Understanding the genetic complexity of puberty timing across the allele frequency spectrum

Author:

Kentistou Katherine A.ORCID,Kaisinger Lena R.ORCID,Stankovic StasaORCID,Vaudel MarcORCID,Mendes de Oliveira Edson,Messina AndreaORCID,Walters Robin G.ORCID,Liu Xiaoxi,Busch Alexander S.,Helgason Hannes,Thompson Deborah J.,Santoni FedericoORCID,Petricek Konstantin M.ORCID,Zouaghi Yassine,Huang-Doran Isabel,Gudbjartsson Daniel F.ORCID,Bratland Eirik,Lin Kuang,Gardner Eugene J.ORCID,Zhao YajieORCID,Jia Raina Y.,Terao ChikashiORCID,Riggan Marjorie J.,Bolla Manjeet K.,Yazdanpanah Mojgan,Yazdanpanah Nahid,Bradfield Jonathan P.,Broer LindaORCID,Campbell ArchieORCID,Chasman Daniel I.ORCID,Cousminer Diana L.,Franceschini NoraORCID,Franke Lude H.ORCID,Girotto GiorgiaORCID,He Chunyan,Järvelin Marjo-RiittaORCID,Joshi Peter K.,Kamatani YoichiroORCID,Karlsson RobertORCID,Luan Jian’anORCID,Lunetta Kathryn L.ORCID,Mägi ReedikORCID,Mangino MassimoORCID,Medland Sarah E.ORCID,Meisinger Christa,Noordam RaymondORCID,Nutile Teresa,Concas Maria PinaORCID,Polašek Ozren,Porcu Eleonora,Ring Susan M.ORCID,Sala CinziaORCID,Smith Albert V.ORCID,Tanaka Toshiko,van der Most Peter J.ORCID,Vitart Veronique,Wang Carol A.ORCID,Willemsen Gonneke,Zygmunt Marek,Ahearn Thomas U.ORCID,Andrulis Irene L.ORCID,Anton-Culver Hoda,Antoniou Antonis C.,Auer Paul L.ORCID,Barnes Catriona L. K.,Beckmann Matthias W.,Berrington de Gonzalez Amy,Bogdanova Natalia V.,Bojesen Stig E.ORCID,Brenner HermannORCID,Buring Julie E.,Canzian Federico,Chang-Claude JennyORCID,Couch Fergus J.,Cox Angela,Crisponi LauraORCID,Czene Kamila,Daly Mary B.,Demerath Ellen W.,Dennis JoeORCID,Devilee PeterORCID,De Vivo Immaculata,Dörk ThiloORCID,Dunning Alison M.ORCID,Dwek MiriamORCID,Eriksson Johan G.,Fasching Peter A.ORCID,Fernandez-Rhodes LindsayORCID,Ferreli Liana,Fletcher OliviaORCID,Gago-Dominguez Manuela,García-Closas MontserratORCID,García-Sáenz José A.ORCID,González-Neira Anna,Grallert Harald,Guénel PascalORCID,Haiman Christopher A.,Hall Per,Hamann Ute,Hakonarson HakonORCID,Hart Roger J.,Hickey Martha,Hooning Maartje J.,Hoppe Reiner,Hopper John L.,Hottenga Jouke-JanORCID,Hu Frank B.,Huebner HannaORCID,Hunter David J., ,Jernström Helena,John Esther M.,Karasik DavidORCID,Khusnutdinova Elza K.,Kristensen Vessela N.ORCID,Lacey James V.,Lambrechts Diether,Launer Lenore J.ORCID,Lind Penelope A.ORCID,Lindblom Annika,Magnusson Patrik K. E.ORCID,Mannermaa Arto,McCarthy Mark I.ORCID,Meitinger ThomasORCID,Menni CristinaORCID,Michailidou KyriakiORCID,Millwood Iona Y.ORCID,Milne Roger L.ORCID,Montgomery Grant W.ORCID,Nevanlinna HeliORCID,Nolte Ilja M.ORCID,Nyholt Dale R.ORCID,Obi Nadia,O’Brien Katie M.,Offit Kenneth,Oldehinkel Albertine J.ORCID,Ostrowski Sisse R.ORCID,Palotie AarnoORCID,Pedersen Ole B.ORCID,Peters Annette,Pianigiani Giulia,Plaseska-Karanfilska DijanaORCID,Pouta Anneli,Pozarickij Alfred,Radice PaoloORCID,Rennert GadORCID,Rosendaal Frits R.ORCID,Ruggiero Daniela,Saloustros EmmanouilORCID,Sandler Dale P.ORCID,Schipf Sabine,Schmidt Carsten O.ORCID,Schmidt Marjanka K.ORCID,Small KerrinORCID,Spedicati BeatriceORCID,Stampfer Meir,Stone JenniferORCID,Tamimi Rulla M.,Teras Lauren R.ORCID,Tikkanen Emmi,Turman Constance,Vachon Celine M.ORCID,Wang Qin,Winqvist RobertORCID,Wolk AlicjaORCID,Zemel Babette S.,Zheng Wei,van Dijk Ko W.ORCID,Alizadeh Behrooz Z.,Bandinelli Stefania,Boerwinkle Eric,Boomsma Dorret I.ORCID,Ciullo Marina,Chenevix-Trench Georgia,Cucca Francesco,Esko Tõnu,Gieger ChristianORCID,Grant Struan F. A.ORCID,Gudnason VilmundurORCID,Hayward CarolineORCID,Kolčić Ivana,Kraft Peter,Lawlor Deborah A.ORCID,Martin Nicholas G.ORCID,Nøhr Ellen A.,Pedersen Nancy L.,Pennell Craig E.ORCID,Ridker Paul M.,Robino Antonietta,Snieder HaroldORCID,Sovio UllaORCID,Spector Tim D.ORCID,Stöckl Doris,Sudlow Cathie,Timpson Nic J.ORCID,Toniolo Daniela,Uitterlinden AndréORCID,Ulivi Sheila,Völzke Henry,Wareham Nicholas J.ORCID,Widen Elisabeth,Wilson James F.ORCID, , , ,John Esther M., ,Hall Per,Winqvis RobertORCID, , ,Pharoah Paul D. P.ORCID,Li LimingORCID,Easton Douglas F.ORCID,Njølstad Pål R.ORCID,Sulem PatrickORCID,Murabito Joanne M.,Murray AnnaORCID,Manousaki Despoina,Juul AndersORCID,Erikstrup ChristianORCID,Stefansson KariORCID,Horikoshi MomokoORCID,Chen ZhengmingORCID,Farooqi I. Sadaf,Pitteloud Nelly,Johansson StefanORCID,Day Felix R.ORCID,Perry John R. B.ORCID,Ong Ken K.ORCID

Abstract

AbstractPubertal 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.

Funder

RCUK | MRC | Medical Research Foundation

Publisher

Springer Science and Business Media LLC

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