Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.
Submitted on January 2, 2008
Accepted on March 14, 2008
Rare Structural Variants Disrupt Multiple Genes in Neurodevelopmental Pathways in Schizophrenia
Tom Walsh 1,Jon M. McClellan 2*,Shane E. McCarthy 3,Anjene M. Addington 4,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
These authors contributed equally to this work.
Schizophrenia is a devastating neurodevelopmental disorder whosegenetic influences remain elusive. We hypothesize that individuallyrare structural variants contribute to the illness. Microdeletionsand microduplications >100 kb were identified by microarraycomparative genomic hybridization (CGH) of genomic DNA from150 individuals with schizophrenia and 268 ancestry-matchedcontrols. 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 youngonset cases (P = 0.0001). The association was independentlyreplicated in patients with childhood-onset schizophrenia comparedto their parents (P = 0.03). Mutations in cases disrupted genesdisproportionately from signaling networks controlling neurodevelopment,including neuregulin and glutamate pathways. These results suggestthat multiple, individually rare mutations impacting genes inneurodevelopmental pathways contribute to schizophrenia.
The editors suggest the following Related Resources on Science sites:
In Science Magazine
LETTERS
Christiana M. Leonard, John M. Kuldau;, Jon M. McClellan, Tom Walsh, Shane E. McCarthy, Mary-Claire King, and Jonathan Sebat (1 August 2008) Science321 (5889), 640a.
[DOI: 10.1126/science.321.5889.640a] |Full Text »|PDF »
In Science Signaling
EDITORS' CHOICE
Barbara R. Jasny (29 April 2008) Sci. Signal.1 (17), ec149.
[DOI: 10.1126/stke.117ec149] |Abstract »
In ScienceNOW
Constance Holden (27 March 2008) ScienceNOW2008 (327), 1.
|Full Text »
THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
The Genetics of Symptom-Based Phenotypes: Toward a Molecular Classification of Schizophrenia.
P. DeRosse, T. Lencz, K. E. Burdick, S. G. Siris, J. M. Kane, and A. K. Malhotra (2008)
Schizophr Bull
|Abstract »|Full Text »|PDF »
Copy Number Variants and Schizophrenia.
(2008)
Journal Watch Psychiatry
2008, 1
|Full Text »
,
