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Peer-reviewedCC BYNature communications

Interrogating DNA methylation associated with Lewy body pathology in a cross brain-region and multi-cohort study.

  • Joshua Harvey1
  • Jennifer Imm1
  • Morteza Kouhsar1
  • Adam R Smith1
  • Byron Creese1,2
  • Rebecca G Smith1
  • Gregory Wheildon1
  • Valentin Laroche3
  • Szi Kay Leung1
  • Leonidas Chouliaras4,5
  • Gemma Shireby6
  • Zane Jaunmuktane7
16 more authors
  • Eduardo De Pablo-Fernández7
  • Thomas Warner7
  • Debra J Lett8
  • Djordje Gveric9
  • Hannah Brooks10
  • Johannes Attems8
  • Alan Thomas8
  • Wilma Dj Van de Berg11,12
  • Emma Dempster1
  • Clive Ballard1
  • John T O'Brien4
  • Dag Aarsland13
  • Jonathan Mill1
  • Lasse Pihlstrøm14,15
  • Ehsan Pishva1,3
  • Katie Lunnon16
16 affiliations
  1. 1Department of Clinical and Biomedical Science, Faculty of Health and Life Sciences, University of Exeter, Exeter, UK.
  2. 2Department of Life Sciences, College of Health, Medicine and Life Sciences, Brunel University of London, London, UK.
  3. 3Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience (MHeNS), Maastricht University, Maastricht, The Netherlands.
  4. 4Department of Psychiatry, University of Cambridge School of Clinical Medicine, Cambridge, UK.
  5. 5Specialty Dementia and Frailty Service, Essex Partnership University NHS Foundation Trust, St Margaret's Hospital, Epping, UK.
  6. 6Great Ormond Street Hospital, University College London, London, UK.
  7. 7Queen Square Brain Bank for Neurological Disorders, University College London Queen Square Institute of Neurology, University College London, London, UK.
  8. 8Newcastle Brain Tissue Resource, Newcastle University, Newcastle, UK.
  9. 9MS and Parkinson's Tissue Bank, Department of Brain Sciences, Imperial College London, London, UK.
  10. 10The Oxford Brain Bank, University of Oxford, Oxford, UK.
  11. 11Department of Anatomy and Neurosciences, Section Clinical Neuroanatomy and Biobanking, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands.
  12. 12Amsterdam Neuroscience, Program Neurodegeneration, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands.
  13. 13Institute of Psychiatry, Psychology & Neuroscience (IoPPN), Kings College London, London, UK.
  14. 14Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
  15. 15Department of Neurology, Oslo University Hospital, Oslo, Norway.
  16. 16Department of Clinical and Biomedical Science, Faculty of Health and Life Sciences, University of Exeter, Exeter, UK. [email protected].
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Abstract

Here, we conduct a large meta-analysis of DNA methylation across multiple cortical brain regions, in relation to increasing burden of Lewy body pathology. Utilizing a dataset of 1205 samples (832 unique donors), we identify 24 false discovery rate significant differentially methylated loci associated with Lewy body pathology, with loci located in UBASH3B and PTAFR, and an intergenic locus passing the genome-wide significance threshold. Ontological enrichment analysis highlights several neurologically relevant traits, including synaptic alterations. We compare methylation signatures between neurodegenerative pathologies and highlight a shared epigenetic profile across Lewy body, Alzheimer's and Huntington's diseases, although the top-ranked loci show disease specificity. Utilizing summary statistics from large-scale genome-wide association studies, we identify significant enrichment of DNA methylation differences with respect to increasing Lewy body pathology in the SNCA genomic region. We also identify specific relationships between genetic risk variants for Lewy body dementia and Parkinson's disease to methylation quantitative trait loci in the SNCA 5' region and expression of alternative transcript isoforms.

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Cite

BibTeXRIS
BibTeX
@article{harvey2026interrogating,
  title = {{Interrogating DNA methylation associated with Lewy body pathology in a cross brain-region and multi-cohort study.}},
  author = {Joshua Harvey and Jennifer Imm and Morteza Kouhsar and Adam R Smith and Byron Creese and Rebecca G Smith and Gregory Wheildon and Valentin Laroche and Szi Kay Leung and Leonidas Chouliaras and Gemma Shireby and Zane Jaunmuktane and Eduardo De Pablo-Fernández and Thomas Warner and Debra J Lett and Djordje Gveric and Hannah Brooks and Johannes Attems and Alan Thomas and Wilma Dj Van de Berg and Emma Dempster and Clive Ballard and John T O'Brien and Dag Aarsland and Jonathan Mill and Lasse Pihlstrøm and Ehsan Pishva and Katie Lunnon},
  journal = {Nature communications},
  year = {2026},
  month = sep,
  doi = {10.1038/s41467-026-77009-x},
  url = {https://europepmc.org/article/MED/42881165},
  note = {CC BY},
}
RIS
TY  - JOUR
TI  - Interrogating DNA methylation associated with Lewy body pathology in a cross brain-region and multi-cohort study.
AU  - Joshua Harvey
AU  - Jennifer Imm
AU  - Morteza Kouhsar
AU  - Adam R Smith
AU  - Byron Creese
AU  - Rebecca G Smith
AU  - Gregory Wheildon
AU  - Valentin Laroche
AU  - Szi Kay Leung
AU  - Leonidas Chouliaras
AU  - Gemma Shireby
AU  - Zane Jaunmuktane
AU  - Eduardo De Pablo-Fernández
AU  - Thomas Warner
AU  - Debra J Lett
AU  - Djordje Gveric
AU  - Hannah Brooks
AU  - Johannes Attems
AU  - Alan Thomas
AU  - Wilma Dj Van de Berg
AU  - Emma Dempster
AU  - Clive Ballard
AU  - John T O'Brien
AU  - Dag Aarsland
AU  - Jonathan Mill
AU  - Lasse Pihlstrøm
AU  - Ehsan Pishva
AU  - Katie Lunnon
PY  - 2026
DA  - 2026/09/15
JO  - Nature communications
DO  - 10.1038/s41467-026-77009-x
UR  - https://europepmc.org/article/MED/42881165
AB  - Here, we conduct a large meta-analysis of DNA methylation across multiple cortical brain regions, in relation to increasing burden of Lewy body pathology. Utilizing a dataset of 1205 samples (832 unique donors), we identify 24 false discovery rate significant differentially methylated loci associated with Lewy body pathology, with loci located in UBASH3B and PTAFR, and an intergenic locus passing the genome-wide significance threshold. Ontological enrichment analysis highlights several neurologically relevant traits, including synaptic alterations. We compare methylation signatures between neurodegenerative pathologies and highlight a shared epigenetic profile across Lewy body, Alzheimer's and Huntington's diseases, although the top-ranked loci show disease specificity. Utilizing summary statistics from large-scale genome-wide association studies, we identify significant enrichment of DNA methylation differences with respect to increasing Lewy body pathology in the SNCA genomic region. We also identify specific relationships between genetic risk variants for Lewy body dementia and Parkinson's disease to methylation quantitative trait loci in the SNCA 5' region and expression of alternative transcript isoforms.
SN  - 2041-1723
ER  -