Cited by 232Alzheimer's disease research and treatmentsGenomics and Chromatin DynamicsDementia and Cognitive Impairment Research

A histone acetylome-wide association study of Alzheimer’s disease identifies disease-associated H3K27ac differences in the entorhinal cortex

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Marzi, Sarah J., Leung, Szi Kay, Ribarska, Teodora, Hannon, Eilis, Smith, Adam R., Pishva, Ehsan, Poschmann, Jeremie, Moore, Karen +7 more·2018·Nature Neuroscience

Published version of a preprint

Abstract

We quantified genome-wide patterns of lysine H3K27 acetylation (H3K27ac) in entorhinal cortex samples from Alzheimer's disease (AD) cases and matched controls using chromatin immunoprecipitation and highly parallel sequencing. We observed widespread acetylomic variation associated with AD neuropathology, identifying 4,162 differential peaks (false discovery rate < 0.05) between AD cases and controls. Differentially acetylated peaks were enriched in disease-related biological pathways and included regions annotated to genes involved in the progression of amyloid-β and tau pathology (for example, APP, PSEN1, PSEN2, and MAPT), as well as regions containing variants associated with sporadic late-onset AD. Partitioned heritability analysis highlighted a highly significant enrichment of AD risk variants in entorhinal cortex H3K27ac peak regions. AD-associated variable H3K27ac was associated with transcriptional variation at proximal genes including CR1, GPR22, KMO, PIM3, PSEN1, and RGCC. In addition to identifying molecular pathways associated with AD neuropathology, we present a framework for genome-wide studies of histone modifications in complex disease.

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Authors
Marzi, S. J., Leung, S. K., Ribarska, T., Hannon, E., Smith, A. R., Pishva, E., Poschmann, J., Moore, K., Troakes, C., Al-Sarraj, S., Beck, S., Newman, S., Lunnon, K., Schalkwyk, L. C., & Mill, J.
Affiliations
  • Queen Mary University of London (GB)
  • University of Exeter (GB)
  • Oslo University Hospital (NO)
  • King's College London (GB)
  • University College London (GB)
  • University of Essex (GB)
Corresponding author
Mill, Jonathan
Venue
Nature Neuroscience
Published
2018-10-22
Volume
21
Issue
11
Pages
1618-1627
ISSN
  • 1097-6256 (ISSN-L)
  • 1546-1726
OpenAlex
W2896025743
Cited by
232
References
80
Citations by year
2026: 22 · 2025: 38 · 2024: 34 · 2023: 34 · 2022: 26 · 2021: 45 · 2020: 20 · 2019: 12 · 2018: 1
FWCI
13.58
Type
journal article
Language
en
Open access
Locations
  • Nature Neuroscience (publishedVersion)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by)
  • PubMed (publishedVersion)
  • Research Publications (Maastricht University) (acceptedVersion, other-oa)
  • Open Research Exeter (University of Exeter) (acceptedVersion)
  • Open Access at Essex (University of Essex) (acceptedVersion)
  • HAL (submittedVersion)
  • UCL Discovery (University College London) (submittedVersion)
  • Figshare (submittedVersion)
  • Research Portal (King's College London) (submittedVersion)
  • Spiral (Imperial College London) (submittedVersion)
  • Spiral (Imperial College London) (submittedVersion, cc-by)
  • Research Publications (Maastricht University) (submittedVersion, other-oa)
Funders
  • Alzheimer's Association (NIRG-14-320878)
  • University of Essex
  • Wellcome Trust (MR/M008924/1, WT101650MA)
  • University of Exeter
  • Genome Institute of Singapore
  • National Institutes of Health
  • Directorate for Biological Sciences
  • Medical Research Council (MR/M008924/1, MR/L016397/1, WT101650MA, M008924)
  • National Institute on Aging (R01AG036039)
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
Keywords
Alzheimer's disease, H3K27 acetylation, entorhinal cortex, ChIP-seq, amyloid-beta pathology, tau pathology, APP, presenilin 1, presenilin 2, MAPT, transcriptional variation, complement receptor 1, KMO, PIM3
MeSH terms
Acetylation, Aged, Aged, 80 and over, Alzheimer Disease, Female, Histones, Humans, Male, Middle Aged, Amyloid beta-Protein Precursor, tau Proteins, Entorhinal Cortex, Genetic Predisposition to Disease

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