4.7 Article

Elevated DNA methylation across a 48-kb region spanning the HOXA gene cluster is associated with Alzheimer's disease neuropathology

Journal

ALZHEIMERS & DEMENTIA
Volume 14, Issue 12, Pages 1580-1588

Publisher

ELSEVIER SCIENCE INC
DOI: 10.1016/j.jalz.2018.01.017

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)

Funding

  1. NIH [AG02219, AG05138, MH064673, R01 AG036039]
  2. Alzheimer's Society [AS-PG-14-038]
  3. Alzheimer's Association [NIRG-14-320878]
  4. BRACE (Bristol Research into Alzheimer's and Care of the Elderly)
  5. Department of Veterans Affairs VISN3 MIRECC
  6. Medical Research Council (MRC)
  7. Brains for Dementia Research (BDR) programme
  8. National Institutes of Health [R01 AG036042, R01AG036836, R01 AG17917, R01 AG15819, R01 AG032990, R01 AG18023, RC2 AG036547, P30 AG10161, P50 AG016574, U01 ES017155, KL2 RR024151, K25 AG041906-01]
  9. Alzheimer's Research UK
  10. Alzheimer's Society
  11. MRC [MR/L016397/1] Funding Source: UKRI

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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 X 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. (C) 2018 The Authors. Published by Elsevier Inc. on behalf of the Alzheimer's Association.

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