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

De Jager, Philip L and Srivastava, Gyan and Lunnon, Katie and Burgess, Jeremy and Schalkwyk, Leonard C and Yu, Lei and Eaton, Matthew L and Keenan, Brendan T and Ernst, Jason and McCabe, Cristin and Tang, Anna and Raj, Towfique and Replogle, Joseph and Brodeur, Wendy and Gabriel, Stacey and Chai, High S and Younkin, Curtis and Younkin, Steven G and Zou, Fanggeng and Szyf, Moshe and Epstein, Charles B and Schneider, Julie A and Bernstein, Bradley E and Meissner, Alex and Ertekin-Taner, Nilufer and Chibnik, Lori B and Kellis, Manolis and Mill, Jonathan and Bennett, David A (2014) 'Alzheimer's disease: early alterations in brain DNA methylation at ANK1, BIN1, RHBDF2 and other loci.' Nature Neuroscience, 17 (9). pp. 1156-1163. ISSN 1097-6256

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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.

Item Type: Article
Uncontrolled Keywords: Brain; Humans; Alzheimer Disease; Amyloidosis; Genetic Predisposition to Disease; Intracellular Signaling Peptides and Proteins; Adaptor Proteins, Signal Transducing; Ankyrins; Carrier Proteins; Tumor Suppressor Proteins; Nuclear Proteins; DNA Methylation; CpG Islands; Aged; Aged, 80 and over; Middle Aged; Female; Male; Genome-Wide Association Study; Protein Interaction Maps
Subjects: Q Science > QH Natural history > QH426 Genetics
Divisions: Faculty of Science and Health
Faculty of Science and Health > Life Sciences, School of
SWORD Depositor: Elements
Depositing User: Elements
Date Deposited: 24 Oct 2014 13:40
Last Modified: 15 Jan 2022 00:42
URI: http://repository.essex.ac.uk/id/eprint/11016

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