Association of Brain DNA methylation in SORL1, ABCA7, HLA-DRB5, SLC24A4, and BIN1 with pathological diagnosis of Alzheimer disease.

JAMA Neurol
Authors
Keywords
Abstract

IMPORTANCE: Recent large-scale genome-wide association studies have discovered several genetic variants associated with Alzheimer disease (AD); however, the extent to which DNA methylation in these AD loci contributes to the disease susceptibility remains unknown.

OBJECTIVE: To examine the association of brain DNA methylation in 28 reported AD loci with AD pathologies.

DESIGN, SETTING, AND PARTICIPANTS: Ongoing community-based clinical pathological cohort studies of aging and dementia (the Religious Orders Study and the Rush Memory and Aging Project) among 740 autopsied participants 66.0 to 108.3 years old.

EXPOSURES: DNA methylation levels at individual CpG sites generated from dorsolateral prefrontal cortex tissue using a bead assay.

MAIN OUTCOMES AND MEASURES: Pathological diagnosis of AD by National Institute on Aging-Reagan criteria following a standard postmortem examination.

RESULTS: Overall, 447 participants (60.4%) met the criteria for pathological diagnosis of AD. Brain DNA methylation in SORL1, ABCA7, HLA-DRB5, SLC24A4, and BIN1 was associated with pathological AD. The association was robustly retained after replacing the binary trait of pathological AD with 2 quantitative and molecular specific hallmarks of AD, namely, Aβ load and paired helical filament tau tangle density. Furthermore, RNA expression of transcripts of SORL1 and ABCA7 was associated with paired helical filament tau tangle density, and the expression of BIN1 was associated with Aβ load.

CONCLUSIONS AND RELEVANCE: Brain DNA methylation in multiple AD loci is associated with AD pathologies. The results provide further evidence that disruption of DNA methylation is involved in the pathological process of AD.

Year of Publication
2015
Journal
JAMA Neurol
Volume
72
Issue
1
Pages
15-24
Date Published
2015 Jan
ISSN
2168-6157
URL
DOI
10.1001/jamaneurol.2014.3049
PubMed ID
25365775
PubMed Central ID
PMC4344367
Links
Grant list
U01 AG046152 / AG / NIA NIH HHS / United States
RF1 AG015819 / AG / NIA NIH HHS / United States
R01AG36836 / AG / NIA NIH HHS / United States
K25 AG041906 / AG / NIA NIH HHS / United States
R01AG36042 / AG / NIA NIH HHS / United States
R01 AG017917 / AG / NIA NIH HHS / United States
R01AG17917 / AG / NIA NIH HHS / United States
U01AG46152 / AG / NIA NIH HHS / United States
R01 AG036042 / AG / NIA NIH HHS / United States
P30 AG010161 / AG / NIA NIH HHS / United States
R01AG15819 / AG / NIA NIH HHS / United States
P30AG10161 / AG / NIA NIH HHS / United States
R01 AG036836 / AG / NIA NIH HHS / United States
R01 AG015819 / AG / NIA NIH HHS / United States