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

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, Wilma D. J. Berg and Mathias Toft
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Lasse Pihlstrøm: Oslo University Hospital
Gemma Shireby: University of Exeter Medical School, College of Medicine and Health, University of Exeter
Hanneke Geut: Amsterdam Neuroscience
Sandra Pilar Henriksen: Oslo University Hospital
Annemieke J. M. Rozemuller: Amsterdam Neuroscience
Jon-Anders Tunold: Oslo University Hospital
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

Nature Communications, 2022, vol. 13, issue 1, 1-10

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-32619-z

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