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Nat Neurosci. 2014 Sep;17(9):1156-63. doi: 10.1038/nn.3786. Epub 2014 Aug 17.

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

Author information

1
1] Program in Translational NeuroPsychiatric Genomics, Institute for the Neurosciences, Departments of Neurology and Psychiatry, Brigham and Women's Hospital, Boston, Massachusetts, USA. [2] Harvard Medical School, Boston, Massachusetts, USA. [3] Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts, USA.
2
1] Program in Translational NeuroPsychiatric Genomics, Institute for the Neurosciences, Departments of Neurology and Psychiatry, Brigham and Women's Hospital, Boston, Massachusetts, USA. [2] Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts, USA.
3
1] University of Exeter Medical School, University of Exeter, Exeter, UK. [2] Institute of Psychiatry, King's College London, London, UK.
4
1] Department of Neuroscience, Mayo Clinic, Jacksonville, Florida, USA. [2] Department of Neurology, Mayo Clinic, Jacksonville, Florida, USA.
5
Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, Illinois, USA.
6
1] Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts, USA. [2] Computer Science and Artificial Intelligence Laboratory (CSAIL), Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.
7
Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts, USA.
8
Program in Translational NeuroPsychiatric Genomics, Institute for the Neurosciences, Departments of Neurology and Psychiatry, Brigham and Women's Hospital, Boston, Massachusetts, USA.
9
Genetic Analysis Platform, Broad Institute, Cambridge, Massachusetts, USA.
10
Department of Neuroscience, Mayo Clinic, Jacksonville, Florida, USA.
11
Department of Pharmacology and Therapeutics, McGill University, Montreal, Québec, Canada.
12
Epigenomics Program, Broad Institute, Cambridge, Massachusetts, USA.
13
1] Harvard Medical School, Boston, Massachusetts, USA. [2] Epigenomics Program, Broad Institute, Cambridge, Massachusetts, USA. [3] Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts, USA.
14
1] Computer Science and Artificial Intelligence Laboratory (CSAIL), Massachusetts Institute of Technology, Cambridge, Massachusetts, USA. [2] Epigenomics Program, Broad Institute, Cambridge, Massachusetts, USA. [3] Harvard Stem Cell Institute, Harvard University, Cambridge, Massachusetts, USA.

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.

PMID:
25129075
PMCID:
PMC4292795
DOI:
10.1038/nn.3786
[Indexed for MEDLINE]
Free PMC Article

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