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 1239 samples across 855 unique donors, we identified a set of 30 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, inflammatory and vascular alterations. We leverage our summary statistics 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. Finally, utilizing summary statistics from previous large-scale genome-wide association studies we report FDR significant enrichment of DNA methylation differences with respect to increasing LB pathology in the SNCA genomic region, a gene previously associated with Parkinson’s disease and dementia with Lewy bodies.