Association Between Telomere Length and Thyrotoxicosis: Insights from a Two-sample Mendelian Randomization Study

Thyrotoxicosis is an endocrine disorder characterized by excess thyroid hormones, yet its etiologic links to systemic aging biology remain incompletely defined. Telomere length (TL) reflects cellular senescence and genome stability and has been implicated in multiple complex diseases. We conducted a two-sample Mendelian randomization (MR) study to evaluate the causal effect of genetically predicted TL on the risk of thyrotoxicosis. Genetic instruments for TL were derived from a large genome-wide association study (GWAS) of European ancestry (n > 470,000). Thyrotoxicosis summary statistics were obtained from the latest FinnGen release (≈4,000 cases and >210,000 controls). Primary inverse-variance-weighted analyses indicated that longer genetically proxied TL is associated with a lower risk of thyrotoxicosis, and the direction and magnitude of the effect were consistent across complementary estimators (MR-Egger, weighted median/maximum likelihood, MR-PRESSO, and MR-RAPS). Sensitivity analyses showed no evidence of directional pleiotropy, and Cochran's Q was used to assess heterogeneity. A Steiger directionality test supported the causal flow from TL to thyrotoxicosis. To our knowledge, this work is among the first MR analyses to assess the causal relationship between overall thyrotoxicosis risk and TL using contemporary GWAS resources, extending prior evidence focused on hyperthyroidism-related phenotypes. These findings suggest that cellular aging processes indexed by TL may contribute to thyrotoxicosis susceptibility and motivate future longitudinal and mechanistic studies on telomere biology in thyroid dysfunction.