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Alzheimers Dement. 2018 Dec;14(12):1580-1588. doi: 10.1016/j.jalz.2018.01.017. Epub 2018 Mar 15.

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

Author information

1
Institute of Clinical and Biomedical Science, University of Exeter Medical School, RILD Building, Royal Devon & Exeter Hospital Campus, Exeter, Devon, UK.
2
Program in Translational NeuroPsychiatric Genomics, Departments of Neurology and Psychiatry, Institute for the Neurosciences, Brigham and Women's Hospital, Boston, MA, USA; Harvard Medical School, Boston, MA, USA; Department of Neurology, Columbia University College of Physicians and Surgeons, Columbia University Medical Center, New York, NY, USA.
3
Program in Translational NeuroPsychiatric Genomics, Departments of Neurology and Psychiatry, Institute for the Neurosciences, Brigham and Women's Hospital, Boston, MA, USA; Harvard Medical School, Boston, MA, USA.
4
Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.
5
Queen Mary University of London, London, UK.
6
Department of Psychiatry, The Icahn School of Medicine at Mount Sinai, New York, NY, USA; Department of Neuroscience, The Icahn School of Medicine at Mount Sinai, New York, NY, USA; JJ Peters VA Medical Center, Bronx, NY, USA.
7
Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, IL, USA.
8
Department of Psychiatry, University of Oxford, Warneford Hospital, Oxford, UK.
9
University of Essex, Colchester, UK.
10
Institute of Clinical and Biomedical Science, University of Exeter Medical School, RILD Building, Royal Devon & Exeter Hospital Campus, Exeter, Devon, UK. Electronic address: j.mill@exeter.ac.uk.
11
Institute of Clinical and Biomedical Science, University of Exeter Medical School, RILD Building, Royal Devon & Exeter Hospital Campus, Exeter, Devon, UK. Electronic address: k.lunnon@exeter.ac.uk.

Abstract

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.

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)

PMID:
29550519
DOI:
10.1016/j.jalz.2018.01.017
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