Scientists Identify Gene That May Raise Schizophrenia Risk

UC Irvine scientists have identified a gene that they believe increases the risk of both schizophrenia and manic-depressive illness--mental disorders that, combined, affect as many as 5 million Americans.

Although the history of attempts to associate genes with mental illness is littered with claimed links that could not be verified, the new finding seems credible, some experts said. They noted that the mutated gene falls into the same class of mutations as recently discovered genes linked to Huntington’s disease, fragile X syndrome and several other disorders of the brain.

UC Irvine geneticist Jay Gargus is scheduled to report today at a Baltimore meeting of the American Society for Human Genetics that the newly identified gene contains an unstable stretch of DNA that grows longer when the gene is passed from parent to child, increasing the severity of the disease and decreasing the age of onset--a hallmark of the new family of genes.

“If our results are confirmed by further studies, this discovery could lead to the development of new tests to identify those at risk for these diseases, and possibly to a new generation of highly targeted drugs with which to treat them,� he said.

But Gargus cautioned that the new gene is only one of several whose products combine with environmental factors to produce the disorders, and its presence in the brain is neither necessary nor sufficient to cause the disease.

Even so, if the finding is confirmed, it “will provide a window into the [cause] of these very complicated illnesses,� said Dr. Edward Ginns of the National Institute of Mental Health. “It’s very exciting,� he said, but the results need to be validated in a much larger study.

Schizophrenia is a complex mixture of behaviors that include hallucinations and delusions, problems relating to other people, flat or inappropriate emotional expression, bizarre behavior, paranoia and suspiciousness. Many researchers believe that the disorder is a set of loosely related diseases that have been mistakenly lumped under one name.

Researchers have long suspected a genetic role in the disease. The odds of developing schizophrenia at some time during an individual’s life are one in 100 but, if a person has a relative with the disorder, the odds are 1 in 10. If both parents have it, the odds are 2 in 5, and if an identical twin has it, the odds climb to 1 in 2.

In January, researchers from the University of Colorado found one gene that increases a person’s risk of schizophrenia. That gene is the blueprint for a receptor that also binds to nicotine, and helps explain why many schizophrenics smoke heavily. Today’s announcement would mark the second gene linked to the disease.

The new finding is based on the earlier discovery that Huntington’s and at least five other brain disorders are caused by an unstable segment of DNA. The healthy gene contains a segment in which three nucleotides--the building blocks of genes--called C, A and G are repeated a few times.

In Huntington’s and the other disorders, genes from the affected individuals contain a much higher number of C-A-G repeats, and this somehow changes the function of the proteins produced from the gene, causing illness.

The mutated genes also show a phenomenon called “anticipation.� When the gene is passed from parent to child, the number of C-A-G repeats increases and the disease appears earlier in life. It also becomes more severe.

Because some families with schizophrenia seem to demonstrate anticipation, researchers have suspected that it might be caused by a similar mutation.

Geneticist Michael O’Donovan of the University of Cardiff in Wales examined DNA from the blood of schizophrenics and found that it contained segments with larger numbers of C-A-G repeats than were in DNA from healthy individuals. But he could not tie the repeats to a specific gene.

Meanwhile, working on a completely different project, UC Irvine physiologist George Chandy was looking through computerized gene databases for the human counterpart of a newly discovered rat gene. The gene he was looking for serves as a blueprint for a protein that allows potassium ions to pass through cellular membranes.

He found the gene and noted that it contained previously unrecognized C-A-G repeats. “It was a fortuitous finding because we don’t normally work on neural genes,� said his collaborator, geneticist George Gutman.

Especially promising was the fact that the gene, called hSKCa3, was in a narrow region of chromosome 22 that researchers already believed was the location of a schizophrenia gene.

Working with researchers from the University of Pittsburgh, as well as German and French collaborators, the team then studied DNA from the blood of 150 patients with either schizophrenia or manic-depressive illness and compared it to similar samples from healthy individuals.

They found that more of the mentally ill patients had long C-A-G segments than did the healthy controls, suggesting that the gene is linked to the disorder.

The next step, Gutman said, is to study a larger number of patients and confirm that their finding is real. The researchers also will attempt to insert proteins produced from the mutated genes into cells grown in the laboratory to find out how the protein works and how it could interfere with mental functioning.