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 & 221 others 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

Research output: Contribution to journalArticle

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 languageEnglish (US)
Pages (from-to)1294-1303
Number of pages10
JournalNature Genetics
Volume47
Issue number11
DOIs
StatePublished - Nov 1 2015
Externally publishedYes

Fingerprint

Menopause
DNA Repair
Breast Neoplasms
Mendelian Randomization Analysis
DNA Damage
Delayed Puberty
Gonadal Steroid Hormones
Infertility
Genes
Alleles
Proteins

ASJC Scopus subject areas

  • Genetics

Cite this

Day, F. R., Ruth, K. S., Thompson, D. J., Lunetta, K. L., Pervjakova, N., Chasman, D. I., ... 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

Large-scale genomic analyses link reproductive aging to hypothalamic signaling, breast cancer susceptibility and BRCA1-mediated DNA repair. / Day, Felix R.; Ruth, Katherine S.; Thompson, Deborah J.; Lunetta, Kathryn L.; Pervjakova, Natalia; Chasman, Daniel I.; Stolk, Lisette; Finucane, Hilary K.; Sulem, Patrick; Bulik-Sullivan, Brendan; Esko, Tõnu; Johnson, Andrew D.; Elks, Cathy E.; Franceschini, Nora; He, Chunyan; Altmaier, Elisabeth; Brody, Jennifer A.; Franke, Lude L.; EHuffman, Jennifer; Keller, Margaux F.; McArdle, Patrick F.; Nutile, Teresa; Porcu, Eleonora; Robino, Antonietta; Rose, Lynda M.; Schick, Ursula M.; Smith, Jennifer A.; Teumer, Alexander; Traglia, Michela; Vuckovic, Dragana; Yao, Jie; Zhao, Wei; Albrecht, Eva; Amin, Najaf; Corre, Tanguy; Hottenga, Jouke Jan; Mangino, Massimo; Smith, Albert V.; Tanaka, Toshiko; Abecasis, Gonçalo R.; Andrulis, Irene L.; Anton-Culver, Hoda; Antoniou, Antonis C.; Arndt, Volker; Arnold, Alice M.; Barbieri, Caterina; Beckmann, Matthias W.; Beeghly-Fadiel, Alicia; Benitez, Javier; Bernstein, Leslie; Bielinski, Suzette J.; Blomqvist, Carl; Boerwinkle, Eric; Bogdanova, Natalia V.; Bojesen, Stig E.; Bolla, Manjeet K.; Borresen-Dale, Anne Lise; Boutin, Thibaud S.; Brauch, Hiltrud; Brenner, Hermann; Brüning, Thomas; Burwinkel, Barbara; Campbell, Archie; Campbell, Harry; Chanock, Stephen J.; Chapman, J. Ross; Chen, Yii Der Ida; Chenevix-Trench, Georgia; Couch, Fergus J.; Coviello, Andrea D.; Cox, Angela; Czene, Kamila; Darabi, Hatef; De Vivo, Immaculata; Demerath, Ellen W.; Dennis, Joe; Devilee, Peter; Dörk, Thilo; Dos-Santos-Silva, Isabel; Dunning, Alison M.; Eicher, John D.; Fasching, Peter A.; Faul, Jessica D.; Figueroa, Jonine; Flesch-Janys, Dieter; Gandin, Ilaria; Garcia, Melissa E.; García-Closas, Montserrat; Giles, Graham G.; Girotto, Giorgia G.; Goldberg, Mark S.; Gonz'lez-Neira, Anna; Goodarzi, Mark O.; Grove, Megan L.; Gudbjartsson, Daniel F.; Guénel, Pascal; Guo, Xiuqing; Haiman, Christopher A.; Hall, Per; Hamann, Ute; Henderson, Brian E.; Hocking, Lynne J.; Hofman, Albert; Homuth, Georg; Hooning, Maartje J.; Hopper, John L.; Hu, Frank B.; Huang, Jinyan; Humphreys, Keith; Hunter, David J.; Jakubowska, Anna; Jones, Samuel E.; Kabisch, Maria; Karasik, David; Knight, Julia A.; Kolcic, Ivana; Kooperberg, Charles; Kosma, Veli Matti; Kriebel, Jennifer; Kristensen, Vessela; Lambrechts, Diether; Langenberg, Claudia; Li, Jingmei; Li, Xin; Lindström, Sara; Liu, Yongmei; Luan, Jian'An; Lubinski, Jan; Mägi, Reedik; Mannermaa, Arto; Manz, Judith; Margolin, Sara; Marten, Jonathan; Martin, Nicholas G.; Masciullo, Corrado; Meindl, Alfons; Michailidou, Kyriaki; Mihailov, Evelin; Milani, Lili; Milne, Roger L.; Müller-Nurasyid, Martina; Nalls, Michael; Neale, Benjamin M.; Nevanlinna, Heli; Neven, Patrick; Newman, Anne B.; Nordestgaard, BØrge G.; Olson, Janet E.; Padmanabhan, Sandosh; Peterlongo, Paolo; Peters, Ulrike; Petersmann, Astrid; Peto, Julian; Pharoah, Paul D P; Pirastu, Nicola N.; Pirie, Ailith; Pistis, Giorgio; Polasek, Ozren; Porteous, David; Psaty, Bruce M.; Pylkäs, Katri; Radice, Paolo; Raffel, Leslie J.; Rivadeneira, Fernando; Rudan, Igor; Rudolph, Anja; Ruggiero, Daniela; Sala, Cinzia F.; Sanna, Serena; Sawyer, Elinor J.; Schlessinger, David; Schmidt, Marjanka K.; Schmidt, Frank; Schmutzler, Rita K.; Schoemaker, Minouk J.; Scott, Robert A.; Seynaeve, Caroline M.; Simard, Jacques; Sorice, Rossella; Southey, Melissa C.; Stöckl, Doris; Strauch, Konstantin; Swerdlow, Anthony; Taylor, Kent D.; Thorsteinsdottir, Unnur; Toland, Amanda E.; Tomlinson, Ian; Truong, Thérèse; Tryggvadottir, Laufey; Turner, Stephen T.; Vozzi, Diego; Wang, Qin; Wellons, Melissa; Willemsen, Gonneke; Wilson, James F.; Winqvist, Robert; Wolffenbuttel, Bruce B H R; Wright, Alan F.; Yannoukakos, Drakoulis; Zemunik, Tatijana; Zheng, Wei; Zygmunt, Marek; Bergmann, Sven; Boomsma, Dorret I.; Buring, Julie E.; Ferrucci, Luigi; Montgomery, Grant W.; Gudnason, Vilmundur; Spector, Tim D.; Duijn, Cornelia Mvan; Alizadeh, Behrooz Z.; Ciullo, Marina; Crisponi, Laura; Easton, Douglas F.; Gasparini, Paolo P.; Gieger, Christian; Harris, Tamara B.; Hayward, Caroline; Kardia, Sharon L R; Kraft, Peter; McKnight, Barbara; Metspalu, Andres; Morrison, Alanna C.; Reiner, Alex P.; Ridker, Paul M.; Rotter, Jerome I.; Toniolo, Daniela; Uitterlinden, André G.; Ulivi, Sheila; Völzke, Henry; Wareham, Nicholas J.; Weir, David R.; Yerges-Armstrong, Laura M.; Price, Alkes L.; Stefansson, Kari; Visser, Jenny A.; Ong, Ken K.; Chang-Claude, Jenny; Murabito, Joanne M.; Perry, John R B; Murray, Anna.

In: Nature Genetics, Vol. 47, No. 11, 01.11.2015, p. 1294-1303.

Research output: Contribution to journalArticle

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
Day, Felix R. ; Ruth, Katherine S. ; Thompson, Deborah J. ; Lunetta, Kathryn L. ; Pervjakova, Natalia ; Chasman, Daniel I. ; Stolk, Lisette ; Finucane, Hilary K. ; Sulem, Patrick ; Bulik-Sullivan, Brendan ; Esko, Tõnu ; Johnson, Andrew D. ; Elks, Cathy E. ; Franceschini, Nora ; He, Chunyan ; Altmaier, Elisabeth ; Brody, Jennifer A. ; Franke, Lude L. ; EHuffman, Jennifer ; Keller, Margaux F. ; McArdle, Patrick F. ; Nutile, Teresa ; Porcu, Eleonora ; Robino, Antonietta ; Rose, Lynda M. ; Schick, Ursula M. ; Smith, Jennifer A. ; Teumer, Alexander ; Traglia, Michela ; Vuckovic, Dragana ; Yao, Jie ; Zhao, Wei ; Albrecht, Eva ; Amin, Najaf ; Corre, Tanguy ; Hottenga, Jouke Jan ; Mangino, Massimo ; Smith, Albert V. ; Tanaka, Toshiko ; Abecasis, Gonçalo R. ; Andrulis, Irene L. ; Anton-Culver, Hoda ; Antoniou, Antonis C. ; Arndt, Volker ; Arnold, Alice M. ; Barbieri, Caterina ; Beckmann, Matthias W. ; Beeghly-Fadiel, Alicia ; Benitez, Javier ; Bernstein, Leslie ; Bielinski, Suzette J. ; Blomqvist, Carl ; Boerwinkle, Eric ; Bogdanova, Natalia V. ; Bojesen, Stig E. ; Bolla, Manjeet K. ; Borresen-Dale, Anne Lise ; Boutin, Thibaud S. ; Brauch, Hiltrud ; Brenner, Hermann ; Brüning, Thomas ; Burwinkel, Barbara ; Campbell, Archie ; Campbell, Harry ; Chanock, Stephen J. ; Chapman, J. Ross ; Chen, Yii Der Ida ; Chenevix-Trench, Georgia ; Couch, Fergus J. ; Coviello, Andrea D. ; Cox, Angela ; Czene, Kamila ; Darabi, Hatef ; De Vivo, Immaculata ; Demerath, Ellen W. ; Dennis, Joe ; Devilee, Peter ; Dörk, Thilo ; Dos-Santos-Silva, Isabel ; Dunning, Alison M. ; Eicher, John D. ; Fasching, Peter A. ; Faul, Jessica D. ; Figueroa, Jonine ; Flesch-Janys, Dieter ; Gandin, Ilaria ; Garcia, Melissa E. ; García-Closas, Montserrat ; Giles, Graham G. ; Girotto, Giorgia G. ; Goldberg, Mark S. ; Gonz'lez-Neira, Anna ; Goodarzi, Mark O. ; Grove, Megan L. ; Gudbjartsson, Daniel F. ; Guénel, Pascal ; Guo, Xiuqing ; Haiman, Christopher A. ; Hall, Per ; Hamann, Ute ; Henderson, Brian E. ; Hocking, Lynne J. ; Hofman, Albert ; Homuth, Georg ; Hooning, Maartje J. ; Hopper, John L. ; Hu, Frank B. ; Huang, Jinyan ; Humphreys, Keith ; Hunter, David J. ; Jakubowska, Anna ; Jones, Samuel E. ; Kabisch, Maria ; Karasik, David ; Knight, Julia A. ; Kolcic, Ivana ; Kooperberg, Charles ; Kosma, Veli Matti ; Kriebel, Jennifer ; Kristensen, Vessela ; Lambrechts, Diether ; Langenberg, Claudia ; Li, Jingmei ; Li, Xin ; Lindström, Sara ; Liu, Yongmei ; Luan, Jian'An ; Lubinski, Jan ; Mägi, Reedik ; Mannermaa, Arto ; Manz, Judith ; Margolin, Sara ; Marten, Jonathan ; Martin, Nicholas G. ; Masciullo, Corrado ; Meindl, Alfons ; Michailidou, Kyriaki ; Mihailov, Evelin ; Milani, Lili ; Milne, Roger L. ; Müller-Nurasyid, Martina ; Nalls, Michael ; Neale, Benjamin M. ; Nevanlinna, Heli ; Neven, Patrick ; Newman, Anne B. ; Nordestgaard, BØrge G. ; Olson, Janet E. ; Padmanabhan, Sandosh ; Peterlongo, Paolo ; Peters, Ulrike ; Petersmann, Astrid ; Peto, Julian ; Pharoah, Paul D P ; Pirastu, Nicola N. ; Pirie, Ailith ; Pistis, Giorgio ; Polasek, Ozren ; Porteous, David ; Psaty, Bruce M. ; Pylkäs, Katri ; Radice, Paolo ; Raffel, Leslie J. ; Rivadeneira, Fernando ; Rudan, Igor ; Rudolph, Anja ; Ruggiero, Daniela ; Sala, Cinzia F. ; Sanna, Serena ; Sawyer, Elinor J. ; Schlessinger, David ; Schmidt, Marjanka K. ; Schmidt, Frank ; Schmutzler, Rita K. ; Schoemaker, Minouk J. ; Scott, Robert A. ; Seynaeve, Caroline M. ; Simard, Jacques ; Sorice, Rossella ; Southey, Melissa C. ; Stöckl, Doris ; Strauch, Konstantin ; Swerdlow, Anthony ; Taylor, Kent D. ; Thorsteinsdottir, Unnur ; Toland, Amanda E. ; Tomlinson, Ian ; Truong, Thérèse ; Tryggvadottir, Laufey ; Turner, Stephen T. ; Vozzi, Diego ; Wang, Qin ; Wellons, Melissa ; Willemsen, Gonneke ; Wilson, James F. ; Winqvist, Robert ; Wolffenbuttel, Bruce B H R ; Wright, Alan F. ; Yannoukakos, Drakoulis ; Zemunik, Tatijana ; Zheng, Wei ; Zygmunt, Marek ; Bergmann, Sven ; Boomsma, Dorret I. ; Buring, Julie E. ; Ferrucci, Luigi ; Montgomery, Grant W. ; Gudnason, Vilmundur ; Spector, Tim D. ; Duijn, Cornelia Mvan ; Alizadeh, Behrooz Z. ; Ciullo, Marina ; Crisponi, Laura ; Easton, Douglas F. ; Gasparini, Paolo P. ; Gieger, Christian ; Harris, Tamara B. ; Hayward, Caroline ; Kardia, Sharon L R ; Kraft, Peter ; McKnight, Barbara ; Metspalu, Andres ; Morrison, Alanna C. ; Reiner, Alex P. ; Ridker, Paul M. ; Rotter, Jerome I. ; Toniolo, Daniela ; Uitterlinden, André G. ; Ulivi, Sheila ; Völzke, Henry ; Wareham, Nicholas J. ; Weir, David R. ; Yerges-Armstrong, Laura M. ; Price, Alkes L. ; Stefansson, Kari ; Visser, Jenny A. ; Ong, Ken K. ; Chang-Claude, Jenny ; Murabito, Joanne M. ; Perry, John R B ; Murray, Anna. / Large-scale genomic analyses link reproductive aging to hypothalamic signaling, breast cancer susceptibility and BRCA1-mediated DNA repair. In: Nature Genetics. 2015 ; Vol. 47, No. 11. pp. 1294-1303.
@article{ffa45ce83efb4e2f891ef6bfe5dd0bab,
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.",
author = "Day, {Felix R.} and Ruth, {Katherine S.} and Thompson, {Deborah J.} and Lunetta, {Kathryn L.} and Natalia Pervjakova and Chasman, {Daniel I.} and Lisette Stolk and Finucane, {Hilary K.} and Patrick Sulem and Brendan Bulik-Sullivan and T{\~o}nu Esko and Johnson, {Andrew D.} and Elks, {Cathy E.} and Nora Franceschini and Chunyan He and Elisabeth Altmaier and Brody, {Jennifer A.} and Franke, {Lude L.} and Jennifer EHuffman and Keller, {Margaux F.} and McArdle, {Patrick F.} and Teresa Nutile and Eleonora Porcu and Antonietta Robino and Rose, {Lynda M.} and Schick, {Ursula M.} and Smith, {Jennifer A.} and Alexander Teumer and Michela Traglia and Dragana Vuckovic and Jie Yao and Wei Zhao and Eva Albrecht and Najaf Amin and Tanguy Corre and Hottenga, {Jouke Jan} and Massimo Mangino and Smith, {Albert V.} and Toshiko Tanaka and Abecasis, {Gon{\cc}alo R.} and Andrulis, {Irene L.} and Hoda Anton-Culver and Antoniou, {Antonis C.} and Volker Arndt and Arnold, {Alice M.} and Caterina Barbieri and Beckmann, {Matthias W.} and Alicia Beeghly-Fadiel and Javier Benitez and Leslie Bernstein and Bielinski, {Suzette J.} and Carl Blomqvist and Eric Boerwinkle and Bogdanova, {Natalia V.} and Bojesen, {Stig E.} and Bolla, {Manjeet K.} and Borresen-Dale, {Anne Lise} and Boutin, {Thibaud S.} and Hiltrud Brauch and Hermann Brenner and Thomas Br{\"u}ning and Barbara Burwinkel and Archie Campbell and Harry Campbell and Chanock, {Stephen J.} and Chapman, {J. Ross} and Chen, {Yii Der Ida} and Georgia Chenevix-Trench and Couch, {Fergus J.} and Coviello, {Andrea D.} and Angela Cox and Kamila Czene and Hatef Darabi and {De Vivo}, Immaculata and Demerath, {Ellen W.} and Joe Dennis and Peter Devilee and Thilo D{\"o}rk and Isabel Dos-Santos-Silva and Dunning, {Alison M.} and Eicher, {John D.} and Fasching, {Peter A.} and Faul, {Jessica D.} and Jonine Figueroa and Dieter Flesch-Janys and Ilaria Gandin and Garcia, {Melissa E.} and Montserrat Garc{\'i}a-Closas and Giles, {Graham G.} and Girotto, {Giorgia G.} and Goldberg, {Mark S.} and Anna Gonz'lez-Neira and Goodarzi, {Mark O.} and Grove, {Megan L.} and Gudbjartsson, {Daniel F.} and Pascal Gu{\'e}nel and Xiuqing Guo and Haiman, {Christopher A.} and Per Hall and Ute Hamann and Henderson, {Brian E.} and Hocking, {Lynne J.} and Albert Hofman and Georg Homuth and Hooning, {Maartje J.} and Hopper, {John L.} and Hu, {Frank B.} and Jinyan Huang and Keith Humphreys and Hunter, {David J.} and Anna Jakubowska and Jones, {Samuel E.} and Maria Kabisch and David Karasik and Knight, {Julia A.} and Ivana Kolcic and Charles Kooperberg and Kosma, {Veli Matti} and Jennifer Kriebel and Vessela Kristensen and Diether Lambrechts and Claudia Langenberg and Jingmei Li and Xin Li and Sara Lindstr{\"o}m and Yongmei Liu and Jian'An Luan and Jan Lubinski and Reedik M{\"a}gi and Arto Mannermaa and Judith Manz and Sara Margolin and Jonathan Marten and Martin, {Nicholas G.} and Corrado Masciullo and Alfons Meindl and Kyriaki Michailidou and Evelin Mihailov and Lili Milani and Milne, {Roger L.} and Martina M{\"u}ller-Nurasyid and Michael Nalls and Neale, {Benjamin M.} and Heli Nevanlinna and Patrick Neven and Newman, {Anne B.} and Nordestgaard, {B{\O}rge G.} and Olson, {Janet E.} and Sandosh Padmanabhan and Paolo Peterlongo and Ulrike Peters and Astrid Petersmann and Julian Peto and Pharoah, {Paul D P} and Pirastu, {Nicola N.} and Ailith Pirie and Giorgio Pistis and Ozren Polasek and David Porteous and Psaty, {Bruce M.} and Katri Pylk{\"a}s and Paolo Radice and Raffel, {Leslie J.} and Fernando Rivadeneira and Igor Rudan and Anja Rudolph and Daniela Ruggiero and Sala, {Cinzia F.} and Serena Sanna and Sawyer, {Elinor J.} and David Schlessinger and Schmidt, {Marjanka K.} and Frank Schmidt and Schmutzler, {Rita K.} and Schoemaker, {Minouk J.} and Scott, {Robert A.} and Seynaeve, {Caroline M.} and Jacques Simard and Rossella Sorice and Southey, {Melissa C.} and Doris St{\"o}ckl and Konstantin Strauch and Anthony Swerdlow and Taylor, {Kent D.} and Unnur Thorsteinsdottir and Toland, {Amanda E.} and Ian Tomlinson and Th{\'e}r{\`e}se Truong and Laufey Tryggvadottir and Turner, {Stephen T.} and Diego Vozzi and Qin Wang and Melissa Wellons and Gonneke Willemsen and Wilson, {James F.} and Robert Winqvist and Wolffenbuttel, {Bruce B H R} and Wright, {Alan F.} and Drakoulis Yannoukakos and Tatijana Zemunik and Wei Zheng and Marek Zygmunt and Sven Bergmann and Boomsma, {Dorret I.} and Buring, {Julie E.} and Luigi Ferrucci and Montgomery, {Grant W.} and Vilmundur Gudnason and Spector, {Tim D.} and Duijn, {Cornelia Mvan} and Alizadeh, {Behrooz Z.} and Marina Ciullo and Laura Crisponi and Easton, {Douglas F.} and Gasparini, {Paolo P.} and Christian Gieger and Harris, {Tamara B.} and Caroline Hayward and Kardia, {Sharon L R} and Peter Kraft and Barbara McKnight and Andres Metspalu and Morrison, {Alanna C.} and Reiner, {Alex P.} and Ridker, {Paul M.} and Rotter, {Jerome I.} and Daniela Toniolo and Uitterlinden, {Andr{\'e} G.} and Sheila Ulivi and Henry V{\"o}lzke and Wareham, {Nicholas J.} and Weir, {David R.} and Yerges-Armstrong, {Laura M.} and Price, {Alkes L.} and Kari Stefansson and Visser, {Jenny A.} and Ong, {Ken K.} and Jenny Chang-Claude and Murabito, {Joanne M.} and Perry, {John R B} and Anna Murray",
year = "2015",
month = "11",
day = "1",
doi = "10.1038/ng.3412",
language = "English (US)",
volume = "47",
pages = "1294--1303",
journal = "Nature Genetics",
issn = "1061-4036",
publisher = "Nature Publishing Group",
number = "11",

}

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.

AU - Guénel, Pascal

AU - Guo, Xiuqing

AU - Haiman, Christopher A.

AU - Hall, Per

AU - Hamann, Ute

AU - Henderson, Brian E.

AU - Hocking, Lynne J.

AU - Hofman, Albert

AU - Homuth, Georg

AU - Hooning, Maartje J.

AU - Hopper, John L.

AU - Hu, Frank B.

AU - Huang, Jinyan

AU - Humphreys, Keith

AU - Hunter, David J.

AU - Jakubowska, Anna

AU - Jones, Samuel E.

AU - Kabisch, Maria

AU - Karasik, David

AU - Knight, Julia A.

AU - Kolcic, Ivana

AU - Kooperberg, Charles

AU - Kosma, Veli Matti

AU - Kriebel, Jennifer

AU - Kristensen, Vessela

AU - Lambrechts, Diether

AU - Langenberg, Claudia

AU - Li, Jingmei

AU - Li, Xin

AU - Lindström, Sara

AU - Liu, Yongmei

AU - Luan, Jian'An

AU - Lubinski, Jan

AU - Mägi, Reedik

AU - Mannermaa, Arto

AU - Manz, Judith

AU - Margolin, Sara

AU - Marten, Jonathan

AU - Martin, Nicholas G.

AU - Masciullo, Corrado

AU - Meindl, Alfons

AU - Michailidou, Kyriaki

AU - Mihailov, Evelin

AU - Milani, Lili

AU - Milne, Roger L.

AU - Müller-Nurasyid, Martina

AU - Nalls, Michael

AU - Neale, Benjamin M.

AU - Nevanlinna, Heli

AU - Neven, Patrick

AU - Newman, Anne B.

AU - Nordestgaard, BØrge G.

AU - Olson, Janet E.

AU - Padmanabhan, Sandosh

AU - Peterlongo, Paolo

AU - Peters, Ulrike

AU - Petersmann, Astrid

AU - Peto, Julian

AU - Pharoah, Paul D P

AU - Pirastu, Nicola N.

AU - Pirie, Ailith

AU - Pistis, Giorgio

AU - Polasek, Ozren

AU - Porteous, David

AU - Psaty, Bruce M.

AU - Pylkäs, Katri

AU - Radice, Paolo

AU - Raffel, Leslie J.

AU - Rivadeneira, Fernando

AU - Rudan, Igor

AU - Rudolph, Anja

AU - Ruggiero, Daniela

AU - Sala, Cinzia F.

AU - Sanna, Serena

AU - Sawyer, Elinor J.

AU - Schlessinger, David

AU - Schmidt, Marjanka K.

AU - Schmidt, Frank

AU - Schmutzler, Rita K.

AU - Schoemaker, Minouk J.

AU - Scott, Robert A.

AU - Seynaeve, Caroline M.

AU - Simard, Jacques

AU - Sorice, Rossella

AU - Southey, Melissa C.

AU - Stöckl, Doris

AU - Strauch, Konstantin

AU - Swerdlow, Anthony

AU - Taylor, Kent D.

AU - Thorsteinsdottir, Unnur

AU - Toland, Amanda E.

AU - Tomlinson, Ian

AU - Truong, Thérèse

AU - Tryggvadottir, Laufey

AU - Turner, Stephen T.

AU - Vozzi, Diego

AU - Wang, Qin

AU - Wellons, Melissa

AU - Willemsen, Gonneke

AU - Wilson, James F.

AU - Winqvist, Robert

AU - Wolffenbuttel, Bruce B H R

AU - Wright, Alan F.

AU - Yannoukakos, Drakoulis

AU - Zemunik, Tatijana

AU - Zheng, Wei

AU - Zygmunt, Marek

AU - Bergmann, Sven

AU - Boomsma, Dorret I.

AU - Buring, Julie E.

AU - Ferrucci, Luigi

AU - Montgomery, Grant W.

AU - Gudnason, Vilmundur

AU - Spector, Tim D.

AU - Duijn, Cornelia Mvan

AU - Alizadeh, Behrooz Z.

AU - Ciullo, Marina

AU - Crisponi, Laura

AU - Easton, Douglas F.

AU - Gasparini, Paolo P.

AU - Gieger, Christian

AU - Harris, Tamara B.

AU - Hayward, Caroline

AU - Kardia, Sharon L R

AU - Kraft, Peter

AU - McKnight, Barbara

AU - Metspalu, Andres

AU - Morrison, Alanna C.

AU - Reiner, Alex P.

AU - Ridker, Paul M.

AU - Rotter, Jerome I.

AU - Toniolo, Daniela

AU - Uitterlinden, André G.

AU - Ulivi, Sheila

AU - Völzke, Henry

AU - Wareham, Nicholas J.

AU - Weir, David R.

AU - Yerges-Armstrong, Laura M.

AU - Price, Alkes L.

AU - Stefansson, Kari

AU - Visser, Jenny A.

AU - Ong, Ken K.

AU - Chang-Claude, Jenny

AU - Murabito, Joanne M.

AU - Perry, John R B

AU - Murray, Anna

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

VL - 47

SP - 1294

EP - 1303

JO - Nature Genetics

JF - Nature Genetics

SN - 1061-4036

IS - 11

ER -