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

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. ClausSara H. Olson, Christoffer Johansen, Margaret R. Wrensch, Beatrice Melin, Robert B. Jenkins, Marc Sanson, Melissa L. Bondy, Richard S. Houlston

Research output: Contribution to journalArticle

3 Scopus citations

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 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 (US)
Pages (from-to)2065-2071
Number of pages7
JournalCancer research
Volume79
Issue number8
DOIs
StatePublished - Apr 15 2019

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Atkins, I., Kinnersley, B., Ostrom, Q. T., Labreche, K., Il'yasova, D., Armstrong, G. N., Eckel-Passow, J. E., Schoemaker, M. J., Nothen, M. M., Barnholtz-Sloan, J. S., Swerdlow, A. J., Simon, M., Rajaraman, P., Chanock, S. J., Shildkraut, J., Bernstein, J. L., Hoffmann, P., Jockel, K. H., Lai, R. K., ... Houlston, R. S. (2019). Transcriptome-wide association study identifies new candidate susceptibility genes for glioma. Cancer research, 79(8), 2065-2071. https://doi.org/10.1158/0008-5472.CAN-18-2888