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Gene discovery and polygenic prediction from a genome-wide association study of educational attainment in 1.1 million individuals

Nature Genetics 50, 1112–1121 (2018) | Download Citation

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Abstract

Here we conducted a large-scale genetic association analysis of educational attainment in a sample of approximately 1.1 million individuals and identify 1,271 independent genome-wide-significant SNPs. For the SNPs taken together, we found evidence of heterogeneous effects across environments. The SNPs implicate genes involved in brain-development processes and neuron-to-neuron communication. In a separate analysis of the X chromosome, we identify 10 independent genome-wide-significant SNPs and estimate a SNP heritability of around 0.3% in both men and women, consistent with partial dosage compensation. A joint (multi-phenotype) analysis of educational attainment and three related cognitive phenotypes generates polygenic scores that explain 11–13% of the variance in educational attainment and 7–10% of the variance in cognitive performance. This prediction accuracy substantially increases the utility of polygenic scores as tools in research.

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              Acknowledgements

              This research was carried out under the auspices of the Social Science Genetic Association Consortium (SSGAC). The research has also been conducted using the UK Biobank Resource under application numbers 11425 and 12512. We acknowledge the Swedish Twin Registry for access to data. The Swedish Twin Registry is managed by the Karolinska Institutet and receives funding through the Swedish Research Council under the grant number 2017-00641. This study was supported by funding from the Ragnar Söderberg Foundation (E9/11, E42/15), 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, The Open Philanthropy Project (2016-152872), and the NIA/NIH through grants P01-AG005842, P01-AG005842-20S2, P30-AG012810 and T32-AG000186-23 to N.B.E.R. and R01-AG042568 to U.S.C. A full list of acknowledgments is provided in the Supplementary Note.

              Author information

              1. These authors contributed equally: James J. Lee, Robbee Wedow, Aysu Okbay.

              2. These authors jointly supervised this work: Patrick Turley, Peter M. Visscher, Daniel J. Benjamin, David Cesarini.

              3. A list of members and affiliations appears at the end of the paper.

              4. A list of members and affiliations appears in the Supplementary Information.

              Affiliations

              1. Department of Psychology, University of Minnesota Twin Cities, Minneapolis, MN, USA

                • James J. Lee
                • , Emily A. Willoughby
                • , James J. Lee
                • , Michael B. Miller
                • , William G. Iacono
                • , Matt McGue
                •  & Robert F. Krueger

              2. Department of Sociology, University of Colorado Boulder, Boulder, CO, USA

                • Robbee Wedow
                •  & Jason D. Boardman

              3. Institute for Behavioral Genetics, University of Colorado Boulder, Boulder, CO, USA

                • Robbee Wedow
                •  & Jason D. Boardman

              4. Institute of Behavioral Science, University of Colorado Boulder, Boulder, CO, USA

                • Robbee Wedow
                •  & Jason D. Boardman

              5. Department of Complex Trait Genetics, Center for Neurogenomics and Cognitive Research, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands

                • Aysu Okbay
                • , Richard Karlsson Linnér
                • , Aysu Okbay
                • , S. Fleur W. Meddens
                • , Christiaan de Leeuw
                • , Danielle Posthuma
                • , Philipp D. Koellinger
                •  & Philipp D. Koellinger

              6. Department of Economics, School of Business and Economics, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands

                • Aysu Okbay
                • , Richard Karlsson Linnér
                • , Aysu Okbay
                • , Philipp D. Koellinger
                •  & Philipp D. Koellinger

              7. Department of Economics, Harvard University, Cambridge, MA, USA

                • Edward Kong
                • , Omeed Maghzian
                • , Peter Bowers
                • , Chanwook Lee
                • , Hui Li
                • , Olga Rostapshova
                • , David I. Laibson
                •  & David I. Laibson

              8. Department of Sociology, Harvard University, Cambridge, MA, USA

                • Meghan Zacher

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

                • Tuan Anh Nguyen-Viet
                • , Mark Alan Fontana
                • , Tushar Kundu
                • , Ruoxi Li
                • , Rebecca Royer
                • , Mark Alan Fontana
                • , Daniel J. Benjamin
                • , Chelsea Watson
                •  & Daniel J. Benjamin

              10. Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland, Australia

                • Julia Sidorenko
                • , Loïc Yengo
                • , Jian Yang
                • , Peter M. Visscher
                • , Kathryn E. Kemper
                • , Yang Wu
                • , Zhili Zheng
                • , Matthew R. Robinson
                • , Jian Yang
                •  & Peter M. Visscher

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

                • Julia Sidorenko
                • , Evelin Mihailov
                • , Natalia Pervjakova
                • , Reedik Mägi
                • , Lili Milani
                • , Andres Metspalu
                • , Markus Perola
                • , Tõnu Esko
                • , Maris Alver
                • , Reedik Mägi
                • , Andres Metspalu
                • , Lili Milani
                •  & Tõnu Esko

              12. Institute for Behavior and Biology, Erasmus University Rotterdam, Rotterdam, The Netherlands

                • Richard Karlsson Linnér
                • , Cornelius A. Rietveld
                • , S. Fleur W. Meddens
                • , Ronald de Vlaming
                • , A. Roy Thurik
                • , Philipp D. Koellinger
                •  & Philipp D. Koellinger

              13. Center for the Advancement of Value in Musculoskeletal Care, Hospital for Special Surgery, New York, NY, USA

                • Mark Alan Fontana
                •  & Mark Alan Fontana

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

                • Pascal N. Timshel
                • , Tune H. Pers
                • , Pascal Timshel
                • , Tarunveer S. Ahluwalia
                • , Thorkild I. A. Sørensen
                •  & Tune H. Pers

              15. Statens Serum Institut, Department of Epidemiology Research, Copenhagen, Denmark

                • Pascal N. Timshel
                • , Tune H. Pers
                • , Pascal Timshel
                •  & Tune H. Pers

              16. Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA

                • Raymond K. Walters
                • , Patrick Turley
                • , Aarno Palotie
                •  & Patrick Turley

              17. Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA

                • Raymond K. Walters
                • , Patrick Turley
                • , Aarno Palotie
                •  & Patrick Turley

              18. Institute for Social and Economic Research, University of Essex, Colchester, UK

                • Yanchun Bao
                • , Pamela Herd
                •  & Meena Kumari

              19. 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
                • , Ozren Polasek
                • , James F. Wilson
                • , David W. Clark
                • , Peter K. Joshi
                • , Harry Campbell
                • , Melissa C. Smart
                •  & James F. Wilson

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

                • Felix R. Day
                • , Claudia Langenberg
                • , Jing Hua Zhao
                • , Jian’an Luan
                • , Ken K. Ong
                • , John R. B. Perry
                •  & Nicholas J. Wareham

              21. 23andMe, Inc., Mountain View, CA, USA

                • Michelle Agee
                • , Babak Alipanahi
                • , Adam Auton
                • , Robert K. Bell
                • , Katarzyna Bryc
                • , Sarah L. Elson
                • , Pierre Fontanillas
                • , David A. Hinds
                • , Jennifer C. McCreight.
                • , Karen E. Huber
                • , Nadia K. Litterman
                • , Matthew H. McIntyre
                • , Joanna L. Mountain
                • , Elizabeth S. Noblin
                • , Carrie A. M. Northover
                • , Steven J. Pitts
                • , J. Fah Sathirapongsasuti
                • , Olga V. Sazonova
                • , Janie F. Shelton
                • , Suyash Shringarpure
                • , Chao Tian
                • , Vladimir Vacic
                • , Catherine H. Wilson
                • , Nicholas A. Furlotte
                • , David A. Hinds
                • , Joyce Y. Tung
                • , Nicholas A. Furlotte
                • , Aaron Kleinman
                •  & Joyce Y. Tung

              22. Institute of Social and Preventive Medicine, University Hospital of Lausanne, Lausanne, Switzerland

                • Peter K. Joshi
                •  & Peter K. Joshi

              23. BrainWorkup, LLC, Santa Monica, CA, USA

                • Joey W. Trampush

              24. Department of Psychiatry and Behavioral Sciences, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA

                • Joey W. Trampush

              25. Department of Biomedical and Translational Informatics, Geisinger Health System, Danville, PA, USA

                • Shefali Setia Verma
                •  & Marylyn D. Ritchie

              26. Institute of Mental Health, Singapore, Singapore

                • Max Lam

              27. Genome Institute, Singapore, Singapore

                • Max Lam

              28. The Eye Hospital, School of Ophthalmology and Optometry, Wenzhou Medical University, Wenzhou, China

                • Zhili Zheng

              29. Department of Sociology, Stanford University, Stanford, CA, USA

                • Jeremy Freese

              30. Department of Sociology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

                • Kathleen Mullan Harris

              31. Carolina Population Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

                • Kathleen Mullan Harris

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

                • Jennifer E. Huffman
                • , Jonathan Marten
                • , Caroline Hayward
                • , Veronique Vitart
                • , James F. Wilson
                • , Alan F. Wright
                • , Caroline Hayward
                •  & James F. Wilson

              33. La Follette School of Public Affairs, University of Wisconsin-Madison, Madison, WI, USA

                • Pamela Herd

              34. Departments of Psychiatry and Molecular Medicine, Hofstra Northwell School of Medicine, Hempstead, NY, USA

                • Todd Lencz
                •  & Anil K. Malhotra

              35. Center for Psychiatric Neuroscience, Feinstein Institute for Medical Research, Manhasset, NY, USA

                • Todd Lencz
                •  & Anil K. Malhotra

              36. Psychiatry Research, The Zucker Hillside Hospital, Glen Oaks, CA, USA

                • Todd Lencz
                •  & Anil K. Malhotra

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

                • Andres Metspalu
                •  & Andres Metspalu

              38. Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK

                • Sarah E. Harris
                • , David J. Porteous
                •  & David J. Porteous

              39. Division of Population Health Sciences, Ninewells Hospital and Medical School, University of Dundee, Dundee, UK

                • Blair H. Smith
                •  & Blair H. Smith

              40. Medical Research Institute, University of Dundee, Dundee, UK

                • Blair H. Smith
                •  & Blair H. Smith

              41. Department of Economics, University of Toronto, Toronto, Ontario, Canada

                • Jonathan P. Beauchamp
                • , Riccardo E. Marioni
                •  & Jonathan P. Beauchamp

              42. Department of Sociology, Princeton University, Princeton, NJ, USA

                • Dalton C. Conley
                •  & Dalton C. Conley

              43. School of Policy Studies, Queen’s University, Kingston, Ontario, Canada

                • Steven F. Lehrer
                •  & Steven F. Lehrer

              44. Department of Economics, New York University Shanghai, Pudong, Shanghai, China

                • Steven F. Lehrer
                •  & Steven F. Lehrer

              45. National Bureau of Economic Research, Cambridge, MA, USA

                • Steven F. Lehrer
                • , David Cesarini
                • , Daniel J. Benjamin
                • , Steven F. Lehrer
                • , Daniel J. Benjamin
                •  & David Cesarini

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

                • Robert Karlsson
                • , Paul Lichtenstein
                • , Nancy L. Pedersen
                • , Patrik K. E. Magnusson
                •  & Patrik K. E. Magnusson

              47. Department of Government, Uppsala University, Uppsala, Sweden

                • Sven Oskarsson
                • , Karl-Oskar Lindgren
                •  & Sven Oskarsson

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

                • Matthew R. Robinson

              49. Department of Economics, New York University, New York, NY, USA

                • Kevin Thom
                • , David Cesarini
                • , Kevin Thom
                •  & David Cesarini

              50. Autism and Developmental Medicine Institute, Geisinger Health System, Lewisburg, PA, USA

                • Christopher F. Chabris
                •  & Christopher F. Chabris

              51. Center for Translational Bioethics and Health Care Policy, Geisinger Health System, Danville, PA, USA

                • Michelle N. Meyer
                •  & Michelle N. Meyer

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

                • Guo-Bo Chen
                • , Zhihong Zhu
                • , Andrew Bakshi
                • , Anna A. E. Vinkhuyzen
                • , Jacob Gratten
                • , Jian Yang
                • , Peter M. Visscher
                • , Jian Yang
                •  & Peter M. Visscher

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

                • Magnus Johannesson
                •  & Magnus Johannesson

              54. Department of Economics, University of Southern California, Los Angeles, CA, USA

                • Daniel J. Benjamin
                •  & Daniel J. Benjamin

              55. Center for Experimental Social Science, New York University, New York, NY, USA

                • David Cesarini
                •  & David Cesarini

              56. Department of Applied Economics, Erasmus School of Economics, Erasmus University Rotterdam, Rotterdam, The Netherlands

                • Cornelius A. Rietveld
                • , Ronald de Vlaming
                •  & A. Roy Thurik

              57. Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands

                • Cornelius A. Rietveld
                • , Ronald de Vlaming
                • , Sven J. van der Lee
                • , Najaf Amin
                • , Frank J. A. van Rooij
                • , Cornelia M. van Duijn
                • , Henning Tiemeier
                • , André G. Uitterlinden
                •  & Albert Hofman

              58. Icelandic Heart Association, Kopavogur, Iceland

                • Valur Emilsson
                • , Albert V. Smith
                •  & Vilmundur Gudnason

              59. Faculty of Pharmaceutical Sciences, University of Iceland, Reykjavík, Iceland

                • Valur Emilsson

              60. Amsterdam Business School, University of Amsterdam, Amsterdam, The Netherlands

                • S. Fleur W. Meddens
                •  & Maël P. Lebreton

              61. New York Genome Center, New York, NY, USA

                • Joseph K. Pickrell

              62. Department of Biological Psychology, VU University Amsterdam, Amsterdam, The Netherlands

                • Abdel Abdellaoui
                • , Jouke-Jan Hottenga
                • , Gonneke Willemsen
                •  & Dorret I. Boomsma

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

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

              64. Steno Diabetes Center, Gentofte, Denmark

                • Tarunveer S. Ahluwalia
                •  & Johannes Waage

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

                • Jonas Bacelis
                •  & Bo Jacobsson

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

                • Clemens Baumbach
                •  & Christian Gieger

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

                • Clemens Baumbach
                •  & Christa Meisinger

              68. deCODE Genetics/Amgen Inc., Reykjavík, Iceland

                • Gyda Bjornsdottir
                • , Augustine Kong
                • , Gudmar Thorleifsson
                • , Bjarni Gunnarsson
                • , Bjarni V. Halldórsson
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              69. Department of Cell Biology, Erasmus Medical Center Rotterdam, Rotterdam, The Netherlands

                • Johannes H. Brandsma
                •  & Raymond A. Poot

              70. Istituto di Ricerca Genetica e Biomedica U.O.S. di Sassari, National Research Council of Italy, Sassari, Italy

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

              71. Psychology, University of Illinois, Champaign, IL, USA

                • Jaime Derringer

              72. Institute for Computing and Information Sciences, Radboud University Nijmegen, Nijmegen, The Netherlands

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                •  & Lambertus A. L. M. Kiemeney

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

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

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

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                • , Antti Latvala
                • , LifeLines Cohort Study, Anu Loukola
                •  & Jaakko Kaprio

              75. Department of Cardiovascular Sciences, University of Leicester, Leicester, UK

                • Leanne M. Hall
                • , Christopher P. Nelson
                •  & Nilesh J. Samani

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

                • Leanne M. Hall
                • , Sarah E. Harris
                • , Gail Davies
                • , David C. M. Liewald
                • , Riccardo E. Marioni
                •  & Ian J. Deary

              77. Department of Neurology, General Hospital and Medical University Graz, Graz, Austria

                • Edith Hofer
                • , Katja E. Petrovic
                • , Helena Schmidt
                •  & Reinhold Schmidt

              78. Institute for Medical Informatics, Statistics and Documentation, General Hospital and Medical University Graz, Graz, Austria

                • Edith Hofer

              79. Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, UK

                • Momoko Horikoshi

              80. Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK

                • Momoko Horikoshi

              81. Institute of Behavioural Sciences, University of Helsinki, Helsinki, Finland

                • Kadri Kaasik
                • , Jari Lahti
                • , Liisa Keltigangas-Järvinen
                •  & Katri Räikkönen

              82. Nutrition and Dietetics, Health Science and Education, Harokopio University, Athens, Greece

                • Ioanna P. Kalafati
                •  & George V. Dedoussis

              83. Folkhälsan Research Centre, Helsingfors, Finland

                • Jari Lahti
                • , Katri Räikkönen
                •  & Johan G. Eriksson

              84. Institute for Computing and Information Sciences, Radboud University Nijmegen, Nijmegen, The Netherlands

                • Christiaan de Leeuw

              85. Quantitative Genetics, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia

                • Penelope A. Lind
                •  & Sarah E. Medland

              86. Lifespan Psychology, Max Planck Institute for Human Development, Berlin, Germany

                • Tian Liu

              87. Department of Twin Research and Genetic Epidemiology, King’s College London, London, UK

                • Massimo Mangino
                • , Lydia Quaye
                • , Cristina Venturini
                •  & Tim D. Spector

              88. NIHR Biomedical Research Centre, Guy’s and St. Thomas’ Foundation Trust, London, UK

                • Massimo Mangino
                •  & Cristina Venturini

              89. Department of Epidemiology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands

                • Peter J. van der Most
                • , Behrooz Z. Alizadeh
                • , Jennifer A. Smith
                •  & Judith M. Vonk

              90. Public Health Stream, Hunter Medical Research Institute, New Lambton, New South Wales, Australia

                • Christopher Oldmeadow
                • , Elizabeth G. Holliday
                •  & John R. Attia

              91. Faculty of Health and Medicine, University of Newcastle, Newcastle, New South Wales, Australia

                • Christopher Oldmeadow
                • , Elizabeth G. Holliday
                • , Rodney J. Scott
                •  & John R. Attia

              92. Centre for Integrated Genomic Medical Research, Institute of Population Health, The University of Manchester, Manchester, UK

                • Antony Payton
                •  & William E. R. Ollier

              93. School of Psychological Sciences, The University of Manchester, Manchester, UK

                • Antony Payton

              94. Department of Health, THL-National Institute for Health and Welfare, Helsinki, Finland

                • Natalia Pervjakova
                • , Niina Eklund
                • , Seppo Koskinen
                • , Tomi Mäki-Opas
                • , Veikko Salomaa
                • , Jaakko Kaprio
                •  & Markus Perola

              95. Psychiatry, VU University Medical Center and GGZ inGeest, Amsterdam, The Netherlands

                • Wouter J. Peyrot
                • , Yusplitri Milaneschi
                •  & Brenda W. J. H. Penninx

              96. Laboratory of Genetics, National Institute on Aging, Baltimore, MD, USA

                • Yong Qian
                • , Jun Ding
                •  & David Schlessinger

              97. Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku, Turku, Finland

                • Olli Raitakari

              98. Department of Medical Genetics, University of Lausanne, Lausanne, Switzerland

                • Rico Rueedi
                •  & Zoltan Kutalik

              99. Swiss Institute of Bioinformatics, Lausanne, Switzerland

                • Rico Rueedi
                •  & Zoltan Kutalik

              100. Department Of Health Sciences, University of Milan, Milan, Italy

                • Erika Salvi
                •  & Daniele Cusi

              101. Institute for Medical Informatics, Biometry and Epidemiology, University Hospital of Essen, Essen, Germany

                • Börge Schmidt
                • , Lewin Eisele
                •  & Karl-Heinz Jöckel

              102. Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA

                • Jianxin Shi

              103. Faculty of Medicine, University of Iceland, Reykjavík, Iceland

                • Albert V. Smith
                • , Vilmundur Gudnason
                • , Kari Stefansson
                •  & Unnur Thorsteinsdottir

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

                • Beate St Pourcain
                • , David M. Evans
                • , George McMahon
                • , Lavinia Paternoster
                • , Susan M. Ring
                • , Thorkild I. A. Sørensen
                • , Nicholas J. Timpson
                •  & George Davey Smith

              105. School of Oral and Dental Sciences, University of Bristol, Bristol, UK

                • Beate St Pourcain

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

                • Alexander Teumer
                • , Sebastian E. Baumeister
                • , Henry Völzke
                •  & Wolfgang Hoffmann

              107. Department of Cardiology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands

                • Niek Verweij
                • , Klaus Berger
                •  & Pim van der Harst

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

                • Juergen Wellmann

              109. Divisions of Genetics and Rheumatology, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA

                • Harm-Jan Westra

              110. Partners Center for Personalized Genetic Medicine, Boston, MA, USA

                • Harm-Jan Westra

              111. Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA

                • Harm-Jan Westra
                • , Philip L. de Jager
                •  & Aarno Palotie

              112. Rush Alzheimer’s Disease Center, Rush University Medical Center, Chicago, IL, USA

                • Jingyun Yang
                • , Patricia A. Boyle
                •  & David A. Bennett

              113. Department of Neurological Sciences, Rush University Medical Center, Chicago, IL, USA

                • Jingyun Yang
                •  & David A. Bennett

              114. Department of Epidemiology, University of Michigan, Ann Arbor, MI, USA

                • Wei Zhao
                • , Erin B. Ware
                •  & Sharon L. R. Kardia

              115. Department of Gastroenterology and Hepatology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands

                • Behrooz Z. Alizadeh

              116. Institute of Epidemiology and Preventive Medicine, University of Regensburg, Regensburg, Germany

                • Sebastian E. Baumeister

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

                • Ginevra Biino

              118. Department of Behavioral Sciences, Rush University Medical Center, Chicago, IL, USA

                • Patricia A. Boyle

              119. Warwick Medical School, University of Warwick, Coventry, UK

                • Francesco P. Cappuccio

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

                • Gail Davies
                • , David C. M. Liewald
                •  & Ian J. Deary

              121. Saïd Business School, University of Oxford, Oxford, UK

                • Jan-Emmanuel De Neve

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

                • Panos Deloukas
                •  & Stavroula Kanoni

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

                • Panos Deloukas

              124. The Berlin Aging Study II; Research Group on Geriatrics, Charité-Universitätsmedizin Berlin, Berlin, Germany

                • Ilja Demuth
                •  & Elisabeth Steinhagen-Thiessen

              125. Institute of Medical and Human Genetics, Charité-Universitätsmedizin Berlin, Berlin, Germany

                • Ilja Demuth

              126. German Socio-Economic Panel Study, DIW Berlin, Berlin, Germany

                • Peter Eibich
                •  & Martin Kroh

              127. Health Economics Research Centre, Nuffield Department of Population Health, University of Oxford, Oxford, UK

                • Peter Eibich

              128. The University of Queensland Diamantina Institute, The Translational Research Institute, Brisbane, Queensland, Australia

                • David M. Evans

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

                • Jessica D. Faul
                •  & David R. Weir

              130. Department of Genetics, Division of Statistical Genomics, Washington University School of Medicine, St Louis, MO, USA

                • Mary F. Feitosa
                • , Aldi T. Kraja
                • , Ingrid B. Borecki
                •  & Michael A. Province

              131. Institute of Human Genetics, University of Bonn, Bonn, Germany

                • Andreas J. Forstner

              132. Department of Genomics, Life and Brain Center, University of Bonn, Bonn, Germany

                • Andreas J. Forstner

              133. Institute of Biomedical and Neural Engineering, School of Science and Engineering, Reykjavík University, Reykjavík, Iceland

                • Bjarni V. Halldórsson

              134. Laboratory of Epidemiology, Demography, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA

                • Tamara B. Harris

              135. Department of Psychiatry, Washington University School of Medicine, St Louis, MO, USA

                • Andrew C. Heath
                •  & Pamela A. Madden

              136. Division of Applied Health Sciences, University of Aberdeen, Aberdeen, UK

                • Lynne J. Hocking

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

                • Georg Homuth
                •  & Uwe Völker

              138. Manchester Medical School, The University of Manchester, Manchester, UK

                • Michael A. Horan

              139. Program in Translational NeuroPsychiatric Genomics, Departments of Neurology and Psychiatry, Brigham and Women’s Hospital, Boston, MA, USA

                • Philip L. de Jager

              140. Harvard Medical School, Boston, MA, USA

                • Philip L. de Jager

              141. Department of Genes and Environment, Norwegian Institute of Public Health, Oslo, Norway

                • Astanand Jugessur
                • , Ronny Myhre
                •  & Bo Jacobsson

              142. Department of Genomics of Common Disease, Imperial College London, London, UK

                • Marika A. Kaakinen

              143. Department of Clinical Physiology, Tampere University Hospital, Tampere, Finland

                • Mika Kähönen

              144. Department of Clinical Physiology, University of Tampere, School of Medicine, Tampere, Finland

                • Mika Kähönen

              145. Public Health, Medical School, University of Split, Split, Croatia

                • Ivana Kolcic

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

                • Zoltan Kutalik

              147. Neuroepidemiology Section, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA

                • Lenore J. Launer

              148. Amsterdam Brain and Cognition Center, University of Amsterdam, Amsterdam, The Netherlands

                • Maël P. Lebreton

              149. Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA, USA

                • Douglas F. Levinson

              150. Institute of Human Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany

                • Peter Lichtner
                •  & Thomas Meitinger

              151. Medical Genetics Section, Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK

                • Riccardo E. Marioni

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

                • Pedro Marques-Vidal
                •  & Peter Vollenweider

              153. Tema BV, Hoofddorp, The Netherlands

                • Gerardus A. Meddens

              154. Molecular Epidemiology, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia

                • Grant W. Montgomery
                •  & Dale R. Nyholt

              155. NIHR Leicester Cardiovascular Biomedical Research Unit, Glenfield Hospital, Leicester, UK

                • Christopher P. Nelson
                •  & Nilesh J. Samani

              156. Institute of Health and Biomedical Innovation, Queensland Institute of Technology, Brisbane, Queensland, Australia

                • Dale R. Nyholt

              157. Psychiatric and Neurodevelopmental Genetics Unit, Department of Psychiatry, Massachusetts General Hospital, Boston, MA, USA

                • Aarno Palotie

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

                • Aarno Palotie
                • , Antti-Pekka Sarin
                •  & Jaakko Kaprio

              159. Department of Neurology, Massachusetts General Hospital, Boston, MA, USA

                • Aarno Palotie

              160. Medical Genetics, Institute for Maternal and Child Health IRCCS “Burlo Garofolo”, Trieste, Italy

                • Antonietta Robino
                • , Sheila Ulivi
                • , Diego Vozzi
                •  & Paolo Gasparini

              161. Social Impact, Arlington, VA, USA

                • Olga Rostapshova

              162. Department of Economics, University of Minnesota Twin Cities, Minneapolis, MN, USA

                • Aldo Rustichini

              163. Department of Psychiatry and Behavioral Sciences, NorthShore University HealthSystem, Evanston, IL, USA

                • Alan R. Sanders
                •  & Pablo V. Gejman

              164. Department of Psychiatry and Behavioral Neuroscience, University of Chicago, Chicago, IL, USA

                • Alan R. Sanders
                •  & Pablo V. Gejman

              165. Public Health Genomics Unit, National Institute for Health and Welfare, Helsinki, Finland

                • Antti-Pekka Sarin

              166. Research Unit for Genetic Epidemiology, Institute of Molecular Biology and Biochemistry, Center of Molecular Medicine, General Hospital and Medical University, Graz, Graz, Austria

                • Helena Schmidt

              167. Information Based Medicine Stream, Hunter Medical Research Institute, New Lambton, New South Wales, Australia

                • Rodney J. Scott

              168. Research Unit Hypertension and Cardiovascular Epidemiology, Department of Cardiovascular Science, University of Leuven, Leuven, Belgium

                • Jan A. Staessen

              169. R&D VitaK Group, Maastricht University, Maastricht, The Netherlands

                • Jan A. Staessen

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

                • Konstantin Strauch

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

                • Konstantin Strauch

              172. Department of Geriatrics, Florida State University College of Medicine, Tallahassee, FL, USA

                • Antonio Terracciano

              173. Department of Health Sciences and Genetics, University of Leicester, Leicester, UK

                • Martin D. Tobin

              174. Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands

                • Frank J. A. van Rooij

              175. Research Center for Group Dynamics, Institute for Social Research, University of Michigan, Ann Arbor, MI, USA

                • Erin B. Ware

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

                • Lars Bertram

              177. Neuroepidemiology and Ageing Research Unit, School of Public Health, Faculty of Medicine, Imperial College London, London, UK

                • Lars Bertram

              178. Department of Health Sciences, Community and Occupational Medicine, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands

                • Ute Bültmann

              179. Istituto di Ricerca Genetica e Biomedica (IRGB), Consiglio Nazionale delle Ricerche, c/o Cittadella Universitaria di Monserrato, Monserrato, Cagliari, Italy

                • Francesco Cucca

              180. Institute of Biomedical Technologies, Italian National Research Council, Segrate, Milan, Italy

                • Daniele Cusi

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

                • Johan G. Eriksson

              182. Departments of Human Genetics and Psychiatry, Donders Centre for Neuroscience, Nijmegen, The Netherlands

                • Barbara Franke

              183. Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands

                • Lude Franke
                •  & Pim van der Harst

              184. Sidra, Experimental Genetics Division, Sidra, Doha, Qatar

                • Paolo Gasparini

              185. Department of Psychiatry and Psychotherapy, University Medicine Greifswald, Greifswald, Germany

                • Hans-Jörgen Grabe

              186. Department of Psychiatry and Psychotherapy, HELIOS-Hospital Stralsund, Stralsund, Germany

                • Hans-Jörgen Grabe

              187. Econometric Institute, Erasmus School of Economics, Erasmus University Rotterdam, Rotterdam, The Netherlands

                • Patrick J. F. Groenen

              188. Durrer Center for Cardiogenetic Research, ICIN-Netherlands Heart Institute, Utrecht, The Netherlands

                • Pim van der Harst

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

                • Elina Hyppönen

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

                • Elina Hyppönen
                •  & Christine Power

              191. Population, Policy and Practice, UCL Institute of Child Health, University College London, London, UK

                • Elina Hyppönen

              192. Department of Epidemiology and Biostatistics, MRC-PHE Centre for Environment and Health, School of Public Health, Imperial College London, London, UK

                • Marjo-Riitta Järvelin

              193. Center for Life Course Epidemiology, Faculty of Medicine, University of Oulu, Oulu, Finland

                • Marjo-Riitta Järvelin

              194. Unit of Primary Care, Oulu University Hospital, Oulu, Finland

                • Marjo-Riitta Järvelin

              195. Biocenter Oulu, University of Oulu, Oulu, Finland

                • Marjo-Riitta Järvelin

              196. Fimlab Laboratories, Tampere, Finland

                • Terho Lehtimäki

              197. Department of Clinical Chemistry, University of Tampere, School of Medicine, Tampere, Finland

                • Terho Lehtimäki

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

                • Nicholas G. Martin

              199. Centre for Clinical and Cognitive Neuroscience, Institute Brain Behaviour and Mental Health, Salford Royal Hospital, Manchester, UK

                • Neil Pendleton

              200. Manchester Institute Collaborative Research in Ageing, University of Manchester, Manchester, UK

                • Neil Pendleton

              201. Faculty of Medicine, University of Split, Split, Croatia

                • Ozren Polasek

              202. Department of Clinical Genetics, VU Medical Centre, Amsterdam, The Netherlands

                • Danielle Posthuma

              203. Institute of Preventive Medicine, Bispebjerg and Frederiksberg Hospitals, The Capital Region, Frederiksberg, Denmark

                • Thorkild I. A. Sørensen

              204. Montpellier Business School, Montpellier, France

                • A. Roy Thurik

              205. Panteia, Zoetermeer, The Netherlands

                • A. Roy Thurik

              206. Department of Psychiatry, Erasmus Medical Center, Rotterdam, The Netherlands

                • Henning Tiemeier

              207. Department of Child and Adolescent Psychiatry, Erasmus Medical Center, Rotterdam, The Netherlands

                • Henning Tiemeier

              208. Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands

                • André G. Uitterlinden

              Authors

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              Consortia

              1. 23andMe Research Team

              1. COGENT (Cognitive Genomics Consortium)

                1. Social Science Genetic Association Consortium

                Contributions

                D.J.B., D.C., P.T. and P.M.V. designed and oversaw the study. A.O. was the lead analyst of the study, responsible for quality control and meta-analyses. Analysts who assisted A.O. in major ways include: E.K. (quality control), O.M. (COJO, MTAG, quality control), T.A.N.-V. (figure preparation), H.L. (quality control), C.L. (quality control), J.S. (UKB association analyses) and R.K.L. (UKB association analyses). P.B. and E.K. conducted the within-family association analyses. The cross-cohort heritability and genetic-correlation analyses were conducted by R.W. and M.Z. The analyses of the X chromosome in UK Biobank were conducted by J.S.; A.O. ran the meta-analysis. J.J.L. organized and oversaw the bioinformatic analyses, with assistance from T.E., E.K., K.T., T.H.P. and P.N.T. Polygenic-prediction analyses were designed and conducted by A.O., K.T. and R.W. Besides the contributions explicitly listed above, T.K., R.L. and R.R. conducted additional analyses for several subsections. C.W. helped with the coordination of the participating cohorts. J.P.B., D.C.C., T.E., M.J., J.J.L., P.D.K., D.I.L., S.F.L., S.O., M.R.R., K.T. and J.Y. provided helpful advice and feedback on various aspects of the study design. All authors contributed to and critically reviewed the manuscript. E.K., J.J.L. and R.W. made especially large contributions to the writing and editing.

                Competing interests

                Anil Malhotra is a consultant for Genomind Inc., Informed DNA, Concert Pharmaceuticals, and Biogen. Nicholas A. Furlotte, Aaron Kleinman and Joyce Tung are employees of 23andMe, Inc.

                Corresponding authors

                Correspondence to Aysu Okbay or Peter M. Visscher or Daniel J. Benjamin.

                Supplementary information

                1. Supplementary Text and Figures

                  Supplementary Note and Supplementary Figures 1–29

                2. Reporting Summary

                3. Supplementary Tables

                  Supplementary Tables 1–44

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                About this article

                Publication history

                Received

                Accepted

                Published

                DOI

                https://doi.org/10.1038/s41588-018-0147-3