AbstractBackgroundHepatocellular carcinoma (HCC) is a common cancer threatening the public health globally. Although HCC has been associated with the telomere length (TL), the causal relationship between them is not well understood. Therefore, we attempted to explore the linear causal relationship between TL and HCC through Mendelian randomization (MR) analysis among Asian and European populations.MethodsThe summary statistics of TL‐associated single nucleotide polymorphisms (SNPs) were obtained from a genome‐wide association study (GWAS) in the Asian population (N= 23,096). The data of TL‐associated SNPs in the European population (N= 472,174) and the GWAS summary statistics of HCC in the Asian population (1866 cases, 195,745 controls) as well as the European population (168 cases, 372,016 controls) were downloaded from the public GWAS database. Two‐sample MR was performed using inverse variance weighting (IVW), weighted median estimate, MR–Egger regression, weighted‐mode estimate, and simple‐mode estimate methods. Sensitivity analysis was performed to text the primary results' robustness.ResultsNine SNPs associated with TL in Asian populations and 98 SNPs in European populations were selected as instrumental variables. No linear causal relationship between heritable TL and the HCC risk was recorded in the Asian (IVW analysis odds ratio [OR] = 1.023, 95% confidence interval [CI] 0.745, 1.405,p= 0.887) and European populations (IVW analysis OR = 0.487, 95% CI 0.180, 1.320,p= 0.157). Other methods also achieved similar outcomes. Sensitivity analysis was performed and revealed no heterogeneity and horizontal pleiotropy.ConclusionsNo linear causal association was recorded between heritable TL and HCC in Asian and European populations.