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

doi:10.1038/s41467-022-33394-7

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
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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