Article | Published:

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

Nature Genetics volume 42, pages 10771085 (2010) | Download Citation


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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  1. 1.

    et al. The timing of normal puberty and the age limits of sexual precocity: variations around the world, secular trends, and changes after migration. Endocr. Rev. 24, 668–693 (2003).

  2. 2.

    Reproductive factors in breast cancer epidemiology. Acta Oncol. 31, 187–194 (1992).

  3. 3.

    & Epidemiology of endometrial cancer. Best Pract. Res. Clin. Obstet. Gynaecol. 15, 341–354 (2001).

  4. 4.

    et al. Earlier mother's age at menarche predicts rapid infancy growth and childhood obesity. PLoS Med. 4, e132 (2007).

  5. 5.

    et al. Age at menarche and risk of type 2 diabetes: results from 2 large prospective cohort studies. Am. J. Epidemiol. 171, 334–344 (2010).

  6. 6.

    et al. Early age at menarche associated with cardiovascular disease and mortality. J. Clin. Endocrinol. Metab. 94, 4953–4960 (2009).

  7. 7.

    et al. Heritability of age at menarche in girls from the Fels Longitudinal Study. Am. J. Phys. Anthropol. 128, 210–219 (2005).

  8. 8.

    et al. Genome-wide association studies identify loci associated with age at menarche and age at natural menopause. Nat. Genet. 41, 724–728 (2009).

  9. 9.

    et al. Genetic variation in LIN28B is associated with the timing of puberty. Nat. Genet. 41, 729–733 (2009).

  10. 10.

    et al. Meta-analysis of genome-wide association data identifies two loci influencing age at menarche. Nat. Genet. 41, 648–650 (2009).

  11. 11.

    et al. Genome-wide association study identifies sequence variants on 6q21 associated with age at menarche. Nat. Genet. 41, 734–738 (2009).

  12. 12.

    & Inhibins in childhood and puberty. Best Pract. Res. Clin. Endocrinol. Metab. 16, 43–52 (2002).

  13. 13.

    et al. Changes in dimeric inhibin A and B during normal early puberty in boys and girls. Clin. Endocrinol. 46, 109–114 (1997).

  14. 14.

    et al. Serum inhibin A and inhibin B in healthy prepubertal, pubertal, and adolescent girls and adult women: relation to age, stage of puberty, menstrual cycle, follicle-stimulating hormone, luteinizing hormone, and estradiol levels. J. Clin. Endocrinol. Metab. 85, 1634–1640 (2000).

  15. 15.

    Evidence for a negative feedback role of inhibin in follicle stimulating hormone regulation in women. Hum. Reprod. 8(Suppl 2), 129–132 (1993).

  16. 16.

    , , & Activin A-induced differentiation of embryonic stem cells into endoderm and pancreatic progenitors—the influence of differentiation factors and culture conditions. Stem Cell Rev. 5, 159–173 (2009).

  17. 17.

    Developmental expression of retinoic acid receptors (RARs). Nucl. Recept. Signal. 7, e006 (2009).

  18. 18.

    et al. A common variant in the FTO gene is associated with body mass index and predisposes to childhood and adult obesity. Science 316, 889–894 (2007).

  19. 19.

    et al. Genome-wide association yields new sequence variants at seven loci that associate with measures of obesity. Nat. Genet. 41, 18–24 (2009).

  20. 20.

    et al. Six new loci associated with body mass index highlight a neuronal influence on body weight regulation. Nat. Genet. 41, 25–34 (2009).

  21. 21.

    et al. A role for brain-specific homeobox factor Bsx in the control of hyperphagia and locomotory behavior. Cell Metab. 5, 450–463 (2007).

  22. 22.

    et al. The Creb1 coactivator Crtc1 is required for energy balance and fertility. Nat. Med. 14, 1112–1117 (2008).

  23. 23.

    , & Expanding the scales: The multiple roles of MCH in regulating energy balance and other biological functions. Endocr. Rev. 27, 606–620 (2006).

  24. 24.

    , , , & Melanin-concentrating hormone directly inhibits GnRH neurons and blocks kisspeptin activation, linking energy balance to reproduction. Proc. Natl. Acad. Sci. USA 106, 17217–17222 (2009).

  25. 25.

    et al. Origins and functional impact of copy number variation in the human genome. Nature 464, 704–712 (2009).

  26. 26.

    et al. Genetics of gene expression and its effect on disease. Nature 452, 423–428 (2008).

  27. 27.

    , & BDNF regulates eating behavior and locomotor activity in mice. EMBO J. 19, 1290–1300 (2000).

  28. 28.

    et al. Brain-derived neurotrophic factor regulates energy balance downstream of melanocortin-4 receptor. Nat. Neurosci. 6, 736–742 (2003).

  29. 29.

    , , , & Isolated imprinting mutation of the DLK1/GTL2 locus associated with a clinical presentation of maternal uniparental disomy of chromosome 14. J. Med. Genet. 44, 637–640 (2007).

  30. 30.

    , , , & The PTX family of homeodomain transcription factors during pituitary developments. Mol. Cell. Endocrinol. 140, 31–36 (1998).

  31. 31.

    et al. TAC3 and TACR3 mutations in familial hypogonadotropic hypogonadism reveal a key role for Neurokinin B in the central control of reproduction. Nat. Genet. 41, 354–358 (2009).

  32. 32.

    et al. Association studies of common variants in 10 hypogonadotropic hypogonadism genes with age at menarche. J. Clin. Endocrinol. Metab. 93, 4290–4298 (2008).

  33. 33.

    , , & Association of polymorphisms of the oestrogen receptor alpha gene with the age of menarche. Hum. Reprod. 17, 1101–1105 (2002).

  34. 34.

    et al. Common genetic influences on BMI and age at menarche. Hum. Biol. 67, 739–753 (1995).

  35. 35.

    et al. Age at menarche in relation to adult height: the EPIC study. Am. J. Epidemiol. 162, 623–632 (2005).

  36. 36.

    et al. Recombinant human leptin in women with hypothalamic amenorrhea. N. Engl. J. Med. 351, 987–997 (2004).

  37. 37.

    et al. Restoration of hypothalamic lipid sensing normalizes energy and glucose homeostasis in overfed rats. J. Clin. Invest. 116, 1081–1091 (2006).

  38. 38.

    , & Genomic Control to the extreme. Nat. Genet. 36, 1129–1130 author reply 1131 (2004).

  39. 39.

    et al. Finding the missing heritability of complex diseases. Nature 461, 747–753 (2009).

  40. 40.

    et al. Recall of early menstrual history and menarcheal body size: after 30 years, how well do women remember? Am. J. Epidemiol. 155, 672–679 (2002).

  41. 41.

    et al. Distinct variants at LIN28B influence growth in height from birth to adulthood. Am. J. Hum. Genet. 86, 773–782 (2010).

  42. 42.

    et al. Secondary sexual characteristics and menses in young girls seen in office practice: a study from the Pediatric Research in Office Settings network. Pediatrics 99, 505–512 (1997).

  43. 43.

    , , , & A new multipoint method for genome-wide association studies by imputation of genotypes. Nat. Genet. 39, 906–913 (2007).

  44. 44.

    et al. Common inherited variation in mitochondrial genes is not enriched for associations with type 2 diabetes or related glycemic traits. PLoS Genet. 6, e1001058 (2010).

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Author information

Author notes

    • Leena Peltonen


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

    These authors contributed equally to this work.

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

    These senior authors jointly supervised this work.


  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. 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
  63. Department of Psychiatry, Washington University School of Medicine, St. Louis, Missouri, USA.

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

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

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

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

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

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

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

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

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

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

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

    • Nicholas G Martin
  75. 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
  76. Genetics Division, GlaxoSmithKline, King of Prussia, Pennsylvania, USA.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

    • Ken K Ong


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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 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 Joanne M Murabito or Ken K Ong or Anna Murray.

Supplementary information

PDF files

  1. 1.

    Supplementary Text and Figures

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

Excel files

  1. 1.

    Supplementary Table 12

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

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