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A R T I C L E S
Alzheimers disease: early alterations in brain DNA methylation at ANK1, BIN1, RHBDF2 and other loci
Philip L De Jager13, Gyan Srivastava1,3, Katie Lunnon4,5, Jeremy Burgess6,7, Leonard C Schalkwyk4,5,
Lei Yu8, Matthew L Eaton3,9, Brendan T Keenan1,3, Jason Ernst3,9, Cristin McCabe3, Anna Tang1,
Towfique Raj13, Joseph Replogle13, Wendy Brodeur10, Stacey Gabriel10, High S Chai6,7, Curtis Younkin6, Steven G Younkin6, Fanggeng Zou6, Moshe Szyf11, Charles B Epstein12, Julie A Schneider8,
Bradley E Bernstein2,12,13, Alex Meissner9,12,14, Nilufer Ertekin-Taner6,7, Lori B Chibnik13, Manolis Kellis3,9, Jonathan Mill4,5 & David A Bennett8
We used a collection of 708 prospectively collected autopsied brains to assess the methylation state of the brains DNA in relation to Alzheimers 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.
npg 201 4 Nature America, Inc. All rights reserved.
genes connected to a previously reported genetically defined AD susceptibility network13.
RESULTSDescription of subjects and data
Our data set consisted of methylation measures at 415,848 discrete CpG dinucleotides in 708 subjects. These methylation profiles were generated using the Illumina HumanMethylation450 beadset and a sample of dorsolateral prefrontal cortex obtained from each individual. Given that we dissected out the gray matter from each sample, we profiled a piece of tissue composed primarily of different neuronal populations and other parenchymal cells such as glia. These subjects were part of the Religious Order Study (ROS) or the Memory and Aging Project (MAP), two prospective cohort studies of aging that include brain donation at the time of death. Given that the subjects were cognitively non-impaired at study entry, we studied a random...