ADHD gene traced

1995

Researchers close in on genetics of attention deficit disorder

A team of researchers from the University of Chicago Medical Center has found evidence of an association between attention deficit hyperactivity disorder (ADHD), an extremely common childhood behavioral disorder, and a gene that regulates the actions of the neurotransmitter dopamine. The finding is reported in the April issue of the American Journal of Human Genetics.

Using a novel methodology, the researchers found an association between the disorder and a DNA marker that is very close to the dopamine transporter gene, which controls the intake of this important neural messenger by the nerve cells that respond to dopamine's signal.

"If we can establish a link between abnormal forms of this gene and ADHD, it could provide us with a powerful new tool for precise diagnosis and early identification of children at risk, and a signpost toward designing better drug treatment," said Ed Cook, associate professor of psychiatry and of pediatrics at the University of Chicago and lead author of the report.

This study does not prove that defects in the dopamine transporter gene cause attention deficit disorder, emphasize the researchers, who remain extremely cautious about their finding. But it does place that gene, already a suspect, at the scene of the crime. "It gives us enough reason to begin to look in earnest for mutations in this specific gene," said Cook.

The genetics of psychiatric disorders have been notoriously difficult to trace. Two previous reports tying ADHD to specific genes have not been replicated. Earlier reports that ADHD was linked to resistance to thyroid hormone or to the dopamine D2 receptor gene have not held up to closer scrutiny.

One problem with studying the genetics of psychiatric disorders has been the difficulty of making a precise diagnosis of the study subjects based on behavioral rather than more precise metabolic criteria. ADHD is often misdiagnosed. Approximately 40 percent of patients referred to the University of Chicago Medical Center's ADHD clinic do not have ADHD.

Cook and colleagues were able to confine their study to patients who unquestionably had the disorder, based on an unusually thorough, six-hour evaluation of each study patient by a multi-disciplinary clinical team that specializes in ADHD.

A second problem stems from the way susceptibility genes are typically sought. Usually disease genes are discovered by first collecting blood from large families with many members, spread over several generations, who suffer from a disease. Then researchers comb through their subjects' entire genomes for variable markers that tend to differ between those who inherited susceptibility to the disease and those who didn't.

This approach, which relies on a few large families, can produce misleading results for a disorder such as ADHD which may involve several genes, unlike single-gene disorders such as cystic fibrosis or Huntington's disease.

In this case, however, the researchers had the advantage of focusing on a candidate gene rather than combing the entire genome. This allowed them to look at fewer members of more families, and to look in much greater detail at the inheritance of one marker that is located next to the target gene. Variations in this marker allowed them to determine which two of the parents' four genes were passed on to children suffering from ADHD, a technique known as haplotype-based haplotype relative risk analysis.

After studying 56 families--whenever possible including the mother, father and affected child--they found that one particular version of the marker accompanied susceptibility to ADHD. The inheritance pattern revealed a significant (p = 0.006) association between attention deficit disorder and inheritance of the marker.

"This certainly doesn't mean that we have bagged the gene," cautions Cook. "There could be other genes that are linked to this marker and contribute to the disorder, or there could be a combination of genes that trigger ADHD," he warns. "And so far no one has replicated our finding.

"But we're sufficiently optimistic to start looking for mutations in this gene."

Symptoms of ADHD include a low attention span and impulsive behavior. It affects an estimated six percent of children and about two percent of adults.

Other members of the research team include Mark Stein, Nancy Cox, Bennett Leventhal, Matthew Krasowski, Deborah Olkon, Bruce Berget, and John Keiffer, all of the University of Chicago Medical Center.