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Nat Neurosci. 2018 Nov;21(11):1618-1627. doi: 10.1038/s41593-018-0253-7. Epub 2018 Oct 22.

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

Author information

1
Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, UK.
2
The Blizard Institute, Queen Mary University of London, London, UK.
3
University of Exeter Medical School, University of Exeter, Exeter, UK.
4
Oslo University Hospital, Oslo, Norway.
5
Department of Psychiatry and Neuropsychology, Maastricht University Medical Centre, Maastricht, The Netherlands.
6
Centre de Recherche en Transplantation et Immunologie, Inserm, Université de Nantes, Nantes, France.
7
UCL Cancer Institute, University College London, London, UK.
8
University of Essex, Colchester, UK.
9
University of Exeter Medical School, University of Exeter, Exeter, UK. J.Mill@exeter.ac.uk.

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.

PMID:
30349106
DOI:
10.1038/s41593-018-0253-7

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