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Discovery and impact of schizophrenia rare genetic variation using next generation sequencing

Fenner, Eilidh 2023. Discovery and impact of schizophrenia rare genetic variation using next generation sequencing. PhD Thesis, Cardiff University.
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Schizophrenia is a complex psychiatric disorder, a key feature of which is impaired cognitive function. Common alleles and copy number variants conferring risk for schizophrenia are associated with lower cognition in the general population, however current understanding of the impact of schizophrenia-associated rare coding variants on cognition in the general population is limited. This thesis explores the impact of damaging rare coding variants in genes with a known role in schizophrenia liability on generalised cognition in individuals without a psychiatric or developmental disorder. The UK Biobank, a large-scale biomedical database, was utilised for this investigation. Chapter 2 describes the processing and analysis of whole exome sequencing and phenotypic data from this cohort. These data were used to demonstrate an association of higher burden of damaging rare coding variants in schizophrenia-associated genes with lower cognition in a volunteer population-based cohort (Chapters 3 and 4). This thesis then examines a potential bias in those who undertook optional cognitive assessments in the UK Biobank, and demonstrates evidence that this bias may, in part, reflect genetic effects (Chapter 5). This research strengthens and extends evidence for overlapping genetic architecture between schizophrenia risk and lower cognition in individuals without a psychiatric disorder. It indicates the presence of shared underlying biology between schizophrenia risk and general cognition in the population, and improves current understanding of the pleiotropic nature of genes involved in cognition and schizophrenia. It also presents evidence for the presence of a participation bias in cognitive measures in the UK Biobank, and evaluates how this bias may impact rare coding variant findings in this thesis, and elsewhere. Furthermore, my analyses demonstrate the utility of large-scale datasets such as the UK Biobank to identify genes with pleiotropic effects, and have the potential to provide a well-powered route towards determining biological processes underlying cognitive impairment in schizophrenia.

Item Type: Thesis (PhD)
Date Type: Completion
Status: Unpublished
Schools: Medicine
Funders: Wellcome Trust Integrative Neuroscience PhD Studentship (108891/B/15/Z/WT).
Date of First Compliant Deposit: 27 February 2024
Last Modified: 27 Feb 2024 16:20

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