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

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; Paul Francis; Eilis Hannon; Jonathan Mill

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

Nat Commun. 2022 Sep 24;13(1):5620. doi: 10.1038/s41467-022-33394-7.

Authors

Gemma Shireby¹, Emma L Dempster¹, Stefania Policicchio¹, Rebecca G Smith¹, Ehsan Pishva², Barry Chioza¹, Jonathan P Davies¹, Joe Burrage¹, Katie Lunnon¹, Dorothea Seiler Vellame¹, Seth Love³, Alan Thomas⁴, Keeley Brookes⁵, Kevin Morgan⁶, Paul Francis^{1

7}, Eilis Hannon¹, Jonathan Mill⁸

Affiliations

¹ Department of Clinical and Biomedical Sciences, Faculty of Health and Life Sciences, University of Exeter Medical School, University of Exeter, Exeter, UK.
² Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience (MHeNS), Maastricht University, Maastricht, The Netherlands.
³ Dementia Research Group, University of Bristol Medical School (Translational Health Sciences), Bristol, UK.
⁴ Translational and Clinical Research Institute, Newcastle University, Newcastle Upon Tyne, UK.
⁵ Biosciences, School of Science & Technology, Nottingham Trent University, Nottingham, UK.
⁶ Human Genetics, School of Life Sciences, University of Nottingham, Nottingham, UK.
⁷ Wolfson Centre for Age-Related Diseases, King's College London, London, UK.
⁸ Department of Clinical and Biomedical Sciences, Faculty of Health and Life Sciences, University of Exeter Medical School, University of Exeter, Exeter, UK. [email protected].

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Alzheimer Disease* / metabolism
DNA Methylation / genetics
Epigenesis, Genetic
Humans
Neurodegenerative Diseases* / genetics
Neurofibrillary Tangles / genetics
Neurofibrillary Tangles / metabolism

Abstract

Publication types

MeSH terms

Grants and funding