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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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.
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.
A list of members and affiliations appears in the Supplementary Note
Supplementary Figures 1–9, Supplementary Tables 1, 4, 6 and 7 and Supplementary Note (PDF 2634 kb)
Summary of data sets and quality control (XLSX 17 kb)
Summary of gene sets (XLSX 13 kb)
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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