Gene Defect Linked to Schizophrenia, Researchers Say

Researchers have identified a genetic defect that they say predisposes some people to schizophrenia, the most common severe mental disorder, and explains why most schizophrenics are heavy smokers.

Studying nine large families in Utah and Colorado with multiple cases of schizophrenia, the scientists report today in the Proceedings of the National Academy of Sciences that the schizophrenics have a defect in the gene for a key receptor in the brain.

The receptor, normally activated by a neurotransmitter called acetylcholine, doesn’t function well in schizophrenics. Interestingly, the receptor is also activated by nicotine, which can thereby temporarily alleviate some symptoms of schizophrenia.

“We previously viewed [heavy smoking among schizophrenics] as just a bad habit or a means of dealing with boredom,” said Dr. Robert Freedman of the University of Colorado School of Medicine, the lead author of the study. “But in fact, it was an attempt to specifically target what is going wrong” in their brains.

Other researchers, however, are cautious in accepting the results because previous attempts to link schizophrenia, manic-depressive illness and other mental disorders to genetic defects could not be replicated.

“It’s an interesting finding that will require replication” and studies in a larger number of families, said geneticist Steven Moldin of the National Institute of Mental Health.

“It’s a small and exciting step forward,” said psychologist Mark Lenzenweger of Cornell University. “The most important thing we can look for now is a very nice and strong effort to replicate it, preferably in an independent laboratory.”

Nevertheless, the researchers say the findings provide a new approach to developing drugs to treat schizophrenia, an extremely disabling disorder that affects as many as 4 million Americans.

Schizophrenia is not a split-personality disorder, as many people mistakenly believe. Rather, it is a complex mixture of behaviors that include hallucinations and delusions, problems relating to other individuals, flat or inappropriate emotional expression, bizarre behavior, paranoia and suspiciousness. Many researchers believe that the disorder is actually a set of loosely related diseases that have been mistakenly lumped under one name. That complexity is a major reason for the slow progress toward identifying a genetic link.

Researchers have long suspected the presence of a genetic component to the disease. The odds of developing schizophrenia at some time during an individual’s life are 1 in 100 but, if a person has a relative with the disorder, the odds are 1 in 10.

It is also clear, however, that environment plays a major role in triggering the disorder in genetically susceptible people. Some possible triggers, researchers believe, include a viral infection during the second trimester of pregnancy and Rh incompatibility between the mother and the infant.

Previous studies have suggested that susceptibility genes for schizophrenia may be present on five separate chromosomes and researchers are working to identify those genes. But “the prey remains elusive,” Moldin said.

Freedman and his colleagues at the Department of Veterans Affairs discovered the newly reported gene, on chromosome 15, by focusing on one very specific aspect of schizophrenia--the patient’s inability to filter out background noise in the environment.

“Normally, the brain adapts to a repeating sound, like a rattling air conditioner,” Freedman said. “You still hear it, but you no longer notice it. A schizophrenic can’t shut that noise out” and suffers information overload that contributes to his or her symptoms.

Freedman and his colleagues developed an EEG screening test to identify this loss of noise-filtering ability, then used conventional genetic techniques to associate the loss with a genetic defect. The gene they ultimately isolated is the blueprint for a protein called the alpha-7 nicotinic cholinergic receptor.

The hippocampus region of the brain is crucial to determining what seems important at any moment and what is not. The hippocampus is alerted by acetylcholine, which binds to the alpha-7 receptor. If the alpha-7 receptor is damaged, the brain cannot ignore some sounds and becomes overloaded.

The team has already shown that inhaled nicotine can suppress sensitivity to such noises in people with a damaged alpha-7 receptor, producing a calming or soothing effect. But that effect is too short-lived to have any real treatment value, Freedman said. The team has already begun working with drug companies to develop compounds that target the receptor more effectively.

The presence of this defective gene alone is not sufficient to cause schizophrenia, Freedman emphasized. Other non-schizophrenic members of the families also carried the defect. “They may have a filtering problem, but you must have other factors present before you get schizophrenia.”

Psychologist Philip Holtzman of Harvard University said the discovery is important because it expands the definition of schizophrenia beyond clinical symptoms to a very specific neurological defect.

Moldin, however, said he would like to see more proof that the defect Freedman studied actually plays a crucial role in schizophrenia before he concludes that the gene is important as well.