Transcriptomics

Dataset Information

8

Cross-tissue methylomic profiling implicates cortical deregulation of ANK1 in Alzheimer’s disease neuropathology


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 three 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. For the first (discovery) stage of our analysis, we used multiple tissues from donors (N = 122) archived in the MRC London Brainbank for Neurodegenerative Disease. From each donor, we isolated genomic DNA from four brain regions (EC, superior temporal gyrus (STG), prefrontal cortex (PFC) and CER) and, where available, from whole blood obtained pre-mortem. Our analyses focused on identifying differentially methylated positions (DMPs) associated with Braak staging, a standardized measure of neurofibrillary tangle burden determined at autopsy.

ORGANISM(S): Homo sapiens  

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

PROVIDER: E-GEOD-59685 | ArrayExpress | 2014-08-17

SECONDARY ACCESSION(S): GSE59685PRJNA256002

REPOSITORIES: GEO, ArrayExpress

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