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

John R.B. Perry, Felix R. Day, Cathy E. Elks, Patrick Sulem, Deborah J Thompson, Teresa Ferreira, Chunyan He, Daniel I Chasman, Tõnu 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 Vernon Smith, Lisette Stolk, Alexander Teumer, Natalia Tšernikova, Emmi Tikkanen, Sheila Ulivi, Erin K. Wagner, Najaf Amin, Laura J. Bierut, Enda M. Byrne, Jouke Jan Hottenga, Daniel L. Koller, Massimo Mangino, Tune H 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 J Chanock, Jinhui Chen, Georgia Chenevix-Trench, J. Margriet Collée, 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 Karina Dieffenbach, Alison M Dunning, Gudny Eiriksdottir, Johan Gunnar Eriksson, Peter A. Fasching, Luigi Ferrucci, Dieter Flesch-Janys, Henrik Flyger, Tatiana Foroud, Lude Franke, Melissa E. Garcia, Montserrat García-Closas, Frank Geller, Eco Jc de Geus, Graham G. Giles, Daniel F. Gudbjartsson, Vilmundur G Gudnason, Pascal Guénel, Suiqun Guo, Per Hall, Ute Hamann, Robin Haring, Catharina A. Hartman, Andrew C. 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 Mägi, Patrik K.E. Magnusson, Arto Mannermaa, Nicholas Gordon 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 Aagaard 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 Pylkäs, Paolo Radice, Susan M 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 Jonathan Stampfer, Doris Stöckl, Anna M. Storniolo, Nicholas J. Timpson, Jonathan Tyrer, Jenny A Visser, Peter Vollenweider, Henry Völzke, Gerard Waeber, Melanie Waldenberger, Henri Wallaschofski, Qin Wang, Gonneke Willemsen, Robert Winqvist, Bruce H.R. Wolffenbuttel, Margaret J Wright, Australian Ovarian Cancer Study (AOCS), The GENICA Network, KConFab, The LifeLines Cohort Study, The InterAct Consortium, Early Growth Genetics (EGG) Consortium, 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 Järvelin, Peter Kraft, Debbie A. Lawlor, Andres Metspalu, Craig E. Pennell, Paul M Ridker, Harold Snieder, Thorkild I A Sørensen, Tim D. Spector, David P Strachan, André G. Uitterlinden, Nicholas J. Wareham, Elisabeth Widen, Marek Zygmunt, Anna Murray, Douglas F Easton, Kari Stefansson, Joanne M. Murabito, Ken K. Ong

Research output: Contribution to journalArticleResearchpeer-review

281 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 - 2 Oct 2014
Externally publishedYes

Cite this