A Transcriptome-Wide Association Study Among 97,898 Women to Identify Candidate Susceptibility Genes for Epithelial Ovarian Cancer Risk
Authors: Lu Yingchang , Beeghly-Fadiel Alicia , Wu Lang , Guo Xingyi , Li Bingshan , Schildkraut Joellen M. , Im Hae Kyung , Chen Yian A. , Permuth Jennifer B. , Reid Brett M. , Teer Jamie K. , Moysich Kirsten B. , Andrulis Irene L. , Anton-Culver Hoda , Arun Banu K. , Bandera Elisa V. , Barkardottir Rosa B. , Barnes Daniel R. , Benitez Javier , Bjorge Line , Brenton James , Butzow Ralf , Caldes Trinidad , Caligo Maria A. , Campbell Ian , Chang-Claude Jenny , Claes Kathleen B.M. , Couch Fergus J. , Cramer Daniel W. , Daly Mary B. , deFazio Anna , Dennis Joe , Diez Orland , Domchek Susan M. , Dörk Thilo , Easton Douglas F. , Eccles Diana M. , Fasching Peter A. , Fortner Renée T. , Fountzilas George , Friedman Eitan , Ganz Patricia A. , Garber Judy , Giles Graham G. , Godwin Andrew K. , Goldgar David E. , Goodman Marc T. , Greene Mark H. , Gronwald Jacek , Hamann Ute , Heitz Florian , Hildebrandt Michelle A.T. , Høgdall Claus K. , Hollestelle Antoinette , Hulick Peter J. , Huntsman David G. , Imyanitov Evgeny N. , Isaacs Claudine , Jakubowska Anna , James Paul , Karlan Beth Y. , Kelemen Linda E. , Kiemeney Lambertus A. , Kjaer Susanne K. , Kwong Ava , Le Nhu D. , Leslie Goska , Lesueur Fabienne , Levine Douglas A. , Mattiello Amalia , May Taymaa , McGuffog Lesley , McNeish Iain A. , Merritt Melissa A. , Modugno Francesmary , Montagna Marco , Neuhausen Susan L. , Nevanlinna Heli , Nielsen Finn C. , Nikitina-Zake Liene , Nussbaum Robert L. , Offit Kenneth , Olah Edith , Olopade Olufunmilayo I. , Olson Sara H. , Olsson Håkan , Osorio Ana , Park Sue K. , Parsons Michael T. , Peeters Petra H.M. , Pejovic Tanja , Peterlongo Paolo , Phelan Catherine M. , Pujana Miquel Angel , Ramus Susan J. , Rennert Gad , Risch Harvey , Rodriguez Gustavo C. , Rodríguez-Antona Cristina , Romieu Isabelle , Rookus Matti A. , Rossing Mary Anne , Rzepecka Iwona K. , Sandler Dale P. , Schmutzler Rita K. , Setiawan Veronica W. , Sharma Priyanka , Sieh Weiva , Simard Jacques , Singer Christian F. , Song Honglin , Southey Melissa C. , Spurdle Amanda B. , Sutphen Rebecca , Swerdlow Anthony J. , Teixeira Manuel R. , Teo Soo H. , Thomassen Mads , Tischkowitz Marc , Toland Amanda E. , Trichopoulou Antonia , Tung Nadine , Tworoger Shelley S. , van Rensburg Elizabeth J. , Vanderstichele Adriaan , Vega Ana , Edwards Digna Velez , Webb Penelope M. , Weitzel Jeffrey N. , Wentzensen Nicolas , White Emily , Wolk Alicja , Wu Anna H. , Yannoukakos Drakoulis , Zorn Kristin K. , Gayther Simon A. , Antoniou Antonis C. , Berchuck Andrew , Goode Ellen L. , Chenevix-Trench Georgia , Sellers Thomas A. , Pharoah Paul D.P. , Zheng Wei , Long Jirong 
Published: July 2018

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 &lt; 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 &lt; 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.