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Title: Epigenomic approaches to neuropsychiatric health and disease across the life-course
Author: Marzi, Sarah Julia
ISNI:       0000 0004 6497 5819
Awarding Body: King's College London
Current Institution: King's College London (University of London)
Date of Award: 2017
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Neuropsychiatric disorders represent an immense global health and economic burden, and identifying genetic and environmental factors contributing to these diseases is a key challenge in contemporary biomedical research. Efforts to identify genetic variation associated with disease risk have had some notable success, however the proportion of variance in disease explained by known genetic risk variants is limited. There is increasing evidence for epigenetic dysregulation in neuropsychiatric disease, with regulatory variation potentially induced by psychosocial and environmental risk factors associated with pathology. My PhD explores how the analysis of epigenetic variation, using novel technologies and unique study designs, can contribute to our understanding of how genetic and environmental factors influence disease risk. The first part of my thesis focuses on epigenetic correlates of early-life adversity, an exposure robustly associated with psychiatric phenotypes. Two complementary epidemiological study designs were used to characterise these associations: a “natural experiment”, using a sample of Romanian adoptees (Chapter 2), and a large longitudinal population-based twin cohort (Chapter 3). I identified a differentially methylated region annotated to CYP2E1 associated with institutional deprivation and socio-cognitive abilities, but found no robust associations between early-life victimisation and DNA methylation in blood. Neither study identified epigenetic variation associated with early-life stress in previously reported HPA-axis genes. The second part of my thesis explores epigenetic variation in the ageing brain and neurodegenerative disease. I undertook a systematic characterisation of allele-specific DNA methylation across multiple human brain regions and blood, finding widespread and tissue-specific patterns of allelic-skewing (Chapter 4). To further understand epigenetic variation in neurodegenerative disease, I investigated the relationship between the histone modification H3K27ac (which marks active gene expression) and Alzheimer’s disease progression (Chapter 5). I found widespread acetylomic dysregulation associated with neuropathology, enriched in disease-specific biological pathways and mapping to regions harbouring genetic variants associated with familial and sporadic AD.
Supervisor: Mill, Jonathan ; Wong, Chloe Chung Yi Sponsor: Marie Curie Initial Training Network (EpiTrain)
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available