Article
作者: Wolk, Alicja ; Lawrenson, Kate ; Antonenkova, Natalia N ; Beane Freeman, Laura E ; 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 ; Vestrheim Thomsen, Liv Cecilie ; McLaughlin, John R ; Moysich, Kirsten B ; 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 ; Webb, Penelope M ; Dennis, Joe ; Kjaer, Susanne K ; Goodman, Marc T ; Onland-Moret, N Charlotte ; Pharoah, Paul D P ; Wentzensen, Nicolas ; 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 ; Ziogas, Argyrios ; Plummer, Jasmine T ; Dürst, Matthias ; Woo, Yin-Ling ; Benitez, Javier ; Vierkant, Robert A ; Van Nieuwenhuysen, Els ; Zeinomar, Nur ; Pearce, Celeste L ; Doherty, Jennifer A ; 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.