Large-scale genomic analyses link reproductive aging to hypothalamic signaling, breast cancer susceptibility and BRCA1-mediated DNA repair

Felix R. Day; Katherine S. Ruth; Deborah J. Thompson; Kathryn L. Lunetta; Natalia Pervjakova; Daniel I. Chasman; Lisette Stolk; Hilary K. Finucane; Patrick Sulem; Brendan Bulik-Sullivan; Tõnu Esko; Andrew D. Johnson; Cathy E. Elks; Nora Franceschini; Chunyan He; Elisabeth Altmaier; Jennifer A. Brody; Lude L. Franke; Jennifer EHuffman; Margaux F. Keller; Patrick F. McArdle; Teresa Nutile; Eleonora Porcu; Antonietta Robino; Lynda M. Rose; Ursula M. Schick; Jennifer A. Smith; Alexander Teumer; Michela Traglia; Dragana Vuckovic; Jie Yao; Wei Zhao; Eva Albrecht; Najaf Amin; Tanguy Corre; Jouke Jan Hottenga; Massimo Mangino; Albert V. Smith; Toshiko Tanaka; Gonçalo R. Abecasis; Irene L. Andrulis; Hoda Anton-Culver; Antonis C. Antoniou; Volker Arndt; Alice M. Arnold; Caterina Barbieri; Matthias W. Beckmann; Alicia Beeghly-Fadiel; Javier Benitez; Leslie Bernstein; Suzette J. Bielinski; Carl Blomqvist; Eric Boerwinkle; Natalia V. Bogdanova; Stig E. Bojesen; Manjeet K. Bolla; Anne Lise Borresen-Dale; Thibaud S. Boutin; Hiltrud Brauch; Hermann Brenner; Thomas Brüning; Barbara Burwinkel; Archie Campbell; Harry Campbell; Stephen J. Chanock; J. Ross Chapman; Yii Der Ida Chen; Georgia Chenevix-Trench; Fergus J. Couch; Andrea D. Coviello; Angela Cox; Kamila Czene; Hatef Darabi; Immaculata De Vivo; Ellen W. Demerath; Joe Dennis; Peter Devilee; Thilo Dörk; Isabel Dos-Santos-Silva; Alison M. Dunning; John D. Eicher; Peter A. Fasching; Jessica D. Faul; Jonine Figueroa; Dieter Flesch-Janys; Ilaria Gandin; Melissa E. Garcia; Montserrat García-Closas; Graham G. Giles; Giorgia G. Girotto; Mark S. Goldberg; Anna Gonz'lez-Neira; Mark O. Goodarzi; Megan L. Grove; Daniel F. Gudbjartsson; Pascal Guénel; Xiuqing Guo; Christopher A. Haiman; Per Hall; Ute Hamann; Brian E. Henderson; Lynne J. Hocking; Albert Hofman; Georg Homuth; Maartje J. Hooning; John L. Hopper; Frank B. Hu; Jinyan Huang; Keith Humphreys; David J. Hunter; Anna Jakubowska; Samuel E. Jones; Maria Kabisch; David Karasik; Julia A. Knight; Ivana Kolcic; Charles Kooperberg; Veli Matti Kosma; Jennifer Kriebel; Vessela Kristensen; Diether Lambrechts; Claudia Langenberg; Jingmei Li; Xin Li; Sara Lindström; Yongmei Liu; Jian'An Luan; Jan Lubinski; Reedik Mägi; Arto Mannermaa; Judith Manz; Sara Margolin; Jonathan Marten; Nicholas G. Martin; Corrado Masciullo; Alfons Meindl; Kyriaki Michailidou; Evelin Mihailov; Lili Milani; Roger L. Milne; Martina Müller-Nurasyid; Michael Nalls; Benjamin M. Neale; Heli Nevanlinna; Patrick Neven; Anne B. Newman; BØrge G. Nordestgaard; Janet E. Olson; Sandosh Padmanabhan; Paolo Peterlongo; Ulrike Peters; Astrid Petersmann; Julian Peto; Paul D P Pharoah; Nicola N. Pirastu; Ailith Pirie; Giorgio Pistis; Ozren Polasek; David Porteous; Bruce M. Psaty; Katri Pylkäs; Paolo Radice; Leslie J. Raffel; Fernando Rivadeneira; Igor Rudan; Anja Rudolph; Daniela Ruggiero; Cinzia F. Sala; Serena Sanna; Elinor J. Sawyer; David Schlessinger; Marjanka K. Schmidt; Frank Schmidt; Rita K. Schmutzler; Minouk J. Schoemaker; Robert A. Scott; Caroline M. Seynaeve; Jacques Simard; Rossella Sorice; Melissa C. Southey; Doris Stöckl; Konstantin Strauch; Anthony Swerdlow; Kent D. Taylor; Unnur Thorsteinsdottir; Amanda E. Toland; Ian Tomlinson; Thérèse Truong; Laufey Tryggvadottir; Stephen T. Turner; Diego Vozzi; Qin Wang; Melissa Wellons; Gonneke Willemsen; James F. Wilson; Robert Winqvist; Bruce B H R Wolffenbuttel; Alan F. Wright; Drakoulis Yannoukakos; Tatijana Zemunik; Wei Zheng; Marek Zygmunt; Sven Bergmann; Dorret I. Boomsma; Julie E. Buring; Luigi Ferrucci; Grant W. Montgomery; Vilmundur Gudnason; Tim D. Spector; Cornelia Mvan Duijn; Behrooz Z. Alizadeh; Marina Ciullo; Laura Crisponi; Douglas F. Easton; Paolo P. Gasparini; Christian Gieger; Tamara B. Harris; Caroline Hayward; Sharon L R Kardia; Peter Kraft; Barbara McKnight; Andres Metspalu; Alanna C. Morrison; Alex P. Reiner; Paul M. Ridker; Jerome I. Rotter; Daniela Toniolo; André G. Uitterlinden; Sheila Ulivi; Henry Völzke; Nicholas J. Wareham; David R. Weir; Laura M. Yerges-Armstrong; Alkes L. Price; Kari Stefansson; Jenny A. Visser; Ken K. Ong; Jenny Chang-Claude; Joanne M. Murabito; John R B Perry; Anna Murray

doi:10.1038/ng.3412

Large-scale genomic analyses link reproductive aging to hypothalamic signaling, breast cancer susceptibility and BRCA1-mediated DNA repair

Felix R. Day, Katherine S. Ruth, Deborah J. Thompson, Kathryn L. Lunetta, Natalia Pervjakova, Daniel I. Chasman, Lisette Stolk, Hilary K. Finucane, Patrick Sulem, Brendan Bulik-Sullivan, Tõnu Esko, Andrew D. Johnson, Cathy E. Elks, Nora Franceschini, Chunyan He, Elisabeth Altmaier, Jennifer A. Brody, Lude L. Franke, Jennifer EHuffman, Margaux F. KellerPatrick F. McArdle, Teresa Nutile, Eleonora Porcu, Antonietta Robino, Lynda M. Rose, Ursula M. Schick, Jennifer A. Smith, Alexander Teumer, Michela Traglia, Dragana Vuckovic, Jie Yao, Wei Zhao, Eva Albrecht, Najaf Amin, Tanguy Corre, Jouke Jan Hottenga, Massimo Mangino, Albert V. Smith, Toshiko Tanaka, Gonçalo R. Abecasis, Irene L. Andrulis, Hoda Anton-Culver, Antonis C. Antoniou, Volker Arndt, Alice M. Arnold, Caterina Barbieri, Matthias W. Beckmann, Alicia Beeghly-Fadiel, Javier Benitez, Leslie Bernstein, Suzette J. Bielinski, Carl Blomqvist, Eric Boerwinkle, Natalia V. Bogdanova, Stig E. Bojesen, Manjeet K. Bolla, Anne Lise Borresen-Dale, Thibaud S. Boutin, Hiltrud Brauch, Hermann Brenner, Thomas Brüning, Barbara Burwinkel, Archie Campbell, Harry Campbell, Stephen J. Chanock, J. Ross Chapman, Yii Der Ida Chen, Georgia Chenevix-Trench, Fergus J. Couch, Andrea D. Coviello, Angela Cox, Kamila Czene, Hatef Darabi, Immaculata De Vivo, Ellen W. Demerath, Joe Dennis, Peter Devilee, Thilo Dörk, Isabel Dos-Santos-Silva, Alison M. Dunning, John D. Eicher, Peter A. Fasching, Jessica D. Faul, Jonine Figueroa, Dieter Flesch-Janys, Ilaria Gandin, Melissa E. Garcia, Montserrat García-Closas, Graham G. Giles, Giorgia G. Girotto, Mark S. Goldberg, Anna Gonz'lez-Neira, Mark O. Goodarzi, Megan L. Grove, Daniel F. Gudbjartsson, Pascal Guénel, Xiuqing Guo, Christopher A. Haiman, Per Hall, Ute Hamann, Brian E. Henderson, Lynne J. Hocking, Albert Hofman, Georg Homuth, Maartje J. Hooning, John L. Hopper, Frank B. Hu, Jinyan Huang, Keith Humphreys, David J. Hunter, Anna Jakubowska, Samuel E. Jones, Maria Kabisch, David Karasik, Julia A. Knight, Ivana Kolcic, Charles Kooperberg, Veli Matti Kosma, Jennifer Kriebel, Vessela Kristensen, Diether Lambrechts, Claudia Langenberg, Jingmei Li, Xin Li, Sara Lindström, Yongmei Liu, Jian'An Luan, Jan Lubinski, Reedik Mägi, Arto Mannermaa, Judith Manz, Sara Margolin, Jonathan Marten, Nicholas G. Martin, Corrado Masciullo, Alfons Meindl, Kyriaki Michailidou, Evelin Mihailov, Lili Milani, Roger L. Milne, Martina Müller-Nurasyid, Michael Nalls, Benjamin M. Neale, Heli Nevanlinna, Patrick Neven, Anne B. Newman, BØrge G. Nordestgaard, Janet E. Olson, Sandosh Padmanabhan, Paolo Peterlongo, Ulrike Peters, Astrid Petersmann, Julian Peto, Paul D P Pharoah, Nicola N. Pirastu, Ailith Pirie, Giorgio Pistis, Ozren Polasek, David Porteous, Bruce M. Psaty, Katri Pylkäs, Paolo Radice, Leslie J. Raffel, Fernando Rivadeneira, Igor Rudan, Anja Rudolph, Daniela Ruggiero, Cinzia F. Sala, Serena Sanna, Elinor J. Sawyer, David Schlessinger, Marjanka K. Schmidt, Frank Schmidt, Rita K. Schmutzler, Minouk J. Schoemaker, Robert A. Scott, Caroline M. Seynaeve, Jacques Simard, Rossella Sorice, Melissa C. Southey, Doris Stöckl, Konstantin Strauch, Anthony Swerdlow, Kent D. Taylor, Unnur Thorsteinsdottir, Amanda E. Toland, Ian Tomlinson, Thérèse Truong, Laufey Tryggvadottir, Stephen T. Turner, Diego Vozzi, Qin Wang, Melissa Wellons, Gonneke Willemsen, James F. Wilson, Robert Winqvist, Bruce B H R Wolffenbuttel, Alan F. Wright, Drakoulis Yannoukakos, Tatijana Zemunik, Wei Zheng, Marek Zygmunt, Sven Bergmann, Dorret I. Boomsma, Julie E. Buring, Luigi Ferrucci, Grant W. Montgomery, Vilmundur Gudnason, Tim D. Spector, Cornelia Mvan Duijn, Behrooz Z. Alizadeh, Marina Ciullo, Laura Crisponi, Douglas F. Easton, Paolo P. Gasparini, Christian Gieger, Tamara B. Harris, Caroline Hayward, Sharon L R Kardia, Peter Kraft, Barbara McKnight, Andres Metspalu, Alanna C. Morrison, Alex P. Reiner, Paul M. Ridker, Jerome I. Rotter, Daniela Toniolo, André G. Uitterlinden, Sheila Ulivi, Henry Völzke, Nicholas J. Wareham, David R. Weir, Laura M. Yerges-Armstrong, Alkes L. Price, Kari Stefansson, Jenny A. Visser, Ken K. Ong, Jenny Chang-Claude, Joanne M. Murabito, John R B Perry, Anna Murray

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

277 Scopus citations

Abstract

Menopause timing has a substantial impact on infertility and risk of disease, including breast cancer, but the underlying mechanisms are poorly understood. We report a dual strategy in -1/470,000 women to identify common and low-frequency protein-coding variation associated with age at natural menopause (ANM). We identified 44 regions with common variants, including two regions harboring additional rare missense alleles of large effect. We found enrichment of signals in or near genes involved in delayed puberty, highlighting the first molecular links between the onset and end of reproductive lifespan. Pathway analyses identified major association with DNA damage response (DDR) genes, including the first common coding variant in BRCA1 associated with any complex trait. Mendelian randomization analyses supported a causal effect of later ANM on breast cancer risk (-1/46% increase in risk per year; P = 3 × 10 -14), likely mediated by prolonged sex hormone exposure rather than DDR mechanisms.

Original language	English (US)
Pages (from-to)	1294-1303
Number of pages	10
Journal	Nature Genetics
Volume	47
Issue number	11
DOIs	https://doi.org/10.1038/ng.3412
State	Published - Nov 1 2015

Bibliographical note

Publisher Copyright:
© 2015 Nature America, Inc.

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This output contributes to the following UN Sustainable Development Goals (SDGs)

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Day, F. R., Ruth, K. S., Thompson, D. J., Lunetta, K. L., Pervjakova, N., Chasman, D. I., Stolk, L., Finucane, H. K., Sulem, P., Bulik-Sullivan, B., Esko, T., Johnson, A. D., Elks, C. E., Franceschini, N., He, C., Altmaier, E., Brody, J. A., Franke, L. L., EHuffman, J., ... Murray, A. (2015). Large-scale genomic analyses link reproductive aging to hypothalamic signaling, breast cancer susceptibility and BRCA1-mediated DNA repair. Nature Genetics, 47(11), 1294-1303. https://doi.org/10.1038/ng.3412

Day, FR, Ruth, KS, Thompson, DJ, Lunetta, KL, Pervjakova, N, Chasman, DI, Stolk, L, Finucane, HK, Sulem, P, Bulik-Sullivan, B, Esko, T, Johnson, AD, Elks, CE, Franceschini, N, He, C, Altmaier, E, Brody, JA, Franke, LL, EHuffman, J, Keller, MF, McArdle, PF, Nutile, T, Porcu, E, Robino, A, Rose, LM, Schick, UM, Smith, JA, Teumer, A, Traglia, M, Vuckovic, D, Yao, J, Zhao, W, Albrecht, E, Amin, N, Corre, T, Hottenga, JJ, Mangino, M, Smith, AV, Tanaka, T, Abecasis, GR, Andrulis, IL, Anton-Culver, H, Antoniou, AC, Arndt, V, Arnold, AM, Barbieri, C, Beckmann, MW, Beeghly-Fadiel, A, Benitez, J, Bernstein, L, Bielinski, SJ, Blomqvist, C, Boerwinkle, E, Bogdanova, NV, Bojesen, SE, Bolla, MK, Borresen-Dale, AL, Boutin, TS, Brauch, H, Brenner, H, Brüning, T, Burwinkel, B, Campbell, A, Campbell, H, Chanock, SJ, Chapman, JR, Chen, YDI, Chenevix-Trench, G, Couch, FJ, Coviello, AD, Cox, A, Czene, K, Darabi, H, De Vivo, I, Demerath, EW, Dennis, J, Devilee, P, Dörk, T, Dos-Santos-Silva, I, Dunning, AM, Eicher, JD, Fasching, PA, Faul, JD, Figueroa, J, Flesch-Janys, D, Gandin, I, Garcia, ME, García-Closas, M, Giles, GG, Girotto, GG, Goldberg, MS, Gonz'lez-Neira, A, Goodarzi, MO, Grove, ML, Gudbjartsson, DF, Guénel, P, Guo, X, Haiman, CA, Hall, P, Hamann, U, Henderson, BE, Hocking, LJ, Hofman, A, Homuth, G, Hooning, MJ, Hopper, JL, Hu, FB, Huang, J, Humphreys, K, Hunter, DJ, Jakubowska, A, Jones, SE, Kabisch, M, Karasik, D, Knight, JA, Kolcic, I, Kooperberg, C, Kosma, VM, Kriebel, J, Kristensen, V, Lambrechts, D, Langenberg, C, Li, J, Li, X, Lindström, S, Liu, Y, Luan, JA, Lubinski, J, Mägi, R, Mannermaa, A, Manz, J, Margolin, S, Marten, J, Martin, NG, Masciullo, C, Meindl, A, Michailidou, K, Mihailov, E, Milani, L, Milne, RL, Müller-Nurasyid, M, Nalls, M, Neale, BM, Nevanlinna, H, Neven, P, Newman, AB, Nordestgaard, BØG, Olson, JE, Padmanabhan, S, Peterlongo, P, Peters, U, Petersmann, A, Peto, J, Pharoah, PDP, Pirastu, NN, Pirie, A, Pistis, G, Polasek, O, Porteous, D, Psaty, BM, Pylkäs, K, Radice, P, Raffel, LJ, Rivadeneira, F, Rudan, I, Rudolph, A, Ruggiero, D, Sala, CF, Sanna, S, Sawyer, EJ, Schlessinger, D, Schmidt, MK, Schmidt, F, Schmutzler, RK, Schoemaker, MJ, Scott, RA, Seynaeve, CM, Simard, J, Sorice, R, Southey, MC, Stöckl, D, Strauch, K, Swerdlow, A, Taylor, KD, Thorsteinsdottir, U, Toland, AE, Tomlinson, I, Truong, T, Tryggvadottir, L, Turner, ST, Vozzi, D, Wang, Q, Wellons, M, Willemsen, G, Wilson, JF, Winqvist, R, Wolffenbuttel, BBHR, Wright, AF, Yannoukakos, D, Zemunik, T, Zheng, W, Zygmunt, M, Bergmann, S, Boomsma, DI, Buring, JE, Ferrucci, L, Montgomery, GW, Gudnason, V, Spector, TD, Duijn, CM, Alizadeh, BZ, Ciullo, M, Crisponi, L, Easton, DF, Gasparini, PP, Gieger, C, Harris, TB, Hayward, C, Kardia, SLR, Kraft, P, McKnight, B, Metspalu, A, Morrison, AC, Reiner, AP, Ridker, PM, Rotter, JI, Toniolo, D, Uitterlinden, AG, Ulivi, S, Völzke, H, Wareham, NJ, Weir, DR, Yerges-Armstrong, LM, Price, AL, Stefansson, K, Visser, JA, Ong, KK, Chang-Claude, J, Murabito, JM, Perry, JRB & Murray, A 2015, 'Large-scale genomic analyses link reproductive aging to hypothalamic signaling, breast cancer susceptibility and BRCA1-mediated DNA repair', Nature Genetics, vol. 47, no. 11, pp. 1294-1303. https://doi.org/10.1038/ng.3412

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title = "Large-scale genomic analyses link reproductive aging to hypothalamic signaling, breast cancer susceptibility and BRCA1-mediated DNA repair",

abstract = "Menopause timing has a substantial impact on infertility and risk of disease, including breast cancer, but the underlying mechanisms are poorly understood. We report a dual strategy in -1/470,000 women to identify common and low-frequency protein-coding variation associated with age at natural menopause (ANM). We identified 44 regions with common variants, including two regions harboring additional rare missense alleles of large effect. We found enrichment of signals in or near genes involved in delayed puberty, highlighting the first molecular links between the onset and end of reproductive lifespan. Pathway analyses identified major association with DNA damage response (DDR) genes, including the first common coding variant in BRCA1 associated with any complex trait. Mendelian randomization analyses supported a causal effect of later ANM on breast cancer risk (-1/46% increase in risk per year; P = 3 × 10 -14), likely mediated by prolonged sex hormone exposure rather than DDR mechanisms.",

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note = "Publisher Copyright: {\textcopyright} 2015 Nature America, Inc.",

year = "2015",

month = nov,

day = "1",

doi = "10.1038/ng.3412",

language = "English (US)",

volume = "47",

pages = "1294--1303",

journal = "Nature Genetics",

issn = "1061-4036",

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TY - JOUR

T1 - Large-scale genomic analyses link reproductive aging to hypothalamic signaling, breast cancer susceptibility and BRCA1-mediated DNA repair

AU - Day, Felix R.

AU - Ruth, Katherine S.

AU - Thompson, Deborah J.

AU - Lunetta, Kathryn L.

AU - Pervjakova, Natalia

AU - Chasman, Daniel I.

AU - Stolk, Lisette

AU - Finucane, Hilary K.

AU - Sulem, Patrick

AU - Bulik-Sullivan, Brendan

AU - Esko, Tõnu

AU - Johnson, Andrew D.

AU - Elks, Cathy E.

AU - Franceschini, Nora

AU - He, Chunyan

AU - Altmaier, Elisabeth

AU - Brody, Jennifer A.

AU - Franke, Lude L.

AU - EHuffman, Jennifer

AU - Keller, Margaux F.

AU - McArdle, Patrick F.

AU - Nutile, Teresa

AU - Porcu, Eleonora

AU - Robino, Antonietta

AU - Rose, Lynda M.

AU - Schick, Ursula M.

AU - Smith, Jennifer A.

AU - Teumer, Alexander

AU - Traglia, Michela

AU - Vuckovic, Dragana

AU - Yao, Jie

AU - Zhao, Wei

AU - Albrecht, Eva

AU - Amin, Najaf

AU - Corre, Tanguy

AU - Hottenga, Jouke Jan

AU - Mangino, Massimo

AU - Smith, Albert V.

AU - Tanaka, Toshiko

AU - Abecasis, Gonçalo R.

AU - Andrulis, Irene L.

AU - Anton-Culver, Hoda

AU - Antoniou, Antonis C.

AU - Arndt, Volker

AU - Arnold, Alice M.

AU - Barbieri, Caterina

AU - Beckmann, Matthias W.

AU - Beeghly-Fadiel, Alicia

AU - Benitez, Javier

AU - Bernstein, Leslie

AU - Bielinski, Suzette J.

AU - Blomqvist, Carl

AU - Boerwinkle, Eric

AU - Bogdanova, Natalia V.

AU - Bojesen, Stig E.

AU - Bolla, Manjeet K.

AU - Borresen-Dale, Anne Lise

AU - Boutin, Thibaud S.

AU - Brauch, Hiltrud

AU - Brenner, Hermann

AU - Brüning, Thomas

AU - Burwinkel, Barbara

AU - Campbell, Archie

AU - Campbell, Harry

AU - Chanock, Stephen J.

AU - Chapman, J. Ross

AU - Chen, Yii Der Ida

AU - Chenevix-Trench, Georgia

AU - Couch, Fergus J.

AU - Coviello, Andrea D.

AU - Cox, Angela

AU - Czene, Kamila

AU - Darabi, Hatef

AU - De Vivo, Immaculata

AU - Demerath, Ellen W.

AU - Dennis, Joe

AU - Devilee, Peter

AU - Dörk, Thilo

AU - Dos-Santos-Silva, Isabel

AU - Dunning, Alison M.

AU - Eicher, John D.

AU - Fasching, Peter A.

AU - Faul, Jessica D.

AU - Figueroa, Jonine

AU - Flesch-Janys, Dieter

AU - Gandin, Ilaria

AU - Garcia, Melissa E.

AU - García-Closas, Montserrat

AU - Giles, Graham G.

AU - Girotto, Giorgia G.

AU - Goldberg, Mark S.

AU - Gonz'lez-Neira, Anna

AU - Goodarzi, Mark O.

AU - Grove, Megan L.

AU - Gudbjartsson, Daniel F.

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PY - 2015/11/1

Y1 - 2015/11/1

N2 - Menopause timing has a substantial impact on infertility and risk of disease, including breast cancer, but the underlying mechanisms are poorly understood. We report a dual strategy in -1/470,000 women to identify common and low-frequency protein-coding variation associated with age at natural menopause (ANM). We identified 44 regions with common variants, including two regions harboring additional rare missense alleles of large effect. We found enrichment of signals in or near genes involved in delayed puberty, highlighting the first molecular links between the onset and end of reproductive lifespan. Pathway analyses identified major association with DNA damage response (DDR) genes, including the first common coding variant in BRCA1 associated with any complex trait. Mendelian randomization analyses supported a causal effect of later ANM on breast cancer risk (-1/46% increase in risk per year; P = 3 × 10 -14), likely mediated by prolonged sex hormone exposure rather than DDR mechanisms.

AB - Menopause timing has a substantial impact on infertility and risk of disease, including breast cancer, but the underlying mechanisms are poorly understood. We report a dual strategy in -1/470,000 women to identify common and low-frequency protein-coding variation associated with age at natural menopause (ANM). We identified 44 regions with common variants, including two regions harboring additional rare missense alleles of large effect. We found enrichment of signals in or near genes involved in delayed puberty, highlighting the first molecular links between the onset and end of reproductive lifespan. Pathway analyses identified major association with DNA damage response (DDR) genes, including the first common coding variant in BRCA1 associated with any complex trait. Mendelian randomization analyses supported a causal effect of later ANM on breast cancer risk (-1/46% increase in risk per year; P = 3 × 10 -14), likely mediated by prolonged sex hormone exposure rather than DDR mechanisms.

UR - http://www.scopus.com/inward/record.url?scp=85000348717&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85000348717&partnerID=8YFLogxK

U2 - 10.1038/ng.3412

DO - 10.1038/ng.3412

M3 - Article

C2 - 26414677

AN - SCOPUS:85000348717

SN - 1061-4036

VL - 47

SP - 1294

EP - 1303

JO - Nature Genetics

JF - Nature Genetics

IS - 11

ER -

Large-scale genomic analyses link reproductive aging to hypothalamic signaling, breast cancer susceptibility and BRCA1-mediated DNA repair

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