Epigenetic profiles of tissue informative CpGs inform ALS disease status and progression

作者：Christa Caggiano, Marco Morselli, Xiaoyu Qian, Barbara Celona, M. J. Thompson, Shivangi Wani, Anela Tosevska, Kodi Taraszka, Galen Heuer, Shyuan T. Ngo, Frederik J. Steyn, Peter J. Nestor, Leanne Wallace, Pamela McCombe, Susan Heggie, Kathryn Thorpe, Caitlin A. T. McElligott, Gemyka English, Anjali K. Henders, Robert D. Henderson, Catherine Lomen-Hoerth, Naomi R. Wray, Allan F. McRae, Matteo Pellegrini, Fleur C. Garton, Noah Zaitlen · 发表于：Genome Medicine · 年份：2025 · DOI：10.1186/s13073-025-01542-5 · 被引用次数：1 · 研究领域：Epigenetics and DNA Methylation、Amyotrophic Lateral Sclerosis Research、Cancer Genomics and Diagnostics

Abstract Background Cell-free DNA (cfDNA), derived from dying cells, has demonstrated utility across multiple clinical applications. However, its potential in neurodegenerative diseases remains underexplored, with most existing cfDNA technologies tailored to specific disease contexts like cancer or non-invasive prenatal screening. Methods To address this gap, we developed a novel approach to characterize epigenetic cfDNA profiles by identifying key regions of DNA methylation that reveal the tissues origins undergoing apoptosis or necrosis. We evaluated this method in the largest cfDNA study of amyotrophic lateral sclerosis (ALS) and other neurological diseases (OND) to date, encompassing two independent cohorts ( n = 192) from Australia (UQ N cases = 48, N controls = 32, N OND = 15) and the USA, (UCSF N cases = 50, N controls = 45)). Results Our approach accurately distinguished ALS patients from controls (UQ AUC = 0.82, UCSF AUC = 0.99) and from individuals with other neurological diseases (AUC = 0.91). It also identified an asymptomatic carrier of a pathogenic C9orf72 variant, and strongly correlated with ALS disease progression measures (Pearson’s R = 0.66, p = 3.71 × 10⁻⁹). Conclusions We identified DNA methylation signals from multiple tissue types in ALS cfDNA, highlighting diverse tissue involvement in ALS pathology. These findings promote epigenetic cfDNA analysis as a powerful tool for advancing our understanding of neurodegenerative disease.