Rates of rare mutations soar 3 to 4 times higher in schizophrenia

Multiple genetic glitches disrupt pathways critical for brain development

People with schizophrenia have high rates of rare genetic deletions and duplications that likely disrupt the developing brain, according to studies funded in part by the National Institutes of Health.

These tiny anomalies were found in 15 percent of adult onset schizophrenia patients and 20 percent of child and adolescent onset patients, compared with only 5 percent of healthy participants. Collectively, the mutations carried by patients were significantly more likely than those in healthy participants to disrupt genes involved in brain development -- potentially implicating hundreds of genes in the illness, which affects about 1 percent of adults.

“This is an important new finding in the genetics of schizophrenia,” said NIMH Director Thomas R. Insel, M.D. “Identifying genes prone to harboring these mutations in brain development pathways holds promise for treatment and prevention of schizophrenia, as well as a wide range of other neurodevelopmental brain disorders.”

Two independent teams of researchers report on their combined findings in an article published online in Science Express, March 27, 2008. One team was led by Judith Rapoport, M.D., and Anjene Addington, Ph.D., National Institute of Mental Health (NIMH), Intramural Research Program. The other team was led by Jonathan Sebat, Ph.D., and Shane McCarthy, Ph.D., Cold Spring Harbor Laboratory, and by Jon McClellan, Ph.D., Tom Walsh, Ph.D., and Mary-Claire King, Ph.D., University of Washington. Their research was supported in part by the NIMH, National Institute of Child Health and Human Development, National Institute of Neurological Disorders and Stroke, National Center for Research Resources, and the National Institute on Aging.

The prevailing genetic model of schizophrenia implicates common variants of certain suspect candidate genes, each exerting modest effects, in interaction with each other and environmental factors. This hypothesis holds that risk stems from common variations in the sequence of the genetic code that result in altered protein products.

About a year ago, Sebat, King and colleagues reported evidence strengthening the case for a different kind of genetic risk. Many people with autism were found to have different, spontaneous and individually rare structural variations -- variations in the number of copies of genes. These copy number variations were scattered throughout the genome, suggesting that many different genes could be involved in autism spectrum disorders.

The new findings in schizophrenia echo those in autism, but also broaden their implications. The results suggest a new approach for discovering genes for schizophrenia and other mental disorders, say the researchers. Any mutation in the hundreds of genes involved in brain development could lead to a different set of neurodevelopmental consequences – schizophrenia, autism, mental retardation, or no illness at all. Each person with one of the illnesses could have a different genetic cause for the disorder.