Abstract
BackgroundThe apolipoprotein E (APOE) ε4 allele is the strongest genetic risk factor for late onset Alzheimer’s disease, whilst the ε2 allele confers protection. Previous studies report differential DNA methylation of APOE between ε4 and ε2 carriers, but associations with epigenome-wide methylation have not previously been characterised.MethodsUsing the EPIC array, we investigated epigenome-wide differences in whole blood DNA methylation patterns between Alzheimer’s disease-free APOE ε4 (n = 2469) and ε2 (n = 1118) carriers from the two largest single-cohort DNA methylation samples profiled to date. Using a discovery, replication and meta-analysis study design, methylation differences were identified using epigenome-wide association analysis and differentially methylated region (DMR) approaches. Results were explored using pathway and methylation quantitative trait loci (meQTL) analyses.ResultsWe obtained replicated evidence for DNA methylation differences in a ~ 169 kb region, which encompasses part of APOE and several upstream genes. Meta-analytic approaches identified DNA methylation differences outside of APOE: differentially methylated positions were identified in DHCR24, LDLR and ABCG1 (2.59 × 10−100 ≤ P ≤ 2.44 × 10−8) and DMRs were identified in SREBF2 and LDLR (1.63 × 10−4 ≤ P ≤ 3.01 × 10−2). Pathway and meQTL analyses implicated lipid-related processes and high-density lipoprotein cholesterol was identified as a partial mediator of the methylation differences in ABCG1 and DHCR24.ConclusionsAPOE ε4 vs. ε2 carrier status is associated with epigenome-wide methylation differences in the blood. The loci identified are located in trans as well as cis to APOE and implicate genes involved in lipid homeostasis.
Highlights
The apolipoprotein E (APOE) ε4 allele is the strongest genetic risk factor for late onset Alzheimer’s disease, whilst the ε2 allele confers protection
Identification of differentially methylated positions and regions in APOE ε4 vs. ε2 carriers An Epigenome-wide association study (EWAS) of APOE ε4 vs. ε2 carriers in the discovery sample identified eight significant Differentially methylated position (DMP), of which half were hypermethylated in APOE ε4 carriers
A sensitivity analysis of the discovery sample in which a methylationbased smoking score [45] was included as a covariate instead of the smoking covariates included in the original analysis (“smoking status” and “pack years”) produced highly similar results across all measured CpGs (correlation between effect sizes = 0.99, 95% confidence interval (CI) 0.99–0.99; P < 2.2 × 10−16; Additional file 1: Table S2)
Summary
The apolipoprotein E (APOE) ε4 allele is the strongest genetic risk factor for late onset Alzheimer’s disease, whilst the ε2 allele confers protection. The ε4 allele of the apolipoprotein E gene (APOE) is the strongest genetic risk factor for late-onset (> 65 years) Alzheimer’s disease (AD) [1,2,3]. DNA methylation is associated with both genetic and environmental factors, and previous studies have identified associations with AD and neuropathological hallmarks of AD [10,11,12], AD risk factors (e.g. ageing [13], obesity [14] and lipid levels [15]), as well as modifiers of APOE genotype effects (e.g. sex [16] and ethnicity [17, 18])
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