Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, EH4 2XU, UK.
Present Address: Centre for Clinical Brain Sciences, Chancellor's Building, 49 Little France Crescent, Edinburgh BioQuarter, Edinburgh, EH16 4SB, UK.
Genome Med. 2021 Jan 4;13(1):1. doi: 10.1186/s13073-020-00808-4.
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.
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.
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 ≤ P ≤ 2.44 × 10) and DMRs were identified in SREBF2 and LDLR (1.63 × 10 ≤ P ≤ 3.01 × 10). 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.
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.
载脂蛋白 E (APOE) ε4 等位基因是导致晚发性阿尔茨海默病的最强遗传风险因素，而 ε2 等位基因则具有保护作用。先前的研究报告称，APOE 的 ε4 和 ε2 携带者之间的 DNA 甲基化存在差异，但与全基因组甲基化的关联尚未得到描述。
使用 EPIC 芯片，我们在迄今为止最大的两个单队列 DNA 甲基化样本中，调查了阿尔茨海默病无病的 APOE ε4（n=2469）和 ε2（n=1118）携带者的全血 DNA 甲基化模式的全基因组差异。采用发现、复制和荟萃分析研究设计，使用全基因组关联分析和差异甲基化区域（DMR）方法识别甲基化差异。使用途径和甲基化数量性状基因座（meQTL）分析来探索结果。
我们获得了在一个约 169kb 区域内 DNA 甲基化差异的复制证据，该区域包含 APOE 的一部分和几个上游基因。荟萃分析方法确定了 APOE 之外的 DNA 甲基化差异：在 DHCR24、LDLR 和 ABCG1 中鉴定出差异甲基化位置（2.59×10≤P≤2.44×10），在 SREBF2 和 LDLR 中鉴定出 DMR（1.63×10≤P≤3.01×10）。途径和 meQTL 分析表明，脂质相关过程与高密度脂蛋白胆固醇有关，被鉴定为 ABCG1 和 DHCR24 甲基化差异的部分中介物。
APOE ε4 与 ε2 携带者状态与血液中的全基因组甲基化差异有关。确定的基因座位于 APOE 的顺式和反式位置，涉及参与脂质稳态的基因。
