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

Journal name:
Nature Genetics
Volume:
42,
Pages:
1077–1085
Year published:
DOI:
doi:10.1038/ng.714
Received
Accepted
Published online

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.

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Author information

  1. These authors contributed equally to this work.

    • Cathy E Elks,
    • John R B Perry &
    • Patrick Sulem

Affiliations

  1. Medical Research Council (MRC) Epidemiology Unit, Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, UK.

    • Cathy E Elks,
    • Jing Hua Zhao,
    • Tuomas O Kilpeläinen,
    • Shengxu Li,
    • Nicholas J Wareham,
    • Ruth J F Loos &
    • Ken K Ong
  2. Genetics of Complex Traits, Peninsula Medical School, University of Exeter, UK.

    • John R B Perry,
    • Michael N Weedon &
    • Anna Murray
  3. deCODE Genetics, Reykjavik, Iceland.

    • Patrick Sulem,
    • Daniel F Gudbjartsson,
    • Thorunn Rafnar,
    • Kari Stefansson &
    • Unnur Thorsteinsdottir
  4. Division of Preventive Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA.

    • Daniel I Chasman,
    • Julie E Buring,
    • Guillaume Paré &
    • Paul M Ridker
  5. Harvard Medical School, Boston, Massachusetts, USA.

    • Daniel I Chasman,
    • Julie E Buring,
    • Guillaume Paré &
    • Paul M Ridker
  6. Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.

    • Nora Franceschini
  7. Department of Public Health, Indiana University School of Medicine, Indiana, USA.

    • Chunyan He
  8. Melvin and Bren Simon Cancer Center, Indiana University, Indiana, USA.

    • Chunyan He
  9. The National Heart, Lung, and Blood Institute's Framingham Heart Study, Framingham, Massachusetts, USA.

    • Kathryn L Lunetta,
    • Andrew D Johnson,
    • Daniel Levy &
    • Joanne M Murabito
  10. Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts, USA.

    • Kathryn L Lunetta &
    • Wei Vivian Zhuang
  11. Department of Internal Medicine, Erasmus Medical Center (MC), Rotterdam, The Netherlands.

    • Jenny A Visser,
    • Lisette Stolk,
    • Fernando Rivadeneira,
    • Joyce B J van Meurs &
    • André G Uitterlinden
  12. Queensland Statistical Genetics, Queensland Institute of Medical Research, Brisbane, Australia.

    • Enda M Byrne
  13. The University of Queensland, Brisbane, Australia.

    • Enda M Byrne
  14. Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Finland.

    • Diana L Cousminer,
    • Aarno Palotie,
    • Leena Peltonen,
    • Emmi Tikkanen &
    • Elisabeth Widen
  15. Estonian Genome Center, University of Tartu, Tartu, Estonia.

    • Tõnu Esko,
    • Helen Alavere,
    • Mari Nelis,
    • Mar-Liis Tammesoo &
    • Andres Metspalu
  16. Department of Biotechnology, Institute of Molecular and Cell Biology, University of Tartu, Tartu, Estonia.

    • Tõnu Esko,
    • Mari Nelis &
    • Andres Metspalu
  17. Genotyping Core Facility, Estonian Biocenter, Tartu, Estonia.

    • Tõnu Esko,
    • Mari Nelis &
    • Andres Metspalu
  18. Department of Epidemiology Research, Statens Serum Institut, Copenhagen, Denmark.

    • Bjarke Feenstra,
    • Frank Geller,
    • Mads Melbye &
    • Heather A Boyd
  19. Department of Biological Psychology, VU University Amsterdam, Amsterdam, The Netherlands.

    • Jouke-Jan Hottenga,
    • Eco J C de Geus,
    • Gonneke Willemsen &
    • Dorret I Boomsma
  20. Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana, USA.

    • Daniel L Koller,
    • Tatiana Foroud &
    • Michael J Econs
  21. Department of Medical Genetics, University of Lausanne, Lausanne, Switzerland.

    • Zoltán Kutalik &
    • Sven Bergmann
  22. Swiss Institute of Bioinformatics, Lausanne, Switzerland.

    • Zoltán Kutalik &
    • Sven Bergmann
  23. Department of Psychiatry, Washington University School of Medicine, St. Louis, Missouri, USA.

    • Peng Lin,
    • John P Rice &
    • Laura J Bierut
  24. Department of Twin Research and Genetic Epidemiology, King's College London, London, UK.

    • Massimo Mangino,
    • Nicole Soranzo,
    • Guangju Zhai &
    • Tim D Spector
  25. Istituto di Neurogenetica e Neurofarmacologia, Consiglio Nazionale delle Ricerche, Cagliari, Italy.

    • Mara Marongiu,
    • Fabio Busonero,
    • Liana Ferreli,
    • Eleonora Porcu,
    • Serena Sanna,
    • Angelo Scuteri,
    • Manuela Uda &
    • Laura Crisponi
  26. Division of Endocrinology, Diabetes and Nutrition, University of Maryland School of Medicine, Baltimore, Maryland, USA.

    • Patrick F McArdle,
    • Alan R Shuldiner &
    • Elizabeth A Streeten
  27. Icelandic Heart Association, Kopavogur, Iceland.

    • Albert V Smith,
    • Thor Aspelund,
    • Gudny Eiriksdottir &
    • Vilmundur Gudnason
  28. University of Iceland, Reykjavik, Iceland.

    • Albert V Smith,
    • Thor Aspelund &
    • Vilmundur Gudnason
  29. Netherlands Consortium of Healthy Aging, Rotterdam, The Netherlands.

    • Lisette Stolk,
    • Albert Hofman,
    • Fernando Rivadeneira,
    • Joyce B J van Meurs,
    • Cornelia M van Duijn &
    • André G Uitterlinden
  30. Genetic-Epidemiology Unit, Department of Epidemiology, Erasmus University Medical Center, Rotterdam, The Netherlands.

    • Sophie H van Wingerden,
    • Najaf Amin,
    • Ben A Oostra &
    • Cornelia M van Duijn
  31. Institute of Epidemiology, Helmholtz Zentrum München-German Research Center for Environmental Health, Neuherberg, Germany.

    • Eva Albrecht,
    • Angela Döring,
    • Christian Gieger,
    • Thomas Illig &
    • H Erich Wichmann
  32. Division of Genetics and Cell Biology, San Raffaele Scientific Institute, Milan, Italy.

    • Tanguy Corre,
    • Cinzia Sala &
    • Daniela Toniolo
  33. Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.

    • Erik Ingelsson,
    • Patrik K E Magnusson,
    • Per Hall &
    • Nancy L Pedersen
  34. MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, Western General Hospital, Edinburgh, UK.

    • Caroline Hayward,
    • Pau Navarro &
    • Alan F Wright
  35. Scripps Genomic Medicine, La Jolla, California, USA.

    • Erin N Smith,
    • Sarah S Murray &
    • Nicholas J Schork
  36. The Scripps Translational Science Institute, La Jolla, California, USA.

    • Erin N Smith,
    • Sarah S Murray &
    • Nicholas J Schork
  37. The Scripps Research Institute, La Jolla, California, USA.

    • Erin N Smith,
    • Sarah S Murray &
    • Nicholas J Schork
  38. Medical Genetics, Department of Reproductive Sciences and Development, University of Trieste, Trieste, Italy.

    • Shelia Ulivi,
    • Pio d'Adamo &
    • Paolo Gasparini
  39. Centre for Genetic Epidemiology and Biostatistics, University of Western Australia, Crawley, Australia.

    • Nicole M Warrington &
    • Lyle J Palmer
  40. Centre for Population Health Sciences, University of Edinburgh, Teviot Place, Edinburgh, Scotland.

    • Lina Zgaga,
    • Harry Campbell,
    • Igor Rudan &
    • James F Wilson
  41. Geriatric Unit, Azienda Sanitaria di Firenze, Florence, Italy.

    • Stefania Bandinelli
  42. Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK.

    • Inês Barroso,
    • Hannah Blackburn,
    • Panos Deloukas,
    • Aarno Palotie,
    • Leena Peltonen &
    • Nicole Soranzo
  43. Tulane University, New Orleans, Louisiana, USA.

    • Gerald S Berenson,
    • Wei Chen &
    • Sathanur R Srinivasan
  44. Human Genetics Center, University of Texas Health Science Center at Houston, Houston, Texas, USA.

    • Eric Boerwinkle
  45. Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts, USA.

    • Julie E Buring,
    • Susan E Hankinson,
    • Frank B Hu,
    • Peter Kraft,
    • David J Hunter &
    • Paul M Ridker
  46. Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland, USA.

    • Stephen J Chanock &
    • David J Hunter
  47. Department of Nutrition, Harvard School of Public Health, Boston, Massachusetts, USA.

    • Marilyn C Cornelis,
    • Frank B Hu,
    • Peter Kraft,
    • Rob M van Dam &
    • David J Hunter
  48. Collaborative Studies Coordinating Center, Department of Biostatistics, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.

    • David Couper
  49. Sections of General Internal Medicine, Preventive Medicine and Endocrinology, Department of Medicine, Boston University School of Medicine, Boston, Massachusetts, USA.

    • Andrea D Coviello &
    • Joanne M Murabito
  50. Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.

    • Ulf de Faire
  51. MRC Centre for Causal Analyses in Translational Epidemiology, Department of Social Medicine, University of Bristol, Bristol, UK.

    • George Davey Smith
  52. Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.

    • Douglas F Easton,
    • Paul Pharoah &
    • Jonathon Tyrer
  53. Department of Oncology, Strangeways Research Laboratories, University of Cambridge, Cambridge, UK.

    • Douglas F Easton,
    • Paul Pharoah &
    • Jonathon Tyrer
  54. Molecular Programming and Research Informatics (MPRI), Merck and Co., Inc., Rahway, New Jersey, USA.

    • Valur Emilsson
  55. National Institute for Health and Welfare, Helsinki, Finland.

    • Johan Eriksson,
    • Leena Peltonen,
    • Anneli Pouta,
    • Veikko Salomaa &
    • Emmi Tikkanen
  56. Department of General Practice and Primary Health Care, University of Helsinki, Helsinki, Finland.

    • Johan Eriksson
  57. Helsinki University Central Hospital, Unit of General Practice, Helsinki, Finland.

    • Johan Eriksson
  58. Folkhalsan Research Centre, Helsinki, Finland.

    • Johan Eriksson
  59. Longitudinal Studies Section, Clinical Research Branch, National Institute on Aging, Baltimore, Maryland, USA.

    • Luigi Ferrucci
  60. Division of Epidemiology and Community Health, School of Public Health, University of Minnesota, Minneapolis, Minnesota, USA.

    • Aaron R Folsom &
    • Ellen W Demerath
  61. Laboratory of Epidemiology, Demography and Biometry, Intramural Research Program, National Institute on Aging, Bethesda, Maryland, USA.

    • Melissa Garcia,
    • Lenore J Launer &
    • Tamara B Harris
  62. A full list of members is provided in the Supplementary Note.

    • The GIANT Consortium
  63. Channing Laboratory, Department of Medicine, Brigham and Women's Hospital, and Harvard Medical School, Boston, Massachusetts, USA.

    • Susan E Hankinson,
    • Frank B Hu,
    • Peter Kraft &
    • David J Hunter
  64. Department of Psychiatry, Washington University School of Medicine, St. Louis, Missouri, USA.

    • Andrew C Heath
  65. Laboratory of Neurogenetics, National Institute of Aging, Bethesda, Maryland, USA.

    • Dena G Hernandez
  66. Department of Epidemiology, Erasmus MC, Rotterdam, The Netherlands.

    • Albert Hofman,
    • Fernando Rivadeneira &
    • André G Uitterlinden
  67. Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, UK.

    • Marjo-Riitta Järvelin &
    • Ulla Sovio
  68. National Heart, Lung, and Blood Institute (NHLBI) Center for Population Studies, Bethesda, Maryland, USA.

    • Andrew D Johnson &
    • Daniel Levy
  69. Hebrew Senior Life Institute for Aging Research and Harvard Medical School, Boston, Massachusetts, USA.

    • David Karasik &
    • Douglas P Kiel
  70. Department of Public Health and Primary Care, Institute of Public Health, University of Cambridge, Cambridge, UK.

    • Kay-Tee Khaw
  71. Medical School, University of Zagreb, Zagreb, Croatia.

    • Ivana Kolcic &
    • Ozren Polasek
  72. Department of Obstetrics and Gynaecology, Erasmus, MC, Rotterdam, The Netherlands.

    • Joop S E Laven
  73. Human Genetics, Genome Institute of Singapore, Singapore.

    • Jianjun Liu
  74. Division of Cardiology, Boston University School of Medicine, Boston, Massachusetts, USA.

    • Daniel Levy
  75. Genetic Epidemiology, Queensland Institute of Medical Research, Brisbane, Australia.

    • Nicholas G Martin
  76. Avon Longitudinal Study of Parents and Children (ALSPAC), Department of Social Medicine, University of Bristol, Bristol, UK.

    • Wendy L McArdle,
    • Kate Northstone &
    • Susan M Ring
  77. Genetics Division, GlaxoSmithKline, King of Prussia, Pennsylvania, USA.

    • Vincent Mooser &
    • Dawn M Waterworth
  78. Department of Pediatrics, University of Iowa, Iowa City, Iowa, USA.

    • Jeffrey C Murray
  79. Laboratory of Neurogenetics, Intramural Research Program, National Institute on Aging, Bethesda, Maryland, USA.

    • Michael A Nalls
  80. Department of Oral and Dental Science, University of Bristol, Bristol, UK.

    • Andrew R Ness
  81. Department of Clinical Genetics, Erasmus University Medical Center, Rotterdam, The Netherlands.

    • Ben A Oostra
  82. Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA.

    • Munro Peacock &
    • Michael J Econs
  83. Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA.

    • Aarno Palotie,
    • Leena Peltonen &
    • Ayellet V Segrè
  84. Genetic and Molecular Epidemiology Laboratory, McMaster University, Hamilton, Ontario, Canada.

    • Guillaume Paré
  85. Amgen, Cambridge, Massachusetts, USA.

    • Alex N Parker,
    • Kim Tsui &
    • Lauren Young
  86. School of Women's and Infants' Health, The University of Western Australia, Crawley, Australia.

    • Craig E Pennell
  87. Gen-Info Ltd., Zagreb, Croatia.

    • Ozren Polasek
  88. Cardiovascular Disease, Merck Research Laboratory, Rahway, New Jersey, USA.

    • Andrew S Plump
  89. Croatian Centre for Global Health, University of Split Medical School, Split, Croatia.

    • Igor Rudan
  90. Gerontology Research Center, National Institute on Aging, Baltimore, Maryland, USA.

    • David Schlessinger
  91. Unità Operativa Geriatria-Istituto Nazionale Ricovero e Cura per Anziani (INRCA), IRCCS, Rome, Italy.

    • Angelo Scuteri
  92. Department of Molecular Biology, Massachusetts General Hospital, Boston, Massachusetts, USA.

    • Ayellet V Segrè
  93. Geriatric Research and Education Clinical Center, Veterans Administration Medical Center, Baltimore, Maryland, USA.

    • Alan R Shuldiner
  94. Division of Community Health Sciences, St. George's, University of London, London, UK.

    • David P Strachan
  95. Icelandic Cancer Registry, Reykjavik, Iceland.

    • Laufey Tryggvadottir
  96. Department of Epidemiology and Public Health, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.

    • Rob M van Dam
  97. Department of Medicine, National University of Singapore, Singapore.

    • Rob M van Dam
  98. Department of Internal Medicine, BH-10 Centre Hospitalier Universitaire Vaudois (CHUV), Lausanne, Switzerland.

    • Peter Vollenweider &
    • Gerard Waeber
  99. Institute of Medical Informatics, Biometry and Epidemiology, Chair of Epidemiology, Ludwig-Maximilians-Universität, Munich, Germany.

    • H Erich Wichmann
  100. Klinikum Grosshadern, Munich, Germany.

    • H Erich Wichmann
  101. Molecular Epidemiology, Queensland Institute of Medical Research, Brisbane, Australia.

    • Grant W Montgomery
  102. Division of Cardiology, Brigham and Women's Hospital, Boston, Massachusetts, USA.

    • Paul M Ridker
  103. Faculty of Medicine, University of Iceland, Reykjavik, Iceland.

    • Kari Stefansson &
    • Unnur Thorsteinsdottir
  104. Department of Paediatrics, University of Cambridge, Cambridge, UK.

    • Ken K Ong
  105. Deceased.

    • Leena Peltonen
  106. These senior authors jointly supervised this work.

    • Joanne M Murabito,
    • Ken K Ong &
    • Anna Murray

Contributions

Writing group: D.I.B., H.A.B., D.I.C., D.L.C., L.C., E.W.D., M.J.E., C.E.E., T.E., B.F., N.F., F.G., D.F.G., C. He, T.B.H., D.J.H., D.L.K., K.K.L., M. Mangino, M. Marongiu, J.M.M., A. Metspalu, A. Murray, K.K.O., J.R.B.P., L.S., E.A.S., P.S., U.T., A.G.U., C.M.v.D., S.H.v.W., J.A.V., E.W., G.Z.

Competing financial interests

P.S., D.F.G., K.S. and U.T. are employed by deCODE Genetics. V.E. and A. Plump are employed by Merck & Co. V.M. and D.M.W. are employed by GlaxoSmithKline. A. Parker, L.Y. and K.T. are employed by Amgen. I.B. and spouse own stock in Incyte Ltd and GlaxoSmithKline.

Corresponding authors

Correspondence to:

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Supplementary information

PDF files

  1. Supplementary Text and Figures (3M)

    Supplementary Figures 1–8, Supplementary Tables 1–11 and 13–17 and Supplementary Note.

Excel files

  1. Supplementary Table 12 (2M)

    Age at menarche associations for 8,770 SNPs in 16 candidate genes and their surrounding regions (+/-300kb).

Additional data