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

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.

We acknowledge the brain banks used in the sourcing of tissue, clinical and neuropathological data used in this study. These include the Oxford, UCL Queen’s Square, Imperial College London Parkinson’s disease Brain Bank and Newcastle Brain Banks, and we thank the donors who contributed to this study. This work was funded by research grants from the Medical Research Council (MRC (MR/S011625/1), the National Institute of Aging (NIA) of the National Institutes of Health (NIH) (R01AG067015), the Alzheimer’s Society (AS-PG-16b-012), Alzheimer’s Research UK (ARUK-PG2023A-037) and the Charles Wolfson Charitable Trust to KL, research grants from the Michael J Fox Foundation (MJFF-023152) and ZonMw Memorabel/Alzheimer Nederland Grant (733050516) to E.P. and a research fellowship from the Alzheimer’s Society (AS-PDF-23-017) to J.I.

Tissue for this study was provided by the Newcastle Brain Tissue Resource which is funded in part by a grant from the UK MRC (G0400074), by NIHR Newcastle Biomedical Research Centre and Unit awarded to the Newcastle upon Tyne NHS Foundation Trust and Newcastle University, and as part of the BDR Programme jointly funded by Alzheimer’s Research UK and the Alzheimer’s Society. The Parkinson’s disease Brain Bank, at Imperial College London is funded by Parkinson’s UK, a charity registered in England and Wales (258197) and in Scotland (SC037554). The Oxford Brain Bank, supported by MRC, the NIHR Oxford Biomedical Research Centre and the BDR programme, jointly funded by Alzheimer’s Research UK and the Alzheimer’s Society.

This project utilized high-performance computing funded by the MRC Clinical Research Infrastructure Initiative (MR/M008924/1). This study was supported by the National Institute for Health and Care Research Exeter Biomedical Research Centre. The views expressed are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care.

These authors contributed equally: Joshua Harvey, Jennifer Imm, Ehsan Pishva, Katie Lunnon. Department of Clinical and Biomedical Science, Faculty of Health and Life Sciences, University of Exeter, Exeter, UK Joshua Harvey, Jennifer Imm, Morteza Kouhsar, Adam R. Smith, Byron Creese, Rebecca G.