Letter | Published:

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

Nature volume 514, pages 9297 (02 October 2014) | Download Citation

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 mortality1. Studies of rare human disorders of puberty and animal models point to a complex hypothalamic-pituitary-hormonal regulation2,3, 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.

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Acknowledgements

A full list of acknowledgements can be found in the Supplementary Information.

Author information

Author notes

    • John R. B. Perry
    • , Felix Day
    • , Cathy E. Elks
    • , Patrick Sulem
    • , Kari Stefansson
    • , Joanne M. Murabito
    •  & Ken K. Ong

    These authors contributed equally to this work.

Affiliations

  1. MRC Epidemiology Unit, University of Cambridge School of Clinical Medicine, Box 285 Institute of Metabolic Science, Cambridge Biomedical Campus, Cambridge CB2 0QQ, UK.

    • John R. B. Perry
    • , Felix Day
    • , Cathy E. Elks
    • , Jing Hua Zhao
    • , Ruth J. F. Loos
    • , Nicholas J. Wareham
    •  & Ken K. Ong
  2. University of Exeter Medical School, University of Exeter, Exeter EX1 2LU, UK.

    • John R. B. Perry
    •  & Anna Murray
  3. Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK.

    • John R. B. Perry
    • , Teresa Ferreira
    •  & Mark I. McCarthy
  4. Department of Twin Research and Genetic Epidemiology, King’s College London, London SE1 7EH, UK.

    • John R. B. Perry
    • , Massimo Mangino
    •  & Tim D. Spector
  5. deCODE Genetics, Reykjavik IS-101, Iceland.

    • Patrick Sulem
    • , Gudmar Thorleifsson
    • , Daniel F. Gudbjartsson
    • , Gisli Masson
    • , Unnur Thorsteinsdottir
    •  & Kari Stefansson
  6. Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge CB1 8RN, UK.

    • Deborah J. Thompson
    • , Manjeet K. Bolla
    • , Joe Dennis
    • , Kyriaki Michailidou
    • , Qin Wang
    •  & Douglas F. Easton
  7. Department of Epidemiology, Indiana University Richard M Fairbanks School of Public Health, Indianapolis, Indiana 46202, USA.

    • Chunyan He
    •  & Erin K. Wagner
  8. Indiana University Melvin and Bren Simon Cancer Center, Indianapolis, Indiana 46202, USA.

    • Chunyan He
    •  & Erin K. Wagner
  9. Division of Preventive Medicine, Brigham and Women’s Hospital, Boston, Massachusetts 02215, USA.

    • Daniel I. Chasman
    • , Julie E. Buring
    • , Lynda M. Rose
    •  & Paul M. Ridker
  10. Harvard Medical School, Boston, Massachusetts 02115, USA.

    • Daniel I. Chasman
    • , Julie E. Buring
    • , David Karasik
    •  & Paul M. Ridker
  11. Estonian Genome Center, University of Tartu, Tartu, 51010, Estonia.

    • Tõnu Esko
    • , Natalia Tšernikova
    • , Reedik Mägi
    • , Evelin Mihailov
    • , Lili Milani
    •  & Andres Metspalu
  12. Divisions of Endocrinology and Genetics and Center for Basic and Translational Obesity Research, Boston Children’s Hospital, Boston, Massachusetts 02115, USA.

    • Tõnu Esko
    •  & Tune H. Pers
  13. Broad Institute of the Massachusetts Institute of Technology and Harvard University, 140 Cambridge, Massachusetts 02142, USA.

    • Tõnu Esko
    • , Tune H. Pers
    •  & David J. Hunter
  14. Department of Genetics, Harvard Medical School, Boston, Massachusetts 02115, USA.

    • Tõnu Esko
  15. Institute of Genetic Epidemiology, Helmholtz Zentrum München - German Research Center for Environmental Health, D-85764 Neuherberg, Germany.

    • Eva Albrecht
    •  & Christian Gieger
  16. School of Women’s and Infants’ Health, The University of Western Australia, WA-6009, Australia.

    • Wei Q. Ang
    •  & Craig E. Pennell
  17. Department of Medical Genetics, University of Lausanne, CH-1005 Lausanne, Switzerland.

    • Tanguy Corre
    • , Zoltan Kutalik
    •  & Sven Bergmann
  18. Swiss Institute of Bioinformatics, CH-1015 Lausanne, Switzerland.

    • Tanguy Corre
    • , Zoltan Kutalik
    •  & Sven Bergmann
  19. Institute for Molecular Medicine Finland (FIMM), University of Helsinki, FI-00014, Finland.

    • Diana L. Cousminer
    • , Emmi Tikkanen
    • , Aarno Palotie
    •  & Elisabeth Widen
  20. Department of Epidemiology Research, Statens Serum Institut, DK-2300 Copenhagen, Denmark.

    • Bjarke Feenstra
    • , Frank Geller
    • , Mads Melbye
    •  & Heather A. Boyd
  21. Department of Epidemiology, University of North Carolina, Chapel Hill, North Carolina 27599-7400, USA.

    • Nora Franceschini
  22. Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, 17177 Stockholm, Sweden.

    • Andrea Ganna
    • , Kamila Czene
    • , Per Hall
    • , Patrik K. Magnusson
    •  & Nancy L. Pedersen
  23. NHLBI’s and Boston University’s Framingham Heart Study, Framingham, Massachusetts 01702-5827, USA.

    • Andrew D. Johnson
    • , Kathryn L. Lunetta
    •  & Joanne M. Murabito
  24. Science for Life Laboratory, Karolinska Institutet, Stockholm, Box 1031, 17121 Solna, Sweden.

    • Sanela Kjellqvist
  25. Boston University School of Public Health, Department of Biostatistics, Boston, Massachusetts 02118, USA.

    • Kathryn L. Lunetta
  26. MRC Integrative Epidemiology Unit, University of Bristol, Bristol BS8 2BN, UK.

    • George McMahon
    • , Lavinia Paternoster
    • , George Davey Smith
    • , Susan Ring
    • , Nicholas J. Timpson
    •  & Debbie Lawlor
  27. School of Social and Community Medicine, University of Bristol, Oakfield House, Oakfield Grove, Bristol BS8 2BN, UK.

    • George McMahon
    • , George Davey Smith
    • , Wendy L. McArdle
    • , Susan Ring
    • , Nicholas J. Timpson
    •  & Debbie Lawlor
  28. Department of Epidemiology, University of Groningen, University Medical Center Groningen, 9700 RB Groningen, The Netherlands.

    • Ilja M. Nolte
    • , Behrooz Z. Alizadeh
    •  & Harold Snieder
  29. Institute of Genetics and Biomedical Research, National Research Council, Cagliari, 09042 Sardinia, Italy.

    • Eleonora Porcu
    • , Sandra Lai
    • , Serena Sanna
    •  & Laura Crisponi
  30. University of Sassari, Department of Biomedical Sciences, 07100 Sassari, Italy.

    • Eleonora Porcu
  31. Icelandic Heart Association, IS-201 Kopavogur, Iceland.

    • Albert V. Smith
    • , Gudny Eiriksdottir
    •  & Vilmundur Gudnason
  32. University of Iceland, IS-101 Reykjavik, Iceland.

    • Albert V. Smith
    •  & Vilmundur Gudnason
  33. Department of Internal Medicine, Erasmus MC, 3015 GE Rotterdam, the Netherlands.

    • Lisette Stolk
    • , Fernando Rivadeneira
    • , Jenny A. Visser
    •  & André G. Uitterlinden
  34. Netherlands Consortium on Health Aging and National Genomics Initiative, 2300 RC Leiden, the Netherlands.

    • Lisette Stolk
    • , Fernando Rivadeneira
    • , Cornelia M. van Duijn
    •  & André G. Uitterlinden
  35. Interfaculty Institute for Genetics and Functional Genomics, University Medicine Greifswald, D-17475 Greifswald, Germany.

    • Alexander Teumer
  36. Department of Biotechnology, University of Tartu, 51010 Tartu, Estonia.

    • Natalia Tšernikova
    • , Evelin Mihailov
    •  & Andres Metspalu
  37. Hjelt Institute, University of Helsinki, FI-00014, Finland.

    • Emmi Tikkanen
  38. Institute for Maternal and Child Health - IRCCS “Burlo Garofolo”, 34137 Trieste, Italy.

    • Sheila Ulivi
    • , Adamo Pio D’adamo
    • , Antonietta Robino
    •  & Paolo Gasparini
  39. Genetic Epidemiology Unit Department of Epidemiology, Erasmus MC, 3015 GE, Rotterdam, the Netherlands.

    • Najaf Amin
    • , Ben A. Oostra
    •  & Cornelia M. van Duijn
  40. Department of Psychiatry, Washington University, St Louis, Missouri 63110, USA.

    • Laura J. Bierut
    •  & John P. Rice
  41. The University of Queensland, Queensland Brain Institute, St Lucia, Queensland 4072, Australia.

    • Enda M. Byrne
  42. QIMR Berghofer Medical Research Institute, Brisbane, Queensland 4006, Australia.

    • Enda M. Byrne
  43. Department of Biological Psychology, VU University Amsterdam, van der Boechorststraat 1, 1081 BT, Amsterdam, The Netherlands.

    • Jouke-Jan Hottenga
    • , Eco E. J. de Geus
    • , Gonneke Willemsen
    •  & Dorret I. Boomsma
  44. Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana 46202-3082, USA.

    • Daniel L. Koller
    • , Tatiana Foroud
    •  & Michael J. Econs
  45. Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts 02142, USA.

    • Tune H. Pers
  46. Center for Biological Sequence Analysis, Department of Systems Biology, Technical 142 University of Denmark, DK-2800 Lyngby, Denmark.

    • Tune H. Pers
  47. Program in Personalized and Genomic Medicine, and Department of Medicine, Division of Endocrinology, Diabetes and Nutrition, University of Maryland School of Medicine, Baltimore, Maryland 21201, USA.

    • Laura M. Yerges-Armstrong
    • , Patrick F. McArdle
    •  & Elizabeth A. Streeten
  48. Ontario Cancer Genetics Network, Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, Ontario M5G 1X5, Canada.

    • Irene L. Andrulis
  49. Department of Molecular Genetics, University of Toronto, Toronto, Ontario M5S 1A8, Canada.

    • Irene L. Andrulis
  50. Department of Epidemiology, University of California Irvine, Irvine, California 92697-7550, USA.

    • Hoda Anton-Culver
  51. Sanquin Research, 6525 GA Nijmegen, The Netherlands.

    • Femke Atsma
  52. Tuscany Regional Health Agency, Florence, Italy, I.O.T. and Department of Medical and Surgical Critical Care, University of Florence, 50134 Florence, Italy.

    • Stefania Bandinelli
  53. Geriatric Unit, Azienda Sanitaria di Firenze, 50122 Florence, Italy.

    • Stefania Bandinelli
  54. University Breast Center Franconia, Department of Gynecology and Obstetrics, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Comprehensive Cancer Center Erlangen-EMN, D-91054 Erlangen, Germany.

    • Matthias W. Beckmann
    •  & Peter A. Fasching
  55. Human Genetics Group, Human Cancer Genetics Program, Spanish National Cancer Research Centre (CNIO), E-28029 Madrid, Spain.

    • Javier Benitez
  56. Centro de Investigación en Red de Enfermedades Raras (CIBERER), E-46010 Valencia, Spain.

    • Javier Benitez
  57. Department of Oncology, University of Helsinki and Helsinki University Central Hospital, FI-00100 Helsinki, Finland.

    • Carl Blomqvist
  58. Copenhagen General Population Study, Herlev Hospital, Copenhagen University Hospital, University of Copenhagen, DK-2100 Copenhagen, Denmark.

    • Stig E. Bojesen
  59. Department of Clinical Biochemistry, Herlev Hospital, Copenhagen University Hospital, University of Copenhagen, DK-2100 Copenhagen, Denmark.

    • Stig E. Bojesen
  60. Division of Cancer Prevention and Genetics, Istituto Europeo di Oncologia (IEO), 20139 Milan, Italy.

    • Bernardo Bonanni
  61. DrMargarete Fischer-Bosch-Institute of Clinical Pharmacology, D-70376 Stuttgart, Germany.

    • Hiltrud Brauch
  62. University of Tübingen, D-72074 Tübingen, Germany.

    • Hiltrud Brauch
  63. Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), D-69120 Heidelberg, Germany.

    • Hermann Brenner
    •  & Aida K. Dieffenbach
  64. German Cancer Consortium (DKTK), D-69120 Heidelberg, Germany.

    • Hermann Brenner
    •  & Aida K. Dieffenbach
  65. Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), D-69120 Heidelberg, Germany.

    • Jenny Chang-Claude
    •  & Anja Rudolph
  66. Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland 20892, USA.

    • Stephen Chanock
  67. Departments of Anatomy and Neurological Surgery, Indiana University school of Medicine, Indianapolis, Indiana 46202, USA.

    • Jinhui Chen
  68. Stark Neuroscience Research Center, Indiana University school of Medicine, Indianapolis, Indiana 46202, USA.

    • Jinhui Chen
  69. Department of Genetics, QIMR Berghofer Medical Research Institute, Brisbane, Queensland 4006 Australia.

    • Georgia Chenevix-Trench
    •  & Nicholas G. Martin
  70. Department of Clinical Genetics, Erasmus University Medical Center, 3000 CA Rotterdam, The Netherlands.

    • J. Margriet Collée
  71. Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota 55905, USA.

    • Fergus J. Couch
  72. Department of Biostatistics, University of North Carolina, Chapel Hill, North Carolina 27599-7420, USA.

    • David Couper
  73. Boston University School of Medicine, Department of Medicine, Sections of Preventive Medicine and Endocrinology, Boston, Massachusetts 02118, USA.

    • Andrea D. Coviello
  74. Sheffield Cancer Research Centre, Department of Oncology, University of Sheffield, Sheffield S10 2RX, UK.

    • Angela Cox
  75. Department of Clinical Medical Sciences, Surgical and Health, University of Trieste, 34149 Trieste, Italy.

    • Adamo Pio D’adamo
    • , Antonietta Robino
    •  & Paolo Gasparini
  76. Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts 02115, USA.

    • Immaculata De Vivo
    • , Frank B. Hu
    • , David J. Hunter
    • , Meir J. Stampfer
    •  & Peter Kraft
  77. Channing Division of Network Medicine, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA.

    • Immaculata De Vivo
    • , Frank B. Hu
    • , David J. Hunter
    •  & Meir J. Stampfer
  78. Division of Epidemiology and Community Health, School of Public Health, University of Minnesota, Minneapolis, Minnesota 55455, USA.

    • Ellen W. Demerath
  79. Department of Human Genetics & Department of Pathology, Leiden University Medical Center, 2300 RC Leiden, The Netherlands.

    • Peter Devilee
  80. Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge CB1 8RN, UK.

    • Alison M. Dunning
    • , Paul D. P. Pharoah
    •  & Jonathan Tyrer
  81. National Institute for Health and Welfare, P.O. Box 30, FI-00271 Helsinki, Finland.

    • Johan G. Eriksson
    • , Anneli Pouta
    •  & Veikko Salomaa
  82. Department of General Practice and Primary health Care, University of Helsinki, FI-00014 Helsinki, Finland.

    • Johan G. Eriksson
  83. Helsinki University Central Hospital, Unit of General Practice, FI-00029 HUS Helsinki, Finland.

    • Johan G. Eriksson
  84. Folkhalsan Research Centre, FI-00290 Helsinki, Finland.

    • Johan G. Eriksson
  85. Longitudinal Studies Section, Clinical Research Branch, Gerontology Research Center, National Institute on Aging, Baltimore, Maryland 20892, USA.

    • Luigi Ferrucci
  86. Department of Cancer Epidemiology/Clinical Cancer Registry and Institute for Medical Biometrics and Epidemiology, University Clinic Hamburg-Eppendorf, D-20246 Hamburg, Germany.

    • Dieter Flesch-Janys
  87. Department of Breast Surgery, Herlev Hospital, Copenhagen University Hospital, DK-2100 Copenhagen, Denmark.

    • Henrik Flyger
  88. Department of Genetics, University of Groningen, University Medical Centre Groningen, P.O. Box 72, 9700 AB Groningen, The Netherlands.

    • Lude Franke
  89. National Insitute on Aging, National Institutes of Health, Baltimore, Maryland 20892, USA.

    • Melissa E. Garcia
    •  & Tamara B. Harris
  90. Division of Genetics and Epidemiology, Institute of Cancer Research, Sutton, Surrey SM2 5NG, UK.

    • Montserrat García-Closas
  91. Breakthrough Breast Cancer Research Centre, Division of Breast Cancer Research, The Institute of Cancer Research, London SW3 6JB, UK.

    • Montserrat García-Closas
  92. EMGO + Institute for Health and Care Research, VU University Medical Centre, Van der Boechorststraat 7, 1081 Bt, Amsterdam, The Netherlands.

    • Eco E. J. de Geus
  93. Cancer Epidemiology Centre, Cancer Council Victoria, Melbourne, Victoria 3004, Australia.

    • Graham G. Giles
    •  & Roger L. Milne
  94. Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Victoria 3010, Australia.

    • Graham G. Giles
    • , John L. Hopper
    •  & Roger L. Milne
  95. Faculty of Medicine, University of Iceland, IS-101 Reykjavik, Iceland.

    • Daniel F. Gudbjartsson
    • , Unnur Thorsteinsdottir
    •  & Kari Stefansson
  96. Inserm (National Institute of Health and Medical Research), CESP (Center for Research in Epidemiology and Population Health), U1018, Environmental Epidemiology of Cancer, F-94807 Villejuif, France.

    • Pascal Guénel
  97. University Paris-Sud, UMRS 1018, F-94807 Villejuif, France.

    • Pascal Guénel
  98. Department of Obstetrics and Gynecology, Southern Medical University, 510515 Guangzhou, China.

    • Suiqun Guo
  99. Molecular Genetics of Breast Cancer, Deutsches Krebsforschungszentrum (DKFZ), D-69120 Heidelberg, Germany.

    • Ute Hamann
  100. Institute of Clinical Chemistry and Laboratory Medicine, University Medicine Greifswald, D-17475 Greifswald, Germany.

    • Robin Haring
    •  & Henri Wallaschofski
  101. Department of Psychiatry, University of Groningen, University Medical Center Groningen, P.O. Box 72, 9700 AB Groningen, The Netherlands.

    • Catharina A. Hartman
  102. Washington University, Department of Psychiatry, St Louis, Missouri 63110, USA.

    • Andrew C. Heath
  103. Department of Epidemiology, Erasmus MC, PO Box 2040, 3000 CA Rotterdam, the Netherlands.

    • Albert Hofman
    • , Fernando Rivadeneira
    •  & André G. Uitterlinden
  104. Department of Medical Oncology, Erasmus University Medical Center, P.O. Box 2040, 3000 CA Rotterdam, The Netherlands.

    • Maartje J. Hooning
  105. Department of Nutrition, Harvard School of Public Health, Boston, Massachusetts 02115, USA.

    • Frank B. Hu
    •  & Meir J. Stampfer
  106. Hebrew SeniorLife Institute for Aging Research, Boston, Massachusetts 02131, USA.

    • David Karasik
    •  & Douglas P. Kiel
  107. Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts 02115, USA.

    • Douglas P. Kiel
  108. Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, Ontario M5G 1X5, Canada.

    • Julia A. Knight
  109. Division of Epidemiology, Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario M5T 3M7, Canada.

    • Julia A. Knight
  110. School of Medicine, Institute of Clinical Medicine, Pathology and Forensic Medicine, University of Eastern Finland, P.O. Box 1627, FI-70211 Kuopio, Finland.

    • Veli-Matti Kosma
    •  & Arto Mannermaa
  111. Imaging Center, Department of Clinical Pathology, Kuopio University Hospital, P.O. Box 100, FI-70029 Kuopio, Finland.

    • Veli-Matti Kosma
    •  & Arto Mannermaa
  112. Vesalius Research Center (VRC), VIB, 3000 Leuven, Belgium.

    • Diether Lambrechts
  113. Laboratory for Translational Genetics, Department of Oncology, University of Leuven, 3000 Leuven, Belgium.

    • Diether Lambrechts
  114. Department of Molecular Medicine and Surgery, Karolinska Institutet, SE-171 77 Stockholm, Sweden.

    • Annika Lindblom
  115. Department of Medicine, Stanford School of Medicine, Stanford, California 94305-5101, USA.

    • Mads Melbye
  116. Department of Obstetrics and Gynecology, University of Helsinki and Helsinki University Central Hospital, P.O. Box 100, FI-00029 HUS Helsinki, Finland.

    • Heli Nevanlinna
  117. KULeuven (University of Leuven), Department of Oncology, Multidisciplinary Breast Center, University Hospitals Leuven, 3000 Leuven, Belgium.

    • Patrick Neven
  118. Research Unit of Obstetrics & Gynecology, Institute of Clinical Research, University of Southern Denmark, DK-5000 Odense C, Denmark.

    • Ellen A. Nohr
  119. Interdisciplinary Center Psychopathology and Emotion Regulation, University of Groningen, University Medical Center Groningen, P.O. Box 30.001, 9700 RB Groningen, The Netherlands.

    • Albertine J. Oldehinkel
  120. Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.

    • Aarno Palotie
  121. Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts 02142, USA.

    • Aarno Palotie
  122. Psychiatric & Neurodevelopmental Genetics Unit, Department of Psychiatry, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.

    • Aarno Palotie
  123. Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA.

    • Munro Peacock
    • , Anna M. Storniolo
    •  & Michael J. Econs
  124. IFOM, Fondazione Istituto FIRC di Oncologia Molecolare, 20139 Milan, Italy.

    • Paolo Peterlongo
  125. Non-communicable Disease Epidemiology Department, London School of Hygiene and Tropical Medicine, London WC1E 7HT, UK.

    • Julian Peto
  126. University Groningen, University Medical Center Groningen, Department Pulmonary Medicine and Tuberculosis, GRIAC Research Institute, P.O. Box 30.001, NL-9700 RB Groningen, The Netherlands.

    • Dirkje S. Postma
  127. Department of Obstetrics and Gynecology, Oulu University Hospital, P.O. Box 10, FI-90029 OYS Oulu, Finland.

    • Anneli Pouta
  128. Laboratory of Cancer Genetics and Tumor Biology, Department of Clinical Chemistry and Biocenter Oulu, University of Oulu, Oulu University Hospital/NordLab Oulu, P.O. Box 3000, FI-90014 Oulu, Finland.

    • Katri Pylkäs
    •  & Robert Winqvist
  129. Unit of Molecular Bases of Genetic Risk and Genetic Testing, Department of Preventive and Predictive Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori (INT), 20133 Milan, Italy.

    • Paolo Radice
  130. National Institute on Aging, Intramural Research Program, Baltimore, Maryland 21224-6825, USA.

    • David Schlessinger
  131. Netherlands Cancer Institute, Antoni van Leeuwenhoek hospital, Postbus 90203, 1006 BE Amsterdam, The Netherlands.

    • Marjanka K. Schmidt
  132. Department of Pathology, The University of Melbourne, Melbourne, Victoria 3010, Australia.

    • Mellissa C. Southey
  133. Department of Epidemiology and Biostatistics, MRC Health Protection Agency (HPA) Centre for Environment and Health, School of Public Health, Imperial College London, London W2 1PG, UK.

    • Ulla Sovio
    •  & Marjo-Riitta Järvelin
  134. Department of Obstetrics and Gynaecology, University of Cambridge, Cambridge CB2 0SW, UK.

    • Ulla Sovio
  135. Institute of Epidemiology II, Helmholtz Zentrum München - German Research Center for Environmental Health, D-8576 Neuherberg, Germany.

    • Doris Stöckl
  136. Department of Obstetrics and Gynaecology, Campus Grosshadern, Ludwig-Maximilians-University, D-81377 Munich, Germany.

    • Doris Stöckl
  137. Department of Internal Medicine, Lausanne University Hospital, CH-1015 Lausanne, Switzerland.

    • Peter Vollenweider
    •  & Gerard Waeber
  138. Institute for Community Medicine, University Medicine Greifswald, D-17475 Greifswald, Germany.

    • Henry Völzke
  139. DZHK (German Centre for Cardiovascular Research), partner site Greifswald, D-17475 Greifswald, Germany.

    • Henry Völzke
    •  & Henri Wallaschofski
  140. Research Unit of Molecular Epidemiology, Helmholtz Zentrum München - German Research Center for Environmental Health, D-8576 Neuherberg, Germany.

    • Melanie Waldenberger
  141. Department of Endocrinology, University of Groningen, University Medical Centre Groningen, P.O. Box 72, 9700 AB Groningen, The Netherlands.

    • Bruce H. R. Wolffenbuttel
  142. Queensland Insitute of Medical Research, Brisbane, Queensland 4029, Australia.

    • Margaret J. Wright
    •  & Grant W. Montgomery
  143. Department of Public Health and Primary Care, Institute of Public Health, University of Cambridge, Cambridge CB2 0QQ, UK.

    • Kay-Tee Khaw
  144. Genetics of Obesity and Related Metabolic Traits Program, The Charles Bronfman Institute for Personalized Medicine, The Mindich Child Health and Development Institute, Department of Preventive Medicine, Icahn School of Medicine at Mount Sinai, 1 Gustave L Levy Place, Box 1003, New York, New York 10029, USA.

    • Ruth J. F. Loos
  145. NIHR Oxford Biomedical Research Centre, Churchill Hospital, Oxford OX3 7LE, UK.

    • Mark I. McCarthy
  146. Oxford Centre for Diabetes, Endocrinology, & Metabolism, University of Oxford, Churchill Hospital, Oxford OX3 7LJ, UK.

    • Mark I. McCarthy
  147. Geriatric Research and Education Clinical Center (GRECC) - Veterans Administration Medical Center, Baltimore, Maryland 21201, USA.

    • Elizabeth A. Streeten
  148. Centre of Medical Systems Biology, PO Box 9600, 2300 RC Leiden, the Netherlands.

    • Cornelia M. van Duijn
  149. Human Genetics Center and Divof Epidemiology, University of Houston, P.O. Box 20186, Texas 77025 USA.

    • Eric Boerwinkle
  150. Department of Medical Sciences, Molecular Epidemiology and Science for Life Laboratory, Uppsala University, Box 256, 751 05 Uppsala, Sweden.

    • Erik Ingelsson
  151. Institute of Health Sciences, University of Oulu, P.O. Box 5000, FI-90014 Oulu, Finland.

    • Marjo-Riitta Järvelin
  152. Biocenter Oulu, University of Oulu, P.O. Box 5000, Aapistie 5A, FI-90014 Oulu, Finland.

    • Marjo-Riitta Järvelin
  153. Department of Children and Young People and Families, National Institute for Health and Welfare, Aapistie 1, Box 310, FI-90101 Oulu, Finland.

    • Marjo-Riitta Järvelin
  154. Unit of Primary Care, Oulu University Hospital, Kajaanintie 50, P.O. Box 20, FI-90220 Oulu, 90029 OYS, Finland.

    • Marjo-Riitta Järvelin
  155. Department of Biostatistics, Harvard School of Public Health, Boston, Massachusetts 02115, USA.

    • Peter Kraft
  156. Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, DK-2200, Denmark.

    • Thorkild I. A. Sørensen
  157. Institute of Preventive Medicine, Bispebjerg and Frederiksberg Hospitals, The Capital Region, Copenhagen, DK-2000 Frederiksberg, Denmark.

    • Thorkild I. A. Sørensen
  158. Division of Population Health Sciences and Education, St George’s, University of London, Cranmer Terrace, London SW17 0RE, UK.

    • David P. Strachan
  159. Department of Obstetrics and Gynecology, University Medicine Greifswald, D-17475 Greifswald, Germany.

    • Marek Zygmunt
  160. Boston University School of Medicine, Department of Medicine, Section of General Internal Medicine, Boston, Massachusetts 02118, USA.

    • Joanne M. Murabito
  161. Department of Paediatrics, University of Cambridge, Cambridge CB2 0QQ, UK.

    • Ken K. Ong
  162. Lists of participants and their affiliations appear in Supplementary Information.

Consortia

  1. Australian Ovarian Cancer Study

  2. The GENICA Network

  3. kConFab

  4. The LifeLines Cohort Study

  5. The InterAct Consortium

  6. Early Growth Genetics (EGG) Consortium

Authors

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Contributions

Overall project management: J.R.B.P., F.D., C.E.E., P.S., D.J.T., D.F.E., K.S., J.M.M. and K.K.O. Core analyses: J.R.B.P., F.D., C.E.E., P.S., T.F., D.J.T., D.I.C. and T.E. Individual study analysts: A.A.R., A.D., A.G., A.J., A.T., A.V.S., B.Z.A., B.F., C.E.E., D.F.G., D.I.C., D.J.T., D.L.C., D.L.K., E.A., E.K.W., E.M., E.M.B., E.T., F.D., G.M., G.McMahon, I.M.N., J.A.V., J.D., J.H., J.R.B.P., J.T., J.Z., K.L.L., K.M., L.L.P., L.M.R., L.M.Y., L.S., M.M., N.F., N.Ts., P.K., P.S., R.M., S.K., S.S., S.S.U., T.C., T.E., T.F., T.Fo., T.H.P., W.Q.A. and Z.K. Individual study data management and generation: A.A.R., A.C.H., A.D., A.D.C., A.G.U., A.J.O., A.M.S., A.Mu., A.P., A.Po., B.A.O., C.A.H., D.C., D.I.C., D.J.H., D.K., D.Lw., D.P.K., D.P.S., D.S., E.A.N., E.P., E.W., F.A., F.B.H., F.G., F.R., G.D., G.E., G.G.W., H.S., H.W., I.D., J.C., J.H., J.P.R., L.F., L.Fr., L.M., L.M.R., M.E.G., M.J.S., M.J.W., M.K.B., M.Melbye, M.P., M.W., N.A., N.J.T., N.L.P., P.K.M., Q.W., R.H., S.B., S.C., S.G., S.L., S.R., S.S.U., T.E., U.S., U.T., V.S. and W.L.M. Individual study principal investigators: A.C., A.G.U., A.H., A.J.O., A.K.D., A.L., A.M., A.M.D., A.Mannermaa, A.Mu., A.R., B.B., B.Z.A., B.H.R.W., C.B., C.E.P., C.G., C.H., C.van Duijn, D.I.B., D.F., D.F.E., D.J.H., D.L., D.Lw., D.S.P., D.P.S., D.Schlessinger, E.A.S., E.B., E.E.J.d.G., E.I., E.W., E.W.D., F.B.H., F.J.C., G.C., G.D., G.G.G., G.Wa., G.Wi., G.W.M., H.A., H.A.B., H.B., H.Be., H.F., H.N., H.S., H.V., I.D., I.L.A., J.A.K., J.B., J.C.C., J.G.E., J.E.B., J.L.H., J.M.C., J.M.M., J.P., K.C., K.K., K.K.O., K.P., K.S., L.C., L.F., L.J.B., M.C.S., M.G., M.I.M., M.J., M.J.E., M.J.H., M.J.S., M.K.S., M.W.B., M.Z., N.G.M., N.J.W., P.A.F., P.D., P.D.P.P., P.F.M., P.G., P.H., P.K., P.M.R., P.N., P.P., P.P.G., P.R., P.V., R.J.F.L., R.L.M., R.W., S.B., S.Bergmann, S.C., S.E.B., T.B.H., T.D.S., T.I.A.S., U.H., V.G., V.K. and V.S.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to John R. B. Perry or Joanne M. Murabito.

Plots of all 106 menarche loci and genome-wide summary level statistics are available at the ReproGen Consortium website: http://www.reprogen.org.

Extended data

Supplementary information

PDF files

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    Supplementary Information

    This file contains Supplementary Tables 1-5 and 8 and 9.

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    Supplementary Data

    This file contains Supplementary Tables 6 and 7.

About this article

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DOI

https://doi.org/10.1038/nature13545

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