Integrative multi-omics analyses to identify the genetic and functional mechanisms underlying ovarian cancer risk regions
Document Type
Article
Publication Date
6-1-2024
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.
Publication Title
American Journal of Human Genetics
Recommended Citation
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.; Freeman, Laura E. Beane; 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; and Campbell, Ian, "Integrative multi-omics analyses to identify the genetic and functional mechanisms underlying ovarian cancer risk regions" (2024). Research Publications (2021 to 2025). 5249.
https://knova.um.edu.my/research_publications_2021_2025/5249
Divisions
surgerydept,ummc
Volume
111
Issue
6
Publisher
Cell Press
Publisher Location
50 HAMPSHIRE ST, FLOOR 5, CAMBRIDGE, MA 02139 USA