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Nat Neurosci. 2014 Sep;17(9):1164-70. doi: 10.1038/nn.3782. Epub 2014 Aug 17.

Methylomic profiling implicates cortical deregulation of ANK1 in Alzheimer's disease.

Author information

  • 1University of Exeter Medical School, Exeter University, Exeter, UK.
  • 2Institute of Psychiatry, King's College London, London, UK.
  • 31] 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, USA.
  • 41] 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, USA.
  • 5Department of Psychiatry, The Icahn School of Medicine at Mount Sinai, New York, USA.
  • 61] Department of Psychiatry, The Icahn School of Medicine at Mount Sinai, New York, USA. [2] Department of Neuroscience, The Icahn School of Medicine at Mount Sinai, New York, USA. [3] JJ Peters Virginia Medical Center, Bronx, New York, USA.
  • 71] Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. [2] Department of Mental Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA.
  • 8Department of Neuropathology, John Radcliffe Hospital, University of Oxford, Oxford, UK.
  • 91] Institute of Psychiatry, King's College London, London, UK. [2] Department of Psychiatry, Warneford Hospital, University of Oxford, Oxford, UK.
  • 10Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, Illinois, USA.
  • 111] Institute of Psychiatry, King's College London, London, UK. [2].
  • 121] University of Exeter Medical School, Exeter University, Exeter, UK. [2] Institute of Psychiatry, King's College London, London, UK. [3].

Abstract

Alzheimer's disease (AD) is a chronic neurodegenerative disorder that is characterized by progressive neuropathology and cognitive decline. We performed a cross-tissue analysis of methylomic variation in AD using samples from four independent human post-mortem brain cohorts. We identified a differentially methylated region in the ankyrin 1 (ANK1) gene that was associated with neuropathology in the entorhinal cortex, a primary site of AD manifestation. This region was confirmed as being substantially hypermethylated in two other cortical regions (superior temporal gyrus and prefrontal cortex), but not in the cerebellum, a region largely protected from neurodegeneration in AD, or whole blood obtained pre-mortem from the same individuals. Neuropathology-associated ANK1 hypermethylation was subsequently confirmed in cortical samples from three independent brain cohorts. This study represents, to the best of our knowledge, the first epigenome-wide association study of AD employing a sequential replication design across multiple tissues and highlights the power of this approach for identifying methylomic variation associated with complex disease.

PMID:
25129077
[PubMed - indexed for MEDLINE]
PMCID:
PMC4410018
Free PMC Article
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