Genomic analyses identify hundreds of variants associated with age at menarche and support a role for puberty timing in cancer risk
Creators: name: Martin, Nicholas G.
name: Gudbjartsson, Daniel F.
name: Nutile, Teresa
name: De Mutsert, Renée
name: Ong, Ken K.
name: Tung, Joyce Y.
name: Timpson, Nicholas J.
name: Easton, Douglas F.
name: Meitinger, Thomas
name: Franceschini, Nora
name: Crisponi, Laura
name: Ulivi, Sheila
name: Sulem, Patrick
name: Völzke, Henry
name: Völker, Uwe
name: Flesch-Janys, Dieter
name: Mulligan, Anna M.
name: Perjakova, Natalia
name: Karasik, David
name: Chenevix-Trench, Georgia
name: Bandinelli, Stefania
name: Järvelin, Marjo-Riitta
name: Pharoah, Paul D.P.
name: Vitart, Veronique
name: Scott, Robert A.
name: Tanaka, Toshiko
name: Paternoster, Lavinia
name: Rueedi, Rico
name: Altmaier, Elisabeth
name: Murray, Anna
name: Palotie, Aarno
name: Mägi, Reedik
name: Catamo, Eulalia
name: Grallert, Harald
name: McMahon, George
name: Mbarek, Hamdi
name: Joshi, Peter K.
name: Tyrer, Jonathan P.
name: Giri, Ayush
name: Hopper, John L.
name: Boerwinkle, Eric
name: Spector, Tim D.
name: Loh, Po-Ru
name: Alizadeh, Behrooz Z.
name: Barbieri, Caterina M.
name: Rahman, Iffat
name: Ikram, M. Arfan
name: Amini, Marzyeh
name: Magnusson, Patrik K.E.
name: Wang, Qin
name: Lawlor, Debbie A.
name: Hu, Frank
name: Hartman, Catharina A.
name: Willemsen, Gonneke
name: Padmanabhan, Sandosh
name: Southey, Melissa C.
name: Schraut, Katharina E.
name: Montgomery, Grant W.
name: Brauch, Hiltrud
name: Couch, Fergus J.
name: Heiss, Gerardo
name: Luan, Jian'An
name: Murabito, Joanne M.
name: Pedersen, Nancy
name: Beckmann, Matthias W.
name: Thorsteindottir, Unnur
name: Wareham, Nicholas J.
name: Cucca, Francesco
name: Noordam, Raymond
name: Im, Hae Kyung
name: Visser, Jenny A.
name: Teumer, Alexander
name: McCarthy, Mark I.
name: Liu, Yongmei
name: Oldehinkel, Albertine J.
name: Rudan, Igor
name: Czene, Kamila
name: Hamann, Ute
name: Menni, Cristina
name: Medland, Sarah E.
name: Kolcic, Ivana
name: Polasek, Ozren
name: Demerath, Ellen
name: Li, Jingmei
name: Mook-Kanamori, Dennis O.
name: Smith, Albert V.
name: Toniolo, Daniela
name: Lenarduzzi, Stefania
name: Zhao, Jing Hua
name: Uitterlinden, André G.
name: Campbell, Harry
name: Stöckl, Doris
name: Segrè, Ayellet V.
name: Day, Felix R.
name: Benitez, Javier
name: Andrulis, Irene L.
name: Ridker, Paul M.
name: Nyholt, Dale R.
name: Edwards, Digna R. Velez
name: Mannermaa, Arto
name: Gabrielson, Marike
name: Boutin, Thibaud
name: Wolffenbuttel, Bruce H.R.
name: Launer, Lenore J.
name: Lindstrom, Sara
name: Meisinger, Christa
name: Buring, Julie E.
name: Whalen, Sean
name: Zoledziewska, Magdalena
name: Milne, Roger L.
name: Rosendaal, Frits R.
name: Helgason, Hannes
name: Lunetta, Kathryn L.
name: Mangino, Massimo
name: Tikkanen, Emmi
name: Hallberg, Emily
name: Cox, Angela
name: Strauch, Konstantin
name: Pollard, Katherine S.
name: Hottenga, Jouke J.
name: Widen, Elisabeth
name: Gieger, Christian
name: Gandin, Ilaria
name: Dunning, Alison M.
name: Kraft, Peter
name: Dos-Santos-Silva, Isabel
name: Van Dijk, Ko Willems
name: Brand, Judith S.
name: Giles, Graham G.
name: Stolk, Lisette
name: Michailidou, Kyriaki
name: Bolla, Manjeet K.
name: Fernández-Rhodes, Lindsay
name: Hinds, David
name: Davey Smith, George
name: Bochud, Murielle
name: Radice, Paolo
name: Marco, Brumat
name: Fasching, Peter A.
name: Chang-Claude, Jenny
name: Price, Alkes L.
name: Lind, Penelope A.
name: Ruggiero, Daniela
name: Campbell, Archie
name: Robino, Antonietta
name: Hall, Per
name: Laven, Joop S.E.
name: Metspalu, Andres
name: Finucane, Hilary
name: Lambrechts, Diether
name: Navarro, Pau
name: Devilee, Peter
name: Nevanlinna, Heli
name: O'Mara, Tracy A.
name: Peto, Julian
name: Ferrucci, Luigi
name: Schmidt, Marjanka K.
name: Corre, Tanguy
name: Sorice, Rossella
name: Ring, Susan M.
name: Winqvist, Robert
name: Harris, Tamara B.
name: Hayward, Caroline
name: De Vivo, Immaculata
name: Dennis, Joe
name: Porteous, David
name: Brenner, Hermann
name: Guénel, Pascal
name: Kutalik, Zoltan
name: Truong, Thérèse
name: Nohr, Ellen A.
name: Perry, John R.B.
name: Porcu, Eleonora
name: Eriksson, Johan G.
name: Karlsson, Robert
name: Chanock, Stephen
name: Esko, Tõnu
name: Zygmunt, Marek
name: Nalls, Mike A.
name: Stampfer, Meir
name: De Geus, Eco J.C.N.
name: Snieder, Harold
name: Franke, Lude
name: Boomsma, Dorret I.
name: Bojesen, Stig E.
name: Sala, Cinzia F.
name: Spurdle, Amanda B.
name: Sarkar, Abhishek K.
name: Brüning, Thomas
name: Hunter, David J.
name: Gudnason, Vilmundur
name: Chasman, Daniel I.
name: Stefansson, Kari
name: Vollenweider, Peter
name: Cousminer, Diana L.
name: Albrecht, Eva
name: Steri, Maristella
name: Milani, Lili
name: Thompson, Deborah J.
name: Broer, Linda
name: Rose, Lynda M.
name: Lachance, Genevieve
name: Shah, Mitul
name: Bergmann, Sven
name: Ciullo, Marina
name: Peters, Annette
name: Pouta, Anneli
name: Hooning, Maartje J.
name: Langenberg, Claudia
name: Ruth, Katherine S.
name: Sovio, Ulla
name: Traglia, Michela
name: Nolte, Ilja M.
name: He, Chunyan
name: Wilson, James F.
name: Kellis, Manolis
Publisher: name: The University of North Carolina at Chapel Hill University Libraries
Year: 2017

description: The timing of puberty is a highly polygenic childhood trait that is epidemiologically associated with various adult diseases. Using 1000 Genomes Project-imputed genotype data in up to similar to 370,000 women, we identify 389 independent signals (P <5 x 10(-8)) for age at menarche, a milestone in female pubertal development. In Icelandic data, these signals explain similar to 7.4% of the population variance in age at menarche, corresponding to similar to 25% of the estimated heritability. We implicate similar to 250 genes via coding variation or associated expression, demonstrating significant enrichment in neural tissues. Rare variants near the imprinted genes MKRN3 and DLK1 were identified, exhibiting large effects when paternally inherited. Mendelian randomization analyses suggest causal inverse associations, independent of body mass index (BMI), between puberty timing and risks for breast and endometrial cancers in women and prostate cancer in men. In aggregate, our findings highlight the complexity of the genetic regulation of puberty timing and support causal links with cancer susceptibility.