Epigenetic characterisation of ANK1, a novel gene implicated in Alzheimer's disease (AD)

• Main Author: Smith, Adam Robert
• Other Authors: Lunnon, Katie ; Mill, Jonathan
• Published: University of Exeter 2018
• Subjects: 610
• Online Access: https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.744068

Alzheimer’s disease is a progressive neurodegenerative disorder that affects approximately twenty eight million people worldwide. Collectively DNA mutations only explain approximately 33% of Alzheimer’s disease incidence. Therefore, Alzheimer’s disease has been hypothesised to have both an environmental and epigenetic contribution to disease aetiology. Epigenetics refers to the heritable changes in gene expression that do not involve changes to the underlying DNA sequence. Epigenetic changes can be transient, varying in levels according to a person’s age, sex, environmental exposure, genetics and disease status. The identification of robust epigenetic changes in Alzheimer’s disease would give the potential to open up a variety of new treatment options for the disease. Previous epigenome-wide association studies in Alzheimer’s disease have highlighted neuropathology-associated DNA hypermethylation in the ANK1 gene. To date, however, no studies have examined whether other epigenetic mechanisms are altered in this gene in Alzheimer’s disease pathology, or whether these ANK1 epigenetic changes are seen in other neurodegenerative diseases. The aim of this thesis was to characterise the epigenetic profile (DNA methylation, DNA hydroxymethylation and histone modifications) of ANK1 in Alzheimer’s disease. In addition, it sought to determine whether the previously identified ANK1 DNA methylation changes in Alzheimer’s disease are specific to this dementia, or are observed in a number of other neurodegenerative diseases. The results provide further support for a role for epigenetic dysfunction of ANK1 in Alzheimer’s disease as well as some other neurodegenerative diseases. In summary, the work presented in this thesis represents the first epigenome-wide association study of DNA methylation and DNA hydroxymethylation simultaneously in Alzheimer’s disease across two brain regions, highlighting changes in DNA modifications in ANK1. The thesis then highlights ANK1 DNA methylation changes in other neurodegenerative diseases and explores the histone modification profile of the ANK1 locus in Alzheimer’s disease.