Schizophrenia Linked to Rare, Often Unique Genetic Glitches

By Rick Weiss
Washington Post Staff Writer
Friday, March 28, 2008

Patients with schizophrenia are three to four times as likely as healthy people to harbor large mutations in genes that control brain development, and many of those glitches are unique to each patient, researchers reported yesterday.

The findings are forcing scientists to rethink the reigning model of how genes and environment conspire to cause the debilitating disease, which affects about 1 percent of the population worldwide.

In part, scientists said, the new view is daunting because it suggests that many people with schizophrenia have their own particular genetic underpinnings.

At the same time, the study shows that new screening techniques can find and differentiate among those various mutations. In the long run that could help doctors choose the best medications for individual schizophrenics and speed the development of drugs tailored to certain patients' needs.

"If the genetics tells us that schizophrenia is really 10 different disorders, then let's have 10 treatments that optimize the outcomes for everyone and not just use the same drugs for everybody," said Thomas Insel, director of the National Institute of Mental Health, which helped fund and conduct the study.

The work also offers evidence that autism shares some genetic roots with schizophrenia.

"Take away schizophrenia's hallucinations and delusions," said Jon McClellan, a child psychiatrist at the University of Washington and a leader of the study, published in yesterday's online issue of the journal Science, "and the symptoms that remain, the lack of social interest and withdrawal, are what we call autism. There is clearly an intersection of the brain systems involved."

"It's not that we're now going to be able to solve schizophrenia tomorrow," said Samuel Barondes, director of the center for neurobiology and psychiatry at the University of California at San Francisco, who was not involved in the work. "But it does present a new way of figuring this puzzle out."

Schizophrenia is a disease of disordered thinking and behavior. Patients have trouble organizing their thoughts or communicating sensibly, and many have auditory or visual hallucinations.

The disease, which typically emerges in early adulthood, used to be blamed on "bad mothering" but has since come to be recognized as having genetic roots.

Yet environmental factors also contribute. Pregnant women who experience famine are at increased risk of giving birth to children who will get schizophrenia. Childhood infections may also add to the risk. Further muddying the picture, most schizophrenics have no family history of the disease. That suggests that, to the extent the disease is genetic, the mutations often arise spontaneously either at conception or during fetal development, perhaps after having inherited a general propensity to get such mutations.

Those and other details led scientists to conclude that the mutations contributing to schizophrenia are probably common in the population but have little impact individually, and that only when several occur together is a critical mass of neurological trouble achieved.

The model emerging from the new study is quite different. It says most cases of schizophrenia may be caused by rare genetic glitches that are individually potent.

The turnaround is the result of sophisticated gene scans conducted on 233 schizophrenics, including 83 who got the disease in childhood, a more serious condition. The scans looked for rare stretches of DNA where more than 100,000 "letters" of genetic code were either missing or mistakenly present in duplicate.

About 15 percent of schizophrenics, and 20 percent of those affected in childhood, had such glitches, compared with 5 percent of healthy individuals who were also studied. Yet the glitches, including one previously associated with autism, were different in each person.

Unlike previous scans based on older technology, which could at best find general genomic "neighborhoods" where mutations associated with schizophrenia are present, the new scans pinpointed the individual genes affected.

"It's fabulous to be able to find these mutations directly rather than indirectly," said Mary-Claire King, a geneticist at the University of Washington who was on the team. "You just go for the jugular."

The genes implicated are diverse, but many are known to play crucial roles in how the brain gets wired early in life. Normally that process starts with a huge overproduction of neurons, followed by a controlled winnowing that leaves only those that have made proper connections.

"Changes in these genes could bias the way circuits get sculpted out and could perhaps lead to a brain in which signals that would normally get filtered out don't get filtered out," which could interfere with thinking and prompt hallucinations, Insel said.

The delayed onset of the disease can be explained by the fact that some genes and brain connections do not take on central roles until young adulthood, said Jonathan Sebat of Cold Spring Harbor Laboratory, one of the study leaders.

"Genes have timing," Sebat said. "They follow developmental programs for where and when they're going to be active."

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