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

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^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

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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.

Original language	English
Article number	5620
Number of pages	14
Journal	Nature Communications
Volume	13
Issue number	1
DOIs	https://doi.org/10.1038/s41467-022-33394-7
Publication status	Published - 24 Sept 2022

Keywords

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

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Pishva-2022-DNA_methylation_signatures_of_Alzheimer’sFinal published version, 2.44 MBLicence: Taverne

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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., & 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(1), Article 5620. https://doi.org/10.1038/s41467-022-33394-7

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

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.",

keywords = "Alzheimer Disease/metabolism, DNA Methylation/genetics, Epigenesis, Genetic, Humans, Neurodegenerative Diseases/genetics, Neurofibrillary Tangles/genetics",

author = "Gemma Shireby and Dempster, {Emma L} and Stefania Policicchio and Smith, {Rebecca G} and Ehsan Pishva and Barry Chioza and Davies, {Jonathan P} and Joe Burrage and Katie Lunnon and {Seiler Vellame}, Dorothea and Seth Love and Alan Thomas and Keeley Brookes and Kevin Morgan and Paul Francis and Eilis Hannon and Jonathan Mill",

note = "{\textcopyright} 2022. The Author(s).",

year = "2022",

month = sep,

day = "24",

doi = "10.1038/s41467-022-33394-7",

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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, Morgan, K, Francis, P, Hannon, E & 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, vol. 13, no. 1, 5620. https://doi.org/10.1038/s41467-022-33394-7

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T1 - DNA methylation signatures of Alzheimer's disease neuropathology in the cortex are primarily driven by variation in non-neuronal cell-types

AU - Shireby, Gemma

AU - Dempster, Emma L

AU - Policicchio, Stefania

AU - Smith, Rebecca G

AU - Pishva, Ehsan

AU - Chioza, Barry

AU - Davies, Jonathan P

AU - Burrage, Joe

AU - Lunnon, Katie

AU - Seiler Vellame, Dorothea

AU - Love, Seth

AU - Thomas, Alan

AU - Brookes, Keeley

AU - Morgan, Kevin

AU - Francis, Paul

AU - Hannon, Eilis

AU - Mill, Jonathan

PY - 2022/9/24

Y1 - 2022/9/24

N2 - 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.

AB - 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.

KW - Alzheimer Disease/metabolism

KW - DNA Methylation/genetics

KW - Epigenesis, Genetic

KW - Humans

KW - Neurodegenerative Diseases/genetics

KW - Neurofibrillary Tangles/genetics

U2 - 10.1038/s41467-022-33394-7

DO - 10.1038/s41467-022-33394-7

M3 - Article

C2 - 36153390

SN - 2041-1723

VL - 13

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 5620

ER -