TY - JOUR
T1 - Sex-specific gene and pathway modeling of inherited glioma risk
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 B.
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.
N1 - Publisher Copyright:
© The Author(s) 2018.
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 â '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 â '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.
UR - http://www.scopus.com/inward/record.url?scp=85059233481&partnerID=8YFLogxK
U2 - 10.1093/neuonc/noy135
DO - 10.1093/neuonc/noy135
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C2 - 30124908
AN - SCOPUS:85059233481
SN - 1522-8517
VL - 21
SP - 71
EP - 82
JO - Neuro-Oncology
JF - Neuro-Oncology
IS - 1
ER -
