Rare Structural Variants Disrupt Multiple Genes in Neurodevelopmental Pathways in Schizophrenia

Tom Walsh(University of Washington), Jon McClellan(University of Washington), Shane McCarthy(University of Washington), Anjené Addington(University of Washington), Sarah B. Pierce(University of Washington), Gregory M. Cooper(University of Washington), Alex S. Nord(University of Washington), Mary Kusenda(State University of New York), Dheeraj Malhotra(University of Washington), Abhishek Bhandari(University of Washington), Sunday M. Stray(University of Washington), Caitlin Rippey(University of Washington), Patricia Roccanova(University of Washington), Vlad Makarov(University of Washington), B. Lakshmi(University of Washington), Robert L. Findling(University of Washington), Linmarie Sikich(University of North Carolina at Chapel Hill), T Stromberg(University of Washington), Barry Merriman(University of California, Los Angeles), Nitin Gogtay(University of Washington), Philip Butler(University of Washington), Kristen Eckstrand(University of Washington), Laila Noory(University of Washington), Peter Gochman(University of Washington), Robert T. Long(University of Washington), Zugen Chen(University of California, Los Angeles), Sean Davis(University of Washington), Carl Baker(University of Washington), Evan E. Eichler(University of Washington), Paul S. Meltzer(University of Washington), Stanley F. Nelson(University of California, Los Angeles), Andrew Singleton(University of Washington), Ming K. Lee(University of Washington), Judith L. Rapoport(University of Washington), Mary‐Claire King(University of Washington), Jonathan Sebat(University of Washington)
Science
March 27, 2008
10.1126/science.1155174
Cited by 1,823

Abstract

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 kilobases were identified by microarray comparative genomic hybridization 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 and 20% of young-onset cases, both highly significant differences. The association was independently replicated in patients with childhood-onset schizophrenia as compared with their parents. Mutations in cases disrupted genes disproportionately from signaling networks controlling neurodevelopment, including neuregulin and glutamate pathways. These results suggest that multiple, individually rare mutations altering genes in neurodevelopmental pathways contribute to schizophrenia.

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