Rare Mutations Hint at Multiple Schizophrenias

Scientists trying to link schizophrenia to a few, common genetic mutations may be missing an important cause of the disease. New research suggests that rare mutations--sometimes so infrequent that they occur in just a single family or individual--can significantly boost schizophrenia risk. Researchers suspect that these variants will prove to have effects on key aspects of brain development.

Schizophrenia afflicts about 1% of the overall population, but a much higher proportion of homeless people and prison inmates. The disease has a strong heritable component, but researchers have struggled to find the genetic culprits. The working hypothesis has been that the disease is caused by combinations of common gene variants. For example, a common variation of the catechol-O-methyltransferase (COMT) gene, which chemically breaks down dopamine, is associated with a slightly higher risk for schizophrenia. But a variant of any of these candidate genes increases a person's risk of schizophrenia only a tiny amount.

Suspecting that rarer mutations might play a stronger role in schizophrenia, two teams of researchers looked for uncommon deletions or duplications of tiny DNA sequences within genes that occur only in individual patients or their close relatives. One team, led by medical geneticist Thomas Walsh at the University of Washington, Seattle, found these rare so-called copy number variants in 15% of 150 schizophrenics they surveyed. Only 5% of 268 healthy controls carried the same variants. The other team, at the National Institute of Mental Health (NIMH) in Bethesda, Maryland, examined DNA from 83 people with severe forms of the disease diagnosed before the age of 13 and compared them with 77 controls. Among this early-onset group, 20% had rare copy number variants--four times the rate in the controls.

In both cases, the rare copy-number variants were "not random. They tend to cluster around genes important for brain development," such as those that control neuronal growth and migration, observed NIMH Director Thomas Insel at an institute press seminar today. Nor are they unique to schizophrenia--they "probably will show in a variety of developmental disorders," particularly mental retardation and autism, added Judith Rapoport, leader of the NIMH team. In fact, some of the authors of the current paper last year reported a similar pattern of rare and idiosyncratic mutations in people with autism (Science, 20 April 2007, p. 445).

The findings, reported online today in Science, support the idea that there are any number of types of schizophrenia. Future treatments might therefore be targeted to specific pathways depending on the patient's genetics.

Schizophrenia researcher Irving Gottesman of the University of Minnesota, Twin Cities, notes that the studies represent a small nibble in a very large pie, because the great majority of patients in both samples did not have rare deletions. Nonetheless, he says, "since nothing else has worked so far to give us a 'breakthrough,' it is past time to look for other strategies." And psychiatrist Kenneth Kendler of Virginia Commonwealth University in Richmond notes that "if this approach is replicated, it could profoundly alter the focus of genetics research" on a variety of complex mental illnesses.

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