UCLA geneticists find location of major gene in ADHD; targeted region also linked to autism

UCLA Neuropsychiatric Institute researchers have localized a region on chromosome 16 that is likely to contain a risk gene for Attention Deficit Hyperactivity Disorder, the most prevalent childhood-onset psychiatric disorder.

Their research, published in the October edition of the American Journal of Human Genetics, suggests that the suspected risk gene may contribute as much as 30 percent of the underlying genetic cause of ADHD and may also be involved in a separate childhood onset disorder, autism.

Pinpointing a gene with a major role in ADHD will help researchers and clinicians better understand the biology of this disorder and likely lead to the development of improved diagnosis, treatment and early intervention.

“We know there are about 35,000 genes in the human genome. By highlighting this region on chromosome 16, we have narrowed our search for a risk gene underlying ADHD to some 100 to 150 genes,” said Susan Smalley, principal investigator of the study and co-director of the Center for Neurobehavioral Genetics at the UCLA Neuropsychiatric Institute.

“Still, we must wait for independent replication of our results to confirm these findings,” said Smalley, also a professor of psychiatry and biobehavioral sciences at the David Geffen School of Medicine at UCLA. “Ultimately, we must identify the specific risk gene from among the 100 to 150 genes in this region before we can move to the next level of using such findings to help individuals with ADHD.”

By studying families in which there are two or more ADHD siblings, the investigators were able to “scan” the entire human genome, containing some 35,000 genes, to focus in on specific regions likely to contain a gene contributing to ADHD.

In their initial scan, several regions showed modest support for a risk gene; however, in a follow-up study of one region on chromosome 16, evidence of a risk gene was striking — with favorable odds of 10,000 to 1. Surprisingly, independent studies have implicated the same region as harboring a risk gene for autism, suggesting that ADHD and autism may have some common genetic underpinnings. Whether a common gene contributes to both remains to be determined.

ADHD and autism are very distinct clinical conditions. Although certain features are shared, the underlying biological mechanisms are thought to be distinct. If a common risk gene on chromosome 16 were found to underlie ADHD and autism, Smalley said, the finding would illustrate that genes affecting neurobiological mechanisms can cut across clinical boundaries, as most geneticists suspect.

“This study provides compelling evidence that ADHD and autism may have a lot more in common than we ever thought, with implications for both diagnosis and treatment,” Smalley said. “However, further investigation is required to determine the significance of this finding, as it is also quite feasible that distinct risk genes underlying each condition just happen to be in close proximity on chromosome 16.”

UCLA researchers spent five years collecting clinical, cognitive and genetic data from 203 families with multiple ADHD children. Their initial search for shared DNA markers suggested regions on chromosomes 16, 10 and 12. Focusing their attention on chromosome 16, researchers found a series of molecular “markers” shared among sibling pairs at a rate higher than the 50 percent sharing expected due to their degree of relationship.

Based on the observed degree of DNA sharing among ADHD siblings, the researchers estimate that the risk gene — if replicated by other scientists studying ADHD — might account for as much as 30 percent of the genetic cause of ADHD. As with any initial finding, however, the investigators caution that replication is necessary and that significant work with more families will be needed to find a specific risk gene in that location.

Previous investigations into a genetic cause for ADHD have focused on specific candidate genes, such as those involved in regulation of dopamine, a chemical in the brain implicated in ADHD. Previous studies of dopamine receptor genes (whose products are important in releasing dopamine in the cells) and dopamine transporter genes (whose products are involved in moving dopamine between cells) suggest they may also be involved in ADHD. The risk for ADHD in individuals carrying these genes, however, is very small, maybe 1.2 to 1.5 times the risk of those without such genes.

ADHD is the most common childhood-onset behavioral disorder, affecting as many as one in 10 children and three times as many boys as girls. Symptoms of both inattention and hyperactivity, which can last into adulthood, can affect school and work performance as well as social skills. Researchers estimate that the cause of ADHD is 70 percent to 80 percent genetic, and the remainder largely environmental.

Autism is a neurological disorder that affects perhaps as many as one in 500 children and usually appears within the first three years of a child’s life. It affects the brain in the areas of social interaction and communication. Autism, like ADHD, is thought to be due to multiple genetic and environmental factors, although genetics seems to dominate, with more than 60 percent to 70 percent of the underlying cause of autism thought to be genetic.

The National Institute of Mental Health, a University of California BioStar grant and the Wellcome Trust, through the Wellcome Trust Centre for Human Genetics in Oxford, England, provided financial support for the research.

A team of investigators at UCLA and the Wellcome Trust Center for Human Genetics in Oxford conducted the research. The UCLA team includes Stanley F. Nelson and members of his lab, Vlad Kustanovich, Jennifer Stone and Matthew Ogdie of the UCLA Center for Neurobehavioral Genetics and Department of Human Genetics; James J. McGough and James T. McCracken of the UCLA Department of Psychiatry and Biobehavioral Sciences; Rita M. Cantor of the UCLA Department of Human Genetics; and Sonia L. Minassian of the UCLA Center for Neurobehavioral Genetics and Department of Biostatistics. The team from Wellcome Trust Centre for Human Genetics, led by Anthony P. Monaco, includes Simon E. Fisher, Laurence MacPhie and Clyde Francks.

The UCLA Neuropsychiatric Institute is an interdisciplinary research and education institute devoted to the understanding of complex human behavior, including the genetic, biological, behavioral and sociocultural underpinnings of normal behavior, and the causes and consequences of neuropsychiatric disorders.

Research at the Institute’s Center for Neurobehavioral Genetics focuses on the discovery of the genetic basis of major neurobehavioral disorders, including autism, attention deficit hyperactivity disorder, dementias, depression, manic-depressive illness (bipolar disorder) and schizophrenia.