Abstract
Schizophrenia is a highly polygenic disorder with important contributions from both common and rare risk alleles. We analyzed exome sequencing data for de novo variants (DNVs) in a new sample of 613 schizophrenia trios and combined this with published data to give a total of 3,444 trios. In this new data, loss-of-function (LoF) DNVs were significantly enriched among 3,471 LoF-intolerant genes, which supports previous findings. In the full dataset, genes associated with neurodevelopmental disorders (n = 159) were significantly enriched for LoF DNVs. Within these neurodevelopmental disorder genes, SLC6A1, which encodes a γ-aminobutyric acid transporter, was associated with missense-damaging DNVs. In 1,122 trios for which genome-wide common variant data were available, schizophrenia and bipolar disorder polygenic risk were significantly overtransmitted to probands. Probands carrying LoF or deletion DNVs in LoF-intolerant or neurodevelopmental disorder genes had significantly less overtransmission of schizophrenia polygenic risk than did non-carriers, which provides a second robust line of evidence that these DNVs increase liability to schizophrenia.
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Data availability
DNVs discovered from the new trios are published in Supplementary Table 12. The data that support the findings of this study are available from the corresponding author upon reasonable request.
Code availability
A description of the R functions used for statistical analysis can be found in the Life Sciences Reporting Summary.
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Acknowledgements
The work at Cardiff University was supported by Medical Research Council Centre Grant no. MR/L010305/1 (M.J.O.) and Program Grant no. G0800509 (M.J.O, M.C.O’D., J.T.R.W., V.E.-P., P.H. and A.J.P.), European Community Seventh Framework Programme Grant no. HEALTH-F2-2010-241909 (Project EU-GEI, M.C.O’D.), and European Union Seventh Framework Programme for research, technological development, and demonstration Grant no. 279227 (CRESTAR Consortium, M.C.O’D. and J.T.R.W.). We acknowledge L. Bates and L. Hopkins, at Cardiff University, for laboratory sample management. We acknowledge M. Einon, at Cardiff University, for support with the use and setup of computational infrastructures.
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M.C.O’D., M.J.O., J.T.R.W., P.H. and E.R. conceived and designed the research. E.R. analyzed the data. J.H., J.M. and N.C. performed and managed the sequencing experiments. J.H. and M.D. performed the Sanger sequencing validation experiment. V.E.-P., A.J.P., L.H., S.E.L., A.F.P. and A.L.R. contributed to the interpretation of the results. T.L., N.K., V.K., V.G., M.P., J.G.-P., C.A., GROUP Investigators, M.G., J.R., G.K., J.T.R.W., M.C.O’D. and M.J.O. led the acquisition of the clinical samples. E.R., M.C.O’D. and M.J.O. wrote the manuscript, which was read, edited and approved by all authors.
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M.C.O’D., M.J.O., P.H., J.T.R.W. and A.J.P. are supported by a collaborative research grant from Takeda. Takeda played no part in the conception, design, implementation, funding or interpretation of this study. All other authors declare no competing interests.
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Peer review information Nature Neuroscience thanks Ryan Yuen and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.
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Supplementary Information
Ethics statement; Sample description; Supplementary Figures 1–4; CNV analysis; Principal component analysis; Sequencing coverage information; Alternative de novo enrichment tests; Supplementary Table legends.
Supplementary Table
Supplementary tables 1–14.
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Rees, E., Han, J., Morgan, J. et al. De novo mutations identified by exome sequencing implicate rare missense variants in SLC6A1 in schizophrenia. Nat Neurosci 23, 179–184 (2020). https://doi.org/10.1038/s41593-019-0565-2
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DOI: https://doi.org/10.1038/s41593-019-0565-2
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