Genome-Wide Analysis Shows Increased Frequency of Copy Number Variation Deletions in Dutch Schizophrenia Patients

• Published in: Biological psychiatry (1969) Vol. 70; no. 7; pp. 655 - 662
• Main Authors: Buizer-Voskamp, Jacobine E, Muntjewerff, Jan-Willem, Strengman, Eric, Sabatti, Chiara, Stefansson, Hreinn, Vorstman, Jacob A.S, Ophoff, Roel A
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.10.2011
• Subjects: Base Sequence - genetics; Candidate gene; Case-Control Studies; copy number variation; cytogenetic abnormality; deletion; DNA Copy Number Variations - genetics; duplication; Genetic Predisposition to Disease - genetics; Genome-Wide Association Study; Humans; Netherlands; Psychiatry; schizophrenia; Schizophrenia - genetics; Sequence Deletion - genetics; Netherlands; cytogenetic abnormality; Candidate gene; schizophrenia; copy number variation; deletion; duplication
• ISSN: 0006-3223; 1873-2402
• DOI: 10.1016/j.biopsych.2011.02.015

Background Since 2008, multiple studies have reported on copy number variations (CNVs) in schizophrenia. However, many regions are unique events with minimal overlap between studies. This makes it difficult to gain a comprehensive overview of all CNVs involved in the etiology of schizophrenia. We performed a systematic CNV study on the basis of a homogeneous genome-wide dataset aiming at all CNVs ≥50 kilobase pair. We complemented this analysis with a review of cytogenetic and chromosomal abnormalities for schizophrenia reported in the literature with the purpose of combining classical genetic findings and our current understanding of genomic variation. Methods We investigated 834 Dutch schizophrenia patients and 672 Dutch control subjects. The CNVs were included if they were detected by QuantiSNP ( http://www.well.ox.ac.uk/QuantiSNP/ ) as well as PennCNV ( http://www.neurogenome.org/cnv/penncnv/ ) and contain known protein coding genes. The integrated identification of CNV regions and cytogenetic loci indicates regions of interest (cytogenetic regions of interest [CROIs]). Results In total, 2437 CNVs were identified with an average number of 2.1 CNVs/subject for both cases and control subjects. We observed significantly more deletions but not duplications in schizophrenia cases versus control subjects. The CNVs identified coincide with loci previously reported in the literature, confirming well-established schizophrenia CROIs 1q42 and 22q11.2 as well as indicating a potentially novel CROI on chromosome 5q35.1. Conclusions Chromosomal deletions are more prevalent in schizophrenia patients than in healthy subjects and therefore confer a risk factor for pathogenicity. The combination of our CNV data with previously reported cytogenetic abnormalities in schizophrenia provides an overview of potentially interesting regions for positional candidate genes.