Oxidative stress (OS) is critically implicated in the onset and progression of neurodegenerative diseases (NDDs), yet its genetic determinants remain insufficiently elucidated. This study aims to delineate the putative causal relationships between OS-related genes (OSRGs) and NDDs, along with the potential regulatory and pathogenic mechanisms. Summary-data-based Mendelian randomization (SMR) was conducted to explore the putative causal associations of 936 OSRGs with NDDs, integrating genome-wide association studies (GWAS) data and expression quantitative trait loci (eQTL) data, using a multi-cohort design with blood eQTLs for discovery and replication, followed by brain eQTL validation. Subsequently, colocalization analysis was used to verify putative causal inferences in SMR. In addition, DNA methylation regulation and pathway enrichment analyses were applied to explore potential regulatory and pathogenic mechanisms. Genetically predicted levels of 15 genes were found to be significantly associated with the risk of NDDs. Higher genetically predicted expression of ACE and TP53INP1 was associated with decreased Alzheimer's disease risk, whereas higher TSFM expression was associated with increased multiple sclerosis risk; these associations were consistently supported by replication cohort and brain eQTL validation for ACE and TSFM, while TP53INP1 showed brain-level consistency without replication. Among 15 genes, the expression levels of ACE, TP53INP1, and other 5 genes were regulated by DNA methylation. Pathway enrichment analysis showed specific enrichment in autophagy-apoptosis and mitochondrial pathways. These findings provide genetic evidence supporting a putative causal role of OSRGs on NDDs, offering mechanistic insights and potential therapeutic targets, and substantially advance the pathobiological understanding of NDDs.
