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Cited by 428

The DOI matches its Crossref record; 101 of the 101 references it cites were found in a registry or an index.

Genetic insights into biological mechanisms governing human ovarian ageing

Open access
Ruth, Katherine S., Day, Felix R., Hussain, Jazib, Martínez-Marchal, Ana, Aiken, Catherine E., Azad, Ajuna, Thompson, Deborah J., Knoblochova, Lucie, Abe, Hironori, Tarry-Adkins, Jane L., Gonzalez, Javier Martin, Fontanillas, Pierre, Claringbould, Annique, Bakker, Olivier B., Sulem, Patrick, Walters, Robin G., Terao, Chikashi, Turon, Sandra, Horikoshi, Momoko, Lin, Kuang, Onland-Moret, N. Charlotte, Sankar, Aditya, Hertz, Emil Peter Thrane, Timshel, Pascal N., Shukla, Vallari, Borup, Rehannah, Olsen, Kristina W., Aguilera, Paula, Ferrer-Roda, Mònica, Huang, Yan, Stankovic, Stasa, Timmers, Paul R. H. J., Ahearn, Thomas U., Alizadeh, Behrooz Z., Naderi, Elnaz, Andrulis, Irene L., Arnold, Alice M., Aronson, Kristan J., Augustinsson, Annelie, Bandinelli, Stefania, Barbieri, Caterina M., Beaumont, Robin N., Becher, Heiko, Beckmann, Matthias W., Benonisdottir, Stefania, Bergmann, Sven, Bochud, Murielle, Boerwinkle, Eric, Bojesen, Stig E., Bolla, Manjeet K., Boomsma, Dorret I., Bowker, Nicholas, Brody, Jennifer A., Broer, Linda, Buring, Julie E., Campbell, Archie, Campbell, Harry, Castelao, Jose E., Catamo, Eulalia, Chanock, Stephen J., Chenevix-Trench, Georgia, Ciullo, Marina, Corre, Tanguy, Couch, Fergus J., Cox, Angela, Crisponi, Laura, Cross, Simon S., Cucca, Francesco, Czene, Kamila, Smith, George Davey, de Geus, Eco J. C. N., de Mutsert, Renée, De Vivo, Immaculata, Demerath, Ellen W., Dennis, Joe, Dunning, Alison M., Dwek, Miriam, Eriksson, Mikael, Esko, Tõnu, Fasching, Peter A., Faul, Jessica D., Ferrucci, Luigi, Franceschini, Nora, Frayling, Timothy M., Gago-Dominguez, Manuela, Mezzavilla, Massimo, García-Closas, Montserrat, Gieger, Christian, Giles, Graham G., Grallert, Harald, Gudbjartsson, Daniel F., Gudnason, Vilmundur, Guénel, Pascal, Haiman, Christopher A., Håkansson, Niclas, Hall, Per, Hayward, Caroline, He, Chunyan, He, Wei, Heiss, Gerardo, Høffding, Miya K., Hopper, John L., Hottenga, Jouke J., Hu, Frank, Hunter, David, Ikram, Mohammad A., Jackson, Rebecca D., Joaquim, Micaella D. R., John, Esther M., Joshi, Peter K., Karasik, David, Kardia, Sharon L. R., Kartsonaki, Christiana, Karlsson, Robert, Kitahara, Cari M., Kolcic, Ivana, Kooperberg, Charles, Kraft, Peter, Kurian, Allison W., Kutalik, Zoltan, La Bianca, Martina, LaChance, Genevieve, Langenberg, Claudia, Launer, Lenore J., Laven, Joop S. E., Lawlor, Deborah A., Le Marchand, Loic, Li, Jingmei, Lindblom, Annika, Lindstrom, Sara, Lindstrom, Tricia, Linet, Martha, Liu, YongMei, Liu, Simin, Luan, Jian’an, Mägi, Reedik, Magnusson, Patrik K. E., Mangino, Massimo, Mannermaa, Arto, Marco, Brumat, Marten, Jonathan, Martin, Nicholas G., Mbarek, Hamdi, McKnight, Barbara, Medland, Sarah E., Meisinger, Christa, Meitinger, Thomas, Menni, Cristina, Metspalu, Andres, Milani, Lili, Milne, Roger L., Montgomery, Grant W., Mook-Kanamori, Dennis O., Mulas, Antonella, Mulligan, Anna M., Murray, Alison, Nalls, Mike A., Newman, Anne, Noordam, Raymond, Nutile, Teresa, Nyholt, Dale R., Olshan, Andrew F., Olsson, Håkan, Painter, Jodie N., Patel, Alpa V., Pedersen, Nancy L., Perjakova, Natalia, Peters, Annette, Peters, Ulrike, Pharoah, Paul D. P., Polasek, Ozren, Porcu, Eleonora, Psaty, Bruce M., Rahman, Iffat, Rennert, Gad, Rennert, Hedy S., Ridker, Paul M., Ring, Susan M., Robino, Antonietta, Rose, Lynda M., Rosendaal, Frits R., Rossouw, Jacques, Rudan, Igor, Rueedi, Rico, Ruggiero, Daniela, Sala, Cinzia F., Saloustros, Emmanouil, Sandler, Dale P., Sanna, Serena, Sawyer, Elinor J., Sarnowski, Chloé, Schlessinger, David, Schmidt, Marjanka K., Schoemaker, Minouk J., Schraut, Katharina E., Scott, Christopher, Shekari, Saleh, Shrikhande, Amruta, Smith, Albert V., Smith, Blair H., Smith, Jennifer A., Sorice, Rossella, Southey, Melissa C., Spector, Tim D., Spinelli, John J., Stampfer, Meir, Stöckl, Doris, van Meurs, Joyce B. J., Strauch, Konstantin, Styrkarsdottir, Unnur, Swerdlow, Anthony J., Tanaka, Toshiko, Teras, Lauren R., Teumer, Alexander, Þorsteinsdottir, Unnur, Timpson, Nicholas J., Toniolo, Daniela, Traglia, Michela, Troester, Melissa A., Truong, Thérèse, Tyrrell, Jessica, Uitterlinden, André G., Ulivi, Sheila, Vachon, Celine M., Vitart, Veronique, Völker, Uwe, Vollenweider, Peter, Völzke, Henry, Wang, Qin, Wareham, Nicholas J., Weinberg, Clarice R., Weir, David R., Wilcox, Amber N., van Dijk, Ko Willems, Willemsen, Gonneke, Wilson, James F., Wolffenbuttel, Bruce H. R., Wolk, Alicja, Wood, Andrew R., Zhao, Wei, Zygmunt, Marek, Biobank-based Integrative Omics Study (BIOS) Consortium, eQTLGen Consortium, The Biobank Japan Project, China Kadoorie Biobank Collaborative Group, kConFab Investigators, The LifeLines Cohort Study, The InterAct consortium, 23andMe Research Team, Chen, Zhengming, Li, Liming, Franke, Lude, Burgess, Stephen, Deelen, Patrick, Pers, Tune H., Grøndahl, Marie Louise, Andersen, Claus Yding, Pujol, Anna, Lopez-Contreras, Andres J., Daniel, Jeremy A., Stefansson, Kari, Chang-Claude, Jenny, van der Schouw, Yvonne T., Lunetta, Kathryn L., Chasman, Daniel I., Easton, Douglas F., Visser, Jenny A., Ozanne, Susan E., Namekawa, Satoshi H., Solc, Petr, Murabito, Joanne M., Ong, Ken K., Hoffmann, Eva R., Murray, Anna, Roig, Ignasi, Perry, John R. B.·2021·Nature
DOI 10.1038/s41586-021-03779-7
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Abstract

Reproductive longevity is essential for fertility and influences healthy ageing in women1,2, but insights into its underlying biological mechanisms and treatments to preserve it are limited. Here we identify 290 genetic determinants of ovarian ageing, assessed using normal variation in age at natural menopause (ANM) in about 200,000 women of European ancestry. These common alleles were associated with clinical extremes of ANM; women in the top 1% of genetic susceptibility have an equivalent risk of premature ovarian insufficiency to those carrying monogenic FMR1 premutations3. The identified loci implicate a broad range of DNA damage response (DDR) processes and include loss-of-function variants in key DDR-associated genes. Integration with experimental models demonstrates that these DDR processes act across the life-course to shape the ovarian reserve and its rate of depletion. Furthermore, we demonstrate that experimental manipulation of DDR pathways highlighted by human genetics increases fertility and extends reproductive life in mice. Causal inference analyses using the identified genetic variants indicate that extending reproductive life in women improves bone health and reduces risk of type 2 diabetes, but increases the risk of hormone-sensitive cancers. These findings provide insight into the mechanisms that govern ovarian ageing, when they act, and how they might be targeted by therapeutic approaches to extend fertility and prevent disease. Hundreds of genetic loci associated with age at menopause, combined with experimental evidence in mice, highlight mechanisms of reproductive ageing across the lifespan.

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Authors
Ruth, K. S., Day, F. R., Hussain, J., Martínez-Marchal, A., Aiken, C. E., Azad, A., Thompson, D. J., Knoblochova, L., Abe, H., Tarry-Adkins, J. L., Gonzalez, J. M., Fontanillas, P., Claringbould, A., Bakker, O. B., Sulem, P., Walters, R. G., Terao, C., Turon, S., Horikoshi, M., Lin, K., Onland-Moret, N. C., Sankar, A., Hertz, E. P. T., Timshel, P. N., Shukla, V., Borup, R., Olsen, K. W., Aguilera, P., Ferrer-Roda, M., Huang, Y., Stankovic, S., Timmers, P. R. H. J., Ahearn, T. U., Alizadeh, B. Z., Naderi, E., Andrulis, I. L., Arnold, A. M., Aronson, K. J., Augustinsson, A., Bandinelli, S., Barbieri, C. M., Beaumont, R. N., Becher, H., Beckmann, M. W., Benonisdottir, S., Bergmann, S., Bochud, M., Boerwinkle, E., Bojesen, S. E., Bolla, M. K., Boomsma, D. I., Bowker, N., Brody, J. A., Broer, L., Buring, J. E., Campbell, A., Campbell, H., Castelao, J. E., Catamo, E., Chanock, S. J., Chenevix-Trench, G., Ciullo, M., Corre, T., Couch, F. J., Cox, A., Crisponi, L., Cross, S. S., Cucca, F., Czene, K., Smith, G. D., de Geus, E. J. C. N., de Mutsert, R., De Vivo, I., Demerath, E. W., Dennis, J., Dunning, A. M., Dwek, M., Eriksson, M., Esko, T., Fasching, P. A., Faul, J. D., Ferrucci, L., Franceschini, N., Frayling, T. M., Gago-Dominguez, M., Mezzavilla, M., García-Closas, M., Gieger, C., Giles, G. G., Grallert, H., Gudbjartsson, D. F., Gudnason, V., Guénel, P., Haiman, C. A., Håkansson, N., Hall, P., Hayward, C., He, C., He, W., Heiss, G., Høffding, M. K., Hopper, J. L., Hottenga, J. J., Hu, F., Hunter, D., Ikram, M. A., Jackson, R. D., Joaquim, M. D. R., John, E. M., Joshi, P. K., Karasik, D., Kardia, S. L. R., Kartsonaki, C., Karlsson, R., Kitahara, C. M., Kolcic, I., Kooperberg, C., Kraft, P., Kurian, A. W., Kutalik, Z., La Bianca, M., LaChance, G., Langenberg, C., Launer, L. J., Laven, J. S. E., Lawlor, D. A., Le Marchand, L., Li, J., Lindblom, A., Lindstrom, S., Lindstrom, T., Linet, M., Liu, Y., Liu, S., Luan, J., Mägi, R., Magnusson, P. K. E., Mangino, M., Mannermaa, A., Marco, B., Marten, J., Martin, N. G., Mbarek, H., McKnight, B., Medland, S. E., Meisinger, C., Meitinger, T., Menni, C., Metspalu, A., Milani, L., Milne, R. L., Montgomery, G. W., Mook-Kanamori, D. O., Mulas, A., Mulligan, A. M., Murray, A., Nalls, M. A., Newman, A., Noordam, R., Nutile, T., Nyholt, D. R., Olshan, A. F., Olsson, H., Painter, J. N., Patel, A. V., Pedersen, N. L., Perjakova, N., Peters, A., Peters, U., Pharoah, P. D. P., Polasek, O., Porcu, E., Psaty, B. M., Rahman, I., Rennert, G., Rennert, H. S., Ridker, P. M., Ring, S. M., Robino, A., Rose, L. M., Rosendaal, F. R., Rossouw, J., Rudan, I., Rueedi, R., Ruggiero, D., Sala, C. F., Saloustros, E., Sandler, D. P., Sanna, S., Sawyer, E. J., Sarnowski, C., Schlessinger, D., Schmidt, M. K., Schoemaker, M. J., Schraut, K. E., Scott, C., Shekari, S., Shrikhande, A., Smith, A. V., Smith, B. H., Smith, J. A., Sorice, R., Southey, M. C., Spector, T. D., Spinelli, J. J., Stampfer, M., Stöckl, D., van Meurs, J. B. J., Strauch, K., Styrkarsdottir, U., Swerdlow, A. J., Tanaka, T., Teras, L. R., Teumer, A., Þorsteinsdottir, U., Timpson, N. J., Toniolo, D., Traglia, M., Troester, M. A., Truong, T., Tyrrell, J., Uitterlinden, A. G., Ulivi, S., Vachon, C. M., Vitart, V., Völker, U., Vollenweider, P., Völzke, H., Wang, Q., Wareham, N. J., Weinberg, C. R., Weir, D. R., Wilcox, A. N., van Dijk, K. W., Willemsen, G., Wilson, J. F., Wolffenbuttel, B. H. R., Wolk, A., Wood, A. R., Zhao, W., Zygmunt, M., Biobank-based Integrative Omics Study (BIOS) Consortium, eQTLGen Consortium, The Biobank Japan Project, China Kadoorie Biobank Collaborative Group, kConFab Investigators, Study, T. L. C., The InterAct consortium, 23andMe Research Team, Chen, Z., Li, L., Franke, L., Burgess, S., Deelen, P., Pers, T. H., Grøndahl, M. L., Andersen, C. Y., Pujol, A., Lopez-Contreras, A. J., Daniel, J. A., Stefansson, K., Chang-Claude, J., van der Schouw, Y. T., Lunetta, K. L., Chasman, D. I., Easton, D. F., Visser, J. A., Ozanne, S. E., Namekawa, S. H., Solc, P., Murabito, J. M., Ong, K. K., Hoffmann, E. R., Murray, A., Roig, I., & Perry, J. R. B.
Venue
Nature
Publisher
Springer Science and Business Media LLC
Published
2021-08-04
Volume
596
Issue
7872
Pages
393-397
ISSN
  • 0028-0836 (ISSN-L)
  • 1476-4687
DOI
10.1038/s41586-021-03779-7
OpenAlex
W3185710912
Cited by
428
References
101
FWCI
56.07
Type
journal article
Language
en
Open access
bronze

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Ruth, K. S., Day, F. R., Hussain, J., Martínez-Marchal, A., Aiken, C. E., Azad, A., Thompson, D. J., Knoblochova, L., Abe, H., Tarry-Adkins, J. L., Gonzalez, J. M., Fontanillas, P., Claringbould, A., Bakker, O. B., Sulem, P., Walters, R. G., Terao, C., Turon, S., Horikoshi, M., . . . Perry, J. R. B. (2021). Genetic insights into biological mechanisms governing human ovarian ageing. Nature. https://doi.org/10.1038/s41586-021-03779-7

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