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. Claus & 8 others Sara H. Olson, Christoffer Johansen, Margaret R. Wrensch, Beatrice Melin, Robert Brian Jenkins, Marc Sanson, Melissa L. Bondy, Richard S. Houlston

Research output: Contribution to journalArticle

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

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Transcriptome
Glioma
Genome-Wide Association Study
Glioblastoma
Genes
Neoplasms
Carcinogenesis
Genotype
Gene Expression

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Atkins, I., Kinnersley, B., Ostrom, Q. T., Labreche, K., Il'yasova, D., Armstrong, G. N., ... 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

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

In: Cancer Research, Vol. 79, No. 8, 15.04.2019, p. 2065-2071.

Research output: Contribution to journalArticle

Atkins, I, Kinnersley, B, Ostrom, QT, Labreche, K, Il'yasova, D, Armstrong, GN, Eckel-Passow, JE, Schoemaker, MJ, Nothen, MM, Barnholtz-Sloan, JS, Swerdlow, AJ, Simon, M, Rajaraman, P, Chanock, SJ, Shildkraut, J, Bernstein, JL, Hoffmann, P, Jockel, KH, Lai, RK, Claus, EB, Olson, SH, Johansen, C, Wrensch, MR, Melin, B, Jenkins, RB, Sanson, M, Bondy, ML & Houlston, RS 2019, 'Transcriptome-wide association study identifies new candidate susceptibility genes for glioma', Cancer Research, vol. 79, no. 8, pp. 2065-2071. https://doi.org/10.1158/0008-5472.CAN-18-2888
Atkins I, Kinnersley B, Ostrom QT, Labreche K, Il'yasova D, Armstrong GN et al. Transcriptome-wide association study identifies new candidate susceptibility genes for glioma. Cancer Research. 2019 Apr 15;79(8):2065-2071. https://doi.org/10.1158/0008-5472.CAN-18-2888
Atkins, Isabelle ; Kinnersley, Ben ; Ostrom, Quinn T. ; Labreche, Karim ; Il'yasova, Dora ; Armstrong, Georgina N. ; Eckel-Passow, Jeanette E ; Schoemaker, Minouk J. ; Nothen, Markus M. ; Barnholtz-Sloan, Jill S. ; Swerdlow, Anthony J. ; Simon, Matthias ; Rajaraman, Preetha ; Chanock, Stephen J. ; Shildkraut, Joellen ; Bernstein, Jonine L. ; Hoffmann, Per ; Jockel, Karl Heinz ; Lai, Rose K. ; Claus, Elizabeth B. ; Olson, Sara H. ; Johansen, Christoffer ; Wrensch, Margaret R. ; Melin, Beatrice ; Jenkins, Robert Brian ; Sanson, Marc ; Bondy, Melissa L. ; Houlston, Richard S. / Transcriptome-wide association study identifies new candidate susceptibility genes for glioma. In: Cancer Research. 2019 ; Vol. 79, No. 8. pp. 2065-2071.
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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.",
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AU - Atkins, Isabelle

AU - Kinnersley, Ben

AU - Ostrom, Quinn T.

AU - Labreche, Karim

AU - Il'yasova, Dora

AU - Armstrong, Georgina N.

AU - Eckel-Passow, Jeanette E

AU - Schoemaker, Minouk J.

AU - Nothen, Markus M.

AU - Barnholtz-Sloan, Jill S.

AU - Swerdlow, Anthony J.

AU - Simon, Matthias

AU - Rajaraman, Preetha

AU - Chanock, Stephen J.

AU - Shildkraut, Joellen

AU - Bernstein, Jonine L.

AU - Hoffmann, Per

AU - Jockel, Karl Heinz

AU - Lai, Rose K.

AU - Claus, Elizabeth B.

AU - Olson, Sara H.

AU - Johansen, Christoffer

AU - Wrensch, Margaret R.

AU - Melin, Beatrice

AU - Jenkins, Robert Brian

AU - Sanson, Marc

AU - Bondy, Melissa L.

AU - Houlston, Richard S.

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N2 - 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.

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