Relationship between genetically determined telomere length and childhood glioma risk

While longer genetically predicted leukocyte telomere length (LTL) has been linked to increased glioma risk in adults, this association has not been investigated in pediatric populations. In this study, we applied Mendelian randomization (MR) and polygenic risk score (PRS) analyses to investigate the relationship between LTL and pediatric glioma risk, using 4,069 cases and 8,778 controls from the largest available childhood glioma meta-GWAS. Results suggested longer genetically predicted LTL was significantly associated with increased childhood glioma risk, with OR per 1 standard deviation increase in LTL of 2.12 (95% CI 1.32–3.39, P = .002) in the multi-ancestry group and 2.16 (95% CI 1.16–4.03; P = .015) in the European group. Key SNPs contributing to risk of childhood glioma included rs59294613 (POT1), rs8105767 (ZNF208), and rs7705526 (TERT), which differed from the top variants previously identified in adult glioma using the same genetic instruments. Age-stratified MR revealed a stronger association in children diagnosed after the age of 6 (OR = 1.89; P < .001) vs. ≤ 6 years (OR = 1.04; P = .732; Phet = .006). PRS analysis further supported this age-stratified findings by demonstrating a positive association between LTL PRS and age at glioma diagnosis, particularly within age 0–10. This trend suggests a progressively greater influence of LTL on glioma risk in older children compared to younger children. In conclusion, this study provides the first genetic evidence linking longer genetically predicted LTL to increased pediatric glioma risk. While overall consistent with adult findings, distinct single-SNP associations, and age-dependent effects highlight unique biological mechanisms in children with glioma, warranting further direct investigation into telomere dynamics in early-life gliomagenesis.