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Schizophrenia Yields Some Genetic Secrets
Date:7/30/2008

Scientists report findings that could someday lead to better treatments

WEDNESDAY, July 30 (HealthDay News) -- Moving closer to the causes and effective treatment of schizophrenia, researchers say they've found specific gene variations linked to the condition.

Specifically, three rare deletions in the human genome appear to raise the risk of developing the devastating brain disease considerably.

"These findings give a great deal of hope -- for individuals with schizophrenia and their families and loved ones and caregivers -- that we're moving towards an understanding of the causes of the disease," said Dr. Pamela Sklar, corresponding author of a paper appearing in Nature and director of genetics at Harvard Medical School, Boston.

Additional findings, all reported at a Tuesday press teleconference, are detailed in two other papers published in the July 30 online editions of Nature and Nature Genetics.

But the current findings are just the tip of the iceberg, the researchers stressed.

"We've only explained a tiny fraction of why people might develop schizophrenia, and much more work needs to be done to connect specific changes to the full spectrum of other types of genetic factors that might influence schizophrenia, as well as ways they might interact with the environment," added Sklar, who is a member of the International Schizophrenia Consortium, which conducted one of the studies.

Schizophrenia, a devastating disorder characterized by hallucinations and delusions, affects some 1 percent of the population, usually appears in late adolescence or early adulthood and, despite some effective treatments, tends to be chronic.

Breakthroughs in understanding this disorder have been few and far between.

"We've been working on schizophrenia for rather more years than we care to think, and successes have not been dramatic," acknowledged Michael O'Donovan, lead author of the Nature Genetics study and professor of psychiatric genetics at Cardiff University in the United Kingdom.

"There has been precious little on diseases of the brain, and what seems to be emerging is that a lot of risk of brain diseases, including schizophrenia and autism, seems to be conferred by rare [gene] variants like rare deletions," said Dr. Kari Stefansson, senior author of one of the Nature papers and CEO of deCODE in Reykjavik, Iceland.

Schizophrenia tends to run in families, hence the focus on genetic determinants of the disease.

The first two papers, in Nature, compared the genomes of 3,300 individuals with schizophrenia against those of 3,200 individuals without the illness.

"We looked at a relatively rare type of DNA change where people have a substantial portion of a chromosome either missing or extra. These are called copy number changes," Sklar explained.

In this case, the consortium found three deletions: one on chromosome 1 and two on chromosome 15, which were seen multiple times in people with schizophrenia. Two of the deletions had never been recognized before. "That triples the number of specific DNA areas that may be responsible for schizophrenia," Sklar said. "All of these together were found in about 1 percent of patients." But they conferred a very large risk, multiplying the odds of getting schizophrenia by a factor of more than 10, Stefansson said.

The Nature Genetics paper identified three "single-nucleotide polymorphisms" (changes) or SNPs that were associated with schizophrenia and appear to be risk factors for the disease. The strongest association was with a variant near the gene ZNF804A, whose function may be to regulate other genes.

According to O'Donovan, other researchers have looked at what are called "whole chapters" in the genome. In contrast, his team honed in on what he described as tiny spelling differences.

The variations identified are much more common than those reported in the previous two papers.

"In addition to rare variants, we were able to convincingly show that common variants are involved in schizophrenia. But we don't know how much of a role they play compared with rare variants," O'Donovan said. "It means that virtually all of us have genes for schizophrenia, but probably those of us who don't have schizophrenia don't have enough of the genes or possibly have not been exposed to [an environmental stimulus]."

"Schizophrenia is the ultimate human disease, affecting the things that characterize us as individuals," Stefansson added. "Perhaps with a little bit of luck, we will gain insight into the pathogenesis of schizophrenia . . . and will discover enough of the variants to put together meaningful diagnostic instruments for this very difficult disease."

More information

There's more on schizophrenia at the U.S. National Institute of Mental Health.



SOURCES: July 29, 2008, teleconference with Pamela Sklar, M.D., Ph.D., director, genetics, Harvard Medical School; Kari Stefansson, M.D., CEO, deCODE, Reykjavik, Iceland; and Michael O'Donovan, Ph.D., professor, psychiatric genetics, Cardiff University, U.K.; July 30, 2008, online editions, Nature and Nature Genetics


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