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Epigenome-wide association study of human frontal cortex identifies differential methylation in Lewy body pathology

Author

Listed:
  • Lasse Pihlstrøm

    (Oslo University Hospital)

  • Gemma Shireby

    (University of Exeter Medical School, College of Medicine and Health, University of Exeter)

  • Hanneke Geut

    (Amsterdam Neuroscience
    Netherlands Brain Bank, Netherlands Institute of Neurosciences)

  • Sandra Pilar Henriksen

    (Oslo University Hospital)

  • Annemieke J. M. Rozemuller

    (Amsterdam Neuroscience)

  • Jon-Anders Tunold

    (Oslo University Hospital
    University of Oslo)

  • Eilis Hannon

    (University of Exeter Medical School, College of Medicine and Health, University of Exeter)

  • Paul Francis

    (University of Exeter Medical School, College of Medicine and Health, University of Exeter)

  • Alan J. Thomas

    (Newcastle University)

  • Seth Love

    (University of Bristol)

  • Jonathan Mill

    (University of Exeter Medical School, College of Medicine and Health, University of Exeter)

  • Wilma D. J. Berg

    (Amsterdam Neuroscience)

  • Mathias Toft

    (Oslo University Hospital
    University of Oslo)

Abstract

Parkinson’s disease (PD) and dementia with Lewy bodies (DLB) are closely related progressive disorders with no available disease-modifying therapy, neuropathologically characterized by intraneuronal aggregates of misfolded α-synuclein. To explore the role of DNA methylation changes in PD and DLB pathogenesis, we performed an epigenome-wide association study (EWAS) of 322 postmortem frontal cortex samples and replicated results in an independent set of 200 donors. We report novel differentially methylated replicating loci associated with Braak Lewy body stage near TMCC2, SFMBT2, AKAP6 and PHYHIP. Differentially methylated probes were independent of known PD genetic risk alleles. Meta-analysis provided suggestive evidence for a differentially methylated locus within the chromosomal region affected by the PD-associated 22q11.2 deletion. Our findings elucidate novel disease pathways in PD and DLB and generate hypotheses for future molecular studies of Lewy body pathology.

Suggested Citation

  • Lasse Pihlstrøm & Gemma Shireby & Hanneke Geut & Sandra Pilar Henriksen & Annemieke J. M. Rozemuller & Jon-Anders Tunold & Eilis Hannon & Paul Francis & Alan J. Thomas & Seth Love & Jonathan Mill & Wi, 2022. "Epigenome-wide association study of human frontal cortex identifies differential methylation in Lewy body pathology," Nature Communications, Nature, vol. 13(1), pages 1-10, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-32619-z
    DOI: 10.1038/s41467-022-32619-z
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    References listed on IDEAS

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    1. 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.
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    3. Costanza L. Vallerga & Futao Zhang & Javed Fowdar & Allan F. McRae & Ting Qi & Marta F. Nabais & Qian Zhang & Irfahan Kassam & Anjali K. Henders & Leanne Wallace & Grant Montgomery & Yu-Hsuan Chuang &, 2020. "Analysis of DNA methylation associates the cystine–glutamate antiporter SLC7A11 with risk of Parkinson’s disease," Nature Communications, Nature, vol. 11(1), pages 1-10, December.
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