Transcriptome-wide association study identifies new candidate susceptibility genes for glioma

Research output: Contribution to journalJournal articleResearchpeer-review

  • Isabelle Atkins
  • Ben Kinnersley
  • Quinn T. Ostrom
  • Karim Labreche
  • Dora Il'yasova
  • Georgina N. Armstrong
  • Jeanette E. Eckel-Passow
  • Minouk J. Schoemaker
  • Markus M. Nothen
  • Jill S. Barnholtz-Sloan
  • Anthony J. Swerdlow
  • Matthias Simon
  • Preetha Rajaraman
  • Stephen J. Chanock
  • Joellen Shildkraut
  • Jonine L. Bernstein
  • Per Hoffmann
  • Karl Heinz Jockel
  • Rose K. Lai
  • Elizabeth B. Claus
  • Sara H. Olson
  • Margaret R. Wrensch
  • Beatrice Melin
  • Robert B. Jenkins
  • Marc Sanson
  • Melissa L. Bondy
  • Richard S. Houlston

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 ¼ 4.43; P ¼ 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.

Original languageEnglish
JournalCancer Research
Volume79
Issue number8
Pages (from-to)2065-2071
ISSN0008-5472
DOIs
Publication statusPublished - 2019

ID: 230250406