Genome-wide association study of glioma subtypes identifies specific differences in genetic susceptibility to glioblastoma and non-glioblastoma tumors

Abstract

Genome-wide association studies (GWAS) have transformed our understanding of glioma susceptibility, but individual studies have had limited power to identify risk loci. We performed a meta-analysis of existing GWAS and two new GWAS, which totaled 12,496 cases and 18,190 controls. We identified five new loci for glioblastoma (GBM) at 1p31.3 (rs12752552; P = 2.04 × 10^-9, odds ratio (OR) = 1.22), 11q14.1 (rs11233250; P = 9.95 × 10^-10, OR = 1.24), 16p13.3 (rs2562152; P = 1.93 × 10^-8, OR = 1.21), 16q12.1 (rs10852606; P = 1.29 × 10^-11, OR = 1.18) and 22q13.1 (rs2235573; P = 1.76 × 10^-10, OR = 1.15), as well as eight loci for non-GBM tumors at 1q32.1 (rs4252707; P = 3.34 × 10^-9, OR = 1.19), 1q44 (rs12076373; P = 2.63 × 10^-10, OR = 1.23), 2q33.3 (rs7572263; P = 2.18 × 10^-10, OR = 1.20), 3p14.1 (rs11706832; P = 7.66 × 10^-9, OR = 1.15), 10q24.33 (rs11598018; P = 3.39 × 10^-8, OR = 1.14), 11q21 (rs7107785; P = 3.87 × 10^-10, OR = 1.16), 14q12 (rs10131032; P = 5.07 × 10^-11, OR = 1.33) and 16p13.3 (rs3751667; P = 2.61 × 10^-9, OR = 1.18). These data substantiate that genetic susceptibility to GBM and non-GBM tumors are highly distinct, which likely reflects different etiology.

Figure 1

Genome-wide discovery-phase meta-analysis P-values (−log₁₀P) plotted against their chromosomal positions. (a) All glioma. (b) GBM. (c) Non-GBM tumors. The red horizontal line corresponds to a significance threshold of P = 5.0 × 10⁻⁸. New and known loci are labeled in red and blue, respectively.

Figure 2

Relative impact of SNP associations at known and newly identified risk loci for GBM and non-GBM tumors. Odds ratios (ORs) derived with respect to the risk allele. Asterisks denote SNPs showing a significant difference between GBM and non-GBM tumors from the case-only analysis as detailed in Supplementary Table 4.