From The Quarterly, Summer 2011

Many studies have shown that schizophrenia is a highly heritable disorder; that it is largely triggered by inherited genetic mutations or abnormal changes in the composition and function of genes. But genetic errors leading to disease can also occur in people spontaneously without those errors having been inherited from parents. These kinds of newly arising abnormal genes are what scientists called de novo mutations.

Now, an international team led by Guy A. Rouleau, M.D., Ph.D., NARSAD Distinguished Investigator Grantee, has found that de novo mutations are significantly more frequent in schizophrenia patients than in the normal population and also that they occur in schizophrenia at a rate significantly greater than had been previously believed. The discovery, published online on July 10 in the journal Nature Genetics, supports the notion that de novo mutations may account for some of the heritability previously reported for schizophrenia as well as an expanded list of genes possibly involved in disease pathogenesis.



Schizophrenia affects 1 percent of the world’s population. “The occurrence of de novo mutations, as observed in this study may in part explain the high worldwide incidence of schizophrenia,” states Dr. Rouleau, a professor at the University of Montreal Hospital and director of the CHU Sainte-Justine Research Center. A leader in studies to identify the genes that cause or predispose people to neurological and psychiatric diseases, Dr. Rouleau received a 2010 NARSAD Distinguished Investigator Grant from the Brain & Behavior Research Foundation.



In addition to its ubiquity, schizophrenia is characterized by a wide spectrum of symptoms and clinical variability, which suggests that it is a highly complex disorder genetically with many genes appearing to be involved. Using advanced DNA sequencing technology, Rouleau and his colleagues analyzed the genes of 14 schizophrenia patients and of their parents, who did not have the disease, to identify genetic mutations associated with schizophrenia; altogether, some 20,000 genes from each participant.



Most of the genes the researchers pinpointed had not been previously linked to schizophrenia, findings that open the door to new understanding and to potential new therapeutic targets. Says team member Simon L. Girard, who performed key experiments in the study: “Because the mutations are located in many different genes, we can now start to establish genetic networks that would define how these gene mutations predispose to schizophrenia.”

Finally, the identification of de novo mutations in schizophrenia supports a hypothesis proposed several years ago by Dr. Rouleau that this type of mutation plays a role in several diseases affecting brain development, such as autism, schizophrenia and mental retardation.

“Our results not only open the door to a better understanding of schizophrenia,” he says, “they also give us valuable information about the molecular mechanisms involved in human brain development and function.”