Alzheimer's loci: epigenetic associations and interaction with genetic factors.

Ann Clin Transl Neurol
Authors
Abstract

OBJECTIVE: We explore the role of DNA methylation in Alzheimer's disease (AD). To elucidate where DNA methylation falls along the causal pathway linking risk factors to disease, we examine causal models to assess its role in the pathology of AD.

METHODS: DNA methylation profiles were generated in 740 brain samples using the Illumina HumanMet450K beadset. We focused our analysis on CpG sites from 11 AD susceptibility gene regions. The primary outcome was a quantitative measure of neuritic amyloid plaque (NP), a key early element of AD pathology. We tested four causal models: (1) independent associations, (2) CpG mediating the association of a variant, (3) reverse causality, and (4) genetic variant by CpG interaction.

RESULTS: Six genes regions (17 CpGs) showed evidence of CpG associations with NP, independent of genetic variation - BIN1 (5), CLU (5), MS4A6A (3), ABCA7 (2), CD2AP (1), and APOE (1). Together they explained 16.8% of the variability in NP. An interaction effect was seen in the CR1 region for two CpGs, cg10021878 (P = 0.01) and cg05922028 (P = 0.001), in relation to NP. In both cases, subjects with the risk allele rs6656401(AT) (/) (AA) display more methylation being associated with more NP burden, whereas subjects with the rs6656401(TT) protective genotype have an inverse association with more methylation being associated with less NP.

INTERPRETATION: These observations suggest that, within known AD susceptibility loci, methylation is related to pathologic processes of AD and may play a largely independent role by influencing gene expression in AD susceptibility loci.

Year of Publication
2015
Journal
Ann Clin Transl Neurol
Volume
2
Issue
6
Pages
636-47
Date Published
2015 Jun
DOI
10.1002/acn3.201
PubMed ID
26125039
PubMed Central ID
PMC4479524
Links
Grant list
U01 AG046152 / AG / NIA NIH HHS / United States
RF1 AG015819 / AG / NIA NIH HHS / United States
R01 HG004037 / HG / NHGRI NIH HHS / United States
K25 AG041906 / AG / NIA NIH HHS / United States
R01 AG017917 / AG / NIA NIH HHS / United States
R01 AG036042 / AG / NIA NIH HHS / United States
P30 AG010161 / AG / NIA NIH HHS / United States
R01 AG036836 / AG / NIA NIH HHS / United States
R01 AG015819 / AG / NIA NIH HHS / United States