Identification Of Epigenome-Wide Dna Methylation Differences Between Carriers Of Apoe Epsilon 4 And Apoe Epsilon 2 Alleles

Background: The apolipoprotein E (APOE) epsilon 4 allele is the strongest genetic risk factor for late onset Alzheimer's disease, whilst the epsilon 2 allele confers protection. Previous studies report differential DNA methylation of APOE between epsilon 4 and epsilon 2 carriers, but associations with epigenome-wide methylation have not previously been characterised.Methods: Using the EPIC array, we investigated epigenome-wide differences in whole blood DNA methylation patterns between Alzheimer's disease-free APOE epsilon 4 (n = 2469) and epsilon 2 (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.Results: We obtained replicated evidence for DNA methylation differences in a similar to 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 x 10(-100) <= P <= 2.44 x 10(-8)) and DMRs were identified in SREBF2 and LDLR (1.63 x 10(-4) <= P <= 3.01 x 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.Conclusions: APOE epsilon 4 vs. epsilon 2 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.