Mosaic copy number variation in schizophrenia

Abstract

Recent reports suggest that somatic structural changes occur in the human genome, but how these genomic alterations might contribute to disease is unknown. Using samples collected as part of the International Schizophrenia Consortium (schizophrenia, n ¼ 3518; control, n ¼ 4238) recruited across multiple university research centers, we assessed single-nucleotide polymorphism genotyping arrays for evidence of chromosomal anomalies. Data from genotyping arrays on each individual were processed using Birdsuite and analyzed with PLINK. We validated potential chromosomal anomalies using custom nanostring probes and quantitative PCR. We estimate chromosomal alterations in the schizophrenia population to be 0.42%, which is not significantly different from controls (0.26%). We identified and validated a set of four extremely large (410 Mb) chromosomal anomalies in subjects with schizophrenia, including a chromosome 8 trisomy and deletion of the q arm of chromosome 7. These data demonstrate that chromosomal anomalies are present at low frequency in blood cells of both control and schizophrenia subjects. Keywords: schizophrenia; copy number variation; mosaic; SNP microarrays INTRODUCTION Schizophrenia (SCZ) is a highly heritable, debilitating psychiatric disorder characterized by psychosis and cognitive deficits, and has a lifetime prevalence of B0.5-0.7%. 1,2 Recent studies into the genetic architecture of this disease have implicated both common singlenucleotide polymorphisms (SNPs) and rare copy number variants (CNVs). [3][4][5] In particular, recent studies of rare CNVs in SCZ have identified both individuals with single events of high penetrance and abundant events across the genome. Specifically, CNVs 4500 kb at 22q11-13, 15q11, 15q13, 3q29, 7q36.3 and 1q21 have been linked to SCZ in B1% of cases. 3,[6][7][8][9] In addition, it has been shown that individuals with SCZ are more likely to carry large, rare CNVs than individuals without the disorder. This 'burden' has also been shown to be significant in singleton CNVs -those CNVs observed only once in a particular sample.Recent reports suggest that somatic structural changes in the nuclear genome are not uncommon and can be identified using SNP genotyping arrays, 10-12 at least when using DNA from white blood cells. These studies have detected a mosaicism rate from 0.23 to 2% and mosaicism has been observed in 7 to 95% of lymphocytes based on probe intensity measures. No disease study has yet revealed a difference between cases and controls on this measure.

Copy number variation in schizophrenia in Sweden

“…60 We identified four schizophrenia cases and three controls as genomic outliers (defined as > 40 CNVs or > 6 Mb, thresholds determined empirically as > 3 SD above the sample means). Six of seven abnormalities were confirmed using a second technology (Table S6 and Figure S2).…”

“…One case and one control had trisomy of chr8 or chr3 (Figure S2a–b), both confirmed using qPCR. 60 Three individuals had deletion (one case) or duplication events (two controls) at 15q11.2 (20.5Mb – 22.5 Mb, Figure S2f), which overlapped a CNV associated with mental retardation. One case (Figure S2g) had multiple deletions that appeared to be consistent with mosaicism.…”

Computational methods for detecting copy number variations in cancer genome using next generation sequencing: principles and challenges

“…Currently, several platforms with different achievable throughputs, coverage, and resolutions are available, including Fluorescence In Situ Hybridization (FISH) [19, 20], NanoString's digital detection technology [21-23], array comparative genomic hybridization (array CGH) [24], Single Nucleotide Polymorphism (SNP) array [7], and Next Generation Sequencing (NGS) [25-33]. In this Review, we focus on NGS-based approaches, as they have been emerging as the primary means of interrogating the CNV in recent investigations.…”

Animal models of gene–environment interaction in schizophrenia: A dimensional perspective

“…Some of these mutations are rare and have a moderate-to-large effect. Most are related to copy number variations (CNVs) as well as other types of structural genomic variation including deletions, duplications, and chromosomal rearrangements with potentially different pathogenic mechanisms and phenotypic outcomes (Levinson et al, 2011; Merikangas et al, 2014; Ruderfer et al, 2013; Timms et al, 2013; Warnica et al, 2014). The rate of CNVs in schizophrenia patients is increased, with deletions being observed more frequently than duplications (Buizer-Voskamp et al, 2011; Szatkiewicz et al, 2014).…”

“…The rate of CNVs in schizophrenia patients is increased, with deletions being observed more frequently than duplications (Buizer-Voskamp et al, 2011; Szatkiewicz et al, 2014). Structural variations can be inherited or originate de novo, and their role appears limited to a small fraction of patients (Ruderfer et al, 2013). There have been reports on prevalence of de novo CNV mutations in genes encoding for synaptic proteins (Xu et al, 2008, 2012; Kirov et al, 2012).…”