Genetic analyses of gynecological disease identify genetic relationships between uterine fibroids and endometrial cancer, and a novel endometrial cancer genetic risk region at the WNT4 1p36.12 locus

Pik Fang Kho; Sally Mortlock; Endometrial Cancer Association Consortium; International Endometriosis Genetics Consortium; Peter A.W. Rogers; Dale R. Nyholt; Grant W. Montgomery; Amanda B. Spurdle; Dylan M. Glubb; Tracy A. O’Mara

doi:10.1007/s00439-021-02312-0

Genetic analyses of gynecological disease identify genetic relationships between uterine fibroids and endometrial cancer, and a novel endometrial cancer genetic risk region at the WNT4 1p36.12 locus

Pik Fang Kho, Sally Mortlock, Endometrial Cancer Association Consortium, International Endometriosis Genetics Consortium, Peter A.W. Rogers, Dale R. Nyholt, Grant W. Montgomery, Amanda B. Spurdle, Dylan M. Glubb, Tracy A. O’Mara

Medicine Monash Health

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

32 Citations (Scopus)

Abstract

Endometriosis, polycystic ovary syndrome (PCOS) and uterine fibroids have been proposed as endometrial cancer risk factors; however, disentangling their relationships with endometrial cancer is complicated due to shared risk factors and comorbidities. Using genome-wide association study (GWAS) data, we explored the relationships between these non-cancerous gynecological diseases and endometrial cancer risk by assessing genetic correlation, causal relationships and shared risk loci. We found significant genetic correlation between endometrial cancer and PCOS, and uterine fibroids. Adjustment for genetically predicted body mass index (a risk factor for PCOS, uterine fibroids and endometrial cancer) substantially attenuated the genetic correlation between endometrial cancer and PCOS but did not affect the correlation with uterine fibroids. Mendelian randomization analyses suggested a causal relationship between only uterine fibroids and endometrial cancer. Gene-based analyses revealed risk regions shared between endometrial cancer and endometriosis, and uterine fibroids. Multi-trait GWAS analysis of endometrial cancer and the genetically correlated gynecological diseases identified a novel genome-wide significant endometrial cancer risk locus at 1p36.12, which replicated in an independent endometrial cancer dataset. Interrogation of functional genomic data at 1p36.12 revealed biologically relevant genes, including WNT4 which is necessary for the development of the female reproductive system. In summary, our study provides genetic evidence for a causal relationship between uterine fibroids and endometrial cancer. It further provides evidence that the comorbidity of endometrial cancer, PCOS and uterine fibroids may partly be due to shared genetic architecture. Notably, this shared architecture has revealed a novel genome-wide risk locus for endometrial cancer.

Original language	English
Pages (from-to)	1353-1365
Number of pages	13
Journal	Human Genetics
Volume	140
Issue number	9
DOIs	https://doi.org/10.1007/s00439-021-02312-0
Publication status	Published - Sept 2021

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10.1007/s00439-021-02312-0

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Kho, P. F., Mortlock, S., Endometrial Cancer Association Consortium, International Endometriosis Genetics Consortium, Rogers, P. A. W., Nyholt, D. R., Montgomery, G. W., Spurdle, A. B., Glubb, D. M., & O’Mara, T. A. (2021). Genetic analyses of gynecological disease identify genetic relationships between uterine fibroids and endometrial cancer, and a novel endometrial cancer genetic risk region at the WNT4 1p36.12 locus. Human Genetics, 140(9), 1353-1365. https://doi.org/10.1007/s00439-021-02312-0

@article{bbd771fb25fd41d59f31e6c4fedd56e2,

title = "Genetic analyses of gynecological disease identify genetic relationships between uterine fibroids and endometrial cancer, and a novel endometrial cancer genetic risk region at the WNT4 1p36.12 locus",

abstract = "Endometriosis, polycystic ovary syndrome (PCOS) and uterine fibroids have been proposed as endometrial cancer risk factors; however, disentangling their relationships with endometrial cancer is complicated due to shared risk factors and comorbidities. Using genome-wide association study (GWAS) data, we explored the relationships between these non-cancerous gynecological diseases and endometrial cancer risk by assessing genetic correlation, causal relationships and shared risk loci. We found significant genetic correlation between endometrial cancer and PCOS, and uterine fibroids. Adjustment for genetically predicted body mass index (a risk factor for PCOS, uterine fibroids and endometrial cancer) substantially attenuated the genetic correlation between endometrial cancer and PCOS but did not affect the correlation with uterine fibroids. Mendelian randomization analyses suggested a causal relationship between only uterine fibroids and endometrial cancer. Gene-based analyses revealed risk regions shared between endometrial cancer and endometriosis, and uterine fibroids. Multi-trait GWAS analysis of endometrial cancer and the genetically correlated gynecological diseases identified a novel genome-wide significant endometrial cancer risk locus at 1p36.12, which replicated in an independent endometrial cancer dataset. Interrogation of functional genomic data at 1p36.12 revealed biologically relevant genes, including WNT4 which is necessary for the development of the female reproductive system. In summary, our study provides genetic evidence for a causal relationship between uterine fibroids and endometrial cancer. It further provides evidence that the comorbidity of endometrial cancer, PCOS and uterine fibroids may partly be due to shared genetic architecture. Notably, this shared architecture has revealed a novel genome-wide risk locus for endometrial cancer.",

author = "Kho, \{Pik Fang\} and Sally Mortlock and Frederic Amant and Daniela Annibali and Katie Ashton and John Attia and Auer, \{Paul L.\} and Beckmann, \{Matthias W.\} and Amanda Black and Louise Brinton and Buchanan, \{Daniel D.\} and Chanock, \{Stephen J.\} and Chu Chen and Chen, \{Maxine M.\} and Cheng, \{Timothy H.T.\} and Cook, \{Linda S.\} and Marta Crous-Bous and Kamila Czene and Immaculata Vivo and Joe Dennis and Thilo D{\"o}rk and Dowdy, \{Sean C.\} and Dunning, \{Alison M.\} and Matthias D{\"u}rst and Easton, \{Douglas F.\} and Ekici, \{Arif B.\} and Fasching, \{Peter A.\} and Fridley, \{Brooke L.\} and Friedenreich, \{Christine M.\} and Montserrat Garc{\'i}a-Closas and Gaudet, \{Mia M.\} and Giles, \{Graham G.\} and Goode, \{Ellen L.\} and Haiman, \{Christopher A.\} and Per Hall and Hankinson, \{Susan E.\} and Healey, \{Catherine S.\} and Alexander Hein and Peter Hillemanns and Shirley Hodgson and Erling Hoivik and Holliday, \{Elizabeth G.\} and Hunter, \{David J.\} and Angela Jones and Peter Kraft and Camilla Krakstad and Diether Lambrechts and Loic Marchand and Xiaolin Liang and Annika Lindblom and Jolanta Lissowska and Jirong Long and Lingeng Lu and Magliocco, \{Anthony M.\} and Lynn Martin and Mark McEvoy and Milne, \{Roger L.\} and Miriam Mints and Rami Nassir and O{\textquoteright}Mara, \{Tracy A.\} and Irene Orlow and Geoffrey Otton and Claire Palles and Pharoah, \{Paul D.P.\} and Loreall Pooler and Tony Proietto and Rebbeck, \{Timothy R.\} and Renner, \{Stefan P.\} and Risch, \{Harvey A.\} and Matthias R{\"u}bner and Ingo Runnebaum and Carlotta Sacerdote and Sarto, \{Gloria E.\} and Fredrick Schumacher and Scott, \{Rodney J.\} and Setiawan, \{V. Wendy\} and Mitul Shah and Xin Sheng and Shu, \{Xiao Ou\} and Southey, \{Melissa C.\} and Emma Tham and Thompson, \{Deborah J.\} and Ian Tomlinson and Jone Trovik and Constance Turman and David Berg and Zhaoming Wang and Webb, \{Penelope M.\} and Nicolas Wentzensen and Winham, \{Stacey J.\} and Lucy Xia and Xiang, \{Yong Bing\} and Yang, \{Hannah P.\} and Herbert Yu and Wei Zheng and Yadav Sapkota and Valgerdur Steinthorsdottir and Morris, \{Andrew P.\} and Amelie Fassbender and Nilufer Rahmioglu and Immaculata Vivo and Buring, \{Julie E.\} and Futao Zhang and Edwards, \{Todd L.\} and Sarah Jones and O. Dorien and Dani{\"e}lle Peterse and Rexrode, \{Kathryn M.\} and Ridker, \{Paul M.\} and Schork, \{Andrew J.\} and Stuart MacGregor and Martin, \{Nicholas G.\} and Becker, \{Christian M.\} and Sosuke Adachi and Kosuke Yoshihara and Takayuki Enomoto and Atsushi Takahashi and Yoichiro Kamatani and Koichi Matsuda and Michiaki Kubo and Gudmar Thorleifsson and Geirsson, \{Reynir T.\} and Unnur Thorsteinsdottir and Wallace, \{Leanne M.\} and Jian Yang and R. Digna and Mette Nyegaard and Low, \{Siew Kee\} and Zondervan, \{Krina T.\} and Missmer, \{Stacey A.\} and Thomas D{\textquoteright}Hooghe and Chasman, \{Daniel I.\} and Kari Stefansson and Tung, \{Joyce Y.\} and \{Endometrial Cancer Association Consortium\} and \{International Endometriosis Genetics Consortium\} and Rogers, \{Peter A.W.\} and Nyholt, \{Dale R.\} and Montgomery, \{Grant W.\} and Spurdle, \{Amanda B.\} and Glubb, \{Dylan M.\} and O{\textquoteright}Mara, \{Tracy A.\}",

note = "Funding Information: This work was conducted using the UK Biobank Resource (application number 25331). We thank the research participants and employees of 23andMe for making this work possible. We thank the participants and investigators of FinnGen study. We thank the many individuals who participated in the Endometrial Cancer Association Consortium and the International Endometriosis Genetics Consortium studies, and the numerous institutions and their staff who supported recruitment. A full list of consortium members and acknowledgements can be found in the Supplementary Note. We thank Dr Matthew Stephens for his help in interpreting SuSiE results of this study. Funding Information: PFK is supported by an Australian Government Research Training Program PhD Scholarship and QIMR Berghofer Postgraduate Top-Up Scholarship, TAO{\textquoteright}M, GWM and ABS are supported by NHMRC Investigator Fellowships (APP1173170, GNT1177194 and APP1177524). This work was supported by National Health and Medical Research Council (NHMRC) Project Grants (APP1109286, GNT1026033, GNT1105321 and GNT1147846). Funding sources had no role in study design, data curation and analysis, data interpretation, report writing and submission for publication. Publisher Copyright: {\textcopyright} 2021, The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.",

year = "2021",

month = sep,

doi = "10.1007/s00439-021-02312-0",

language = "English",

volume = "140",

pages = "1353--1365",

journal = "Human Genetics",

issn = "0340-6717",

publisher = "Springer-Verlag London Ltd.",

number = "9",

}

Kho, PF, Mortlock, S, Endometrial Cancer Association Consortium, International Endometriosis Genetics Consortium, Rogers, PAW, Nyholt, DR, Montgomery, GW, Spurdle, AB, Glubb, DM & O’Mara, TA 2021, 'Genetic analyses of gynecological disease identify genetic relationships between uterine fibroids and endometrial cancer, and a novel endometrial cancer genetic risk region at the WNT4 1p36.12 locus', Human Genetics, vol. 140, no. 9, pp. 1353-1365. https://doi.org/10.1007/s00439-021-02312-0

Genetic analyses of gynecological disease identify genetic relationships between uterine fibroids and endometrial cancer, and a novel endometrial cancer genetic risk region at the WNT4 1p36.12 locus. / Kho, Pik Fang; Mortlock, Sally; Endometrial Cancer Association Consortium et al.
In: Human Genetics, Vol. 140, No. 9, 09.2021, p. 1353-1365.

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

TY - JOUR

T1 - Genetic analyses of gynecological disease identify genetic relationships between uterine fibroids and endometrial cancer, and a novel endometrial cancer genetic risk region at the WNT4 1p36.12 locus

AU - Kho, Pik Fang

AU - Mortlock, Sally

AU - Amant, Frederic

AU - Annibali, Daniela

AU - Ashton, Katie

AU - Attia, John

AU - Auer, Paul L.

AU - Beckmann, Matthias W.

AU - Black, Amanda

AU - Brinton, Louise

AU - Buchanan, Daniel D.

AU - Chanock, Stephen J.

AU - Chen, Chu

AU - Chen, Maxine M.

AU - Cheng, Timothy H.T.

AU - Cook, Linda S.

AU - Crous-Bous, Marta

AU - Czene, Kamila

AU - Vivo, Immaculata

AU - Dennis, Joe

AU - Dörk, Thilo

AU - Dowdy, Sean C.

AU - Dunning, Alison M.

AU - Dürst, Matthias

AU - Easton, Douglas F.

AU - Ekici, Arif B.

AU - Fasching, Peter A.

AU - Fridley, Brooke L.

AU - Friedenreich, Christine M.

AU - García-Closas, Montserrat

AU - Gaudet, Mia M.

AU - Giles, Graham G.

AU - Goode, Ellen L.

AU - Haiman, Christopher A.

AU - Hall, Per

AU - Hankinson, Susan E.

AU - Healey, Catherine S.

AU - Hein, Alexander

AU - Hillemanns, Peter

AU - Hodgson, Shirley

AU - Hoivik, Erling

AU - Holliday, Elizabeth G.

AU - Hunter, David J.

AU - Jones, Angela

AU - Kraft, Peter

AU - Krakstad, Camilla

AU - Lambrechts, Diether

AU - Marchand, Loic

AU - Liang, Xiaolin

AU - Lindblom, Annika

AU - Lissowska, Jolanta

AU - Long, Jirong

AU - Lu, Lingeng

AU - Magliocco, Anthony M.

AU - Martin, Lynn

AU - McEvoy, Mark

AU - Milne, Roger L.

AU - Mints, Miriam

AU - Nassir, Rami

AU - O’Mara, Tracy A.

AU - Orlow, Irene

AU - Otton, Geoffrey

AU - Palles, Claire

AU - Pharoah, Paul D.P.

AU - Pooler, Loreall

AU - Proietto, Tony

AU - Rebbeck, Timothy R.

AU - Renner, Stefan P.

AU - Risch, Harvey A.

AU - Rübner, Matthias

AU - Runnebaum, Ingo

AU - Sacerdote, Carlotta

AU - Sarto, Gloria E.

AU - Schumacher, Fredrick

AU - Scott, Rodney J.

AU - Setiawan, V. Wendy

AU - Shah, Mitul

AU - Sheng, Xin

AU - Shu, Xiao Ou

AU - Southey, Melissa C.

AU - Tham, Emma

AU - Thompson, Deborah J.

AU - Tomlinson, Ian

AU - Trovik, Jone

AU - Turman, Constance

AU - Berg, David

AU - Wang, Zhaoming

AU - Webb, Penelope M.

AU - Wentzensen, Nicolas

AU - Winham, Stacey J.

AU - Xia, Lucy

AU - Xiang, Yong Bing

AU - Yang, Hannah P.

AU - Yu, Herbert

AU - Zheng, Wei

AU - Sapkota, Yadav

AU - Steinthorsdottir, Valgerdur

AU - Morris, Andrew P.

AU - Fassbender, Amelie

AU - Rahmioglu, Nilufer

AU - Vivo, Immaculata

AU - Buring, Julie E.

AU - Zhang, Futao

AU - Edwards, Todd L.

AU - Jones, Sarah

AU - Dorien, O.

AU - Peterse, Daniëlle

AU - Rexrode, Kathryn M.

AU - Ridker, Paul M.

AU - Schork, Andrew J.

AU - MacGregor, Stuart

AU - Martin, Nicholas G.

AU - Becker, Christian M.

AU - Adachi, Sosuke

AU - Yoshihara, Kosuke

AU - Enomoto, Takayuki

AU - Takahashi, Atsushi

AU - Kamatani, Yoichiro

AU - Matsuda, Koichi

AU - Kubo, Michiaki

AU - Thorleifsson, Gudmar

AU - Geirsson, Reynir T.

AU - Thorsteinsdottir, Unnur

AU - Wallace, Leanne M.

AU - Yang, Jian

AU - Digna, R.

AU - Nyegaard, Mette

AU - Low, Siew Kee

AU - Zondervan, Krina T.

AU - Missmer, Stacey A.

AU - D’Hooghe, Thomas

AU - Chasman, Daniel I.

AU - Stefansson, Kari

AU - Tung, Joyce Y.

AU - Endometrial Cancer Association Consortium

AU - International Endometriosis Genetics Consortium

AU - Rogers, Peter A.W.

AU - Nyholt, Dale R.

AU - Montgomery, Grant W.

AU - Spurdle, Amanda B.

AU - Glubb, Dylan M.

AU - O’Mara, Tracy A.

N1 - Funding Information: This work was conducted using the UK Biobank Resource (application number 25331). We thank the research participants and employees of 23andMe for making this work possible. We thank the participants and investigators of FinnGen study. We thank the many individuals who participated in the Endometrial Cancer Association Consortium and the International Endometriosis Genetics Consortium studies, and the numerous institutions and their staff who supported recruitment. A full list of consortium members and acknowledgements can be found in the Supplementary Note. We thank Dr Matthew Stephens for his help in interpreting SuSiE results of this study. Funding Information: PFK is supported by an Australian Government Research Training Program PhD Scholarship and QIMR Berghofer Postgraduate Top-Up Scholarship, TAO’M, GWM and ABS are supported by NHMRC Investigator Fellowships (APP1173170, GNT1177194 and APP1177524). This work was supported by National Health and Medical Research Council (NHMRC) Project Grants (APP1109286, GNT1026033, GNT1105321 and GNT1147846). Funding sources had no role in study design, data curation and analysis, data interpretation, report writing and submission for publication. Publisher Copyright: © 2021, The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.

PY - 2021/9

Y1 - 2021/9

N2 - Endometriosis, polycystic ovary syndrome (PCOS) and uterine fibroids have been proposed as endometrial cancer risk factors; however, disentangling their relationships with endometrial cancer is complicated due to shared risk factors and comorbidities. Using genome-wide association study (GWAS) data, we explored the relationships between these non-cancerous gynecological diseases and endometrial cancer risk by assessing genetic correlation, causal relationships and shared risk loci. We found significant genetic correlation between endometrial cancer and PCOS, and uterine fibroids. Adjustment for genetically predicted body mass index (a risk factor for PCOS, uterine fibroids and endometrial cancer) substantially attenuated the genetic correlation between endometrial cancer and PCOS but did not affect the correlation with uterine fibroids. Mendelian randomization analyses suggested a causal relationship between only uterine fibroids and endometrial cancer. Gene-based analyses revealed risk regions shared between endometrial cancer and endometriosis, and uterine fibroids. Multi-trait GWAS analysis of endometrial cancer and the genetically correlated gynecological diseases identified a novel genome-wide significant endometrial cancer risk locus at 1p36.12, which replicated in an independent endometrial cancer dataset. Interrogation of functional genomic data at 1p36.12 revealed biologically relevant genes, including WNT4 which is necessary for the development of the female reproductive system. In summary, our study provides genetic evidence for a causal relationship between uterine fibroids and endometrial cancer. It further provides evidence that the comorbidity of endometrial cancer, PCOS and uterine fibroids may partly be due to shared genetic architecture. Notably, this shared architecture has revealed a novel genome-wide risk locus for endometrial cancer.

AB - Endometriosis, polycystic ovary syndrome (PCOS) and uterine fibroids have been proposed as endometrial cancer risk factors; however, disentangling their relationships with endometrial cancer is complicated due to shared risk factors and comorbidities. Using genome-wide association study (GWAS) data, we explored the relationships between these non-cancerous gynecological diseases and endometrial cancer risk by assessing genetic correlation, causal relationships and shared risk loci. We found significant genetic correlation between endometrial cancer and PCOS, and uterine fibroids. Adjustment for genetically predicted body mass index (a risk factor for PCOS, uterine fibroids and endometrial cancer) substantially attenuated the genetic correlation between endometrial cancer and PCOS but did not affect the correlation with uterine fibroids. Mendelian randomization analyses suggested a causal relationship between only uterine fibroids and endometrial cancer. Gene-based analyses revealed risk regions shared between endometrial cancer and endometriosis, and uterine fibroids. Multi-trait GWAS analysis of endometrial cancer and the genetically correlated gynecological diseases identified a novel genome-wide significant endometrial cancer risk locus at 1p36.12, which replicated in an independent endometrial cancer dataset. Interrogation of functional genomic data at 1p36.12 revealed biologically relevant genes, including WNT4 which is necessary for the development of the female reproductive system. In summary, our study provides genetic evidence for a causal relationship between uterine fibroids and endometrial cancer. It further provides evidence that the comorbidity of endometrial cancer, PCOS and uterine fibroids may partly be due to shared genetic architecture. Notably, this shared architecture has revealed a novel genome-wide risk locus for endometrial cancer.

UR - https://www.scopus.com/pages/publications/85114055546

U2 - 10.1007/s00439-021-02312-0

DO - 10.1007/s00439-021-02312-0

M3 - Article

C2 - 34268601

AN - SCOPUS:85114055546

SN - 0340-6717

VL - 140

SP - 1353

EP - 1365

JO - Human Genetics

JF - Human Genetics

IS - 9

ER -

Kho PF, Mortlock S, Endometrial Cancer Association Consortium, International Endometriosis Genetics Consortium, Rogers PAW, Nyholt DR et al. Genetic analyses of gynecological disease identify genetic relationships between uterine fibroids and endometrial cancer, and a novel endometrial cancer genetic risk region at the WNT4 1p36.12 locus. Human Genetics. 2021 Sept;140(9):1353-1365. doi: 10.1007/s00439-021-02312-0

Genetic analyses of gynecological disease identify genetic relationships between uterine fibroids and endometrial cancer, and a novel endometrial cancer genetic risk region at the WNT4 1p36.12 locus

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