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

doi:10.1038/s41588-018-0147-3

Meta-Analysis

. 2018 Jul 23;50(8):1112-1121.

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

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

James J Lee¹, Robbee Wedow^{2

3

4}, Aysu Okbay^{5

6}, Edward Kong⁷, Omeed Maghzian⁷, Meghan Zacher⁸, Tuan Anh Nguyen-Viet⁹, Peter Bowers⁷, Julia Sidorenko^{10

11}, Richard Karlsson Linnér^{12

13

14}, Mark Alan Fontana^{9

15}, Tushar Kundu⁹, Chanwook Lee⁷, Hui Li⁷, Ruoxi Li⁹, Rebecca Royer⁹, Pascal N Timshel^{16

17}, Raymond K Walters^{18

19}, Emily A Willoughby¹, Loïc Yengo¹⁰; 23andMe Research Team; COGENT (Cognitive Genomics Consortium); Social Science Genetic Association Consortium; Maris Alver¹¹, Yanchun Bao²⁰, David W Clark²¹, Felix R Day²², Nicholas A Furlotte²³, Peter K Joshi^{21

24}, Kathryn E Kemper¹⁰, Aaron Kleinman²³, Claudia Langenberg²², Reedik Mägi¹¹, Joey W Trampush^{25

26}, Shefali Setia Verma²⁷, Yang Wu¹⁰, Max Lam^{28

29}, Jing Hua Zhao²², Zhili Zheng^{10

30}, Jason D Boardman^{2

3

4}, Harry Campbell²¹, Jeremy Freese³¹, Kathleen Mullan Harris^{32

33}, Caroline Hayward³⁴, Pamela Herd^{20

35}, Meena Kumari²⁰, Todd Lencz^{36

37

38}, Jian'an Luan²², Anil K Malhotra^{36

37

38}, Andres Metspalu^{11

39}, Lili Milani¹¹, Ken K Ong²², John R B Perry²², David J Porteous⁴⁰, Marylyn D Ritchie²⁷, Melissa C Smart²¹, Blair H Smith^{41

42}, Joyce Y Tung²³, Nicholas J Wareham²², James F Wilson^{21

34}, Jonathan P Beauchamp⁴³, Dalton C Conley⁴⁴, Tõnu Esko¹¹, Steven F Lehrer^{45

46

47}, Patrik K E Magnusson⁴⁸, Sven Oskarsson⁴⁹, Tune H Pers^{16

17}, Matthew R Robinson^{10

50}, Kevin Thom⁵¹, Chelsea Watson⁹, Christopher F Chabris⁵², Michelle N Meyer⁵³, David I Laibson⁷, Jian Yang^{10

54}, Magnus Johannesson⁵⁵, Philipp D Koellinger^{12

13

14}, Patrick Turley^{18

19}, Peter M Visscher^{56

57}, Daniel J Benjamin^{58

59

60}, David Cesarini^{47

51

61}

Collaborators, Affiliations

Collaborators

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, Aysu Okbay, Jonathan P Beauchamp, Mark Alan Fontana, James J Lee, Tune H Pers, Cornelius A Rietveld, Patrick Turley, Guo-Bo Chen, Valur Emilsson, S Fleur W Meddens, Sven Oskarsson, Joseph K Pickrell, Kevin Thom, Pascal Timshel, Ronald de Vlaming, Abdel Abdellaoui, Tarunveer S Ahluwalia, Jonas Bacelis, Clemens Baumbach, Gyda Bjornsdottir, Johannes H Brandsma, Maria Pina Concas, Jaime Derringer, Nicholas A Furlotte, Tessel E Galesloot, Giorgia Girotto, Richa Gupta, Leanne M Hall, Sarah E Harris, Edith Hofer, Momoko Horikoshi, Jennifer E Huffman, Kadri Kaasik, Ioanna P Kalafati, Robert Karlsson, Augustine Kong, Jari Lahti, Sven J van der Lee, Christiaan de Leeuw, Penelope A Lind, Karl-Oskar Lindgren, Tian Liu, Massimo Mangino, Jonathan Marten, Evelin Mihailov, Michael B Miller, Peter J van der Most, Christopher Oldmeadow, Antony Payton, Natalia Pervjakova, Wouter J Peyrot, Yong Qian, Olli Raitakari, Rico Rueedi, Erika Salvi, Börge Schmidt, Katharina E Schraut, Jianxin Shi, Albert V Smith, Raymond A Poot, Beate St Pourcain, Alexander Teumer, Gudmar Thorleifsson, Niek Verweij, Dragana Vuckovic, Juergen Wellmann, Harm-Jan Westra, Jingyun Yang, Wei Zhao, Zhihong Zhu, Behrooz Z Alizadeh, Najaf Amin, Andrew Bakshi, Sebastian E Baumeister, Ginevra Biino, Klaus Bønnelykke, Patricia A Boyle, Harry Campbell, Francesco P Cappuccio, Gail Davies, Jan-Emmanuel De Neve, Panos Deloukas, Ilja Demuth, Jun Ding, Peter Eibich, Lewin Eisele, Niina Eklund, David M Evans, Jessica D Faul, Mary F Feitosa, Andreas J Forstner, Ilaria Gandin, Bjarni Gunnarsson, Bjarni V Halldórsson, Tamara B Harris, Andrew C Heath, Lynne J Hocking, Elizabeth G Holliday, Georg Homuth, Michael A Horan, Jouke-Jan Hottenga, Philip L de Jager, Peter K Joshi, Astanand Jugessur, Marika A Kaakinen, Mika Kähönen, Stavroula Kanoni, Liisa Keltigangas-Järvinen, Lambertus A L M Kiemeney, Ivana Kolcic, Seppo Koskinen, Aldi T Kraja, Martin Kroh, Zoltan Kutalik, Antti Latvala, Lenore J Launer, Maël P Lebreton, Douglas F Levinson, Paul Lichtenstein, Peter Lichtner, David C M Liewald, LifeLines Cohort Study Anu Loukola, Pamela A Madden, Reedik Mägi, Tomi Mäki-Opas, Riccardo E Marioni, Pedro Marques-Vidal, Gerardus A Meddens, George McMahon, Christa Meisinger, Thomas Meitinger, Yusplitri Milaneschi, Lili Milani, Grant W Montgomery, Ronny Myhre, Christopher P Nelson, Dale R Nyholt, William E R Ollier, Aarno Palotie, Lavinia Paternoster, Nancy L Pedersen, Katja E Petrovic, David J Porteous, Katri Räikkönen, Susan M Ring, Antonietta Robino, Olga Rostapshova, Igor Rudan, Aldo Rustichini, Veikko Salomaa, Alan R Sanders, Antti-Pekka Sarin, Helena Schmidt, Rodney J Scott, Blair H Smith, Jennifer A Smith, Jan A Staessen, Elisabeth Steinhagen-Thiessen, Konstantin Strauch, Antonio Terracciano, Martin D Tobin, Sheila Ulivi, Simona Vaccargiu, Lydia Quaye, Frank J A van Rooij, Cristina Venturini, Anna A E Vinkhuyzen, Uwe Völker, Henry Völzke, Judith M Vonk, Diego Vozzi, Johannes Waage, Erin B Ware, Gonneke Willemsen, John R Attia, David A Bennett, Klaus Berger, Lars Bertram, Hans Bisgaard, Dorret I Boomsma, Ingrid B Borecki, Ute Bültmann, Christopher F Chabris, Francesco Cucca, Daniele Cusi, Ian J Deary, George V Dedoussis, Cornelia M van Duijn, Johan G Eriksson, Barbara Franke, Lude Franke, Paolo Gasparini, Pablo V Gejman, Christian Gieger, Hans-Jörgen Grabe, Jacob Gratten, Patrick J F Groenen, Vilmundur Gudnason, Pim van der Harst, Caroline Hayward, David A Hinds, Wolfgang Hoffmann, Elina Hyppönen, William G Iacono, Bo Jacobsson, Marjo-Riitta Järvelin, Karl-Heinz Jöckel, Jaakko Kaprio, Sharon L R Kardia, Terho Lehtimäki, Steven F Lehrer, Patrik K E Magnusson, Nicholas G Martin, Matt McGue, Andres Metspalu, Neil Pendleton, Brenda W J H Penninx, Markus Perola, Nicola Pirastu, Mario Pirastu, Ozren Polasek, Danielle Posthuma, Christine Power, Michael A Province, Nilesh J Samani, David Schlessinger, Reinhold Schmidt, Thorkild I A Sørensen, Tim D Spector, Kari Stefansson, Unnur Thorsteinsdottir, A Roy Thurik, Nicholas J Timpson, Henning Tiemeier, Joyce Y Tung, André G Uitterlinden, Veronique Vitart, Peter Vollenweider, David R Weir, James F Wilson, Alan F Wright, Dalton C Conley, Robert F Krueger, George Davey Smith, Albert Hofman, David I Laibson, Sarah E Medland, Michelle N Meyer, Jian Yang, Magnus Johannesson, Peter M Visscher, Tõnu Esko, Philipp D Koellinger, David Cesarini, Daniel J Benjamin

Affiliations

¹ Department of Psychology, University of Minnesota Twin Cities, Minneapolis, MN, USA.
² Department of Sociology, University of Colorado Boulder, Boulder, CO, USA.
³ Institute for Behavioral Genetics, University of Colorado Boulder, Boulder, CO, USA.
⁴ Institute of Behavioral Science, University of Colorado Boulder, Boulder, CO, USA.
⁵ Department of Complex Trait Genetics, Center for Neurogenomics and Cognitive Research, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands. a.okbay@vu.nl.
⁶ Department of Economics, School of Business and Economics, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands. a.okbay@vu.nl.
⁷ Department of Economics, Harvard University, Cambridge, MA, USA.
⁸ Department of Sociology, Harvard University, Cambridge, MA, USA.
⁹ Center for Economic and Social Research, University of Southern California, Los Angeles, CA, USA.
¹⁰ Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland, Australia.
¹¹ Estonian Genome Center, University of Tartu, Tartu, Estonia.
¹² Department of Complex Trait Genetics, Center for Neurogenomics and Cognitive Research, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands.
¹³ Department of Economics, School of Business and Economics, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands.
¹⁴ Institute for Behavior and Biology, Erasmus University Rotterdam, Rotterdam, The Netherlands.
¹⁵ Center for the Advancement of Value in Musculoskeletal Care, Hospital for Special Surgery, New York, NY, USA.
¹⁶ The Novo Nordisk Foundation Center for Basic Metabolic Research, Section of Metabolic Genetics, University of Copenhagen, Faculty of Health and Medical Sciences, Copenhagen, Denmark.
¹⁷ Statens Serum Institut, Department of Epidemiology Research, Copenhagen, Denmark.
¹⁸ Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA.
¹⁹ Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
²⁰ Institute for Social and Economic Research, University of Essex, Colchester, UK.
²¹ Centre for Global Health Research, Usher Institute of Population Health Sciences and Informatics, University of Edinburgh, Edinburgh, UK.
²² MRC Epidemiology Unit, Institute of Metabolic Science, University of Cambridge, Cambridge, UK.
²³ 23andMe, Inc., Mountain View, CA, USA.
²⁴ Institute of Social and Preventive Medicine, University Hospital of Lausanne, Lausanne, Switzerland.
²⁵ BrainWorkup, LLC, Santa Monica, CA, USA.
²⁶ Department of Psychiatry and Behavioral Sciences, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
²⁷ Department of Biomedical and Translational Informatics, Geisinger Health System, Danville, PA, USA.
²⁸ Institute of Mental Health, Singapore, Singapore.
²⁹ Genome Institute, Singapore, Singapore.
³⁰ The Eye Hospital, School of Ophthalmology and Optometry, Wenzhou Medical University, Wenzhou, China.
³¹ Department of Sociology, Stanford University, Stanford, CA, USA.
³² Department of Sociology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
³³ Carolina Population Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
³⁴ MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK.
³⁵ La Follette School of Public Affairs, University of Wisconsin-Madison, Madison, WI, USA.
³⁶ Departments of Psychiatry and Molecular Medicine, Hofstra Northwell School of Medicine, Hempstead, NY, USA.
³⁷ Center for Psychiatric Neuroscience, Feinstein Institute for Medical Research, Manhasset, NY, USA.
³⁸ Psychiatry Research, The Zucker Hillside Hospital, Glen Oaks, CA, USA.
³⁹ Institute of Molecular and Cell Biology, University of Tartu, Tartu, Estonia.
⁴⁰ Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK.
⁴¹ Division of Population Health Sciences, Ninewells Hospital and Medical School, University of Dundee, Dundee, UK.
⁴² Medical Research Institute, University of Dundee, Dundee, UK.
⁴³ Department of Economics, University of Toronto, Toronto, Ontario, Canada.
⁴⁴ Department of Sociology, Princeton University, Princeton, NJ, USA.
⁴⁵ School of Policy Studies, Queen's University, Kingston, Ontario, Canada.
⁴⁶ Department of Economics, New York University Shanghai, Pudong, Shanghai, China.
⁴⁷ National Bureau of Economic Research, Cambridge, MA, USA.
⁴⁸ Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
⁴⁹ Department of Government, Uppsala University, Uppsala, Sweden.
⁵⁰ Department of Computational Biology, University of Lausanne, Lausanne, Switzerland.
⁵¹ Department of Economics, New York University, New York, NY, USA.
⁵² Autism and Developmental Medicine Institute, Geisinger Health System, Lewisburg, PA, USA.
⁵³ Center for Translational Bioethics and Health Care Policy, Geisinger Health System, Danville, PA, USA.
⁵⁴ Queensland Brain Institute, University of Queensland, Brisbane, Queensland, Australia.
⁵⁵ Department of Economics, Stockholm School of Economics, Stockholm, Sweden.
⁵⁶ Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland, Australia. peter.visscher@uq.edu.au.
⁵⁷ Queensland Brain Institute, University of Queensland, Brisbane, Queensland, Australia. peter.visscher@uq.edu.au.
⁵⁸ Center for Economic and Social Research, University of Southern California, Los Angeles, CA, USA. daniel.benjamin@gmail.com.
⁵⁹ National Bureau of Economic Research, Cambridge, MA, USA. daniel.benjamin@gmail.com.
⁶⁰ Department of Economics, University of Southern California, Los Angeles, CA, USA. daniel.benjamin@gmail.com.
⁶¹ Center for Experimental Social Science, New York University, New York, NY, USA.

PMID: 30038396
PMCID: PMC6393768
DOI: 10.1038/s41588-018-0147-3

Meta-Analysis

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

James J Lee et al. Nat Genet. 2018.

. 2018 Jul 23;50(8):1112-1121.

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

Authors

Collaborators

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, Aysu Okbay, Jonathan P Beauchamp, Mark Alan Fontana, James J Lee, Tune H Pers, Cornelius A Rietveld, Patrick Turley, Guo-Bo Chen, Valur Emilsson, S Fleur W Meddens, Sven Oskarsson, Joseph K Pickrell, Kevin Thom, Pascal Timshel, Ronald de Vlaming, Abdel Abdellaoui, Tarunveer S Ahluwalia, Jonas Bacelis, Clemens Baumbach, Gyda Bjornsdottir, Johannes H Brandsma, Maria Pina Concas, Jaime Derringer, Nicholas A Furlotte, Tessel E Galesloot, Giorgia Girotto, Richa Gupta, Leanne M Hall, Sarah E Harris, Edith Hofer, Momoko Horikoshi, Jennifer E Huffman, Kadri Kaasik, Ioanna P Kalafati, Robert Karlsson, Augustine Kong, Jari Lahti, Sven J van der Lee, Christiaan de Leeuw, Penelope A Lind, Karl-Oskar Lindgren, Tian Liu, Massimo Mangino, Jonathan Marten, Evelin Mihailov, Michael B Miller, Peter J van der Most, Christopher Oldmeadow, Antony Payton, Natalia Pervjakova, Wouter J Peyrot, Yong Qian, Olli Raitakari, Rico Rueedi, Erika Salvi, Börge Schmidt, Katharina E Schraut, Jianxin Shi, Albert V Smith, Raymond A Poot, Beate St Pourcain, Alexander Teumer, Gudmar Thorleifsson, Niek Verweij, Dragana Vuckovic, Juergen Wellmann, Harm-Jan Westra, Jingyun Yang, Wei Zhao, Zhihong Zhu, Behrooz Z Alizadeh, Najaf Amin, Andrew Bakshi, Sebastian E Baumeister, Ginevra Biino, Klaus Bønnelykke, Patricia A Boyle, Harry Campbell, Francesco P Cappuccio, Gail Davies, Jan-Emmanuel De Neve, Panos Deloukas, Ilja Demuth, Jun Ding, Peter Eibich, Lewin Eisele, Niina Eklund, David M Evans, Jessica D Faul, Mary F Feitosa, Andreas J Forstner, Ilaria Gandin, Bjarni Gunnarsson, Bjarni V Halldórsson, Tamara B Harris, Andrew C Heath, Lynne J Hocking, Elizabeth G Holliday, Georg Homuth, Michael A Horan, Jouke-Jan Hottenga, Philip L de Jager, Peter K Joshi, Astanand Jugessur, Marika A Kaakinen, Mika Kähönen, Stavroula Kanoni, Liisa Keltigangas-Järvinen, Lambertus A L M Kiemeney, Ivana Kolcic, Seppo Koskinen, Aldi T Kraja, Martin Kroh, Zoltan Kutalik, Antti Latvala, Lenore J Launer, Maël P Lebreton, Douglas F Levinson, Paul Lichtenstein, Peter Lichtner, David C M Liewald, LifeLines Cohort Study Anu Loukola, Pamela A Madden, Reedik Mägi, Tomi Mäki-Opas, Riccardo E Marioni, Pedro Marques-Vidal, Gerardus A Meddens, George McMahon, Christa Meisinger, Thomas Meitinger, Yusplitri Milaneschi, Lili Milani, Grant W Montgomery, Ronny Myhre, Christopher P Nelson, Dale R Nyholt, William E R Ollier, Aarno Palotie, Lavinia Paternoster, Nancy L Pedersen, Katja E Petrovic, David J Porteous, Katri Räikkönen, Susan M Ring, Antonietta Robino, Olga Rostapshova, Igor Rudan, Aldo Rustichini, Veikko Salomaa, Alan R Sanders, Antti-Pekka Sarin, Helena Schmidt, Rodney J Scott, Blair H Smith, Jennifer A Smith, Jan A Staessen, Elisabeth Steinhagen-Thiessen, Konstantin Strauch, Antonio Terracciano, Martin D Tobin, Sheila Ulivi, Simona Vaccargiu, Lydia Quaye, Frank J A van Rooij, Cristina Venturini, Anna A E Vinkhuyzen, Uwe Völker, Henry Völzke, Judith M Vonk, Diego Vozzi, Johannes Waage, Erin B Ware, Gonneke Willemsen, John R Attia, David A Bennett, Klaus Berger, Lars Bertram, Hans Bisgaard, Dorret I Boomsma, Ingrid B Borecki, Ute Bültmann, Christopher F Chabris, Francesco Cucca, Daniele Cusi, Ian J Deary, George V Dedoussis, Cornelia M van Duijn, Johan G Eriksson, Barbara Franke, Lude Franke, Paolo Gasparini, Pablo V Gejman, Christian Gieger, Hans-Jörgen Grabe, Jacob Gratten, Patrick J F Groenen, Vilmundur Gudnason, Pim van der Harst, Caroline Hayward, David A Hinds, Wolfgang Hoffmann, Elina Hyppönen, William G Iacono, Bo Jacobsson, Marjo-Riitta Järvelin, Karl-Heinz Jöckel, Jaakko Kaprio, Sharon L R Kardia, Terho Lehtimäki, Steven F Lehrer, Patrik K E Magnusson, Nicholas G Martin, Matt McGue, Andres Metspalu, Neil Pendleton, Brenda W J H Penninx, Markus Perola, Nicola Pirastu, Mario Pirastu, Ozren Polasek, Danielle Posthuma, Christine Power, Michael A Province, Nilesh J Samani, David Schlessinger, Reinhold Schmidt, Thorkild I A Sørensen, Tim D Spector, Kari Stefansson, Unnur Thorsteinsdottir, A Roy Thurik, Nicholas J Timpson, Henning Tiemeier, Joyce Y Tung, André G Uitterlinden, Veronique Vitart, Peter Vollenweider, David R Weir, James F Wilson, Alan F Wright, Dalton C Conley, Robert F Krueger, George Davey Smith, Albert Hofman, David I Laibson, Sarah E Medland, Michelle N Meyer, Jian Yang, Magnus Johannesson, Peter M Visscher, Tõnu Esko, Philipp D Koellinger, David Cesarini, Daniel J Benjamin

Affiliations

¹ Department of Psychology, University of Minnesota Twin Cities, Minneapolis, MN, USA.
² Department of Sociology, University of Colorado Boulder, Boulder, CO, USA.
³ Institute for Behavioral Genetics, University of Colorado Boulder, Boulder, CO, USA.
⁴ Institute of Behavioral Science, University of Colorado Boulder, Boulder, CO, USA.
⁵ Department of Complex Trait Genetics, Center for Neurogenomics and Cognitive Research, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands. a.okbay@vu.nl.
⁶ Department of Economics, School of Business and Economics, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands. a.okbay@vu.nl.
⁷ Department of Economics, Harvard University, Cambridge, MA, USA.
⁸ Department of Sociology, Harvard University, Cambridge, MA, USA.
⁹ Center for Economic and Social Research, University of Southern California, Los Angeles, CA, USA.
¹⁰ Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland, Australia.
¹¹ Estonian Genome Center, University of Tartu, Tartu, Estonia.
¹² Department of Complex Trait Genetics, Center for Neurogenomics and Cognitive Research, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands.
¹³ Department of Economics, School of Business and Economics, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands.
¹⁴ Institute for Behavior and Biology, Erasmus University Rotterdam, Rotterdam, The Netherlands.
¹⁵ Center for the Advancement of Value in Musculoskeletal Care, Hospital for Special Surgery, New York, NY, USA.
¹⁶ The Novo Nordisk Foundation Center for Basic Metabolic Research, Section of Metabolic Genetics, University of Copenhagen, Faculty of Health and Medical Sciences, Copenhagen, Denmark.
¹⁷ Statens Serum Institut, Department of Epidemiology Research, Copenhagen, Denmark.
¹⁸ Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA.
¹⁹ Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
²⁰ Institute for Social and Economic Research, University of Essex, Colchester, UK.
²¹ Centre for Global Health Research, Usher Institute of Population Health Sciences and Informatics, University of Edinburgh, Edinburgh, UK.
²² MRC Epidemiology Unit, Institute of Metabolic Science, University of Cambridge, Cambridge, UK.
²³ 23andMe, Inc., Mountain View, CA, USA.
²⁴ Institute of Social and Preventive Medicine, University Hospital of Lausanne, Lausanne, Switzerland.
²⁵ BrainWorkup, LLC, Santa Monica, CA, USA.
²⁶ Department of Psychiatry and Behavioral Sciences, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
²⁷ Department of Biomedical and Translational Informatics, Geisinger Health System, Danville, PA, USA.
²⁸ Institute of Mental Health, Singapore, Singapore.
²⁹ Genome Institute, Singapore, Singapore.
³⁰ The Eye Hospital, School of Ophthalmology and Optometry, Wenzhou Medical University, Wenzhou, China.
³¹ Department of Sociology, Stanford University, Stanford, CA, USA.
³² Department of Sociology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
³³ Carolina Population Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
³⁴ MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK.
³⁵ La Follette School of Public Affairs, University of Wisconsin-Madison, Madison, WI, USA.
³⁶ Departments of Psychiatry and Molecular Medicine, Hofstra Northwell School of Medicine, Hempstead, NY, USA.
³⁷ Center for Psychiatric Neuroscience, Feinstein Institute for Medical Research, Manhasset, NY, USA.
³⁸ Psychiatry Research, The Zucker Hillside Hospital, Glen Oaks, CA, USA.
³⁹ Institute of Molecular and Cell Biology, University of Tartu, Tartu, Estonia.
⁴⁰ Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK.
⁴¹ Division of Population Health Sciences, Ninewells Hospital and Medical School, University of Dundee, Dundee, UK.
⁴² Medical Research Institute, University of Dundee, Dundee, UK.
⁴³ Department of Economics, University of Toronto, Toronto, Ontario, Canada.
⁴⁴ Department of Sociology, Princeton University, Princeton, NJ, USA.
⁴⁵ School of Policy Studies, Queen's University, Kingston, Ontario, Canada.
⁴⁶ Department of Economics, New York University Shanghai, Pudong, Shanghai, China.
⁴⁷ National Bureau of Economic Research, Cambridge, MA, USA.
⁴⁸ Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
⁴⁹ Department of Government, Uppsala University, Uppsala, Sweden.
⁵⁰ Department of Computational Biology, University of Lausanne, Lausanne, Switzerland.
⁵¹ Department of Economics, New York University, New York, NY, USA.
⁵² Autism and Developmental Medicine Institute, Geisinger Health System, Lewisburg, PA, USA.
⁵³ Center for Translational Bioethics and Health Care Policy, Geisinger Health System, Danville, PA, USA.
⁵⁴ Queensland Brain Institute, University of Queensland, Brisbane, Queensland, Australia.
⁵⁵ Department of Economics, Stockholm School of Economics, Stockholm, Sweden.
⁵⁶ Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland, Australia. peter.visscher@uq.edu.au.
⁵⁷ Queensland Brain Institute, University of Queensland, Brisbane, Queensland, Australia. peter.visscher@uq.edu.au.
⁵⁸ Center for Economic and Social Research, University of Southern California, Los Angeles, CA, USA. daniel.benjamin@gmail.com.
⁵⁹ National Bureau of Economic Research, Cambridge, MA, USA. daniel.benjamin@gmail.com.
⁶⁰ Department of Economics, University of Southern California, Los Angeles, CA, USA. daniel.benjamin@gmail.com.
⁶¹ Center for Experimental Social Science, New York University, New York, NY, USA.

PMID: 30038396
PMCID: PMC6393768
DOI: 10.1038/s41588-018-0147-3

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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Conflict of interest statement

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

Figures

**Fig. 1.. Manhattan Plot for GWAS of *EduYears* (N = 1,131,881).**
P values and the mean χ² shown in figure are based on inflation-adjusted test statistics. The x-axis is chromosomal position, and the y-axis is the significance on a −log₁₀ scale. The dashed line marks the threshold for genome-wide significance (P = 5×10⁻⁸).

**Fig 2.. Sign Concordance in Within-Family Association Analyses.**
The set of LD-pruned SNPs is limited to SNPs with **(a)** P < 5×10⁻³, **(b)** P < 5×10⁻⁵, or **(c)** P < 5×10⁻⁸. Each panel compares the observed sign concordance between within-family and GWAS estimates to the distributions expected (i) by chance alone (pink); (ii) according to a Bayesian framework that adjusts the GWAS estimates for bias due to winner’s curse (green); and (iii) according to the same framework with an additional adjustment for bias due to assortative mating (blue). These results are based on a GWAS sample size of 1,070,751 individuals and a within-family sample of 22,135 sibling pairs (44,270 individuals).

**Fig. 3.. Tissue-specific expression of genes in DEPICT-defined loci.**
**(a)** We took microarray measurements from the Gene Expression Omnibus and determined whether the genes overlapping *EduYears*-associated loci (as defined by DEPICT) are significantly overexpressed (relative to genes in random sets of loci) in each of 180 tissues/cell types. These types are grouped in the figure by Medical Subject Headings (MeSH) first-level term. The y-axis is the one-sided P value from DEPICT on a –log₁₀ scale. The 28 dark bars correspond to tissues/cell types in which the genes are significantly overexpressed (FDR < 0.01), including all 22 classified as part of the central nervous system (see Supplementary Table 6 for identifiers of all tissues/cell types). **(b)** Whereas genes prioritized by DEPICT in a previous analysis based on a smaller sample tend to be more strongly expressed in the brain prenatally (red curve), the 1,703 newly prioritized genes show a flat trajectory of expression across development (blue curve). Both groups of DEPICT-prioritized genes show elevated levels of expression relative to protein-coding genes that are not prioritized (gray curve). Analyses were based on RNA-seq data from the BrainSpan Developmental Transcriptome. These results are based on the full GWAS sample of 1,131,881 individuals. Error bars represents 95% confidence intervals.

**Fig. 4.. Prediction Accuracy.**
**(a)** Mean prevalence of college completion by *EduYears* PGS quintile. Error bars show the 95% confidence interval for the mean. **(b)** Incremental R² of the *EduYears* PGS compared to that of other variables. (c) Incremental R² of the PGS for *EduYears* and *Cognitive Performance* constructed from the respective GWAS or MTAG summary statistics. Error bars for the R² values show bootstrapped 95% confidence intervals with 1000 iterations each. Sample sizes are N = 4,775 for Add Health and N = 8,609 for HRS.

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Lessons from 1 million genomes.
Trenkmann M. Trenkmann M. Nat Rev Genet. 2018 Oct;19(10):592-593. doi: 10.1038/s41576-018-0047-5. Nat Rev Genet. 2018. PMID: 30093724 No abstract available.

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References

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1. Conti G, Heckman J & Urzua S The Education-Health Gradient. Am. Econ. Rev 100, 234–238 (2010). - PMC - PubMed
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[1] Branigan AR et al. Variation in the Heritability of Educational Attainment: An International Meta-Analysis. Soc. Forces 92, 109–140 (2013).

[2] Branigan AR et al. Variation in the Heritability of Educational Attainment: An International Meta-Analysis. Soc. Forces 92, 109–140 (2013).

[3] Conti G, Heckman J & Urzua S The Education-Health Gradient. Am. Econ. Rev 100, 234–238 (2010). - PMC - PubMed

[4] Conti G, Heckman J & Urzua S The Education-Health Gradient. Am. Econ. Rev 100, 234–238 (2010). - PMC - PubMed

[5] Cutler DM & Lleras-Muney A Education and Health: Evaluating Theories and Evidence in Making Americans Healthier: Social and Economic Policy as Health Policy (eds. House J, Schoeni R, Kaplan G & Pollack H) (Russell Sage Foundation, 2008).

[6] Cutler DM & Lleras-Muney A Education and Health: Evaluating Theories and Evidence in Making Americans Healthier: Social and Economic Policy as Health Policy (eds. House J, Schoeni R, Kaplan G & Pollack H) (Russell Sage Foundation, 2008).

[7] Rietveld CA et al. GWAS of 126,559 individuals identifies genetic variants associated with educational attainment. Science (80−. ). 340, 1467–1471 (2013). - PMC - PubMed

[8] Rietveld CA et al. GWAS of 126,559 individuals identifies genetic variants associated with educational attainment. Science (80−. ). 340, 1467–1471 (2013). - PMC - PubMed

[9] Pickrell JK et al. Detection and interpretation of shared genetic influences on 42 human traits. Nat. Genet 48, 709–717 (2016). - PMC - PubMed

[10] Pickrell JK et al. Detection and interpretation of shared genetic influences on 42 human traits. Nat. Genet 48, 709–717 (2016). - PMC - PubMed

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

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

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