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

Lunnon, Katie and Smith, Rebecca and Hannon, Eilis and De Jager, Philip L and Srivastava, Gyan and Volta, Manuela and Troakes, Claire and Al-Sarraj, Safa and Burrage, Joe and Macdonald, Ruby and Condliffe, Daniel and Harries, Lorna W and Katsel, Pavel and Haroutunian, Vahram and Kaminsky, Zachary and Joachim, Catharine and Powell, John and Lovestone, Simon and Bennett, David A and Schalkwyk, Leonard C and Mill, Jonathan (2014) 'Methylomic profiling implicates cortical deregulation of ANK1 in Alzheimer's disease.' Nature Neuroscience, 17 (9). pp. 1164-1170. ISSN 1097-6256

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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 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.

Item Type: Article
Uncontrolled Keywords: Entorhinal Cortex; Cerebral Cortex; Prefrontal Cortex; Temporal Lobe; Humans; Alzheimer Disease; Ankyrins; DNA Methylation; Epigenesis, Genetic; Aged; Aged, 80 and over; Middle Aged; Female; Male; Genome-Wide Association Study; Transcriptome
Subjects: Q Science > QH Natural history > QH426 Genetics
Divisions: Faculty of Science and Health
Faculty of Science and Health > Life Sciences, School of
SWORD Depositor: Elements
Depositing User: Elements
Date Deposited: 24 Oct 2014 13:47
Last Modified: 15 Jan 2022 00:42
URI: http://repository.essex.ac.uk/id/eprint/11059

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