Schizophrenia Predicted by a Gene Variant

Medical Authors and Editors: Barbara K. Hecht, Ph.D. and Frederick Hecht, M.D.

Aug 13, 2004 -- A gene that influences the management of a messenger molecule called glutamate has been found to be a leading candidate for predicting the risk of schizophrenia. The gene known as GRM3 encodes the glutamate receptor. It regulates glutamate at the synapse, the space between neurons in the brain, where glutamate is a transmitter of information from one neuron to the next.

These findings were published online by Michael Egan and colleagues at the National Institute of Mental Health and will appear in print in the August 24th issue of the prestigious Proceedings of the National Academy of Sciences (PNAS).

Schizophrenia and GRM3

Schizophrenia affects several regions in the prefrontal cortex (the front part of the brain) that are involved in cognition including the processes of higher thinking and decision-making. Many of the genes already identified as likely candidates in schizophrenia affect the glutamate system. This study implicates the GRM3 gene.

GRM3 alters glutamate transmission, cognition, and increases the risk for schizophrenia. To pinpoint the section of GRM3 responsible for these changes, a region where the gene may differ by one letter at a location called SNP4 was studied. Normal variants of GRM3 are spelled with an A or, less often, a G.

The A Variant of GRM3

People with schizophrenia were found to be more likely to have the A variant. In other words, the A variant increases the risk of schizophrenia. People with the A variant have lower levels of the chemical that promotes gene expression for the protein responsible for regulating the level of glutamate in the cell. A measure of cell health (called N-acetylaspartate) was lower in people with the A variant. People with the A variant also had poorer performance on several cognitive tests of prefrontal function.

The G Variant of GRM3

The G variant was associated with relatively more efficient processing in the prefrontal cortex. Those who inherit the G variant scored higher on verbal and cognitive tests than those who have two copies of the A variant. In other words, the G variant may exert a protective effect against schizophrenia

People with schizophrenia and some of their healthy brothers and sisters share the inefficient brain physiology and their cognition patterns, which suggests a link to genetic risk to the disease itself. .


The usual mantra now is that schizophrenia is most likely caused by a combination of genetic and environmental factors. Whether this is true or not is unproven, since the causes of schizophrenia have not been clearly and unmistakably identified.

This research on a gene that influences the risk of schizophrenia is of great interest. Why? The A variant of GRM3 gene surely does not cause schizophrenia. It is also not "linked" in the genetic sense to the schizophrenia gene. Rather it is simply "associated" with an increased risk of schizophrenia.

What that means is that there is at least one gene for schizophrenia. (Our guess is that there are multiple genes involved in schizophrenia.)

This research is a step ahead for mankind, a very small step to be sure, but a step nonetheless toward a complete understanding of the causes of schizophrenia.


Michael F. Egan, Richard E. Straub, Terry E. Goldberg, Imtiaz Yakub, Joseph H. Callicott, Ahmad R. Hariri, Venkata S. Mattay, Alessandro Bertolino, Thomas M. Hyde, Cynthia Shannon-Weickert, Mayada Akil, Jeremy Crook, Radha Krishna Vakkalanka, Rishi Balkissoon, Richard A. Gibbs, Joel E. Kleinman, and Daniel R. Weinberger Variation in GRM3 affects cognition, prefrontal glutamate, and risk for schizophrenia. PNAS, published online August 13, 2004, 10.1073/pnas.040507710

Related Links

  • Schizophrenia
  • Antipsychotic Medications


Schizophrenia is the most disabling mental illness. See Answer

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