Genetics to Improve Outcomes in Schizophrenia (GENios): A within-case molecular genetic study protocol

Smart, Sophie E. ORCID: https://orcid.org/0000-0002-6709-5425, Fenner, Eilidh, Humphreys, Rhys, Wells, Amanda, Fender, Katherine, Bresner, Catherine, Trauzzi, Giulia, Willcocks, Isabella R. ORCID: https://orcid.org/0000-0002-3568-5236, Legge, Sophie E., Pardiñas, Antonio F. ORCID: https://orcid.org/0000-0001-6845-7590, Rees, Elliott ORCID: https://orcid.org/0000-0002-6168-9222, Escott-Price, Valentina ORCID: https://orcid.org/0000-0003-1784-5483, 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 and Walters, James T. R. ORCID: https://orcid.org/0000-0002-6980-4053 2026. Genetics to Improve Outcomes in Schizophrenia (GENios): A within-case molecular genetic study protocol. PLoS ONE 21 (2) , e0340584. 10.1371/journal.pone.0340584

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Abstract

Introduction: Despite significant progress in understanding the genetic basis of schizophrenia, there is a clear gap in our understanding of the genetics of outcomes in schizophrenia, particularly those prioritised by people with the condition. This has impeded progress towards precision psychiatry for schizophrenia and the improvement of outcomes. As genomic cohorts continue to increase in number, size, diversity, and phenotypic detail, sufficient data are now available to enable within-case studies focusing on the genetic basis of outcomes in schizophrenia. Methods and analysis: The GENios programme of research will use existing and new data to undertake large-scale genomic studies of schizophrenia outcomes. The project focuses on four key outcomes that were prioritised for research by individuals with lived experience of schizophrenia and align with priorities identified in the literature: antipsychotic treatment response; hospital admissions; occupational functioning; and social functioning. The aims of this project are to understand the genetic contributions to these outcomes in schizophrenia to (i) advance current understanding of the biological mechanisms that drive variability in outcomes, (ii) highlight novel drug targets, and (iii) identify genomic predictors of outcomes that can be leveraged for precision medicine. Ethics and dissemination: The GENios project has been granted ethical approval and collaborators are required to have the appropriate ethical permission in place to contribute data to the project. Findings from this study will be interpreted and disseminated with the involvement of lived experience experts in scientific publications and conferences as well as to wider non-scientific communities. Plain English summary: Schizophrenia is a severe mental illness that affects how people think, feel, and behave. Whilst current treatments help with some symptoms and effects of the disorder, many people continue to struggle with poor long-term outcomes. Outcomes like repeated hospital stays, difficulties with socialising and relationships, and difficulties with finding and maintaining employment. People with lived experience of schizophrenia have identified some outcomes as research priorities. These research priorities are treatment response, hospital admissions, day-to-day living (e.g. having a job), and having relationships. Many people with schizophrenia are given antipsychotic medications to treat ‘positive’ symptoms (such as unusual (false or disturbing) thoughts and beliefs, and seeing and hearing things that are not there). These medications work for some people but around 25% to 30% of people with the disorder have symptoms that are not helped by standard antipsychotic treatments. These symptoms are classed as treatment-resistant. Many more people find that antipsychotic medications do not help with ‘negative’ symptoms (such as feeling emotionally blank and having trouble with motivation) and difficulty with cognitive abilities (such as concentrating, planning, and memory). This project, called GENios, aims to understand why outcomes differ between people with schizophrenia by looking at their genetics. We understand that social factors play an important role in outcomes but this project is specifically focused on genetics. We will analyse data from people with schizophrenia with an aim to uncover the genetic factors that influence outcomes by using data has already been collected by other research projects. We are carrying out this research in order to identify how genes and knowledge of people’s genetics can help develop healthcare that is more tailored to an individual, so-called precision psychiatry. A plain English glossary of terms is included (S1 Table) to help explain technical language used in the main text.

Item Type:	Article
Date Type:	Published Online
Status:	Published
Schools:	Schools > Medicine
Additional Information:	License information from Publisher: LICENSE 1: URL: http://creativecommons.org/licenses/by/4.0/
Publisher:	Public Library of Science
Date of First Compliant Deposit:	10 February 2026
Date of Acceptance:	22 December 2025
Last Modified:	10 Feb 2026 12:30
URI:	https://orca.cardiff.ac.uk/id/eprint/184615

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