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

Dareng, EO; Coetzee, SG; Tyrer, JP; Peng, PC; Rosenow, W; Chen, S; Davis, BD; Dezem, FS; Seo, JH; Nameki, R; Reyes, AL; Aben, KKH; Anton-Culver, H; Antonenkova, NN; Aravantinos, G; Bandera, EV; Beane Freeman, LE; Beckmann, MW; Beeghly-Fadiel, A; Benitez, J; Bernardini, MQ; Bjorge, L; Black, A; Bogdanova, NV; Bolton, KL; Brenton, JD; Budzilowska, A; Butzow, R; Cai, H; Campbell, I; Cannioto, R; Chang-Claude, J; Chanock, SJ; Chen, K; Chenevix-Trench, G; AOCS Group; Chiew, YE; Cook, LS; DeFazio, A; Dennis, J; Doherty, JA; D&#246;rk, T; du Bois, A; D&#252;rst, M; Eccles, DM; Ene, G; Fasching, PA; Flanagan, JM; Fortner, RT; Fostira, F; Gentry-Maharaj, A; Giles, GG; Goodman, MT; Gronwald, J; Haiman, CA; H&#229;kansson, N; Heitz, F; Hildebrandt, MAT; H&#248;gdall, E; H&#248;gdall, CK; Huang, RY; Jensen, A; Jones, ME; Kang, D; Karlan, BY; Karnezis, AN; Kelemen, LE; Kennedy, CJ; Khusnutdinova, EK; Kiemeney, LA; Kjaer, SK; Kupryjanczyk, J; Labrie, M; Lambrechts, D; Larson, MC; Le, ND; Lester, J; Li, L; Lubiński, J; Lush, M; Marks, JR; Matsuo, K; May, T; McLaughlin, JR; McNeish, IA; Menon, U; Missmer, S; Modugno, F; Moffitt, M; Monteiro, AN; Moysich, KB; Narod, SA; Nguyen-Dumont, T; Odunsi, K; Olsson, H; Onland-Moret, NC; Park, SK; Pejovic, T; Permuth, JB; Piskorz, A; Prokofyeva, D; Riggan, MJ; Risch, HA; Rodr&#237;guez-Antona, C; Rossing, MA; Sandler, DP; Setiawan, VW; Shan, K; Song, H; Southey, MC; Steed, H; Sutphen, R; Swerdlow, AJ; Teo, SH; Terry, KL; Thompson, PJ; Vestrheim Thomsen, LC; Titus, L; Trabert, B; Travis, R; Tworoger, SS; Valen, E; Van Nieuwenhuysen, E; Edwards, DV; Vierkant, RA; Webb, PM; Weinberg, CR; Weise, RM; Wentzensen, N; White, E; Winham, SJ; Wolk, A; Woo, YL; Wu, AH; Yan, L; Yannoukakos, D; Zeinomar, N; Zheng, W; Ziogas, A; Berchuck, A; Goode, EL; Huntsman, DG; Pearce, CL; Ramus, SJ; Sellers, TA; Freedman, ML; Lawrenson, K; Schildkraut, JM; Hazelett, D; Plummer, JT; Kar, S; Jones, MR; Pharoah, PDP; Gayther, SA

Author(s): Dareng, EO; Coetzee, SG; Tyrer, JP; Peng, PC; Rosenow, W; Chen, S; Davis, BD; Dezem, FS; Seo, JH; Nameki, R; Reyes, AL; Aben, KKH; Anton-Culver, H; Antonenkova, NN; Aravantinos, G; Bandera, EV; Beane Freeman, LE; Beckmann, MW; Beeghly-Fadiel, A; Benitez, J; Bernardini, MQ; Bjorge, L; Black, A; Bogdanova, NV; Bolton, KL; Brenton, JD; Budzilowska, A; Butzow, R; Cai, H; Campbell, I; Cannioto, R; Chang-Claude, J; Chanock, SJ; Chen, K; Chenevix-Trench, G; AOCS Group; Chiew, YE; Cook, LS; DeFazio, A; Dennis, J; Doherty, JA; Dörk, T; du Bois, A; Dürst, M; Eccles, DM; Ene, G; Fasching, PA; Flanagan, JM; Fortner, RT; Fostira, F; Gentry-Maharaj, A; Giles, GG; Goodman, MT; Gronwald, J; Haiman, CA; Håkansson, N; Heitz, F; Hildebrandt, MAT; Høgdall, E; Høgdall, CK; Huang, RY; Jensen, A; Jones, ME; Kang, D; Karlan, BY; Karnezis, AN; Kelemen, LE; Kennedy, CJ; Khusnutdinova, EK; Kiemeney, LA; Kjaer, SK; Kupryjanczyk, J; Labrie, M; Lambrechts, D; Larson, MC; Le, ND; Lester, J; Li, L; Lubiński, J; Lush, M; Marks, JR; Matsuo, K; May, T; McLaughlin, JR; McNeish, IA; Menon, U; Missmer, S; Modugno, F; Moffitt, M; Monteiro, AN; Moysich, KB; Narod, SA; Nguyen-Dumont, T; Odunsi, K; Olsson, H; Onland-Moret, NC; Park, SK; Pejovic, T; Permuth, JB; Piskorz, A; Prokofyeva, D; Riggan, MJ; Risch, HA; Rodríguez-Antona, C; Rossing, MA; Sandler, DP; Setiawan, VW; Shan, K; Song, H; Southey, MC; Steed, H; Sutphen, R; Swerdlow, AJ; Teo, SH; Terry, KL; Thompson, PJ; Vestrheim Thomsen, LC; Titus, L; Trabert, B; Travis, R; Tworoger, SS; Valen, E; Van Nieuwenhuysen, E; Edwards, DV; Vierkant, RA; Webb, PM; Weinberg, CR; Weise, RM; Wentzensen, N; White, E; Winham, SJ; Wolk, A; Woo, YL; Wu, AH; Yan, L; Yannoukakos, D; Zeinomar, N; Zheng, W; Ziogas, A; Berchuck, A; Goode, EL; Huntsman, DG; Pearce, CL; Ramus, SJ; Sellers, TA; Freedman, ML; Lawrenson, K; Schildkraut, JM; Hazelett, D; Plummer, JT; Kar, S; Jones, MR; Pharoah, PDP; Gayther, SA;
Details: Publication Year 2024-05-07,Volume 111,Issue #6,Page 1061-1083
Journal Title: American Journal of Human Genetics
Publication Type: Research article
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 × 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.
Publisher: Cell Press
Keywords: Gwas; epithelial ovarian cancer risk; fine mapping; functional mechanisms
Department(s): Laboratory Research
Publisher's Version: https://doi.org/10.1016/j.ajhg.2024.04.011
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2024-07-04 04:37:38

Last Modified: 2024-07-04 04:49:35