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

Am J Hum Genet. 2024 Jun 6;111(6):1061-1083. doi: 10.1016/j.ajhg.2024.04.011. Epub 2024 May 8.

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.

Keywords: GWAS; epithelial ovarian cancer risk; fine mapping; functional mechanisms.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Carcinoma, Ovarian Epithelial / genetics
  • Case-Control Studies
  • Female
  • Genetic Predisposition to Disease*
  • Genome-Wide Association Study*
  • Genomics / methods
  • Humans
  • Multiomics
  • Ovarian Neoplasms* / genetics
  • Ovarian Neoplasms* / pathology
  • Polymorphism, Single Nucleotide*
  • Risk Factors
  • Transcriptome