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Clinical features of UK Biobank subjects carrying protein-truncating variants in genes implicated in schizophrenia pathogenesis

Curtis, David; (2022) Clinical features of UK Biobank subjects carrying protein-truncating variants in genes implicated in schizophrenia pathogenesis. Psychiatric Genetics , 32 (4) pp. 156-161. 10.1097/YPG.0000000000000318. Green open access

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Abstract

OBJECTIVE: The SCHEMA consortium has identified 10 genes in which protein-truncating variants (PTVs) confer a substantial risk of schizophrenia. This study aimed to determine whether carrying these PTVs was associated with neuropsychiatric impairment in the general population. METHODS: Phenotype fields of exome-sequenced participants in the UK Biobank who carried PTVs in these genes were studied to determine to what extent they demonstrated features of schizophrenia or had neuropsychiatric impairment. RESULTS: Following automated quality control and visual inspection of reads, 251 subjects were identified as having well-supported PTVs in one of these genes. The frequency of PTVs in CACNA1G was higher than that had been observed in SCHEMA cases, casting doubt on its role in schizophrenia pathogenesis, but otherwise rates were similar to those observed in SCHEMA controls. Numbers were too small to allow formal statistical analysis but in general carriers of PTVs did not appear to have high rates of psychiatric illness or reduced educational or occupational functioning. One subject with a PTV in SETD1A had a diagnosis of schizophrenia, one with a PTV in HERC1 had psychotic depression and two subjects seemed to have developmental disorders, one with a PTV in GRIN2A and one with a PTV in RBCC1. There seemed to be somewhat increased rates of affective disorders among carriers of PTVs in HERC1 and RB1CC1 . CONCLUSION: Carriers of PTVs did not appear to have subclinical manifestations of schizophrenia. Although PTVs in these genes can substantially increase schizophrenia risk, their effect seems to be dichotomous and most carriers appear psychiatrically well. This research has been conducted using the UK Biobank Resource.

Type: Article
Title: Clinical features of UK Biobank subjects carrying protein-truncating variants in genes implicated in schizophrenia pathogenesis
Location: England
Open access status: An open access version is available from UCL Discovery
DOI: 10.1097/YPG.0000000000000318
Publisher version: https://doi.org/10.1097/YPG.0000000000000318
Language: English
Additional information: This version is the author accepted manuscript. For information on re-use, please refer to the publisher's terms and conditions.
Keywords: Schizophrenia; protein truncating variant; subclinical; HERC1; RB1CC1
UCL classification: UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences > Genetics, Evolution and Environment
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences
URI: https://discovery.ucl.ac.uk/id/eprint/10153802
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