Copy number variants in schizophrenia: confirmation of five previous findings and new evidence for 3q29 microdeletions and VIPR2 duplications
Open accessAbstract
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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None of the donors had large copy-number variants (>100 kb).
“All donors were also analysed for copy-number variants, and none had large copy-number variants (>100 kb)61”
From PICALM Alzheimer’s risk allele causes aberrant lipid droplets in microglia (2025) · cites this paper as [61]
The Methods (GWAS Assay and Detection of CNVs; Analysis of CNV Association) describe testing samples for CNVs, including variants larger than 100 kb. The Results instead report large CNVs in the paper’s own subjects; the paper does not establish that none of the citing study’s donors had them. (LLM, conf=0.84)
Experimental — accuracy not yet measuredC16orf72 was recently identified in a schizophrenia CNV study.
“C16orf72, coding for a protein of unknown function, recently identified in a schizophrenia CNV study (Levinson et al., 2011)”
From Multiple recurrent de novo CNVs, including duplications of the 7q11.23 Williams syndrome region, are strongly associated with autism (2011) · cites this paper as Levinson et al., 2011
The enriched pathways were tested in rare CNVs from large independent case-control datasets: 8,290 schizophrenia cases and 7,431 controls from Vacic et al., a combined sample from three studies, and a bipolar disorder case-control set of 2,777 cases and 3,508 controls from BiGS.
“We extended our analysis of pathways identified in this study (Table 4 and Table 5, and S7) to rare CNVs from large case-controls studies of SCZ and BD. These included rare CNVs from 8,290 SCZ cases and 7,431 controls from Vacic et al. (2011), a combined sample of three studies from our group, MGS (Levinson et al., 2011), and the International Schizophrenia Consortium (International Schizophrenia”
From High frequencies of de novo CNVs in bipolar disorder and schizophrenia (2011) · cites this paper as Levinson et al., 2011
Several individual CNV loci have been strongly implicated as risk factors for schizophrenia.
“several individual CNV loci have been strongly implicated as risk factors for schizophrenia with high degrees of statistical confidence. These include deletions at 1q21.1, NRXN1, 3q29, 15q11.2, 15q13.3, 22q11.2 and duplications at VIPR2, 16p11.2, 16p13.1 and 15q11-q13.2, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13”
From De novo CNV analysis implicates specific abnormalities of postsynaptic signalling complexes in the pathogenesis of schizophrenia (2012) · cites this paper as [4]
One large study has reported no overall excess of CNVs in cases at all.
“indeed, one large study has reported no overall excess of CNVs in cases at all.4”
From De novo CNV analysis implicates specific abnormalities of postsynaptic signalling complexes in the pathogenesis of schizophrenia (2012) · cites this paper as [4]
The marked elevation in the rate of de novo CNVs contrasts with the relatively modest elevation in the rate of CNVs seen in case-control studies, and suggests that sets of de novos might be more informative for gene-set enrichment analyses.
“This marked elevation in the rate of de novo CNVs contrasts with the relatively modest elevation in the rate of CNVs seen in case–control studies,2, 4 and suggests that sets of de novos might be more informative for gene-set enrichment analyses.”
From De novo CNV analysis implicates specific abnormalities of postsynaptic signalling complexes in the pathogenesis of schizophrenia (2012) · cites this paper as [4]
The elevation of CNVs at loci affected by case de novos is much higher than the overall increase in CNV burden in cases in large published studies.
“This elevation is much higher than the overall increase in CNV burden in cases in the large published studies.2, 4”
From De novo CNV analysis implicates specific abnormalities of postsynaptic signalling complexes in the pathogenesis of schizophrenia (2012) · cites this paper as [4]
The 15q11.2 locus was not significantly enriched in the MGS study.
“this locus was not significantly enriched in the MGS study,4”
From De novo CNV analysis implicates specific abnormalities of postsynaptic signalling complexes in the pathogenesis of schizophrenia (2012) · cites this paper as [4]
CNVs spanning DLG1 and DLG2 have been reported before in schizophrenia.
“CNVs spanning DLG1 and DLG2 have been reported before in schizophrenia4, 6, 17”
From De novo CNV analysis implicates specific abnormalities of postsynaptic signalling complexes in the pathogenesis of schizophrenia (2012) · cites this paper as [4]
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References 43 · Cited by 434
- Authors
- Levinson, D. F., Duan, J., Oh, S., Wang, K., Sanders, A. R., Shi, J., Zhang, N., Mowry, B. J., Olincy, A., Amin, F., Cloninger, C. R., Silverman, J. M., Buccola, N. G., Byerley, W. F., Black, D. W., Kendler, K. S., Freedman, R., Dudbridge, F., Pe'er, I., Hakonarson, H., Bergen, S. E., Fanous, A. H., Holmans, P. A., & Gejman, P. V.
- Affiliations
- Children's Hospital of Philadelphia (US)
- From the Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, Calif.; the NorthShore University HealthSystem Research Institute, Evanston, Ill.; the Children's Hospital of Philadelphia and University of Pennsylvania, Philadelphia; the National Cancer Institute, Bethesda, Md.; the Queensland Centre for Mental Health Research and Queensland Institute for Medical Research, Brisbane, Queensland, Australia; the Department of Psychiatry, University of Colorado Denver, Aurora, Colo.;...
- ORCID
- Venue
- American Journal of Psychiatry
- Published
- 2011-03
- Volume
- 168
- Issue
- 3
- Pages
- 302-316
- ISSN
- 0002-953X (ISSN-L)
- 1535-7228
- PMC
- PMC4441324
- OpenAlex
- W2022825972
- Cited by
- 434
- References
- 43
- Citations by year
- 2026: 7 · 2025: 15 · 2024: 15 · 2023: 9 · 2022: 8 · 2021: 9 · 2020: 24 · 2019: 26 · 2018: 15 · 2017: 27 · 2016: 28 · 2015: 53 · 2014: 47 · 2013: 58 · 2012: 61
- FWCI
- 38.96
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- American Journal of Psychiatry (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (6u54rr020278-06)
- National Institute of Mental Health (U01MH046276, R01MH059566, U01MH046318, R01MH059571, R01MH060879, R01MH059565, R01MH081800, R01MH060870, U01MH046289, U01MH079469, R01MH061675, R01MH059586, R01MH059588, R01MH067257, U01MH079470, R01MH059587)
- National Center for Research Resources (U54-RR020278)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomic variations and chromosomal abnormalities
- Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Keywords
- copy number variation, schizophrenia, 1q21.1 deletion, 16p11.2 duplication, schizoaffective disorder, intellectual disability, autism spectrum disorder, epilepsy, candidate genes
- MeSH terms
- Chromosome Deletion, Chromosomes, Human, Pair 3, Ethnicity, Humans, Schizophrenia, Genetic Predisposition to Disease, Genome-Wide Association Study, DNA Copy Number Variations
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