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

Lewy body (LB) diseases are an umbrella term encompassing a range of neurodegenerative conditions all characterized by the hallmark of intra-neuronal α-synuclein associated with the development of motor and cognitive dysfunction. In this study, we have conducted a large meta-analysis of DNA methylation across multiple cortical brain regions, in relation to increasing burden of LB pathology. Utilizing a combined dataset of 1,217 samples across 844 unique donors, we identified a set of 24 false discovery rate (FDR) significant loci that are differentially methylated in association with LB pathology, the most significant of which were located in UBASH3B and PTAFR , as well as an intergenic locus. Ontological enrichment analysis of our meta-analysis results highlights several neurologically relevant traits, including synaptic alterations. We leverage our data to compare DNA methylation signatures between different neurodegenerative pathologies and highlight a shared epigenetic profile across LB diseases, Alzheimer’s disease and Huntington’s disease, although the top-ranked loci show disease specificity. Utilizing summary statistics from previous large-scale genome-wide association studies we identified significant enrichment of DNA methylation differences with respect to increasing LB pathology in the SNCA genomic region. We identified specific relationships between genetic risk variants for LB-Dementia and Parkinson’s disease to methylation quantitative trait loci in the promoter region and expression of SNCA transcript isoforms.