CSHL scientists part of team that discovers role of rare gene mutations in schizophrenia

“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.