Skip to main content

Research Repository

Advanced Search

DNA methylation signatures of Alzheimer’s disease neuropathology in the cortex are primarily driven by variation in non-neuronal cell-types

Shireby, Gemma; Dempster, Emma L.; Policicchio, Stefania; Smith, Rebecca G.; Pishva, Ehsan; Chioza, Barry; Davies, Jonathan P.; Burrage, Joe; Lunnon, Katie; Seiler Vellame, Dorothea; Love, Seth; Thomas, Alan; Brookes, Keeley; Morgan, Kevin; Francis, Paul; Hannon, Eilis; Mill, Jonathan

Authors

Gemma Shireby

Emma L. Dempster

Stefania Policicchio

Rebecca G. Smith

Ehsan Pishva

Barry Chioza

Jonathan P. Davies

Joe Burrage

Katie Lunnon

Dorothea Seiler Vellame

Seth Love

Alan Thomas

Keeley Brookes

KEVIN MORGAN kevin.morgan@nottingham.ac.uk
Professor of Human Genomics and Molecular Genetics

Paul Francis

Eilis Hannon

Jonathan Mill



Abstract

Alzheimer’s disease (AD) is a chronic neurodegenerative disease characterized by the progressive accumulation of amyloid-beta and neurofibrillary tangles of tau in the neocortex. We profiled DNA methylation in two regions of the cortex from 631 donors, performing an epigenome-wide association study of multiple measures of AD neuropathology. We meta-analyzed our results with those from previous studies of DNA methylation in AD cortex (total n = 2013 donors), identifying 334 cortical differentially methylated positions (DMPs) associated with AD pathology including methylomic variation at loci not previously implicated in dementia. We subsequently profiled DNA methylation in NeuN+ (neuronal-enriched), SOX10+ (oligodendrocyte-enriched) and NeuN–/SOX10– (microglia- and astrocyte-enriched) nuclei, finding that the majority of DMPs identified in ‘bulk’ cortex tissue reflect DNA methylation differences occurring in non-neuronal cells. Our study highlights the power of utilizing multiple measures of neuropathology to identify epigenetic signatures of AD and the importance of characterizing disease-associated variation in purified cell-types.

Citation

Shireby, G., Dempster, E. L., Policicchio, S., Smith, R. G., Pishva, E., Chioza, B., …Mill, J. (2022). DNA methylation signatures of Alzheimer’s disease neuropathology in the cortex are primarily driven by variation in non-neuronal cell-types. Nature Communications, 13, Article 5620. https://doi.org/10.1038/s41467-022-33394-7

Journal Article Type Article
Acceptance Date Sep 13, 2022
Online Publication Date Sep 24, 2022
Publication Date Sep 24, 2022
Deposit Date Nov 29, 2022
Publicly Available Date Nov 29, 2022
Journal Nature Communications
Electronic ISSN 2041-1723
Peer Reviewed Peer Reviewed
Volume 13
Article Number 5620
DOI https://doi.org/10.1038/s41467-022-33394-7
Keywords General Physics and Astronomy; General Biochemistry, Genetics and Molecular Biology; General Chemistry; Multidisciplinary
Public URL https://nottingham-repository.worktribe.com/output/11742473
Publisher URL https://www.nature.com/articles/s41467-022-33394-7

Files

DNA methylation signatures of Alzheimer’s disease neuropathology in the cortex are primarily driven by variation in non-neuronal cell-types (2.6 Mb)
PDF

Publisher Licence URL
https://creativecommons.org/licenses/by/4.0/

Copyright Statement
Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.




You might also like



Downloadable Citations