Alzheimer's Disease: Early Alterations in Brain DNA Methylation at ANK1, BIN1, RHBDF2 and Other Loci

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

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics*
  • Aged
  • Aged, 80 and over
  • Alzheimer Disease / epidemiology
  • Alzheimer Disease / genetics*
  • Alzheimer Disease / pathology*
  • Amyloidosis / epidemiology
  • Amyloidosis / genetics
  • Amyloidosis / pathology
  • Ankyrins / genetics*
  • Brain / pathology
  • Brain / physiology
  • Carrier Proteins / genetics*
  • CpG Islands / genetics
  • DNA Methylation / genetics*
  • Female
  • Genetic Predisposition to Disease / epidemiology
  • Genetic Predisposition to Disease / genetics
  • Genome-Wide Association Study
  • Humans
  • Intracellular Signaling Peptides and Proteins
  • Male
  • Middle Aged
  • Nuclear Proteins / genetics*
  • Protein Interaction Maps
  • Tumor Suppressor Proteins / genetics*

Substances

  • ANK1 protein, human
  • Adaptor Proteins, Signal Transducing
  • Ankyrins
  • BIN1 protein, human
  • Carrier Proteins
  • Intracellular Signaling Peptides and Proteins
  • Nuclear Proteins
  • RHBDF2 protein, human
  • Tumor Suppressor Proteins