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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 publication

DOI

10.1038/nn.3782

Type

Journal article

Journal

Nat Neurosci

Publication Date

09/2014

Volume

17

Pages

1164 - 1170

Keywords

Aged, 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