Cardiff University | Prifysgol Caerdydd ORCA
Online Research @ Cardiff 
WelshClear Cookie - decide language by browser settings

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

Rees, Elliott ORCID:, GROUP Investigators, Han, Jun, Morgan, Joanne, Carrera, Noa ORCID:, Escott-Price, Valentina ORCID:, Pocklington, Andrew J. ORCID:, Duffield, Madeleine, Hall, Lynsey S., Legge, Sophie E., Pardinas, Antonio F. ORCID:, Richards, Alexander L., Roth, Julian, Lezheiko, Tatyana, Kondratyev, Nikolay, Golimbat, Vera, Parellada, Mara, González-Peñas, Javier, Arango, Celso, Gawlik, Micha, Kirov, George ORCID:, Walters, James T. R. ORCID:, Holmans, Peter ORCID:, O'Donovan, Michael C. ORCID: and Owen, Michael J. ORCID: 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

[thumbnail of Exome_prs_main-text_revision_clean.pdf] PDF - Accepted Post-Print Version
Download (798kB)


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: 23 Apr 2024 17:36

Citation Data

Cited 49 times in Scopus. View in Scopus. Powered By Scopus® Data

Actions (repository staff only)

Edit Item Edit Item


Downloads per month over past year

View more statistics