Dareng, Eileen O. and Coetzee, Simon G. and Tyrer, Jonathan P. and Peng, Pei-Chen and Rosenow, Will and Chen, Stephanie and Davis, Brian D. and Dezem, Felipe Segato and Seo, Ji-Heui and Nameki, Robbin and Reyes, Alberto L. and Aben, Katja K. H. and Anton-Culver, Hoda and Antonenkova, Natalia N. and Aravantinos, Gerasimos and Bandera, Elisa V. and Freeman, Laura E. Beane and Beckmann, Matthias W. and Beeghly-Fadiel, Alicia and Benitez, Javier and Bernardini, Marcus Q. and Bjorge, Line and Black, Amanda and Bogdanova, Natalia V. and Bolton, Kelly L. and Brenton, James D. and Budzilowska, Agnieszka and Butzow, Ralf and Cai, Hui and Campbell, Ian and Cannioto, Rikki and Chang-Claude, Jenny and Chanock, Stephen J. and Chen, Kexin and Chenevix-Trench, Georgia and Chiew, Yoke-Eng and Cook, Linda S. and DeFazio, Anna and Dennis, Joe and Doherty, Jennifer A. and Doerk, Thilo and du Bois, Andreas and Duerst, Matthias and Eccles, Diana M. and Ene, Gabrielle and Fasching, Peter A. and Flanagan, James M. and Fortner, Renee T. and Fostira, Florentia and Gentry-Maharaj, Aleksandra and Giles, Graham G. and Goodman, Marc T. and Gronwald, Jacek and Haiman, Christopher A. and Hakansson, Niclas and Heitz, Florian and Hildebrandt, Michelle A. T. and Hogdall, Estrid and Hogdall, Claus K. and Huang, Ruea-Yea and Jensen, Allan and Jones, Michael E. and Kang, Daehee and Karlan, Beth Y. and Karnezis, Anthony N. and Kelemen, Linda E. and Kennedy, Catherine J. and Khusnutdinova, Elza K. and Kiemeney, Lambertus A. and Kjaer, Susanne K. and Kupryjanczyk, Jolanta and Labrie, Marilyne and Lambrechts, Diether and Larson, Melissa C. and Le, Nhu D. and Lester, Jenny and Li, Lian and Lubinski, Jan and Lush, Michael and Marks, Jeffrey R. and Matsuo, Keitaro and May, Taymaa and McLaughlin, John R. and McNeish, Iain A. and Menon, Usha and Missmer, Stacey and Modugno, Francesmary and Moffitt, Melissa and Monteiro, Alvaro N. and Moysich, Kirsten B. and Narod, Steven A. and Nguyen-Dumont, Tu and Odunsi, Kunle and Olsson, Hakan and Onland-Moret, N. Charlotte and Park, Sue K. and Pejovic, Tanja and Permuth, Jennifer B. and Piskorz, Anna and Prokofyeva, Darya and Riggan, Marjorie J. and Risch, Harvey A. and Rodriguez-Antona, Cristina and Rossing, Mary Anne and Sandler, Dale P. and Setiawan, V. Wendy and Shan, Kang and Song, Honglin and Southey, Melissa C. and Steed, Helen and Sutphen, Rebecca and Swerdlow, Anthony J. and Teo, Soo Hwang and Terry, Kathryn L. and Thompson, Pamela J. and Thomsen, Liv Cecilie Vestrheim and Titus, Linda and Trabert, Britton and Travis, Ruth and Tworoger, Shelley S. and Valen, Ellen and Van Nieuwenhuysen, Els and Edwards, Digna Velez and Vierkant, Robert A. and Webb, Penelope M. and Weinberg, Clarice R. and Weise, Rayna Matsuno and Wentzensen, Nicolas and White, Emily and Winham, Stacey J. and Wolk, Alicja and Woo, Yin-Ling and Wu, Anna H. and Yan, Li and Yannoukakos, Drakoulis and Zeinomar, Nur and Zheng, Wei and Ziogas, Argyrios and Berchuck, Andrew and Goode, Ellen L. and Huntsman, David G. and Pearce, Celeste L. and Ramus, Susan J. and Sellers, Thomas A. and Freedman, Matthew L. and Lawrenson, Kate and Schildkraut, Joellen M. and Hazelett, Dennis and Plummer, Jasmine T. and Kar, Siddhartha and Jones, Michelle R. and Pharoah, Paul D. P. and Gayther, Simon A. and Grp, AOCS and Grp, OPAL Study and OCAC, Ovarian Canc Assoc Consortium (2024) Integrative multi-omics analyses to identify the genetic and functional mechanisms underlying ovarian cancer risk regions. American Journal of Human Genetics, 111 (6). pp. 1061-1083. ISSN 0002-9297, DOI https://doi.org/10.1016/j.ajhg.2024.04.011.
Full text not available from this repository.Abstract
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 x 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.
| Item Type: | Article |
|---|---|
| Funders: | UNSPECIFIED |
| Subjects: | R Medicine |
| Divisions: | Faculty of Medicine > Surgery Department Universiti Malaya Medical Centre (UMMC) |
| Depositing User: | Ms. Juhaida Abd Rahim |
| Date Deposited: | 15 Jan 2025 08:36 |
| Last Modified: | 15 Jan 2025 08:36 |
| URI: | http://eprints.um.edu.my/id/eprint/46900 |
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