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Rare Structural Variants Disrupt Multiple Genes in Neurodevelopmental Pathways in Schizophrenia
Tom Walsh,1*Jon M. McClellan,2*Shane E. McCarthy,3*Anjené M. Addington,4*Sarah B. Pierce,1Greg M. Cooper,5Alex S. Nord,5Mary Kusenda,3,6Dheeraj Malhotra,3Abhishek Bhandari,3Sunday M. Stray,1Caitlin F. Rippey,5Patricia Roccanova,3Vlad Makarov,3B. Lakshmi,3Robert L. Findling,7Linmarie Sikich,8Thomas Stromberg,4Barry Merriman,9Nitin Gogtay,4Philip Butler,4Kristen Eckstrand,4Laila Noory,4Peter Gochman,4Robert Long,4Zugen Chen,9Sean Davis,10Carl Baker,5Evan E. Eichler,5Paul S. Meltzer,10Stanley F. Nelson,9Andrew B. Singleton,11Ming K. Lee,1Judith L. Rapoport,4Mary-Claire King,1,5Jonathan Sebat3
Schizophrenia is a devastating neurodevelopmental disorder whosegenetic influences remain elusive. We hypothesize that individuallyrare structural variants contribute to the illness. Microdeletionsand microduplications >100 kilobases were identified by microarraycomparative genomic hybridization of genomic DNA from 150 individualswith schizophrenia and 268 ancestry-matched controls. All variantswere validated by high-resolution platforms. Novel deletionsand duplications of genes were present in 5% of controls versus15% of cases and 20% of young-onset cases, both highly significantdifferences. The association was independently replicated inpatients with childhood-onset schizophrenia as compared withtheir parents. Mutations in cases disrupted genes disproportionatelyfrom signaling networks controlling neurodevelopment, includingneuregulin and glutamate pathways. These results suggest thatmultiple, individually rare mutations altering genes in neurodevelopmentalpathways contribute to schizophrenia.
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, National Institutes of Health (NIH), Bethesda, MD 20892, USA. 5 Department of Genome Sciences, University of Washington, Seattle, WA98195, USA. 6 Graduate Program in Genetics, State University of New York, Stony Brook, NY 11794, USA. 7 Department of Psychiatry, Case Medical Center, Cleveland, OH 44106, USA. 8 Department of Psychiatry, University of North Carolina, Chapel Hill, NC 27599, USA. 9 Department of Human Genetics, University of California, Los Angeles, CA 90095, USA. 10 Cancer Genetics Branch, National Cancer Institute, NIH, Bethesda, MD 20892, USA. 11 Neurogenetics Laboratory, National Institute on Aging, NIH, Bethesda, MD20892, USA.
* These authors contributed equally to this work.
To whom correspondence should be addressed. E-mail: drjack{at}u.washington.edu
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To whom correspondence should be addressed. E-mail: 
