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

Shireby, G, Dempster, EL, Policicchio, S, Smith, RG, Pishva, E, Chioza, B, Davies, JP, Burrage, J, Lunnon, K, Seiler Vellame, D, Love, S, Thomas, A, Brookes, K ORCID: https://orcid.org/0000-0003-2427-2513, Morgan, K, Francis, P, Hannon, E and 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: 5620. ISSN 2041-1723

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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.

Item Type:	Journal article
Publication Title:	Nature Communications
Creators:	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. and Mill, J.
Publisher:	Springer
Date:	24 September 2022
Volume:	13
ISSN:	2041-1723
Identifiers:	Number Type 10.1038/s41467-022-33394-7 DOI 1610948 Other
Rights:	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/.
Divisions:	Schools > School of Science and Technology
Record created by:	Jonathan Gallacher
Date Added:	20 Oct 2022 12:02
Last Modified:	20 Oct 2022 12:02
URI:	https://irep.ntu.ac.uk/id/eprint/47286

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