%0 Journal Article
%A Dareng, Eileen O
%A Coetzee, Simon G
%A Tyrer, Jonathan P
%A Peng, Pei-Chen
%A Rosenow, Will
%A Chen, Stephanie
%A Davis, Brian D
%A Dezem, Felipe Segato
%A Seo, Ji-Heui
%A Nameki, Robbin
%A Reyes, Alberto L
%A Aben, Katja K H
%A Anton-Culver, Hoda
%A Antonenkova, Natalia N
%A Aravantinos, Gerasimos
%A Bandera, Elisa V
%A Beane Freeman, Laura E
%A Beckmann, Matthias W
%A Beeghly-Fadiel, Alicia
%A Benitez, Javier
%A Bernardini, Marcus Q
%A Bjorge, Line
%A Black, Amanda
%A Bogdanova, Natalia V
%A Bolton, Kelly L
%A Brenton, James D
%A Budzilowska, Agnieszka
%A Butzow, Ralf
%A Cai, Hui
%A Campbell, Ian
%A Cannioto, Rikki
%A Chang-Claude, Jenny
%A Chanock, Stephen J
%A Chen, Kexin
%A Chenevix-Trench, Georgia
%A Chiew, Yoke-Eng
%A Cook, Linda S
%A DeFazio, Anna
%A Dennis, Joe
%A Doherty, Jennifer A
%A Dörk, Thilo
%A du Bois, Andreas
%A Dürst, Matthias
%A Eccles, Diana M
%A Ene, Gabrielle
%A Fasching, Peter A
%A Flanagan, James M
%A Fortner, Renée T
%A Fostira, Florentia
%A Gentry-Maharaj, Aleksandra
%A Giles, Graham G
%A Goodman, Marc T
%A Gronwald, Jacek
%A Haiman, Christopher A
%A Håkansson, Niclas
%A Heitz, Florian
%A Hildebrandt, Michelle A T
%A Høgdall, Estrid
%A Høgdall, Claus K
%A Huang, Ruea-Yea
%A Jensen, Allan
%A Jones, Michael E
%A Kang, Daehee
%A Karlan, Beth Y
%A Karnezis, Anthony N
%A Kelemen, Linda E
%A Kennedy, Catherine J
%A Khusnutdinova, Elza K
%A Kiemeney, Lambertus A
%A Kjaer, Susanne K
%A Kupryjanczyk, Jolanta
%A Labrie, Marilyne
%A Lambrechts, Diether
%A Larson, Melissa C
%A Le, Nhu D
%A Lester, Jenny
%A Li, Lian
%A Lubiński, Jan
%A Lush, Michael
%A Marks, Jeffrey R
%A Matsuo, Keitaro
%A May, Taymaa
%A McLaughlin, John R
%A McNeish, Iain A
%A Menon, Usha
%A Missmer, Stacey
%A Modugno, Francesmary
%A Moffitt, Melissa
%A Monteiro, Alvaro N
%A Moysich, Kirsten B
%A Narod, Steven A
%A Nguyen-Dumont, Tu
%A Odunsi, Kunle
%A Olsson, Håkan
%A Onland-Moret, N Charlotte
%A Park, Sue K
%A Pejovic, Tanja
%A Permuth, Jennifer B
%A Piskorz, Anna
%A Prokofyeva, Darya
%A Riggan, Marjorie J
%A Risch, Harvey A
%A Rodríguez-Antona, Cristina
%A Rossing, Mary Anne
%A Sandler, Dale P
%A Setiawan, V Wendy
%A Shan, Kang
%A Song, Honglin
%A Southey, Melissa C
%A Steed, Helen
%A Sutphen, Rebecca
%A Swerdlow, Anthony J
%A Teo, Soo Hwang
%A Terry, Kathryn L
%A Thompson, Pamela J
%A Vestrheim Thomsen, Liv Cecilie
%A Titus, Linda
%A Trabert, Britton
%A Travis, Ruth
%A Tworoger, Shelley S
%A Valen, Ellen
%A Van Nieuwenhuysen, Els
%A Edwards, Digna Velez
%A Vierkant, Robert A
%A Webb, Penelope M
%A Weinberg, Clarice R
%A Weise, Rayna Matsuno
%A Wentzensen, Nicolas
%A White, Emily
%A Winham, Stacey J
%A Wolk, Alicja
%A Woo, Yin-Ling
%A Wu, Anna H
%A Yan, Li
%A Yannoukakos, Drakoulis
%A Zeinomar, Nur
%A Zheng, Wei
%A Ziogas, Argyrios
%A Berchuck, Andrew
%A Goode, Ellen L
%A Huntsman, David G
%A Pearce, Celeste L
%A Ramus, Susan J
%A Sellers, Thomas A
%A Freedman, Matthew L
%A Lawrenson, Kate
%A Schildkraut, Joellen M
%A Hazelett, Dennis
%A Plummer, Jasmine T
%A Kar, Siddhartha
%A Jones, Michelle R
%A Pharoah, Paul D P
%A Gayther, Simon A
%T Integrative multi-omics analyses to identify the genetic and functional mechanisms underlying ovarian cancer risk regions.
%J The American journal of human genetics
%V 111
%N 6
%@ 0002-9297
%C New York, NY
%I Elsevier
%M DKFZ-2024-00995
%P 1061-1083
%D 2024
%Z 2024 Jun 6;111(6):1061-1083
%X 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.
%K GWAS (Other)
%K epithelial ovarian cancer risk (Other)
%K fine mapping (Other)
%K functional mechanisms (Other)
%F PUB:(DE-HGF)16
%9 Journal Article
%$ pmid:38723632
%R 10.1016/j.ajhg.2024.04.011
%U https://inrepo02.dkfz.de/record/290096