دورية أكاديمية
Genetic insights into biological mechanisms governing human ovarian ageing
| العنوان: | Genetic insights into biological mechanisms governing human ovarian ageing |
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| المؤلفون: | Ruth K. S., Day F. R., Hussain J., Martinez-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., Garcia-Closas M., Gieger C., Giles G. G., Grallert H., Gudbjartsson D. F., Gudnason V., Guenel P., Haiman C. A., Hakansson N., Hall P., Hayward C., He C., He W., Heiss G., Hoffding 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. M., Liu S., Luan J., Magi 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., Stockl D., van Meurs J. B. J., Strauch K., Styrkarsdottir U., Swerdlow A. J., Tanaka T., Teras L. R., Teumer A., Thorsteinsdottir 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., Volker U., Vollenweider P., Volzke 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., Chen Z., Li L., Franke L., Burgess S., Deelen P., Pers T. H., Grondahl 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., Roig I., Perry J. R. B. |
| المساهمون: | Ruth, K. S., Day, F. R., Hussain, J., Martinez-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., Garcia-Closas, M., Gieger, C., Giles, G. G., Grallert, H., Gudbjartsson, D. F., Gudnason, V., Guenel, P., Haiman, C. A., Hakansson, N., Hall, P., Hayward, C., He, C., He, W., Heiss, G. |
| بيانات النشر: | Nature Research |
| سنة النشر: | 2021 |
| المجموعة: | Padua Research Archive (IRIS - Università degli Studi di Padova) |
| مصطلحات موضوعية: | Adult, Aging, Allele, Animal, Bone and Bone, Checkpoint Kinase 1, Checkpoint Kinase 2, Diabetes Mellitus, Type 2, Diet, Europe, Far East, Female, Fertility, Fragile X Mental Retardation Protein, Genetic Predisposition to Disease, Genome-Wide Association Study, Healthy Aging, Human, Longevity, Menopause, Premature, Mice, Inbred C57BL, Middle Aged, Ovary, Primary Ovarian Insufficiency, Uterus |
| الوصف: | 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. |
| نوع الوثيقة: | article in journal/newspaper |
| اللغة: | English |
| العلاقة: | info:eu-repo/semantics/altIdentifier/pmid/34349265; info:eu-repo/semantics/altIdentifier/wos/WOS:000681278500003; volume:596; issue:7872; firstpage:393; lastpage:397; numberofpages:5; journal:NATURE; http://hdl.handle.net/11577/3455576Test; info:eu-repo/semantics/altIdentifier/scopus/2-s2.0-85112666642 |
| DOI: | 10.1038/s41586-021-03779-7 |
| الإتاحة: | https://doi.org/10.1038/s41586-021-03779-7Test http://hdl.handle.net/11577/3455576Test |
| حقوق: | info:eu-repo/semantics/openAccess |
| رقم الانضمام: | edsbas.C75575F2 |
| قاعدة البيانات: | BASE |
| DOI: | 10.1038/s41586-021-03779-7 |
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