Y Lu, A Beeghly-Fadiel, L Wu, X Guo, B Li, JM Schildkraut, HK Im, YA Chen, JB Permuth, BM Reid, JK Teer, KB Moysich, IL Andrulis, H Anton-Culver, BK Arun, EV Bandera, RB Barkardottir, DR Barnes, J Benitez, L Bjørge, J Brenton, R Butzow, T Caldes, MA Caligo, IG Campbell, J Chang-Claude, KBM Claes, FJ Couch, DW Cramer, MB Daly, A DeFazio, J Dennis, O Díez, SM Domchek, T Dork, DF Easton, DM Eccles, PA Fasching, RT Fortner, G Fountzilas, E Friedman, PA Ganz, J Garber, GG Giles, AK Godwin, DE Goldgar, MT Goodman, MH Greene, J Gronwald, U Hamann, F Heitz, MAT Hildebrandt, CK Høgdall, A Hollestelle, PJ Hulick, DG Huntsman, EN Imyanitov, C Isaacs, A Jakubowska, P James, BY Karlan, LE Kelemen, LA Kiemeney, SK Kjaer, A Kwong, ND Le, G Leslie, F Lesueur, DA Levine, A Mattiello, T May, L McGuffog, IA McNeish, MA Merritt, F Modugno, M Montagna, SL Neuhausen, H Nevanlinna, FC Cilius Nielsen, L Nikitina-Zake, RL Nussbaum, K Offit, E Olah, OI Olopade, SH Olson, H Olsson, A Osorio, SK Park, MT Parsons, PHM Peeters, T Pejovic, P Peterlongo, CM Phelan, MA Pujana, SJ Ramus, G Rennert, H Risch, GC Rodriguez, C Rodríguez-Antona, I Romieu, MA Rookus, MA Rossing, IK Rzepecka, DP Sandler, RK Schmutzler, VW Setiawan, P Sharma, W Sieh, J Simard, CF Singer, H Song, MC Southey, AB Spurdle, R Sutphen, AJ Swerdlow, MR Teixeira, SH Teo, M Thomassen, M Tischkowitz, AE Toland, A Trichopoulou, N Tung, SS Tworoger, EJ van Rensburg, A Vanderstichele, A Vega, D Velez Edwards, PM Webb, JN Weitzel, N Wentzensen, E White, A Wolk, AH Wu, D Yannoukakos, KK Zorn, SA Gayther, AC Antoniou, A Berchuck, EL Goode, G Chenevix-Trench, TA Sellers, PDP Pharoah, W Zheng, J Long
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 non-coding 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 3 genes remained (P<1.47 x 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.