A low-frequency variant at 8q24.21 is strongly associated with risk of oligodendroglial tumors and astrocytomas with IDH1 or IDH2 mutation

Variants at 8q24.21 have been shown to be associated with glioma development. By means of tag SNP genotyping and imputation, pooled next-generation sequencing using long-range PCR and subsequent validation SNP genotyping, we identified seven low-frequency SNPs at 8q24.21 that were strongly associated with glioma risk (P = 1 x 10(-25) to 1 x 10(-14)). The most strongly associated SNP, rs55705857, remained highly significant after individual adjustment for the other top six SNPs and two previously published SNPs. After stratifying by histological and tumor genetic subtype, the most significant associations of rs55705857 were with oligodendroglial tumors and gliomas with mutant IDH1 or IDH2 (odds ratio (OR) = 5.1, P = 1.1 x 10(-31) and OR = 4.8, P = 6.6 x 10(-22), respectively). Strong associations were observed for astrocytomas with mutated IDH1 or IDH2 (grades 2-4) (OR = 5.16-6.66, P = 4.7 x 10(-12) to 2.2 x 10(-8)) but not for astrocytomas with wild-type IDH1 and IDH2 (smallest P = 0.26). The conserved sequence block that includes rs55705857 is consistently modeled as a microRNA.