TY - JOUR
T1 - Integrative multi-omics analyses to identify the genetic and functional mechanisms underlying ovarian cancer risk regions
AU - AOCS Group
AU - OPAL Study Group
AU - The Ovarian Cancer Association Consortium (OCAC)
AU - Dareng, Eileen O.
AU - Coetzee, Simon G.
AU - Tyrer, Jonathan P.
AU - Peng, Pei Chen
AU - Rosenow, Will
AU - Chen, Stephanie
AU - Davis, Brian D.
AU - Dezem, Felipe Segato
AU - Seo, Ji Heui
AU - Nameki, Robbin
AU - Reyes, Alberto L.
AU - Aben, Katja K.H.
AU - Anton-Culver, Hoda
AU - Antonenkova, Natalia N.
AU - Aravantinos, Gerasimos
AU - Bandera, Elisa V.
AU - Beane Freeman, Laura E.
AU - Beckmann, Matthias W.
AU - Beeghly-Fadiel, Alicia
AU - Benitez, Javier
AU - Bernardini, Marcus Q.
AU - Bjorge, Line
AU - Black, Amanda
AU - Bogdanova, Natalia V.
AU - Bolton, Kelly L.
AU - Brenton, James D.
AU - Budzilowska, Agnieszka
AU - Butzow, Ralf
AU - Cai, Hui
AU - Campbell, Ian
AU - Cannioto, Rikki
AU - Chang-Claude, Jenny
AU - Chanock, Stephen J.
AU - Chen, Kexin
AU - Chenevix-Trench, Georgia
AU - Chiew, Yoke Eng
AU - Cook, Linda S.
AU - DeFazio, Anna
AU - Dennis, Joe
AU - Doherty, Jennifer A.
AU - Dörk, Thilo
AU - du Bois, Andreas
AU - Dürst, Matthias
AU - Eccles, Diana M.
AU - Ene, Gabrielle
AU - Fasching, Peter A.
AU - Flanagan, James M.
AU - Fortner, Renée T.
AU - Fostira, Florentia
AU - Gayther, Simon A.
N1 - Publisher Copyright:
© 2024 American Society of Human Genetics
PY - 2024/6/6
Y1 - 2024/6/6
N2 - 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.
AB - 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.
KW - GWAS
KW - epithelial ovarian cancer risk
KW - fine mapping
KW - functional mechanisms
UR - http://www.scopus.com/inward/record.url?scp=85193787656&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85193787656&partnerID=8YFLogxK
U2 - 10.1016/j.ajhg.2024.04.011
DO - 10.1016/j.ajhg.2024.04.011
M3 - Article
C2 - 38723632
AN - SCOPUS:85193787656
SN - 0002-9297
VL - 111
SP - 1061
EP - 1083
JO - American Journal of Human Genetics
JF - American Journal of Human Genetics
IS - 6
ER -