Two large studies of schizophrenia patients have yielded the most convincing evidence yet that the disease can be caused by mistakes in genes. The researchers linked a much higher risk for schizophrenia to three chromosomal regions that are missing chunks of DNA. Although only a tiny fraction of patients carried these particular glitches, similar errors may help explain other cases of the disease.
Schizophrenia is a severe mental disorder involving hallucinations and delusions that affects as many as 1 in 100 people; it often runs in families. So far, searches for common genes linked to schizophrenia have been unsuccessful. In March, however, researchers reported a new clue in Science: Schizophrenics are more likely than healthy people to have rare variations in gene copy number--that is, they have fewer or more copies of a gene than most other people. Many of these copy number changes occurred in only one individual or one family, however, and the study could not pin down the risks associated with a particular variant.
Now the largest studies to date have bolstered the case for copy number variants. The U.S.–European International Schizophrenia Consortium, which compared copy numbers in about 3400 patients and 3200 controls, found that large chunks of extra or missing DNA were 15% more common in people with the disease compared with controls. Moreover, the researchers found a much greater risk for patients with DNA deletions in two specific locations on chromosome 1 and chromosome 15. A second study by deCODE Genetics in Reykjavik, Iceland, and a European consortium known as SGENE, which involved about 4700 schizophrenia cases and 41,200 controls, pinpointed these same two variants and an additional one on chromosome 15. Both papers are published online today in Nature.
One of the variants increased the risk at least threefold, and the other two boosted it more than 10-fold, the teams reported. These are "very large risks," said deCODE CEO Kári Stefánsson at a telephone press conference yesterday. Both studies also confirmed a previously reported deletion on chromosome 22 that is associated with a disease called velocardiofacial syndrome that often leads to schizophrenia.
Although each of the copy number variants is carried by less than 1% of the population, these and other copy number variants may be part of common biochemical pathways involved in brain development, Stefánsson and others say. "They give a great deal of hope ... that we're moving towards understanding the causes of the disease," Pamela Sklar of Massachusetts General Hospital in Boston said during the press conference. Sklar, a psychiatrist and geneticist, coordinated the International Schizophrenia Consortium. Some of the same regions have been linked to autism and mental retardation, pointing to a possible common mechanism.
Psychiatrist Jon McClellan of the University of Washington, Seattle, corresponding author of the Science paper earlier this year, explains that the copy number changes tend to occur in known DNA "hot spots" where mistakes are sometimes made when chromosomes get copied during egg and sperm formation. "If any one gets disrupted, that could lead to illness," he says. But disentangling these pathways in the brain--the most complicated organ--won't be easy, he says.
A third paper, appearing today in Nature Genetics from a team led by Michael O'Donovan at the University of Cardiff in the United Kingdom, reports a mutation that may raise the risk of schizophrenia in the general population. The study, which scanned the entire genome for common markers associated with disease, pointed to a gene involved in gene expression. However, people with this variant had only a 12% higher risk of developing schizophrenia, which suggests it plays a minor role, McClellan notes. And as with other genome-wide association studies, he adds, the finding needs to be replicated by other researchers.