Dareng, Eileen O;
Coetzee, Simon G;
Tyrer, Jonathan P;
Peng, Pei-Chen;
Rosenow, Will;
Chen, Stephanie;
Davis, Brian D;
... Gayther, Simon A; + view all
(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.
10.1016/j.ajhg.2024.04.011.
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Jones_Integrative multi-omics analyses to identify the genetic and functional mechanisms underlying ovarian cancer risk regions_AAM.pdf - Accepted Version Access restricted to UCL open access staff until 7 December 2024. Download (10MB) |
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.
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