Human Molecular Genetics Advance Access published online on November 6, 2007
Human Molecular Genetics, doi:10.1093/hmg/ddm323
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Comparative genome hybridization suggests a role for NRXN1 and APBA2 in schizophrenia
1 Department of Psychological Medicine, Cardiff University, Henry Wellcome Building, Heath Park, Cardiff CF14 4XN, UK 2 Max Planck Institute for Molecular Genetics, Department of Human Molecular Genetics, Ihnestr. 73, 14195 Berlin, Germany
* Corresponding author: Michael J Owen, Department of Psychological Medicine, Cardiff University, Henry Wellcome Building, Heath Park, Cardiff CF14 4XN, UK Tel: +442920743058Fax: +442920746554 e-mail: owenmj{at}cardiff.ac.uk
Received September 21, 2007; Revised October 29, 2007; Accepted November 5, 2007
Copy number variations (CNVs) account for a substantial proportion of human genomic variation, and have been shown to cause neurodevelopmental disorders. We sought to determine the relevance of CNVs to the aetiology of schizophrenia. Whole genome, high resolution, tiling path BAC array comparative genomic hybridization (array CGH) was employed to test DNA from 93 individuals with DSM-IV schizophrenia. Common DNA copy number changes that are unlikely to be directly pathogenic in schizophrenia were filtered out by comparison to a reference dataset of 372 control individuals analysed in our laboratory, and a screen against the Database of Genomic Variants. The remaining aberrations were validated with Affymetrix 250K SNP arrays or 244K Agilent oligo-arrays and tested for inheritance from the parents. Thirteen aberrations satisfied our criteria. Two of them are very likely to be pathogenic. The first one is a deletion at 2p16.3 that was present in an affected sibling and disrupts NRXN1. The second one is a de novo duplication at 15q13.1 spanning APBA2. The proteins of these two genes interact directly and play a role in synaptic development and function. Both genes have been affected by CNVs in patients with autism and mental retardation but neither has been previously implicated in schizophrenia.
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