Exploring Epigenetic Drift and Rare Epivariations in Amyotrophic Lateral Sclerosis by an Epigenome-Wide Association Study

ABSTRACT: During the last decades, our knowledge about the genetic architecture of sporadic ALS has significantly increased. However, besides the recognized genetic risk factors, also the environment is supposed to have a role in disease pathogenesis. Epigenetic modifications reflect the results of the interaction between environmental factors and genes and may play a role in the development and progression of ALS. A recent large epigenome-wide association study (EWAS) in blood identified differentially methylated positions mapping to 42 different genes involved in cholesterol biosynthesis and immune-related pathways. Here we performed a genome-wide DNA methylation analysis in peripheral blood cells on an Italian cohort of 61 sporadic ALS patients and 61 healthy controls. Initially, a conventional genome-wide association analysis was performed, and results were subsequently integrated with the findings from the previous EWAS using a meta-analytical approach. To delve deeper into the significant outcomes, over-representation analysis (ORA) was employed. Moreover, the epigenetic signature obtained from the meta-analysis was examined to determine potential associations with chemical compounds, utilizing the Toxicogenomic Database. Expanding the scope of the epigenetic analysis, we explored both epigenetic drift and rare epivariations. Notably, we observed an elevated epigenetic drift in individuals with ALS compared to the control group, both at a global and single gene level. Interestingly, epigenetic drift at a single gene level revealed an enrichment of genes related to the neurotrophin signaling pathway. Moreover, for the first time rare we identified epivariations exclusively enriched in ALS cases associated with 153 genes, 88 of whom with a strong expression in cerebral areas. Overall, our study reinforces the evidence that epigenetics may contribute to the pathogenesis of ALS and that epigenetic drift may be a useful diagnostic marker. Further research is needed to determine the role of epivariations in the identified candidate genes.

ORGANISM(S): Homo sapiens

PROVIDER: GSE239901 | GEO | 2023/11/23

REPOSITORIES: GEO