Schizophrenia is a complex mental illness that affects millions
of people in Europe. The EU-funded project EMASS is studying the genes
behind schizophrenia. The scientists involved have been homing in
on a gene, which codes for an important brain receptor. This gene
has two variants; inherit the less common one, and your chances of
developing schizophrenia are increased. Researchers think that if
you have the bad luck to possess this variant in combination with
several other susceptibility genes, as yet unknown, schizophrenia
becomes almost inevitable.
Drawing by Aloyse - Collection de l'art
Schizophrenia is a serious mental illness.
About 1% of the population of Europe suffers from schizophrenia during
the course of their lifetime - a staggering 3.7 million people. Although
the disease usually first affects young adults, three-quarters of
them continue to experience symptoms throughout their lives and need
constant treatment. This means distress for the schizophrenic and
their family and places a huge burden on health care resources.
Unravelling the genetic
Twin studies have also proved important. If, for example, one of an
identical pair of twins develops schizophrenia, the other twin has
a 50% chance of also developing the disease. In non-identical twins,
the risk is the same as for any brother/sister pair - only 10%. "This
is interesting," says Peter McGuffin, "because, while it shows there
is a strong genetic component, it also indicates that the genetics
are very complex. There are probably several genes involved and they
may be influencing other genes. After all, if schizophrenia were a
single-gene disorder, identical twins - who share exactly the same
genes - would always both develop the disease."
basis of schizophrenia is not an easy task because researchers do
not yet properly understand exactly what goes wrong in the brain.
Circumstantial evidence suggests that problems occur in communication
pathways that involve the chemical transmitters dopamine and serotonin.
Taking lots of amphetamines, for example, which are known to cause
an outpouring of dopamine in the brain, causes symptoms exactly
like those of schizophrenia. Also, drugs that alleviate the symptoms
of schizophrenia block the dopamine receptors and the most effective
modern drugs also block the serotonin systems. Schizophrenics are
born, not made Embarking on research to identify the genes behind
schizophrenia without knowing the biochemical processes behind the
illness might be a tall order, but projects like the European Multicentre
Association Study of Schizophrenia (EMASS) have gone ahead because
of the strong evidence that genes are important. Peter McGuffin,
co-ordinator of EMASS, comments: "For many years, doctors noticed
that schizophrenia runs in families and there are two very clear
experiments of nature that clearly indicate that the disease has
a strong genetic component. One is adoption studies. Children with
schizophrenic biological parents who are subsequently adopted by
unaffected parents always show a greater tendency to develop the
disease later in life. The corollary is also true: children with
unaffected biological parents show no higher risk when adopted by
people who later show signs of schizophrenia."
Taking lots of amphetamines, for example,
which are known to cause an outpouring of dopamine in the
brain, causes symptoms exactly like those of schizophrenia.
The search for marker
genes Several approaches are being used to tackle the problem from
- In the first, researchers look at families which have several
affected members. Genetic analysis of schizophrenics and unaffected
people from the same family is done to try to identify 'markers'
- variations of genes which are always present in people with
the disease but which never occur in unaffected people.
- In the second, research has concentrated on sibling pairs -
brothers/sisters who both suffer from schizophrenia to identify
genes that are common between the siblings.
- The third approach is the one currently being taken by EMASS.
Peter McGuffin explains, "We decided to use a broader brush and
to study large numbers of unrelated patients, comparing their
genes with the genes of a similarly large number of controls.
By collaborating with seven other groups across Europe we were
able to get the patient numbers we needed. We shared the workload
and we were able to look at a wider spread of people than would
have been possible if the research had been limited to one country
or geographical area."
Of course, the human genome is vast and so the first step for EMASS
was to narrow down the search. The teams decided to look for candidate
genes - genes that are most likely to be involved in the disease
process. Since earlier research had strongly suggested a link between
schizophrenia and the dopamine and serotonin systems in the brain,
the first genes chosen were those that code for their protein receptors.
The serotonin receptor proved to be a good choice. In the population
as a whole, one of the genes that codes for a serotonin receptor
has two versions called allele 1 and allele 2. These are spread
through the population and people have either one or the other.
Interestingly, people with allele 2 do not always get schizophrenia,
but schizophrenics very often have this allele. This suggests that
the allele 2 version of their serotonin receptor gene adds to their
risk of developing the disease. Of course, they must have been unlucky
enough to inherit several other susceptibility genes as well - as
yet unknown - but this is an important piece of the jigsaw.
Although the EMASS project is now complete, the collaborations
on which it was founded are still going strong. McGuffin's group
at Cardiff are still working with several of the original partners
on exciting and promising new research.