Relationship between genetically determined telomere length and glioma risk.
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Background Telomere maintenance is increasingly recognised as being fundamental to glioma oncogenesis with longer leucocyte telomere length (LTL) reported to increase risk of glioma. To gain further insight into the relationship between telomere genetics and risk of glioma we conducted several complementary analyses, using GWAS data on LTL (78,592 individuals) and glioma (12,488 cases and 18,169 controls). Methods We performed both classical and Summary Mendelian Randomization (SMR), coupled with heterogeneity in dependent instruments tests, at genome-wide significant LTL loci to examine if an association was mediated by the same causal variant in glioma. To prioritize genes underscoring glioma-LTL associations we analysed gene expression and DNA methylation data. Results Genetically increased LTL was significantly associated with increased glioma risk, IVW-RE ORSD 4.79 (95% CI: 2.11-10.85, P = 1.76 × 10 -4). SMR confirmed the previously reported LTL associations at 3q26.2 (TERC; PSMR = 1.33 × 10 -5), 5p15.33 (TERT; PSMR = 9.80 × 10 -27), 10q24.33 (STN1 alias OBFC1; PSMR = 4.31 × 10 -5) and 20q13.3 (STMN3/RTEL1; PSMR = 2.47 × 10 -4) glioma risk loci. Our analysis implicates variation at 1q42.12 (PSMR = 1.55 × 10 -2), 6p21.3 (PSMR = 9.76 × 10 -3), 6p22.2 (PSMR = 5.45 × 10 -3), 7q31.33 (PSMR = 6.52 × 10 -3) and 11q22.3 (PSMR = 8.89 × 10 -4) as risk factors for glioma risk. Whilst complicated by patterns of linkage disequilibrium, genetic variation involving PARP1, PRRC2A, CARMIL1, POT1 and ATM-NPAT1 was implicated in the aetiology of glioma. Conclusions These observations extend the role of telomere-related genes in the development of glioma.
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