrine, might be involved in some cases of ADHD. However, to date scientists have failed to identify functional mutations in the NET gene (SLC6A2) in children with ADHD.

“We believe that both norepinephrine and dopamine play key roles in cortical circuits supporting arousal and attention,” said Randy Blakely, Ph.D., the Allan D. Bass Professor of Pharmacology and investigator for the Vanderbilt Kennedy Center for Research on Human Development.

Of particular interest, Blakely said, is the ability of NET to inactivate both of these molecules. “Therefore, genetic alterations in NET may have a double impact on chemical signals in the brain and could be important for understanding the neurochemical changes underlying ADHD.”

Blakely and Vanderbilt cardiovascular researcher David Robertson, M.D., had initially collected DNA samples from subjects with ADHD to examine whether NET changes lead to alterations both in heart and brain function. Within this population, Blakely and Harvard colleagues searched for variants in the promoter of the SLC6A2 gene, a region that controls how much NET is produced.

The researchers identified a common gene variant (carried by about 20 percent of the population) in this region of the NET gene.

However, the variant was found more frequently in children with ADHD — 37 percent of children with ADHD carried the variant compared to only 22 percent of children without the disorder. Children with ADHD were also three times more likely than controls to have two copies of the less effective variant.

The genetic variation reduced the activity of the NET gene in cultured cells by about 50 percent, the researchers found. The Harvard team, led by Kwang-Soo Kim, Ph.D., showed that the variant created a sequence within the promoter that can bind to “repressor proteins,” which inactivate the gene. Since these proteins can block or reduce the expression of NET, this finding might explain the observed reduction in NET.

Although the study involved a relatively small number of patients, the findings suggest that children with this gene variant might be at higher risk of developing ADHD. Further studies in larger populations should be done to verify the findings, the authors said.

While finding this specific change in the NET gene and elucidating how it can influence NET expression in ADHD is important, Blakely notes that the work now draws attention more sharply to the disrupted signaling of norepinephrine and dopamine as key facets of ADHD.

And since many other genes control how these chemicals are made and degraded and how they signal, “we now have these genes on our radar both for future diagnosis of ADHD risk as well as the development of medications,” he said.

“Faced with the complexities of how the brain works, a foot in the door is welcome.”

Kwang-Soo Kim, Ph.D., of McLean Hospital at Harvard, was lead author on the study. Other Vanderbilt authors include: Maureen Hahn, Ph.D., Angela Steele, Michelle Mazei-Robison, and David Robertson, M.D. The research was supported by grants from the National Institutes of Health and the National Alliance for Research on Schizophrenia and Depression (NARSAD).

Blakely is also professor of Psychiatry and director of the Center for Molecular Neuroscience and the Vanderbilt Brain Institute.