Researchers have found a variant gene in schizophrenics that appears to be implicated in defective working memory and other cognitive problems that characterize the disease. The study is among the first to reveal the way a specific gene contributes to mental illness.
The search for the genetic roots of schizophrenia has been frustrating. It's tough to learn which gene variants are associated with the disorder because many genes seem to be involved. To get around that problem, psychiatrists Michael Egan and Daniel Weinberger of the National Institute of Mental Health (NIMH) in Bethesda, Maryland, decided to look instead for mental traits in schizophrenia-prone families that might track with schizophrenia in the same way that high cholesterol tracks with heart disease.
The team used a standard card-sorting test to probe the ability to briefly retain a series of numbers. Called working memory, this task relies on the prefrontal cortex via the neurotransmitter dopamine and a dopamine-degrading enzyme called catechol-O-methyltransferase (COMT). Researchers had already found hints that a variant gene encoding a faster version of this enzyme--which would mean lower levels of dopamine--seemed to be more common in schizophrenics. Sure enough, the 146 individuals with only the fast version of the enzyme performed worse on the card-sorting test, the researchers report in the 29 May Proceedings of the National Academy of Sciences. In a separate experiment, both schizophrenics and their siblings did worse than controls.
Egan and his colleagues also showed with brain imaging that the prefrontal cortex was abnormally active in subjects with the faster enzyme when they were trying to keep in mind a set of numbers. The results "really strongly suggest" that the COMT gene affects working memory by altering dopamine signaling in the prefrontal cortex, Egan says.
Next the NIMH team plans to test whether COMT-blocking drugs, currently used to treat Parkinson's disease, can improve working memory in schizophrenics. "This is a major paper," says psychiatrist Michael Flaum of the University of Iowa College of Medicine in Iowa City. It "gets to a particular [brain] mechanism involving a single protein," thus linking genetics with function, he notes.