Genetic hot spots tied to schizophrenia
DNA glitches appear to boost risk, studies say
Researchers in Boston and around the world have pinpointed three genetic hot spots where deletions of big chunks of DNA appear to multiply a child's chances of developing schizophrenia up to tenfold.
The discoveries, reported online in the journal Nature yesterday, stem from a mammoth effort to scan the genomes of more than 3,000 schizophrenia patients, the most extensive search for abnormalities published to date. Scientists said the work represents a significant step toward revealing the genetic roots of a devastating disease that has long stymied them.
"These papers represent the first rock-solid foundation knowledge of what can cause schizophrenia," said Michael O'Donovan, a professor at Cardiff University in Wales and lead author of a related paper in the journal Nature Genetics.
Taken together, the three hot spots are uncommon, accounting for only about 1 percent of schizophrenia cases. But the findings may point the way toward many more such genetic glitches that explain many more cases, researchers say.
The findings are "the tip of the iceberg," said Deborah Levy, a researcher in schizophrenia genetics at McLean Hospital in Belmont who was not involved in the studies. "They reveal an entirely unsuspected genetic mechanism responsible for a substantial proportion of schizophrenia. They also indicate that oftentimes, these genetic events occur spontaneously rather than being inherited."
Schizophrenia, which affects at least 2 million Americans, has long posed a major mystery. It clearly involves a strong genetic element, often running in families. And its prevalence in the population tends to remain steady over time, at about 1 percent. Yet people with schizophrenia usually start having symptoms - hallucinations, thinking problems, and more - in young adulthood, so many do not end up having children. So how does it remain so common in successive generations?
Two theories currently prevail. One suggests that families may pass along common genes that contribute to schizophrenia, but for various reasons, in most members, those genes do not combine to produce the disease.
The other suggests that schizophrenia is often caused by rare mutations that occur spontaneously in earliest development, rather than being passed on by a parent. Recent findings suggest that such mutations, called "copy number variants," may also play a significant role in autism.
Both theories about schizophrenia could be true, researchers say. And the two types of mutation could even interact.
In one of today's papers, O'Donovan reports a strong link between schizophrenia and a common, small gene mutation - a change in a single "letter" of the 3 billion-letter DNA code, the equivalent of a single typo in a book. The other two papers report on copy number variants - rare, structural changes involving longer stretches of DNA that have been compared to the deletion or duplication of a whole chapter in a book. They were found on chromosomes 1, 15, and 22.
The studies also found that, though many different copy number variants occur in everyone, they show up about 15 percent more frequently in people with schizophrenia. It is not yet clear how that frequency may translate into disease.
Scientists also have no explanation for why such spontaneous mutations happen, except that they seem to occur randomly during the reshuffling of parental genes in earliest development, and that certain spots in the genome are especially susceptible to them.
The schizophrenia findings are not ready to be used for testing individuals, said Dr. Kari Stefansson, the Icelandic geneticist known for mining his country's population for genomic knowledge and co-author of one of the Nature papers.
Even someone who carried the gene mutation found to have the highest risk at this point would still have an 85 percent chance of not developing schizophrenia, he said.
But the hope, said Stefansson, who is also chief executive officer of
And in the longer run, he said, once researchers know which genes are involved, they can figure out how best to target them to develop better therapies.
The new genetic insights into schizophrenia should give people new hope, he said, "though we have miles to go before we solve the whole puzzle." That puzzle includes environmental influences as well as genes, researchers agree.
Psychiatric geneticist Dr. Pamela Sklar, coauthor of another Nature paper, said she feels particularly hopeful because she is seeing unprecedented cooperation among schizophrenia researchers from around the globe.
More than 100 research groups are working together to pool genetic data, said Sklar, of Massachusetts General Hospital and the Broad Institute's Stanley Center for Psychiatric Research. The Nature paper she led involved an international schizophrenia consortium that brought together data from more than 3,300 patients, and she expects future studies to get up to 10,000 or 15,000 patients.
"It's really quite a tour de force for our field, which is often not seen to come together in that way," she said.
Carey Goldberg can be reached at goldberg@globe.com.
