A transcriptome-wide association study among 97,898 women to identify candidate susceptibility genes for epithelial ovarian cancer risk

Yingchang Lu, Alicia Beeghly-Fadiel, Lang Wu, Xingyi Guo, Bingshan Li, Joellen M. Schildkraut, Hae Kyung Im, Yian A. Chen, Jennifer B. Permuth, Brett M. Reid, Jamie K. Teer, Kirsten B. Moysich, Irene L. Andrulis, Hoda Anton-Culver, Banu K. Arun, Elisa V. Bandera, Rosa B. Barkardottir, Daniel R. Barnes, Javier Benitez, Line BjorgeJames Brenton, Ralf Butzow, Trinidad Caldes, Maria A. Caligo, Ian Campbell, Jenny Chang-Claude, Kathleen B.M. Claes, Fergus J. Couch, Daniel W. Cramer, Mary B. Daly, Anna DeFazio, Joe Dennis, Orland Diez, Susan M. Domchek, Thilo D rk, Douglas F. Easton, Diana M. Eccles, Peter A. Fasching, Ren e.T. Fortner, George Fountzilas, Eitan Friedman, Patricia A. Ganz, Judy Garber, Graham G. Giles, Andrew K. Godwin, David E. Goldgar, Marc T. Goodman, Mark H. Greene, Jacek Gronwald, Ute Hamann, Florian Heitz, Michelle A.T. Hildebrandt, Claus K. Høgdall, Antoinette Hollestelle, Peter J. Hulick, David G. Huntsman, Evgeny N. Imyanitov, Claudine Isaacs, Anna Jakubowska, Paul James, Beth Y. Karlan, Linda E. Kelemen, Lambertus A. Kiemeney, Susanne K. Kjaer, Ava Kwong, Nhu D. Le, Goska Leslie, Fabienne Lesueur, Douglas A. Levine, Amalia Mattiello, Taymaa May, Lesley McGuffog, Iain A. McNeish, Melissa A. Merritt, Francesmary Modugno, Marco Montagna, Susan L. Neuhausen, Heli Nevanlinna, Finn C. Nielsen, Liene Nikitina-Zake, Robert L. Nussbaum, Kenneth Offit, Edith Olah, Olufunmilayo I. Olopade, Sara H. Olson, H. kan Olsson, Ana Osorio, Sue K. Park, Michael T. Parsons, Petra H.M. Peeters, Tanja Pejovic, Paolo Peterlongo, Catherine M. Phelan, Miquel Angel Pujana, Susan J. Ramus, Gad Rennert, Harvey Risch, Gustavo C. Rodriguez, Cristina Rodríguez-Antona, Isabelle Romieu, Matti A. Rookus, Mary Anne Rossing, Iwona K. Rzepecka, Dale P. Sandler, Rita K. Schmutzler, Veronica W. Setiawan, Priyanka Sharma, Weiva Sieh, Jacques Simard, Christian F. Singer, Honglin Song, Melissa C. Southey, Amanda B. Spurdle, Rebecca Sutphen, Anthony J. Swerdlow, Manuel R. Teixeira, Soo H. Teo, Mads Thomassen, Marc Tischkowitz, Amanda E. Toland, Antonia Trichopoulou, Nadine Tung, Shelley S. Tworoger, Elizabeth J. Van Rensburg, Adriaan Vanderstichele, Ana Vega, Digna Velez Edwards, Penelope M. Webb, Jeffrey N. Weitzel, Nicolas Wentzensen, Emily White, Alicja Wolk, Anna H. Wu, Drakoulis Yannoukakos, Kristin K. Zorn, Simon A. Gayther, Antonis C. Antoniou, Andrew Berchuck, Ellen L. Goode, Georgia Chenevix-Trench, Thomas A. Sellers, Paul D.P. Pharoah, Wei Zheng, Jirong Long

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Abstract

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 < 2.2 106, we identified 35 genes, including FZD4 at 11q14.2 (Z ¼ 5.08, P ¼ 3.83 107, 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 < 1.47 103). 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.

Original languageEnglish (US)
Pages (from-to)5419-5430
Number of pages12
JournalCancer Research
Volume78
Issue number18
DOIs
StatePublished - Sep 15 2018

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ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Lu, Y., Beeghly-Fadiel, A., Wu, L., Guo, X., Li, B., Schildkraut, J. M., Im, H. K., Chen, Y. A., Permuth, J. B., Reid, B. M., Teer, J. K., Moysich, K. B., Andrulis, I. L., Anton-Culver, H., Arun, B. K., Bandera, E. V., Barkardottir, R. B., Barnes, D. R., Benitez, J., ... Long, J. (2018). A transcriptome-wide association study among 97,898 women to identify candidate susceptibility genes for epithelial ovarian cancer risk. Cancer Research, 78(18), 5419-5430. https://doi.org/10.1158/0008-5472.CAN-18-0951