De novo mutations identified by exome sequencing implicate rare missense variants in SLC6A1 in schizophrenia

Elliott Rees, Jun Han, Joanne Morgan, Noa Carrera, Valentina Escott-Price, Andrew J. Pocklington, Madeleine Duffield, Lynsey S. Hall, Sophie E. Legge, Antonio F. Pardinas, Alexander L. Richards, Julian Roth, Tatyana Lezheiko, Nikolay Kondratyev, Vasilii Kaleda, Vera Golimbet, Mara Parellada, Javier Gonzalez-Penas, Celso Arango, Behrooz Z. AlizadehTherese van Amelsvoort, Richard Bruggeman, Wiepke Cahn, Lieuwe de Haan, Jurjen J. Luykx, Bart P. F. Rutten, Jim van Os, Ruud van Winkel, Micha Gawlik, George Kirov, James T. R. Walters, Peter Holmans, Michael C. O'Donovan*, Michael J. Owen*, GRP Investigators

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review


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.

Original languageEnglish
Pages (from-to)179-184
Number of pages11
JournalNature Neuroscience
Issue number2
Publication statusPublished - Feb 2020


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