Using an important new method that can be applied in the study of other psychiatric illnesses, scientists at Cold Spring Harbor Laboratory (CSHL) in collaboration with colleagues at the University of Washington (UW) and the National Institute of Mental Health (NIMH), have identified multiple, individually rare gene mutations in people with schizophrenia that may help explain how that devastating illness is caused.

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.

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.

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 over-represented in any particular pathway."

In the paper 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.

Cold Spring Harbor Laboratory