当前位置： SCI文献检索 > Genome Medicine期刊下所有文献 > Identification of epigenome-wide DNA methylation differences between carriers of APOE ε4 and APOE ε2 alleles.

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

Abstract：

BACKGROUND: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. METHODS:Using 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. 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 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.

journal_name

Genome Med

journal_title

Genome medicine

authors

Walker RM,Vaher K,Bermingham ML,Morris SW,Bretherick AD,Zeng Y,Rawlik K,Amador C,Campbell A,Haley CS,Hayward C,Porteous DJ,McIntosh AM,Marioni RE,Evans KL

doi

10.1186/s13073-020-00808-4

subject

Has Abstract

pub_date

2021-01-04 00:00:00

pages

issue

issn

1756-994X

pii

10.1186/s13073-020-00808-4

journal_volume

pub_type

杂志文章

在线工具

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