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

Sarah J. Marzi, Szi Kay Leung, Teodora Ribarska, Eilis Hannon, Adam R. Smith, Ehsan Pishva, Jeremie Poschmann, Karen Moore, Claire Troakes, Safa Al-Sarraj, Stephan Beck, Stuart Newman, Katie Lunnon, Leonard C. Schalkwyk, Jonathan Mill*

*Corresponding author for this work

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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-beta 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.
Original languageEnglish
Pages (from-to)1618-1627
Number of pages17
JournalNature Neuroscience
Volume21
Issue number11
DOIs
Publication statusPublished - 1 Nov 2018

Keywords

  • AMYLOID PRECURSOR PROTEIN
  • DNA METHYLATION
  • GENE-EXPRESSION
  • BRAIN
  • NEURODEGENERATION
  • QUANTIFICATION
  • PRESENILIN-1
  • ACETYLATION
  • PROGRESSION
  • HYPOTHESIS

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