Understanding the genetic complexity of puberty timing across the allele frequency spectrum
Authors: Kentistou Katherine A , Kaisinger Lena R , Stankovic Stasa , Vaudel Marc , de Oliveira Edson M , Messina Andrea , Walters Robin G , Liu Xiaoxi , Busch Alexander S , Helgason Hannes , Thompson Deborah J , Santon Federico , Petricek Konstantin M , Zouaghi Yassine , Huang-Doran Isabel , Gudbjartsson Daniel F , Bratland Eirik , Lin Kuang , Gardner Eugene J , Zhao Yajie , Jia Raina , Terao Chikashi , Riggan Margie , Bolla Manjeet K , Yazdanpanah Mojgan , Yazdanpanah Nahid , Bradfield Jonath 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 LK , Beckmann Matthias W , Berrington 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 , Hübner 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 KE , 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 FA , 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,   The Breast Cancer Association Consortium,   The Biobank Japan Project,   The China Kadoorie Biobank Collaborative Group, Pharoah Paul DP , Li Liming , Easton Douglas F , Njølstad Pål , 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 RB , Ong Ken K 
Published: June 2023

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 inZNF483which abolished the impact of polygenic risk. Next, we implicated 660 genes in pubertal development using a combination ofin silicovariant-to-gene mapping approaches and integration with dynamic gene expression data from mouse embryonic GnRH neurons. This included an uncharacterized G-protein coupled receptorGPR83, which we demonstrate amplifies signaling ofMC3R, 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.