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

Rees, Elliott ORCID: https://orcid.org/0000-0002-6168-9222, GROUP Investigators, Han, Jun, Morgan, Joanne, Carrera, Noa ORCID: https://orcid.org/0000-0003-0739-0382, Escott-Price, Valentina ORCID: https://orcid.org/0000-0003-1784-5483, Pocklington, Andrew J. ORCID: https://orcid.org/0000-0002-2137-0452, Duffield, Madeleine, Hall, Lynsey S., Legge, Sophie E., Pardinas, Antonio F. ORCID: https://orcid.org/0000-0001-6845-7590, Richards, Alexander L., Roth, Julian, Lezheiko, Tatyana, Kondratyev, Nikolay, Golimbat, Vera, Parellada, Mara, González-Peñas, Javier, Arango, Celso, Gawlik, Micha, Kirov, George ORCID: https://orcid.org/0000-0002-3427-3950, Walters, James T. R. ORCID: https://orcid.org/0000-0002-6980-4053, Holmans, Peter ORCID: https://orcid.org/0000-0003-0870-9412, O'Donovan, Michael C. ORCID: https://orcid.org/0000-0001-7073-2379 and Owen, Michael J. ORCID: https://orcid.org/0000-0003-4798-0862 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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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.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Professional Services > Advanced Research Computing @ Cardiff (ARCCA) Research Institutes & Centres > MRC Centre for Neuropsychiatric Genetics and Genomics (CNGG) Schools > Medicine
Publisher:	Nature Publishing Group
ISSN:	1097-6256
Date of First Compliant Deposit:	14 October 2019
Date of Acceptance:	22 November 2019
Last Modified:	06 Nov 2024 10:00
URI:	https://orca.cardiff.ac.uk/id/eprint/125992

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