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

By Rosie Walker, Kadi Vaher, Mairead L. Bermingham, Stewart W Morris, Andrew D Bretherick, Yanni Zeng, Konrad Rawlik, Carmen Amador, Archie Campbell, Chris S Haley, Caroline Hayward, David J Porteous, Andrew M. McIntosh, Riccardo E Marioni, Kathryn L Evans

Posted 23 Oct 2019
bioRxiv DOI: 10.1101/815035

BACKGROUND The Apolipoprotein E ( APOE ) ε4 allele is the strongest genetic risk factor for late onset Alzheimer’s disease, while 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 ~169kb 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 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. ### Competing Interest Statement AMM has received grant support from Pfizer, Eli Lilly, Janssen and The Sackler Trust. These sources are not connected to the current investigation. AMM has also received speaker fees from Janssen and Illumina. The remaining authors report no conflicts of interest. * Aβ : amyloid beta AD : Alzheimer’s disease CI : confidence interval DMP : differentially methylated position DMR : differentially methylated region EWAS : epigenome-wide association study GS:SFHS : Generation Scotland: Scottish Family Health Study HDL : high density lipoprotein LDL : low density lipoprotein PC : principal component SNP : single nucleotide polymorphism

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