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Ann Clin Transl Neurol. 2015 Jun;2(6):636-47. doi: 10.1002/acn3.201. Epub 2015 Apr 24.

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

Author information

1
Program in Translational NeuroPsychiatric Genomics, Institute for the Neurosciences, Departments of Neurology and Psychiatry, Brigham and Women's Hospital Boston, Massachusetts, 02115 ; Department of Neurology, Harvard Medical School Boston, Massachusetts, 02115 ; Medical and Population Genetics, Broad Institute of MIT and Harvard Cambridge, Massachusetts, 02142 ; Department of Epidemiology, Harvard T.H. Chan School of Public Health Boston, Massachusetts, 02115.
2
Medical and Population Genetics, Broad Institute of MIT and Harvard Cambridge, Massachusetts, 02142 ; Rush Alzheimer's Disease Center, Rush University Medical Center Chicago, Illinois, 60612.
3
Medical and Population Genetics, Broad Institute of MIT and Harvard Cambridge, Massachusetts, 02142 ; Computer Science and Artificial Intelligence Laboratory, MIT Cambridge, Massachusetts, 02124.
4
Program in Translational NeuroPsychiatric Genomics, Institute for the Neurosciences, Departments of Neurology and Psychiatry, Brigham and Women's Hospital Boston, Massachusetts, 02115 ; Department of Neurology, Harvard Medical School Boston, Massachusetts, 02115 ; Medical and Population Genetics, Broad Institute of MIT and Harvard Cambridge, Massachusetts, 02142.
5
Rush Alzheimer's Disease Center, Rush University Medical Center Chicago, Illinois, 60612.

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.

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