Genome-wide analysis shows increased frequency of copy number variation deletions in Dutch schizophrenia patients

Abstract

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.

Figure 1. Copy Number Variations in 834 Dutch schizophrenia patients and 672 Dutch controls

Representation of a systematic genome-wide survey for CNVs in 834 Dutch schizophrenia cases and 672 Dutch controls. On the left side of each chromosome, CNVs of controls are indicated. On the right side of each chromosome, CNVs of schizophrenia cases are indicated. Blue bars represent duplications, red bars represent deletions. In green, schizophrenia associated genes from CNV literature are indicated.

Figure 2. Copy Number Variations in 834 Dutch schizophrenia cases compared with cytogenetic aberrations from literature

On the left side of each chromosome, chromosomal aberrations from literature are indicated. On the right side of each chromosome, copy number variants in 834 Dutch schizophrenia cases are indicated. Blue bars represent duplications or gains, red bars represent deletions or losses, and green bars represent balanced translocations/inversions. Blue boxes indicate regions where at least one chromosomal aberration and two copy number cases overlapped. The regions 1q42.3-q43 and 22q11.2 were previously indicated by linkage (54;55) or association studies (56;57) and often supported by CNV findings from literature. The regions on chromosome 5q35 and on chromosome 7q21.12-q21.13 are potentially novel regions, not indicated in association or linkage studies (–57). For the exact basepair boundaries of overlap regions we refer to Table S1 and S4 in the Supplement.