Schizophrenia Gene Variant Linked to Risk Traits
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,
will be in the August 24th issue of the Proceedings of the National
Academy of Sciences, published online the week of August 9,
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
"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,
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.
In the study, people with an 'A' variant have differences in measures
of brain glutamate. In a postmortem study of brain tissue, the 'A'
variant was associated with lower levels of the chemical that promotes
gene expression for the protein responsible for regulating the level
of glutamate in the cell. N-acetylaspartate, a measure of cell health
evaluated through the use of MRI spectroscopy, was lower in 'A'
participants. 'A' carriers had poorer performance on several cognitive
tests of prefrontal and hippocampal function than people with the
'G' variant. The 'G' marker 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 of the 'A' variant. Scientists think the less
common 'G' variant may exert a protective effect against the disease.
People with schizophrenia and their healthy siblings share the
inefficient brain physiology, and cognition patterns, which suggests
a link to genetic risk, though the disease itself is most likely
caused by a combination of genetic and environmental factors. The
gene seems to affect the mechanism of memory encoding only as there
was no genotype effect seen during retrieval in the memory tests.
Although scientists could not be certain that the 'A/G' difference
accounts for all the affects on brain function, there may be yet
undiscovered variations located near SNP4 on the GRM3 gene. It is
unclear as to why the higher-risk 'A' variant is more common in
humans. Researchers speculate that it may provide a counterbalancing
advantage, perhaps related to reduced glutamate in the cells.
Also participating in the research were: Drs. Richard Straub, Terry Goldberg, Joseph Callicott, Ahmad Hariri, Venkata Mattay, Thomas Hyde, Cynthia Shannon-Weickert, Mayada Akil, Radha Krishna Vakkalanka, Rishi Balkissoon, Joel Kleinman; Alessandro Bertolino, NIMH and Universita Study Bari, Italy; Jeremy Crook, NIMH and ES Cell International; Imtiaz Yakub, and Richard Gibbs, Baylor College of Medicine.
NIMH is part of the National Institutes of Health (NIH), the
Federal Government's primary agency for biomedical and behavioral
research. NIH is a component of the U.S. Department of Health and