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

Rees, Elliott, Han, Jun, Morgan, Joanne, Carrera, Noa, Escott-Price, Valentina, Pocklington, Andrew, Duffield, Madeleine, Hall, Lynsey, Legge, Sophie, Pardinas, Antonio, Richards, Alexander, Roth, Julian, Lezheiko, Tatyana, Kondratyev, Nikolay, Golimbat, Vera, Parellada, Mara, González-Peñas, Javier, Arango, Celso, Gawlik, Micha, Kirov, George, Walters, James, Holmans, Peter, O'Donovan, Michael and Owen, Michael 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: 25 Nov 2020 07:45

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