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

dos-Santos-Silva, Isabel; van Duijn, Cornelia M.; 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.; Huffman, Jennifer E.; Keller, Margaux F.; McArdle, Patrick F.; Nutile, Teresa; Porcu, Eleonora; Fr, Day; Robino, Antonietta; EHuffman, J.; Rose, Lynda M.; Schick, Ursula M.; Smith, Jennifer A.; Teumer, Alexander; Traglia, Michela; Vuckovic, Dragana; Yao, Jie; Zhao, Wei; Albrecht, Eva; Ks, Ruth; 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.; Dj, Thompson; 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; Kl, Lunetta; Burwinkel, Barbara; Campbell, Archie; Campbell, Harry; Chanock, Stephen J.; Chapman, J. Ross; Ida Chen, Yii-Der; Chenevix-Trench, Georgia; Couch, Fergus J.; Chen, Yii-Der Ida; Coviello, Andrea D.; Cox, Angela; Czene, Kamila; Darabi, Hatef; De Vivo, Immaculata; Demerath, Ellen W.; Dennis, Joe; Devilee, Peter; Dörk, Thilo; Dunning, Alison M.; Dos-Santos-Silva, I.; Eicher, John D.; Fasching, Peter A.; Faul, Jessica D.; Figueroa, Jonine; Flesch-Janys, Dieter; Gandin, Ilaria; Garcia, Melissa E.; García-Closas, Montserrat; Di, Chasman; Giles, Graham G.; Girotto, Giorgia G.; Goldberg, Mark S.; González-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; Van Duijn, C. M.; 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; Hk, Finucane; Mägi, Reedik; Mannermaa, Arto; Manz, Judith; Margolin, Sara; Marten, Jonathan; Martin, Nicholas G.; Masciullo, Corrado; Meindl, Alfons; Nordestgaard, Børge G.; 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, B. 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; Nordestgaard, B.-Ø. G.; 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; Swerdlow, Anthony; Strauch, Konstantin; 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; Ad, Johnson; Wolffenbuttel, Bruce B. H. R.; Wright, Alan F.; Yannoukakos, Drakoulis; Zemunik, Tatijana; Ce, Elks; Zheng, Wei; Zygmunt, Marek; Bergmann, Sven; Boomsma, Dorret I.; Buring, Julie E.; Ferrucci, Luigi; Montgomery, Grant W.; Gudnason, Vilmundur; Spector, Tim D.; Ja, Brody; Alizadeh, Behrooz Z.; Ciullo, Marina; Crisponi, Laura; Easton, Douglas F.; Gasparini, Paolo P.; Duijn, C. M.; Gieger, Christian; Harris, Tamara B.; Hayward, Caroline; Ll, Franke; 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.; Je, Huffman; Price, Alkes L.; Stefansson, Kari; Visser, Jenny A.; Ong, Ken K.; Chang-Claude, Jenny; Murabito, Joanne M.; Perry, John R. B.; Mf, Keller; Murray, Anna

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Felix Day
dos-Santos-Silva et al., 2015

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Lippincott, Williams & Wilkins, Obstetrical & Gynecological Survey, 12(70), p. 758-762, 2015

DOI: 10.1097/01.ogx.0000473766.71624.99

Nature Research, Nature Genetics, 11(47), p. 1294-1303, 2015

DOI: 10.1038/ng.3412

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@article{dos-Santos-Silva2015,
  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 ~70,000 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 harbouring additional rare missense alleles of large effect. We found enrichment of signals in/near genes involved in delayed puberty, highlighting the first molecular links between the onset and end of reproductive lifespan. Pathway analyses revealed a major association with DNA damage-response (DDR) genes, including the first common coding variant in BRCA1 associated with any complex trait. Mendelian randomisation analyses supported a causal effect of later ANM on breast cancer risk (~6% risk increase per-year, P=3×10−14), likely mediated by prolonged sex hormone exposure, rather than DDR mechanisms.},
  author = {dos-Santos-Silva, Isabel and van Duijn, Cornelia M. and Day, Felix R. and Ruth, Katherine S. and Thompson, Deborah J. and Lunetta, Kathryn L. and Pervjakova, Natalia and Chasman, Daniel I. and Stolk, Lisette and Finucane, Hilary K. and Sulem, Patrick and Bulik-Sullivan, Brendan and Esko, Tõnu and Johnson, Andrew D. and Elks, Cathy E. and Franceschini, Nora and He, Chunyan and Altmaier, Elisabeth and Brody, Jennifer A. and Franke, Lude L. and Huffman, Jennifer E. and Keller, Margaux F. and McArdle, Patrick F. and Nutile, Teresa and Porcu, Eleonora and Fr, Day and Robino, Antonietta and EHuffman, J. and Rose, Lynda M. and Schick, Ursula M. and Smith, Jennifer A. and Teumer, Alexander and Traglia, Michela and Vuckovic, Dragana and Yao, Jie and Zhao, Wei and Albrecht, Eva and Ks, Ruth and Amin, Najaf and Corre, Tanguy and Hottenga, Jouke-Jan and Mangino, Massimo and Smith, Albert V. and Tanaka, Toshiko and Abecasis, Gonçalo R. and Andrulis, Irene L. and Anton-Culver, Hoda and Antoniou, Antonis C. and Dj, Thompson and Arndt, Volker and Arnold, Alice M. and Barbieri, Caterina and Beckmann, Matthias W. and Beeghly-Fadiel, Alicia and Benitez, Javier and Bernstein, Leslie and Bielinski, Suzette J. and Blomqvist, Carl and Boerwinkle, Eric and Bogdanova, Natalia V. and Bojesen, Stig E. and Bolla, Manjeet K. and Borresen-Dale, Anne-Lise and Boutin, Thibaud S. and Brauch, Hiltrud and Brenner, Hermann and Brüning, Thomas and Kl, Lunetta and Burwinkel, Barbara and Campbell, Archie and Campbell, Harry and Chanock, Stephen J. and Chapman, J. Ross and Ida Chen, Yii-Der and Chenevix-Trench, Georgia and Couch, Fergus J. and Chen, Yii-Der Ida and Coviello, Andrea D. and Cox, Angela and Czene, Kamila and Darabi, Hatef and De Vivo, Immaculata and Demerath, Ellen W. and Dennis, Joe and Devilee, Peter and Dörk, Thilo and Dunning, Alison M. and Dos-Santos-Silva, I. and Eicher, John D. and Fasching, Peter A. and Faul, Jessica D. and Figueroa, Jonine and Flesch-Janys, Dieter and Gandin, Ilaria and Garcia, Melissa E. and García-Closas, Montserrat and Di, Chasman and Giles, Graham G. and Girotto, Giorgia G. and Goldberg, Mark S. and González-Neira, Anna and Goodarzi, Mark O. and Grove, Megan L. and Gudbjartsson, Daniel F. and Guénel, Pascal and Guo, Xiuqing and Haiman, Christopher A. and Hall, Per and Hamann, Ute and Henderson, Brian E. and Hocking, Lynne J. and Hofman, Albert and Homuth, Georg and Hooning, Maartje J. and Hopper, John L. and Hu, Frank B. and Huang, Jinyan and Van Duijn, C. M. and Humphreys, Keith and Hunter, David J. and Jakubowska, Anna and Jones, Samuel E. and Kabisch, Maria and Karasik, David and Knight, Julia A. and Kolcic, Ivana and Kooperberg, Charles and Kosma, Veli-Matti and Kriebel, Jennifer and Kristensen, Vessela and Lambrechts, Diether and Langenberg, Claudia and Li, Jingmei and Li, Xin and Lindström, Sara and Liu, Yongmei and Luan, Jian'an and Lubinski, Jan and Hk, Finucane and Mägi, Reedik and Mannermaa, Arto and Manz, Judith and Margolin, Sara and Marten, Jonathan and Martin, Nicholas G. and Masciullo, Corrado and Meindl, Alfons and Nordestgaard, Børge G. and Michailidou, Kyriaki and Mihailov, Evelin and Milani, Lili and Milne, Roger L. and Müller-Nurasyid, Martina and Nalls, Michael and Neale, Benjamin M. and Nevanlinna, Heli and Neven, Patrick and Newman, Anne B. and Nordestgaard, B. G. and Olson, Janet E. and Padmanabhan, Sandosh and Peterlongo, Paolo and Peters, Ulrike and Petersmann, Astrid and Peto, Julian and Pharoah, Paul D. P. and Pirastu, Nicola N. and Pirie, Ailith and Pistis, Giorgio and Polasek, Ozren and Porteous, David and Psaty, Bruce M. and Pylkäs, Katri and Radice, Paolo and Raffel, Leslie J. and Rivadeneira, Fernando and Rudan, Igor and Rudolph, Anja and Ruggiero, Daniela and Sala, Cinzia F. and Sanna, Serena and Nordestgaard, B.-Ø. G. and Sawyer, Elinor J. and Schlessinger, David and Schmidt, Marjanka K. and Schmidt, Frank and Schmutzler, Rita K. and Schoemaker, Minouk J. and Scott, Robert A. and Seynaeve, Caroline M. and Simard, Jacques and Sorice, Rossella and Southey, Melissa C. and Stöckl, Doris and Swerdlow, Anthony and Strauch, Konstantin and Taylor, Kent D. and Thorsteinsdottir, Unnur and Toland, Amanda E. and Tomlinson, Ian and Truong, Thérèse and Tryggvadottir, Laufey and Turner, Stephen T. and Vozzi, Diego and Wang, Qin and Wellons, Melissa and Willemsen, Gonneke and Wilson, James F. and Winqvist, Robert and Ad, Johnson and Wolffenbuttel, Bruce B. H. R. and Wright, Alan F. and Yannoukakos, Drakoulis and Zemunik, Tatijana and Ce, Elks and Zheng, Wei and Zygmunt, Marek and Bergmann, Sven and Boomsma, Dorret I. and Buring, Julie E. and Ferrucci, Luigi and Montgomery, Grant W. and Gudnason, Vilmundur and Spector, Tim D. and Ja, Brody and Alizadeh, Behrooz Z. and Ciullo, Marina and Crisponi, Laura and Easton, Douglas F. and Gasparini, Paolo P. and Duijn, C. M. and Gieger, Christian and Harris, Tamara B. and Hayward, Caroline and Ll, Franke and Kardia, Sharon L. R. and Kraft, Peter and McKnight, Barbara and Metspalu, Andres and Morrison, Alanna C. and Reiner, Alex P. and Ridker, Paul M. and Rotter, Jerome I. and Toniolo, Daniela and Uitterlinden, André G. and Ulivi, Sheila and Völzke, Henry and Wareham, Nicholas J. and Weir, David R. and Yerges-Armstrong, Laura M. and Je, Huffman and Price, Alkes L. and Stefansson, Kari and Visser, Jenny A. and Ong, Ken K. and Chang-Claude, Jenny and Murabito, Joanne M. and Perry, John R. B. and Mf, Keller and Murray, Anna},
  doi = {10.1097/01.ogx.0000473766.71624.99},
  journal = {Nature Genetics},
  month = {sep},
  pages = {1294-1303},
  title = {Large-scale genomic analyses link reproductive aging to hypothalamic signaling, breast cancer susceptibility and BRCA1-mediated DNA repair},
  url = {http://www.nature.com/articles/ng.3412.pdf},
  volume = {47},
  year = {2015}
}

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

Journal article published in 2015 by Isabel dos-Santos-Silva, Cornelia M. van Duijn, 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 and other authors. Isabel dos-Santos-Silva, Cornelia M. van Duijn, 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 E. Huffman, Margaux F. Keller, Patrick F. McArdle, Teresa Nutile, Eleonora Porcu, Day Fr, Antonietta Robino

, J. EHuffman, Lynda M. Rose, Ursula M. Schick, Jennifer A. Smith

, Alexander Teumer, Michela Traglia, Dragana Vuckovic, Jie Yao, Wei Zhao, Eva Albrecht, Ruth Ks, 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, Thompson Dj, 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, Lunetta Kl, Barbara Burwinkel, Archie Campbell

, Harry Campbell, Stephen J. Chanock, J. Ross Chapman, Yii-Der Ida Chen, Georgia Chenevix-Trench, Fergus J. Couch, Yii-Der Ida Chen, Andrea D. Coviello, Angela Cox

, Kamila Czene, Hatef Darabi, Immaculata De Vivo, Ellen W. Demerath, Joe Dennis, Peter Devilee, Thilo Dörk, Alison M. Dunning

, I. Dos-Santos-Silva, John D. Eicher, Peter A. Fasching, Jessica D. Faul

, Jonine Figueroa, Dieter Flesch-Janys, Ilaria Gandin, Melissa E. Garcia, Montserrat García-Closas, Chasman Di, Graham G. Giles, Giorgia G. Girotto, Mark S. Goldberg, Anna González-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, C. M. Van Duijn, 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, Finucane Hk, Reedik Mägi, Arto Mannermaa, Judith Manz, Sara Margolin, Jonathan Marten, Nicholas G. Martin, Corrado Masciullo, Alfons Meindl, Børge G. Nordestgaard, Kyriaki Michailidou, Evelin Mihailov, Lili Milani, Roger L. Milne, Martina Müller-Nurasyid, Michael Nalls, Benjamin M. Neale, Heli Nevanlinna, Patrick Neven, Anne B. Newman, B. 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, B.-Ø. G. Nordestgaard, 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, Anthony Swerdlow, Konstantin Strauch, 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, Johnson Ad, Bruce B. H. R. Wolffenbuttel, Alan F. Wright, Drakoulis Yannoukakos, Tatijana Zemunik, Elks Ce, Wei Zheng, Marek Zygmunt, Sven Bergmann, Dorret I. Boomsma, Julie E. Buring, Luigi Ferrucci, Grant W. Montgomery, Vilmundur Gudnason, Tim D. Spector, Brody Ja, Behrooz Z. Alizadeh, Marina Ciullo, Laura Crisponi, Douglas F. Easton, Paolo P. Gasparini, C. M. Duijn, Christian Gieger

, Tamara B. Harris, Caroline Hayward, Franke Ll, 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, Huffman Je, Alkes L. Price, Kari Stefansson, Jenny A. Visser, Ken K. Ong, Jenny Chang-Claude, Joanne M. Murabito, John R. B. Perry, Keller Mf, Anna Murray

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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 ~70,000 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 harbouring additional rare missense alleles of large effect. We found enrichment of signals in/near genes involved in delayed puberty, highlighting the first molecular links between the onset and end of reproductive lifespan. Pathway analyses revealed a major association with DNA damage-response (DDR) genes, including the first common coding variant in BRCA1 associated with any complex trait. Mendelian randomisation analyses supported a causal effect of later ANM on breast cancer risk (~6% risk increase per-year, P=3×10−14), likely mediated by prolonged sex hormone exposure, rather than DDR mechanisms.

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

Abstract