title: Using DNA methylation data and haplotypes to investigate predisposition to Alzheimer’s disease
Creators: name: Longshaw, Sarah
Publisher: name: The University of Edinburgh
Year: 2023
Subjects: subject: DNA methylation data
subject: haplotypes
subject: Alzheimer’s disease
subject: predisposition to Alzheimer’s disease
subject: complex neurodegenerative disease
subject: polygenic risk scores
subject: epigenome wide association studies
subject: differentially methylated (DM) CpGs
subject: CpGs
subject: meQTL analyses
subject: genome wide association study
subject: (GWS) DM loci

description: Alzheimer’s disease (AD) is a complex neurodegenerative disease resulting in cognitive decline, memory issues and alterations in mood, behaviour, and personality. AD is the most common form of dementia, which accounts for 50-75% of cases globally. Individuals with AD may become impulsive and disorientated in the early stages but as the disease progresses many require full time care support and die prematurely. AD pathophysiology is characterised by amyloid-beta plaques and tau neurofibrillary tangles within the brain. AD has a high heritability (60-80%) yet much of this remains largely unexplained. There are predicted to be between 100-10,000 causal variants; exemplifying the necessity to identify and characterise new genetic risk factors. In some cases, epigenetic changes in the genome may be studied to provide additional understanding into the effect the heritable risk of AD has on gene expression. Epigenetic changes may be investigated using polygenic risk scores (PRS) and epigenome wide association studies (EWAS), which may provide insight into an individual’s genetic susceptibility to AD and the association between AD and DNA methylation. Previously, Walker et al used 26 lead loci to identify 68 significant differentially methylated (DM) CpGs. Walker et al carried out meQTL analyses using the DM CpGs identified, finding 48 CpGs were associated in cis with genetic variants in the genome wide association study (GWAS) loci. The aim of the study was to use additional AD associated loci to identify and characterise further genome wide significant (GWS) DM loci, using individual SNPs and haplotypes. Additionally, the individual effects of functional haplotypes on epigenetic variation were investigated. The most recent and relevant AD-GWAS results were used in this study, with up to 75 AD risk loci identified, to generate an AD PRS. The AD PRS were used to identify significant AD associated, DM CpGs. meQTL analysis was carried out to investigate the association of the significant CpGs with the SNPs in the PRS. SORL1 and APOE have previously been identified as AD susceptibly genes, and functional studies have been carried out. The functional studies have identified SNPs within APOE and SORL1 which directly influence the function of the genes and protein production, altering an individual’s risk to AD. Therefore, haplotypes spanning these gene regions were used in meQTL analyses to consider whether the individual SNPs or haplotypes have a different association with DM at the significant CpGs. Further EWAS were carried out using only haplotypes which contain the AD-risk allele at the SNPs comprising the functional haplotype in SORL1 and APOE. Schwartzentruber et al and Bellenguez et al AD GWAS were identified as the most suitable for the PRS generation. EWAS meta-analyses using the Bellenguez et al and Schwartzentruber et al derived PRS identified 116 and 203 GWS DM CpGs, respectively. meQTL analyses identified 45/116 and 109/203 of these GWS CpGs were significantly associated with SNPs in the PRS. With 31 and 21independant GWS lead CpGs identified using the Bellenguez et al and Schwartzentruber et al PRS in the EWAS, respectively. meQTL analysis found SNPs in the SORL1 region had the strongest association with DM at CpG sites, as opposed to haplotypes and/or when the APOE region were investigated. Functional haplotypes dependent upon carrier status identified additional GWS DM CpGs and associated genes, of particular interest was FEM1C. Ultimately this study may allow further investigation into the importance and relevance of the GWS DM loci in AD progression, disease pathogenesis and aetiology.