Regulatory genomic consequences of polygenic risk burden for Alzheimer’s disease

Abstract

Dementia is an umbrella term used to describe a group of symptoms associated with global cognitive impairment and is a major contributor to the global burden of disease; currently there are over 50 million individuals affected world-wide. Due to the ageing population and lack of effective disease-modifying treatments, this number is expected to triple by 2050. Dementia encompasses a number of neurological diseases, including Alzheimer’s disease (AD), which accounts for 60-80% of cases. There is a well-established genetic component to AD and genome wide-association studies have identified >75 variants robustly associated with disease. Little is known about the functional mechanisms by which risk variants mediate disease susceptibility; as the majority of these variants do not index coding variants affecting protein structure they are hypothesised to influence gene regulation, supported by the observation that they are enriched in regulatory domains including enhancers. The primary aim of this thesis was to assess whether genetic liability for AD is associated with regulatory genomic variation (i.e. epigenetic and transcriptomic) in whole blood and the human cortex. Epigenome-wide association studies and multi-omic methods were utilised to explore the molecular mechanisms leading to disease. The results from this thesis indicate that epigenetic mechanisms are involved in AD pathogenesis and provide further support for several established AD pathways such as lipid and cholesterol metabolism, Aβ, tau and APP processing as well as a role for the immune system. The analyses incorporating AD genetic variation with DNA methylation infer that there are both direct cis genetic effects and indirect polygenic effects on regulatory processes which are involved in the aetiology of AD. Although there were consistencies at some loci across the whole blood and cortex analyses, there was also evidence for heterogeneity across tissues which might represent tissue specific effects in areas primarily affected in AD (e.g. the cortex) in comparison to peripheral tissues. In summary, using multiple approaches, I characterised the complex relationship between genetic and epigenetic variation, enabling the exploration of molecular genomic mechanisms driving AD pathogenesis in both peripheral and brain tissues and prioritised genes which could be targeted in future functional studies.