Hypothyroidism and glioblastoma risk: a two-sample Mendelian randomization study.

BACKGROUND: Prior observational evidence suggests a potential link between hypothyroidism and glioblastoma (GBM) risk. To investigate causality, we conducted a two-sample Mendelian randomization (MR) study. METHODS: Between April 2025 and July 2025, we leveraged summary - level data from European - ancestry genome-wide association studies (GWAS). The inverse - variance weighted (IVW) approach served as the primary method for causal inference. Robustness was evaluated using four complementary Mendelian randomization (MR) techniques: MR-Egger techniques: MR-Egger, weighted median (WM), weighted mode, and simple mode. Multiple sensitivity analyses were performed to assess stability, heterogeneity, and potential horizontal pleiotropy. RESULTS: Twenty-nine hypothyroidism-associated single nucleotide polymorphisms (SNPs) were used as instruments. IVW analysis indicated a significant protective effect of hypothyroidism on glioblastoma (GBM) risk (odds ratio, OR = 0.759; 95% confidence interval, CI: 0.606-0.949; p = 0.016). Consistent estimates were obtained via MR-Egger (OR = 0.565, p = 0.032), weighted median (OR = 0.674, p = 0.017), and weighted mode (OR = 0.581, p = 0.02). Simple mode was non-significant but directionally consistent. Sensitivity analyses showed no heterogeneity or horizontal pleiotropy. CONCLUSION: Employing Mendelian randomization, this investigation provides preliminary genetic evidence suggesting a potential protective association between hypothyroidism and glioblastoma risk. However, the limited case sample (N = 406) and the hypothesis-generating nature of Mendelian randomization (MR) warrant cautious interpretation and replication in larger cohorts.