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

Day, Felix R.; Thompson, Deborah J.; Van Duijn, C. M.; Teumer, Alexander; Traglia, Michela; Vuckovic, Dragana; Yao, Jie; Ruth, Katherine S.; Zhao, Wei; Lunetta, Kathryn L.; Chasman, Daniel I.; Tanaka, Toshiko; Finucane, Hilary K.; Johnson, Andrew D.; Elks, Cathy E.; Brody, Jennifer A.; Pervjakova, Natalia; Franke, Lude L.; Huffman, Jennifer E.; Keller, Margaux F.; McArdle, Patrick F.; Nutile, Teresa; Fr, Day; Porcu, Eleonora; Robino, Antonietta; Rose, Lynda M.; Schick, Ursula M.; dos-Santos-Silva, Isabel; Ks, Ruth; Smith, Jennifer A.; Stolk, Lisette; Albrecht, Eva; Amin, Najaf; Corre, Tanguy; Hottenga, Jouke-Jan; Mangino, Massimo; Smith, Albert V.; Dj, Thompson; EHuffman, J.; Abecasis, Gonçalo R.; Sulem, Patrick; Andrulis, Irene L.; Anton-Culver, Hoda; Antoniou, Antonis C.; Arndt, Volker; Arnold, Alice M.; Bulik-Sullivan, Brendan; Barbieri, Caterina; Beckmann, Matthias W.; Beeghly-Fadiel, Alicia; Benitez, Javier; Bernstein, Leslie; Esko, Tõnu; Bielinski, Suzette J.; Blomqvist, Carl; Kl, Lunetta; 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; Franceschini, Nora; Chanock, Stephen J.; Chapman, J. Ross; Ida Chen, Yii-Der; Chenevix-Trench, Georgia; Couch, Fergus J.; Coviello, Andrea D.; He, Chunyan; Cox, Angela; Czene, Kamila; Darabi, Hatef; De Vivo, Immaculata; Demerath, Ellen W.; Di, Chasman; Dennis, Joe; Altmaier, Elisabeth; Devilee, Peter; Dörk, Thilo; Chen, Yii-Der Ida; Dunning, Alison M.; Eicher, John D.; Fasching, Peter A.; Faul, Jessica D.; Figueroa, Jonine; Swerdlow, Anthony; Flesch-Janys, Dieter; Taylor, Kent D.; Gandin, Ilaria; Thorsteinsdottir, Unnur; Garcia, Melissa E.; Toland, Amanda E.; García-Closas, Montserrat; Tomlinson, Ian; Truong, Thérèse; Giles, Graham G.; Tryggvadottir, Laufey; Girotto, Giorgia G.; Turner, Stephen T.; Goldberg, Mark S.; Dos-Santos-Silva, I.; Vozzi, Diego; González-Neira, Anna; Wang, Qin; Goodarzi, Mark O.; van Duijn, Cornelia M.; Wellons, Melissa; Grove, Megan L.; Willemsen, Gonneke; Gudbjartsson, Daniel F.; Wilson, James F.; Guénel, Pascal; Winqvist, Robert; Guo, Xiuqing; Wolffenbuttel, Bruce B. H. R.; Haiman, Christopher A.; Wright, Alan F.; Hall, Per; Yannoukakos, Drakoulis; Hamann, Ute; Zemunik, Tatijana; Henderson, Brian E.; Zheng, Wei; Hocking, Lynne J.; Zygmunt, Marek; Hofman, Albert; Homuth, Georg; Hk, Finucane; 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.; Toniolo, Daniela; Kolcic, Ivana; Uitterlinden, André G.; Kooperberg, Charles; Ulivi, Sheila; Kosma, Veli-Matti; Völzke, Henry; Kriebel, Jennifer; Wareham, Nicholas J.; Kristensen, Vessela; Weir, David R.; Lambrechts, Diether; Yerges-Armstrong, Laura M.; Langenberg, Claudia; Li, Jingmei; Visser, Jenny A.; 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.; Ad, Johnson; 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.; Ce, Elks; 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; Nordestgaard, B.-Ø. G.; Bergmann, Sven; Boomsma, Dorret I.; Buring, Julie E.; Ferrucci, Luigi; Ja, Brody; Montgomery, Grant W.; Gudnason, Vilmundur; Spector, Tim D.; Alizadeh, Behrooz Z.; Ciullo, Marina; Crisponi, Laura; Easton, Douglas F.; Gasparini, Paolo P.; Duijn, C. M.; Gieger, Christian; Harris, Tamara B.; Ll, Franke; Hayward, Caroline; Kardia, Sharon L. R.; Kraft, Peter; McKnight, Barbara; Metspalu, Andres; Morrison, Alanna C.; Reiner, Alex P.; Ridker, Paul M.; Rotter, Jerome I.; Je, Huffman; Price, Alkes L.; Stefansson, Kari; Ong, Ken K.; Chang-Claude, Jenny; Murabito, Joanne M.; Perry, John R. B.; Mf, Keller; Murray, Anna

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Felix Day
Day 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{Day2015,
  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 = {Day, Felix R. and Thompson, Deborah J. and Van Duijn, C. M. and Teumer, Alexander and Traglia, Michela and Vuckovic, Dragana and Yao, Jie and Ruth, Katherine S. and Zhao, Wei and Lunetta, Kathryn L. and Chasman, Daniel I. and Tanaka, Toshiko and Finucane, Hilary K. and Johnson, Andrew D. and Elks, Cathy E. and Brody, Jennifer A. and Pervjakova, Natalia and Franke, Lude L. and Huffman, Jennifer E. and Keller, Margaux F. and McArdle, Patrick F. and Nutile, Teresa and Fr, Day and Porcu, Eleonora and Robino, Antonietta and Rose, Lynda M. and Schick, Ursula M. and dos-Santos-Silva, Isabel and Ks, Ruth and Smith, Jennifer A. and Stolk, Lisette and Albrecht, Eva and Amin, Najaf and Corre, Tanguy and Hottenga, Jouke-Jan and Mangino, Massimo and Smith, Albert V. and Dj, Thompson and EHuffman, J. and Abecasis, Gonçalo R. and Sulem, Patrick and Andrulis, Irene L. and Anton-Culver, Hoda and Antoniou, Antonis C. and Arndt, Volker and Arnold, Alice M. and Bulik-Sullivan, Brendan and Barbieri, Caterina and Beckmann, Matthias W. and Beeghly-Fadiel, Alicia and Benitez, Javier and Bernstein, Leslie and Esko, Tõnu and Bielinski, Suzette J. and Blomqvist, Carl and Kl, Lunetta 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 Burwinkel, Barbara and Campbell, Archie and Campbell, Harry and Franceschini, Nora and Chanock, Stephen J. and Chapman, J. Ross and Ida Chen, Yii-Der and Chenevix-Trench, Georgia and Couch, Fergus J. and Coviello, Andrea D. and He, Chunyan and Cox, Angela and Czene, Kamila and Darabi, Hatef and De Vivo, Immaculata and Demerath, Ellen W. and Di, Chasman and Dennis, Joe and Altmaier, Elisabeth and Devilee, Peter and Dörk, Thilo and Chen, Yii-Der Ida and Dunning, Alison M. and Eicher, John D. and Fasching, Peter A. and Faul, Jessica D. and Figueroa, Jonine and Swerdlow, Anthony and Flesch-Janys, Dieter and Taylor, Kent D. and Gandin, Ilaria and Thorsteinsdottir, Unnur and Garcia, Melissa E. and Toland, Amanda E. and García-Closas, Montserrat and Tomlinson, Ian and Truong, Thérèse and Giles, Graham G. and Tryggvadottir, Laufey and Girotto, Giorgia G. and Turner, Stephen T. and Goldberg, Mark S. and Dos-Santos-Silva, I. and Vozzi, Diego and González-Neira, Anna and Wang, Qin and Goodarzi, Mark O. and van Duijn, Cornelia M. and Wellons, Melissa and Grove, Megan L. and Willemsen, Gonneke and Gudbjartsson, Daniel F. and Wilson, James F. and Guénel, Pascal and Winqvist, Robert and Guo, Xiuqing and Wolffenbuttel, Bruce B. H. R. and Haiman, Christopher A. and Wright, Alan F. and Hall, Per and Yannoukakos, Drakoulis and Hamann, Ute and Zemunik, Tatijana and Henderson, Brian E. and Zheng, Wei and Hocking, Lynne J. and Zygmunt, Marek and Hofman, Albert and Homuth, Georg and Hk, Finucane and Hooning, Maartje J. and Hopper, John L. and Hu, Frank B. and Huang, Jinyan 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 Toniolo, Daniela and Kolcic, Ivana and Uitterlinden, André G. and Kooperberg, Charles and Ulivi, Sheila and Kosma, Veli-Matti and Völzke, Henry and Kriebel, Jennifer and Wareham, Nicholas J. and Kristensen, Vessela and Weir, David R. and Lambrechts, Diether and Yerges-Armstrong, Laura M. and Langenberg, Claudia and Li, Jingmei and Visser, Jenny A. and Li, Xin and Lindström, Sara and Liu, Yongmei and Luan, Jian'an and Lubinski, Jan 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 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, Børge 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 Ad, Johnson 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 Ce, Elks and Sanna, Serena 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 Strauch, Konstantin and Nordestgaard, B.-Ø. G. and Bergmann, Sven and Boomsma, Dorret I. and Buring, Julie E. and Ferrucci, Luigi and Ja, Brody and Montgomery, Grant W. and Gudnason, Vilmundur and Spector, Tim D. 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 Ll, Franke and Hayward, Caroline 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 Je, Huffman and Price, Alkes L. and Stefansson, Kari 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 Felix R. Day

, Deborah J. Thompson, C. M. Van Duijn, Alexander Teumer, Michela Traglia, Dragana Vuckovic

, Jie Yao, Katherine S. Ruth, Wei Zhao, Kathryn L. Lunetta

, Daniel I. Chasman, Toshiko Tanaka, Hilary K. Finucane, Andrew D. Johnson, Cathy E. Elks and other authors. Felix R. Day

, Deborah J. Thompson, C. M. Van Duijn, Alexander Teumer, Michela Traglia, Dragana Vuckovic

, Jie Yao, Katherine S. Ruth, Wei Zhao, Kathryn L. Lunetta

, Daniel I. Chasman, Toshiko Tanaka, Hilary K. Finucane, Andrew D. Johnson, Cathy E. Elks, Jennifer A. Brody, Natalia Pervjakova, Lude L. Franke, Jennifer E. Huffman, Margaux F. Keller, Patrick F. McArdle, Teresa Nutile, Day Fr, Eleonora Porcu, Antonietta Robino

, Lynda M. Rose, Ursula M. Schick, Isabel dos-Santos-Silva, Ruth Ks, Jennifer A. Smith

, Lisette Stolk, Eva Albrecht, Najaf Amin, Tanguy Corre, Jouke-Jan Hottenga, Massimo Mangino, Albert V. Smith

, Thompson Dj, J. EHuffman, Gonçalo R. Abecasis, Patrick Sulem, Irene L. Andrulis, Hoda Anton-Culver, Antonis C. Antoniou, Volker Arndt, Alice M. Arnold, Brendan Bulik-Sullivan, Caterina Barbieri, Matthias W. Beckmann, Alicia Beeghly-Fadiel, Javier Benitez, Leslie Bernstein, Tõnu Esko, Suzette J. Bielinski, Carl Blomqvist, Lunetta Kl, 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, Nora Franceschini, Stephen J. Chanock, J. Ross Chapman, Yii-Der Ida Chen, Georgia Chenevix-Trench, Fergus J. Couch, Andrea D. Coviello, Chunyan He, Angela Cox

, Kamila Czene, Hatef Darabi, Immaculata De Vivo, Ellen W. Demerath, Chasman Di, Joe Dennis, Elisabeth Altmaier, Peter Devilee, Thilo Dörk, Yii-Der Ida Chen, Alison M. Dunning

, John D. Eicher, Peter A. Fasching, Jessica D. Faul

, Jonine Figueroa, Anthony Swerdlow, Dieter Flesch-Janys, Kent D. Taylor, Ilaria Gandin, Unnur Thorsteinsdottir, Melissa E. Garcia, Amanda E. Toland, Montserrat García-Closas, Ian Tomlinson, Thérèse Truong, Graham G. Giles, Laufey Tryggvadottir, Giorgia G. Girotto, Stephen T. Turner, Mark S. Goldberg, I. Dos-Santos-Silva, Diego Vozzi, Anna González-Neira, Qin Wang, Mark O. Goodarzi, Cornelia M. van Duijn, Melissa Wellons, Megan L. Grove, Gonneke Willemsen, Daniel F. Gudbjartsson, James F. Wilson, Pascal Guénel, Robert Winqvist, Xiuqing Guo, Bruce B. H. R. Wolffenbuttel, Christopher A. Haiman, Alan F. Wright, Per Hall, Drakoulis Yannoukakos, Ute Hamann, Tatijana Zemunik, Brian E. Henderson, Wei Zheng, Lynne J. Hocking, Marek Zygmunt, Albert Hofman, Georg Homuth, Finucane Hk, 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, Daniela Toniolo, Ivana Kolcic, André G. Uitterlinden, Charles Kooperberg, Sheila Ulivi, Veli-Matti Kosma, Henry Völzke, Jennifer Kriebel, Nicholas J. Wareham, Vessela Kristensen, David R. Weir, Diether Lambrechts

, Laura M. Yerges-Armstrong, Claudia Langenberg, Jingmei Li, Jenny A. Visser, 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, Johnson Ad, 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, Elks Ce, 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, B.-Ø. G. Nordestgaard, Sven Bergmann, Dorret I. Boomsma, Julie E. Buring, Luigi Ferrucci, Brody Ja, Grant W. Montgomery, Vilmundur Gudnason, Tim D. Spector, Behrooz Z. Alizadeh, Marina Ciullo, Laura Crisponi, Douglas F. Easton, Paolo P. Gasparini, C. M. Duijn, Christian Gieger

, Tamara B. Harris, Franke Ll, Caroline Hayward, Sharon L. R. Kardia, Peter Kraft, Barbara McKnight, Andres Metspalu, Alanna C. Morrison, Alex P. Reiner, Paul M. Ridker, Jerome I. Rotter, Huffman Je, Alkes L. Price, Kari Stefansson, 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