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American journal of human genetics · 2024

Integrative multi-omics analyses to identify the genetic and functional mechanisms underlying ovarian cancer risk regions.

СтатьяПоддержка NIH: внешняя программаНазвание и аннотация: Перевод в очереди
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Dareng Eileen O, Coetzee Simon G, Tyrer Jonathan P, Peng Pei-Chen, Rosenow Will, Chen Stephanie, Davis Brian D, Dezem Felipe Segato, Seo Ji-Heui, Nameki Robbin, Reyes Alberto L, Aben Katja K H, Anton-Culver Hoda, Antonenkova Natalia N, Aravantinos Gerasimos, Bandera Elisa V, Beane Freeman Laura E, Beckmann Matthias W, Beeghly-Fadiel Alicia, Benitez Javier, Bernardini Marcus Q, Bjorge Line, Black Amanda, Bogdanova Natalia V, Bolton Kelly L, Brenton James D, Budzilowska Agnieszka, Butzow Ralf, Cai Hui, Campbell Ian, Cannioto Rikki, Chang-Claude Jenny, Chanock Stephen J, Chen Kexin, Chenevix-Trench Georgia, AOCS Group, Chiew Yoke-Eng, Cook Linda S, DeFazio Anna, Dennis Joe, Doherty Jennifer A, Dörk Thilo, du Bois Andreas, Dürst Matthias, Eccles Diana M, Ene Gabrielle, Fasching Peter A, Flanagan James M, Fortner Renée T, Fostira Florentia, Gentry-Maharaj Aleksandra, Giles Graham G, Goodman Marc T, Gronwald Jacek, Haiman Christopher A, Håkansson Niclas, Heitz Florian, Hildebrandt Michelle A T, Høgdall Estrid, Høgdall Claus K, Huang Ruea-Yea, Jensen Allan, Jones Michael E, Kang Daehee, Karlan Beth Y, Karnezis Anthony N, Kelemen Linda E, Kennedy Catherine J, Khusnutdinova Elza K, Kiemeney Lambertus A, Kjaer Susanne K, Kupryjanczyk Jolanta, Labrie Marilyne, Lambrechts Diether, Larson Melissa C, Le Nhu D, Lester Jenny, Li Lian, Lubiński Jan, Lush Michael, Marks Jeffrey R, Matsuo Keitaro, May Taymaa, McLaughlin John R, McNeish Iain A, Menon Usha, Missmer Stacey, Modugno Francesmary, Moffitt Melissa, Monteiro Alvaro N, Moysich Kirsten B, Narod Steven A, Nguyen-Dumont Tu, Odunsi Kunle, Olsson Håkan, Onland-Moret N Charlotte, Park Sue K, Pejovic Tanja, Permuth Jennifer B, Piskorz Anna, Prokofyeva Darya, Riggan Marjorie J, Risch Harvey A, Rodríguez-Antona Cristina, Rossing Mary Anne, Sandler Dale P, Setiawan V Wendy, Shan Kang, Song Honglin, Southey Melissa C, Steed Helen, Sutphen Rebecca, Swerdlow Anthony J, Teo Soo Hwang, Terry Kathryn L, Thompson Pamela J, Vestrheim Thomsen Liv Cecilie, Titus Linda, Trabert Britton, Travis Ruth, Tworoger Shelley S, Valen Ellen, Van Nieuwenhuysen Els, Edwards Digna Velez, Vierkant Robert A, Webb Penelope M, OPAL Study Group, Weinberg Clarice R, Weise Rayna Matsuno, Wentzensen Nicolas, White Emily, Winham Stacey J, Wolk Alicja, Woo Yin-Ling, Wu Anna H, Yan Li, Yannoukakos Drakoulis, Zeinomar Nur, Zheng Wei, Ziogas Argyrios, Berchuck Andrew, Goode Ellen L, Huntsman David G, Pearce Celeste L, Ramus Susan J, Sellers Thomas A, Ovarian Cancer Association Consortium (OCAC), Freedman Matthew L, Lawrenson Kate, Schildkraut Joellen M, Hazelett Dennis, Plummer Jasmine T, Kar Siddhartha, Jones Michelle R, Pharoah Paul D P, Gayther Simon A

Аннотация

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.

Предметные рубрики MeSH

ИП Урсолов Владлен Сергеевич

ИНН 500118482352 · ОГРНИП 314500117700049

Реквизиты и контакты