Variants in the CDKN2B and RTEL1 regions are associated with high-grade glioma susceptibility

Abstract

The causes of glioblastoma and other gliomas remain obscure. To discover new candidate genes influencing glioma susceptibility, we conducted a principal component-adjusted genome-wide association study (GWAS) of 275,895 autosomal variants among 692 adult high-grade glioma cases (622 from the San Francisco Adult Glioma Study (AGS) and 70 from the Cancer Genome Atlas (TCGA)) and 3,992 controls (602 from AGS and 3,390 from Illumina iControlDB (iControls)). For replication, we analyzed the 13 SNPs with P < 10(-6) using independent data from 176 high-grade glioma cases and 174 controls from the Mayo Clinic. On 9p21, rs1412829 near CDKN2B had discovery P = 3.4 x 10(-8), replication P = 0.0038 and combined P = 1.85 x 10(-10). On 20q13.3, rs6010620 intronic to RTEL1 had discovery P = 1.5 x 10(-7), replication P = 0.00035 and combined P = 3.40 x 10(-9). For both SNPs, the direction of association was the same in discovery and replication phases.

Figure 1

The distribution of p-values from principal component adjusted logistic regression additive model across the genome for high grade glioma cases versus controls. The 13 SNPs with p<10⁻⁶ are shown in red.

Figure 2

Map of the associated 9p region in high grade glioma. A. Genes within region. B. Location of hemizygous deletion regions previously linked to familial melanoma/glioblastoma syndrome (blue) . SNPs within the region that have been previously reported to be associated with heart disease and diabetes risk . C. −log p for SNPs within region; note different scales for UCSF discovery phase (blue bars, left x-axis) and Mayo Clinic replication phase (red bars, right x-axis). P-values are from single point association tests of principal component adjusted additive logistic regression of cases versus controls for 0, 1, or 2 minor alleles. D. Linkage disequilibrium of HapMap SNPs in region.