Would you summarize the significance of your paper in layman’s terms?

In this paper, we demonstrated that schizophrenia may be caused by many different, individually rare severe mutations. My colleagues at the University of Washington, and at Cold Spring Harbor Laboratory, used new technologies to screen genome-wide for rare genomic deletions and duplications that disrupt genes in individuals with schizophrenia, and in healthy controls. Rare structural mutations were much more common in people with schizophrenia. Most patients had a different mutation. The genes altered by these mutations were disproportionately involved in neurodevelopmental pathways.

Our findings challenge the conventional belief that schizophrenia stems from the collective action of shared common mutations, each one of which may only have small to moderate effects on disease risk. The results of our study suggest that many, perhaps most individuals with schizophrenia have a unique genetic cause. If so, this has enormous implications for future genetic research. Most current studies are designed to detect mutations shared by a substantial proportion of people with the illness, and will predictably fail if most patients have a different genetic cause.

Where do you see your research leading in the future?

This model also has important implications for treatment development. Although most people with the illness may have a different genetic cause, the genes disrupted by rare mutations may work in the same, or overlapping, neurodevelopmental pathways. As they are identified, these pathways will become the target for future treatment efforts.

Jon McClellan, M.D.
Professor
Department of Psychiatry and Behavioral Sciences
University of Washington
Seattle, Washington, USA

Keywords: schizophrenia, severe mutations, structural mutations, unique genetic cause, future genetic research, neurodevelopmental pathways.