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

Genome Medicine

Rosie M. Walker¹  Riccardo E. Marioni¹  Mairead L. Bermingham¹  David J. Porteous¹  Kathryn L. Evans¹  Kadi Vaher¹  Stewart W. Morris¹  Konrad Rawlik²  Andrew M. McIntosh³  Archie Campbell⁴  Andrew D. Bretherick⁵  Chris S. Haley⁵  Caroline Hayward⁵  Carmen Amador⁵  Yanni Zeng⁵ 

[1] Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, University of Edinburgh;Division of Genetics and Genomics, The Roslin Institute and Royal (Dick) School of Veterinary Studies, University of Edinburgh, Easter Bush;Division of Psychiatry, University of Edinburgh, Royal Edinburgh Hospital;Generation Scotland, Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, University of Edinburgh;MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh;

关键词: Alzheimer’s disease;    APOE;    Apolipoprotein E;    DNA methylation;    Cholesterol;    Lipids;   

DOI  :  10.1186/s13073-020-00808-4

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown