Understanding the genetic complexity of puberty timing across the allele frequency spectrum
Creators: name: Tikkanen, Emmi
name: Offit, Kenneth
name: Pharoah, Paul D. P.
name: Gudbjartsson, Daniel F.
name: Beckmann, Matthias W.
name: Zouaghi, Yassine
name: Cucca, Francesco
name: Fletcher, Olivia
name: Broer, Linda
name: Pennell, Craig E.
name: Chenevix-Trench, Georgia
name: Helgason, Hannes
name: John, Esther M.
name: Hopper, John L.
name: Wilson, James F.
name: Ruggiero, Daniela
name: Zhao, Yajie
name: Ong, Ken K.
name: Timpson, Nic J.
name: Wolk, Alicja
name: Sudlow, Cathie
name: Pianigiani, Giulia
name: Schmidt, Carsten O.
name: Porcu, Eleonora
name: Petricek, Konstantin M.
name: Meitinger, Thomas
name: Haiman, Christopher A.
name: Radice, Paolo
name: Canzian, Federico
name: Brenner, Hermann
name: Vachon, Celine M.
name: Stöckl, Doris
name: Winqvist, Robert
name: Kentistou, Katherine A.
name: De Vivo, Immaculata
name: Murabito, Joanne M.
name: Martin, Nicholas G.
name: Thompson, Deborah J.
name: Small, Kerrin
name: Montgomery, Grant W.
name: Wang, Carol A.
name: González-Neira, Anna
name: Bojesen, Stig E.
name: Hickey, Martha
name: Obi, Nadia
name: Easton, Douglas F.
name: Vaudel, Marc
name: Messina, Andrea
name: Hamann, Ute
name: Huebner, Hanna
name: Kolčić, Ivana
name: Nutile, Teresa
name: Karasik, David
name: Andrulis, Irene L.
name: Perry, John R. B.
name: Michailidou, Kyriaki
name: McCarthy, Mark I.
name: Ahearn, Thomas U.
name: Day, Felix R.
name: Bolla, Manjeet K.
name: Zygmunt, Marek
name: van Dijk, Ko W.
name: Lambrechts, Diether
name: Grant, Struan F. A.
name: Fasching, Peter A.
name: Smith, Albert V.
name: Zheng, Wei
name: Joshi, Peter K.
name: Cox, Angela
name: Mannermaa, Arto
name: Cousminer, Diana L.
name: Toniolo, Daniela
name: Hoppe, Reiner
name: Nolte, Ilja M.
name: Chasman, Daniel I.
name: Willemsen, Gonneke
name: Demerath, Ellen W.
name: Järvelin, Marjo-Riitta
name: Daly, Mary B.
name: Juul, Anders
name: Dunning, Alison M.
name: Girotto, Giorgia
name: Guénel, Pascal
name: Rosendaal, Frits R.
name: Stone, Jennifer
name: Franke, Lude H.
name: Ciullo, Marina
name: Santoni, Federico
name: Yazdanpanah, Nahid
name: Stampfer, Meir
name: Hunter, David J.
name: Gudnason, Vilmundur
name: Terao, Chikashi
name: Auer, Paul L.
name: García-Sáenz, José A.
name: Pozarickij, Alfred
name: Mangino, Massimo
name: Gardner, Eugene J.
name: Kristensen, Vessela N.
name: Mägi, Reedik
name: Luan, Jian’an
name: Lindblom, Annika
name: Horikoshi, Momoko
name: Robino, Antonietta
name: Bandinelli, Stefania
name: Kaisinger, Lena R.
name: Bratland, Eirik
name: Lin, Kuang
name: Dennis, Joe
name: Menni, Cristina
name: Hakonarson, Hakon
name: Palotie, Aarno
name: Lacey, James V.
name: Karlsson, Robert
name: Barnes, Catriona L. K.
name: Ostrowski, Sisse R.
name: Murray, Anna
name: Pedersen, Nancy L.
name: Nøhr, Ellen A.
name: Sandler, Dale P.
name: Polašek, Ozren
name: Widen, Elisabeth
name: Nevanlinna, Heli
name: García-Closas, Montserrat
name: Concas, Maria Pina
name: Jernström, Helena
name: Campbell, Archie
name: O’Brien, Katie M.
name: Gieger, Christian
name: Eriksson, Johan G.
name: Lawlor, Deborah A.
name: Schipf, Sabine
name: Kraft, Peter
name: Zemel, Babette S.
name: Völzke, Henry
name: Rennert, Gad
name: Milne, Roger L.
name: Bradfield, Jonathan P.
name: Gago-Dominguez, Manuela
name: Millwood, Iona Y.
name: Hayward, Caroline
name: Buring, Julie E.
name: Ferreli, Liana
name: Pitteloud, Nelly
name: Pouta, Anneli
name: Farooqi, I. Sadaf
name: Dörk, Thilo
name: Ring, Susan M.
name: Jia, Raina Y.
name: Antoniou, Antonis C.
name: Ulivi, Sheila
name: Sulem, Patrick
name: Uitterlinden, André
name: Busch, Alexander S.
name: Fernandez-Rhodes, Lindsay
name: Lind, Penelope A.
name: Crisponi, Laura
name: Vitart, Veronique
name: Bogdanova, Natalia V.
name: Stefansson, Kari
name: Peters, Annette
name: Erikstrup, Christian
name: Hart, Roger J.
name: Nyholt, Dale R.
name: Li, Liming
name: Boomsma, Dorret I.
name: Teras, Lauren R.
name: Hall, Per
name: Wang, Qin
name: Manousaki, Despoina
name: Noordam, Raymond
name: van der Most, Peter J.
name: Khusnutdinova, Elza K.
name: Riggan, Marjorie J.
name: Alizadeh, Behrooz Z.
name: Spedicati, Beatrice
name: Saloustros, Emmanouil
name: Magnusson, Patrik K. E.
name: Anton-Culver, Hoda
name: Hu, Frank B.
name: Chen, Zhengming
name: Esko, Tõnu
name: Dwek, Miriam
name: Turman, Constance
name: Chang-Claude, Jenny
name: Oldehinkel, Albertine J.
name: He, Chunyan
name: Hottenga, Jouke-Jan
name: Stankovic, Stasa
name: Franceschini, Nora
name: Mendes de Oliveira, Edson
name: Sala, Cinzia
name: Grallert, Harald
name: Spector, Tim D.
name: Sovio, Ulla
name: Ridker, Paul M.
name: Hooning, Maartje J.
name: Njølstad, Pål R.
name: Liu, Xiaoxi
name: Yazdanpanah, Mojgan
name: Boerwinkle, Eric
name: Plaseska-Karanfilska, Dijana
name: Lunetta, Kathryn L.
name: Schmidt, Marjanka K.
name: Wareham, Nicholas J.
name: Huang-Doran, Isabel
name: Meisinger, Christa
name: Tamimi, Rulla M.
name: Johansson, Stefan
name: Kamatani, Yoichiro
name: Pedersen, Ole B.
name: Devilee, Peter
name: Medland, Sarah E.
name: Couch, Fergus J.
name: Walters, Robin G.
name: Czene, Kamila
name: Launer, Lenore J.
name: Snieder, Harold
name: Berrington de Gonzalez, Amy
name: Tanaka, Toshiko
Publisher: name: Springer Nature
Year: 2024

description: 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.