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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.

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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.

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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.

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Authors and 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.

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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)

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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

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