Ovarian Cancer Risk Variants Are Enriched in Histotype-Specific Enhancers and Disrupt Transcription Factor Binding Sites

Ovarian Cancer Association Consortium

Research output: Contribution to journalArticlepeer-review

13 Scopus citations


Quantifying the functional effects of complex disease risk variants can provide insights into mechanisms underlying disease biology. Genome-wide association studies have identified 39 regions associated with risk of epithelial ovarian cancer (EOC). The vast majority of these variants lie in the non-coding genome, where they likely function through interaction with gene regulatory elements. In this study we first estimated the heritability explained by known common low penetrance risk alleles for EOC. The narrow sense heritability (hg2) of EOC overall and high-grade serous ovarian cancer (HGSOCs) were estimated to be 5%–6%. Partitioned SNP heritability across broad functional categories indicated a significant contribution of regulatory elements to EOC heritability. We collated epigenomic profiling data for 77 cell and tissue types from Roadmap Epigenomics and ENCODE, and from H3K27Ac ChIP-seq data generated in 26 ovarian cancer and precursor-related cell and tissue types. We identified significant enrichment of risk single-nucleotide polymorphisms (SNPs) in active regulatory elements marked by H3K27Ac in HGSOCs. To further investigate how risk SNPs in active regulatory elements influence predisposition to ovarian cancer, we used motifbreakR to predict the disruption of transcription factor binding sites. We identified 469 candidate causal risk variants in H3K27Ac peaks that are predicted to significantly break transcription factor (TF) motifs. The most frequently broken motif was REST (p value = 0.0028), which has been reported as both a tumor suppressor and an oncogene. Overall, these systematic functional annotations with epigenomic data improve interpretation of EOC risk variants and shed light on likely cells of origin.

Original languageAmerican English
Pages (from-to)622-635
Number of pages14
JournalAmerican Journal of Human Genetics
Issue number4
StatePublished - 1 Oct 2020

Bibliographical note

Publisher Copyright:
© 2020


  • cells of origin
  • epigenomics
  • epithelial ovarian cancer
  • functional enrichment
  • genome-wide association studies
  • heritability
  • motif


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