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Scientists Home In On Gene Linked to OCD

The case is building that a gene on chromosome 9 causes or contributes to obsessive-compulsive disorder (OCD). The gene makes a glutamate transporter, and abnormal glutamate activity has been implicated in OCD.

Although dozens of genes have been linked with various psychiatric disorders, determining whether and how they truly contribute to those illnesses remains a challenge.

Nonetheless, the case is building that a gene on chromosome 9 causes or contributes to OCD and that it does so by sabotaging normal functions of the neurotransmitter glutamate in the brain.

During the past 40 years, family and twin studies have revealed that OCD has a strong genetic component. Then several years ago, investigators linked the disorder to a region of chromosome 9 that includes, among various known genes, one called SLC1A1.

This gene is the only one in that region known to be expressed in the brain. It makes a transporter that is crucial in terminating the action of the excitatory neurotransmitter glutamate. Meanwhile, neuroimaging, neurochemical, and animal studies had been implicating abnormal glutamate activity in OCD. So it seemed plausible that SLC1A1 might be a cause of the disorder. Two research teams—one American and one Canadian—decided to explore this possibility.

The U.S. study included 71 individuals with OCD and their parents. The Canadian study included 157 persons with the illness as well as 319 of their first-degree relatives. The scientists conducting each study took gene samples and analyzed them to see whether various stretches of genetic material spanning the SLC1A1 gene could be linked with having OCD.

Both groups found such a link. Two stretches of genetic material that the U.S. group analyzed were found to be significantly associated with OCD. Two stretches of genetic material that the Canadian group analyzed could also be significantly linked with it. And while the stretches linked to the illness by the two groups were not located in identical regions of the SLC1A1 gene, the regions overlapped.

Gender Surprise Appears

Moreover, both groups found that stretches of genetic material could be linked with OCD mostly in male subjects. "We were surprised by the differential effects in males and females in that we had not expected to find such a pronounced sex effect," Gregory Hanna, M.D., told Psychiatric News. Hanna, an associate professor of psychiatry at the University of Michigan, was the senior investigator of the U.S. study.

Thus, those stretches of the SLC1A1 gene linked with OCD may cause or contribute to the illness, at least in males, Hanna and his team concluded.

The Canadian researchers—James Kennedy, M.D., and his colleagues at the Center for Addiction and Mental Health in Toronto—came to a similar conclusion. Both reports were published in the July Archives of General Psychiatry.

In an editorial that accompanied the two reports, James Leckman, M.D., and Young-Shin Kim, M.D., Ph.D., commented: "These data add to a growing body of work that suggests that SLC1A1 is perhaps a primary candidate gene for OCD." But "if it is true that SLC1A1 is a vulnerability gene for OCD, then there is a lot of work to be done."

Leckman is director of research at Yale University's Child Study Center. Kim is an assistant professor there.

For example, the findings obtained by the two research groups need to be replicated in larger population samples. The regions of the SLC1A1 gene implicated in OCD need to be further narrowed until the precise susceptibility region responsible for the illness is identified. And once the precise susceptibility region is identified and sequenced, then scientists need to learn which variant or variants of the sequence cause the illness. Then they need to determine, in experimental animals, how the complicit variant or variants affect early neural development and whether drugs that act on those variants might benefit individuals with obsessive-compulsive disorder.

Dragnet Widened

Also of great importance, Leckman and Kim asserted, will be determining what other genes or genetic variants might conspire with the SLC1A1 variants in causing OCD. One candidate is the SLC6A4 gene, which codes for the serotonin transporter, and a rare combination of two mutations in it has been linked with a severe form of OCD (Psychiatric News, November 21, 2003).

Another candidate is the SLITrk1 gene. It is involved in neuronal growth, and a rare variant of a sequence within it was recently identified in subjects with Tourette syndrome and obsessive-compulsive symptoms.

The investigation by Hanna and his team was funded by the National Institutes of Health, Jean Young and Walden W. Shaw Foundation, Harris Foundation, Brain Research Foundation, and Obsessive-Compulsive Foundation. The study by Kennedy and his group was financed by the Ontario Mental Health Foundation, Canadian Institutes for Health, National Alliance for Research on Schizophrenia and Depression, and Obsessive-Compulsive Foundation.

An abstract of "Association Testing of the Positional and Functional Candidate Gene SLC1A1/EAAC1 in Early-Onset Obsessive-Compulsive Disorder" is posted at <http://archpsyc.ama-assn.org/cgi/content/abstract/63/7/778>. An abstract of "Glutamate Transporter Gene SLC1A1 Associated With Obsessive-Compulsive Disorder" is posted at <http://archpsyc.ama-assn.org/cgi/content/abstract/63/7/769>.

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