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Published Online March 27, 2008
Science DOI: 10.1126/science.1155174

Reports

Submitted on January 2, 2008
Accepted on March 14, 2008

Rare Structural Variants Disrupt Multiple Genes in Neurodevelopmental Pathways in Schizophrenia

Tom Walsh 1{dagger}, Jon M. McClellan 2{dagger}*, Shane E. McCarthy 3{dagger}, Anjene M. Addington 4{dagger}, Sarah B. Pierce 1, Greg M. Cooper 5, Alex S. Nord 5, Mary Kusenda 6, Dheeraj Malhotra 3, Abishek Bhandari 3, Sunday M. Stray 1, Caitlin F. Rippey 5, Patricia Roccanova 3, Vlad Makarov 3, B. Lakshmi 3, Robert L. Findling 7, Linmarie Sikich 8, Thomas Stromberg 4, Barry Merriman 9, Nitin Gogtay 4, Philip Butler 4, Kristen Eckstrand 4, Laila Noory 4, Peter Gochman 4, Robert Long 4, Zugen Chen 9, Sean Davis 10, Carl Baker 5, Evan E. Eichler 5, Paul S. Meltzer 10, Stanley F. Nelson 9, Andrew B. Singleton 11, Ming K. Lee 1, Judith L. Rapoport 4, Mary-Claire King 12, Jonathan Sebat 3

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 Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA.; Graduate Program in Genetics, State University of New York at 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, MD 20892, USA.
12 Department of Medicine, University of Washington, Seattle, WA 98195, USA.; Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA.

* To whom correspondence should be addressed.
Jon M. McClellan , E-mail: drjack{at}u.washington.edu

{dagger}These authors contributed equally to this work.

Schizophrenia is a devastating neurodevelopmental disorder whose genetic influences remain elusive. We hypothesize that individually rare structural variants contribute to the illness. Microdeletions and microduplications >100 kb were identified by microarray comparative genomic hybridization (CGH) of genomic DNA from 150 individuals with schizophrenia and 268 ancestry-matched controls. All variants were validated by high-resolution platforms. Novel deletions and duplications of genes were present in 5% of controls versus 15% of cases (P = 0.0008) and 20% of young onset cases (P = 0.0001). The association was independently replicated in patients with childhood-onset schizophrenia compared to their parents (P = 0.03). Mutations in cases disrupted genes disproportionately from signaling networks controlling neurodevelopment, including neuregulin and glutamate pathways. These results suggest that multiple, individually rare mutations impacting genes in neurodevelopmental pathways contribute to schizophrenia.


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