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Understanding the genetic complexity of puberty timing across the allele frequency spectrum.

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  • معلومة اضافية
    • بيانات النشر:
      Springer Nature
    • الموضوع:
      2024
    • Collection:
      University of Westminster: WestminsterResearch
    • نبذة مختصرة :
      Pubertal timing varies considerably and is associated with later health outcomes. We performed multi-ancestry genetic analyses on ~800,000 women, identifying 1,080 signals for age at menarche. Collectively, these explained 11% of trait variance in an independent sample. Women at the top and bottom 1% of polygenic risk exhibited ~11 and ~14-fold higher risks of delayed and precocious puberty, respectively. We identified several genes harboring rare loss-of-function variants in ~200,000 women, including variants in ZNF483, which abolished the impact of polygenic risk. Variant-to-gene mapping approaches and mouse gonadotropin-releasing hormone neuron RNA sequencing implicated 665 genes, including an uncharacterized G-protein-coupled receptor, GPR83, which amplified the signaling of MC3R, a key nutritional sensor. Shared signals with menopause timing at genes involved in DNA damage response suggest that the ovarian reserve might signal centrally to trigger puberty. We also highlight body size-dependent and independent mechanisms that potentially link reproductive timing to later life disease. [Abstract copyright: © 2024. The Author(s).]
    • File Description:
      application/pdf
    • Relation:
      https://westminsterresearch.westminster.ac.uk/download/37f47c6747fefa62c0e54a85c0d058245297397d922435d5994dbb1cdbd54428/37408365/s41588-024-01798-4.pdf; https://doi.org/10.1038/s41588-024-01798-4; Kentistou, K., Kaisinger, L., Stankovic, S., Vaudel, M., Mendes de Oliveira, Edson, Messina, A., Walters, R., Liu, Xiaoxi, Busch, Alexander S., Helgason, Hannes, Thompson, Deborah J., Santoni, F., Petricek, K., Zouaghi, Yassine, Huang-Doran, Isabel, Gudbjartsson, D., Bratland, Eirik, Lin, Kuang, Gardner, E., Zhao, Y., Jia, Raina Y., Terao, C., Riggan, Marjorie J., Bolla, Manjeet K., Yazdanpanah, Mojgan, Yazdanpanah, Nahid, Bradfield, Jonathan P., Broer, L., Campbell, A., Chasman, D., Cousminer, Diana L., Franceschini, N., Franke, L., Girotto, G., He, Chunyan, Järvelin, M., Joshi, Peter K, Kamatani, Y., Karlsson, R., Luan, J., Lunetta, K., Mägi, R., Mangino, M., Medland, S., Meisinger, Christa, Noordam, R., Nutile, Teresa, Concas, M., Polašek, Ozren, Porcu, Eleonora, Ring, S., Sala, C., Smith, A., Tanaka, Toshiko, van der Most, P., Vitart, Veronique, Wang, C., Willemsen, Gonneke, Zygmunt, Marek, Ahearn, T., Andrulis, I., Anton-Culver, Hoda, Antoniou, Antonis C., Auer, P., Barnes, Catriona L.K., Beckmann, Matthias W., Berrington de Gonzalez, Amy, Bogdanova, Natalia V., Bojesen, S., Brenner, H., Buring, Julie E., Canzian, Federico, Chang-Claude, J., Couch, Fergus J., Cox, Angela, Crisponi, L., Czene, Kamila, Daly, Mary B., Demerath, Ellen W., Dennis, J., Devilee, P., De Vivo, Immaculata, Dörk, T., Dunning, A., Dwek, M., Eriksson, Johan G., Fasching, P., Fernandez-Rhodes, L., Ferreli, Liana, Fletcher, O., Gago-Dominguez, Manuela, Garcia-Closas, M., Garcia-Saenz, J., González-Neira, Anna, Grallert, Harald, Guénel, P., Haiman, Christopher A., Hall, Per, Hamann, Ute, Hakonarson, H., Hart, Roger J., Hickey, Martha, Hooning, Maartje J., Hoppe, Reiner, Hopper, John L., Hottenga, J., Hu, Frank B., Huebner, H., Hunter, David J., ABCTB Investigators, Jernström, Helena, John, Esther M., Karasik, D., Khusnutdinova, Elza K., Kristensen, V., Lacey, James V., Lambrechts, Diether, Launer, L., Lind, P., Lindblom, Annika, Magnusson, P., Mannermaa, Arto, McCarthy, M., Meitinger, T., Menni, C., Michailidou, K., Millwood, I., Milne, R., Montgomery, G., Nevanlinna, H., Nolte, I., Nyholt, D., Obi, Nadia, O'Brien, Katie M., Offit, Kenneth, Oldehinkel, A., Ostrowski, S., Palotie, A., Pedersen, O., Peters, Annette, Pianigiani, Giulia, Plaseska-Karanfilska, D., Pouta, Anneli, Pozarickij, Alfred, Radice, P., Rennert, G., Rosendaal, F., Ruggiero, Daniela, Saloustros, E., Sandler, D., Schipf, Sabine, Schmidt, C., Schmidt, M., Small, K., Spedicati, B., Stampfer, Meir, Stone, J., Tamimi, Rulla M., Teras, L., Tikkanen, Emmi, Turman, Constance, Vachon, C., Wang, Qin, Winqvist, R., Wolk, A., Zemel, Babette S., Zheng, Wei, van Dijk, K., Alizadeh, Behrooz Z., Bandinelli, Stefania, Boerwinkle, Eric, Boomsma, D., Ciullo, Marina, Chenevix-Trench, Georgia, Cucca, Francesco, Esko, Tõnu, Gieger, C., Grant, S., Gudnason, V., Hayward, C., Kolčić, Ivana, Kraft, Peter, Lawlor, D., Martin, N., Nøhr, Ellen A., Pedersen, Nancy L., Pennell, C., Ridker, Paul M., Robino, Antonietta, Snieder, H., Sovio, U., Spector, T., Stöckl, Doris, Sudlow, Cathie, Timpson, N., Toniolo, Daniela, Uitterlinden, A., Ulivi, Sheila, Völzke, Henry, Wareham, N., Widen, Elisabeth, Wilson, J., Lifelines Cohort Study, Danish Blood Donor Study, Ovarian Cancer Association Consortium, Breast Cancer Association Consortium, Biobank Japan Project, China Kadoorie Biobank Collaborative Group, Pharoah, P., Li, L., Easton, D., Njølstad, P., Sulem, P., Murabito, Joanne M., Murray, A., Manousaki, Despoina, Juul, A., Erikstrup, C., Stefansson, K., Horikoshi, M., Chen, Z., Farooqi, I Sadaf, Pitteloud, Nelly, Johansson, S., Day, F., Perry, J. and Ong, K. 2024. Understanding the genetic complexity of puberty timing across the allele frequency spectrum. Nature Genetics. Advanced online publication. https://doi.org/10.1038/s41588-024-01798-4
    • الرقم المعرف:
      10.1038/s41588-024-01798-4
    • Rights:
      CC BY 4.0
    • الرقم المعرف:
      edsbas.AABC01EF