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Genome-wide analysis identifies 12 loci influencing human reproductive behavior

Nature Genetics 48, 1462–1472 (2016) | Download Citation

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Abstract

The genetic architecture of human reproductive behavior—age at first birth (AFB) and number of children ever born (NEB)—has a strong relationship with fitness, human development, infertility and risk of neuropsychiatric disorders. However, very few genetic loci have been identified, and the underlying mechanisms of AFB and NEB are poorly understood. We report a large genome-wide association study of both sexes including 251,151 individuals for AFB and 343,072 individuals for NEB. We identified 12 independent loci that are significantly associated with AFB and/or NEB in a SNP-based genome-wide association study and 4 additional loci associated in a gene-based effort. These loci harbor genes that are likely to have a role, either directly or by affecting non-local gene expression, in human reproduction and infertility, thereby increasing understanding of these complex traits.

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Acknowledgements

For full acknowledgments, see the Supplementary Note. Funding to lead this consortium was provided by grants awarded to M.C.M.: ERC Consolidator Grant SOCIOGENOME (615603), a Dutch Science Foundation (NWO) grant (VIDI grant 452-10-012), a UK ESRC/NCRM SOCGEN grant (ES/N011856/1), the European Union's FP7 Families And Societies project (320116), and the Wellcome Trust ISSF and John Fell Fund. M.d.H. was supported by grants from the Swedish Research Council (2015-03657) and the Swedish Heart-Lung Foundation (20140543). Research was carried out in collaboration with the Social Science Genetic Association Consortium (SSGAC), with funding from the US National Science Foundation (EAGER: 'Workshop for the Formation of a Social Science Genetic Association Consortium'), a Supplementary grant from the National Institutes of Health Office of Behavioral and Social Science Research, the Ragnar Söderberg Foundation (E9/11), the Swedish Research Council (421-2013-1061), the Jan Wallander and Tom Hedelius Foundation, an ERC Consolidator Grant (647648 EdGe), the Pershing Square Fund of the Foundations of Human Behavior and the NIA/NIH through grants P01-AG005842, P01-AG005842-20S2, P30-AG012810 and T32-AG000186-23 to NBER and R01-AG042568-02 to the University of Southern California. X.S. was supported by a grant from the Swedish Research Council (537-2014-371). We thank X. Ding for research assistance, N. Pirastu, K. Coward and L. Layman for valuable comments, and the University of Oxford Advanced Research Computing (ARC) facility (http://dx.doi.org/10.5281/zenodo.22558). This research has been conducted using the UK Biobank Resource.

Author information

    • Nicola Barban
    • , Marcel den Hoed
    • , Harold Snieder
    •  & Melinda C Mills

    These authors contributed equally to this work.

Affiliations

  1. Department of Sociology and Nuffield College, University of Oxford, Oxford, UK.

    • Nicola Barban
    • , Felix C Tropf
    •  & Melinda C Mills

  2. Department of Psychiatry, VU University Medical Center, Amsterdam, the Netherlands.

    • Rick Jansen
    • , Brenda W J H Penninx
    •  & Johannes Smit

  3. Department of Applied Economics, Erasmus School of Economics, Rotterdam, the Netherlands.

    • Ronald de Vlaming
    • , Cornelius A Rietveld
    • , A Roy Thurik
    • , André G Uitterlinden
    •  & Philipp D Koellinger

  4. Department of Epidemiology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands.

    • Ronald de Vlaming
    • , Janine F Felix
    • , Claire Monnereau
    • , Cornelius A Rietveld
    • , Najaf Amin
    • , Cornelia M van Duijn
    • , Albert Hofman
    •  & Vincent W V Jaddoe

  5. Erasmus University Rotterdam Institute for Behavior and Biology, Rotterdam, the Netherlands.

    • Ronald de Vlaming
    • , S Fleur W Meddens
    • , Cornelius A Rietveld
    • , Patrick J F Groenen
    • , Albert Hofman
    • , A Roy Thurik
    • , André G Uitterlinden
    •  & Philipp D Koellinger

  6. Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.

    • Ahmad Vaez
    • , Ilja M Nolte
    • , Fahimeh Falahi
    • , Peter J van der Most
    •  & Harold Snieder

  7. Research Institute for Primordial Prevention of Non-Communicable Disease, Isfahan University of Medical Sciences, Isfahan, Iran.

    • Ahmad Vaez

  8. Sociology of Consumption and Households, Wageningen University Research, Wageningen, the Netherlands.

    • Jornt J Mandemakers

  9. Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.

    • Xia Shen
    • , Robert Karlsson
    •  & Patrik K E Magnusson

  10. MRC Human Genetics Unit, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK.

    • Xia Shen
    • , James F Wilson
    • , Caroline Hayward
    • , Veronique Vitart
    •  & Alan F Wright

  11. Centre for Global Health Research, Usher Institute of Population Health Sciences and Informatics, University of Edinburgh, Edinburgh, UK.

    • Xia Shen
    • , James F Wilson
    • , Peter K Joshi
    • , Harry Campbell
    • , Ruth McQuillan
    •  & Igor Rudan

  12. Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.

    • Daniel I Chasman
    • , Lynda M Rose
    • , Julie E Buring
    •  & Paul M Ridker

  13. Department of Cardiology, Division of Heart and Lungs, University Medical Center Utrecht, Utrecht, the Netherlands.

    • Vinicius Tragante

  14. Laboratory of Experimental Cardiology, Division of Heart and Lungs, University Medical Center Utrecht, Utrecht, the Netherlands.

    • Sander W van der Laan

  15. MRC Epidemiology Unit, Institute of Metabolic Science, University of Cambridge, Cambridge, UK.

    • John R B Perry
    • , Jing Hua Zhao
    • , Ken K Ong
    •  & Nicholas J Wareham

  16. School of Engineering and Natural Sciences, University of Iceland, Reykjavik, Iceland.

    • Augustine Kong

  17. deCODE Genetics/Amgen, Inc., Reykjavik, Iceland.

    • Augustine Kong
    • , Gyda Bjornsdottir
    • , Gudmar Thorleifsson
    • , Unnur Thorsteinsdottir
    •  & Kari Stefansson

  18. Novo Nordisk Foundation Centre for Basic Metabolic Research, Section of Metabolic Genetics, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.

    • Tarunveer S Ahluwalia

  19. Steno Diabetes Center, Gentofte, Denmark.

    • Tarunveer S Ahluwalia

  20. COPSAC, Copenhagen Prospective Studies on Asthma in Childhood, Herlev and Gentofte Hospital, University of Copenhagen, Copenhagen, Denmark.

    • Tarunveer S Ahluwalia
    • , Hans Bisgaard
    • , Klaus Bønnelykke
    •  & Johannes Waage

  21. Institute of Genetic Epidemiology, Helmholtz Zentrum München–German Research Center for Environmental Health, Neuherberg, Germany.

    • Eva Albrecht
    •  & Konstantin Strauch

  22. Division of Endocrinology, Diabetes and Nutrition, University of Maryland School of Medicine, Baltimore, Maryland, USA.

    • Laura Yerges-Armstrong
    • , Patrick F McArdle
    • , Kathleen A Ryan
    •  & Elizabeth Streeten

  23. Department of Medicine, Institute for Aging Research and the Diabetes Research Center, Albert Einstein College of Medicine, Bronx, New York, USA.

    • Gil Atzmon
    •  & Nir Barzilai

  24. Department of Genetics, Institute for Aging Research and the Diabetes Research Center, Albert Einstein College of Medicine, Bronx, New York, USA.

    • Gil Atzmon
    •  & Danny Ben-Avraham

  25. Department of Natural Science, University of Haifa, Haifa, Israel.

    • Gil Atzmon

  26. Department of Health, National Institute for Health and Welfare, Helsinki, Finland.

    • Kirsi Auro
    • , Markus Perola
    • , Jaakko Kaprio
    •  & Veikko Salomaa

  27. Institute for Molecular Medicine (FIMM), University of Helsinki, Helsinki, Finland.

    • Kirsi Auro
    • , Kauko Heikkilä
    • , Markus Perola
    •  & Jaakko Kaprio

  28. Institute of Genetic Medicine, Newcastle University, Newcastle-upon-Tyne, UK.

    • Kristin Ayers
    • , Heather J Cordell
    • , Crysovalanto Mamasoula
    •  & Bernard Keavney

  29. Queensland Brain Institute, University of Queensland, Brisbane, Queensland, Australia.

    • Andrew Bakshi

  30. Institute of Epidemiology and Social Medicine, University of Münster, Münster, Germany.

    • Klaus Berger
    •  & Juergen Wellmann

  31. Departments of Systems and Computational Biology, of Pathology and of Neuroscience, Albert Einstein College of Medicine, Bronx, New York, USA.

    • Aviv Bergman

  32. Lübeck Interdisciplinary Platform for Genome Analytics, Institutes of Neurogenetics and of Integrative and Experimental Genomics, University of Lübeck, Lübeck, Germany.

    • Lars Bertram

  33. School of Public Health, Faculty of Medicine, Imperial College, London, UK.

    • Lars Bertram

  34. Department of Epidemiology, University of Michigan, Ann Arbor, Michigan, USA.

    • Lawrence F Bielak
    • , Jennifer A Smith
    • , Wei Zhao
    • , Sharon L R Kardia
    •  & Patricia A Peyser

  35. Department of Genetics, Genomics Coordination Center, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.

    • Marc Jan Bonder
    • , Lude Franke
    • , Daria V Zhernakova
    •  & Morris A Swertz

  36. Department of Internal Medicine, Erasmus Medical Center, Rotterdam, the Netherlands.

    • Linda Broer
    • , Lisette Stolk
    •  & André G Uitterlinden

  37. Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, University of Melbourne, Melbourne, Victoria, Australia.

    • Minh Bui
    • , Enes Makalic
    • , Daniel Schmidt
    •  & John Hopper

  38. Division of Genetics and Cell Biology, San Raffaele Research Institute, Milan, Italy.

    • Caterina Barbieri
    • , Daniela Toniolo
    • , Cinzia Felicita Sala
    •  & Michela Traglia

  39. Population, Policy and Practice, UCL Institute of Child Health, London, UK.

    • Alana Cavadino
    • , Elina Hyppönen
    •  & Chris Power

  40. Centre for Environmental and Preventive Medicine, Wolfson Institute of Preventative Medicine, Queen Mary University of London, London, UK.

    • Alana Cavadino

  41. Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA.

    • Jorge E Chavarro
    •  & Audrey J Gaskins

  42. Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.

    • Jorge E Chavarro
    •  & Janet Rich-Edwards

  43. Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA.

    • Jorge E Chavarro
    • , Constance Turman
    • , Hongyan Huang
    • , Peter Kraft
    • , Stacey A Missmer
    • , Janet Rich-Edwards
    •  & Albert Hofman

  44. Institute of Genetic and Biomedical Research, National Research Council, UOS of Sassari, Sassari, Italy.

    • Maria Pina Concas
    • , Mario Pirastu
    •  & Simona Vaccargiu

  45. Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, UK.

    • Gail Davies
    • , Simon R Cox
    • , Ian J Deary
    • , David C Liewald
    •  & John M Starr

  46. Department of Psychology, University of Edinburgh, Edinburgh, UK.

    • Gail Davies
    • , Simon R Cox
    • , Ian J Deary
    •  & Alison Pattie

  47. Health Economics Research Centre, University of Oxford, Oxford, UK.

    • Peter Eibich

  48. 23andMe, Inc., Mountain View, California, USA.

    • Nicholas Eriksson
    •  & Joyce Y Tung

  49. Estonian Genome Center, University of Tartu, Tartu, Estonia.

    • Tõnu Esko
    • , Evelin Mihailov
    • , Andres Metspalu
    • , Lili Milani
    •  & Markus Perola

  50. Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.

    • Tõnu Esko

  51. Centre for Bone and Arthritis Research, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.

    • Joel Eriksson
    • , Dan Mellström
    •  & Claes Ohlsson

  52. Generation R Study Group, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands.

    • Janine F Felix
    • , Claire Monnereau
    •  & Vincent W V Jaddoe

  53. Department of Pediatrics, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands.

    • Janine F Felix
    • , Claire Monnereau
    •  & Vincent W V Jaddoe

  54. Center for Economic and Social Research, University of Southern California, Los Angeles, California, USA.

    • Mark Alan Fontana
    •  & Daniel J Benjamin

  55. Department of Medical, Surgical and Health Sciences, University of Trieste, Trieste, Italy.

    • Ilaria Gandin
    • , Paolo Gasparini
    • , Giorgia Girotto
    •  & Dragana Vuckovic

  56. Research Unit of Molecular Epidemiology, Helmholtz Zentrum München–German Research Center for Environmental Health, Neuherberg, Germany.

    • Christian Gieger

  57. Institute of Epidemiology II, Helmholtz Zentrum München–German Research Center for Environmental Health, Neuherberg, Germany.

    • Christian Gieger
    •  & Christa Meisinger

  58. Cardiovascular and Metabolic Conditions Section, Division of Research, Kaiser Permanente Northern California, Oakland, California, USA.

    • Erica P Gunderson

  59. Institute for Translational Genomics and Population Sciences, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, California, USA.

    • Xiuqing Guo
    • , Jie Yao
    •  & Kathryn Roll

  60. Department of Epidemiology, Indiana University Richard M. Fairbanks School of Public Health, Indianapolis, Indiana, USA.

    • Chunyan He

  61. Clinical Division of Neurogeriatrics, Department of Neurology, Medical University of Graz, Graz, Austria.

    • Edith Hofer
    •  & Reinhold Schmidt

  62. Institute of Medical Informatics, Statistics and Documentation, Medical University of Graz, Graz, Austria.

    • Edith Hofer

  63. William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK.

    • Stavroula Kanoni
    •  & Panos Deloukas

  64. Department of Neurology, Medical University of Innsbruck, Innsbruck, Austria.

    • Stefan Kiechl
    • , Peter Willeit
    •  & Johann Willeit

  65. Centre for Vision Research, Department of Ophthalmology and Westmead Institute for Medical Research, University of Sydney, Westmead, New South Wales, Australia.

    • Annette Kifley
    • , Paul Mitchell
    •  & Jie Jin Wang

  66. Institute of Medical Epidemiology, Biostatistics and Informatics, Martin Luther University Halle-Wittenberg, Halle (Saale), Germany.

    • Alexander Kluttig
    •  & Johannes Haerting

  67. Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA.

    • Peter Kraft

  68. Department of Neurosciences, KU Leuven, Leuven, Belgium.

    • Vasiliki Lagou

  69. Department of Microbiology and Immunology, KU Leuven, Leuven, Belgium.

    • Vasiliki Lagou

  70. Translational Immunology Laboratory, VIB, Leuven, Belgium.

    • Vasiliki Lagou

  71. University of Lille, CNRS, Institut Pasteur of Lille, Lille, France.

    • Cecile Lecoeur
    • , Loic Yengo
    • , Beverley Balkau
    •  & Philippe Froguel

  72. Institute of Behavioral Sciences, University of Helsinki, Helsinki, Finland.

    • Jari Lahti
    •  & Katri Räikkönen

  73. Helsinki Collegium for Advanced Studies, University of Helsinki, Helsinki, Finland.

    • Jari Lahti

  74. Folkhälsan Research Centre, Helsinki, Finland.

    • Jari Lahti
    •  & Johan G Eriksson

  75. Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, the Netherlands.

    • Ruifang Li-Gao
    • , Hugoline G de Haan
    • , Dennis Mook-Kanamori
    •  & Renée de Mutsert

  76. Psychiatric Genetics, QIMR Berghofer Medical Research Institute, Herston Brisbane, Queensland, Australia.

    • Penelope A Lind
    • , Nicholas G Martin
    •  & Sarah E Medland

  77. Center for Lifespan Psychology, Max Planck Institute for Human Development and Department of Vertebrate Genomics, Max Planck Institute for Molecular Genetics, Berlin, Germany.

    • Tian Liu

  78. Minnesota Center for Twin and Family Research, Department of Psychology, University of Minnesota, Minneapolis, Minnesota, USA.

    • Lindsay Matteson

  79. Department of Biological Psychology, VU University, Amsterdam, the Netherlands.

    • Hamdi Mbarek
    • , Dorret I Boomsma
    • , Eco J C de Geus
    •  & Gonneke Willemsen

  80. EMGO+ Institute for Health and Care Research, Amsterdam, the Netherlands.

    • Hamdi Mbarek
    • , Dorret I Boomsma
    • , Eco J C de Geus
    • , Brenda W J H Penninx
    • , Johannes Smit
    •  & Gonneke Willemsen

  81. School of Social and Community Medicine, University of Bristol, Bristol, UK.

    • George McMahon

  82. Complex Trait Genetics, VU University, Amsterdam, the Netherlands.

    • S Fleur W Meddens
    •  & Philipp D Koellinger

  83. Department of Psychology, University of Minnesota, Minneapolis, Minnesota, USA.

    • Mike Miller
    • , William G Iacono
    • , Matt McGue
    • , Robert F Krueger
    •  & James J Lee

  84. Department of Obstetrics, Gynecology and Reproductive Biology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.

    • Stacey A Missmer

  85. Department of Genetics and Bioinformatics, Area of Health Data and Digitalization, Institute of Public Health, Oslo, Norway.

    • Ronny Myhre
    • , Bo Jacobsson
    • , Astanand Jugessur
    •  & Per Magnus

  86. Laboratory of Neurogenetics, National Institute on Aging, US National Institutes of Health, Bethesda, Maryland, USA.

    • Mike A Nalls

  87. Institute of Genetics and Biophysics 'A. Buzzati-Traverso', CNR, Naples, Italy.

    • Teresa Nutile
    • , Marina Ciullo
    • , Daniela Ruggiero
    •  & Rossella Sorice

  88. Department of Nutrition and Dietetics, School of Health Science and Education, Harokopio University, Athens, Greece.

    • Ioanna Panagiota Kalafati
    •  & George Dedoussis

  89. Istituto di Ricerca Genetica e Biomedica, CMR, Cittadella Universitaria di Monserrato, Monserrato, Cagliari, Italy.

    • Eleonora Porcu
    • , Francesco Cucca
    •  & Sandra Lai

  90. Dipartimento di Scienze Biomediche, Università di Sassari, Sassari, Italy.

    • Eleonora Porcu
    •  & Francesco Cucca

  91. Department of Genomics of Common Disease, School of Public Health, Imperial College London, London, UK.

    • Inga Prokopenko

  92. Wellcome Trust Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford, UK.

    • Inga Prokopenko
    •  & Cecilia M Lindgren

  93. Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, University of Oxford, Oxford, UK.

    • Inga Prokopenko
    •  & Cecilia M Lindgren

  94. Rush University Medical Center, Chicago, Illinois, USA.

    • Kumar B Rajan
    •  & Denis A Evans

  95. Connors Center for Women's Health and Gender Biology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.

    • Janet Rich-Edwards

  96. Institute for Maternal and Child Health, IRCCS 'Burlo Garofolo', Trieste, Italy.

    • Antonietta Robino
    • , Sheila Ulivi
    • , Stefania Cappellani
    •  & Martina La Bianca

  97. Department of Computational Biology, University of Lausanne, Lausanne, Switzerland.

    • Rico Rueedi
    •  & Sven Bergmann

  98. Swiss Institute of Bioinformatics, Lausanne, Switzerland.

    • Rico Rueedi
    • , Sven Bergmann
    •  & Zoltan Kutalik

  99. Institute of Molecular Biology and Biochemistry, Centre for Molecular Medicine, Medical University of Graz, Graz, Austria.

    • Yasaman Saba
    •  & Helena Schmidt

  100. Department of Medicine, University of Leipzig, Leipzig, Germany.

    • Anke Tönjes
    •  & Michael Stumvoll

  101. Department of Public Health, University of Helsinki, Helsinki, Finland.

    • Juho Wedenoja
    •  & Jaakko Kaprio

  102. King's British Heart Foundation Centre, King's College London, London, UK.

    • Peter Willeit

  103. Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.

    • Peter Willeit

  104. Centre for Neurogenetics and Statistical Genomics, University of Queensland, Brisbane, Queensland, Australia.

    • Loic Yengo

  105. Data Coordinating Center, New York State Psychiatric Institute, New York, New York, USA.

    • Howard Andrews

  106. Institute of Molecular Genetics, National Research Council of Italy, Pavia, Italy.

    • Ginevra Biino

  107. IRCCS Neuromed, Pozzilli, Isernia, Italy.

    • Marina Ciullo
    •  & Rossella Sorice

  108. MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK.

    • George Davey-Smith
    • , Lavinia Paternoster
    • , Susan M Ring
    •  & Nicholas J Timpson

  109. Princess Al-Jawhara Al-Brahim Centre of Excellence in Research of Hereditary Disorders (PACER-HD), King Abdulaziz University, Jeddah, Saudi Arabia.

    • Panos Deloukas

  110. Department of Chronic Disease Prevention, National Institute for Health and Welfare, Helsinki, Finland.

    • Johan G Eriksson
    •  & Michael Lucht

  111. Department of General Practice and Primary Health Care, University of Helsinki, Helsinki, Finland.

    • Johan G Eriksson

  112. Unit of General Practice, Helsinki University Central Hospital, Helsinki, Finland.

    • Johan G Eriksson

  113. Vasa Central Hospital, Vasa, Finland.

    • Johan G Eriksson

  114. Survey Research Center, Institute for Social Research, University of Michigan, Ann Arbor, Michigan, USA.

    • Jessica D Faul
    •  & David R Weir

  115. Division of Experimental Genetics, Sidra, Doha, Qatar.

    • Paolo Gasparini
    • , Giorgia Girotto
    •  & Dragana Vuckovic

  116. Department of Psychiatry, University Medicine Greifswald, Greifswald, Germany.

    • Hans-Jörgen Grabe

  117. Division of Cancer Epidemiology, German Cancer Research Center, Heidelberg, Germany.

    • Karin Halina Greiser

  118. Econometric Institute, Erasmus School of Economics, Erasmus University Rotterdam, Rotterdam, the Netherlands.

    • Patrick J F Groenen

  119. Laboratory of Epidemiology and Population Sciences, National Institute on Aging, Bethesda, Maryland, USA.

    • Tamara B Harris

  120. Genetic Epidemiology, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.

    • Andrew C Heath
    •  & Grant W Montgomery

  121. Interfaculty Institute for Genetics and Functional Genomics, University Medicine Greifswald, Greifswald, Germany.

    • Georg Homuth

  122. School of Medicine and Public Health, University of Newcastle, Newcastle, New South Wales, Australia.

    • Elizabeth G Holliday

  123. Hunter Medical Research Institute, Newcastle, New South Wales, Australia.

    • Elizabeth G Holliday

  124. Centre for Population Health Research, Sansom Institute of Health Research and School of Health Sciences, University of South Australia, Adelaide, South Australia, Australia.

    • Elina Hyppönen

  125. South Australian Health and Medical Research Institute, Adelaide, South Australia, Australia.

    • Elina Hyppönen

  126. Department of Obstetrics and Gynecology, Institute of Clinical Sciences, Sahlgrenska Academy, Gothenburg University, Gothenburg, Sweden.

    • Bo Jacobsson

  127. Department of Economics, Stockholm School of Economics, Stockholm, Sweden.

    • Magnus Johannesson

  128. Department of Clinical Physiology, University of Tampere and Tampere University Hospital, Tampere, Finland.

    • Mika Kähönen

  129. Diabetes Prevention Unit, National Institute for Health and Welfare, Helsinki, Finland.

    • Eero Kajantie

  130. Children's Hospital, Helsinki University Central Hospital and University of Helsinki, Helsinki, Finland.

    • Eero Kajantie

  131. Department of Obstetrics and Gynecology, MRC Oulu, Oulu University Hospital and University of Oulu, Oulu, Finland.

    • Eero Kajantie

  132. Institute of Cardiovascular Sciences, University of Manchester, Manchester, UK.

    • Bernard Keavney

  133. Department of Public Health, Faculty of Medicine, University of Split, Split, Croatia.

    • Ivana Kolcic
    •  & Ozren Polasek

  134. Health Monitoring Unit, National Institute for Health and Welfare, Helsinki, Finland.

    • Päivikki Koponen

  135. IFB Adiposity Diseases, University of Leipzig, Leipzig, Germany.

    • Peter Kovacs
    •  & Michael Stumvoll

  136. Division of Genetic Epidemiology, Medical University of Innsbruck, Innsbruck, Austria.

    • Florian Kronenberg

  137. Institute of Social and Preventive Medicine, Lausanne University Hospital (CHUV), Lausanne, Switzerland.

    • Zoltan Kutalik

  138. Department of Twin Research and Genetic Epidemiology, King's College London, London, UK.

    • Genevieve Lachance
    •  & Tim D Spector

  139. Department of Clinical Chemistry, Fimlab Laboratories and School of Medicine, University of Tampere, Tampere, Finland.

    • Terho Lehtimäki

  140. NIHR Oxford Biomedical Research Centre, Oxford, UK.

    • Cecilia M Lindgren

  141. Strangeways Research Laboratory, University of Cambridge, Cambridge, UK.

    • Cecilia M Lindgren

  142. Division of Public Health Sciences, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA.

    • Yongmei Liu

  143. Strangeways Research Laboratory, University of Cambridge, Cambridge, UK.

    • Robert Luben

  144. UKK Institute for Health Promotion,Tampere, Finland.

    • Riitta Luoto

  145. Danish Aging Research Center and Danish Twin Registry, Institute of Public Health, University of Southern Denmark, Odense, Denmark.

    • Matt McGue

  146. MONICA/KORA Myocardial Infarction Registry, Central Hospital of Augsburg, Augsburg, Germany.

    • Christa Meisinger

  147. Institute of Molecular and Cell Biology, University of Tartu, Tartu, Estonia.

    • Andres Metspalu

  148. Molecular Bioscience, University of Queensland, Brisbane, Queensland, Australia.

    • Grant W Montgomery

  149. Department of Public Health and Primary Care, Leiden University Medical Center, Leiden, the Netherlands.

    • Dennis Mook-Kanamori

  150. Department of BESC, Epidemiology Section, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia.

    • Dennis Mook-Kanamori

  151. Research Unit for Gynecology and Obstetrics, Department of Clinical Research, University of Southern Denmark, Odense, Denmark.

    • Ellen A Nohr

  152. Department of Clinical Epidemiology, Aarhus University, Aarhus, Denmark.

    • Jørn Olsen

  153. Medical Genetics Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA.

    • Leslie J Raffel

  154. Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku and Department of Clinical Physiology and Nuclear Medicine, Turku University Hospital, Turku, Finland.

    • Olli Raitakari

  155. Department of Psychiatry, Martin Luther University Halle-Wittenberg, Halle (Saale), Germany.

    • Dan Rujescu

  156. Laboratory of Genetics, National Institute on Aging, Baltimore, Maryland, USA.

    • David Schlessinger

  157. Departments of Epidemiology and Psychiatry, Columbia University Medical Center, New York, New York, USA.

    • Nicole Schupf
    •  & Doris Stöckl

  158. Alzheimer Scotland Dementia Research Centre, University of Edinburgh, Edinburgh, UK.

    • John M Starr

  159. Institute of Medical Informatics, Biometry and Epidemiology, Chair of Genetic Epidemiology, Ludwig Maximilians Universität, Munich, Germany.

    • Konstantin Strauch

  160. Faculty of Medicine, University of Iceland, Reykjavik, Iceland.

    • Unnur Thorsteinsdottir
    •  & Kari Stefansson

  161. Montpellier Business School, Montpellier, France.

    • A Roy Thurik

  162. Department of Medicine, University of Turku and Division of Medicine, Turku University Hospital, Turku, Finland.

    • Jorma Viikari

  163. Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany.

    • Henry Völzke

  164. Department of Internal Medicine, Lausanne University Hospital (CHUV), Lausanne, Switzerland.

    • Peter Vollenweider

  165. German Socio-Economic Panel Study (SOEP), Max Planck Institute for Human Development and Berlin University of Technology (TUB), Berlin, Germany.

    • Gert G Wagner

  166. Genetic and Genomic Epidemiology Unit, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.

    • Krina T Zondervan

  167. Endometriosis CaRe Centre, Nuffield Department of Obstetrics and Gynaecology, University of Oxford, Oxford, UK.

    • Krina T Zondervan

  168. National Bureau of Economic Research, Cambridge, Massachusetts, USA.

    • Daniel J Benjamin

  169. Department of Economics, New York University, New York, New York, USA.

    • David Cesarini

  170. Research Institute for Industrial Economics, Stockholm, Sweden.

    • David Cesarini

  171. Department of Medical Sciences, Molecular Epidemiology and Science for Life Laboratory, Uppsala University, Uppsala, Sweden.

    • Marcel den Hoed

Consortia

  1. BIOS Consortium

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

  2. LifeLines Cohort Study

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

Authors

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Contributions

Senior investigators who led writing, analysis and study design: M.C.M., H. Snieder and M.d.H. Senior investigators who participated in study design: P.D.K., D.J.B. and D.C. Junior investigator who contributed to the study design and management: N. Barban. Population stratification: N. Barban and F.C.T. Genetic correlations and polygenic score prediction: N. Barban. Meta-analysis and quality control: N. Barban, R.d.V., J.J.M. and I.M.N. Biological annotation: R.J., M.d.H. and A.V. Sex-specific genetic effects: N. Barban and F.C.T. Bivariate and conditional analysis of the two fertility traits: X.S., J.F.W. and D.I.C. Gene-based analysis V.T. and S.W.v.d.L. Authors not listed contributed to recruitment, genotyping or data processing for the meta-analysis (Supplementary Table 43).

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Nicola Barban or Marcel den Hoed or Harold Snieder or Melinda C Mills.

Supplementary information

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    Supplementary Text and Figures

    Supplementary Figures 1–37 and Supplementary Note.

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  1. 1.

    Supplementary Tables 1–43

    Supplementary Tables 1–43.

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DOI

https://doi.org/10.1038/ng.3698

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