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

doi:10.1158/0008-5472.can-18-2888

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

^*Corresponding author for this work

Department of Clinical Medicine

6 Citations (Scopus)

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 language	English
Journal	Cancer Research
Volume	79
Issue number	8
Pages (from-to)	2065-2071
Number of pages	7
ISSN	0008-5472
DOIs	https://doi.org/10.1158/0008-5472.can-18-2888
Publication status	Published - 2019

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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

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

@article{d8a50e4dde864a4bbb1cb49f7165193d,

title = "Transcriptome-wide association study identifies new candidate susceptibility genes for glioma",

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. ",

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

year = "2019",

doi = "10.1158/0008-5472.can-18-2888",

language = "English",

volume = "79",

pages = "2065--2071",

journal = "Cancer Research",

issn = "0008-5472",

publisher = "American Association for Cancer Research",

number = "8",

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TY - JOUR

T1 - Transcriptome-wide association study identifies new candidate susceptibility genes for glioma

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 B.

AU - Sanson, Marc

AU - Bondy, Melissa L.

AU - Houlston, Richard S.

PY - 2019

Y1 - 2019

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.

AB - 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.

U2 - 10.1158/0008-5472.can-18-2888

DO - 10.1158/0008-5472.can-18-2888

M3 - Journal article

C2 - 30709929

AN - SCOPUS:85064463582

SN - 0008-5472

VL - 79

SP - 2065

EP - 2071

JO - Cancer Research

JF - Cancer Research

IS - 8

ER -

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

Abstract

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