Transcriptome-Wide Association Study Identifies New Candidate Susceptibility Genes for Glioma

Cancer Res. 2019 Apr 15;79(8):2065-2071. doi: 10.1158/0008-5472.CAN-18-2888. Epub 2019 Feb 1.

Abstract

Genome-wide association studies (GWAS) have so far identified 25 loci associated with glioma risk, with most showing specificity for either glioblastoma (GBM) or non-GBM tumors. The majority of these GWAS susceptibility variants reside in noncoding regions and the causal genes underlying the associations are largely unknown. Here we performed a transcriptome-wide association study to search for novel risk loci and candidate causal genes at known GWAS loci using Genotype-Tissue Expression Project (GTEx) data to predict cis-predicted gene expression in relation to GBM and non-GBM risk in conjunction with GWAS summary statistics on 12,488 glioma cases (6,183 GBM and 5,820 non-GBM) and 18,169 controls. Imposing a Bonferroni-corrected significance level of P < 5.69 × 10-6, we identified 31 genes, including GALNT6 at 12q13.33, as a candidate novel risk locus for GBM (mean Z = 4.43; P = 5.68 × 10-6). GALNT6 resides at least 55 Mb away from any previously identified glioma risk variant, while all other 30 significantly associated genes were located within 1 Mb of known GWAS-identified loci and were not significant after conditioning on the known GWAS-identified variants. These data identify a novel locus (GALNT6 at 12q13.33) and 30 genes at 12 known glioma risk loci associated with glioma risk, providing further insights into glioma tumorigenesis. SIGNIFICANCE: This study identifies new genes associated with glioma risk, increasing understanding of how these tumors develop.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Biomarkers, Tumor / genetics*
  • Case-Control Studies
  • Gene Expression Regulation, Neoplastic
  • Genetic Predisposition to Disease*
  • Genome-Wide Association Study
  • Genotype
  • Glioma / genetics*
  • Glioma / pathology*
  • Humans
  • Polymorphism, Single Nucleotide*
  • Prognosis
  • Quantitative Trait Loci
  • Transcriptome*

Substances

  • Biomarkers, Tumor