Multi-trait genome-wide association study identifies a novel endometrial cancer risk locus that associates with testosterone levels

Xuemin Wang; Pik Fang Kho; Dhanya Ramachandran; Cemsel Bafligil; Frederic Amant; Ellen L. Goode; Rodney J. Scott; Ian Tomlinson; D. Gareth Evans; Emma J. Crosbie; Thilo Dörk; Amanda B. Spurdle; Dylan M. Glubb; Tracy A. O'Mara

doi:https://doi.org/10.1016/j.isci.2023.106590

Multi-trait genome-wide association study identifies a novel endometrial cancer risk locus that associates with testosterone levels

Xuemin Wang, Pik Fang Kho, Dhanya Ramachandran, Cemsel Bafligil, Frederic Amant, Ellen L. Goode, Rodney J. Scott, Ian Tomlinson, D. Gareth Evans, Emma J. Crosbie, Thilo Dörk, Amanda B. Spurdle, Dylan M. Glubb, Tracy A. O'Mara

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

2 Citations (Scopus)

Abstract

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.

Original language	English
Article number	106590
Journal	iScience
Volume	26
Issue number	5
DOIs	https://doi.org/10.1016/j.isci.2023.106590
Publication status	Published - 19 May 2023

Keywords

Bioinformatics
Cancer
Genomics
Systems biology

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https://doi.org/10.1016/j.isci.2023.106590

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Wang, X., Kho, P. F., Ramachandran, D., Bafligil, C., Amant, F., Goode, E. L., Scott, R. J., Tomlinson, I., Evans, D. G., Crosbie, E. J., Dörk, T., Spurdle, A. B., Glubb, D. M., & O'Mara, T. A. (2023). Multi-trait genome-wide association study identifies a novel endometrial cancer risk locus that associates with testosterone levels. iScience, 26(5), Article 106590. https://doi.org/10.1016/j.isci.2023.106590

@article{91c95b3b15714221a4372785c320e9c3,

title = "Multi-trait genome-wide association study identifies a novel endometrial cancer risk locus that associates with testosterone levels",

abstract = "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.",

keywords = "Bioinformatics, Cancer, Genomics, Systems biology",

author = "Xuemin Wang and Kho, {Pik Fang} and Dhanya Ramachandran and Cemsel Bafligil and Frederic Amant and Goode, {Ellen L.} and Scott, {Rodney J.} and Ian Tomlinson and Evans, {D. Gareth} and Crosbie, {Emma J.} and Thilo D{\"o}rk and Spurdle, {Amanda B.} and Glubb, {Dylan M.} and O'Mara, {Tracy A.}",

note = "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{\textquoteright}M, an NHMRC Project Grant ( APP1158083 ) awarded to T.A.O{\textquoteright}M and D.M.G, and a project grant awarded to T.A.O{\textquoteright}M co-funded by Worldwide Cancer Research and Cancer Australia (grant number 22-0253 ). T.A.O{\textquoteright}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) Funding Information: 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. Funding Information: 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{\textquoteright}Mara et al. (2018). Full acknowledgments and funding for ECAC can be found in the Supplementary Note. 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. 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. Publisher Copyright: {\textcopyright} 2023 The Author(s)",

year = "2023",

month = may,

day = "19",

doi = "https://doi.org/10.1016/j.isci.2023.106590",

language = "English",

volume = "26",

journal = "iScience",

issn = "2589-0042",

publisher = "Elsevier",

number = "5",

}

Wang, X, Kho, PF, Ramachandran, D, Bafligil, C, Amant, F, Goode, EL, Scott, RJ, Tomlinson, I, Evans, DG, Crosbie, EJ, Dörk, T, Spurdle, AB, Glubb, DM & O'Mara, TA 2023, 'Multi-trait genome-wide association study identifies a novel endometrial cancer risk locus that associates with testosterone levels', iScience, vol. 26, no. 5, 106590. https://doi.org/10.1016/j.isci.2023.106590

TY - JOUR

T1 - Multi-trait genome-wide association study identifies a novel endometrial cancer risk locus that associates with testosterone levels

AU - Wang, Xuemin

AU - Kho, Pik Fang

AU - Ramachandran, Dhanya

AU - Bafligil, Cemsel

AU - Amant, Frederic

AU - Goode, Ellen L.

AU - Scott, Rodney J.

AU - Tomlinson, Ian

AU - Evans, D. Gareth

AU - Crosbie, Emma J.

AU - Dörk, Thilo

AU - Spurdle, Amanda B.

AU - Glubb, Dylan M.

AU - O'Mara, Tracy A.

N1 - 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) Funding Information: 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. Funding Information: 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. 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. 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. Publisher Copyright: © 2023 The Author(s)

PY - 2023/5/19

Y1 - 2023/5/19

N2 - 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.

AB - 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.

KW - Bioinformatics

KW - Cancer

KW - Genomics

KW - Systems biology

UR - http://www.scopus.com/inward/record.url?scp=85153504129&partnerID=8YFLogxK

U2 - https://doi.org/10.1016/j.isci.2023.106590

DO - https://doi.org/10.1016/j.isci.2023.106590

M3 - Article

C2 - 37168552

SN - 2589-0042

VL - 26

JO - iScience

JF - iScience

IS - 5

M1 - 106590

ER -

Multi-trait genome-wide association study identifies a novel endometrial cancer risk locus that associates with testosterone levels

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