Brain structural alterations, genetic risk variants and the onset of psychosis

Abstract

One of the central motivations behind research of the at-risk mental state is to prevent or delay potential transition to psychosis and further progression to schizophrenia, by studying the early signs and symptoms without potential confounding effects of disease progression and medication. And although the pathophysiological mechanism is still poorly understood, it is known that there is a large genetic heritability where a combination of different genetic variants sets a predisposition. Therefore, the identification of markers that characterise all states of the disease, namely schizophrenia, first-episode of psychosis and the at-risk mental state, are a main goal. A very robust marker is hippocampal volume reduction in schizophrenia, first- episode of psychosis and the at-risk mental state. In this thesis, I will present research for a deeper characterisation of the hippocampus in schizophrenia, first-episode of psychosis and the at-risk mental state and the association to genetic risk variants. First, we we found no association of the brain- derived neurotrophic factor rs6265 polymorphism with the hippocampal volumes neither in the original analysis of large cohort of young healthy individuals nor a meta-analysis with 5298 healthy subjects in total. Moreover, we detected differences between the applied hippocampal measuring techniques, i.e. manual or automated segmentation. Second, a meta-analysis of the same association but in 18 independent neuropsychiatric patient cohorts including schizophrenia revealed again no association. Also, we showed similar hippocampal reductions for Val/Val homozygote and Met-carrier patients compared to healthy controls. Third, group- related comparison of subcortical volumes revealed hippocampal and thalamic reductions in at-risk mental state individuals compared to healthy controls. Moreover, we found comparable medium effect sizes for both structures assessed with two different statistical methods. Fourth, in a cohort of at-risk mental state individuals and first-episode of psychosis patients we found a negative association between the hippocampal volumes and a polygenic schizophrenia-related risk score. Furthermore, a higher polygenic schizophrenia-related risk score was significantly associated with a higher probability of an individual being assigned to the first-episode of psychosis group compared to the total at-risk mental state group. These studies aid a better understanding of hippocampal volume reduction and genetic variants associated with schizophrenia, first-episode of psychosis and the at- risk mental state.