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INTRODUCTION: Alzheimer's disease is a neurodegenerative disorder that is hypothesized to involve epigenetic dysregulation of gene expression in the brain. METHODS: We performed an epigenome-wide association study to identify differential DNA methylation associated with neuropathology in prefrontal cortex and superior temporal gyrus samples from 147 individuals, replicating our findings in two independent data sets (N = 117 and 740). RESULTS: We identify elevated DNA methylation associated with neuropathology across a 48-kb region spanning 208 CpG sites within the HOXA gene cluster. A meta-analysis of the top-ranked probe within the HOXA3 gene (cg22962123) highlighted significant hypermethylation across all three cohorts (P = 3.11 × 10-18). DISCUSSION: We present robust evidence for elevated DNA methylation associated with Alzheimer's disease neuropathology spanning the HOXA gene cluster on chromosome 7. These data add to the growing evidence highlighting a role for epigenetic variation in Alzheimer's disease, implicating the HOX gene family as a target for future investigation.

Original publication

DOI

10.1016/j.jalz.2018.01.017

Type

Journal article

Journal

Alzheimers Dement

Publication Date

14/03/2018

Keywords

Alzheimer's disease (AD), Braak stage, DNA methylation, Epigenetics, Epigenome-wide association study (EWAS), HOXA, Illumina Infinium 450K BeadChip (450K array), Meta-analysis, Neuropathology, Prefrontal cortex (PFC), Superior temporal gyrus (STG)