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 | |
Publication status | Published - Sept 2021 |
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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 - http://www.scopus.com/inward/record.url?scp=85114055546&partnerID=8YFLogxK
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 -