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

Rees, Elliott, GROUP Investigators, Han, Jun, Morgan, Joanne, Carrera, Noa, Escott-Price, Valentina, Pocklington, Andrew J., Duffield, Madeleine, Hall, Lynsey S., Legge, Sophie E., Pardinas, Antonio F., Richards, Alexander L., Roth, Julian, Lezheiko, Tatyana, Kondratyev, Nikolay, Golimbat, Vera, Parellada, Mara, González-Peñas, Javier, Arango, Celso, Gawlik, Micha, Kirov, George, Walters, James T. R., Holmans, Peter, O'Donovan, Michael C. and Owen, Michael J. 2020. De novo mutations identified by exome sequencing implicate rare missense variants in SLC6A1 in schizophrenia. Nature Neuroscience 23 (2) , pp. 179-184. 10.1038/s41593-019-0565-2

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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.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
MRC Centre for Neuropsychiatric Genetics and Genomics (CNGG)
Publisher: Nature Publishing Group
ISSN: 1097-6256
Date of First Compliant Deposit: 14 October 2019
Date of Acceptance: 22 November 2019
Last Modified: 09 Jun 2022 02:39

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