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A Transcriptome-Wide Association Study Among 97,898 Women to Identify Candidate Susceptibility Genes for Epithelial Ovarian Cancer Risk.

Publication ,  Journal Article
Lu, Y; Beeghly-Fadiel, A; Wu, L; Guo, X; Li, B; Schildkraut, JM; Im, HK; Chen, YA; Permuth, JB; Reid, BM; Teer, JK; Moysich, KB; Andrulis, IL ...
Published in: Cancer Res
September 15, 2018

Large-scale genome-wide association studies (GWAS) have identified approximately 35 loci associated with epithelial ovarian cancer (EOC) risk. The majority of GWAS-identified disease susceptibility variants are located in noncoding regions, and causal genes underlying these associations remain largely unknown. Here, we performed a transcriptome-wide association study to search for novel genetic loci and plausible causal genes at known GWAS loci. We used RNA sequencing data (68 normal ovarian tissue samples from 68 individuals and 6,124 cross-tissue samples from 369 individuals) and high-density genotyping data from European descendants of the Genotype-Tissue Expression (GTEx V6) project to build ovarian and cross-tissue models of genetically regulated expression using elastic net methods. We evaluated 17,121 genes for their cis-predicted gene expression in relation to EOC risk using summary statistics data from GWAS of 97,898 women, including 29,396 EOC cases. With a Bonferroni-corrected significance level of P < 2.2 × 10-6, we identified 35 genes, including FZD4 at 11q14.2 (Z = 5.08, P = 3.83 × 10-7, the cross-tissue model; 1 Mb away from any GWAS-identified EOC risk variant), a potential novel locus for EOC risk. All other 34 significantly associated genes were located within 1 Mb of known GWAS-identified loci, including 23 genes at 6 loci not previously linked to EOC risk. Upon conditioning on nearby known EOC GWAS-identified variants, the associations for 31 genes disappeared and three genes remained (P < 1.47 × 10-3). These data identify one novel locus (FZD4) and 34 genes at 13 known EOC risk loci associated with EOC risk, providing new insights into EOC carcinogenesis.Significance: Transcriptomic analysis of a large cohort confirms earlier GWAS loci and reveals FZD4 as a novel locus associated with EOC risk. Cancer Res; 78(18); 5419-30. ©2018 AACR.

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Published In

Cancer Res

DOI

EISSN

1538-7445

Publication Date

September 15, 2018

Volume

78

Issue

18

Start / End Page

5419 / 5430

Location

United States

Related Subject Headings

  • Transcriptome
  • Risk Factors
  • Quantitative Trait Loci
  • Prognosis
  • Polymorphism, Single Nucleotide
  • Ovarian Neoplasms
  • Oncology & Carcinogenesis
  • Humans
  • Genotype
  • Genome-Wide Association Study
 

Citation

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Lu, Y., Beeghly-Fadiel, A., Wu, L., Guo, X., Li, B., Schildkraut, J. M., … Long, J. (2018). A Transcriptome-Wide Association Study Among 97,898 Women to Identify Candidate Susceptibility Genes for Epithelial Ovarian Cancer Risk. Cancer Res, 78(18), 5419–5430. https://doi.org/10.1158/0008-5472.CAN-18-0951
Lu, Yingchang, Alicia Beeghly-Fadiel, Lang Wu, Xingyi Guo, Bingshan Li, Joellen M. Schildkraut, Hae Kyung Im, et al. “A Transcriptome-Wide Association Study Among 97,898 Women to Identify Candidate Susceptibility Genes for Epithelial Ovarian Cancer Risk.Cancer Res 78, no. 18 (September 15, 2018): 5419–30. https://doi.org/10.1158/0008-5472.CAN-18-0951.
Lu Y, Beeghly-Fadiel A, Wu L, Guo X, Li B, Schildkraut JM, et al. A Transcriptome-Wide Association Study Among 97,898 Women to Identify Candidate Susceptibility Genes for Epithelial Ovarian Cancer Risk. Cancer Res. 2018 Sep 15;78(18):5419–30.
Lu, Yingchang, et al. “A Transcriptome-Wide Association Study Among 97,898 Women to Identify Candidate Susceptibility Genes for Epithelial Ovarian Cancer Risk.Cancer Res, vol. 78, no. 18, Sept. 2018, pp. 5419–30. Pubmed, doi:10.1158/0008-5472.CAN-18-0951.
Lu Y, Beeghly-Fadiel A, Wu L, Guo X, Li B, Schildkraut JM, Im HK, Chen YA, Permuth JB, Reid BM, Teer JK, Moysich KB, Andrulis IL, Anton-Culver H, Arun BK, Bandera EV, Barkardottir RB, Barnes DR, Benitez J, Bjorge L, Brenton J, Butzow R, Caldes T, Caligo MA, Campbell I, Chang-Claude J, Claes KBM, Couch FJ, Cramer DW, Daly MB, deFazio A, Dennis J, Diez O, Domchek SM, Dörk T, Easton DF, Eccles DM, Fasching PA, Fortner RT, Fountzilas G, Friedman E, Ganz PA, Garber J, Giles GG, Godwin AK, Goldgar DE, Goodman MT, Greene MH, Gronwald J, Hamann U, Heitz F, Hildebrandt MAT, Høgdall CK, Hollestelle A, Hulick PJ, Huntsman DG, Imyanitov EN, Isaacs C, Jakubowska A, James P, Karlan BY, Kelemen LE, Kiemeney LA, Kjaer SK, Kwong A, Le ND, Leslie G, Lesueur F, Levine DA, Mattiello A, May T, McGuffog L, McNeish IA, Merritt MA, Modugno F, Montagna M, Neuhausen SL, Nevanlinna H, Nielsen FC, Nikitina-Zake L, Nussbaum RL, Offit K, Olah E, Olopade OI, Olson SH, Olsson H, Osorio A, Park SK, Parsons MT, Peeters PHM, Pejovic T, Peterlongo P, Phelan CM, Pujana MA, Ramus SJ, Rennert G, Risch H, Rodriguez GC, Rodríguez-Antona C, Romieu I, Rookus MA, Rossing MA, Rzepecka IK, Sandler DP, Schmutzler RK, Setiawan VW, Sharma P, Sieh W, Simard J, Singer CF, Song H, Southey MC, Spurdle AB, Sutphen R, Swerdlow AJ, Teixeira MR, Teo SH, Thomassen M, Tischkowitz M, Toland AE, Trichopoulou A, Tung N, Tworoger SS, van Rensburg EJ, Vanderstichele A, Vega A, Edwards DV, Webb PM, Weitzel JN, Wentzensen N, White E, Wolk A, Wu AH, Yannoukakos D, Zorn KK, Gayther SA, Antoniou AC, Berchuck A, Goode EL, Chenevix-Trench G, Sellers TA, Pharoah PDP, Zheng W, Long J. A Transcriptome-Wide Association Study Among 97,898 Women to Identify Candidate Susceptibility Genes for Epithelial Ovarian Cancer Risk. Cancer Res. 2018 Sep 15;78(18):5419–5430.

Published In

Cancer Res

DOI

EISSN

1538-7445

Publication Date

September 15, 2018

Volume

78

Issue

18

Start / End Page

5419 / 5430

Location

United States

Related Subject Headings

  • Transcriptome
  • Risk Factors
  • Quantitative Trait Loci
  • Prognosis
  • Polymorphism, Single Nucleotide
  • Ovarian Neoplasms
  • Oncology & Carcinogenesis
  • Humans
  • Genotype
  • Genome-Wide Association Study