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

Philip L. De Jager, Gyan Srivastava, Katie Lunnon, Jeremy Burgess, Leonard C. Schalkwyk, Lei Yu, Matthew L. Eaton, Brendan T. Keenan, Jason Ernst, Cristin McCabe, Anna Tang, Towfique Raj, Joseph Replogle, Wendy Brodeur, Stacey Gabriel, High S. Chai, Curtis Younkin, Steven G. Younkin, Fanggeng Zou, Moshe SzyfCharles B. Epstein, Julie A. Schneider, Bradley E. Bernstein, Alex Meissner, Nilufer Ertekin-Taner, Lori B. Chibnik, Manolis Kellis, Jonathan Mill, David A. Bennett

Research output: Contribution to journalArticle

400 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1156-1163
Number of pages8
JournalNature Neuroscience
Volume17
Issue number9
DOIs
StatePublished - Sep 1 2014

ASJC Scopus subject areas

  • Neuroscience(all)

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  • Cite this

    De Jager, P. L., Srivastava, G., Lunnon, K., Burgess, J., Schalkwyk, L. C., Yu, L., Eaton, M. L., Keenan, B. T., Ernst, J., McCabe, C., Tang, A., Raj, T., Replogle, J., Brodeur, W., Gabriel, S., Chai, H. S., Younkin, C., Younkin, S. G., Zou, F., ... Bennett, D. A. (2014). Alzheimer's disease: Early alterations in brain DNA methylation at ANK1, BIN1, RHBDF2 and other loci. Nature Neuroscience, 17(9), 1156-1163. https://doi.org/10.1038/nn.3786