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Monday, March 31, 2008

People with schizophrenia may have the disease because they are unlucky enough to end up with an extremely rare combination of genes,

Rare gene
defects might add up to schizophrenia
18:03 27 March 2008
NewScientist.com news service
Ewen Callaway

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Jack McClellan, University of Washington
Daniel Weinberger, National Institute of Mental Health
Schizophrenia, Royal College of Physiatrists
People with schizophrenia may have the disease because they are unlucky enough to end up with an extremely rare combination of genes, according to a genetic study of the devastating illness.

The comparison of schizophrenics and healthy people reveals that the former are far likelier to possess extremely rare gene mutations. It is these mutations, the researchers hypothesise, that underlie many cases of schizophrenia.

About 1% of people suffer from the disease, which typically hits people in their twenties.

"It may well be that some substantial portion of cases comes by rare events – each one is unique. If you collectively add them together, it can explain a large percentage of the disorder," says Jack McClellan, a psychiatrist at the University of Washington in Seattle, who led the study.

Many of the schizophrenia-linked mutations occurred in genes linked to brain development. These might provide the best targets for drug therapies to aim at, he says.

Genetic glitches
Like most mental illnesses, no single genetic mutation sparks schizophrenia, but studies of families hint that genes play a large part. For instance, if one identical twin has the disease, the other has about a 50/50 chance of also developing schizophrenia.

Most researchers think that schizophrenia is caused by lots of gene mutations that are relatively common among humans. By itself, a single mutation plays a bit part in the disease. Together, many of these mutations add up to schizophrenia.

As an alternative explanation, McClellan's team tested whether extremely rare mutations might cause the illness. His team looked at genetic changes called duplications and deletions, where large swaths of DNA are either missing or repeated in the genome of a single person or family.

Among the 150 schizophrenics and 268 healthy people McClellan's team studied, schizophrenics were three times likelier than healthy people to have such genetic glitches.

Five percent of healthy people had very rare deletions or duplications in their DNA, while 15% of schizophrenia patients had such mutations. The difference was even more striking among a second group of patients, who developed schizophrenia as children – a full 20% possessed rare gene deletions or duplications.

'Crossword puzzle'
Many of the mutations occurred in genes linked to brain development, a likely culprit for the disease. "A lot of them help regulate how neurons get from point A to point B over time," McClellan says.

Individual mutations might contribute to schizophrenia and other mental illness, but proving a cause-effect relationship in a single patient is nearly impossible, says Daniel Weinberger, a schizophrenia expert at the National Institute of Mental Health in Bethesda, Maryland.

"Changes in the genome found in only a single individual, are difficult to establish as pathogenic factors," he says.

However, Ben Packard, a geneticist at the University of Edinburgh, says the study agrees with recent findings that rare gene deletions and duplications might cause autism.

Homing in on such mutations in schizophrenia patients should offer quick insights into more general causes of the disease, McClellan says. The mutations could hit many of the same genes, he says. "It's like solving a crossword puzzle. You have to get one letter first."

Journal reference: Science (DOI: 10.1126/science.1155174

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