Rare structural variants disrupt multiple genes in neurodevelopmental pathways in schizophrenia

Tom Walsh, Jon M. McClellan, Shane E. McCarthy, Anjené M. Addington, Sarah B. Pierce, Greg M. Cooper, Alex S. Nord, Mary Kusenda, Dheeraj Malhotra, Abhishek Bhandari, Sunday M. Stray, Caitlin F. Rippey, Patricia Roccanova, Vlad Makarov, B. Lakshmi, Robert L. Findling, Linmarie Sikich, Thomas Stromberg, Barry Merriman, Nitin GogtayPhilip Butler, Kristen Eckstrand, Laila Noory, Peter Gochman, Robert Long, Zugen Chen, Sean Davis, Carl Baker, Evan E. Eichler, Paul S. Meltzer, Stanley F. Nelson, Andrew B. Singleton, Ming K. Lee, Judith L. Rapoport, Mary Claire King, Jonathan Sebat

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Pages (from-to)539-543
Number of pages5
JournalScience
Volume320
Issue number5875
DOIs
StatePublished - Apr 25 2008

ASJC Scopus subject areas

  • General

Fingerprint Dive into the research topics of 'Rare structural variants disrupt multiple genes in neurodevelopmental pathways in schizophrenia'. Together they form a unique fingerprint.

Cite this