Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Contribution of copy number variants to schizophrenia from a genome-wide study of 41,321 subjects

An Erratum to this article was published on 01 October 2017

An Erratum to this article was published on 30 March 2017

This article has been updated

Abstract

Copy number variants (CNVs) have been strongly implicated in the genetic etiology of schizophrenia (SCZ). However, genome-wide investigation of the contribution of CNV to risk has been hampered by limited sample sizes. We sought to address this obstacle by applying a centralized analysis pipeline to a SCZ cohort of 21,094 cases and 20,227 controls. A global enrichment of CNV burden was observed in cases (odds ratio (OR) = 1.11, P = 5.7 × 10−15), which persisted after excluding loci implicated in previous studies (OR = 1.07, P = 1.7 × 10−6). CNV burden was enriched for genes associated with synaptic function (OR = 1.68, P = 2.8 × 10−11) and neurobehavioral phenotypes in mouse (OR = 1.18, P = 7.3 × 10−5). Genome-wide significant evidence was obtained for eight loci, including 1q21.1, 2p16.3 (NRXN1), 3q29, 7q11.2, 15q13.3, distal 16p11.2, proximal 16p11.2 and 22q11.2. Suggestive support was found for eight additional candidate susceptibility and protective loci, which consisted predominantly of CNVs mediated by nonallelic homologous recombination.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Figure 1: CNV burden.
Figure 2: Gene set burden.
Figure 3: Encoded-protein interaction network for synaptic genes.
Figure 4: Gene-based Manhattan plot.
Figure 5: Manhattan plot of breakpoint-level associations across the NRXN1 locus.

Change history

  • 05 December 2016

    In the version of this article initially published online, author Daniel P. Howrigan was not listed as having contributed equally to this work. The error has been corrected for the print, PDF and HTML versions of this article.

  • 11 July 2017

    In the version of this article initially published, the members of the CNV and Schizophrenia Working Groups of the Psychiatric Genomics Consortium were listed as collaborators but should have appeared as authors. The error has been corrected in the HTML and PDF versions of the article.

References

  1. 1

    Malhotra, D. & Sebat, J. CNVs: harbingers of a rare variant revolution in psychiatric genetics. Cell 148, 1223–1241 (2012).

    CAS  Article  Google Scholar 

  2. 2

    Walsh, T. et al. Rare structural variants disrupt multiple genes in neurodevelopmental pathways in schizophrenia. Science 320, 539–543 (2008).

    CAS  Article  Google Scholar 

  3. 3

    International Schizophrenia Consortium. Rare chromosomal deletions and duplications increase risk of schizophrenia. Nature 455, 237–241 (2008).

  4. 4

    Malhotra, D. et al. High frequencies of de novo CNVs in bipolar disorder and schizophrenia. Neuron 72, 951–963 (2011).

    CAS  Article  Google Scholar 

  5. 5

    Xu, B. et al. Strong association of de novo copy number mutations with sporadic schizophrenia. Nat. Genet. 40, 880–885 (2008).

    CAS  Article  Google Scholar 

  6. 6

    Kirov, G. et al. De novo CNV analysis implicates specific abnormalities of postsynaptic signalling complexes in the pathogenesis of schizophrenia. Mol. Psychiatry 17, 142–153 (2012).

    CAS  Article  Google Scholar 

  7. 7

    McCarthy, S.E. et al. Microduplications of 16p11.2 are associated with schizophrenia. Nat. Genet. 41, 1223–1227 (2009).

    CAS  Article  Google Scholar 

  8. 8

    Mulle, J.G. et al. Microdeletions of 3q29 confer high risk for schizophrenia. Am. J. Hum. Genet. 87, 229–236 (2010).

    CAS  Article  Google Scholar 

  9. 9

    Rujescu, D. et al. Disruption of the neurexin 1 gene is associated with schizophrenia. Hum. Mol. Genet. 18, 988–996 (2009).

    CAS  Article  Google Scholar 

  10. 10

    Pocklington, A.J. et al. Novel findings from CNVs implicate inhibitory and excitatory signaling complexes in schizophrenia. Neuron 86, 1203–1214 (2015).

    CAS  Article  Google Scholar 

  11. 11

    Horev, G. et al. Dosage-dependent phenotypes in models of 16p11.2 lesions found in autism. Proc. Natl. Acad. Sci. USA 108, 17076–17081 (2011).

    Article  Google Scholar 

  12. 12

    Golzio, C. et al. KCTD13 is a major driver of mirrored neuroanatomical phenotypes of the 16p11.2 copy number variant. Nature 485, 363–367 (2012).

    CAS  Article  Google Scholar 

  13. 13

    Holmes, A.J. et al. Individual differences in amygdala-medial prefrontal anatomy link negative affect, impaired social functioning, and polygenic depression risk. J. Neurosci. 32, 18087–18100 (2012).

    CAS  Article  Google Scholar 

  14. 14

    Schizophrenia Working Group of the Psychiatric Genomics Consortium. Biological insights from 108 schizophrenia-associated genetic loci. Nature 511, 421–427 (2014).

  15. 15

    Wang, K. et al. PennCNV: an integrated hidden Markov model designed for high-resolution copy number variation detection in whole-genome SNP genotyping data. Genome Res. 17, 1665–1674 (2007).

    CAS  Article  Google Scholar 

  16. 16

    Pinto, D. et al. Functional impact of global rare copy number variation in autism spectrum disorders. Nature 466, 368–372 (2010).

    CAS  Article  Google Scholar 

  17. 17

    Korn, J.M. et al. Integrated genotype calling and association analysis of SNPs, common copy number polymorphisms and rare CNVs. Nat. Genet. 40, 1253–1260 (2008).

    CAS  Article  Google Scholar 

  18. 18

    Vacic, V. et al. Duplications of the neuropeptide receptor gene VIPR2 confer significant risk for schizophrenia. Nature 471, 499–503 (2011).

    CAS  Article  Google Scholar 

  19. 19

    Raychaudhuri, S. et al. Accurately assessing the risk of schizophrenia conferred by rare copy-number variation affecting genes with brain function. PLoS Genet. 6, e1001097 (2010).

    Article  Google Scholar 

  20. 20

    Kirov, G. et al. Comparative genome hybridization suggests a role for NRXN1 and APBA2 in schizophrenia. Hum. Mol. Genet. 17, 458–465 (2008).

    CAS  Article  Google Scholar 

  21. 21

    Lupski, J.R. Genomic disorders: structural features of the genome can lead to DNA rearrangements and human disease traits. Trends Genet. 14, 417–422 (1998).

    CAS  Article  Google Scholar 

  22. 22

    DeLisi, L.E. et al. Schizophrenia and sex chromosome anomalies. Schizophr. Bull. 20, 495–505 (1994).

    CAS  Article  Google Scholar 

  23. 23

    El-Hattab, A.W. et al. Int22h-1/int22h-2-mediated Xq28 rearrangements: intellectual disability associated with duplications and in utero male lethality with deletions. J. Med. Genet. 48, 840–850 (2011).

    CAS  Article  Google Scholar 

  24. 24

    El-Hattab, A.W. et al. Clinical characterization of int22h1/int22h2-mediated Xq28 duplication/deletion: new cases and literature review. BMC Med. Genet. 16, 12 (2015).

    Article  Google Scholar 

  25. 25

    Sebat, J., Levy, D.L. & McCarthy, S.E. Rare structural variants in schizophrenia: one disorder, multiple mutations; one mutation, multiple disorders. Trends Genet. 25, 528–535 (2009).

    CAS  Article  Google Scholar 

  26. 26

    Rees, E. et al. Evidence that duplications of 22q11.2 protect against schizophrenia. Mol. Psychiatry 19, 37–40 (2014).

    CAS  Article  Google Scholar 

  27. 27

    Van Campenhout, S. et al. Microduplication 22q11.2: a description of the clinical, developmental and behavioral characteristics during childhood. Genet. Couns. 23, 135–148 (2012).

    CAS  PubMed  Google Scholar 

  28. 28

    Fromer, M. et al. De novo mutations in schizophrenia implicate synaptic networks. Nature 506, 179–184 (2014).

    CAS  Article  Google Scholar 

  29. 29

    Zatz, M. et al. Cosegregation of schizophrenia with Becker muscular dystrophy: susceptibility locus for schizophrenia at Xp21 or an effect of the dystrophin gene in the brain? J. Med. Genet. 30, 131–134 (1993).

    CAS  Article  Google Scholar 

  30. 30

    Straub, R.E. et al. Genetic variation in the 6p22.3 gene DTNBP1, the human ortholog of the mouse dysbindin gene, is associated with schizophrenia. Am. J. Hum. Genet. 71, 337–348 (2002).

    CAS  Article  Google Scholar 

  31. 31

    Mutsuddi, M. et al. Analysis of high-resolution HapMap of DTNBP1 (Dysbindin) suggests no consistency between reported common variant associations and schizophrenia. Am. J. Hum. Genet. 79, 903–909 (2006).

    CAS  Article  Google Scholar 

  32. 32

    Sekar, A. et al. Schizophrenia risk from complex variation of complement component 4. Nature 530, 177–183 (2016).

    CAS  Article  Google Scholar 

  33. 33

    Sudmant, P.H. et al. An integrated map of structural variation in 2,504 human genomes. Nature 526, 75–81 (2015).

    CAS  Article  Google Scholar 

  34. 34

    Brandler, W.M. et al. Frequency and complexity of de novo structural mutation in autism. Am. J. Hum. Genet. 98, 667–679 (2016).

    CAS  Article  Google Scholar 

  35. 35

    Gymrek, M. et al. Abundant contribution of short tandem repeats to gene expression variation in humans. Nat. Genet. 48, 22–29 (2016).

    CAS  Article  Google Scholar 

  36. 36

    Zuberi, K. et al. GeneMANIA prediction server 2013 update. Nucleic Acids Res. 41, W115–W122 (2013).

    Article  Google Scholar 

Download references

Acknowledgements

Core funding for the Psychiatric Genomics Consortium is from the US National Institute of Mental Health (NIMH, U01 MH094421). We thank T. Lehner, A. Addington and G. Senthil (NIMH). The work of the contributing groups was supported by numerous grants from governmental and charitable bodies as well as philanthropic donation. Details are provided in the Supplementary Note.

Author information

Affiliations

Authors

Consortia

Contributions

Management of the study, core analyses and content of the manuscript was the responsibility of the CNV Analysis Group, chaired by J. Sebat and jointly supervised by S.W.S. and B.M.N. together with the Schizophrenia Working Group, chaired by M.C.O'D. Core analyses were carried out by D.P.H., D. Merico, and C.R.M. Data Processing pipeline was implemented by C.R.M., B.T., W.W., D.S.G., M. Gujral, A. Shetty, and W.B. The A custom PGC CNV browser was developed by C.R.M., D.P.H. and B.T. Additional analyses and interpretations were contributed by W.W., D.A. and P.A.H. The individual studies or consortia contributing to the CNV meta-analysis were led by R.A., O.A.A., D.H.R.B., E. Bramon, J.D.B., A.C., D.A.C., S.C., A.D., E. Domenici, T.E., P.V.G., M.G., H.G., C.M.H., N.I., A.V.J., E.G.J., K.S.K., G.K., J. Knight, D.F.L., Q.S.L., J. Liu, S.A.M., A. McQuillin, J.L.M., B.J.M., M.M.N., M.C.O'D., R.A.O., M.J.O., A. Palotie, C.N.P., T.L.P., M.R., B.P.R., D.R., P. Sklar, D.S.C., P.F.S., J.T.R.W. and T.W. The remaining authors contributed to the recruitment, genotyping, or data processing for the contributing components of the meta-analysis. J. Sebat, B.M.N., M.C.O'D., C.R.M., D.P.H., and D. Merico drafted the manuscript, which was shaped by the management group. All other authors saw, had the opportunity to comment on and approved the final draft.

Corresponding author

Correspondence to Jonathan Sebat.

Ethics declarations

Competing interests

J. Sebat is a co-inventor on patents granted (8554488) and pending (20140171371) on genetic methods for the diagnosis of psychiatric disorders. Several of the authors are employees of the following pharmaceutical companies: F. Hoffman-La Roche (D. Malhotra, L.E.), Eli Lilly (D.A.C., Y.M., L.N.) and Janssen (A. Savitz, Q.S.L.). None of these companies influenced the design of the study, the interpretation of the data or the amount of data reported or financially profit by publication of the results, which are precompetitive.

Additional information

A list of members and affiliations appears in the Supplementary Note

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–9, Supplementary Tables 1, 4, 6 and 7 and Supplementary Note (PDF 2634 kb)

Supplementary Table 2

Summary of data sets and quality control (XLSX 17 kb)

Supplementary Table 3

Summary of gene sets (XLSX 13 kb)

Supplementary Table 5

Summary of digital droplet PCR results (XLSX 1958 kb)

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Marshall, C., Howrigan, D., Merico, D. et al. Contribution of copy number variants to schizophrenia from a genome-wide study of 41,321 subjects. Nat Genet 49, 27–35 (2017). https://doi.org/10.1038/ng.3725

Download citation

Further reading

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing