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Investigating genetic liability and phenotypic presentations in schizophrenia

Woolway, Grace 2023. Investigating genetic liability and phenotypic presentations in schizophrenia. PhD Thesis, Cardiff University.
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Common genetic liability to schizophrenia has provided insights into the clinical heterogeneity of schizophrenia, specifically within the context of environmental risk factors, diagnostic definitions and phenotypic presentations. I conducted a systematic review including the first meta-analysis of the association between schizophrenia polygenic risk score (PRS) and experiences of childhood adversity, a known environmental risk factor for schizophrenia. The meta-analysis of 14 studies found a small yet significant association between schizophrenia PRS and childhood adversity (r=0.02; 95% CI=0.01,0.03; P=0.001), indicating that common genetic liability for schizophrenia explains a small proportion of the relationship between childhood adversity and psychosis. Next, I assessed the validity of a self-reported schizophrenia diagnosis and compared phenotypic and genetic variables across participants defined by self-report and by research interview diagnosis in a clinically ascertained sample and by medical record diagnosis in UK Biobank. A self-reported schizophrenia diagnosis had a moderate to high positive predictive value (PPV) compared to a research interview diagnosis of schizophrenia (PPV=70). There were no differences in schizophrenia PRS in participants who only had a self-reported diagnosis compared to a research interview diagnosis (OR=0.97; 95%CI=0.86,1.09; p=0.59) or a medical record diagnosis (OR=1.01; 95%CI=-0.87,1.19; p=0.85), although phenotypic differences in age, education and employment status were found. Lastly, I recruited and interviewed 101 existing Cardiff University participants from the top and bottom 30% of the schizophrenia polygenic distribution. I found that participants with a higher schizophrenia PRS were more likely to experience negative symptoms (β=0.43, 95% CI=0.05,0.81, p=0.03) and have poorer cognitive performance (β= -0.20, 95% CI = -0.36, - 0.04, p=0.014). This thesis contributes to the current understanding of gene-environment associations in schizophrenia, provides novel evidence for using a self-reported schizophrenia diagnosis in psychiatric research and finds preliminary evidence for different clinical presentations in participants sampled from the polygenic extremes.

Item Type: Thesis (PhD)
Date Type: Completion
Status: Unpublished
Schools: MRC Centre for Neuropsychiatric Genetics and Genomics (CNGG)
Date of First Compliant Deposit: 12 June 2023
Last Modified: 12 Jun 2024 01:30

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