A histone acetylome-wide association study of Alzheimer’s disease identifies disease-associated H3K27ac differences in the entorhinal cortex
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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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Studies in AD have revealed changes in gene regulation manifested by differences in H3K27ac in bulk tissue.
“Studies in AD have revealed changes in gene regulation manifested by differences in H3K27ac in bulk tissue38, but how this relates to cell-type-specific vulnerability is not known.”
From Neuronal and glial 3D chromatin architecture informs the cellular etiology of brain disorders (2021) · cites this paper as [38]
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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
- ORCID
- 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
- green
- doi.org
- Licence
- 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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