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

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

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...

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Bibliographic Details
Main Authors: Srivastava, Gyan, Lunnon, Katie, Burgess, Jeremy, Yu, Lei, Ernst, Jason, McCabe, Cristin, Tang, Anna, Raj, Towfique, Replogle, Joseph, Brodeur, Wendy, Gabriel, Stacey, Younkin, Curtis, Zou, Fanggeng, Szyf, Moshe, Meissner, Alexander, Ertekin-Taner, Nilufer, Kellis, Manolis, Mill, Jonathan, De Jager, Philip L., Schalkwyk, Leonard C., Eaton, Matthew Lucas, Eaton, Matthew L., Keenan, Brendan T., Chai, High S., Younkin, Steven G., Epstein, Charles B., Schneider, Julie A., Bernstein, Bradley E., Chibnik, Lori B., Bennett, David A.
Other Authors: Massachusetts Institute of Technology. Computer Science and Artificial Intelligence Laboratory
Format: Article
Language:en_US
Published: Nature Publishing Group 2016
Online Access:http://hdl.handle.net/1721.1/100770
https://orcid.org/0000-0002-8305-9125
Description
Summary: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.

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