Methylomic profiling implicates cortical deregulation of ANK1 in Alzheimer's disease
Lunnon, Katie; Smith, Rebecca; Hannon, E; et al.De Jager, PL; Srivastava, G.P.; Volta, M; Troakes, C; Al-Sarraj, S; Burrage, J; Macdonald, Ruby; Condliffe, Daniel; Harries, LW; Katsel, Pavel; Haroutunian, Vahram; Kaminsky, Zachary; Joachim, Catharine; Powell, J; Lovestone, Simon; Bennett, DA; Schalkwyk, Leonard; Mill, J
Date: 17 August 2014
Article
Journal
Nature Neuroscience
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Nature Publishing Group
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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 ...
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.
Institute of Biomedical & Clinical Science
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