Schizophrenia Gene Variant Linked to Risk Traits

Press Release- August 11th 2004

Researchers at the NIH's National Institute of Mental Health (NIMH) have identified a relationship between a small section of one gene, the brain chemical messenger glutamate, and a collection of traits known to be associated with schizophrenia . The finding confirms the gene responsible for management of glutamate is a promising candidate in determining risk for schizophrenia. The study, conducted by Michael Egan, M.D., Daniel Weinberger, M.D., and colleagues, is in the August 24th issue of the Proceedings of the National Academy of Sciences, published online the week of August 9, 2004.

Glutamate is a key neurotransmitter long thought to play a role in schizophrenia. The gene identified in this study makes the glutamate receptor (GRM3), which is responsible for regulating glutamate in synapses-spaces in between brain cells-where chemicals like glutamate transfer information from cell to cell. The amount of glutamate remaining in the synapse may have a downstream impact on cognition.

"Because of the small effects of individual genes in complex genetic disorders like schizophrenia, it is difficult to make significant associations with any one particular marker. However, this study brings us closer to unlocking the genetic clues that increase the risk for schizophrenia," said NIMH Director Thomas R. Insel, M.D.

Researchers know that schizophrenia affects several regions in the front part of the brain that are involved in higher order thinking and decision-making and neurotransmitter systems like glutamate. Many of the genes already identified as likely candidates for the disorder have been thought to affect the glutamate system. The study implicates the GRM3 gene as well.

GRM3 alters glutamate transmission, brain physiology and cognition, increasing the risk for schizophrenia. To pinpoint the section of the gene responsible for these changes, scientists are exploring a region where the gene may differ by one letter at a location called SNP4. The normal variation is spelled with either an 'A'-the more common of the two-or a 'G'. Patients with schizophrenia are more likely to inherit an 'A' from either parent, indicating the 'A' variant slightly increases risk. The 'A' variant is also associated with the pattern of traits linked with the disorder. This was true in patients, their healthy siblings, and normal volunteers.