Genetically predicted leukocyte telomere length and risk of benign bone and articular cartilage tumors: a bidirectional Mendelian randomization study

Background Telomere length (TL) has been implicated in tumor biology, but its causal relationship with benign bone and articular cartilage tumors remains unclear. We investigated this association using bidirectional Mendelian randomization (MR). Methods A bidirectional two-sample MR study was conducted using summary-level GWAS data. Leukocyte TL GWAS data from 472,174 individuals of European ancestry were used as the primary exposure, with an independent TL GWAS used for replication. FinnGen provided data on overall benign bone and articular cartilage tumors and four anatomical subgroups. The inverse-variance weighted (IVW) method was the primary analysis, complemented by MR-Egger, weighted median, and other sensitivity analyses. Sensitivity analyses included Cochran's Q test, MR-Egger intercept, MR-PRESSO, and leave-one-out analysis. Results Genetically predicted longer leukocyte TL was associated with an increased risk of benign bone and articular cartilage tumors in the primary analysis (OR = 1.739, 95% CI = 1.251–2.418; p = 0.001). Exploratory site-specific analyses identified associations with tumors of the skull and facial bones (OR = 3.171, 95% CI = 1.145–8.781; p = 0.026) and scapula and long bones of the upper limb (OR = 2.963, 95% CI = 1.033–8.500; p = 0.043). Replication analyses supported the association for the overall phenotype (OR = 1.888, 95% CI = 1.385–2.574; p = 5.87 × 10⁻⁵) and skull and facial bone tumors (OR = 9.554, 95% CI = 3.657–24.964; p = 4.11 × 10⁻⁶). Reverse MR analyses showed no evidence of tumor liability affecting leukocyte TL, although statistical power was limited by the small number of instruments. Conclusion Genetically predicted longer leukocyte TL was associated with a higher risk of benign bone and articular cartilage tumors. These findings provide etiological and hypothesis-generating genetic evidence but do not establish diagnostic, prognostic, or treatment-guiding utility. Further pathology-confirmed, histology-specific and mechanistic studies are warranted.