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Nat Neurosci DOI:10.1038/nn.3782

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

Publication TypeJournal Article
Year of Publication2014
AuthorsLunnon, K, Smith, R, Hannon, E, De Jager, PL, Srivastava, G, Volta, M, Troakes, C, Al-Sarraj, S, Burrage, J, Macdonald, R, Condliffe, D, Harries, LW, Katsel, P, Haroutunian, V, Kaminsky, Z, Joachim, C, Powell, J, Lovestone, S, Bennett, DA, Schalkwyk, LC, Mill, J
JournalNat Neurosci
Volume17
Issue9
Pages1164-70
Date Published2014 Sep
ISSN1546-1726
KeywordsAged, Aged, 80 and over, Alzheimer Disease, Ankyrins, Cerebral Cortex, DNA Methylation, Entorhinal Cortex, Epigenesis, Genetic, Female, Genome-Wide Association Study, Humans, Male, Middle Aged, Prefrontal Cortex, Temporal Lobe, Transcriptome
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.

URLhttp://dx.doi.org/10.1038/nn.3782
DOI10.1038/nn.3782
Pubmed

http://www.ncbi.nlm.nih.gov/pubmed/25129077?dopt=Abstract

Alternate JournalNat. Neurosci.
PubMed ID25129077
PubMed Central IDPMC4410018
Grant ListR01 AG17917 / AG / NIA NIH HHS / United States
MH064673 / MH / NIMH NIH HHS / United States
AG05138 / AG / NIA NIH HHS / United States
P50 AG016574 / AG / NIA NIH HHS / United States
K25 AG041906 / AG / NIA NIH HHS / United States
R01 MH064673 / MH / NIMH NIH HHS / United States
R01 AG017917 / AG / NIA NIH HHS / United States
P30 AG10161 / AG / NIA NIH HHS / United States
KL2 RR024151 / RR / NCRR NIH HHS / United States
G1100695 / / Medical Research Council / United Kingdom
AG02219 / AG / NIA NIH HHS / United States
K25 AG041906-01 / AG / NIA NIH HHS / United States
R01 AG036042 / AG / NIA NIH HHS / United States
P30 AG010161 / AG / NIA NIH HHS / United States
R01 AG15819 / AG / NIA NIH HHS / United States
R01 AG032990 / AG / NIA NIH HHS / United States
RC2 AG036547 / AG / NIA NIH HHS / United States
P01 AG002219 / AG / NIA NIH HHS / United States
P50 AG005138 / AG / NIA NIH HHS / United States
R01 AG036039 / AG / NIA NIH HHS / United States
R01 AG18023 / AG / NIA NIH HHS / United States
R01AG036836 / AG / NIA NIH HHS / United States
U01 ES017155 / ES / NIEHS NIH HHS / United States
R01 AG018023 / AG / NIA NIH HHS / United States
R01 AG036836 / AG / NIA NIH HHS / United States
R01 AG015819 / AG / NIA NIH HHS / United States