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

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