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Bad luck and -the legacy of schizophrenia

Drawing by Aloyse - Collection de l'art brut, Lausanne.
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.


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
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."

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."

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 different angles.

  • 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.



Project Title:  
The European Multi-Centre Association Study of Schizophrenia (EMASS)


Contract Reference: CT 941556