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Gene regulation in microglia and genetic risk for complex brain disorders

Cameron, Darren 2019. Gene regulation in microglia and genetic risk for complex brain disorders. PhD Thesis, Cardiff University.
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In recent years, genome wide association studies (GWAS) have established that common genetic variation plays an important role in complex brain disorders, such as autism spectrum disorder, schizophrenia and Alzheimer’s disease. However, as the vast majority of GWAS risk loci are located in poorly characterised non-coding regions, interpretation of GWAS data is difficult. As very few associations can be attributed to effects on protein-coding sequence, the majority of common risk loci for complex brain disorders are believed to operate through effects on gene regulation. In order to elucidate genetic risk mechanisms for complex brain disorders, it is important to establish in which cell types these risk loci are operating. Microglia are the primary immune cell of the central nervous system and are important regulators of brain function throughout life. As such, there has been growing interest in the potential role of microglia in brain disorders. One means of interpreting the function of the non-coding genome in a cell of interest is to measure the cell’s chromatin landscape. For example, the assay for transposase accessible chromatin with sequencing (ATAC-seq) maps regions of ‘open’ chromatin, which have the potential to regulate gene expression through binding of transcription factors. In this thesis, I use ATAC-seq to map open chromatin in adult ex vivo microglia, 2nd trimester foetal microglia, and in vitro human cell models of microglia. I then integrate this with complex brain disorder GWAS data to investigate whether gene regulatory processes in human microglia contribute to genetic risk for complex brain disorders. I find evidence that risk variants for late onset Alzheimer’s disease, autism spectrum disorder, bipolar disorder, major depressive disorder and schizophrenia are enriched within regulatory regions utilised by foetal and / or adult microglia, suggesting a primary role for this cell type in these conditions. Using the electrophoretic mobility shift assay, I further show that two single nucleotide polymorphisms associated with Alzheimer’s disease, and within regions of open chromatin in adult microglia, alter binding of protein from microglial nuclei.

Item Type: Thesis (PhD)
Date Type: Completion
Status: Unpublished
Schools: Medicine
Date of First Compliant Deposit: 14 January 2020
Last Modified: 14 Jan 2020 09:56

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