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 PF, Mortlock S, Rogers PAW, Nyholt DR, Montgomery GW, Spurdle AB, Glubb DM, O'Mara TA (2021)
Publication Type: Journal article
Publication year: 2021
Journal
Book Volume: 140
Pages Range: 1353-1365
Journal Issue: 9
DOI: 10.1007/s00439-021-02312-0
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.
Involved external institutions
QIMR Berghofer Medical Research Institute (früher: the Queensland Institute of Medical Research)
Australia (AU)
University of Queensland
Australia (AU)
Queensland University of Technology (QUT)
Australia (AU)
The University of Melbourne
Australia (AU)
Australia (AU)
University of Queensland
Australia (AU)
Queensland University of Technology (QUT)
Australia (AU)
The University of Melbourne
Australia (AU)
How to cite
APA:
Kho, P.F., Mortlock, S., Rogers, P.A.W., Nyholt, D.R., Montgomery, G.W., Spurdle, A.B.,... 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://dx.doi.org/10.1007/s00439-021-02312-0
MLA:
Kho, Pik Fang, 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 140.9 (2021): 1353-1365.
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