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

Katie Lunnon, Rebecca Smith, Eilis Hannon, Philip L. De Jager, Gyan Srivastava, Manuela Volta, Claire Troakes, Safa Al-Sarraj, Joe Burrage, Ruby Macdonald, Daniel Condliffe, Lorna W. Harries, Pavel Katsel, Vahram Haroutunian, Zachary Kaminsky, Catharine Joachim, John Powell, Simon Lovestone, David A. Bennett, Leonard C. SchalkwykJonathan Mill

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Pages (from-to)1164-1170
Number of pages7
JournalNature neuroscience
Volume17
Issue number9
DOIs
StatePublished - Sep 1 2014

ASJC Scopus subject areas

  • Neuroscience(all)

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