Two groups of researchers hunting for schizophrenia genes on a larger scale than ever before have found new genetic variants that point toward a different understanding of the disease.
The variants discovered by the two groups, one led by Dr. Kari Stefansson of Decode Genetics in Iceland and the other by Dr. Pamela Sklar of Massachusetts General Hospital in the United States, are rare. They substantially increase the risk of schizophrenia but account for a tiny fraction of the total number of cases.
This finding, coupled with the general lack of success so far in finding common variants for schizophrenia, raises the possibility that the genetic component of the disease is the result of a large number of variants, each of which is very rare, rather than of a handful of common variants.
“What is beginning to emerge is that a lot of the risk of brain diseases is conferred by rare deletions,” Stefansson said. The three variants discovered by his group and Sklar##s involve the deletion of large sections of DNA from specific sites in a patient##s genome.
Their report, published online Wednesday by the journal Nature, follows a finding in March from researchers at the University of Washington in Seattle that rare deletions and duplications of DNA figure prominently in schizophrenia.
The new focus on rare mutations suggests that natural selection is highly efficient at removing schizophrenia-causing genes from the population. Despite selection against the disease, according to this new idea, schizophrenia continues to appear because it is driven by a spate of new mutations that occur all the time in the population.
“We##ve looked for common variants in schizophrenia and get almost nothing,” said Dr. David Goldstein, a geneticist at Duke University and one of Stefansson##s co-authors. “This means natural selection has done a really good job of purging them away, and we##re left with rare variants, a constant flow of them, as the principal driver of the disease.”
“This may be the case in other brain diseases, too,” Goldstein said, “because successful cognitive functioning is a highly complex system and there are many independent ways to take it down. ” One obvious way in which natural selection acts against the disease is that schizophrenics have fewer children than others. “The brain diseases are those where we find the biggest evidence for negative selection,” Stefansson said, which he found surprising because “I would have thought the brain was a luxury organ when it comes to reproductive success.”
Devising treatments for schizophrenia could be more difficult if the disease is caused by subsets of 2,000 rare variants, say, rather than by just 20 common ones. But several experts said it was too early to know what mix of common and rare variants may cause the disease and whether that might affect the search for treatments.
The search for common variants in schizophrenia, however, has not been very successful so far, though not for want of trying. There have been more than a thousand studies, implicating 3,608 genetic variants.
But when all the data are pooled, only 24 of those variants turn out to be statistically significant, according to an analysis in the current issue of Nature Genetics by a group led by Dr. Lars Bertram of Massachusetts General Hospital.
Most of the early studies had too few patients and focused on mutations in what seemed to be plausible genes, an approach that is rarely successful. A new and more fruitful method is to survey the whole genome without any prior assumptions, a strategy made possible by new gene chips and a database of human genetic variation known as the hapmap.
But even these genome-wide association studies have had little success in finding common variants. Five such studies of schizophrenia have now been completed, and one of the largest found no common variants, Bertram said.
The consortiums led by Stefansson and Sklar are still looking for common variants but published their rare deletions now because they were so prominent, Sklar said.
Should most of the genetic component of the disease turn out to depend on multiple rare variants, the task of finding general treatments might seem to be far harder than if a few common variants were involved. Stefansson said, however, that was not the case.
“The only thing you need is to find pathways that are up- or down-regulated,” he said. “The assumption that this is a more difficult situation is just not correct.”
Dr. Thomas Insel, director of the National Institute of Mental Health, said the new landscape might complicate development of genetic diagnostics for schizophrenia but not necessarily of therapies.
“If you can understand the mechanism,” Insel said, “you should be able to devise new treatments. So I think this is a big advance, not a signal for hopelessness.”
The New York Times