Integrative multi-omics analyses to identify the genetic and functional mechanisms underlying ovarian cancer risk regions
Dareng, E.O. ; Olsson, H. LU
and Gayther, S.A.
(2024)
In American Journal of Human Genetics
111(6).
p.1061-1083
- 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... (More)
- 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. (Less)
Please use this url to cite or link to this publication:
https://lup.lub.lu.se/record/38afd769-7c4b-4a3d-b43c-b6d4511e661a
- author
- Dareng, E.O.
; Olsson, H.
LU
and Gayther, S.A.
- author collaboration
- organization
- publishing date
- 2024
- type
- Contribution to journal
- publication status
- published
- subject
- keywords
- epithelial ovarian cancer risk, fine mapping, functional mechanisms, GWAS
- in
- American Journal of Human Genetics
- volume
- 111
- issue
- 6
- pages
- 23 pages
- publisher
- Cell Press
- external identifiers
-
- scopus:85193787656
- pmid:38723632
- ISSN
- 0002-9297
- DOI
- 10.1016/j.ajhg.2024.04.011
- language
- English
- LU publication?
- yes
- id
- 38afd769-7c4b-4a3d-b43c-b6d4511e661a
- date added to LUP
- 2024-08-22 13:56:12
- date last changed
- 2024-08-23 03:00:03
@article{38afd769-7c4b-4a3d-b43c-b6d4511e661a,
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.}},
author = {{Dareng, E.O. and Olsson, H. and Gayther, S.A.}},
issn = {{0002-9297}},
keywords = {{epithelial ovarian cancer risk; fine mapping; functional mechanisms; GWAS}},
language = {{eng}},
number = {{6}},
pages = {{1061--1083}},
publisher = {{Cell Press}},
series = {{American Journal of Human Genetics}},
title = {{Integrative multi-omics analyses to identify the genetic and functional mechanisms underlying ovarian cancer risk regions}},
url = {{http://dx.doi.org/10.1016/j.ajhg.2024.04.011}},
doi = {{10.1016/j.ajhg.2024.04.011}},
volume = {{111}},
year = {{2024}},
}