Analysis of rare coding variants in schizophrenia-associated genes and generalised cognition in the UK Biobank

Fenner, Eilidh, Holmans, Peter ORCID: https://orcid.org/0000-0003-0870-9412, O’Donovan, Michael C. ORCID: https://orcid.org/0000-0001-7073-2379, Owen, Michael J. ORCID: https://orcid.org/0000-0003-4798-0862, Walters, James T. R. ORCID: https://orcid.org/0000-0002-6980-4053 and Rees, Elliott ORCID: https://orcid.org/0000-0002-6168-9222 2026. Analysis of rare coding variants in schizophrenia-associated genes and generalised cognition in the UK Biobank. Molecular Psychiatry 31 , pp. 5104-5113. 10.1038/s41380-026-03601-8

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Abstract

Cognitive impairments in schizophrenia are associated with poor outcomes and are largely unimproved by current medications. It remains uncertain to what extent cognitive impairments arise from shared aetiology and biology with schizophrenia, or are a consequence of having the condition. We analysed exome-sequencing data from 76,783 UK Biobank participants without schizophrenia to test for association between generalised cognition (g) and rare (minor allele count ≤ 5) variants in schizophrenia-associated genes. Protein-truncating and deleterious missense variants in loss-of-function intolerant genes were associated with lower g. Significantly stronger effects on g were found for protein-truncating variants in genes implicated in schizophrenia by rare coding variation, and for deleterious missense variants in credible causal genes at schizophrenia common allele loci. These findings indicate that biological processes disrupted in schizophrenia by common and rare variants are associated with g in unaffected individuals, suggesting the relationship between impaired cognition and schizophrenia reflects, in part, a shared underlying biology.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Schools > Medicine Research Institutes & Centres > MRC Centre for Neuropsychiatric Genetics and Genomics (CNGG)
Publisher:	Springer Science and Business Media LLC
ISSN:	1359-4184
Funders:	MRC, Wellcome Trust
Projects:	MR/Y004094/1, MR/T018712/1, MR/Y033922/1, MR/Y004094/1, MR/Y004094/1, MR/Y004094/1, MR/Y004094/1, 108891/B/15/Z /WT
Date of First Compliant Deposit:	22 April 2026
Date of Acceptance:	30 March 2026
Last Modified:	02 Sep 2026 13:23
URI:	https://orca.cardiff.ac.uk/id/eprint/186582

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