Article | Published:

Genomic analyses identify hundreds of variants associated with age at menarche and support a role for puberty timing in cancer risk

Nature Genetics volume 49, pages 834841 (2017) | Download Citation

Abstract

The timing of puberty is a highly polygenic childhood trait that is epidemiologically associated with various adult diseases. Using 1000 Genomes Project–imputed genotype data in up to 370,000 women, we identify 389 independent signals (P < 5 × 10−8) for age at menarche, a milestone in female pubertal development. In Icelandic data, these signals explain 7.4% of the population variance in age at menarche, corresponding to 25% of the estimated heritability. We implicate 250 genes via coding variation or associated expression, demonstrating significant enrichment in neural tissues. Rare variants near the imprinted genes MKRN3 and DLK1 were identified, exhibiting large effects when paternally inherited. Mendelian randomization analyses suggest causal inverse associations, independent of body mass index (BMI), between puberty timing and risks for breast and endometrial cancers in women and prostate cancer in men. In aggregate, our findings highlight the complexity of the genetic regulation of puberty timing and support causal links with cancer susceptibility.

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Acknowledgements

This research has been conducted using the UK Biobank Resource under applications 5122 and 9797. Full study-specific acknowledgments can be found in the Supplementary Note.

Author information

Author notes

    • Felix R Day
    • , Deborah J Thompson
    •  & Hannes Helgason

    These authors contributed equally to this work.

    • Kari Stefansson
    • , Ken K Ong
    •  & John R B Perry

    These authors jointly directed this work.

Affiliations

  1. MRC Epidemiology Unit, University of Cambridge School of Clinical Medicine, Institute of Metabolic Science, Cambridge Biomedical Campus, Cambridge, UK.

    • Felix R Day
    • , Claudia Langenberg
    • , Jian'an Luan
    • , Robert A Scott
    • , Jing Hua Zhao
    • , Nicholas J Wareham
    • , Ken K Ong
    •  & John R B Perry
  2. Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.

    • Deborah J Thompson
    • , Manjeet K Bolla
    • , Joe Dennis
    • , Kyriaki Michailidou
    • , Paul D P Pharoah
    • , Qin Wang
    •  & Douglas F Easton
  3. deCODE Genetics/Amgen, Inc., Reykjavik, Iceland.

    • Hannes Helgason
    • , Patrick Sulem
    • , Daniel F Gudbjartsson
    • , Unnur Thorsteindottir
    •  & Kari Stefansson
  4. School of Engineering and Natural Sciences, University of Iceland, Reykjavik, Iceland.

    • Hannes Helgason
    •  & Daniel F Gudbjartsson
  5. Division of Preventive Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA.

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

    • Daniel I Chasman
    • , Julie E Buring
    • , David Karasik
    •  & Paul M Ridker
  7. Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts, USA.

    • Hilary Finucane
    • , Po-Ru Loh
    • , Immaculata De Vivo
    • , David J Hunter
    • , Meir Stampfer
    • , Peter Kraft
    •  & Alkes L Price
  8. Department of Mathematics, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.

    • Hilary Finucane
    •  & Alkes L Price
  9. Genetics of Complex Traits, University of Exeter Medical School, University of Exeter, Exeter, UK.

    • Katherine S Ruth
    •  & Anna Murray
  10. Gladstone Institutes, San Francisco, California, USA.

    • Sean Whalen
    •  & Katherine S Pollard
  11. Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.

    • Abhishek K Sarkar
    •  & Manolis Kellis
  12. Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.

    • Abhishek K Sarkar
    •  & Manolis Kellis
  13. Institute of Genetic Epidemiology, Helmholtz Zentrum München–German Research Center for Environmental Health, Neuherberg, Germany.

    • Eva Albrecht
    •  & Konstantin Strauch
  14. Institute of Epidemiology II, Helmholtz Zentrum München–German Research Center for Environmental Health, Neuherberg, Germany.

    • Elisabeth Altmaier
    • , Harald Grallert
    • , Christa Meisinger
    • , Annette Peters
    • , Christian Gieger
    •  & Doris Stöckl
  15. Research Unit of Molecular Epidemiology, Helmholtz Zentrum München–German Research Center for Environmental Health, Neuherberg, Germany.

    • Elisabeth Altmaier
    • , Harald Grallert
    •  & Christian Gieger
  16. Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.

    • Marzyeh Amini
    • , Ilja M Nolte
    • , Behrooz Z Alizadeh
    •  & Harold Snieder
  17. Genetics of Common Disorders Unit, IRCCS San Raffaele Scientific Institute and Vita-Salute San Raffaele University, Milan, Italy.

    • Caterina M Barbieri
    • , Cinzia F Sala
    • , Michela Traglia
    •  & Daniela Toniolo
  18. Medical Research Council Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK.

    • Thibaud Boutin
    • , Pau Navarro
    • , Veronique Vitart
    • , Caroline Hayward
    •  & James F Wilson
  19. Medical Genetics Section, Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK.

    • Archie Campbell
    •  & David Porteous
  20. Division of Epidemiology and Community Health, University of Minnesota, Minneapolis, Minnesota, USA.

    • Ellen Demerath
  21. Division of Epidemiology, Institute for Medicine and Public Health, Vanderbilt University, Nashville, Tennessee, USA.

    • Ayush Giri
  22. Vanderbilt Genetics Institute, Vanderbilt University, Nashville, Tennessee, USA.

    • Ayush Giri
    •  & Digna R Velez Edwards
  23. Department of Epidemiology, Indiana University Richard M. Fairbanks School of Public Health, Indianapolis, Indiana, USA.

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

    • Chunyan He
  25. Department of Biological Psychology, VU University Amsterdam, Amsterdam, the Netherlands.

    • Jouke J Hottenga
    • , Eco J C N de Geus
    • , Hamdi Mbarek
    • , Gonneke Willemsen
    •  & Dorret I Boomsma
  26. Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.

    • Robert Karlsson
    • , Judith S Brand
    • , Kamila Czene
    • , Marike Gabrielson
    • , Per Hall
    • , Jingmei Li
    • , Nancy Pedersen
    •  & Patrik K E Magnusson
  27. Faculty of Medicine, University of Split, Split, Croatia.

    • Ivana Kolcic
    •  & Ozren Polasek
  28. Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts, USA.

    • Po-Ru Loh
    • , Aarno Palotie
    • , Tõnu Esko
    •  & Alkes L Price
  29. Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts, USA.

    • Kathryn L Lunetta
  30. NHLBI's and Boston University's Framingham Heart Study, Framingham, Massachusetts, USA.

    • Kathryn L Lunetta
    •  & Joanne M Murabito
  31. Department of Twin Research and Genetic Epidemiology, King's College London, London, UK.

    • Massimo Mangino
    • , Genevieve LaChance
    • , Cristina Menni
    •  & Tim D Spector
  32. National Institute for Health Research (NIHR) Biomedical Research Centre at Guy's and St Thomas' Foundation Trust, London, UK.

    • Massimo Mangino
  33. Department of Clinical Medical Sciences, Surgical and Health, University of Trieste, Trieste, Italy.

    • Brumat Marco
    •  & Ilaria Gandin
  34. School of Social and Community Medicine, University of Bristol, Bristol, UK.

    • George McMahon
    • , Lavinia Paternoster
    • , George Davey Smith
    • , Susan M Ring
    • , Nicholas J Timpson
    •  & Debbie A Lawlor
  35. QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.

    • Sarah E Medland
    • , Penelope A Lind
    •  & Nicholas G Martin
  36. Department of Internal Medicine, Section of Gerontology and Geriatrics, Leiden University Medical Center, Leiden, the Netherlands.

    • Raymond Noordam
  37. Institute of Genetics and Biophysics, CNR, Naples, Italy.

    • Teresa Nutile
    • , Daniela Ruggiero
    • , Rossella Sorice
    •  & Marina Ciullo
  38. MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK.

    • Lavinia Paternoster
    • , George Davey Smith
    • , Susan M Ring
    • , Nicholas J Timpson
    •  & Debbie A Lawlor
  39. Estonian Genome Center, University of Tartu, Tartu, Estonia.

    • Natalia Perjakova
    • , Reedik Mägi
    • , Andres Metspalu
    • , Lili Milani
    •  & Tõnu Esko
  40. Institute of Genetics and Biomedical Research, National Research Council, Cagliari, Italy.

    • Eleonora Porcu
    • , Laura Crisponi
    • , Maristella Steri
    • , Magdalena Zoledziewska
    •  & Francesco Cucca
  41. Centre for Cardiovascular Sciences, Queen's Medical Research Institute, University of Edinburgh, Royal Infirmary of Edinburgh, Edinburgh, UK.

    • Katharina E Schraut
  42. Centre for Global Health Research, Usher Institute of Population Health Sciences and Informatics, University of Edinburgh, Edinburgh, UK.

    • Katharina E Schraut
    • , Harry Campbell
    • , Peter K Joshi
    • , Igor Rudan
    •  & James F Wilson
  43. Cancer Program, Broad Institute, Cambridge, Massachusetts, USA.

    • Ayellet V Segrè
  44. Faculty of Medicine, University of Iceland, Reykjavik, Iceland.

    • Albert V Smith
    • , Vilmundur Gudnason
    • , Unnur Thorsteindottir
    •  & Kari Stefansson
  45. Icelandic Heart Association, Kopavogur, Iceland.

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

    • Lisette Stolk
    • , Linda Broer
    • , André G Uitterlinden
    •  & Jenny A Visser
  47. Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany.

    • Alexander Teumer
    •  & Henry Völzke
  48. Fred A. Litwin Center for Cancer Genetics, Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, Ontario, Canada.

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

    • Irene L Andrulis
  50. Geriatric Unit, Azienda Sanitaria di Firenze, Florence, Italy.

    • Stefania Bandinelli
  51. Department of Gynaecology and Obstetrics, University Hospital Erlangen, Friedrich Alexander University Erlangen-Nuremberg, Erlangen, Germany.

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

    • Javier Benitez
  53. Centro de Investigación en Red de Enfermedades Raras (CIBERER), Valencia, Spain.

    • Javier Benitez
  54. Swiss Institute of Bioinformatics, Lausanne, Switzerland.

    • Sven Bergmann
    • , Tanguy Corre
    • , Zoltan Kutalik
    •  & Rico Rueedi
  55. Department of Computational Biology, University of Lausanne, Lausanne, Switzerland.

    • Sven Bergmann
    • , Tanguy Corre
    •  & Rico Rueedi
  56. Institute of Social and Preventive Medicine, University Hospital of Lausanne, Lausanne, Switzerland.

    • Murielle Bochud
    • , Tanguy Corre
    •  & Zoltan Kutalik
  57. Human Genetics Center, School of Public Health, University of Texas Health Science Center at Houston, Houston, Texas, USA.

    • Eric Boerwinkle
  58. Copenhagen General Population Study, Herlev Hospital, Copenhagen University Hospital, University of Copenhagen, Copenhagen, Denmark.

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

    • Stig E Bojesen
  60. Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.

    • Stig E Bojesen
  61. Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany.

    • Hiltrud Brauch
  62. University of Tübingen, Tübingen, Germany.

    • Hiltrud Brauch
  63. German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.

    • Hiltrud Brauch
    •  & Hermann Brenner
  64. Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany.

    • Hermann Brenner
  65. Division of Preventive Oncology, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT), Heidelberg, Germany.

    • Hermann Brenner
  66. Institute for Prevention and Occupational Medicine of German Social Accident Insurance, Institute of Ruhr University Bochum (IPA), Bochum, Germany.

    • Thomas Brüning
  67. Institute for Maternal and Child Health, IRCCS “Burlo Garofolo”, Trieste, Italy.

    • Eulalia Catamo
    • , Stefania Lenarduzzi
    • , Antonietta Robino
    •  & Sheila Ulivi
  68. Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland, USA.

    • Stephen Chanock
  69. Department of Genetics, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.

    • Georgia Chenevix-Trench
    • , Tracy A O'Mara
    •  & Amanda B Spurdle
  70. Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA.

    • Fergus J Couch
  71. Division of Genetics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.

    • Diana L Cousminer
  72. Department of Genetics, University of Pennsylvania, Philadelphia, Pennsylvania, USA.

    • Diana L Cousminer
  73. Academic Unit of Molecular Oncology, Department of Oncology and Metabolism, University of Sheffield, Sheffield, UK.

    • Angela Cox
  74. Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, the Netherlands.

    • Renée de Mutsert
    • , Frits R Rosendaal
    •  & Dennis O Mook-Kanamori
  75. Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.

    • Immaculata De Vivo
    • , Frank Hu
    • , David J Hunter
    •  & Meir Stampfer
  76. Department of Pathology, Leiden University Medical Center, Leiden, the Netherlands.

    • Peter Devilee
  77. Department of Human Genetics, Leiden University Medical Center, Leiden, the Netherlands.

    • Peter Devilee
    •  & Ko Willems van Dijk
  78. Non-Communicable Disease Epidemiology Department, London School of Hygiene and Tropical Medicine, London, UK.

    • Isabel dos-Santos-Silva
    •  & Julian Peto
  79. Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, UK.

    • Alison M Dunning
    • , Paul D P Pharoah
    • , Mitul Shah
    • , Jonathan P Tyrer
    •  & Douglas F Easton
  80. Department of General Practice and Primary Health Care, University of Helsinki, Helsinki, Finland.

    • Johan G Eriksson
  81. David Geffen School of Medicine, Department of Medicine, Division of Hematology and Oncology, University of California at Los Angeles, Los Angles, California, USA.

    • Peter A Fasching
  82. Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, Chapel Hill, North Carolina, USA.

    • Lindsay Fernández-Rhodes
    • , Gerardo Heiss
    •  & Nora Franceschini
  83. Longitudinal Studies Section, Translational Gerontology Branch, National Institute on Aging, Baltimore, Maryland, USA.

    • Luigi Ferrucci
    •  & Toshiko Tanaka
  84. Institute for Medical Biometrics and Epidemiology, University Clinic Hamburg-Eppendorf, Hamburg, Germany.

    • Dieter Flesch-Janys
  85. Department of Cancer Epidemiology/Clinical Cancer Registry, University Clinic Hamburg-Eppendorf, Hamburg, Germany.

    • Dieter Flesch-Janys
  86. Department of Genetics, University of Groningen, University Medical Centre Groningen, Groningen, the Netherlands.

    • Lude Franke
  87. Cancer Epidemiology Centre, Cancer Council Victoria, Melbourne, Victoria, Australia.

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

    • Graham G Giles
    • , John L Hopper
    •  & Roger L Milne
  89. German Center for Diabetes Research, Neuherberg, Germany.

    • Harald Grallert
    • , Annette Peters
    •  & Christian Gieger
  90. Cancer and Environment Group, Center for Research in Epidemiology and Population Health (CESP), INSERM, University Paris–Sud, University Paris–Saclay, Villejuif, France.

    • Pascal Guénel
    •  & Thérèse Truong
  91. Division of Epidemiology, Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota, USA.

    • Emily Hallberg
  92. Molecular Genetics of Breast Cancer, Deutsches Krebsforschungszentrum (DKFZ), Heidelberg, Germany.

    • Ute Hamann
  93. Laboratory of Epidemiology and Population Sciences, National Institute on Aging, Intramural Research Program, US National Institutes of Health, Bethesda, Maryland, USA.

    • Tamara B Harris
    •  & Lenore J Launer
  94. Department of Psychiatry, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.

    • Catharina A Hartman
  95. Department of Medical Oncology, Family Cancer Clinic, Erasmus MC Cancer Institute, Rotterdam, the Netherlands.

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

    • Frank Hu
    •  & David J Hunter
  97. Department of Epidemiology, Erasmus MC, Rotterdam, the Netherlands.

    • M Arfan Ikram
    •  & André G Uitterlinden
  98. Section of Genetic Medicine, Department of Medicine, University of Chicago, Chicago, Illinois, USA.

    • Hae Kyung Im
  99. Department of Epidemiology and Biostatistics, MRC Health Protection Agency (HPA) Centre for Environment and Health, School of Public Health, Imperial College London, London, UK.

    • Marjo-Riitta Järvelin
    •  & Ulla Sovio
  100. Biocenter Oulu, University of Oulu, Oulu, Finland.

    • Marjo-Riitta Järvelin
  101. Department of Children and Young People and Families, National Institute for Health and Welfare, Oulu, Finland.

    • Marjo-Riitta Järvelin
  102. Institute of Health Sciences, University of Oulu, Oulu, Finland.

    • Marjo-Riitta Järvelin
  103. Unit of Primary Care, Oulu University Hospital, Oulu, Finland.

    • Marjo-Riitta Järvelin
  104. Hebrew SeniorLife Institute for Aging Research, Boston, Massachusetts, USA.

    • David Karasik
  105. Laboratory for Translational Genetics, Department of Oncology, University of Leuven, Leuven, Belgium.

    • Diether Lambrechts
  106. Vesalius Research Center (VRC), VIB, Leuven, Belgium.

    • Diether Lambrechts
  107. Division of Reproductive Medicine, Department of Obstetrics and Gynaecology, Erasmus MC, Rotterdam, the Netherlands.

    • Joop S E Laven
  108. Department of Epidemiology, School of Public Health, University of Washington, Seattle, Washington, USA.

    • Sara Lindstrom
  109. Center for Human Genetics, Division of Public Health Sciences, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA.

    • YongMei Liu
  110. Translational Cancer Research Area, University of Eastern Finland, Kuopio, Finland.

    • Arto Mannermaa
  111. Institute of Clinical Medicine, Pathology and Forensic Medicine, University of Eastern Finland, Kuopio, Finland.

    • Arto Mannermaa
  112. Imaging Center, Department of Clinical Pathology, Kuopio University Hospital, Kuopio, Finland.

    • Arto Mannermaa
  113. NIHR Oxford Biomedical Research Centre, Churchill Hospital, Oxford, UK.

    • Mark I McCarthy
  114. Oxford Centre for Diabetes, Endocrinology, and Metabolism, University of Oxford, Churchill Hospital, Oxford, UK.

    • Mark I McCarthy
  115. Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.

    • Mark I McCarthy
  116. Central Hospital of Augsburg, MONICA/KORA Myocardial Infarction Registry, Augsburg, Germany.

    • Christa Meisinger
  117. Institute of Human Genetics, Helmholtz Zentrum München–German Research Center for Environmental Health, Neuherberg, Germany.

    • Thomas Meitinger
  118. Department of Electron Microscopy/Molecular Pathology, Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus.

    • Kyriaki Michailidou
  119. Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland, Australia.

    • Grant W Montgomery
  120. Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada.

    • Anna M Mulligan
  121. Laboratory Medicine Program, University Health Network, Toronto, Ontario, Canada.

    • Anna M Mulligan
  122. Laboratory of Neurogenetics, National Institute on Aging, Bethesda, Maryland, USA.

    • Mike A Nalls
  123. Department of Obstetrics and Gynecology, Helsinki University Hospital, University of Helsinki, Helsinki, Finland.

    • Heli Nevanlinna
  124. Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, Queensland, Australia.

    • Dale R Nyholt
  125. Interdisciplinary Center Psychopathology and Emotion Regulation, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.

    • Albertine J Oldehinkel
  126. British Heart Foundation Glasgow Cardiovascular Research Centre, Institute of Cardiovascular and Medical Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK.

    • Sandosh Padmanabhan
  127. Psychiatric and Neurodevelopmental Genetics Unit, Department of Psychiatry, Massachusetts General Hospital, Boston, Massachusetts, USA.

    • Aarno Palotie
  128. Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.

    • Aarno Palotie
  129. Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, UK.

    • Aarno Palotie
  130. Analytic and Translational Genetics Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.

    • Aarno Palotie
  131. Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland.

    • Aarno Palotie
    • , Emmi Tikkanen
    •  & Elisabeth Widen
  132. National Institute for Health and Welfare, Helsinki, Finland.

    • Anneli Pouta
  133. Unit of Molecular Bases of Genetic Risk and Genetic Testing, Department of Preventive and Predictive Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori (INT), Milan, Italy.

    • Paolo Radice
  134. Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.

    • Iffat Rahman
  135. Division of Molecular Pathology, Netherlands Cancer Institute–Antoni van Leeuwenhoek Hospital, Amsterdam, the Netherlands.

    • Marjanka K Schmidt
  136. Division of Psychosocial Research and Epidemiology, Netherlands Cancer Institute–Antoni van Leeuwenhoek Hospital, Amsterdam, the Netherlands.

    • Marjanka K Schmidt
  137. Department of Pathology, University of Melbourne, Melbourne, Victoria, Australia.

    • Melissa C Southey
  138. Department of Obstetrics and Gynaecology, University of Cambridge, Cambridge, UK.

    • Ulla Sovio
  139. Institute of Medical Informatics, Biometry and Epidemiology, Chair of Genetic Epidemiology, Ludwig-Maximilians-Universität, Munich, Germany.

    • Konstantin Strauch
  140. Department of Public Health, University of Helsinki, Helsinki, Finland.

    • Emmi Tikkanen
  141. Vanderbilt Epidemiology Center, Institute for Medicine and Public Health, Vanderbilt University, Nashville, Tennessee, USA.

    • Digna R Velez Edwards
  142. Department of Obstetrics and Gynecology, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.

    • Digna R Velez Edwards
  143. Interfaculty Institute for Genetics and Functional Genomics, University Medicine Greifswald, Greifswald, Germany.

    • Uwe Völker
  144. University Hospital of Lausanne, Lausanne, Switzerland.

    • Peter Vollenweider
  145. Department of Internal Medicine, Division of Endocrinology, Leiden University Medical Center, Leiden, the Netherlands.

    • Ko Willems van Dijk
  146. Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, the Netherlands.

    • Ko Willems van Dijk
  147. Laboratory of Cancer Genetics and Tumor Biology, Cancer and Translational Medicine Research Unit, Biocenter Oulu, University of Oulu, Oulu, Finland.

    • Robert Winqvist
  148. Laboratory of Cancer Genetics and Tumor Biology, Northern Finland Laboratory Centre NordLab, Oulu, Finland.

    • Robert Winqvist
  149. Department of Endocrinology, University of Groningen, University Medical Centre Groningen, Groningen, the Netherlands.

    • Bruce H R Wolffenbuttel
  150. Department of Obstetrics and Gynecology, University Medicine Greifswald, Greifswald, Germany.

    • Marek Zygmunt
  151. Department of Biomedical Sciences, University of Sassari, Sassari, Italy.

    • Francesco Cucca
  152. Department of Biostatistics, Harvard School of Public Health, Boston, Massachusetts, USA.

    • Peter Kraft
  153. Department of Public Health and Primary Care, Leiden University Medical Center, Leiden, the Netherlands.

    • Dennis O Mook-Kanamori
  154. Research Unit for Gynaecology and Obstetrics, Department of Clinical Research, University of Southern Denmark, Odense, Denmark.

    • Ellen A Nohr
  155. Department of Obstetrics and Gynaecology, Campus Grosshadern, Ludwig Maximilians University, Munich, Germany.

    • Doris Stöckl
  156. Division of Biostatistics, Institute for Human Genetics, and Institute for Computational Health Sciences, University of California, San Francisco, San Francisco, California, USA.

    • Katherine S Pollard
  157. 23andMe, Inc., Mountain View, California, USA.

    • Joyce Y Tung
    •  & David Hinds
  158. Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.

    • Jenny Chang-Claude
  159. University Cancer Center Hamburg (UCCH), University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

    • Jenny Chang-Claude
  160. Boston University School of Medicine, Department of Medicine, Section of General Internal Medicine, Boston, Massachusetts, USA.

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

    • Ken K Ong

Consortia

  1. The LifeLines Cohort Study

    A full list of members and affiliations appears in the Supplementary Note.

  2. The InterAct Consortium

    A full list of members and affiliations appears in the Supplementary Note.

  3. kConFab/AOCS Investigators

    A full list of members and affiliations appears in the Supplementary Note.

  4. Endometrial Cancer Association Consortium

    A full list of members and affiliations appears in the Supplementary Note.

  5. Ovarian Cancer Association Consortium

    A full list of members and affiliations appears in the Supplementary Note.

  6. PRACTICAL consortium

    A full list of members and affiliations appears in the Supplementary Note.

Authors

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Contributions

All authors reviewed the original and revised manuscripts. Statistical analysis: F.R.D., D.J.T., H.H., D.I.C., H.F., P.S., K.S.R., S.W., A.K.S., E. Albrecht, E. Altmaier, M.A., C.M.B., T. Boutin, A. Campbell, E.D., A.G., C. He, J.J.H., R.K., I.K., P.-R.L., K.L.L., M.M., B.M., G.M., S.E.M., I.M.N., R.N., T.N., L.P., N. Perjakova, E.P., L.M.R., K.E.S., A.V. Segrè, A.V. Smith, L.S., A.T., J.R.B.P. Sample collection, genotyping and phenotyping: I.L.A., S. Bandinelli, M.W.B., J.B., S. Bergmann, M.B., E.B., S.E.B., M.K.B., J.S.B., H. Brauch, H. Brenner, L.B., T. Brüning, J.E.B., H.C., E.C., S.C., G.C.-T., T.C., F.J.C., D.L.C., A. Cox, L.C., K.C., G.D.S., E.J.C.N.d., R.d., I.D.V., J.D., P.D., I.d.-S.-S., A.M.D., J.G.E., P.A.F., L.F.-R., L. Ferrucci, D.F.-J., L. Franke, M.G., I.G., G.G.G., H.G., D.F.G., P.G., P.H., E.H., U.H., T.B.H., C.A.H., G.H., M.J.H., J.L.H., F.H., D.J.H., H.K.I., M.-R.J., P.K.J., D.K., Z.K., G.L., D.L., C.L., L.J.L., J.S.E.L., S. Lenarduzzi, J. Li, P.A.L., S. Lindstrom, Y.L., J. Luan, R.M., A. Mannermaa, H.M., M.I.M., C. Meisinger, T.M., C. Menni, A. Metspalu, K.M., L.M., R.L.M., G.W.M., A.M.M., M.A.N., P.N., H.N., D.R.N., A.J.O., T.A.O., S.P., A. Palotie, N. Pedersen, A. Peters, J.P., P.D.P.P., A. Pouta, P.R., I. Rahman, S.M.R., A.R., F.R.R., I. Rudan, R.R., D.R., C.F.S., M.K.S., R.A.S., M. Shah, R.S., M.C.S., U.S., M. Stampfer, M. Steri, K. Strauch, T. Tanaka, E.T., N.J.T., M.T., T. Truong, J.P.T., A.G.U., D.R.V.E., V.V., U.V., P.V., Q.W., E.W., K.W.v.D., G.W., R.W., B.H.R.W., J.H.Z., M. Zoledziewska, M. Zygmunt. Individual study principal investigators: B.Z.A., D.I.B., M.C., F.C., T.E., N.F., C.G., V.G., C. Hayward, P.K., D.A.L., P.K.E.M., N.G.M., D.O.M.-K., E.A.N., O.P., D.P., A.L.P., P.M.R., H.S., T.D.S., D.S., D.T., S.U., J.A.V., H.V., N.J.W., J.F.W., A.B.S., U.T., K.S.P., D.F.E., J.Y.T., J.C.-C., D.H., A. Murray, J.M.M., K. Stefansson, K.K.O., J.R.B.P. Working group: F.R.D., D.J.T., H.H., D.I.C., H.F., P.S., K.S.R., S.W., A.K.S., A.B.S., U.T., K.S.P., D.F.E., J.Y.T., J.C., D.H., A. Murray, J.M.M., K. Stefansson, K.K.O., J.R.B.P.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Ken K Ong or John R B Perry.

Integrated supplementary information

Supplementary information

PDF files

  1. 1.

    Supplementary Text and Figures

    Supplementary Figures 1–7 and Supplementary Note

Excel files

  1. 1.

    Supplementary Tables

    Supplementary Tables 1–16

About this article

Publication history

Received

Accepted

Published

DOI

https://doi.org/10.1038/ng.3841

Further reading