Understanding the genetic complexity of puberty timing across the allele frequency spectrum.
Katherine A Kentistou,
Lena R Kaisinger,
Stasa Stankovic,
Marc Vaudel,
Edson Mendes de Oliveira,
Andrea Messina,
Robin G Walters,
Xiaoxi Liu,
Alexander S Busch,
Hannes Helgason,
Deborah J Thompson,
Federico Santoni,
Konstantin M Petricek,
Yassine Zouaghi,
Isabel Huang-Doran,
Daniel F Gudbjartsson,
Eirik Bratland,
Kuang Lin,
Eugene J Gardner,
Yajie Zhao,
Raina Y Jia,
Chikashi Terao,
Marjorie J Riggan,
Manjeet K Bolla,
Mojgan Yazdanpanah,
Nahid Yazdanpanah,
Jonathan P Bradfield,
Linda Broer,
Archie Campbell,
Daniel I Chasman,
Diana L Cousminer,
Nora Franceschini,
Lude H Franke,
Giorgia Girotto,
Chunyan He,
Marjo-Riitta Järvelin,
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,
Veronique 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 Gonzalez,
Natalia V 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 Fernandez-Rhodes,
Liana Ferreli,
Olivia Fletcher,
Manuela Gago-Dominguez,
Montserrat García-Closas,
José A García-Sáenz,
Anna González-Neira,
Harald Grallert,
Pascal Guénel,
Christopher A Haiman,
Per Hall,
Ute Hamann,
Hakon Hakonarson,
Roger J Hart,
Martha Hickey,
Maartje J Hooning,
Reiner Hoppe,
John L Hopper,
Jouke-Jan Hottenga,
Frank B Hu,
Hanna Huebner,
David J Hunter,
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Helena Jernström,
Esther M John,
David Karasik,
Elza K Khusnutdinova,
Vessela N Kristensen,
James V Lacey,
Diether Lambrechts,
Lenore J Launer,
Penelope A Lind,
Annika Lindblom,
Patrik K E Magnusson,
Arto Mannermaa,
Mark I McCarthy,
Thomas Meitinger,
Cristina Menni,
Kyriaki Michailidou,
Iona Y Millwood,
Roger L Milne,
Grant W Montgomery,
Heli Nevanlinna,
Ilja M Nolte,
Dale R Nyholt,
Nadia Obi,
Katie M O'Brien,
Kenneth Offit,
Albertine J Oldehinkel,
Sisse R Ostrowski,
Aarno Palotie,
Ole B Pedersen,
Annette Peters,
Giulia Pianigiani,
Dijana Plaseska-Karanfilska,
Anneli Pouta,
Alfred Pozarickij,
Paolo Radice,
Gad Rennert,
Frits R Rosendaal,
Daniela Ruggiero,
Emmanouil Saloustros,
Dale P Sandler,
Sabine Schipf,
Carsten O Schmidt,
Marjanka K Schmidt,
Kerrin Small,
Beatrice Spedicati,
Meir Stampfer,
Jennifer Stone,
Rulla M Tamimi,
Lauren R Teras,
Emmi Tikkanen,
Constance Turman,
Celine M Vachon,
Qin Wang,
Robert Winqvist,
Alicja Wolk,
Babette S Zemel,
Wei Zheng,
Ko W van Dijk,
Behrooz Z Alizadeh,
Stefania Bandinelli,
Eric Boerwinkle,
Dorret I Boomsma,
Marina Ciullo,
Georgia Chenevix-Trench,
Francesco Cucca,
Tõnu Esko,
Christian Gieger,
Struan F A Grant,
Vilmundur Gudnason,
Caroline Hayward,
Ivana Kolčić,
Peter Kraft,
Deborah A Lawlor,
Nicholas G Martin,
Ellen A Nøhr,
Nancy L Pedersen,
Craig E Pennell,
Paul M Ridker,
Antonietta Robino,
Harold Snieder,
Ulla Sovio,
Tim D Spector,
Doris Stöckl,
Cathie Sudlow,
Nic J Timpson,
Daniela Toniolo,
André Uitterlinden,
Sheila Ulivi,
Henry Völzke,
Nicholas J Wareham,
Elisabeth Widen,
James F Wilson,
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Paul D P Pharoah,
Liming Li,
Douglas F Easton,
Pål R Njølstad,
Patrick Sulem,
Joanne M Murabito,
Anna Murray,
Despoina Manousaki,
Anders Juul,
Christian Erikstrup,
Kari Stefansson,
Momoko Horikoshi,
Zhengming Chen,
I Sadaf Farooqi,
Nelly Pitteloud,
Stefan Johansson,
Felix R Day,
John R B Perry,
Ken K Ong
Abstract
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.