Gemma Shireby
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
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
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., Davies, J. P., Burrage, J., Lunnon, K., Seiler Vellame, D., Love, S., Thomas, A., Brookes, K., Morgan, K., Francis, P., Hannon, E., & 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 |
Publisher | Nature Publishing Group |
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 |
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DNA methylation signatures of Alzheimer’s disease neuropathology in the cortex are primarily driven by variation in non-neuronal cell-types
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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/.
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