Faculty, Staff and Student Publications

Publication Date

6-6-2024

Journal

American Journal of Human Genetics

DOI

10.1016/j.ajhg.2024.04.011

PMID

38723632

PMCID

PMC11179261

PubMedCentral® Posted Date

5-8-2024

PubMedCentral® Full Text Version

Post-print

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

Humans, Female, Genome-Wide Association Study, Polymorphism, Single Nucleotide, Ovarian Neoplasms, Genetic Predisposition to Disease, Carcinoma, Ovarian Epithelial, Transcriptome, Risk Factors, Genomics, Case-Control Studies, Multiomics, epithelial ovarian cancer risk, GWAS, fine mapping, functional mechanisms

Published Open-Access

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