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

• Main Authors: Chibnik, Lori B. (Author), Yu, Lei (Author), Srivastava, Gyan (Author), Schneider, Julie A. (Author), Kellis, Manolis (Contributor), Bennett, David A. (Author), De Jager, Philip L. (Author), Eaton, Matthew Lucas (Contributor)
• Other Authors: Massachusetts Institute of Technology. Computer Science and Artificial Intelligence Laboratory (Contributor), Massachusetts Institute of Technology. Department of Electrical Engineering and Computer Science (Contributor)
• Format: Article
• Language: English
• Published: American Neurological Association, 2016-01-10T21:21:48Z.
• Subjects: Article
• Online Access: Get fulltext

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[superscript AT/AA] display more methylation being associated with more NP burden, whereas subjects with the rs6656401[superscript 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.
National Institutes of Health (U.S.) (Grant K25AG041906)
National Institutes of Health (U.S.) (Grant P30AG10161)
National Institutes of Health (U.S.) (Grant R01AG15819)
National Institutes of Health (U.S.) (Grant R01AG17917)
National Institutes of Health (U.S.) (Grant R01AG36042)
National Institutes of Health (U.S.) (Grant R01AG36836)
National Institutes of Health (U.S.) (Grant U01AG46152)