Article
Author: Wolk, Alicja  ; Lawrenson, Kate  ; Beane Freeman, Laura E  ; Antonenkova, Natalia N  ; Titus, Linda  ; Monteiro, Alvaro N  ; Lester, Jenny  ; Gentry-Maharaj, Aleksandra  ; Cook, Linda S  ; Kiemeney, Lambertus A  ; Missmer, Stacey  ; Tyrer, Jonathan P  ; Jones, Michelle R  ; Hildebrandt, Michelle A T  ; Yannoukakos, Drakoulis  ; Rossing, Mary Anne  ; Høgdall, Claus K  ; Kar, Siddhartha  ; Marks, Jeffrey R  ; Budzilowska, Agnieszka  ; Yan, Li  ; Moffitt, Melissa  ; Flanagan, James M  ; Eccles, Diana M  ; Høgdall, Estrid  ; Zheng, Wei  ; Risch, Harvey A  ; Terry, Kathryn L  ; Edwards, Digna Velez  ; White, Emily  ; Sandler, Dale P  ; Kelemen, Linda E  ; Piskorz, Anna  ; Tworoger, Shelley S  ; Anton-Culver, Hoda  ; Modugno, Francesmary  ; Huang, Ruea-Yea  ; Kang, Daehee  ; Freedman, Matthew L  ; McLaughlin, John R  ; Moysich, Kirsten B  ; Vestrheim Thomsen, Liv Cecilie  ; Winham, Stacey J  ; Jones, Michael E  ; Schildkraut, Joellen M  ; Bogdanova, Natalia V  ; Karnezis, Anthony N  ; Black, Amanda  ; Pejovic, Tanja  ; DeFazio, Anna  ; Fostira, Florentia  ; Fortner, Renée T  ; Sutphen, Rebecca  ; Haiman, Christopher A  ; Weise, Rayna Matsuno  ; Song, Honglin  ; Chen, Stephanie  ; Teo, Soo Hwang  ; Dennis, Joe  ; Webb, Penelope M  ; Goodman, Marc T  ; Kjaer, Susanne K  ; Onland-Moret, N Charlotte  ; Wentzensen, Nicolas  ; Pharoah, Paul D P  ; Odunsi, Kunle  ; Weinberg, Clarice R  ; Nguyen-Dumont, Tu  ; Seo, Ji-Heui  ; Wu, Anna H  ; Giles, Graham G  ; Chiew, Yoke-Eng  ; Heitz, Florian  ; Peng, Pei-Chen  ; Chang-Claude, Jenny  ; Menon, Usha  ; du Bois, Andreas  ; Prokofyeva, Darya  ; Sellers, Thomas A  ; Beckmann, Matthias W  ; Khusnutdinova, Elza K  ; Jensen, Allan  ; Gayther, Simon A  ; Berchuck, Andrew  ; Bandera, Elisa V  ; Butzow, Ralf  ; Fasching, Peter A  ; Matsuo, Keitaro  ; Lubiński, Jan  ; McNeish, Iain A  ; Park, Sue K  ; Steed, Helen  ; Rodríguez-Antona, Cristina  ; Setiawan, V Wendy  ; Chanock, Stephen J  ; Swerdlow, Anthony J  ; Bernardini, Marcus Q  ; Lush, Michael  ; Ramus, Susan J  ; Karlan, Beth Y  ; Travis, Ruth  ; Dareng, Eileen O  ; Davis, Brian D  ; Reyes, Alberto L  ; Le, Nhu D  ; Aravantinos, Gerasimos  ; Narod, Steven A  ; Huntsman, David G  ; Kupryjanczyk, Jolanta  ; Permuth, Jennifer B  ; Plummer, Jasmine T  ; Ziogas, Argyrios  ; Dürst, Matthias  ; Woo, Yin-Ling  ; Benitez, Javier  ; Vierkant, Robert A  ; Van Nieuwenhuysen, Els  ; Zeinomar, Nur  ; Doherty, Jennifer A  ; Pearce, Celeste L  ; Kennedy, Catherine J  ; Riggan, Marjorie J  ; Goode, Ellen L  ; Campbell, Ian  ; Gronwald, Jacek  ; Lambrechts, Diether  ; Larson, Melissa C  ; Coetzee, Simon G  ; Nameki, Robbin  ; Olsson, Håkan  ; Aben, Katja K H  ; Dörk, Thilo  ; Håkansson, Niclas  ; Ene, Gabrielle  ; May, Taymaa  ; Dezem, Felipe Segato  ; Valen, Ellen  ; Shan, Kang  ; Thompson, Pamela J  ; Cannioto, Rikki  ; Labrie, Marilyne  ; Li, Lian  ; Brenton, James D  ; Southey, Melissa C  ; Bolton, Kelly L  ; Chen, Kexin  ; Chenevix-Trench, Georgia  ; Hazelett, Dennis  ; Bjorge, Line  ; Cai, Hui  ; Beeghly-Fadiel, Alicia  ; Rosenow, Will  ; Trabert, Britton 
To identify credible causal risk variants (CCVs) associated with different histotypes of epithelial ovarian cancer (EOC), we performed genome-wide association analysis for 470,825 genotyped and 10,163,797 imputed SNPs in 25,981 EOC cases and 105,724 controls of European origin. We identified five histotype-specific EOC risk regions (p value <5 × 10-8) and confirmed previously reported associations for 27 risk regions. Conditional analyses identified an additional 11 signals independent of the primary signal at six risk regions (p value <10-5). Fine mapping identified 4,008 CCVs in these regions, of which 1,452 CCVs were located in ovarian cancer-related chromatin marks with significant enrichment in active enhancers, active promoters, and active regions for CCVs from each EOC histotype. Transcriptome-wide association and colocalization analyses across histotypes using tissue-specific and cross-tissue datasets identified 86 candidate susceptibility genes in known EOC risk regions and 32 genes in 23 additional genomic regions that may represent novel EOC risk loci (false discovery rate <0.05). Finally, by integrating genome-wide HiChIP interactome analysis with transcriptome-wide association study (TWAS), variant effect predictor, transcription factor ChIP-seq, and motifbreakR data, we identified candidate gene-CCV interactions at each locus. This included risk loci where TWAS identified one or more candidate susceptibility genes (e.g., HOXD-AS2, HOXD8, and HOXD3 at 2q31) and other loci where no candidate gene was identified (e.g., MYC and PVT1 at 8q24) by TWAS. In summary, this study describes a functional framework and provides a greater understanding of the biological significance of risk alleles and candidate gene targets at EOC susceptibility loci identified by a genome-wide association study.