Multiomic analysis of neuropsychiatric disorders

Neuropsychiatric disorders (NPD) are a complex group of common disorders affect- ing brain function, behaviour and cognition, which includes bipolar disorder (BD), major depressive disorder (MDD) and schizophrenia (SZ). A wide range of factors (e.g. genetic, environmental, immmune) contribute to NPDs, which has resulted in complex etiologies and clinical presentations. In this thesis, I aim to apply a comprehensive, integrative multiomic approach, using genomic and transcriptomic datasets, to explore the genetic factors involved in NPDs. I explore these using advanced bioinformatics tools, used to dissect the pathophysiology of NPDs. In the first analysis chapter, I apply Mendelian randomisation (MR) analysis with genome wide association studies (GWAS) summary statistics to explore the causal relationship between NPDs and a sleep-related phenotype called chronotype. I also use MR to explore gene expression alterations associated with NPDs through expression quantitative trait loci (eQTL). In the second chapter, I perform GWAS on individual-level genotype data for patient subphenotypes within BD (e.g. psychosis, rapid cycling) to tease apart the complex inter-patient heterogeneity and revealing loci associated with features within BD. In the third analysis chapter, I apply RNA-sequencing (RNA-seq) analysis, as part of the Immune Response & Social Cognition in Schizophrenia (iRELATE) study, consisting of differential expression analysis (DEA), gene enrichment analysis, weighted gene co-expression network analysis (WCGNA) and cellular deconvolution. This RNA-seq analysis explored gene expression differences due to Trier social stress test (TSST). These integrative methods allow me to identify gene expression changes that support the role of immune function and stress-response in SZ. Through the integration of multiomic data and use of bioinformatics tools, this thesis sheds light on the complex interplay of genetic and other factors in NPDs, such as behavioural (e.g. chronotype) or immune function. These findings improve our understanding of the genes, pathways and main tissues and cell types implicated in NPDs.

Publisher

University of Galway

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CC BY-NC-ND

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University of Galway Theses (PhD Theses)