Investigating genetic liability and phenotypic presentations in schizophrenia

Abstract

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