A histone acetylome-wide association study of Alzheimer’s disease identifies disease-associated H3K27ac differences in the entorhinal cortex
© The Author(s), under exclusive licence to Springer Nature America, Inc. 2018.
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Under embargo until 22 April 2019 in compliance with publisher policy.
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 (ChIP-seq). We observed widespread acetylomic variation associated with AD neuropathology, identifying 4,162 differential peaks (FDR < 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 Aβ and tau pathology (e.g. 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.
This work was funded by US National Institutes of Health grant R01 AG036039 to J.M. S.J.M. and T.R. were funded by the EU-FP7 Marie Curie ITN EpiTrain (REA grant agreement no. 316758). S.K.L. is funded by a Medical Research Council (MRC) CASE PhD studentship. Sequencing infrastructure was supported by a Wellcome Trust Multi User Equipment Award (WT101650MA) and Medical Research Council (MRC) Clinical Infrastructure Funding (MR/M008924/1). Generation of DNA hydroxymethylation data was funded by an Alzheimer’s Association US New Investigator Research Grant (grant number NIRG-14-320878) to K.L., and a grant from BRACE (Bristol Research into Alzheimer’s and Care of the Elderly) to K.L.
This is the author accepted manuscript. The final version is available from Springer Nature via the DOI in this record.
Data availability: Raw data has been deposited in GEO under accession number GSE102538. Browsable UCSC genome browser tracks of our processed H3K27ac ChIP-seq data are available as a resource at: https://epigenetics.essex.ac.uk/AD_H3K27ac/.
Code availability: Analysis code is given in Supplementary Software and also available to download from https://epigenetics.essex.ac.uk/AD_H3K27ac/code/index.html.
Published online 22 October 2018.