A multi-level investigation of the genetic relationship between endometriosis and ovarian cancer histotypes

Ovarian Cancer Association Consortium, International Endometriosis Genetics Consortium

doi:10.1016/j.xcrm.2022.100542

A multi-level investigation of the genetic relationship between endometriosis and ovarian cancer histotypes

Ovarian Cancer Association Consortium, International Endometriosis Genetics Consortium

Research output: Contribution to journal › Article › peer-review

41 Scopus citations

Abstract

Endometriosis is associated with increased risk of epithelial ovarian cancers (EOCs). Using data from large endometriosis and EOC genome-wide association meta-analyses, we estimate the genetic correlation and evaluate the causal relationship between genetic liability to endometriosis and EOC histotypes, and identify shared susceptibility loci. We estimate a significant genetic correlation (r_g) between endometriosis and clear cell (r_g = 0.71), endometrioid (r_g = 0.48), and high-grade serous (r_g = 0.19) ovarian cancer, associations supported by Mendelian randomization analyses. Bivariate meta-analysis identified 28 loci associated with both endometriosis and EOC, including 19 with evidence for a shared underlying association signal. Differences in the shared risk suggest different underlying pathways may contribute to the relationship between endometriosis and the different histotypes. Functional annotation using transcriptomic and epigenomic profiles of relevant tissues/cells highlights several target genes. This comprehensive analysis reveals profound genetic overlap between endometriosis and EOC histotypes with valuable genomic targets for understanding the biological mechanisms linking the diseases.

Original language	English (US)
Article number	100542
Journal	Cell Reports Medicine
Volume	3
Issue number	3
DOIs	https://doi.org/10.1016/j.xcrm.2022.100542
State	Published - Mar 15 2022
Externally published	Yes

Keywords

Mendelian randomization
endometriosis
epithelial ovarian cancer
genetic association
genetic correlation
genetic risk
histotype
meta-analysis

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

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10.1016/j.xcrm.2022.100542

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title = "A multi-level investigation of the genetic relationship between endometriosis and ovarian cancer histotypes",

abstract = "Endometriosis is associated with increased risk of epithelial ovarian cancers (EOCs). Using data from large endometriosis and EOC genome-wide association meta-analyses, we estimate the genetic correlation and evaluate the causal relationship between genetic liability to endometriosis and EOC histotypes, and identify shared susceptibility loci. We estimate a significant genetic correlation (rg) between endometriosis and clear cell (rg = 0.71), endometrioid (rg = 0.48), and high-grade serous (rg = 0.19) ovarian cancer, associations supported by Mendelian randomization analyses. Bivariate meta-analysis identified 28 loci associated with both endometriosis and EOC, including 19 with evidence for a shared underlying association signal. Differences in the shared risk suggest different underlying pathways may contribute to the relationship between endometriosis and the different histotypes. Functional annotation using transcriptomic and epigenomic profiles of relevant tissues/cells highlights several target genes. This comprehensive analysis reveals profound genetic overlap between endometriosis and EOC histotypes with valuable genomic targets for understanding the biological mechanisms linking the diseases.",

keywords = "Mendelian randomization, endometriosis, epithelial ovarian cancer, genetic association, genetic correlation, genetic risk, histotype, meta-analysis",

author = "{Ovarian Cancer Association Consortium, International Endometriosis Genetics Consortium} and Sally Mortlock and Corona, {Rosario I.} and Kho, {Pik Fang} and Paul Pharoah and Seo, {Ji Heui} and Freedman, {Matthew L.} and Gayther, {Simon A.} and Siedhoff, {Matthew T.} and Rogers, {Peter A.W.} and Ronald Leuchter and Walsh, {Christine S.} and Ilana Cass and Karlan, {Beth Y.} and Rimel, {B. J.} and Montgomery, {Grant W.} and Kate Lawrenson and Kar, {Siddhartha P.}",

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doi = "10.1016/j.xcrm.2022.100542",

language = "English (US)",

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T1 - A multi-level investigation of the genetic relationship between endometriosis and ovarian cancer histotypes

AU - Ovarian Cancer Association Consortium, International Endometriosis Genetics Consortium

AU - Mortlock, Sally

AU - Corona, Rosario I.

AU - Kho, Pik Fang

AU - Pharoah, Paul

AU - Seo, Ji Heui

AU - Freedman, Matthew L.

AU - Gayther, Simon A.

AU - Siedhoff, Matthew T.

AU - Rogers, Peter A.W.

AU - Leuchter, Ronald

AU - Walsh, Christine S.

AU - Cass, Ilana

AU - Karlan, Beth Y.

AU - Rimel, B. J.

AU - Montgomery, Grant W.

AU - Lawrenson, Kate

AU - Kar, Siddhartha P.

PY - 2022/3/15

Y1 - 2022/3/15

N2 - Endometriosis is associated with increased risk of epithelial ovarian cancers (EOCs). Using data from large endometriosis and EOC genome-wide association meta-analyses, we estimate the genetic correlation and evaluate the causal relationship between genetic liability to endometriosis and EOC histotypes, and identify shared susceptibility loci. We estimate a significant genetic correlation (rg) between endometriosis and clear cell (rg = 0.71), endometrioid (rg = 0.48), and high-grade serous (rg = 0.19) ovarian cancer, associations supported by Mendelian randomization analyses. Bivariate meta-analysis identified 28 loci associated with both endometriosis and EOC, including 19 with evidence for a shared underlying association signal. Differences in the shared risk suggest different underlying pathways may contribute to the relationship between endometriosis and the different histotypes. Functional annotation using transcriptomic and epigenomic profiles of relevant tissues/cells highlights several target genes. This comprehensive analysis reveals profound genetic overlap between endometriosis and EOC histotypes with valuable genomic targets for understanding the biological mechanisms linking the diseases.

AB - Endometriosis is associated with increased risk of epithelial ovarian cancers (EOCs). Using data from large endometriosis and EOC genome-wide association meta-analyses, we estimate the genetic correlation and evaluate the causal relationship between genetic liability to endometriosis and EOC histotypes, and identify shared susceptibility loci. We estimate a significant genetic correlation (rg) between endometriosis and clear cell (rg = 0.71), endometrioid (rg = 0.48), and high-grade serous (rg = 0.19) ovarian cancer, associations supported by Mendelian randomization analyses. Bivariate meta-analysis identified 28 loci associated with both endometriosis and EOC, including 19 with evidence for a shared underlying association signal. Differences in the shared risk suggest different underlying pathways may contribute to the relationship between endometriosis and the different histotypes. Functional annotation using transcriptomic and epigenomic profiles of relevant tissues/cells highlights several target genes. This comprehensive analysis reveals profound genetic overlap between endometriosis and EOC histotypes with valuable genomic targets for understanding the biological mechanisms linking the diseases.

KW - Mendelian randomization

KW - endometriosis

KW - epithelial ovarian cancer

KW - genetic association

KW - genetic correlation

KW - genetic risk

KW - histotype

KW - meta-analysis

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A multi-level investigation of the genetic relationship between endometriosis and ovarian cancer histotypes

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Keywords

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