Deciphering the 8q24.21 association for glioma.
Enciso-Mora V., Hosking FJ., Kinnersley B., Wang Y., Shete S., Zelenika D., Broderick P., Idbaih A., Delattre J-Y., Hoang-Xuan K., Marie Y., Di Stefano AL., Labussière M., Dobbins S., Boisselier B., Ciccarino P., Rossetto M., Armstrong G., Liu Y., Gousias K., Schramm J., Lau C., Hepworth SJ., Strauch K., Müller-Nurasyid M., Schreiber S., Franke A., Moebus S., Eisele L., Forsti A., Hemminki K., Tomlinson IP., Swerdlow A., Lathrop M., Simon M., Bondy M., Sanson M., Houlston RS.
We have previously identified tagSNPs at 8q24.21 influencing glioma risk. We have sought to fine-map the location of the functional basis of this association using data from four genome-wide association studies, comprising a total of 4147 glioma cases and 7435 controls. To improve marker density across the 700 kb region, we imputed genotypes using 1000 Genomes Project data and high-coverage sequencing data generated on 253 individuals. Analysis revealed an imputed low-frequency SNP rs55705857 (P = 2.24 × 10(-38)) which was sufficient to fully capture the 8q24.21 association. Analysis by glioma subtype showed the association with rs55705857 confined to non-glioblastoma multiforme (non-GBM) tumours (P = 1.07 × 10(-67)). Validation of the non-GBM association was shown in three additional datasets (625 non-GBM cases, 2412 controls; P = 1.41 × 10(-28)). In the pooled analysis, the odds ratio for low-grade glioma associated with rs55705857 was 4.3 (P = 2.31 × 10(-94)). rs55705857 maps to a highly evolutionarily conserved sequence within the long non-coding RNA CCDC26 raising the possibility of direct functionality. These data provide additional insights into the aetiological basis of glioma development.