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

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

90 Citations (Scopus)

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
Pages (from-to)	5620
Journal	Nature Communications
Volume	13
Issue number	1
DOIs	https://doi.org/10.1038/s41467-022-33394-7
Publication status	Published - 24 Sept 2022

Bibliographical note

Funding Information:
G.S. was supported by a PhD studentship from the Alzheimer’s Society. E.H., E.L.D., and J.M. were supported by Medical Research Council (MRC) grants K013807 and W004984 (awarded to J.M.). Data analysis was undertaken using high-performance computing supported by a Medical Research Council (MRC) Clinical Infrastructure award (M008924 awarded to J.M.). The analysis of FANS-purified nuclei was supported by Alzheimer’s Research UK (ARUK) grant ARUK-PPG2018A-010 to E.L.D. DNA methylation data generated in the Brains for Dementia Research (BDR) cohort were supported by the Alzheimer’s Society and Alzheimer’s Research UK (ARUK). The BDR is jointly funded by Alzheimer’s Research UK (ARUK) and the Alzheimer’s Society in association with the Medical Research Council. The South West Dementia Brain Bank is part of the Brains for Dementia Research program, jointly funded by Alzheimer’s Research UK (ARUK) and Alzheimer’s Society, and is also supported by BRACE (Bristol Research into Alzheimer’s and Care of the Elderly) and the Medical Research Council (MRC).

Publisher Copyright:
© 2022, The Author(s).

Research Groups and Themes

Cerebrovascular and Dementia Research Group

Keywords

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

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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), 5620. 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 = "Funding Information: G.S. was supported by a PhD studentship from the Alzheimer{\textquoteright}s Society. E.H., E.L.D., and J.M. were supported by Medical Research Council (MRC) grants K013807 and W004984 (awarded to J.M.). Data analysis was undertaken using high-performance computing supported by a Medical Research Council (MRC) Clinical Infrastructure award (M008924 awarded to J.M.). The analysis of FANS-purified nuclei was supported by Alzheimer{\textquoteright}s Research UK (ARUK) grant ARUK-PPG2018A-010 to E.L.D. DNA methylation data generated in the Brains for Dementia Research (BDR) cohort were supported by the Alzheimer{\textquoteright}s Society and Alzheimer{\textquoteright}s Research UK (ARUK). The BDR is jointly funded by Alzheimer{\textquoteright}s Research UK (ARUK) and the Alzheimer{\textquoteright}s Society in association with the Medical Research Council. The South West Dementia Brain Bank is part of the Brains for Dementia Research program, jointly funded by Alzheimer{\textquoteright}s Research UK (ARUK) and Alzheimer{\textquoteright}s Society, and is also supported by BRACE (Bristol Research into Alzheimer{\textquoteright}s and Care of the Elderly) and the Medical Research Council (MRC). Publisher Copyright: {\textcopyright} 2022, The Author(s).",

year = "2022",

month = sep,

day = "24",

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

language = "English",

volume = "13",

pages = "5620",

journal = "Nature Communications",

issn = "2041-1723",

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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, pp. 5620. https://doi.org/10.1038/s41467-022-33394-7

TY - JOUR

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

N1 - Funding Information: G.S. was supported by a PhD studentship from the Alzheimer’s Society. E.H., E.L.D., and J.M. were supported by Medical Research Council (MRC) grants K013807 and W004984 (awarded to J.M.). Data analysis was undertaken using high-performance computing supported by a Medical Research Council (MRC) Clinical Infrastructure award (M008924 awarded to J.M.). The analysis of FANS-purified nuclei was supported by Alzheimer’s Research UK (ARUK) grant ARUK-PPG2018A-010 to E.L.D. DNA methylation data generated in the Brains for Dementia Research (BDR) cohort were supported by the Alzheimer’s Society and Alzheimer’s Research UK (ARUK). The BDR is jointly funded by Alzheimer’s Research UK (ARUK) and the Alzheimer’s Society in association with the Medical Research Council. The South West Dementia Brain Bank is part of the Brains for Dementia Research program, jointly funded by Alzheimer’s Research UK (ARUK) and Alzheimer’s Society, and is also supported by BRACE (Bristol Research into Alzheimer’s and Care of the Elderly) and the Medical Research Council (MRC). Publisher Copyright: © 2022, The Author(s).

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 (Academic Journal)

C2 - 36153390

SN - 2041-1723

VL - 13

SP - 5620

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 5620

ER -

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

Abstract

Bibliographical note

Research Groups and Themes

Keywords

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