UW Today

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April 10, 2008

Researchers link genetic errors to schizophrenia

A team of researchers at the UW and Cold Spring Harbor Laboratories has uncovered genetic errors that may shed light on the causes of schizophrenia.

The scientists found that deletions and duplications of DNA are three to four times more common in people with the mental disorder, and that many of those errors occur in genes related to brain development and neurological function.

The findings, which were replicated by a team at the National Institute of Mental Health, appear in the March 27 online edition of the journal Science.

Schizophrenia, a debilitating psychiatric disorder, affects approximately 1 percent of the population. People with schizophrenia suffer from hallucinations, delusions and disorganized thinking and are at risk for unusual or bizarre behaviors. The illness greatly impacts social and occupational functioning and has enormous public health costs.

The team of investigators examined whether the genetic errors, which are individually rare DNA deletions and duplications, contribute to the development of schizophrenia. Some deletions and duplications are common and found in all humans. The researchers studied such mutations that were found only in individuals with the illness, and compared them to mutations found only in healthy persons. They theorized that rare mutations found only in schizophrenic patients would be more likely to disrupt genes related to brain functioning and thus may cause schizophrenia.

The researchers found that in individuals with schizophrenia, mutations were more likely to disrupt signaling genes that help organize brain development. Each mutation was different, and impacted different genes. However, several of the disrupted genes function in related neurobiological pathways.

The findings suggest that schizophrenia is caused by many different mutations in many different genes, with each mutation leading to a disruption in key pathways important to a developing brain. The results have important implications for schizophrenia research. Currently, most genetic studies look for mutations that are shared among different individuals with the illness. These approaches will not work if most patients have different mutations causing their condition.

Fortunately, there are now genomic technologies available that allow researchers to discover rare mutations within each individual with a disorder. As these technologies improve, it will be possible to detect other types of disease-causing mutations and hopefully develop new treatments more specifically targeted to disrupted pathways.

The team was led by UW researchers Tom Walsh, research assistant professor of medicine in the Division of Medical Genetics; Jon McClellan, associate professor of psychiatry and behavioral sciences; and Mary-Claire King, American Cancer Society professor of medicine and genome sciences; and by their Cold Spring Harbor collaborators Shane McCarthy and Jonathan Sebat.