Parent-of-origin-specific allelic associations among 106 genomic loci for age at menarche

John R. B. Perry, Felix Day, Cathy E. Elks, Patrick Sulem, Deborah J. Thompson, Teresa Ferreira, Chunyan He, Daniel I. Chasman, Toenu Esko, Gudmar Thorleifsson, Eva Albrecht, Wei Q. Ang, Tanguy Corre, Diana L. Cousminer, Bjarke Feenstra, Nora Franceschini, Andrea Ganna, Andrew D. Johnson, Sanela Kjellqvist, Kathryn L. LunettaGeorge McMahon, Ilja M. Nolte, Lavinia Paternoster, Eleonora Porcu, Albert V. Smith, Lisette Stolk, Alexander Teumer, Natalia Tsernikova, Emmi Tikkanen, Sheila Ulivi, Erin K. Wagner, Najaf Amin, Laura J. Bierut, Enda M. Byrne, Jouke-Jan Hottenga, Daniel L. Koller, Massimo Mangino, Tune Hannes Pers, Laura M. Yerges-Armstrong, Jing Hua Zhao, Irene L. Andrulis, Hoda Anton-Culver, Femke Atsma, Stefania Bandinelli, Matthias W. Beckmann, Javier Benitez, Carl Blomqvist, Stig E. Bojesen, Manjeet K. Bolla, Bernardo Bonanni, Hiltrud Brauch, Hermann Brenner, Julie E. Buring, Jenny Chang-Claude, Stephen Chanock, Jinhui Chen, Georgia Chenevix-Trench, J. Margriet Collee, Fergus J. Couch, David Couper, Andrea D. Coviello, Angela Cox, Kamila Czene, Adamo Pio D'adamo, George Davey Smith, Immaculata De Vivo, Ellen W. Demerath, Joe Dennis, Peter Devilee, Aida K. Dieffenbach, Alison M. Dunning, Gudny Eiriksdottir, Johan G. Eriksson, Peter A. Fasching, Luigi Ferrucci, Dieter Flesch-Janys, Henrik Flyger, Tatiana Foroud, Lude Franke, Melissa E. Garcia, Montserrat Garcia-Closas, Frank Geller, Eco E. J. de Geus, Graham G. Giles, Daniel F. Gudbjartsson, Vilmundur Gudnason, Pascal Guenel, Suiqun Guo, Per Hall, Ute Hamann, Robin Haring, Catharina A. Hartman, AndrewC Heath, Albert Hofman, Maartje J. Hooning, John L. Hopper, Frank B. Hu, David J. Hunter, David Karasik, Douglas P. Kiel, Julia A. Knight, Veli-Matti Kosma, Zoltan Kutalik, Sandra Lai, Diether Lambrechts, Annika Lindblom, Reedik Maegi, Patrik K. Magnusson, Arto Mannermaa, Nicholas G. Martin, Gisli Masson, Patrick F. McArdle, Wendy L. McArdle, Mads Melbye, Kyriaki Michailidou, Evelin Mihailov, Lili Milani, Roger L. Milne, Heli Nevanlinna, Patrick Neven, Ellen A. Nohr, Albertine J. Oldehinkel, Ben A. Oostra, Aarno Palotie, Munro Peacock, Nancy L. Pedersen, Paolo Peterlongo, Julian Peto, Paul D. P. Pharoah, Dirkje S. Postma, Anneli Pouta, Katri Pylkaes, Paolo Radice, Susan Ring, Fernando Rivadeneira, Antonietta Robino, Lynda M. Rose, Anja Rudolph, Veikko Salomaa, Serena Sanna, David Schlessinger, Marjanka K. Schmidt, Mellissa C. Southey, Ulla Sovio, Meir J. Stampfer, Doris Stoeckl, Anna M. Storniolo, Nicholas J. Timpson, Jonathan Tyrer, Jenny A. Visser, Peter Vollenweider, Henry Voelzke, Gerard Waeber, Melanie Waldenberger, Henri Wallaschofski, Qin Wang, Gonneke Willemsen, Robert Winqvist, Bruce H. R. Wolffenbuttel, Margaret J. Wright, Dorret I. Boomsma, Michael J. Econs, Kay-Tee Khaw, Ruth J. F. Loos, Mark I. McCarthy, Grant W. Montgomery, John P. Rice, Elizabeth A. Streeten, Unnur Thorsteinsdottir, Cornelia M. van Duijn, Behrooz Z. Alizadeh, Sven Bergmann, Eric Boerwinkle, Heather A. Boyd, Laura Crisponi, Paolo Gasparini, Christian Gieger, Tamara B. Harris, Erik Ingelsson, Marjo-Riitta Jaervelin, Peter Kraft, Debbie Lawlor, Andres Metspalu, Craig E. Pennell, Paul M. Ridker, Harold Snieder, Thorkild I. A. Sorensen, Tim D. Spector, David P. Strachan, Andre G. Uitterlinden, Nicholas J. Wareham, Elisabeth Widen, Marek Zygmunt, Anna Murray, Douglas F. Easton, Kari Stefansson, Joanne M. Murabito, Ken K. Ong, Australian Ovarian Canc Study, GENICA Network, kConFabt LifeLines Cohort Study, InterAct Consortium, Early Growth Genetics EGG Consorti

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    Abstract

    Age at menarche is a marker of timing of puberty in females. It varies widely between individuals, is a heritable trait and is associated with risks for obesity, type 2 diabetes, cardiovascular disease, breast cancer and all-causemortality(1). Studies of rare human disorders of puberty and animal models point to a complex hypothalamic-pituitary-hormonal regulation(2,3), but the mechanisms that determine pubertal timing and underlie its links to disease risk remain unclear. Here, using genome-wide and custom-genotyping arrays in up to 182,416 women of European descent from 57 studies, we found robust evidence (P <5 x 10(-8)) for 123 signals at 106 genomic loci associated with age at menarche. Many loci were associated with other pubertal traits in both sexes, and there was substantial overlap with genes implicated in body mass index and various diseases, including rare disorders of puberty. Menarche signals were enriched in imprinted regions, with three loci (DLK1-WDR25, MKRN3-MAGEL2 and KCNK9) demonstrating parent-of-origin-specific associations concordant with known parental expression patterns. Pathway analyses implicated nuclear hormone receptors, particularly retinoic acid and gamma-aminobutyric acid-B2 receptor signalling, among novel mechanisms that regulate pubertal timing in humans. Our findings suggest a genetic architecture involving at least hundreds of common variants in the coordinated timing of the pubertal transition.
    Original languageEnglish
    JournalNature
    Volume514
    Issue number7520
    Pages (from-to)92-97
    ISSN0028-0836
    DOIs
    Publication statusPublished - 2014

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