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

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

    Research output: Contribution to journalArticle

    279 Citations (Scopus)

    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-cause mortality. Studies of rare human disorders of puberty and animal models point to a complex hypothalamic-pituitary-hormonal regulation, 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 × 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 γ-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
    Pages (from-to)92-97
    Number of pages6
    JournalNature
    Volume514
    Issue number7520
    DOIs
    Publication statusPublished - 2014

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