Sex-specific gene and pathway modeling of inherited glioma risk

GliomaScan Consortium

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

Background: To date, genome-wide association studies (GWAS) have identified 25 risk variants for glioma, explaining 30% of heritable risk. Most histologies occur with significantly higher incidence in males, and this difference is not explained by currently known risk factors. A previous GWAS identified sex-specific glioma risk variants, and this analysis aims to further elucidate risk variation by sex using gene- and pathway-based approaches. Methods: Results from the Glioma International Case-Control Study were used as a testing set, and results from 3 GWAS were combined via meta-analysis and used as a validation set. Using summary statistics for nominally significant autosomal SNPs (P < 0.01 in a previous meta-analysis) and nominally significant X-chromosome SNPs (P < 0.01), 3 algorithms (Pascal, BimBam, and GATES) were used to generate gene scores, and Pascal was used to generate pathway scores. Results were considered statistically significant in the discovery set when P < 3.3 × 10-6 and in the validation set when P < 0.001 in 2 of 3 algorithms. Results: Twenty-five genes within 5 regions and 19 genes within 6 regions reached statistical significance in at least 2 of 3 algorithms in males and females, respectively. EGFR was significantly associated with all glioma and glioblastoma in males only and a female-specific association in TERT, all of which remained nominally significant after conditioning on known risk loci. There were nominal associations with the BioCarta telomeres pathway in both males and females. Conclusions: These results provide additional evidence that there may be differences by sex in genetic risk for glioma. Additional analyses may further elucidate the biological processes through which this risk is conferred.

Original languageEnglish (US)
Pages (from-to)71-82
Number of pages12
JournalNeuro-Oncology
Volume21
Issue number1
DOIs
StatePublished - Jan 1 2019

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Glioma
Genome-Wide Association Study
Genes
Single Nucleotide Polymorphism
Meta-Analysis
Biological Phenomena
Telomere
X Chromosome
Glioblastoma
Sex Characteristics
Case-Control Studies
Histology
Incidence

ASJC Scopus subject areas

  • Oncology
  • Clinical Neurology
  • Cancer Research

Cite this

Sex-specific gene and pathway modeling of inherited glioma risk. / GliomaScan Consortium.

In: Neuro-Oncology, Vol. 21, No. 1, 01.01.2019, p. 71-82.

Research output: Contribution to journalArticle

GliomaScan Consortium. / Sex-specific gene and pathway modeling of inherited glioma risk. In: Neuro-Oncology. 2019 ; Vol. 21, No. 1. pp. 71-82.
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title = "Sex-specific gene and pathway modeling of inherited glioma risk",
abstract = "Background: To date, genome-wide association studies (GWAS) have identified 25 risk variants for glioma, explaining 30{\%} of heritable risk. Most histologies occur with significantly higher incidence in males, and this difference is not explained by currently known risk factors. A previous GWAS identified sex-specific glioma risk variants, and this analysis aims to further elucidate risk variation by sex using gene- and pathway-based approaches. Methods: Results from the Glioma International Case-Control Study were used as a testing set, and results from 3 GWAS were combined via meta-analysis and used as a validation set. Using summary statistics for nominally significant autosomal SNPs (P < 0.01 in a previous meta-analysis) and nominally significant X-chromosome SNPs (P < 0.01), 3 algorithms (Pascal, BimBam, and GATES) were used to generate gene scores, and Pascal was used to generate pathway scores. Results were considered statistically significant in the discovery set when P < 3.3 × 10-6 and in the validation set when P < 0.001 in 2 of 3 algorithms. Results: Twenty-five genes within 5 regions and 19 genes within 6 regions reached statistical significance in at least 2 of 3 algorithms in males and females, respectively. EGFR was significantly associated with all glioma and glioblastoma in males only and a female-specific association in TERT, all of which remained nominally significant after conditioning on known risk loci. There were nominal associations with the BioCarta telomeres pathway in both males and females. Conclusions: These results provide additional evidence that there may be differences by sex in genetic risk for glioma. Additional analyses may further elucidate the biological processes through which this risk is conferred.",
author = "{GliomaScan Consortium} and Ostrom, {Quinn T.} and Warren Coleman and William Huang and Rubin, {Joshua B.} and Lathia, {Justin D.} and Berens, {Michael E.} and Gil Speyer and Peter Liao and Wrensch, {Margaret R.} and Eckel-Passow, {Jeanette E} and Georgina Armstrong and Terri Rice and Wiencke, {John K.} and McCoy, {Lucie S.} and Hansen, {Helen M.} and Amos, {Christopher I.} and Bernstein, {Jonine L.} and Claus, {Elizabeth B.} and Houlston, {Richard S.} and Dora Il'yasova and Jenkins, {Robert Brian} and Christoffer Johansen and Lachance, {Daniel H} and Lai, {Rose K.} and Merrell, {Ryan T.} and Olson, {Sara H.} and Siegal Sadetzki and Schildkraut, {Joellen M.} and Sanjay Shete and Ulrika Andersson and Preetha Rajaraman and Chanock, {Stephen J.} and Linet, {Martha S.} and Zhaoming Wang and Meredith Yeager and Beatrice Melin and Bondy, {Melissa L.} and Barnholtz-Sloan, {Jill S.}",
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T1 - Sex-specific gene and pathway modeling of inherited glioma risk

AU - GliomaScan Consortium

AU - Ostrom, Quinn T.

AU - Coleman, Warren

AU - Huang, William

AU - Rubin, Joshua B.

AU - Lathia, Justin D.

AU - Berens, Michael E.

AU - Speyer, Gil

AU - Liao, Peter

AU - Wrensch, Margaret R.

AU - Eckel-Passow, Jeanette E

AU - Armstrong, Georgina

AU - Rice, Terri

AU - Wiencke, John K.

AU - McCoy, Lucie S.

AU - Hansen, Helen M.

AU - Amos, Christopher I.

AU - Bernstein, Jonine L.

AU - Claus, Elizabeth B.

AU - Houlston, Richard S.

AU - Il'yasova, Dora

AU - Jenkins, Robert Brian

AU - Johansen, Christoffer

AU - Lachance, Daniel H

AU - Lai, Rose K.

AU - Merrell, Ryan T.

AU - Olson, Sara H.

AU - Sadetzki, Siegal

AU - Schildkraut, Joellen M.

AU - Shete, Sanjay

AU - Andersson, Ulrika

AU - Rajaraman, Preetha

AU - Chanock, Stephen J.

AU - Linet, Martha S.

AU - Wang, Zhaoming

AU - Yeager, Meredith

AU - Melin, Beatrice

AU - Bondy, Melissa L.

AU - Barnholtz-Sloan, Jill S.

PY - 2019/1/1

Y1 - 2019/1/1

N2 - Background: To date, genome-wide association studies (GWAS) have identified 25 risk variants for glioma, explaining 30% of heritable risk. Most histologies occur with significantly higher incidence in males, and this difference is not explained by currently known risk factors. A previous GWAS identified sex-specific glioma risk variants, and this analysis aims to further elucidate risk variation by sex using gene- and pathway-based approaches. Methods: Results from the Glioma International Case-Control Study were used as a testing set, and results from 3 GWAS were combined via meta-analysis and used as a validation set. Using summary statistics for nominally significant autosomal SNPs (P < 0.01 in a previous meta-analysis) and nominally significant X-chromosome SNPs (P < 0.01), 3 algorithms (Pascal, BimBam, and GATES) were used to generate gene scores, and Pascal was used to generate pathway scores. Results were considered statistically significant in the discovery set when P < 3.3 × 10-6 and in the validation set when P < 0.001 in 2 of 3 algorithms. Results: Twenty-five genes within 5 regions and 19 genes within 6 regions reached statistical significance in at least 2 of 3 algorithms in males and females, respectively. EGFR was significantly associated with all glioma and glioblastoma in males only and a female-specific association in TERT, all of which remained nominally significant after conditioning on known risk loci. There were nominal associations with the BioCarta telomeres pathway in both males and females. Conclusions: These results provide additional evidence that there may be differences by sex in genetic risk for glioma. Additional analyses may further elucidate the biological processes through which this risk is conferred.

AB - Background: To date, genome-wide association studies (GWAS) have identified 25 risk variants for glioma, explaining 30% of heritable risk. Most histologies occur with significantly higher incidence in males, and this difference is not explained by currently known risk factors. A previous GWAS identified sex-specific glioma risk variants, and this analysis aims to further elucidate risk variation by sex using gene- and pathway-based approaches. Methods: Results from the Glioma International Case-Control Study were used as a testing set, and results from 3 GWAS were combined via meta-analysis and used as a validation set. Using summary statistics for nominally significant autosomal SNPs (P < 0.01 in a previous meta-analysis) and nominally significant X-chromosome SNPs (P < 0.01), 3 algorithms (Pascal, BimBam, and GATES) were used to generate gene scores, and Pascal was used to generate pathway scores. Results were considered statistically significant in the discovery set when P < 3.3 × 10-6 and in the validation set when P < 0.001 in 2 of 3 algorithms. Results: Twenty-five genes within 5 regions and 19 genes within 6 regions reached statistical significance in at least 2 of 3 algorithms in males and females, respectively. EGFR was significantly associated with all glioma and glioblastoma in males only and a female-specific association in TERT, all of which remained nominally significant after conditioning on known risk loci. There were nominal associations with the BioCarta telomeres pathway in both males and females. Conclusions: These results provide additional evidence that there may be differences by sex in genetic risk for glioma. Additional analyses may further elucidate the biological processes through which this risk is conferred.

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DO - 10.1093/neuonc/noy135

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JO - Neuro-Oncology

JF - Neuro-Oncology

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