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Comparative Study
. 2011 Mar;168(3):302-16.
doi: 10.1176/appi.ajp.2010.10060876. Epub 2011 Feb 1.

Copy number variants in schizophrenia: confirmation of five previous findings and new evidence for 3q29 microdeletions and VIPR2 duplications

Douglas F Levinson  1 , Jubao Duan, Sang Oh, Kai Wang, Alan R Sanders, Jianxin Shi, Nancy Zhang, Bryan J Mowry, Ann Olincy, Farooq Amin, C Robert Cloninger, Jeremy M Silverman, Nancy G Buccola, William F Byerley, Donald W Black, Kenneth S Kendler, Robert Freedman, Frank Dudbridge, Itsik Pe'er, Hakon Hakonarson, Sarah E Bergen, Ayman H Fanous, Peter A Holmans, Pablo V Gejman
Affiliations
Comparative Study

Copy number variants in schizophrenia: confirmation of five previous findings and new evidence for 3q29 microdeletions and VIPR2 duplications

Douglas F Levinson et al. Am J Psychiatry. 2011 Mar.

Abstract

Objective: To evaluate previously reported associations of copy number variants (CNVs) with schizophrenia and to identify additional associations, the authors analyzed CNVs in the Molecular Genetics of Schizophrenia study (MGS) and additional available data.

Method: After quality control, MGS data for 3,945 subjects with schizophrenia or schizoaffective disorder and 3,611 screened comparison subjects were available for analysis of rare CNVs (<1% frequency). CNV detection thresholds were chosen that maximized concordance in 151 duplicate assays. Pointwise and genewise analyses were carried out, as well as analyses of previously reported regions. Selected regions were visually inspected and confirmed with quantitative polymerase chain reaction.

Results: In analyses of MGS data combined with other available data sets, odds ratios of 7.5 or greater were observed for previously reported deletions in chromosomes 1q21.1, 15q13.3, and 22q11.21, duplications in 16p11.2, and exon-disrupting deletions in NRXN1. The most consistently supported candidate associations across data sets included a 1.6-Mb deletion in chromosome 3q29 (21 genes, TFRC to BDH1) that was previously described in a mild-moderate mental retardation syndrome, exonic duplications in the gene for vasoactive intestinal peptide receptor 2 (VIPR2), and exonic duplications in C16orf72. The case subjects had a modestly higher genome-wide number of gene-containing deletions (>100 kb and >1 Mb) but not duplications.

Conclusions: The data strongly confirm the association of schizophrenia with 1q21.1, 15q13.3, and 22q11.21 deletions, 16p11.2 duplications, and exonic NRXN1 deletions. These CNVs, as well as 3q29 deletions, are also associated with mental retardation, autism spectrum disorders, and epilepsy. Additional candidate genes and regions, including VIPR2, were identified. Study of the mechanisms underlying these associations should shed light on the pathophysiology of schizophrenia.

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Figures

FIGURE 1
FIGURE 1
Intensity Plots of Large 3q29 Microdeletions in Five Subjects With Schizophrenia or Schizoaffective Disordera a Deletions of approximately 1.6 Mb were observed in five case subjects from the Molecular Genetics of Schizophrenia study (MGS), two in the International Schizophrenia Consortium study (ISC), and none of the comparison subjects in MGS, ISC, or the Children’s Hospital of Philadelphia group (plotted with genomic coordinates from the Human Genome 18 reference sequence). Each subject’s mean intensity for probes at each location was divided by the mean intensity for all subjects on the DNA plate; each point in the plot is the log of this result. Values of −1, 0, and 1 represent copy numbers of 0, 2, and 4, respectively; the deletions shown here have a copy number of 1. Copy number variants (CNVs) were called with the Birdseye module of the Birdsuite software package (15), version 2 (internal version 1.3). Copy numbers were also estimated for each point by a second algorithm (16). The browser plot at the bottom of the figure (from the University of California, Santa Cruz, Genome Browser, http://genome.ucsc.edu) shows the genes in the region and the segmental duplications that surround (and probably generate) the typical 21-gene deletion, including TFRC to BDH1 (see Table S7 in the online data supplement). The first plot illustrates the ambiguities of microarray intensity data, with the two algorithms interpreting the variability of intensity somewhat differently at each boundary. Several small CNVs in the region, including some in comparison subjects, are not shown.
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