@article{81b3fbe8cd1d4e7d9cc28aee1f748539,
title = "De novo mutations identified by exome sequencing implicate rare missense variants in SLC6A1 in schizophrenia",
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.",
keywords = "RISK, FRAMEWORK, ARCHITECTURE, INDIVIDUALS, ASSOCIATION, DISORDERS, INSIGHTS, BURDEN, COMMON, Insights, Architecture, Disorders, Risk, Burden, Common, Association, Individuals, Framework",
author = "Elliott Rees and Jun Han and Joanne Morgan and Noa Carrera and Valentina Escott-Price and Pocklington, {Andrew J.} and Madeleine Duffield and Hall, {Lynsey S.} and Legge, {Sophie E.} and Pardinas, {Antonio F.} and Richards, {Alexander L.} and Julian Roth and Tatyana Lezheiko and Nikolay Kondratyev and Vasilii Kaleda and Vera Golimbet and Mara Parellada and Javier Gonzalez-Penas and Celso Arango and Alizadeh, {Behrooz Z.} and {van Amelsvoort}, Therese and Richard Bruggeman and Wiepke Cahn and {de Haan}, Lieuwe and Luykx, {Jurjen J.} and Rutten, {Bart P. F.} and {van Os}, Jim and {van Winkel}, Ruud and Micha Gawlik and George Kirov and Walters, {James T. R.} and Peter Holmans and O'Donovan, {Michael C.} and Owen, {Michael J.} and {GRP Investigators}",
note = "Funding Information: M.C.O{\textquoteright}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. Funding Information: 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{\textquoteright}D., J.T.R.W., V.E.P., P.H. and A.J.P.), European Community Seventh Framework Programme Grant no. HEALTHF22010241909 (Project EUGEI, M.C.O{\textquoteright}D.), and European Union Seventh Framework Programme for research, technological development, and demonstration Grant no. 279227 (CRESTAR Consortium, M.C.O{\textquoteright}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. Publisher Copyright: {\textcopyright} 2020, The Author(s), under exclusive licence to Springer Nature America, Inc.",
year = "2020",
month = feb,
doi = "10.1038/s41593-019-0565-2",
language = "English",
volume = "23",
pages = "179--184",
journal = "Nature Neuroscience",
issn = "1097-6256",
publisher = "Nature Publishing Group",
number = "2",
}