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, Tonu, 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, 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, Goncalo 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, Bruening, 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, Doerk, 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., Garcia-Closas, Montserrat, Giles, Graham G., Girotto, Giorgia G., Goldberg, Mark S., Gonzalez-Neira, Anna, Goodarzi, Mark O., Grove, Megan L., Gudbjartsson, Daniel F., Guenel, 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, Lindstroem, Sara, Liu, Yongmei, Luan, Jian'an, Lubinski, Jan, Maegi, 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., Mueller-Nurasyid, Martina, Nalls, Michael, Neale, Benjamin M., Nevanlinna, Heli, Neven, Patrick, Newman, Anne B., Nordestgaard, Borge 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., Pylkas, 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., Stoeckl, Doris, Strauch, Konstantin, Swerdlow, Anthony, Taylor, Kent D., Thorsteinsdottir, Unnur, Toland, Amanda E., Tomlinson, Ian, Truong, Therese, 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., van Duijn, Cornelia M., 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, Andre G., Ulivi, Sheila, Voelzke, 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. and Murray, Anna (2015) Large-scale genomic analyses link reproductive aging to hypothalamic signaling, breast cancer susceptibility and BRCA1-mediated DNA repair. Nature Genetics, 47 11: 1294-1305. doi:10.1038/ng.3412


Author 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, Tonu
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
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, Goncalo 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
Bruening, 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
Doerk, 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.
Garcia-Closas, Montserrat
Giles, Graham G.
Girotto, Giorgia G.
Goldberg, Mark S.
Gonzalez-Neira, Anna
Goodarzi, Mark O.
Grove, Megan L.
Gudbjartsson, Daniel F.
Guenel, 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
Lindstroem, Sara
Liu, Yongmei
Luan, Jian'an
Lubinski, Jan
Maegi, 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.
Mueller-Nurasyid, Martina
Nalls, Michael
Neale, Benjamin M.
Nevanlinna, Heli
Neven, Patrick
Newman, Anne B.
Nordestgaard, Borge 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.
Pylkas, 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.
Stoeckl, Doris
Strauch, Konstantin
Swerdlow, Anthony
Taylor, Kent D.
Thorsteinsdottir, Unnur
Toland, Amanda E.
Tomlinson, Ian
Truong, Therese
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.
van Duijn, Cornelia M.
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, Andre G.
Ulivi, Sheila
Voelzke, 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
Title Large-scale genomic analyses link reproductive aging to hypothalamic signaling, breast cancer susceptibility and BRCA1-mediated DNA repair
Journal name Nature Genetics   Check publisher's open access policy
ISSN 1061-4036
1546-1718
Publication date 2015-11-01
Year available 2015
Sub-type Article (original research)
DOI 10.1038/ng.3412
Open Access Status Not yet assessed
Volume 47
Issue 11
Start page 1294
End page 1305
Total pages 12
Place of publication New York, United States
Publisher Nature Publishing Group
Language eng
Subject 1311 Genetics
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 similar to 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 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 (similar to 6% increase in risk per year; P = 3 x 10(-14)), likely mediated by prolonged sex hormone exposure rather than DDR mechanisms.
Formatted 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 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 (~6% increase in risk per year; P = 3 × 10−14), likely mediated by prolonged sex hormone exposure rather than DDR mechanisms.
Keyword Premature ovarian failure
Brca2 mutation carriers
Body mass index
Natural menopause
Homologous recombination
Chromosomal instability
Q-Index Code C1
Q-Index Status Provisional Code
Grant ID 10124
CZD/16/6/4
MC_PC_U127561128
UL1 TR000124
1U19 CA148065
UL1RR025005
HG005552
5RC2HL102419
1R01AG032098-01A1
DK063491
HHSN268200625226C
090532
Institutional Status Non-UQ

Document type: Journal Article
Sub-type: Article (original research)
Collection: Institute for Molecular Bioscience - Publications
 
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