Researchers close in on genetics of attention-deficit disorder

A team of researchers at the Medical Center and Biological Sciences Division 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, which is reported in the April issue of the American Journal of Human Genetics, could lead to earlier diagnosis and better treatment for people with the disorder.

ADHD, which is characterized by a low attention span and impulsive behavior, affects an estimated 6 percent of children and about 2 percent of adults in this country.

"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 Edwin Cook Jr., Associate Professor in Psychiatry and Pediatrics and lead author of the report.

The researchers emphasize that this study does not prove that defects in the dopamine transporter gene cause attention-deficit disorder. But it does place that gene, already a suspect, at the scene. "It gives us enough reason to begin to look in earnest for mutations in this specific gene," Cook said.

The genetics of psychiatric disorders have been notoriously difficult to trace. Two previous reports tying ADHD to specific genes have not been replicated.

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 Medical Center's ADHD clinic do not have ADHD.

Cook and his 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 multidisciplinary 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 in which many members, spread over several generations, suffer from the 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 did not.

This approach, which relies on a few large families, can produce misleading results for a disorder such as ADHD that 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.

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 association between attention-deficit disorder and inheritance of the marker.

"This doesn't mean that we have bagged the gene -- there could be other genes that are linked to the marker and contribute to the disorder, or there could be a combination of genes that triggers ADHD, and the finding has yet to be replicated. But we're sufficiently optimistic to start looking for mutations in this gene," Cook said.