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

Author

Listed:
  • Gemma Shireby

    (University of Exeter Medical School, University of Exeter)

  • Emma L. Dempster

    (University of Exeter Medical School, University of Exeter)

  • Stefania Policicchio

    (University of Exeter Medical School, University of Exeter)

  • Rebecca G. Smith

    (University of Exeter Medical School, University of Exeter)

  • Ehsan Pishva

    (Maastricht University)

  • Barry Chioza

    (University of Exeter Medical School, University of Exeter)

  • Jonathan P. Davies

    (University of Exeter Medical School, University of Exeter)

  • Joe Burrage

    (University of Exeter Medical School, University of Exeter)

  • Katie Lunnon

    (University of Exeter Medical School, University of Exeter)

  • Dorothea Seiler Vellame

    (University of Exeter Medical School, University of Exeter)

  • Seth Love

    (University of Bristol Medical School (Translational Health Sciences))

  • Alan Thomas

    (Newcastle University)

  • Keeley Brookes

    (Nottingham Trent University)

  • Kevin Morgan

    (University of Nottingham)

  • Paul Francis

    (University of Exeter Medical School, University of Exeter
    King’s College London)

  • Eilis Hannon

    (University of Exeter Medical School, University of Exeter)

  • Jonathan Mill

    (University of Exeter Medical School, University of Exeter)

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.

Suggested Citation

  • 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 , 2022. "DNA methylation signatures of Alzheimer’s disease neuropathology in the cortex are primarily driven by variation in non-neuronal cell-types," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-33394-7
    DOI: 10.1038/s41467-022-33394-7
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    References listed on IDEAS

    as
    1. Yang I. Li & Garrett Wong & Jack Humphrey & Towfique Raj, 2019. "Prioritizing Parkinson’s disease genes using population-scale transcriptomic data," Nature Communications, Nature, vol. 10(1), pages 1-10, December.
    2. Bates, Douglas & Mächler, Martin & Bolker, Ben & Walker, Steve, 2015. "Fitting Linear Mixed-Effects Models Using lme4," Journal of Statistical Software, Foundation for Open Access Statistics, vol. 67(i01).
    3. Rebecca G. Smith & Ehsan Pishva & Gemma Shireby & Adam R. Smith & Janou A. Y. Roubroeks & Eilis Hannon & Gregory Wheildon & Diego Mastroeni & Gilles Gasparoni & Matthias Riemenschneider & Armin Giese , 2021. "A meta-analysis of epigenome-wide association studies in Alzheimer’s disease highlights novel differentially methylated loci across cortex," Nature Communications, Nature, vol. 12(1), pages 1-13, December.
    4. Itziar Rojas & Sonia Moreno-Grau & Niccolo Tesi & Benjamin Grenier-Boley & Victor Andrade & Iris E. Jansen & Nancy L. Pedersen & Najada Stringa & Anna Zettergren & Isabel Hernández & Laura Montrreal &, 2021. "Common variants in Alzheimer’s disease and risk stratification by polygenic risk scores," Nature Communications, Nature, vol. 12(1), pages 1-16, December.
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