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

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder whose genetic architecture and molecular mechanisms remain incompletely understood, particularly in sporadic disease. To investigate whether genetically regulated DNA methylation may help interpret ALS susceptibility, we conducted a methylome-wide association study of genetically predicted blood methylation using the PrediXcan framework. CpG-specific models from the ARIES and Understanding Society cohorts were applied to ALS genome-wide association study (GWAS) summary statistics from 27,205 cases and 110,881 controls of European ancestry. Using S-PrediXcan, we evaluated 192,378 unique CpG sites. At nominal p < 0.05, 3741 CpGs were associated with ALS risk using ARIES models and 13,127 using Understanding Society models. After Bonferroni correction, 25 CpGs across eight genomic regions remained significant, including signals near established ALS and ALS–frontotemporal dementia loci (C9orf72, TBK1, SCFD1, and MOB3B). Three CpGs mapped to WHAMM at 15q25.2, a region not previously implicated by ALS GWAS. Predicted methylation was positively associated with risk at 18 CpGs and inversely associated at seven. Complementary whole-blood transcriptome-wide association analysis identified 11 significant genes, including C9orf72. Together, these findings prioritize regulatory candidates for functional investigation without establishing that methylation changes cause ALS.