Genetically Predicted Blood DNA Methylation Reveals Putative Regulatory Signals Associated with ALS Risk

The study investigated genetically regulated DNA methylation as a factor influencing the risk of amyotrophic lateral sclerosis (ALS), a severe neurodegenerative disease. Researchers analyzed data from 27,205 ALS patients and 110,881 controls of European ancestry using the PrediXcan method. They evaluated 192,378 unique CpG sites and identified 25 CpG sites across eight genomic regions significantly associated with ALS risk. The identified signals included regions near known ALS genes such as C9orf72, TBK1, SCFD1, and MOB3B, as well as three CpG sites in the WHAMM gene, which had not been previously associated with ALS. Methylation was positively associated with ALS risk at 18 CpG sites and inversely associated at seven. Gene analysis identified 11 genes associated with ALS risk, including convergent signals at C9orf72. The findings provide new insights into the genetic mechanisms of ALS and identify regulatory processes for further investigation.