Rare coding variants in schizophrenia-associated genes affect generalised cognition in the UK Biobank

Impairments in cognitive function are a feature of schizophrenia that strongly predict functional outcome and are generally not improved by current medications. However, the nature of the relationship between cognitive impairment and schizophrenia risk, and particularly the extent to which this reflects shared underlying biology, remains uncertain. We analysed exome-sequencing data from the UK Biobank to test for association between generalised cognition and damaging rare coding variation in genes and loci associated with schizophrenia in 30,487 people without the disorder. Rare protein-truncating variants (PTVs) and damaging missense variants in loss-of-function intolerant (LoFi) genes were associated with lower generalised cognition. Moreover, we found significantly stronger effects for damaging missense variants in credible causal genes at schizophrenia GWAS loci and for rare PTVs affecting LoFi genes in regions defined by schizophrenia-enriched CNVs. This suggests shared underlying biology between schizophrenia risk and general cognitive function in the population, and that exploiting large population sequencing datasets to identify genes with shared effects on cognition and schizophrenia can provide a route towards determining biological processes underlying cognitive impairment in schizophrenia. ### Competing Interest Statement ER, JTRW, MCO and MJO reported receiving grants from Akrivia Health outside the submitted work. JTRW, MJO and MCO reported receiving grants from Takeda Pharmaceutical Company Ltd outside the submitted work. Takeda and Akrivia played no part in the conception, design, implementation, or interpretation of this study. ### Funding Statement This work was supported by a Wellcome Trust Integrative Neuroscience PhD Studentship to EF (108891/B/15/Z /WT), and a UKRI Future Leaders Fellowship Grant to ER (MR/T018712/1). This work uses data provided by patients and collected by the NHS as part of their care and support: Copyright (2023), NHS England; Re-used with the permission of the NHS England and UK Biobank; All rights reserved. This research used data assets made available by National Safe Haven as part of the Data and Connectivity National Core Study, led by Health Data Research UK in partnership with the Office for National Statistics and funded by UK Research and Innovation (research which commenced between 1st October 2020 - 31st March 2021 (MC\_PC\_20029); 1st April 2021 - 30th September 2022 (MC\_PC\_20058). ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The research presented in this study has been conducted using the UK Biobank resource under Application Number 13310. Ethical approval was granted to UK Biobank by several committees as it spans England, Scotland, and Wales: The Northwest Multi-Centre Research Ethics Committee; The Patient Information Advisory Group, which has since been replaced by the National Information Governance Board for Health and Social Care; and The Community Health Index Advisory Group. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes This study used data from the UK Biobank, which is available for health-related research upon registration and application through the UK Biobank Access Management System (). The code required to reproduce our analyses is publicly available ([https://github.com/eilidhfenner/UKBB\_WES\_data_processing][1]). [https://github.com/eilidhfenner/UKBB\_WES\_data_processing][1] [1]: https://github.com/eilidhfenner/UKBB_WES_data_processing