Thirty new loci for age at menarche identified by a meta-analysis of genome-wide association studies

Cathy E. Elks, John R B Perry, Patrick Sulem, Daniel I. Chasman, Nora Franceschini, Chunyan He, Kathryn L. Lunetta, Jenny A. Visser, Enda M. Byrne, Diana L. Cousminer, Daniel F. Gudbjartsson, Tõnu Esko, Bjarke Feenstra, Jouke Jan Hottenga, Daniel L. Koller, Zoltán Kutalik, Peng Lin, Massimo Mangino, Mara Marongiu, Patrick F. McArdleAlbert V. Smith, Lisette Stolk, Sophie H. Van Wingerden, Jing Hua Zhao, Eva Albrecht, Tanguy Corre, Erik Ingelsson, Caroline Hayward, Patrik K E Magnusson, Erin N. Smith, Shelia Ulivi, Nicole M. Warrington, Lina Zgaga, Helen Alavere, Najaf Amin, Thor Aspelund, Stefania Bandinelli, Inês Barroso, Gerald S. Berenson, Sven Bergmann, Hannah Blackburn, Eric Boerwinkle, Julie E. Buring, Fabio Busonero, Harry Campbell, Stephen J. Chanock, Wei Chen, Marilyn C. Cornelis, David Couper, Andrea D. Coviello, Pio D'Adamo, Ulf De Faire, Eco J C De Geus, Panos Deloukas, Angela Döring, George Davey Smith, Douglas F. Easton, Gudny Eiriksdottir, Valur Emilsson, Johan Eriksson, Luigi Ferrucci, Aaron R. Folsom, Tatiana Foroud, Melissa Garcia, Paolo Gasparini, Frank Geller, Christian Gieger, Vilmundur Gudnason, Per Hall, Susan E. Hankinson, Liana Ferreli, Andrew C. Heath, Dena G. Hernandez, Albert Hofman, Frank B. Hu, Thomas Illig, Marjo Riitta Järvelin, Andrew D. Johnson, David Karasik, Kay Tee Khaw, Douglas P. Kiel, Tuomas O. Kilpelänen, Ivana Kolcic, Peter Kraft, Lenore J. Launer, Joop S E Laven, Shengxu Li, Jianjun Liu, Daniel Levy, Nicholas G. Martin, Wendy L. McArdle, Mads Melbye, Vincent Mooser, Jeffrey C. Murray, Sarah S. Murray, Michael A. Nalls, Pau Navarro, Mari Nelis, Andrew R. Ness, Kate Northstone, Ben A. Oostra, Munro Peacock, Lyle J. Palmer, Aarno Palotie, Guillaume Paré, Alex N. Parker, Nancy L. Pedersen, Leena Peltonen, Craig E. Pennell, Paul Pharoah, Ozren Polasek, Andrew S. Plump, Anneli Pouta, Eleonora Porcu, Thorunn Rafnar, John P. Rice, Susan M. Ring, Fernando Rivadeneira, Igor Rudan, Cinzia Sala, Veikko Salomaa, Serena Sanna, David Schlessinger, Nicholas J. Schork, Angelo Scuteri, Ayellet V. Segrè, Alan R. Shuldiner, Nicole Soranzo, Ulla Sovio, Sathanur R. Srinivasan, David P. Strachan, Mar Liis Tammesoo, Emmi Tikkanen, Daniela Toniolo, Kim Tsui, Laufey Tryggvadottir, Jonathon Tyrer, Manuela Uda, Rob M. Van Dam, Joyce B J Van Meurs, Peter Vollenweider, Gerard Waeber, Nicholas J. Wareham, Dawn M. Waterworth, Michael N. Weedon, H. Erich Wichmann, Gonneke Willemsen, James F. Wilson, Alan F. Wright, Lauren Young, Guangju Zhai, Wei Vivian Zhuang, Laura J. Bierut, Dorret I. Boomsma, Heather A. Boyd, Laura Crisponi, Ellen W. Demerath, Cornelia M. Van Duijn, Michael J. Econs, Tamara B. Harris, David J. Hunter, Ruth J F Loos, Andres Metspalu, Grant W. Montgomery, Paul M. Ridker, Tim D. Spector, Elizabeth A. Streeten, Kari Stefansson, Unnur Thorsteinsdottir, André G. Uitterlinden, Elisabeth Widen, Joanne M. Murabito, Ken K. Ong, Anna Murray

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347 Scopus citations

Abstract

To identify loci for age at menarche, we performed a meta-analysis of 32 genome-wide association studies in 87,802 women of European descent, with replication in up to 14,731 women. In addition to the known loci at LIN28B (P = 5.4 × 10 -60) and 9q31.2 (P = 2.2 × 10 -33), we identified 30 new menarche loci (all P < 5 × 10 -8) and found suggestive evidence for a further 10 loci (P < 1.9 × 10 -6). The new loci included four previously associated with body mass index (in or near FTO, SEC16B, TRA2B and TMEM18), three in or near other genes implicated in energy homeostasis (BSX, CRTC1 and MCHR2) and three in or near genes implicated in hormonal regulation (INHBA, PCSK2 and RXRG). Ingenuity and gene-set enrichment pathway analyses identified coenzyme A and fatty acid biosynthesis as biological processes related to menarche timing.

Original languageEnglish (US)
Pages (from-to)1077-1085
Number of pages9
JournalNature Genetics
Volume42
Issue number12
DOIs
StatePublished - Dec 1 2010

Bibliographical note

Funding Information:
Academy of Finland (Finnish Centre of Excellence in Complex Disease Genetics 129680, 120315, 129287, 129494); Affymetrix (N02-HL-6-4278); Agency of Science, Technology and Research of Singapore (A*STAR); Althingi (the Icelandic Parliament); American Heart Association (0855082E); Amgen; Augustinus Foundation; Australian National Health and Medical Research Council (241944, 339462, 389927, 389875, 389891, 389892, 389938, 442915, 442981, 496739, 552485, 552498, 619667); Australian Research Council (A7960034, A79801419, A79906588, DP0212016, DP0343921, DP0770096); Baltimore Veterans Administration Medical Center Geriatrics Research; Canadian Institutes of Health Research (grant ID 166067); Cancer Research United Kingdom; the Cariplo Foundation; Center for Disease Control and Prevention (USA), Centre for Medical Systems Biology (CMSB); the Chief Scientist Office of the Scottish Government; Clinical Nutrition Research Unit of Maryland (P30 DK072488); Danish National Research Foundation; Danish Pharmacists’ Fund; the Egmont Foundation; Erasmus Medical Center; Erasmus University; Estonian Government (SF0180142s08); the European Commision (212111 BBMRI, 205419 ECOGENE, 201413 ENGAGE, HEALTH-F2-2008-201865 - GEFOS, HEALTH-F2-2008-35627, HEALTH-F4-2007-201413, HEALTH-F4-2007-201550 HYPERGENES, 245536 OPENGENE, TREAT-OA, GenomEUtwin Project QLG2-CT-2002-01254, EU/QLRT-2001-01254; ERC-230374); European Union framework program 6 EUROSPAN project (LSHG-CT-2006-018947, LSHM-CT-2003-503041); European Regional Development Fund; Faculty of Biology and Medicine of Lausanne, Switzerland; Fondazione Compagnia di San Paolo Health Ministry, Framingham Heart Study (N01-HC-25195); GENEVA Coordinating Center (U01HG004446); German Federal Ministry of Education and Research; German National Genome Research Network (NGFN-2 and NGFNPlus: 01GS0823); Giorgi-Cavaglieri Foundation; GlaxoSmithKline; Health Fund of the Danish Health Insurance Societies; Helmholtz Zentrum München-German Research Center for Environmental Health; Hjartavernd (the Icelandic Heart Association); Italian Ministry of Health (ICS110.1/RF97.71, RF-FSR-2007-647201); Juvenile Diabetes Research Foundation International (JDRF); Leenaards Foundation; March of Dimes Birth Defects Foundation; the Medical Research Council (G0000934, G0500539, G0701863); National Cancer Institute (CA40356, CA98233, P01CA087969, P01CA055075, CA047988, CA63464, CA54281, CA136792, CA089392, CA104021); Munich Center of Health Sciences (MC Health, LMUinnovativ); National Health and Medical Research Council of Australia (572613 and 003209); National Heart, Lung, and Blood Institute (HL 043851, HL087679, HL69757, N01-HC-55015, N01-HC-55016, N01-HC-55018, N01-HC-55019, N01-HC-55020, N01-HC-55021, N01-HC-55022, R01HL087641, R01HL59367, R01HL086694, RC2 HL102419); National Human Genome Research Institute (NHGRI); National Institute of Aging (263 MD 9164, 263 MD 821336, N.1-AG-1-1, N.1-AG-1-2111, N01-AG-5-0002, AG-16592, Genetics of Reproductive Life Period and Health Outcomes - R21AG032598); National Institute of Arthritis and Musculoskeletal and Skin Diseases and National Institute on Aging ((NIAMS/NIA) R01 AR/AG 41398); National Institute of Child Health and Human Development (HD-061437); National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK, R01DK058845, U01 DK062418); National Institute on Alcohol Abuse and Alcoholism (NIAAA); National Institute of Allergy and Infectious Diseases (NIAID); National Institute on

Funding Information:
Drug Abuse (NIDA); National Institutes of Health (AA07535, AA10248, AA13320, AA13321, AA13326, AA14041, HHSN268200782096C, M01 RR-00750, MH66206, N01-AG-12100, N01-AG-1-2109, P01-AG-18397, R01-088119, R01-DA013423, RFAHG006033, U01DE018993, U01DE018903, U01HG004422, U01HG004446, U01HL72515, U01 HL84756, U01HG004399, U01HG004402, U01HG004415, U01HG004423, U01HG004436, U01HG004438, U01HG004402, U01HG004446, U01HG004726, U01HG004728, U01HG004729, U01HG004735, U01HG004738, U01HG04424, U10AA008401, U54RR025204-01, UL1RR025005, UL1 RR025774, Z01CP010200, HHSN268200625226C); the National Institute for Health Research Cambridge Biomedical Research Centre; Netherlands Organization for Scientific Research (904-61-193, 575-25-006, 480-04-004, 56-464-14192, NWO 480-05-003, 175.010.2005.011, 911-03-012, 014-93-015); Netherlands Genomic Initiative (NGI, 050-060-810), National Institute on Aging (NIA) Intramural Research Program; and Laboratory of Neurogenetics; US National Institutes of Health Genes, Environment and Health Initiative; Republic of Croatia Ministry of Science, Education and Sports (108-1080315-0302); Robert Dawson Evans Endowment; the Royal Society, Royal Swedish Academy of Science; State of Bavaria, Germany; Susan G. Komen Breast Cancer Foundation; Swedish Foundation for Strategic Research (SSF); Swedish Heart-Lung Foundation; Swedish Ministry of Higher Education and Research; Swedish Research Council; Swedish Society of Medicine; Swiss National Science Foundation (Ref: 33CSCO-122661, 3100AO-116323/1); the University of Bristol, University of Maryland General Clinical Research Center (M01 RR 16500); the Wellcome Trust (068545/Z/02, 076467/Z/05/Z, 077016/Z/05/Z, 89061/Z/09/Z, strategic award 079895); Western Australian DNA Bank; Western Australian Genetic Epidemiology Resource (see Supplementary Note for extended acknowledgments).

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