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Get Free AccessAbstract Pubertal timing varies considerably and has been associated with a range of health outcomes in later life. To elucidate the underlying biological mechanisms, we performed multi-ancestry genetic analyses in ∼800,000 women, identifying 1,080 independent signals associated with age at menarche. Collectively these loci explained 11% of the trait variance in an independent sample, with women at the top and bottom 1% of polygenic risk exhibiting a ∼11 and ∼14-fold higher risk of delayed and precocious pubertal development, respectively. These common variant analyses were supported by exome sequence analysis of ∼220,000 women, identifying several genes, including rare loss of function variants in ZNF483 which abolished the impact of polygenic risk. Next, we implicated 660 genes in pubertal development using a combination of in silico variant-to-gene mapping approaches and integration with dynamic gene expression data from mouse embryonic GnRH neurons. This included an uncharacterized G-protein coupled receptor GPR83 , which we demonstrate amplifies signaling of MC3R , a key sensor of nutritional status. Finally, we identified several genes, including ovary-expressed genes involved in DNA damage response that co-localize with signals associated with menopause timing, leading us to hypothesize that the ovarian reserve might signal centrally to trigger puberty. Collectively these findings extend our understanding of the biological complexity of puberty timing and highlight body size dependent and independent mechanisms that potentially link reproductive timing to later life disease.
Katherine A. Kentistou, Lena R Kaisinger, Stasa Stankovic, Marc Vaudel, Edson Mendes de Oliveira, Andrea Messina, Robin Walters, Xiaoxi Liu, Alexander S. Busch, Hannes Helgason, Deborah J. Thompson, Federico Santon, Konstantin M. Petricek, Yassine Zouaghi, Isabel Huang‐Doran, Daníel F. Guðbjartsson, Eirik Bratland, Kuang Lin, Eugene J. Gardner, Yajie Zhao, Raina Y Jia, Chikashi Terao, Margie Riggan, Manjeet K. Bolla, Mojgan Yazdanpanah, Nahid Yazdanpanah, Jonath P Bradfield, Linda Broer, Archie Campbell, Daniel I. Chasman, Diana L. Cousminer, Nora Franceschini, Lude Franke, Giorgia Girotto, Chunyan He, Paul M Ridker, Peter K. Joshi, Yoichiro Kamatani, Robert Karlsson, Jian’an Luan, Kathryn L. Lunetta, Reedik Mägi, Massimo Mangino, Sarah E. Medland, Christa Meisinger, Raymond Noordam, Teresa Nutile, Maria Pina Concas, Ozren Polašek, Eleonora Porcu, Susan M. Ring, Cinzia Sala, Albert V. Smith, Toshiko Tanaka, Peter J. van der Most, Véronique Vitart, Carol A. Wang, Gonneke Willemsen, Marek Zygmunt, Thomas U. Ahearn, Irene L. Andrulis, Hoda Anton‐Culver, Antonis C. Antoniou, Paul L. Auer, Catriona L. K. Barnes, Matthias W. Beckmann, Amy Berrington de González, Natalia Bogdanova, Stig E. Bojesen, Hermann Brenner, Julie E. Buring, Federico Canzian, Jenny Chang‐Claude, Fergus J. Couch, Angela Cox, Laura Crisponi, Kamila Czene, Mary B. Daly, Ellen W. Demerath, Joe Dennis, Peter Devilee, Immaculata De Vivo, Thilo Dörk, Alison M. Dunning, Miriam Dwek, Johan G. Eriksson, Peter A. Fasching, Lindsay Fernández‐Rhodes, Liana Ferreli, Olivia Fletcher, Manuela Gago-Domínguez, Montserrat García‐Closas, José Á. García-Sáenz, Anna González‐Neira, Harald Grallert, Pascal Guénel, Christopher A. Haiman, Per Hall, Ute Hamann, Hákon Hákonarson (2023). Understanding the genetic complexity of puberty timing across the allele frequency spectrum. , DOI: https://doi.org/10.1101/2023.06.14.23291322.
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Type
Preprint
Year
2023
Authors
100
Datasets
0
Total Files
0
Language
en
DOI
https://doi.org/10.1101/2023.06.14.23291322
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