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

Katherine A KentistouLena R KaisingerStasa StankovicMarc VaudelEdson M de OliveiraAndrea MessinaRobin G WaltersXiaoxi LiuAlexander S BuschHannes HelgasonDeborah J ThompsonFederico SantonKonstantin M PetricekYassine ZouaghiIsabel Huang-DoranDaniel F GudbjartssonEirik BratlandKuang LinEugene J GardnerYajie ZhaoRaina JiaChikashi TeraoMargie RigganManjeet K BollaMojgan YazdanpanahNahid YazdanpanahJonath P BradfieldLinda BroerArchie CampbellDaniel I ChasmanDiana L CousminerNora FranceschiniLude H FrankeGiorgia GirottoChunyan HeMarjo-Riitta JärvelinPeter K JoshiYoichiro KamataniRobert KarlssonJian'an LuanKathryn L LunettaReedik MägiMassimo ManginoSarah E MedlandChrista MeisingerRaymond NoordamTeresa NutileMaria Pina ConcasOzren PolašekEleonora PorcuSusan M RingCinzia SalaAlbert V SmithToshiko TanakaPeter J van der MostVeronique VitartCarol A WangGonneke WillemsenMarek ZygmuntThomas U AhearnIrene L AndrulisHoda Anton-CulverAntonis C AntoniouPaul L AuerCatriona Lk BarnesMatthias W BeckmannAmy BerringtonNatalia V BogdanovaStig E BojesenHermann BrennerJulie E BuringFederico CanzianJenny Chang-ClaudeFergus J CouchAngela CoxLaura CrisponiKamila CzeneMary B DalyEllen W DemerathJoe DennisPeter DevileeImmaculata De VivoThilo DörkAlison M DunningMiriam DwekJohan G ErikssonPeter A FaschingLindsay Fernandez-RhodesLiana FerreliOlivia FletcherManuela Gago-DominguezMontserrat García-ClosasJosé A García-SáenzAnna González-NeiraHarald GrallertPascal GuénelChristopher A HaimanPer HallUte HamannHakon HakonarsonRoger J HartMartha HickeyMaartje J HooningReiner HoppeJohn L HopperJouke-Jan HottengaFrank B HuHanna HübnerDavid J Hunternull nullHelena JernströmEsther M JohnDavid KarasikElza K KhusnutdinovaVessela N KristensenJames V LaceyDiether LambrechtsLenore J LaunerPenelope A LindAnnika LindblomPatrik Ke MagnussonArto MannermaaMark I McCarthyThomas MeitingerCristina MenniKyriaki MichailidouIona Y MillwoodRoger L MilneGrant W MontgomeryHeli NevanlinnaIlja M NolteDale R NyholtNadia ObiKatie M O'BrienKenneth OffitAlbertine J OldehinkelSisse R OstrowskiAarno PalotieOle B PedersenAnnette PetersGiulia PianigianiDijana Plaseska-KaranfilskaAnneli PoutaAlfred PozarickijPaolo RadiceGad RennertFrits R RosendaalDaniela RuggieroEmmanouil SaloustrosDale P SandlerSabine SchipfCarsten O SchmidtMarjanka K SchmidtKerrin SmallBeatrice SpedicatiMeir StampferJennifer StoneRulla M TamimiLauren R TerasEmmi TikkanenConstance TurmanCeline M VachonQin WangRobert WinqvistAlicja WolkBabette S ZemelWei ZhengKo W van DijkBehrooz Z AlizadehStefania BandinelliEric BoerwinkleDorret I BoomsmaMarina CiulloGeorgia Chenevix-TrenchFrancesco CuccaTõnu EskoChristian GiegerStruan Fa GrantVilmundur GudnasonCaroline HaywardIvana KolčićPeter KraftDeborah A LawlorNicholas G MartinEllen A NøhrNancy L PedersenCraig E PennellPaul M RidkerAntonietta RobinoHarold SniederUlla SovioTim D SpectorDoris StöcklCathie SudlowNic J TimpsonDaniela TonioloAndré UitterlindenSheila UliviHenry VölzkeNicholas J WarehamElisabeth WidenJames F Wilsonnull nullnull nullnull nullnull nullnull nullnull nullPaul Dp PharoahLiming LiDouglas F EastonPål NjølstadPatrick SulemJoanne M MurabitoAnna MurrayDespoina ManousakiAnders JuulChristian ErikstrupKari StefanssonMomoko HorikoshiZhengming ChenI Sadaf FarooqiNelly PitteloudStefan JohanssonFelix R DayJohn Rb PerryKen K Ong
Published in: medRxiv : the preprint server for health sciences (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 in ZNF483 which abolished the impact of polygenic risk. Next, we implicated 660 genes in pubertal development using a combination of in silico variant-to-gene mapping approaches and integration with dynamic gene expression data from mouse embryonic GnRH neurons. This included an uncharacterized G-protein coupled receptor GPR83 , which we demonstrate amplifies signaling of MC3R , 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.
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