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People with schizophrenia (http://www.nimh.nih.gov/health/topics/schizophrenia/index.shtml) have higher 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.

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, M.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 (http://www.nimh.nih.gov/science-news/2007/tiny-spontaneous-gene-mutations-may-boost-autism-risk.shtml). 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 many different genes could be involved in autism spectrum disorders (http://www.nimh.nih.gov/health/topics/autism-spectrum-disorders-pervasive-developmental-disorders/index.shtml).

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.

The functional consequences of these structural genetic variations may differ, depending on interactions with other genes or environmental events, say the researchers, making any gene harboring a deleterious structural mutation a "candidate gene." Any gene harboring one mutation likely contains others. Although each might be individually rare, together such disease-causing variations in one gene could explain a substantial number of illness cases, they suggest.

Among key study findings:

• Genes disrupted in patients, as opposed to healthy participants, were significantly over-represented in pathways critical for brain development. These included genes involved in creating the infrastructure by which neurons communicate — and for neuronal growth, migration, proliferation, differentiation, and cell death. Among these were genes important for neuronal communications via glutamate and neuregulin, both of which have previously been implicated in schizophrenia.
• The mutations were often specific to single cases or families. Virtually every mutation detected by King, Sebat and colleagues was different in a sample of 150 adults with schizophrenia and 268 healthy controls.
• In families affected by childhood onset schizophrenia, Rapoport and colleagues found that 28 percent (23) of 83 patients harbored mutations, compared with 13 percent (10) of 77 controls. By using the non-transmitted chromosomes of the patients' parents as controls, the researchers were able to determine if the mutations in their children were likely inherited or spontaneous. The majority turned out to be inherited rather than spontaneous, some from parents unaffected by the illness. Childhood onset schizophrenia is thought to be a more severe and more genetically influenced form of the illness.

The research was also funded by the Forrest C. and Frances H. Lattner Foundation, NARSAD, the Simons Foundation, the Stanley Medical Research Foundation, the Howard Hughes Medical Institute.

Rare Structural Variants Distrupt Multiple Genes in Neurodevelopmental Pathways in Schizophrenia
Tom Walsh^1*, Jon M. McClellan^2*#, Shane E. McCarthy^3*, Anjene M. Addington^4*, Sarah B. Pierce¹, Greg M. Cooper⁵, Alex S. Nord⁵, Mary Kusenda³, Dheeraj Malhotra³, Abishek Bhandari³, Sunday M. Stray¹, Caitlin F. Rippey⁵, Patricia Roccanova³, Vlad Makarov³, B. Lakshmi³, Robert L. Findling⁶, Linmarie Sikich⁷, Thomas Stromberg⁴, Barry Merriman⁸, Nitin Gogtay⁴, Philip Butler⁴, Kristen Eckstrand⁴, Laila Noory⁴, Peter Gochman⁴, Robert Long⁴, Amalia Dutra⁹, Zugen Chen⁸, Sean Davis¹⁰, Carl Baker⁵, Evan E. Eichler⁵, Paul S. Meltzer¹⁰, Stanley Nelson⁸, Andrew B. Singleton¹¹, Ming K. Lee¹, Judith L. Rapoport⁴, Mary-Claire King^1,5, Jonathan Sebat³.

1 Department of Medicine, University of Washington, Seattle, WA 98195, USA
2 Department of Psychiatry, University of Washington, Seattle, WA 98195, USA
3 Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA
4 Child Psychiatry Branch, National Institute of Mental Health, NIH, Bethesda, MD 20892, USA
5 Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA
6 Department of Psychiatry, Case Medical Center, Cleveland, OH 44106, USA
7 Department of Psychiatry, University of North Carolina, Chapel Hill, NC 27599, USA
8 Department of Human Genetics, University of California, Los Angeles, CA 90095, USA
9 Genetic Disease Research Branch, National Human Genome Research Institute, NIH, Bethesda, MD 20892, USA
10 Cancer Genetics Branch, National Cancer Institute, NIH, Bethesda, MD 20892, USA
11 Neurogenetics Laboratory, National Institute on Aging, NIH, Bethesda, MD 20892, USA
* These authors contributed equally to this work.
# To whom correspondence should be addressed. E-mail: drjack@u.washington.edu

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