Genes yield clues to schizophrenia's roots. (Psychotic Biology).

Scientists have identified two genes that, in certain molecular guises, may contribute to schizophrenia by disrupting transmission of a crucial chemical messenger in the brain.

While the presence of each gene variant by itself makes it more likely that a person will develop this severe mental disorder, this risk is greatly magnified when the two occur together, according to a team led by geneticist Daniel Cohen of the biotechnology firm Genset S.A. in Evry, France.

Both genes produce proteins that influence the activity of NMDA receptors, a class of molecular docking stations on brain cells. Since 1996, researchers have proposed that disturbances of these receptors for the neurotransmitter glutamate contribute to schizophrenia symptoms, including confused thinking and hallucinations.

"The association of both [genes] with schizophrenia points to the involvement of this NMDA-receptor regulation pathway," Cohen says. "The same pathway may influence psychotic problems in other diagnoses, such as bipolar disorder."

The new report appears in an upcoming Proceedings of the National Academy of Sciences.

If the findings hold up, people who inherit either or both of the critical gene versions still aren't doomed to develop schizophrenia, Cohen cautions. Further research is needed to identify other genes, as well as environmental factors, that influence the same NMDA-receptor pathway, he says.

Cohen's team obtained DNA from about 200 people with schizophrenia and about the same number who had no past or current psychiatric disorders living in Quebec, Canada, and from a similar sample in Moscow, Russia. The scientists first used chemical markers to tag different genetic patterns along a stretch of chromosome 13 that had previously been linked to schizophrenia. They then identified a specific sequence of nucleotides--DNA's basic chemical units--that appeared more often in participants with schizophrenia than in the others.

Cloning of this DNA sequence led to the isolation of a new gene, dubbed G72 by the scientists. Laboratory experiments indicated that G72 produces a protein that interacts with the enzyme D-amino acid oxidase (DAAO). The latter substance triggers chemical processes that lower the propensity of NMDA receptors to welcome glutamate.

The researchers were unable to find a gene comparable to G72 in mice. Shortened versions of G72 turned up in chimpanzees, gorillas, and two monkey species. G72 may represent a primate-specific gene that has evolved rapidly in people in connection with changes in brain development, Cohen theorizes.

His group also found an association between schizophrenia and a specific nucleotide sequence on the gene for DAAO.

These results coincide with a growing body of data implicating a disturbed transmission of signals carried by glutamate in schizophrenia, comments psychiatrist Joseph T. Coyle of Harvard Medical School in Boston. If the G72 gene indeed contributes to this disorder, its discovery may aid in developing improved drug treatments, he says.

Ann E. Pulver, a psychiatric epidemiologist at Johns Hopkins University, calls the new report "very interesting" but awaits confirmation of the findings in further studies.