Investigating structural cerebellar differences associated with schizophrenia pathophysiology

While historically overlooked, there is growing interest in the possible pathophysiological roles played by the cerebellum in various psychiatric and neurodevelopmental disorders, including schizophrenia. While structural cerebellar differences have been noted in individuals with psychiatric diagnoses compared to normative controls, whether these effects reflect true underlying neuropathology, confounding (spurious associations caused by uncontrolled for demographic, medical or imaging factors) or reverse causation (i.e. arising following principal symptom onset) is still to be established. The use of large datasets of homogeneously collected Magnetic Resonance Imaging (MRI), with genetic and health record data will help advance our knowledge in this regard. Chapter 1 provides an overview of the relevant literature around schizophrenia, its genetic aetiology, pathophysiology, genetic neuroimaging techniques, the cerebellum and its relevance to schizophrenia. In Chapter 2 I investigate whether psychiatric disorders are associated with reduced cerebellar volume in a large population-based cohort, when taking into account any shared medical comorbidities, sub-clinical comorbidities and other imaging and non-imaging based confounding measures. In Chapter 3, to circumvent the problem of reverse causation, in a cohort of non-psychiatric participants, I use genetic imaging analyses to investigate whether an individual’s increased common and rare genetic risk burden for schizophrenia is similarly associated with cerebellar reductions. In Chapter 4, I identify the common genetic variants important for cerebellar structure volume and use these results to ascertain the genetic correlation between the cerebellum and schizophrenia liability. Finally, in Chapter 5, I use these introduced cerebellar-associated variants to explore their significance in a clinical cohort, investigating whether those individuals with treatment-resistant schizophrenia, a feature associated with impairment brain development, showed a lower genetic predisposition for cerebellar growth. Chapter 6 provides a summary of the findings presented in this thesis, their relevance to the wider scientific literature and avenues for future research