Dataset Information

Identification of epigenome-wide DNA methylation differences between carriers of APOE ?4 and APOE ?2 alleles.

ABSTRACT:

Background

The apolipoprotein E (APOE) ?4 allele is the strongest genetic risk factor for late onset Alzheimer's disease, whilst the ?2 allele confers protection. Previous studies report differential DNA methylation of APOE between ?4 and ?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 ?4 (n?=?2469) and ?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 ~?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.

Conclusions

APOE ?4 vs. ?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.

SUBMITTER: Walker RM

PROVIDER: S-EPMC7784364 | biostudies-literature | 2021 Jan

REPOSITORIES: biostudies-literature

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Publications

Identification of epigenome-wide DNA methylation differences between carriers of APOE ε4 and APOE ε2 alleles.

Walker Rosie M RM Vaher Kadi K Bermingham Mairead L ML Morris Stewart W SW Bretherick Andrew D AD Zeng Yanni Y Rawlik Konrad K Amador Carmen C Campbell Archie A Haley Chris S CS Hayward Caroline C Porteous David J DJ McIntosh Andrew M AM Marioni Riccardo E RE Evans Kathryn L KL

Genome medicine 20210104 1

<h4>Background</h4>The 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.<h4>Methods</h4>Using the EPIC array, we investigated epigenome-wide differences in whole blood DNA methylation patterns between Alzheimer's disease-fre ...[more]

PMID: 33397400

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