{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"medRxiv"}],"indexed":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T13:24:19Z","timestamp":1792157059537,"version":"4.4.0"},"posted":{"date-parts":[[2025,3,14]]},"group-title":"Neurology","reference-count":61,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,3,14]],"date-time":"2025-03-14T00:00:00Z","timestamp":1741910400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,11,12]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                <jats:p>\n                  Lewy body (LB) diseases are an umbrella term encompassing a range of neurodegenerative conditions all characterized by the hallmark of intra-neuronal \u03b1-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\n                  <jats:italic>UBASH3B<\/jats:italic>\n                  and\n                  <jats:italic>PTAFR<\/jats:italic>\n                  , 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\u2019s disease and Huntington\u2019s 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\n                  <jats:italic>SNCA<\/jats:italic>\n                  genomic region. We identified specific relationships between genetic risk variants for LB-Dementia and Parkinson\u2019s disease to methylation quantitative trait loci in the promoter region and expression of SNCA transcript isoforms.\n                <\/jats:p>","DOI":"10.1101\/2025.03.13.25323837","type":"posted-content","created":{"date-parts":[[2025,3,14]],"date-time":"2025-03-14T18:40:17Z","timestamp":1741977617000},"source":"Crossref","is-referenced-by-count":9,"title":["Interrogating DNA methylation associated with Lewy body pathology in a cross brain-region and multi-cohort 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