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

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.