New Copy Number Variations in Schizophrenia

Chiara Magri,Paolo Valsecchi,Massimo Gennarelli,Michele Traversa,Sergio Barlati,Cristian Bonvicini,Emilio Sacchetti,Alessandra Minelli,Rita Gardella,Thomas Burne

doi:10.1371/journal.pone.0013422

Abstract

Genome-wide screenings for copy number variations (CNVs) in patients with schizophrenia have demonstrated the presence of several CNVs that increase the risk of developing the disease and a growing number of large rare CNVs; the contribution of these rare CNVs to schizophrenia remains unknown. Using Affymetrix 6.0 arrays, we undertook a systematic search for CNVs in 172 patients with schizophrenia and 160 healthy controls, all of Italian origin, with the aim of confirming previously identified loci and identifying novel schizophrenia susceptibility genes. We found five patients with a CNV occurring in one of the regions most convincingly implicated as risk factors for schizophrenia: NRXN1 and the 16p13.1 regions were found to be deleted in single patients and 15q11.2 in 2 patients, whereas the 15q13.3 region was duplicated in one patient. Furthermore, we found three distinct patients with CNVs in 2q12.2, 3q29 and 17p12 loci, respectively. These loci were previously reported to be deleted or duplicated in patients with schizophrenia but were never formally associated with the disease. We found 5 large CNVs (>900 kb) in 4q32, 5q14.3, 8q23.3, 11q25 and 17q12 in five different patients that could include some new candidate schizophrenia susceptibility genes. In conclusion, the identification of previously reported CNVs and of new, rare, large CNVs further supports a model of schizophrenia that includes the effect of multiple, rare, highly penetrant variants.

Highlights

In recent years, the availability of high throughput technologies investigating the genome at a resolution intermediate between that of cytogenetic analysis (.2–5 Mb) and DNA sequencing (1– 700 bp) led to the demonstration that a large number of genomic sequences, many of which encompass entire genes, vary in copy number among individuals
Overall copy number variations (CNVs) Of the 180 patients with schizophrenia and healthy controls who were analyzed with the Affymetrix 6.0 microarrays, cases and 160 controls survived the filtering for quality control and population stratification
The study contributes to the growing list of specific CNVs potentially implicated in schizophrenia

Summary

Introduction

The availability of high throughput technologies investigating the genome at a resolution intermediate between that of cytogenetic analysis (.2–5 Mb) and DNA sequencing (1– 700 bp) led to the demonstration that a large number of genomic sequences, many of which encompass entire genes, vary in copy number among individuals. Mb) and DNA sequencing (1– 700 bp) led to the demonstration that a large number of genomic sequences, many of which encompass entire genes, vary in copy number among individuals These intermediate size deletions and duplications, referred to as copy number variations (CNVs), are more common in the general population than ever imagined before and could account for more genomic differences among sindividuals than single nucleotide polymorphisms (SNPs) [1,2]. Genome-wide screening for CNVs has demonstrated that deletions and duplications that disrupt genes are more common in patients than in healthy subjects [11,12] The pathogenicity of these CNVs seems to be correlated with their size, because patient–control differences have involved mainly large copy number variants [11,13,14]. The observation that deletions greater than 2 Mb occur extremely rarely, less than

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Conclusion