Multi-trait genome-wide association study identifies a novel endometrial cancer risk locus that associates with testosterone levels
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Description
To detect novel endometrial cancer risk variants, we leveraged information from endometrial cancer risk factors in a multi-trait GWAS analysis. We first assessed causal relationships between established and suspected endometrial cancer risk factors, and endometrial cancer using Mendelian randomization. Following multivariable analysis, five independent risk factors (waist circumference, testosterone levels, sex hormone binding globulin levels, age at menarche, and age at natural menopause) were included in a multi-trait Bayesian GWAS analysis. We identified three potentially novel loci that associate with endometrial cancer risk, one of which (7q22.1) replicated in an independent endometrial cancer GWAS dataset and was genome-wide significant in a meta-analysis. This locus may affect endometrial cancer risk through altered testosterone levels. Consistent with this, we observed colocalization between the signals for endometrial cancer risk and expression of CYP3A7, a gene involved in testosterone metabolism. Thus, our findings suggest opportunities for hormone therapy to prevent or treat endometrial cancer.
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| ID Code: | 241271 |
|---|---|
| Item Type: | Contribution to Journal (Journal Article) |
| Refereed: | Yes |
| Additional Information: | Acknowledgments This work was supported by a National Health and Medical Research Council (NHMRC) of Australia Investigator Grant (APP1173170), a Cancer Australia PdCCRS Project Grant, funded by Cure Cancer Australia and the Compton Foundation (#1138084) awarded to T.A.O’M, an NHMRC Project Grant (APP1158083) awarded to T.A.O’M and D.M.G, and a project grant awarded to T.A.O’M co-funded by Worldwide Cancer Research and Cancer Australia (grant number 22-0253). T.A.O’M and A.B.S. are supported by NHMRC Investigator Fellowships (APP1173170 and APP1177524). P.F.K. was supported by an Australian Government Research Training Program PhD Scholarship and QIMR Berghofer Postgraduate Top-Up Scholarship. E.J.C. is supported by a National Institute for Health Research (NIHR) Advanced Fellowship (NIHR300650). E.J.C., C.B., and D.G.E. were supported by the NIHR Manchester Biomedical Research Centre (IS-BRC-1215-20007). D.R. and T.D. were supported by the Wilhelm Sander Foundation (2021.142.1) This work was conducted using the UK Biobank Resource (application number 25331). We thank the participants and investigators of the FinnGen study and the Biobank Japan Project. The Genotype-Tissue Expression (GTEx) Project was supported by the Common Fund of the Office of the Director of the U.S. National Institutes of Health, and by NCI, NHGRI, NHLBI, NIDA, NIMH, and NINDS. The data used for the analyses described in this article were obtained from the GTEx Portal in February 2021. We thank the many individuals who participated in the Endometrial Cancer Association Consortium and the numerous institutions and their staff who supported recruitment. We particularly thank the efforts of Deborah Thompson. The endometrial cancer genome-wide association analyses were supported by the National Health and Medical Research Council of Australia (APP552402, APP1031333, APP1109286, APP1111246, and APP1061779), the U.S. National Institutes of Health (R01-CA134958), European Research Council (EU FP7 Grant), Wellcome Trust Centre for Human Genetics (090532/Z/09Z) and Cancer Research UK. OncoArray genotyping of ECAC cases was performed with the generous assistance of the Ovarian Cancer Association Consortium (OCAC), which was funded through grants from the U.S. National Institutes of Health (CA1X01HG007491-01 (C.I. Amos), U19-CA148112 (T.A. Sellers), R01-CA149429 (C.M. Phelan) and R01-CA058598 (M.T. Goodman); Canadian Institutes of Health Research (MOP-86727 (L.E. Kelemen)) and the Ovarian Cancer Research Fund (A. Berchuck). We particularly thank the efforts of Cathy Phelan. OncoArray genotyping of the BCAC controls was funded by Genome Canada Grant GPH-129344, U.S. National Institutes of Health Grant U19 CA148065, and Cancer UK Grant C1287/A16563. All studies and funders are listed in O’Mara et al. (2018). Full acknowledgments and funding for ECAC can be found in the Supplementary Note. |
| Measurements or Duration: | 18 pages |
| Keywords: | Bioinformatics, Cancer, Genomics, Systems biology |
| DOI: | 10.1016/j.isci.2023.106590 |
| ISSN: | 2589-0042 |
| Pure ID: | 139166910 |
| Divisions: | Current > QUT Faculties and Divisions > Faculty of Health Current > Schools > School of Biomedical Sciences |
| Funding Information: | This work was supported by a National Health and Medical Research Council ( NHMRC ) of Australia Investigator Grant ( APP1173170 ), a Cancer Australia PdCCRS Project Grant, funded by Cure Cancer Australia and the Compton Foundation (#1138084) awarded to T.A.O’M, an NHMRC Project Grant ( APP1158083 ) awarded to T.A.O’M and D.M.G, and a project grant awarded to T.A.O’M co-funded by Worldwide Cancer Research and Cancer Australia (grant number 22-0253 ). T.A.O’M and A.B.S. are supported by NHMRC Investigator Fellowships ( APP1173170 and APP1177524 ). P.F.K. was supported by an Australian Government Research Training Program PhD Scholarship and QIMR Berghofer Postgraduate Top-Up Scholarship. E.J.C. is supported by a National Institute for Health Research ( NIHR ) Advanced Fellowship ( NIHR300650 ). E.J.C., C.B., and D.G.E. were supported by the NIHR Manchester Biomedical Research Centre ( IS-BRC-1215-20007 ). D.R. and T.D. were supported by the Wilhelm Sander Foundation (2021.142.1) This work was conducted using the UK Biobank Resource (application number 25331). We thank the participants and investigators of the FinnGen study and the Biobank Japan Project. The Genotype-Tissue Expression (GTEx) Project was supported by the Common Fund of the Office of the Director of the U.S. National Institutes of Health , and by NCI , NHGRI , NHLBI , NIDA , NIMH , and NINDS . The data used for the analyses described in this article were obtained from the GTEx Portal in February 2021. We thank the many individuals who participated in the Endometrial Cancer Association Consortium and the numerous institutions and their staff who supported recruitment. We particularly thank the efforts of Deborah Thompson. The endometrial cancer genome-wide association analyses were supported by the National Health and Medical Research Council of Australia ( APP552402 , APP1031333 , APP1109286 , APP1111246 , and APP1061779 ), the U.S. National Institutes of Health ( R01-CA134958 ), European Research Council ( EU FP7 Grant), Wellcome Trust Centre for Human Genetics ( 090532/Z/09Z ) and Cancer Research UK . OncoArray genotyping of ECAC cases was performed with the generous assistance of the Ovarian Cancer Association Consortium (OCAC), which was funded through grants from the U.S. National Institutes of Health ( CA1X01HG007491-01 (C.I. Amos), U19-CA148112 (T.A. Sellers), R01-CA149429 (C.M. Phelan) and R01-CA058598 (M.T. Goodman); Canadian Institutes of Health Research ( MOP-86727 (L.E. Kelemen)) and the Ovarian Cancer Research Fund (A. Berchuck). We particularly thank the efforts of Cathy Phelan. OncoArray genotyping of the BCAC controls was funded by Genome Canada Grant GPH-129344 , U.S. National Institutes of Health Grant U19 CA148065 , and Cancer UK Grant C1287/A16563 . All studies and funders are listed in O’Mara et al. (2018). Full acknowledgments and funding for ECAC can be found in the Supplementary Note. This work was supported by a National Health and Medical Research Council (NHMRC) of Australia Investigator Grant (APP1173170), a Cancer Australia PdCCRS Project Grant, funded by Cure Cancer Australia and the Compton Foundation (#1138084) awarded to T.A.O'M, an NHMRC Project Grant (APP1158083) awarded to T.A.O'M and D.M.G, and a project grant awarded to T.A.O'M co-funded by Worldwide Cancer Research and Cancer Australia (grant number 22-0253). T.A.O'M and A.B.S. are supported by NHMRC Investigator Fellowships (APP1173170 and APP1177524). P.F.K. was supported by an Australian Government Research Training Program PhD Scholarship and QIMR Berghofer Postgraduate Top-Up Scholarship. E.J.C. is supported by a National Institute for Health Research (NIHR) Advanced Fellowship (NIHR300650). E.J.C. C.B. and D.G.E. were supported by the NIHR Manchester Biomedical Research Centre (IS-BRC-1215-20007). D.R. and T.D. were supported by the Wilhelm Sander Foundation (2021.142.1), This work was conducted using the UK Biobank Resource (application number 25331). We thank the participants and investigators of the FinnGen study and the Biobank Japan Project. The Genotype-Tissue Expression (GTEx) Project was supported by the Common Fund of the Office of the Director of the U.S. National Institutes of Health, and by NCI, NHGRI, NHLBI, NIDA, NIMH, and NINDS. The data used for the analyses described in this article were obtained from the GTEx Portal in February 2021. We thank the many individuals who participated in the Endometrial Cancer Association Consortium and the numerous institutions and their staff who supported recruitment. We particularly thank the efforts of Deborah Thompson. The endometrial cancer genome-wide association analyses were supported by the National Health and Medical Research Council of Australia (APP552402, APP1031333, APP1109286, APP1111246, and APP1061779), the U.S. National Institutes of Health (R01-CA134958), European Research Council (EU FP7 Grant), Wellcome Trust Centre for Human Genetics (090532/Z/09Z) and Cancer Research UK. OncoArray genotyping of ECAC cases was performed with the generous assistance of the Ovarian Cancer Association Consortium (OCAC), which was funded through grants from the U.S. National Institutes of Health (CA1X01HG007491-01 (C.I. Amos), U19-CA148112 (T.A. Sellers), R01-CA149429 (C.M. Phelan) and R01-CA058598 (M.T. Goodman); Canadian Institutes of Health Research (MOP-86727 (L.E. Kelemen)) and the Ovarian Cancer Research Fund (A. Berchuck). We particularly thank the efforts of Cathy Phelan. OncoArray genotyping of the BCAC controls was funded by Genome Canada Grant GPH-129344, U.S. National Institutes of Health Grant U19 CA148065, and Cancer UK Grant C1287/A16563. All studies and funders are listed in O'Mara et al. (2018). Full acknowledgments and funding for ECAC can be found in the Supplementary Note. Conceptualization, T.A.O, X.W. and D.M.G. and.; methodology, X.W. D.M.G. and T.A.O.; investigation, X.W. D.M.G. T.A.O. P.F.K. D.R. and T.D.; data curation, X.W. D.G.M. T.A.O; writing – original draft, X.W. DMG, and TAO; writing – review & editing, all authors; funding acquisition, T.A.O.; resources, T.A.O. D.M.G. T.D. A.B.S, C.B. F.A. E.L.G. R.J.S. I.T. D.G.E. and E.J.C.; supervision, T.O.M. The authors declare no competing interests. We support inclusive, diverse, and equitable conduct of research. |
| Copyright Owner: | 2023 The Authors |
| Copyright Statement: | This work is covered by copyright. Unless the document is being made available under a Creative Commons Licence, you must assume that re-use is limited to personal use and that permission from the copyright owner must be obtained for all other uses. If the document is available under a Creative Commons License (or other specified license) then refer to the Licence for details of permitted re-use. It is a condition of access that users recognise and abide by the legal requirements associated with these rights. If you believe that this work infringes copyright please provide details by email to qut.copyright@qut.edu.au |
| Deposited On: | 06 Jul 2023 06:03 |
| Last Modified: | 04 Aug 2024 20:59 |
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