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Genomic analyses for age at menarche identify 389 independent signals and indicate BMI-independent effects of puberty timing on cancer susceptibility

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

Posted 23 Sep 2016
bioRxiv DOI: 10.1101/076794

The timing of puberty is a highly polygenic childhood trait that is epidemiologically associated with various adult diseases. Here, we analyse 1000-Genome reference panel imputed genotype data on up to ~370,000 women and identify 389 independent signals (all P<5x10-8) for age at menarche, a notable milestone in female pubertal development. In Icelandic data from deCODE, these signals explain ~7.4% of the population variance in age at menarche, corresponding to one quarter of the estimated heritability. We implicate over 250 genes via coding variation or associated gene expression, and demonstrate enrichment across genes active in neural tissues. We identify multiple rare variants near the imprinted genes MKRN3 and DLK1 that exhibit large effects on menarche only when paternally inherited. Disproportionate effects of variants on early or late puberty timing are observed: single variant and heritability estimates are larger for early than late puberty timing in females. The opposite pattern is seen in males, with larger estimates for late than early puberty timing. Mendelian randomization analyses indicate causal inverse associations, independent of BMI, between puberty timing and risks for breast and endometrial cancers in women, and prostate cancer in men. In aggregate, our findings reveal new complexity in the genetic regulation of puberty timing and support new causal links with adult cancer risks.

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