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. .
Comment
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.
Source
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
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Last Editorial Review: 8/13/2004
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