CYP19A1 fine-mapping and Mendelian randomization: estradiol is causal for endometrial cancer

Deborah J. Thompson; Tracy A. O'Mara; Dylan M. Glubb; Jodie N. Painter; Timothy Cheng; Elizabeth Folkerd; Deborah Doody; Joe Dennis; Penelope M. Webb; Maggie Gorman; Lynn Martin; Shirley Hodgson; Kyriaki Michailidou; Jonathan P. Tyrer; Mel J. Maranian; Per Hall; Kamila Czene; Hatef Darabi; Jingmei Li; Peter A. Fasching; Alexander Hein; Matthias W. Beckmann; Arif B. Ekici; Thilo Dörk; Peter Hillemanns; Matthias Dürst; Ingo Runnebaum; Hui Zhao; Jeroen Depreeuw; Stefanie Schrauwen; Frederic Amant; Ellen L. Goode; Brooke L. Fridley; Sean C. Dowdy; Stacey J. Winham; Helga B. Salvesen; Jone Trovik; Tormund S. Njolstad; Henrica M. J. Werner; Katie Ashton; Tony Proietto; Geoffrey Otton; Luis Carvajal-Carmona; Emma Tham; Tao Liu; Miriam Mints; Rodney J. Scott; Mark McEvoy; John Attia; Elizabeth G. Holliday; Grant W. Montgomery; Nicholas G. Martin; Dale R. Nyholt; Anjali K. Henders; John L. Hopper; Nadia Traficante; Matthias Ruebner; Anthony J. Swerdlow; Barbara Burwinkel; Hermann Brenner; Alfons Meindl; Hiltrud Brauch; Annika Lindblom; Diether Lambrechts; Jenny Chang-Claude; Fergus J. Couch; Graham G. Giles; Vessela N. Kristensen; Angela Cox; Manjeet K. Bolla; Qin Wang; Stig E. Bojesen; Mitul Shah; Robert Luben; Kay-Tee Khaw; Paul D. P. Pharoah; Alison M. Dunning; Ian Tomlinson; Mitch Dowsett; Douglas F. Easton; Amanda B. Spurdle

doi:https://doi.org/10.1530/ERC-15-0386

CYP19A1 fine-mapping and Mendelian randomization: estradiol is causal for endometrial cancer

Deborah J. Thompson, Tracy A. O'Mara, Dylan M. Glubb, Jodie N. Painter, Timothy Cheng, Elizabeth Folkerd, Deborah Doody, Joe Dennis, Penelope M. Webb, Maggie Gorman, Lynn Martin, Shirley Hodgson, Kyriaki Michailidou, Jonathan P. Tyrer, Mel J. Maranian, Per Hall, Kamila Czene, Hatef Darabi, Jingmei Li, Peter A. FaschingAlexander Hein, Matthias W. Beckmann, Arif B. Ekici, Thilo Dörk, Peter Hillemanns, Matthias Dürst, Ingo Runnebaum, Hui Zhao, Jeroen Depreeuw, Stefanie Schrauwen, Frederic Amant, Ellen L. Goode, Brooke L. Fridley, Sean C. Dowdy, Stacey J. Winham, Helga B. Salvesen, Jone Trovik, Tormund S. Njolstad, Henrica M. J. Werner, Katie Ashton, Tony Proietto, Geoffrey Otton, Luis Carvajal-Carmona, Emma Tham, Tao Liu, Miriam Mints, Rodney J. Scott, Mark McEvoy, John Attia, Elizabeth G. Holliday, Grant W. Montgomery, Nicholas G. Martin, Dale R. Nyholt, Anjali K. Henders, John L. Hopper, Nadia Traficante, Matthias Ruebner, Anthony J. Swerdlow, Barbara Burwinkel, Hermann Brenner, Alfons Meindl, Hiltrud Brauch, Annika Lindblom, Diether Lambrechts, Jenny Chang-Claude, Fergus J. Couch, Graham G. Giles, Vessela N. Kristensen, Angela Cox, Manjeet K. Bolla, Qin Wang, Stig E. Bojesen, Mitul Shah, Robert Luben, Kay-Tee Khaw, Paul D. P. Pharoah, Alison M. Dunning, Ian Tomlinson, Mitch Dowsett, Douglas F. Easton, Amanda B. Spurdle

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Abstract

Candidate gene studies have reported CYP19A1 variants to be associated with endometrial cancer and with estradiol (E-2) concentrations. We analyzed 2937 single nucleotide polymorphisms (SNPs) in 6608 endometrial cancer cases and 37 925 controls and report the first genome wide-significant association between endometrial cancer and a CYP19A1 SNP (rs727479 in intron 2, P=4.8x10(-11)). SNP rs727479 was also among those most strongly associated with circulating E-2 concentrations in 2767 post-menopausal controls (P=7.4x10(-8)). The observed endometrial cancer odds ratio per rs727479 A-allele (1.15, CI=1.11-1.21) is compatible with that predicted by the observed effect on E-2 concentrations (1.09, CI=1.03-1.21), consistent with the hypothesis that endometrial cancer risk is driven by E-2. From 28 candidate-causal SNPs, 12 co-located with three putative gene-regulatory elements and their risk alleles associated with higher CYP19A1 expression in bioinformatical analyses. For both phenotypes, the associations with rs727479 were stronger among women with a higher BMI (P-interaction=0.034 and 0.066 respectively), suggesting a biologically plausible gene-environment interaction

Original language	English
Pages (from-to)	77-91
Journal	Endocrine-related cancer
Volume	23
Issue number	2
DOIs	https://doi.org/10.1530/ERC-15-0386
Publication status	Published - 2016

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https://doi.org/10.1530/ERC-15-0386

Cite this

Thompson, D. J., O'Mara, T. A., Glubb, D. M., Painter, J. N., Cheng, T., Folkerd, E., Doody, D., Dennis, J., Webb, P. M., Gorman, M., Martin, L., Hodgson, S., Michailidou, K., Tyrer, J. P., Maranian, M. J., Hall, P., Czene, K., Darabi, H., Li, J., ... Spurdle, A. B. (2016). CYP19A1 fine-mapping and Mendelian randomization: estradiol is causal for endometrial cancer. Endocrine-related cancer, 23(2), 77-91. https://doi.org/10.1530/ERC-15-0386

@article{6fd6a93219ea4d8dbe3db46ffcd0a590,

title = "CYP19A1 fine-mapping and Mendelian randomization: estradiol is causal for endometrial cancer",

abstract = "Candidate gene studies have reported CYP19A1 variants to be associated with endometrial cancer and with estradiol (E-2) concentrations. We analyzed 2937 single nucleotide polymorphisms (SNPs) in 6608 endometrial cancer cases and 37 925 controls and report the first genome wide-significant association between endometrial cancer and a CYP19A1 SNP (rs727479 in intron 2, P=4.8x10(-11)). SNP rs727479 was also among those most strongly associated with circulating E-2 concentrations in 2767 post-menopausal controls (P=7.4x10(-8)). The observed endometrial cancer odds ratio per rs727479 A-allele (1.15, CI=1.11-1.21) is compatible with that predicted by the observed effect on E-2 concentrations (1.09, CI=1.03-1.21), consistent with the hypothesis that endometrial cancer risk is driven by E-2. From 28 candidate-causal SNPs, 12 co-located with three putative gene-regulatory elements and their risk alleles associated with higher CYP19A1 expression in bioinformatical analyses. For both phenotypes, the associations with rs727479 were stronger among women with a higher BMI (P-interaction=0.034 and 0.066 respectively), suggesting a biologically plausible gene-environment interaction",

author = "Thompson, {Deborah J.} and O'Mara, {Tracy A.} and Glubb, {Dylan M.} and Painter, {Jodie N.} and Timothy Cheng and Elizabeth Folkerd and Deborah Doody and Joe Dennis and Webb, {Penelope M.} and Maggie Gorman and Lynn Martin and Shirley Hodgson and Kyriaki Michailidou and Tyrer, {Jonathan P.} and Maranian, {Mel J.} and Per Hall and Kamila Czene and Hatef Darabi and Jingmei Li and Fasching, {Peter A.} and Alexander Hein and Beckmann, {Matthias W.} and Ekici, {Arif B.} and Thilo D{\"o}rk and Peter Hillemanns and Matthias D{\"u}rst and Ingo Runnebaum and Hui Zhao and Jeroen Depreeuw and Stefanie Schrauwen and Frederic Amant and Goode, {Ellen L.} and Fridley, {Brooke L.} and Dowdy, {Sean C.} and Winham, {Stacey J.} and Salvesen, {Helga B.} and Jone Trovik and Njolstad, {Tormund S.} and Werner, {Henrica M. J.} and Katie Ashton and Tony Proietto and Geoffrey Otton and Luis Carvajal-Carmona and Emma Tham and Tao Liu and Miriam Mints and Scott, {Rodney J.} and Mark McEvoy and John Attia and Holliday, {Elizabeth G.} and Montgomery, {Grant W.} and Martin, {Nicholas G.} and Nyholt, {Dale R.} and Henders, {Anjali K.} and Hopper, {John L.} and Nadia Traficante and Matthias Ruebner and Swerdlow, {Anthony J.} and Barbara Burwinkel and Hermann Brenner and Alfons Meindl and Hiltrud Brauch and Annika Lindblom and Diether Lambrechts and Jenny Chang-Claude and Couch, {Fergus J.} and Giles, {Graham G.} and Kristensen, {Vessela N.} and Angela Cox and Bolla, {Manjeet K.} and Qin Wang and Bojesen, {Stig E.} and Mitul Shah and Robert Luben and Kay-Tee Khaw and Pharoah, {Paul D. P.} and Dunning, {Alison M.} and Ian Tomlinson and Mitch Dowsett and Easton, {Douglas F.} and Spurdle, {Amanda B.}",

year = "2016",

doi = "https://doi.org/10.1530/ERC-15-0386",

language = "English",

volume = "23",

pages = "77--91",

journal = "Endocrine-related cancer",

issn = "1351-0088",

publisher = "Society for Endocrinology",

number = "2",

}

Thompson, DJ, O'Mara, TA, Glubb, DM, Painter, JN, Cheng, T, Folkerd, E, Doody, D, Dennis, J, Webb, PM, Gorman, M, Martin, L, Hodgson, S, Michailidou, K, Tyrer, JP, Maranian, MJ, Hall, P, Czene, K, Darabi, H, Li, J, Fasching, PA, Hein, A, Beckmann, MW, Ekici, AB, Dörk, T, Hillemanns, P, Dürst, M, Runnebaum, I, Zhao, H, Depreeuw, J, Schrauwen, S, Amant, F, Goode, EL, Fridley, BL, Dowdy, SC, Winham, SJ, Salvesen, HB, Trovik, J, Njolstad, TS, Werner, HMJ, Ashton, K, Proietto, T, Otton, G, Carvajal-Carmona, L, Tham, E, Liu, T, Mints, M, Scott, RJ, McEvoy, M, Attia, J, Holliday, EG, Montgomery, GW, Martin, NG, Nyholt, DR, Henders, AK, Hopper, JL, Traficante, N, Ruebner, M, Swerdlow, AJ, Burwinkel, B, Brenner, H, Meindl, A, Brauch, H, Lindblom, A, Lambrechts, D, Chang-Claude, J, Couch, FJ, Giles, GG, Kristensen, VN, Cox, A, Bolla, MK, Wang, Q, Bojesen, SE, Shah, M, Luben, R, Khaw, K-T, Pharoah, PDP, Dunning, AM, Tomlinson, I, Dowsett, M, Easton, DF & Spurdle, AB 2016, 'CYP19A1 fine-mapping and Mendelian randomization: estradiol is causal for endometrial cancer', Endocrine-related cancer, vol. 23, no. 2, pp. 77-91. https://doi.org/10.1530/ERC-15-0386

TY - JOUR

T1 - CYP19A1 fine-mapping and Mendelian randomization: estradiol is causal for endometrial cancer

AU - Thompson, Deborah J.

AU - O'Mara, Tracy A.

AU - Glubb, Dylan M.

AU - Painter, Jodie N.

AU - Cheng, Timothy

AU - Folkerd, Elizabeth

AU - Doody, Deborah

AU - Dennis, Joe

AU - Webb, Penelope M.

AU - Gorman, Maggie

AU - Martin, Lynn

AU - Hodgson, Shirley

AU - Michailidou, Kyriaki

AU - Tyrer, Jonathan P.

AU - Maranian, Mel J.

AU - Hall, Per

AU - Czene, Kamila

AU - Darabi, Hatef

AU - Li, Jingmei

AU - Fasching, Peter A.

AU - Hein, Alexander

AU - Beckmann, Matthias W.

AU - Ekici, Arif B.

AU - Dörk, Thilo

AU - Hillemanns, Peter

AU - Dürst, Matthias

AU - Runnebaum, Ingo

AU - Zhao, Hui

AU - Depreeuw, Jeroen

AU - Schrauwen, Stefanie

AU - Amant, Frederic

AU - Goode, Ellen L.

AU - Fridley, Brooke L.

AU - Dowdy, Sean C.

AU - Winham, Stacey J.

AU - Salvesen, Helga B.

AU - Trovik, Jone

AU - Njolstad, Tormund S.

AU - Werner, Henrica M. J.

AU - Ashton, Katie

AU - Proietto, Tony

AU - Otton, Geoffrey

AU - Carvajal-Carmona, Luis

AU - Tham, Emma

AU - Liu, Tao

AU - Mints, Miriam

AU - Scott, Rodney J.

AU - McEvoy, Mark

AU - Attia, John

AU - Holliday, Elizabeth G.

AU - Montgomery, Grant W.

AU - Martin, Nicholas G.

AU - Nyholt, Dale R.

AU - Henders, Anjali K.

AU - Hopper, John L.

AU - Traficante, Nadia

AU - Ruebner, Matthias

AU - Swerdlow, Anthony J.

AU - Burwinkel, Barbara

AU - Brenner, Hermann

AU - Meindl, Alfons

AU - Brauch, Hiltrud

AU - Lindblom, Annika

AU - Lambrechts, Diether

AU - Chang-Claude, Jenny

AU - Couch, Fergus J.

AU - Giles, Graham G.

AU - Kristensen, Vessela N.

AU - Cox, Angela

AU - Bolla, Manjeet K.

AU - Wang, Qin

AU - Bojesen, Stig E.

AU - Shah, Mitul

AU - Luben, Robert

AU - Khaw, Kay-Tee

AU - Pharoah, Paul D. P.

AU - Dunning, Alison M.

AU - Tomlinson, Ian

AU - Dowsett, Mitch

AU - Easton, Douglas F.

AU - Spurdle, Amanda B.

PY - 2016

Y1 - 2016

N2 - Candidate gene studies have reported CYP19A1 variants to be associated with endometrial cancer and with estradiol (E-2) concentrations. We analyzed 2937 single nucleotide polymorphisms (SNPs) in 6608 endometrial cancer cases and 37 925 controls and report the first genome wide-significant association between endometrial cancer and a CYP19A1 SNP (rs727479 in intron 2, P=4.8x10(-11)). SNP rs727479 was also among those most strongly associated with circulating E-2 concentrations in 2767 post-menopausal controls (P=7.4x10(-8)). The observed endometrial cancer odds ratio per rs727479 A-allele (1.15, CI=1.11-1.21) is compatible with that predicted by the observed effect on E-2 concentrations (1.09, CI=1.03-1.21), consistent with the hypothesis that endometrial cancer risk is driven by E-2. From 28 candidate-causal SNPs, 12 co-located with three putative gene-regulatory elements and their risk alleles associated with higher CYP19A1 expression in bioinformatical analyses. For both phenotypes, the associations with rs727479 were stronger among women with a higher BMI (P-interaction=0.034 and 0.066 respectively), suggesting a biologically plausible gene-environment interaction

AB - Candidate gene studies have reported CYP19A1 variants to be associated with endometrial cancer and with estradiol (E-2) concentrations. We analyzed 2937 single nucleotide polymorphisms (SNPs) in 6608 endometrial cancer cases and 37 925 controls and report the first genome wide-significant association between endometrial cancer and a CYP19A1 SNP (rs727479 in intron 2, P=4.8x10(-11)). SNP rs727479 was also among those most strongly associated with circulating E-2 concentrations in 2767 post-menopausal controls (P=7.4x10(-8)). The observed endometrial cancer odds ratio per rs727479 A-allele (1.15, CI=1.11-1.21) is compatible with that predicted by the observed effect on E-2 concentrations (1.09, CI=1.03-1.21), consistent with the hypothesis that endometrial cancer risk is driven by E-2. From 28 candidate-causal SNPs, 12 co-located with three putative gene-regulatory elements and their risk alleles associated with higher CYP19A1 expression in bioinformatical analyses. For both phenotypes, the associations with rs727479 were stronger among women with a higher BMI (P-interaction=0.034 and 0.066 respectively), suggesting a biologically plausible gene-environment interaction

U2 - https://doi.org/10.1530/ERC-15-0386

DO - https://doi.org/10.1530/ERC-15-0386

M3 - Article

C2 - 26574572

SN - 1351-0088

VL - 23

SP - 77

EP - 91

JO - Endocrine-related cancer

JF - Endocrine-related cancer

IS - 2

ER -