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Nat Neurosci DOI:10.1038/nn.3786

Alzheimer's disease: early alterations in brain DNA methylation at ANK1, BIN1, RHBDF2 and other loci.

Publication TypeJournal Article
Year of Publication2014
AuthorsDe Jager, PL, Srivastava, G, Lunnon, K, Burgess, J, Schalkwyk, LC, Yu, L, Eaton, ML, Keenan, BT, Ernst, J, McCabe, C, Tang, A, Raj, T, Replogle, J, Brodeur, W, Gabriel, S, Chai, HS, Younkin, C, Younkin, SG, Zou, F, Szyf, M, Epstein, CB, Schneider, JA, Bernstein, BE, Meissner, A, Ertekin-Taner, N, Chibnik, LB, Kellis, M, Mill, J, Bennett, DA
JournalNat Neurosci
Volume17
Issue9
Pages1156-63
Date Published2014 Sep
ISSN1546-1726
KeywordsAdaptor Proteins, Signal Transducing, Aged, Aged, 80 and over, Alzheimer Disease, Amyloidosis, Ankyrins, Brain, Carrier Proteins, CpG Islands, DNA Methylation, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Male, Middle Aged, Nuclear Proteins, Protein Interaction Maps, Tumor Suppressor Proteins
Abstract

We used a collection of 708 prospectively collected autopsied brains to assess the methylation state of the brain's DNA in relation to Alzheimer's disease (AD). We found that the level of methylation at 71 of the 415,848 interrogated CpGs was significantly associated with the burden of AD pathology, including CpGs in the ABCA7 and BIN1 regions, which harbor known AD susceptibility variants. We validated 11 of the differentially methylated regions in an independent set of 117 subjects. Furthermore, we functionally validated these CpG associations and identified the nearby genes whose RNA expression was altered in AD: ANK1, CDH23, DIP2A, RHBDF2, RPL13, SERPINF1 and SERPINF2. Our analyses suggest that these DNA methylation changes may have a role in the onset of AD given that we observed them in presymptomatic subjects and that six of the validated genes connect to a known AD susceptibility gene network.

URLhttp://dx.doi.org/10.1038/nn.3786
DOI10.1038/nn.3786
Pubmed

http://www.ncbi.nlm.nih.gov/pubmed/25129075?dopt=Abstract

Alternate JournalNat. Neurosci.
PubMed ID25129075
PubMed Central IDPMC4292795
Grant ListU01 AG046152 / AG / NIA NIH HHS / United States
R01 AG17917 / AG / NIA NIH HHS / United States
RF1 AG015819 / AG / NIA NIH HHS / United States
R01 HG004037 / HG / NHGRI NIH HHS / United States
P50 AG016574 / AG / NIA NIH HHS / United States
K25 AG041906 / AG / NIA NIH HHS / United States
AG036039 / AG / NIA NIH HHS / United States
R01 AG017917 / AG / NIA NIH HHS / United States
P30 AG10161 / AG / NIA NIH HHS / United States
KL2 RR024151 / RR / NCRR NIH HHS / United States
K25 AG041906-01 / AG / NIA NIH HHS / United States
R01 AG036042 / AG / NIA NIH HHS / United States
P30 AG010161 / AG / NIA NIH HHS / United States
R01 AG15819 / AG / NIA NIH HHS / United States
R01 AG032990 / AG / NIA NIH HHS / United States
R01 NS080820 / NS / NINDS NIH HHS / United States
RC2 AG036547 / AG / NIA NIH HHS / United States
U01 AG046139 / AG / NIA NIH HHS / United States
R01 AG036039 / AG / NIA NIH HHS / United States
R01 AG18023 / AG / NIA NIH HHS / United States
R01AG036836 / AG / NIA NIH HHS / United States
U01 ES017155 / ES / NIEHS NIH HHS / United States
R01 AG018023 / AG / NIA NIH HHS / United States
R01 AG036836 / AG / NIA NIH HHS / United States
R01 AG015819 / AG / NIA NIH HHS / United States