Lack of a Causal Association between DNA Methylation GrimAge Acceleration and Brain Tumor Incidence: A Two-Sample Mendelian Randomization Study

OBJECTIVE: To investigate the potential causal relationship between DNA methylation GrimAge acceleration (GAA) and brain tumor incidence using a two-sample Mendelian randomization (MR) approach. METHODS: We leveraged publicly available genome-wide association study (GWAS) summary data for GAA (34,467 participants) and brain tumor incidence (491,542 participants). Twenty-six single nucleotide polymorphisms (SNPs) served as instrumental variables for GAA. Inverse variance weighted (IVW) was the primary method, complemented by MR-Egger, weighted median, simple mode, and weighted mode. Sensitivity analyses tested heterogeneity and pleiotropy. RESULTS: The IVW analysis indicated no significant causal effect of GAA on brain tumor risk (β = -0.006, p = 0.908). Other MR methods concurred. Sensitivity checks, including heterogeneity and MR-Egger intercept tests, supported these null findings. CONCLUSION: Our results do not support a causal association between GrimAge acceleration and brain tumor incidence. Accelerated epigenetic aging, as measured by GAA, may not be a direct driver of brain tumor risk. Further investigations should explore other epigenetic or genetic factors implicated in brain tumor etiology.