A rare gene variant discovered by UCL scientists is
associated with an increased risk of developing schizophrenia,
bipolar disorder and alcoholism, confirms new research.
People with the variant are around two to three times more
likely to develop schizophrenia or alcohol dependence, according to
the study, published in Psychiatric Genetics.
The variant, which is found in approximately one in every 200
people, is also associated with a threefold risk of developing
bipolar disorder, as previously shown by the same UCL group. The
research is based on genetic analysis of 4,971 people diagnosed
with one of the three disorders compared with 1,309 healthy
controls. It found that people with the variant of the GRM3 gene,
thought to be important in brain signalling, were at increased risk
of developing bipolar disorder, schizophrenia and alcohol
dependence.
GRM3's association with schizophrenia was also confirmed by a
global study involving a consortium of over 200 institutions
including UCL. The research, published in Nature, involved
searching the genomes of 36,989 people with schizophrenia and
113,075 healthy subjects from across the world. 108 different
genetic locations were found to be associated with the disease, but
GRM3 is the only one for which a specific mutation responsible has
been identified.
"We could be looking at the next big drug target for treating
mental illness," said Professor David Curtis of UCL
Psychiatry and co-author on both papers. "The work opens up new
ways to prevent and treat mental illnesses by revealing the
mechanisms involved in their development. The result for GRM3 from
the consortium is particularly compelling, as the odds of this
occurring by chance are only one in a billion."
At present, schizophrenia is treated with drugs that reduce the
activity of the chemical dopamine. Dopamine is important for
transmitting messages between brain cells, but over-active dopamine
signalling may cause parts of the brain that are supposed to be
separate to communicate with each other. For example, some
scientists suspect that such signalling between the speech and
hearing centres of the brain may explain why people with
schizophrenia 'hear voices'.
Yet dopamine is not the only chemical that brain cells use to
communicate with each other. Glutamate is also involved and GRM3
codes for a protein which brain cells use to detect glutamate.
Brain cell activation is controlled by calcium 'channels'. The
latest research implicates both glutamate transmission and calcium
channels in schizophrenia development.
"Drug treatments for schizophrenia have barely changed over the
past few decades, as they still target dopamine receptors," said
study co-author Dr Andrew McQuillin, head of the UCL team that
first discovered GRM3. "Schizophrenia treatments targeting
glutamate receptors have been tested in the past without success.
However, they might be more effective at treating patient groups
with mutations in glutamate receptors such as GRM3.
"Drugs targeting calcium channels have been tested against
bipolar disorder with some success, although only in open-label
trials and not double-blind clinical trials. The results should
therefore be interpreted with caution, although the Nature paper
findings do suggest that calcium channels are a viable drug target.
Overall I expect we will see increased interest in drugs against
both glutamate receptors and calcium channels as a result of the
research."
The paper, The functional GRM3 Kozak sequence variant rs148754219 affects the
risk of schizophrenia and alcohol dependence as well as bipolar
disorder is published in Psychiatric
Genetics.
Biological insights from 108 schizophrenia-associated genetic
loci, is published in the Nature.