Identification of Epigenome-Wide DNA Methylation Differences Between Carriers of APOE Ε4 and APOE Ε2 Alleles.

AbstractBackgroundTheapolipoprotein 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 ofAPOEbetween 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-freeAPOEε4 (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 ofAPOEand several upstream genes. Meta-analytic approaches identified DNA methylation differences outside ofAPOE: differentially methylated positions were identified inDHCR24,LDLRandABCG1(2.59 × 10−100 ≤ P ≤ 2.44 × 10−8) and DMRs were identified inSREBF2andLDLR(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 inABCG1andDHCR24.ConclusionsAPOEε4 vs. ε2 carrier status is associated with epigenome-wide methylation differences in the blood. The loci identified are located intransas well ascistoAPOEand implicate genes involved in lipid homeostasis.