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DNA Methylation Differences in Amyotrophic Lateral Sclerosis Point to Risk Pathways

NEW YORK – An international team led by investigators in the Netherlands and the UK has identified distinct methylation features in blood samples from individuals with amyotrophic lateral sclerosis that provide clues to the condition's underlying biology, prognostic patterns, and potential treatment avenues.

"[T]he identified ALS- and survival-associated DNA methylation patterns could be of interest as potential starting points for new disease-modifying treatments," co-senior and corresponding author Jan Veldink, a neurology researcher at the University Medical Center Utrecht's Utrecht Brain Center, and his colleagues wrote in a study published in Science Translational Medicine on Wednesday.

Using methylation arrays, the researchers performed an epigenome-wide association study searching for ALS-associated methylation patterns in blood samples from 6,763 individuals with ALS and 2,943 unaffected control individuals. In the process, they flagged dozens of differentially methylated positions, or DMPs, in or around 42 genes in patients with the fatal neurodegenerative condition.

"After thorough quality control and extensive sensitivity analyses, we identified a total of 45 DMPs at which variable DNA methylation is robustly associated with ALS," the authors reported.

With follow-up gene set enrichment analyses, the team highlighted apparent ties between ALS and metabolic, inflammatory, and cholesterol biosynthesis pathways. Likewise, traits, conditions, or lifestyle factors such as high-density lipoprotein levels, body mass index, white blood cell counts, and alcohol use each appeared to be independently linked to ALS in an analysis focused on 39 published polymethylation score-based proxies for these risk factors.

The researchers cautioned that more research is needed to find methylation marks and pathways that are causally linked to ALS. Even so, they noted that a Mendelian randomization that incorporated additional genome-wide association study insights indicated that blood levels of cholesterol may be causal for ALS in a manner that was not found for other metabolic traits or conditions.

Similarly, a survival analyses that focused on 5,138 patients pointed to five DMPs linked to ALS survival times. Methylation scores corresponding to higher or lower levels of different white blood cell types in the blood also showed apparent ties to survival, the team reported. On the other hand, ALS survival was not significantly associated with the presence of epigenetic signatures previously implicated in accelerated aging.

"DNA methylation at several DMPs and blood cell proportion estimates derived from DNA methylation data were associated with survival rate in patients," the authors wrote, "suggesting that they might represent indicators of underlying disease processes potentially amenable to therapeutic interventions."