DNA methylation signatures of Alzheimer’s disease neuropathology in the cortex are primarily driven by variation in non-neuronal cell-types
| Autor: | 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 |
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| Přispěvatelé: | Basic Neuroscience 1, RS: MHeNs - R3 - Neuroscience, Psychiatrie & Neuropsychologie |
| Rok vydání: | 2022 |
| Předmět: |
Multidisciplinary
General Physics and Astronomy Neurodegenerative Diseases Neurofibrillary Tangles Neurofibrillary Tangles/genetics General Chemistry DNA Methylation General Biochemistry Genetics and Molecular Biology Epigenesis Genetic Genetic Alzheimer Disease Humans Neurodegenerative Diseases/genetics Alzheimer Disease/metabolism DNA Methylation/genetics Epigenesis |
| Zdroj: | Nature Communications, 13(1):5620. Nature Publishing Group |
| ISSN: | 2041-1723 |
| DOI: | 10.1038/s41467-022-33394-7 |
| Popis: | 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. Utilizing extensive neuropathology data from the Brains for Dementia Research (BDR) cohort we performed the most systematic epigenome-wide association study (EWAS) of multiple measures of AD neuropathology yet undertaken, profiling DNA methylation in two cortical regions from 631 donors. We meta-analyzed our results with those from previous studies of DNA methylation in AD cortex (total n = 2,013 donors), identifying 334 cortical differentially methylated positions (DMPs) associated with AD pathology including methylomic variation at novel loci not previously implicated in dementia. We subsequently characterized DNA methylation in purified nuclei populations - enriched for neurons, oligodendrocytes and microglia - exploring the extent to which cortex AD-associated DMPs reflect differences manifest in specific cell populations. We find that the majority of DMPs identified in ‘bulk’ cortex tissue actually reflect DNA methylation differences occurring in non-neuronal cells, with dramatically increased effect sizes observed in microglia-enriched nuclei populations. 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 neural cell-types. |
| Databáze: | OpenAIRE |
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