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 - iPSYCH-SSI-Broad Groupw
AU - International Endometriosis Genetics Consortium
AU - Endometrial Cancer Association Consortium
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 - Winham, Stacey J.
N1 - 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.
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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 -