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

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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, Troakes, Claire, Al-Sarraj, Safa, Beck, Stephan, Newman, Stuart, Lunnon, Katie, Schalkwyk, Leonard C., Mill, Jonathan·2018·Nature Neuroscience

DOI 10.1038/s41593-018-0253-7

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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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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: Marzi, Sarah J.
Leung, Szi Kay
Hannon, Eilis
Smith, Adam R.
Pishva, Ehsan
Moore, Karen
Troakes, Claire
Beck, Stephan
Lunnon, Katie
Schalkwyk, Leonard C.
Mill, Jonathan
Venue: Nature Neuroscience
Publisher: Springer Science and Business Media LLC
Published: 2018-10-22
Volume: 21
Issue: 11
Pages: 1618-1627
ISSN: 1097-6256 (ISSN-L)
1546-1726
DOI: 10.1038/s41593-018-0253-7
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: cc-by
www.springer.com/tdm (tdm)
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: Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › 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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A histone acetylome-wide association study of Alzheimer’s disease identifies disease-associated H3K27ac differences in the entorhinal cortex

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