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Sites of active gene regulation in the developing human brain and their role in neuropsychiatric disorders

Kouakou, Manuela Rosa 2021. Sites of active gene regulation in the developing human brain and their role in neuropsychiatric disorders. PhD Thesis, Cardiff University.
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Neuropsychiatric conditions such as schizophrenia, autism and attention deficit hyperactivity disorder (ADHD) are complex disorders with a hypothesized early neurodevelopmental component. Most common risk loci for these disorders are located in non-coding regions of the genome and are therefore likely to index functional variants that alter gene regulation rather than protein structure. It is possible to elucidate the biology underpinning these conditions by testing for enrichment of associated genetic variation within regulatory genomic regions operating in the developing human brain. In this thesis, I have used ATAC-Seq to map open chromatin (an index of active regulatory genomic regions) in bulk tissue, neuron-enriched (NeuN+) and neuron-depleted (NeuN-) nuclei from the prenatal human frontal cortex, and tested enrichment of single nucleotide polymorphism (SNP) heritability for 5 neuropsychiatric disorders (autism spectrum disorder, ADHD, bipolar disorder, major depressive disorder and schizophrenia) within these regions. I found significant enrichment of SNP heritability for schizophrenia within open chromatin regions mapped in bulk foetal frontal cortex, and for all 5 tested neuropsychiatric conditions when I restricted these sites to those overlapping histone modifications indicative of enhancers (H3K4me1) or promoters (H3K4me3) in foetal brain. SNP heritability for schizophrenia was significantly enriched in foetal NeuN+ nuclei overlapping H3K4me1 sites and for all 5 neuropsychiatric disorders in foetal NeuN- nuclei overlapping either H3K4me1 or H3K4me3 sites. I further used my mapped open chromatin regions to identify potentially functional SNPs at genome-wide significant risk loci for schizophrenia.

Item Type: Thesis (PhD)
Date Type: Completion
Status: Unpublished
Schools: Medicine
Date of First Compliant Deposit: 1 June 2021
Last Modified: 28 May 2022 01:30

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