TY - JOUR T1 - Assessment of DNA methylation differences between carriers of <em>APOE</em> ε4 and <em>APOE</em> ε2 JF - bioRxiv DO - 10.1101/815035 SP - 815035 AU - Rosie M. Walker AU - Kadi Vaher AU - Mairead L. Bermingham AU - Stewart W. Morris AU - Andrew D. Bretherick AU - Yanni Zeng AU - Konrad Rawlik AU - Carmen Amador AU - Archie Campbell AU - Chris S. Haley AU - Caroline Hayward AU - David J. Porteous AU - Andrew M. McIntosh AU - Riccardo E. Marioni AU - Kathryn L. Evans Y1 - 2019/01/01 UR - http://biorxiv.org/content/early/2019/10/23/815035.abstract N2 - INTRODUCTION The Apolipoprotein E (APOE) ε4 allele is the strongest genetic risk factor for Alzheimer’s disease (AD), 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 are unknown.METHODS The EPIC array was used to identify methylation differences between AD-free APOE ε4 (n=2469) and ε2 (n=1108) carriers using epigenome-wide association analysis and differentially methylated region (DMR) approaches. Results were explored using pathway and meQTL analyses.RESULTS Differentially methylated positions were identified in APOE, surrounding genes and genes outside of this locus (DHCR24, LDLR and ABCG1). DMRs were identified in SREBF2, LDLR and SQLE. Pathway and meQTL analyses implicated lipid-related processes; however, blood cholesterol levels could not fully account for the associations.DISCUSSION APOE ε4 vs. ε2 carrier status is associated with epigenome-wide methylation differences in cis and trans in genes involved in lipid homeostasis. ER -