The team screened for novel deletions and duplications in the genome -- what are called gene copy-number variations, or CNVs. They found that deletions, disruptions and duplications of normal genes, most of them rare, were three to four times more frequent in people with schizophrenia than in controls.
CSHL’s contribution to the research effort was led by Assistant Professor Jonathan Sebat, Ph.D., and Shane E. McCarthy, Ph.D. Drs. Tom Walsh, Jon McClellan and Mary-Claire King led the UW team, while Drs. Anjene Addington and Judith Rapoport led the researchers at NIMH.
A New Method of Finding Candidate Genes
The researchers used a novel method to study their two-cohort sample, which included 418 individuals, 150 of whom had schizophrenia or schizoaffective disorder. Instead of trying to show a statistical correspondence between a large group of people with schizophrenia and irregularities in common versions of genes, the team began by looking for “glitches” or changes in DNA that are likely to disrupt gene function. Then they compared which genes -- with what kinds of functions -- were impaired, both in the healthy subjects and those with schizophrenia.
The results were striking. Rare mutations showed up in only 5 percent of the healthy controls versus 15 percent of those with schizophrenia. The rate of rare mutation was higher still -- 20 percent -- among an “early-onset” subset of patients, who had developed schizophrenia before age 19.
“This part of our findings indicates something we didn’t know before: that rare structural mutations in genes, while present in both healthy people and people with schizophrenia, are much more likely to occur among people with the illness. This suggests a previously unknown role for rare mutations in the causation of schizophrenia,” said Dr. Sebat.
Rare Mutations and What They Do
The second part of the research aimed to answer a key question about the genes discovered to be irregular: What were their functions? Were their functions similar or different in healthy people versus those with schizophrenia?
Here, too, the results were striking. “In people with schizophrenia, almost half the
time the disrupted genes were involved in pathways important in brain development,” Dr. Sebat said. “By contrast, when we looked at the set of genes that were disrupted in healthy people, we found that they were not overrepresented in any particular pathway.”
In a paper that will first appear March 27 in the online edition of Science, the team notes that of 24 rare mutations seen in the schizophrenia group, 11, or 45 percent, affect cellular signaling pathways critical to neuronal cell growth, migration, proliferation, differentiation, apoptosis and synapse formation. Some of the affected pathways have turned up in past studies of schizophrenia, notably those involving signaling in neuregulin, a growth factor, and glutamate, a neurotransmitter.
Implications and Future Studies
While the study, as the scientists directly concede in their paper, “does not prove the involvement with the illness of any specific variant, or even the involvement of any specific gene,” it does, however, indicate a role for rare mutations that disrupt genes in pathways of neuronal development and regulation.
The results are powerful because they link specific structural variation in genes with specific functions known to be important in the early years of life, during which schizophrenia develops in many patients.
This important result leads the scientists to advocate broad use of the method they employed in the study. Gene discovery in complex psychiatric illnesses “should focus on methods that allow detection of structural mutations” across the genome in affected individuals, the team urges.
“Although each mutation discovered may be individually rare,” they maintain, “collectively the total number of disease-causing variants in a gene [found to be] relevant to the disorder may explain a substantial number of cases.”
Dr. Sebat is currently applying the mutation-screening method in studies involving a greater number of patients and in other illnesses. Among other things, he seeks to determine whether spontaneous mutations play as significant a role in schizophrenia as they do in autism, as revealed by a study he co-authored a year ago with CSHL Professor Michael Wigler.
“Rare Structural Variants Disrupt Multiple Genes in Neurodevelopmental Pathways in Schizophrenia” appears March 27 in Science online:10.1126/science.1155174. Its citation is as follows: Tom Walsh, Jon M. McClellan, Shane E. McCarthy, Anjene M. Addington, Sarah B. Pierce, Greg M. Cooper, Alex S. Nord, Mary Kusenda, Dheeraj Malhotra, Abishek Bhandari, Sunday M. Stray, Caitlin F. Rippey, Patricia Roccanova, Vlad Makarov, B. Lakshmi, Robert L. Findling, Linmarie Sikich, Thomas Stromberg, Barry Merriman, Nitin Gogtay, Philip Butler, Kristen Eckstrand, Laila Noory, Peter Gochman, Robert Long, Zugen Chen, Sean Davis1, Carl Baker, Evan E. Eichler, Paul S. Meltzer, Stanley F. Nelson, Andrew B. Singleton, Ming K. Lee, Judith L. Rapoport, Mary-Claire King, Jonathan Sebat.
The work in this study was supported by the Forrest C. and Frances H. Lattner Foundation, NARSAD, The National Institute of Mental Health and a gift from Ted and Vada Stanley. Just last year, as a result of the Stanleys’ support, CSHL established the Stanley Center for Psychiatric Genomics.