Investigating the cell-type specific biology of schizophrenia using multi-omic data

Schizophrenia (SCZ) is a complex neuropsychiatric disorder which affects approximately 1% of the population. It carries a high societal burden accounting for 1.7% of disease burden across all possible diseases or disorders despite its low global prevalence. It is clinically characterised by a combination of symptoms including psychotic episodes, cognitive deficits and social withdrawal. Yet, its full etiology is still unknown and is thought to be impacted by a mixture of genetic and environmental factors and begin in neurodevelopment. SCZ is highly heritable with the heritability of SCZ thought to be approximately 79%. Genetic studies such as genome-wide association studies (GWAS) and exome sequencing studies had uncovered a number of genes thought to convey increased risk to SCZ. However, the functional impact of genetic mutation in SCZ must also be considered. Functional genomics studies have aimed to bridge the gap between genomic variation and phenotype by characterising the underlying neurobiology of the disorder. Extensive changes have been observed at the transcriptomic and epigenomic levels in SCZ using postmortem brain tissue samples. Yet the vast majority of these studies use bulk tissue samples which only shows overall trends in a tissue rather than cell-type specific effects. Functional changes are thought to vary widely between cell-type with excitatory neurons primarily implicated in SCZ thus far. This thesis comprises three studies which all aim to explore which cell-types are impacted in SCZ and characterise these cell-type specific changes. Chapter 2 utilised cell-type deconvolution to uncover new insights from published bulk gene expression data isolated from SCZ cases and controls. Chapter 3 investigated the cell-types affected by sets of differentially expressed genes derived from knockout models of MEF2C, a gene that has been implicated in a variety of neurodevelopmental disorders including SCZ and autism spectrum disorder (ASD). My final study which is outlined in Chapter 4 of this thesis explored the transcriptomic and chromatin accessibility landscapes in SCZ at the cell-type level.

Publisher

University of Galway

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Attribution-NonCommercial-NoDerivatives 4.0 International

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University of Galway Theses (PhD Theses)