Letter | Published:

Genome-wide association meta-analysis in 269,867 individuals identifies new genetic and functional links to intelligence

Nature Geneticsvolume 50pages912919 (2018) | Download Citation

Abstract

Intelligence is highly heritable1 and a major determinant of human health and well-being2. Recent genome-wide meta-analyses have identified 24 genomic loci linked to variation in intelligence3,4,5,6,7, but much about its genetic underpinnings remains to be discovered. Here, we present a large-scale genetic association study of intelligence (n = 269,867), identifying 205 associated genomic loci (190 new) and 1,016 genes (939 new) via positional mapping, expression quantitative trait locus (eQTL) mapping, chromatin interaction mapping, and gene-based association analysis. We find enrichment of genetic effects in conserved and coding regions and associations with 146 nonsynonymous exonic variants. Associated genes are strongly expressed in the brain, specifically in striatal medium spiny neurons and hippocampal pyramidal neurons. Gene set analyses implicate pathways related to nervous system development and synaptic structure. We confirm previous strong genetic correlations with multiple health-related outcomes, and Mendelian randomization analysis results suggest protective effects of intelligence for Alzheimer’s disease and ADHD and bidirectional causation with pleiotropic effects for schizophrenia. These results are a major step forward in understanding the neurobiology of cognitive function as well as genetically related neurological and psychiatric disorders.

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Acknowledgements

This work was funded by the Netherlands Organization for Scientific Research through the following grants: NWO Brain and Cognition 433­-09-228 (D.P.), NWO MagW VIDI 452­-12-­014 (S.v.d.S.), NWO VICI 453-13-005 (D.P.), and 645­-000-­003 (D.P.). P.R.J. was funded by the Sophia Foundation for Scientific Research (SSWO, grant S14-27 to P.R.J.). The analyses were carried out on the Genetic Cluster Computer, which is financed by the Netherlands Scientific Organization (NWO: 480-05-003 to D.P.), Vrije Universiteit, Amsterdam, The Netherlands, and the Dutch Brain Foundation, and is hosted by the Dutch National Computing and Networking Services, SurfSARA. J.H.-­L. was funded by the Swedish Research Council (Vetenskapsrådet, award 2014­3863), StratNeuro, the Wellcome Trust (108726/Z/15/Z), and the Swedish Brain Foundation (Hjärnfonden). N.G.S. was supported by the Wellcome Trust (108726/Z/15/Z). J.B. was funded by the Swiss National Science Foundation. This research has been conducted using the UK Biobank resource under application 16406. We thank the numerous participants, researchers, and staff from many studies who collected and contributed to the data. Additional acknowledgements can be found in the Supplementary Information.

Author information

Author notes

  1. These authors contributed equally: Jeanne E. Savage, Philip R. Jansen.

Affiliations

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

    • Jeanne E. Savage
    • , Philip R. Jansen
    • , Sven Stringer
    • , Kyoko Watanabe
    • , Christiaan A. de Leeuw
    • , Anke R. Hammerschlag
    • , Tinca J. C. Polderman
    •  & Danielle Posthuma
  2. Department of Child and Adolescent Psychiatry, Erasmus Medical Center, Rotterdam, The Netherlands

    • Philip R. Jansen
    • , Tonya White
    •  & Henning Tiemeier
  3. Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden

    • Julien Bryois
    • , Robert Karlsson
    • , Sara Hägg
    • , Ida K. Karlsson
    • , Nancy L. Pedersen
    •  & Patrick F. Sullivan
  4. Department of Clinical Genetics, Section of Complex Trait Genetics, Neuroscience Campus Amsterdam, VU Medical Center, Amsterdam, The Netherlands

    • Mats Nagel
    • , Sophie van der Sluis
    •  & Danielle Posthuma
  5. Department of Psychiatry and Psychotherapy, Charité Universitätsmedizin Berlin, Campus Mitte, Berlin, Germany

    • Swapnil Awasthi
    • , Jakob A. Kaminski
    • , Andreas Heinz
    •  & Stephan Ripke
  6. Department of Psychology, Virginia Commonwealth University, Richmond, VA, USA

    • Peter B. Barr
    •  & Danielle M. Dick
  7. Social, Genetic, and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology, and Neuroscience, King’s College London, London, UK

    • Jonathan R. I. Coleman
    • , Eva Krapohl
    • , Delilah Zabaneh
    • , Gerome Breen
    •  & Robert Plomin
  8. NIHR Biomedical Research Centre for Mental Health, South London and Maudsley NHS Trust, London, UK

    • Jonathan R. I. Coleman
    •  & Gerome Breen
  9. QIMR Berghofer Medical Research Institute, Herston, Brisbane, Queensland, Australia

    • Katrina L. Grasby
    • , Grant W. Montgomery
    • , Nicholas G. Martin
    •  & Sarah E. Medland
  10. Berlin Institute of Health (BIH), Berlin, Germany

    • Jakob A. Kaminski
  11. Institute of Mental Health, Singapore, Singapore

    • Max Lam
  12. The Danish Twin Registry and the Danish Aging Research Center, Department of Public Health, University of Southern Denmark, Odense, Denmark

    • Marianne Nygaard
    •  & Lene Christiansen
  13. Epidemiology, Biostatistics, and Biodemography, Department of Public Health, University of Southern Denmark, Odense, Denmark

    • Marianne Nygaard
    • , Lene Christiansen
    •  & Birgit Debrabant
  14. Department of Psychology, University of California Riverside, Riverside, CA, USA

    • Chandra A. Reynolds
  15. BrainWorkup, LLC, Los Angeles, CA, USA

    • Joey W. Trampush
  16. Department of Psychiatry and the Behavioral Sciences, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA

    • Joey W. Trampush
  17. Department of Psychology, University of Minnesota, St. Paul, MN, USA

    • Hannah Young
    •  & Scott I. Vrieze
  18. Queensland Brain Institute, University of Queensland, Brisbane, Queensland, Australia

    • Narelle K. Hansell
    •  & Margaret J. Wright
  19. Laboratory of Molecular Neurobiology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden

    • Sten Linnarsson
    • , Ana B. Muñoz-Manchado
    • , Nathan G. Skene
    •  & Jens Hjerling-Leffler
  20. Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland, Australia

    • Grant W. Montgomery
  21. Centre for Population Neuroscience and Precision Medicine (PONS), Institute of Psychiatry, Psychology, and Neuroscience, MRC-SGDP Centre, King’s College London, London, UK

    • Erin B. Quinlan
    •  & Gunter Schumann
  22. UCL Institute of Neurology, Queen Square, London, UK

    • Nathan G. Skene
  23. Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, VA, USA

    • Bradley T. Webb
    •  & Kenneth S. Kendler
  24. Department of Psychiatry, Virginia Commonwealth University, Richmond, VA, USA

    • Bradley T. Webb
    •  & Kenneth S. Kendler
  25. McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    • Dan E. Arking
    •  & Dimitrios Avramopoulos
  26. Department of Psychiatry, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    • Dimitrios Avramopoulos
  27. UCLA Semel Institute for Neuroscience and Human Behavior, Los Angeles, CA, USA

    • Robert M. Bilder
    • , Eliza Congdon
    • , Nelson A. Freimer
    •  & Edythe London
  28. Department of Psychiatry and Behavioral Sciences, Faculty of Medicine, University of Crete, Heraklion, Greece

    • Panos Bitsios
  29. Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    • Katherine E. Burdick
    •  & Panos Roussos
  30. Mental Illness Research, Education and Clinical Center (VISN 2), James J. Peters VA Medical Center, Bronx, NY, USA

    • Katherine E. Burdick
    •  & Panos Roussos
  31. Department of Psychiatry, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA

    • Katherine E. Burdick
  32. Department of Psychology, Yale University, New Haven, CT, USA

    • Tyrone D. Cannon
  33. Department of Neurology, Bryan Alzheimer’s Disease Research Center, and Center for Genomic and Computational Biology, Duke University Medical Center, Durham, NC, USA

    • Ornit Chiba-Falek
  34. Dr. Einar Martens Research Group for Biological Psychiatry, Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital, Bergen, Norway

    • Andrea Christoforou
    • , Stephanie Le Hellard
    •  & Vidar M. Steen
  35. Human Longevity, Inc., Durham, NC, USA

    • Elizabeth T. Cirulli
  36. Neuropsychiatric Genetics Research Group, Department of Psychiatry and Trinity College Institute of Neuroscience, Trinity College Dublin, Dublin, Ireland

    • Aiden Corvin
    •  & Michael Gill
  37. Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, UK

    • Gail Davies
    • , Ian J. Deary
    •  & John M. Starr
  38. Department of Psychology, University of Edinburgh, Edinburgh, UK

    • Gail Davies
    • , Ian J. Deary
    •  & David C. Liewald
  39. Division of Psychiatry Research, Zucker Hillside Hospital, Glen Oaks, NY, USA

    • Pamela DeRosse
    • , Todd Lencz
    • , Anil K. Malhotra
    •  & Jin Yu
  40. Department of Psychiatry, Hofstra Northwell School of Medicine, Hempstead, NY, USA

    • Pamela DeRosse
    • , Todd Lencz
    •  & Anil K. Malhotra
  41. Center for Psychiatric Neuroscience, Feinstein Institute for Medical Research, Manhasset, NY, USA

    • Pamela DeRosse
    • , Todd Lencz
    •  & Anil K. Malhotra
  42. Clinical and Translational Neuroscience Branch, Intramural Research Program, National Institute of Mental Health, US National Institutes of Health, Bethesda, MD, USA

    • Dwight Dickinson
  43. Department of Medical Genetics, Oslo University Hospital, University of Bergen, Oslo, Norway

    • Srdjan Djurovic
  44. NORMENT, K.G. Jebsen Centre for Psychosis Research, University of Bergen, Bergen, Norway

    • Srdjan Djurovic
    • , Stephanie Le Hellard
    • , Ingrid Melle
    •  & Vidar M. Steen
  45. Neuroimaging, Cognition, and Genomics (NICOG) Centre, School of Psychology and Discipline of Biochemistry, National University of Ireland, Galway, Ireland

    • Gary Donohoe
    •  & Derek Morris
  46. 23andMe, Inc., Mountain View, CA, USA

    • Emily Drabant Conley
  47. Department of General Practice and Primary Health Care, University of Helsinki and Helsinki University Hospital, Helsinki, Finland

    • Johan G. Eriksson
  48. Department of Psychology, University of Oslo, Oslo, Norway

    • Thomas Espeseth
    • , Ivar Reinvang
    •  & Kjetil Sundet
  49. Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway

    • Thomas Espeseth
    • , Ingrid Melle
    • , Kjetil Sundet
    •  & Ole A. Andreassen
  50. Department of Psychology, University of Crete, Rethymno, Greece

    • Stella Giakoumaki
  51. Department of Psychiatry, Martin Luther University of Halle-Wittenberg, Halle, Germany

    • Ina Giegling
    • , Bettina Konte
    •  & Dan Rujescu
  52. Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA

    • David C. Glahn
    •  & Emma Knowles
  53. Laboratory of NeuroGenetics, Department of Psychology and Neuroscience, Duke University, Durham, NC, USA

    • Ahmad R. Hariri
    •  & Matthew A. Scult
  54. Department of Psychiatry, National and Kapodistrian University of Athens Medical School, Eginition Hospital, Athens, Greece

    • Alex Hatzimanolis
    • , Nikolaos Smyrnis
    •  & Nikos C. Stefanis
  55. University Mental Health Research Institute, Athens, Greece

    • Alex Hatzimanolis
    • , Nikolaos Smyrnis
    •  & Nikos C. Stefanis
  56. Neurobiology Research Institute, Theodor-Theohari Cozzika Foundation, Athens, Greece

    • Alex Hatzimanolis
    •  & Nikos C. Stefanis
  57. Institute for Behavioral Genetics, University of Colorado, Boulder, CO, USA

    • Matthew C. Keller
  58. Psychiatry and Behavioral Sciences, Division of Medical Psychology and Department of Neurology, Duke University Medical Center, Durham, NC, USA

    • Deborah Koltai
  59. Department of Psychology and Logopedics, Faculty of Medicine, University of Helsinki, Helsinki, Finland

    • Jari Lahti
  60. Helsinki Collegium for Advanced Studies, University of Helsinki, Helsinki, Finland

    • Jari Lahti
  61. Department of Psychiatry and Biobehavioral Sciences and Department of Molecular and Medical Pharmacology, University of California, Los Angeles, Los Angeles, CA, USA

    • Edythe London
  62. Department of Biological and Medical Psychology, University of Bergen, Bergen, Norway

    • Astri J. Lundervold
  63. K.G. Jebsen Center for Research on Neuropsychiatric Disorders, University of Bergen, Bergen, Norway

    • Astri J. Lundervold
  64. Division of Brain Sciences, Department of Medicine, Imperial College London, London, UK

    • Anna C. Need
  65. Centre for Integrated Genomic Medical Research, Institute of Population Health, University of Manchester, Manchester, UK

    • William Ollier
  66. Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland

    • Aarno Palotie
    •  & Elisabeth Widen
  67. Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Cambridge, UK

    • Aarno Palotie
  68. Center for Human Genetic Research, Psychiatric and Neurodevelopmental Genetics Unit, Massachusetts General Hospital, Boston, MA, USA

    • Aarno Palotie
  69. Centre for Epidemiology, Division of Population Health, Health Services Research, and Primary Care, University of Manchester, Manchester, UK

    • Antony Payton
  70. Division of Neuroscience and Experimental Psychology/School of Biological Sciences, Faculty of Biology Medicine and Health, University of Manchester, Manchester Academic Health Science Centre, Salford Royal NHS Foundation Trust, Manchester, UK

    • Neil Pendleton
  71. Department of Psychology, Stanford University, Palo Alto, CA, USA

    • Russell A. Poldrack
  72. Institute of Behavioural Sciences, University of Helsinki, Helsinki, Finland

    • Katri Räikkönen
  73. Department of Genetics and Genomic Science and Institute for Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    • Panos Roussos
  74. Robert and Beverly Lewis Center for Neuroimaging, University of Oregon, Eugene, OR, USA

    • Fred W. Sabb
  75. NORMENT, K.G. Jebsen Centre for Psychosis Research, Institute of Clinical Medicine, University of Oslo and Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway

    • Olav B. Smeland
    •  & Ole A. Andreassen
  76. Alzheimer Scotland Dementia Research Centre, University of Edinburgh, Edinburgh, UK

    • John M. Starr
  77. Lieber Institute for Brain Development, Johns Hopkins University Medical Campus, Baltimore, MD, USA

    • Richard E. Straub
    •  & Daniel R. Weinberger
  78. Department of Epidemiology, Erasmus University Medical Center, Rotterdam, The Netherlands

    • Henning Tiemeier
    •  & M. Arfan Ikram
  79. Campbell Family Mental Health Institute, Centre for Addiction and Mental Health, University of Toronto, Toronto, Ontario, Canada

    • Aristotle N. Voineskos
  80. Department of Biostatistics, University of Michigan, Ann Arbor, MI, USA

    • Goncalo Abecasis
  81. Center for Statistical Genetics, University of Michigan, Ann Arbor, MI, USA

    • Goncalo Abecasis
  82. Institute of Clinical Medicine, University of Oslo, Oslo, Norway

    • Ole A. Andreassen
  83. Department of Human and Molecular Genetics, Virginia Commonwealth University, Richmond, VA, USA

    • Danielle M. Dick
    •  & Kenneth S. Kendler
  84. College Behavioral and Emotional Health Institute, Virginia Commonwealth University, Richmond, VA, USA

    • Danielle M. Dick
  85. Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA

    • Stephan Ripke
  86. Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA

    • Stephan Ripke
  87. Department of Genetics, University of North Carolina, Chapel Hill, NC, USA

    • Patrick F. Sullivan
  88. Centre for Advanced Imaging, University of Queensland, Brisbane, Queensland, Australia

    • Margaret J. Wright

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Contributions

D.P., J.E.S., and P.R.J. performed the analyses. D.P. conceived the idea of the study and supervised analyses. S. Stringer performed quality control on the UK Biobank data and wrote the analysis pipeline. K.W. constructed and applied the FUMA pipeline for performing follow-up analyses. J.B. conducted the single-cell enrichment analyses. C.A.d.L., M. Nagel, A.R. Hammerschlag, T.J.C.P., and S.v.d.S. assisted with pipeline development and data analysis. S.A., P.B.B., J.R.I.C., K.L.G., J.A.K., R.K., E. Krapohl, M.L., M. Nygaard, C.A.R., J.W.T., H.Y., D.Z., S.H., N.K.H., I.K.K., S.L., G.W.M., A.B.M.-M., E.B.Q., G.S., N.G.S., B.T.W., D.E.A., D.K., D.A., R.M.B., P.B., K.E.B., T.D.C., O.C.-F., A. Christoforou, E.T.C., E.C., A. Corvin, G. Davies, I.J.D., P.D., D.D., S.D., G. Donohoe, E.D.C., J.G.E., T.E., N.A.F., D.C.G., I.G., M.G., S.G., A.R. Hariri, A. Hatzimanolis, M.C.K., E. Knowles, B.K., J.L., S.L.-H., T.L., D.C.L., E.L., A.J.L., A.K.M., I.M., D.M., A.C.N., W.O., A. Palotie, A. Payton, N.P., R.A.P., K.R., I.R., P.R., D.R., F.W.S., M.A.S., O.B.S., N.S., J.M.S., V.M.S., N.C.S., R.E.S., K.S., A.N.V., D.R.W., E.W., J.Y., G.A., O.A.A., G.B., L.C., B.D., D.M.D., A. Heinz, J.H.-L., M.A.I., K.S.K., N.G.M., S.E.M., N.L.P., R.P., T.J.C.P., S.R., P.F.S., H.T., S.I.V., and M.J.W. contributed data. T.W. read and commented on the paper. D.P., J.E.S., and P.R.J. wrote the paper. All authors critically reviewed the paper.

Competing interests

P.F.S. reports the following potentially competing financial interests: Lundbeck (advisory committee), Pfizer (scientific advisory board member), and Roche (grant recipient, speaker reimbursement). G.B. reports consultancy and speaker fees from Eli Lilly and Illumina and grant funding from Eli Lilly. J.H.-L. reports interests from Cartana (scientific advisor) and Roche (grant recipient). T.D.C. is a consultant to Boehringer Ingelheim Pharmaceuticals and Lundbeck. All other authors declare no financial interests or potential conflicts of interest.

Corresponding author

Correspondence to Danielle Posthuma.

Supplementary information

  1. Supplementary Text and Figures

    Supplementary Note and Supplementary Figures 1–12

  2. Reporting Summary

  3. Supplementary Tables

    Supplementary Tables 1–26

About this article

Publication history

Received

Accepted

Published

DOI

https://doi.org/10.1038/s41588-018-0152-6

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