Genome-wide study of DNA methylation shows alterations in metabolic, inflammatory, and cholesterol pathways in ALS.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with an estimated heritability between 40 and 50%. DNA methylation patterns can serve as proxies of (past) exposures and disease progression, as well as providing a potential mechanism that mediates genetic or environmental risk. Here, we present a blood-based epigenome-wide association study meta-analysis in 9706 samples passing stringent quality control (6763 patients, 2943 controls). We identified a total of 45 differentially methylated positions (DMPs) annotated to 42 genes, which are enriched for pathways and traits related to metabolism, cholesterol biosynthesis, and immunity. We then tested 39 DNA methylation–based proxies of putative ALS risk factors and found that high-density lipoprotein cholesterol, body mass index, white blood cell proportions, and alcohol intake were independently associated with ALS. Integration of these results with our latest genome-wide association study showed that cholesterol biosynthesis was potentially causally related to ALS. Last, DNA methylation at several DMPs and blood cell proportion estimates derived from DNA methylation data were associated with survival rate in patients, suggesting that they might represent indicators of underlying disease processes potentially amenable to therapeutic interventions. Understanding ALS epigenetics: Neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS), have been associated to epigenetic modifications, suggesting that identification of specific epigenetic patterns could provide insights into disease pathophysiology and help the identification of potential pharmacological targets. Here, Hop et al. analyzed DNA methylation pattern, one of the most characterized epigenetic modifications, in almost 10,000 individuals with ALS and controls and identified 45 differentially methylated positions (DMPs) annotated to 42 genes. The changes involved genes associated to metabolic and inflammatory pathways, and the authors identified several DMPs associated with disease progression in their cohort. The results will help the identification of disease-relevant mechanisms that could be targeted to block or delay ALS progression. [ABSTRACT FROM AUTHOR]