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Discovery of the first genome-wide significant risk loci for attention deficit/hyperactivity disorder

Nature Genetics (2018) | Download Citation

Abstract

Attention deficit/hyperactivity disorder (ADHD) is a highly heritable childhood behavioral disorder affecting 5% of children and 2.5% of adults. Common genetic variants contribute substantially to ADHD susceptibility, but no variants have been robustly associated with ADHD. We report a genome-wide association meta-analysis of 20,183 individuals diagnosed with ADHD and 35,191 controls that identifies variants surpassing genome-wide significance in 12 independent loci, finding important new information about the underlying biology of ADHD. Associations are enriched in evolutionarily constrained genomic regions and loss-of-function intolerant genes and around brain-expressed regulatory marks. Analyses of three replication studies: a cohort of individuals diagnosed with ADHD, a self-reported ADHD sample and a meta-analysis of quantitative measures of ADHD symptoms in the population, support these findings while highlighting study-specific differences on genetic overlap with educational attainment. Strong concordance with GWAS of quantitative population measures of ADHD symptoms supports that clinical diagnosis of ADHD is an extreme expression of continuous heritable traits.

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Data availability

The PGC’s policy is to make genome-wide summary results public. Summary statistics with the results from the ADHD GWAs meta-analysis of iPSYCH and the PGC samples are available on the PGC and iPSYCH websites (https://www.med.unc.edu/pgc/results-and-downloads and http://ipsych.au.dk/downloads/). GWA summary statistics with results from the GWAS of ADHD symptom scores analyzed in the EAGLE sample can be accessed at the PGC website (link above). Summary statistics for the 23andMe dataset can be obtained by qualified researchers under an agreement with 23andMe that protects the privacy of the 23andMe participants. For access to genotypes from the PGC cohorts and the iPSYCH sample, interested researchers should contact the lead PIs (iPSYCH, A.D.B.; P.G.C., B.M.N. and S.V.F.).

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Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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Acknowledgements

The iPSYCH team acknowledges funding from the Lundbeck Foundation (grant no. R102-A9118 and R155-2014-1724), the Stanley Medical Research Institute, the European Research Council (project 294838), the European Community (EC) Horizon 2020 Programme (grant 667302 (CoCA)), from EC Seventh Framework Programme (grant 602805 (Aggressotype)), the Novo Nordisk Foundation for supporting the Danish National Biobank resource and grants from Aarhus and Copenhagen Universities and University Hospitals, including support to the iSEQ Center, the GenomeDK HPC facility, and the CIRRAU Center.

The Broad Institute and Massachusetts General Hospital investigators would like to acknowledge support from the Stanley Medical Research Institute and NIH grants: 5U01MH094432-04(PI: Daly), 1R01MH094469 (PI: Neale), 1R01MH107649-01 (PI: Neale), 1R01MH109539-01 (PI: Daly).

We thank T. Lehner, A. Addington and G. Senthil for their support in the Psychiatric Genomics Consortium.

S.V.F. is supported by the K.G. Jebsen Centre for Research on Neuropsychiatric Disorders, University of Bergen, Norway, the EC’s Seventh Framework Programme (grant 602805), the EC’s Horizon 2020 (grant 667302) and NIMH grants 5R01MH101519 and U01 MH109536-01.

J.M. was supported by the Wellcome Trust (grant 106047).

B.F.’s research is supported by funding from a personal Vici grant of the Netherlands Organisation for Scientific Research (NWO; grant 016-130-669, to B.F.), the EC’s Seventh Framework Programme (grant 602805 (Aggressotype), 602450 (IMAGEMEND), and 278948 (TACTICS)), and from the EC’s Horizon 2020 Programme (grant643051 (MiND) and 667302 (CoCA)). Additionally, this work was supported by the European College of Neuropsychopharmacology (ECNP Network ‘ADHD across the Lifespan’).

J.H. is supported by grants from Stiftelsen K.G. Jebsen, University of Bergen and The Research Council of Norway.

B.C. received financial support for this research from the Spanish ‘Ministerio de Economía y Competitividad’ (SAF2015-68341-R) and ‘Generalitat de Catalunya/AGAUR’ (2017-SGR-738). B.B., A.R. and collaborators received funding from the EC’s Seventh Framework Programme (grant 602805, Aggressotype), the EC’s H2020 Programme (grants 667302, CoCA, and 402003, MiND), the ECNP network ‘ADHD across the lifespan’ and DFG CRC 1193, subproject Z03.

O.A.A. is supported by the Research Council of Norway (grants: 223273, 248778, 213694, 249711), and KG Jebsen Stiftelsen.

A.T. received ADHD funding from the Wellcome Trust, Medical Research Council (MRC UK), Action Medical Research.

We thank the customers of 23andMe who answered surveys, as well as the employees of 23andMe who together made this research possible. The QIMR studies were supported by funding from the Australian National Health and Medical Research Council (grant numbers: 241944, 339462, 389927, 389875, 389891, 389892, 389938, 443036, 442915, 442981, 496739, 552485, and 552498, and, most recently, 1049894) and the Australian Research Council (grant numbers: A7960034, A79906588, A79801419, DP0212016, and DP0343921). SEM is supported by an NHMRC fellowship (1103623).

Additional acknowledgements can be found in the Supplementary Note.

Author information

Author notes

  1. These authors contributed equally: Ditte Demontis, Raymond K. Walters.

  2. These authors jointly supervised this work: Stephen V. Faraone, Anders D. Børglum, Benjamin M. Neale.

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

Affiliations

  1. The Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Aarhus, Denmark

    • Ditte Demontis
    • , Manuel Mattheisen
    • , Thomas D. Als
    • , Esben Agerbo
    • , Jonas Bybjerg-Grauholm
    • , Marie Bækvad-Hansen
    • , Jakob Grove
    • , Christine S. Hansen
    • , Mads Engel Hauberg
    • , Mads V. Hollegaard
    • , Jonatan Pallesen
    • , Carsten Bøcker Pedersen
    • , Marianne Giørtz Pedersen
    • , Jesper Buchhave Poulsen
    • , Merete Nordentoft
    • , David M. Hougaard
    • , Thomas Werge
    • , Ole Mors
    • , Preben Bo Mortensen
    •  & Anders D. Børglum
  2. Centre for Integrative Sequencing, iSEQ, Aarhus University, Aarhus, Denmark

    • Ditte Demontis
    • , Manuel Mattheisen
    • , Thomas D. Als
    • , Jakob Grove
    • , Mads Engel Hauberg
    • , Jonatan Pallesen
    • , Preben Bo Mortensen
    •  & Anders D. Børglum
  3. Department of Biomedicine - Human Genetics, Aarhus University, Aarhus, Denmark

    • Ditte Demontis
    • , Manuel Mattheisen
    • , Thomas D. Als
    • , Jakob Grove
    • , Mads Engel Hauberg
    • , Jonatan Pallesen
    •  & Anders D. Børglum
  4. Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA

    • Raymond K. Walters
    • , Claire Churchhouse
    • , Jacqueline I. Goldstein
    • , Daniel P. Howrigan
    • , Hailiang Huang
    • , Alicia R. Martin
    • , Duncan S. Palmer
    • , Timothy Poterba
    • , Stephan Ripke
    • , Elise B. Robinson
    • , F. Kyle Satterstrom
    • , Patrick Turley
    • , Mark J. Daly
    •  & Benjamin M. Neale
  5. Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA

    • Raymond K. Walters
    • , Joanna Martin
    • , Rich Belliveau
    • , Felecia Cerrato
    • , Kimberly Chambert
    • , Claire Churchhouse
    • , Ashley Dumont
    • , Jacqueline I. Goldstein
    • , Daniel P. Howrigan
    • , Hailiang Huang
    • , Julian B. Maller
    • , Alicia R. Martin
    • , Jennifer Moran
    • , Duncan S. Palmer
    • , Timothy Poterba
    • , Stephan Ripke
    • , F. Kyle Satterstrom
    • , Christine Stevens
    • , Patrick Turley
    • , Mark J. Daly
    •  & Benjamin M. Neale
  6. Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden

    • Joanna Martin
    •  & Patrick F. Sullivan
  7. MRC Centre for Neuropsychiatric Genetics & Genomics, School of Medicine, Cardiff University, Cardiff, UK

    • Joanna Martin
    • , Kate Langley
    •  & Anita Thapar
  8. Centre for Psychiatry Research, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden

    • Manuel Mattheisen
  9. Stockholm Health Care Services, Stockholm County Council, Stockholm, Sweden

    • Manuel Mattheisen
  10. Department of Psychiatry, Psychosomatics and Psychotherapy, University of Wuerzburg, Wuerzburg, Germany

    • Manuel Mattheisen
  11. National Centre for Register-Based Research, Aarhus University, Aarhus, Denmark

    • Esben Agerbo
    • , Carsten Bøcker Pedersen
    • , Marianne Giørtz Pedersen
    • , Søren Dalsgaard
    •  & Preben Bo Mortensen
  12. Centre for Integrated Register-based Research, Aarhus University, Aarhus, Denmark

    • Esben Agerbo
    • , Carsten Bøcker Pedersen
    • , Marianne Giørtz Pedersen
    •  & Preben Bo Mortensen
  13. Department of Child and Adolescent Psychiatry, National University Hospital, Reykjavik, Iceland

    • Gísli Baldursson
    •  & Olafur O. Gudmundsson
  14. Center for Neonatal Screening, Department for Congenital Disorders, Statens Serum Institut, Copenhagen, Denmark

    • Jonas Bybjerg-Grauholm
    • , Marie Bækvad-Hansen
    • , Christine S. Hansen
    • , Mads V. Hollegaard
    • , Jesper Buchhave Poulsen
    •  & David M. Hougaard
  15. Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA

    • Claire Churchhouse
    • , Jacqueline I. Goldstein
    • , Alicia R. Martin
    • , Timothy Poterba
    • , F. Kyle Satterstrom
    • , Mark J. Daly
    •  & Benjamin M. Neale
  16. 23andMe, Inc, Mountain View, CA, USA

    • Nicholas Eriksson
    • , Michelle Agee
    • , Babak Alipanahi
    • , Adam Auton
    • , Robert K. Bell
    • , Katarzyna Bryc
    • , Sarah L. Elson
    • , Pierre Fontanillas
    • , Nicholas A. Furlotte
    • , David A. Hinds
    • , Bethann S. Hromatka
    • , Karen E. Huber
    • , Aaron Kleinman
    • , Nadia K. Litterman
    • , Matthew H. McIntyre
    • , Joanna L. Mountain
    • , 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
    •  & Joyce Y. Tung
  17. Program in Neurogenetics, Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA

    • Michael Gandal
    • , Hyejung Won
    •  & Daniel Geschwind
  18. Center for Autism Research and Treatment and Center for Neurobehavioral Genetics, Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, Los Angeles, CA, USA

    • Michael Gandal
    • , Hyejung Won
    •  & Daniel Geschwind
  19. Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA

    • Michael Gandal
    •  & Daniel Geschwind
  20. Department of Psychiatry, Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, Los Angeles, CA, USA

    • Michael Gandal
  21. QIMR Berghofer Medical Research Institute, Brisbane, Australia

    • Katrina L. Grasby
    • , Nicholas G. Martin
    •  & Sarah E. Medland
  22. Bioinformatics Research Centre, Aarhus University, Aarhus, Denmark

    • Jakob Grove
  23. deCODE genetics/Amgen, Reykjavík, Iceland

    • Olafur O. Gudmundsson
    • , Hreinn Stefansson
    • , G. Bragi Walters
    •  & Kari Stefansson
  24. Faculty of Medicine, University of Iceland, Reykjavík, Iceland

    • Olafur O. Gudmundsson
    • , G. Bragi Walters
    •  & Kari Stefansson
  25. Institute of Biological Psychiatry, MHC Sct. Hans, Mental Health Services Copenhagen, Roskilde, Denmark

    • Christine S. Hansen
    •  & Thomas Werge
  26. Genomics plc, Oxford, UK

    • Julian B. Maller
  27. Department of Psychiatry and Psychotherapy, Charité - Universitätsmedizin, Berlin, Germany

    • Stephan Ripke
  28. Department of Epidemiology, Harvard Chan School of Public Health, Boston, MA, USA

    • Elise B. Robinson
  29. Queensland Brain Institute, University of Queensland, Brisbane, Australia

    • Margaret J. Wright
    •  & Maciej Trzaskowski
  30. NORMENT KG Jebsen Centre for Psychosis Research, Division of Mental Health and Addiction, University of Oslo and Oslo University Hospital, Oslo, Norway

    • Ole A. Andreassen
  31. Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, UK

    • Philip Asherson
    •  & Jonna Kuntsi
  32. Psychiatry, Neurosciences and Mental Health, The Hospital for Sick Children, University of Toronto, Toronto, Canada

    • Christie L. Burton
    •  & Russell Schachar
  33. Department of Biological Psychology, Neuroscience Campus Amsterdam, VU University, Amsterdam, The Netherlands

    • Gareth E. Davies
    • , Iryna O. Fedko
    • , Klaasjan G. Ouwens
    • , Dorret I. Boomsma
    •  & Christel Middeldorp
  34. EMGO Institute for Health and Care Research, Amsterdam, The Netherlands

    • Dorret I. Boomsma
  35. Departament de Genètica, Microbiologia i Estadística, Facultat de Biologia, Universitat de Barcelona, Barcelona, Catalonia, Spain

    • Bru Cormand
  36. Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III, Madrid, Spain

    • Josep Antoni Ramos-Quiroga
    • , Marta Ribasés
    • , Christina Sánchez-Mora
    • , Monica Guxens
    • , Mario Murcia
    •  & Bru Cormand
  37. Institut de Biomedicina de la Universitat de Barcelona (IBUB), Barcelona, Catalonia, Spain

    • Bru Cormand
  38. Institut de Recerca Sant Joan de Déu (IRSJD), Esplugues de Llobregat, Barcelona, Catalonia, Spain

    • Bru Cormand
  39. Departments of Human Genetics (855) and Psychiatry, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Centre, Nijmegen, The Netherlands

    • Barbara Franke
  40. Department of Psychiatry, Genetics, and Neuroscience, Yale University School of Medicine, New Haven, CT, USA

    • Joel Gelernter
  41. Veterans Affairs Connecticut Healthcare Center, West Haven, CT, USA

    • Joel Gelernter
  42. The Center for Applied Genomics, The Children´s Hospital of Philadelphia, The Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA

    • Hakon Hakonarson
  43. K.G. Jebsen Centre for Neuropsychiatric Disorders, Department of Biomedicine, University of Bergen, Bergen, Norway

    • Tetyana Zayats
    •  & Jan Haavik
  44. Haukeland University Hospital, Bergen, Norway

    • Jan Haavik
  45. Department of Psychiatry, The Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA

    • Henry R. Kranzler
  46. Veterans Integrated Service Network (VISN4) Mental Illness Research, Education, and Clinical Center (MIRECC), Crescenz VA Medical Center, Philadephia, PA, USA

    • Henry R. Kranzler
  47. School of Psychology, Cardiff University, Cardiff, UK

    • Kate Langley
  48. Division of Molecular Psychiatry, Center of Mental Health, University of Wuerzburg, Wuerzburg, Germany

    • Olga Rivero
    •  & Klaus-Peter Lesch
  49. Department of Neuroscience, School for Mental Health and Neuroscience (MHENS), Maastricht University, Maastricht, The Netherlands

    • Klaus-Peter Lesch
  50. Laboratory of Psychiatric Neurobiology, Institute of Molecular Medicine, I.M. Sechenov First Moscow State Medical University, Moscow, Russia

    • Klaus-Peter Lesch
  51. Child Health Research Centre, University of Queensland, Brisbane, Australia

    • Christel Middeldorp
  52. Child and Youth Mental Health Service, Children’s Health Queensland Hospital and Health Service, Brisbane, Australia

    • Christel Middeldorp
  53. Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, University Hospital Frankfurt, Frankfurt am Main, Germany

    • Andreas Reif
  54. Department of Psychiatry, Faculty of Medicine, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil

    • Eugenio Grevet
    •  & Luis Augusto Rohde
  55. ADHD Outpatient Clinic, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil

    • Claiton Bau
    • , Eugenio Grevet
    • , Nina Roth Mota
    •  & Luis Augusto Rohde
  56. Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    • Panos Roussos
    •  & Pamela Sklar
  57. Institute for Genomics and Multiscale Biology, Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    • Panos Roussos
    •  & Pamela Sklar
  58. Friedman Brain Institute, Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    • Panos Roussos
    •  & Pamela Sklar
  59. Mental Illness Research Education and Clinical Center (MIRECC), James J. Peters VA Medical Center, Bronx, New York, USA

    • Panos Roussos
  60. Institute of Psychiatry, Psychology & Neuroscience, Kings College, London, UK

    • Edmund J. S. Sonuga-Barke
  61. Departments of Genetics and Psychiatry, University of North Carolina, Chapel Hill, NC, USA

    • Patrick F. Sullivan
  62. Department of Psychology, Emory University, Atlanta, GA, USA

    • Irwin D. Waldman
  63. Mental Health Services in the Capital Region of Denmark, Mental Health Center Copenhagen, University of Copenhagen, Copenhagen, Denmark

    • Merete Nordentoft
  64. Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark

    • Thomas Werge
  65. Psychosis Research Unit, Aarhus University Hospital, Risskov, Denmark

    • Ole Mors
  66. Institute for Molecular Medicine Finland (FIMM), Helsinki, Finland

    • Mark J. Daly
  67. Departments of Psychiatry and Neuroscience and Physiology, SUNY Upstate Medical University, Syracuse, NY, USA

    • Stephen V. Faraone
  68. Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, University Hospital Essen, University of Duisburg-Essen, Essen, Germany

    • Özgür Albayrak
    • , Manuel Föcker
    • , Johannes Hebebrand
    •  & Anke Hinney
  69. Department of Psychosomatic Medicine and Psychotherapy, Hannover Medical School (MHH), Hannover, Germany

    • Özgür Albayrak
  70. MRC Centre for Neuropsychiatric Genetics and Genomics, Department of Psychological Medicine and Neurology, School of Medicine, Cardiff University, Cardiff, Wales, UK

    • Richard J. L. Anney
    • , Peter Holmans
    • , Michael C. O’Donovan
    •  & Michael J. Owen
  71. University Hospital Mutua Terrassa, Barcelona, Spain

    • Maria Jesús Arranz
    •  & Amaia Hervas
  72. Department of Child and Adolescent Psychiatry, Central Institute of Mental Health and Mannheim Medical Faculty, University of Heidelberg, Heidelberg, Germany

    • Tobias J. Banaschewski
    •  & Sarah Hohmann
  73. Department of Genetics, Instituto de Biociências, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil

    • Claiton Bau
    •  & Mara Hutz
  74. Pediatric Psychopharmacology Unit, Massachusetts General Hospital, Boston, MA, USA

    • Joseph Biederman
  75. Department of Psychiatry, Harvard Medical School, Boston, MA, USA

    • Joseph Biederman
  76. Department of Cognitive Neuroscience, Donders Institute for Brain, Cognition and Behavior, Radboud University Medical Centre, Nijmegen, The Netherlands

    • Jan K. Buitelaar
  77. Karakter Child and Adolescent Psychiatry University Center, Nijmegen, The Netherlands

    • Jan K. Buitelaar
    •  & Corina U. Greven
  78. Universitat Autònoma de Barcelona, Barcelona, Spain

    • Miguel Casas
  79. Programa Corporatiu “Neurodevelopment Disorders along Life Span”, Institut Català de la Salut, Barcelona, Spain

    • Miguel Casas
  80. Department of Psychiatry, Hospital Universitari Vall d’Hebron, Barcelona, Spain

    • Miguel Casas
    • , Josep Antoni Ramos-Quiroga
    • , Marta Ribasés
    •  & Christina Sánchez-Mora
  81. Clinica Galatea y PAIMM, Mental Health Program for Impaired Physicians, Barcelona, Spain

    • Miguel Casas
  82. The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada

    • Alice Charach
    • , Jennifer Crosbie
    •  & Abel Ickowitz
  83. Institute of Medical Informatics and Statistics, Kiel University, Kiel, Germany

    • Astrid Dempfle
  84. Massachusetts General Hospital, Boston, MA, USA

    • Alysa E. Doyle
  85. Harvard Medical School, Boston, MA, USA

    • Alysa E. Doyle
  86. National University of Singapore, Singapore, Singapore

    • Richard P. Ebstein
  87. Department of Pediatrics, Nemours A.I. duPont Hospital for Children, Wilmington, DE, USA

    • Josephine Elia
  88. Department of Psychiatry, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA, USA

    • Josephine Elia
  89. Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, University Hospital Frankfurt, Goethe University, Frankfurt am Main, Germany

    • Christine Freitag
  90. Department of Psychiatry, Trinity College Dublin, Trinity Centre for Health Sciences, St. James’s Hospital, Dublin, Ireland

    • Michael Gill
  91. School of Psychological Sciences and Monash Institute for Cognitive and Clinical Neurosciences, Monash University, Melbourne, Australia

    • Ziarih Hawi
  92. Department of Child & Adolescent Psychiatry & Psychosomatic Medicine of University Clinics, RWTH Aachen, Aachen, Germany

    • Beate Herpertz-Dahlmann
  93. K.G.Jebsen Centre for Psychiatric Disorders, Department of Clinical Science, University of Bergen, Bergen, Norway

    • Stefan Johansson
  94. University of St Andrews, St Andrews, UK

    • Lindsey Kent
  95. Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, University Hospital, Frankfurt, Germany

    • Sarah Kittel-Schneider
  96. Karakter Child and Adolescent Psychiatry University Center and department of Psychiatry, Donders Institute for Brain, Cognition and Behavior, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands

    • Nanda Lambregts-Rommelse
  97. Department of Child and Adolescent Psychiatry, University of Cologne, Cologne, Germany

    • Gerd Lehmkuhl
    •  & Judith Sinzig
  98. Department of Psychiatry, University of California, Los Angeles, Los Angeles, CA, USA

    • Sandra K. Loo
  99. Semel Institute for Neuroscience & Human Behavior, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA, USA

    • James J. McGough
  100. Institute of Psychobiology, Department of Neurobehavioral Genetics, University of Trier, Trier, Germany

    • Jobst Meyer
  101. Quantitative Health Sciences University of Massachusetts Medical School, Worcester, MA, USA

    • Eric Mick
  102. Department of Psychiatry, SUNY Upstate Medical University, Syracuse, NY, USA

    • Frank Middletion
    •  & Yanli Zhang-James
  103. Department of Developmental and Educational Psychology, University of Valencia, Valencia, Spain

    • Ana Miranda
  104. Department of Human Genetics, Radboud University Medical Center, Nijmegen, Netherlands

    • Nina Roth Mota
  105. Instituto Valenciano de Neurologia Pediatrica (INVANEP), Valencia, Spain

    • Fernando Mulas
  106. Senior Lecturer in Child and Adolescent Psychiatry, University College Dublin, Dublin, Ireland

    • Aisling Mulligan
  107. Center for Neurobehavioral Genetics, Semel Institute for Neuroscience & Human Behavior, University of California at Los Angeles, Los Angeles, CA, USA

    • Freimer Nelson
  108. University of Marburg, Marburg, Germany

    • T. Trang Nguyen
    •  & Helmut Schäfer
  109. Clinic for Child and Adolescent Psychiatry and Psychotherapy, University of Duisburg-Essen, Essen, Germany

    • Robert D. Oades
  110. Landspitali National University Hospital, Reykjavik, Iceland

    • Haukur Palmason
  111. Psychiatric Genetics Unit, Group of Psychiatry, Mental Health and Addiction, Vall d’Hebron Research Institute (VHIR), Universitat Autònoma de Barcelona, Barcelona, Spain

    • Josep Antoni Ramos-Quiroga
    • , Marta Ribasés
    •  & Christina Sánchez-Mora
  112. Department of Psychiatry and Legal Medicine, Universitat Autònoma de Barcelona, Barcelona, Spain

    • Josep Antoni Ramos-Quiroga
  113. Department of Child and Adolescent Psychiatry, Universitätsklinikum Tübingen, Tübingen, Germany

    • Tobias J. Renner
  114. Division of Molecular Psychiatry, ADHD Clinical Research Unit, Department of Psychiatry, Psychosomatics and Psychotherapy, University of Wuerzburg, Wuerzburg, Germany

    • Tobias J. Renner
  115. Central Institute of Mental Health, Department of Genetic Epidemiology in Psychiatry, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany

    • Marcella Rietschel
    •  & Stephanie H. Witt
  116. Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, University of Wuerzburg, Wuerzburg, Germany

    • Jasmin Romanos
    • , Susanne Walitza
    •  & Andreas Warnke
  117. University Hospital of Würzburg, Center of Mental Health, Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, Wuerzburg, Germany

    • Marcel Romanos
  118. Child and Adolescent Psychiatry/Psychotherapy, University Medical Center, Goettingen, Germany

    • Aribert Rothenberger
  119. Ghent University, Dunantlaan, Ghent, Belgium

    • Herbert Royers
  120. Institute for Medical Informatics, Biometry and Epidemiology (IMIBE), University of Duisburg-Essen, Essen, Germany

    • André Scherag
  121. Clinical Epidemiology, Integrated Research and Treatment Center, Center for Sepsis Control and Care (CSCC), Jena University Hospital, Jena, Germany

    • André Scherag
  122. University Hospital of Child- and Adolescent Psychiatry, University of Bern, Bern, Switzerland

    • Benno G. Schimmelmann
  123. Vrije Universiteit, De Boelelaan, Amsterdam, The Netherlands

    • Joseph Sergeant
  124. Department of Child and Adolescent Psychiatry and Psychotherapy, LVR – Clinic Bonn, Bonn, Germany

    • Judith Sinzig
  125. University of California Los Angeles, Los Angeles, CA, USA

    • Susan L. Smalley
  126. University of Zurich, Zurich, Switzerland

    • Hans-Christoph Steinhausen
  127. Aalborg University, Aalborg, Denmark

    • Hans-Christoph Steinhausen
  128. University of Basel, Basel, Switzerland

    • Hans-Christoph Steinhausen
  129. University of Southampton, Southampton, UK

    • Margaret Thompson
  130. Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, USA

    • Alexandre Todorov
  131. Department of Psychiatry & Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands

    • Alejandro Arias Vasquez
  132. Department of Child and Adolescent Psychiatry, University of Zurich, Zurich, Switzerland

    • Susanne Walitza
  133. Peking University Institute of Mental Health, Beijing Shi, China

    • Yufeng Wang
    •  & Li Yang
  134. Cardiff University, Medical Research Council Center for Neuropsychiatric Genetics & Genomics, Institute of Psychology, Medicine & Clinical Neuroscience, Cardiff, UK

    • Nigel Williams
  135. Analytic Translational Genetics Unit, Massachusetts General Hospital Harvard Medical School, Boston, MA, USA

    • Tetyana Zayats
  136. Medical Research Council Integrative Epidemiology Unit, University of Bristol, Bristol, UK

    • George Davey Smith
    • , David M. Evans
    • , John P. Kemp
    • , Susan Ring
    • , Evie Stergiakouli
    • , Beate St Pourcain
    •  & Nicholas J. Timpson
  137. Avera Institute for Human Genetics, Sioux Falls, SD, USA

    • Gareth E. Davies
    •  & Erik A. Ehli
  138. University of Queensland Diamantina Institute, Translational Research Institute, Brisbane, Queensland, Australia

    • David M. Evans
    • , John P. Kemp
    •  & Evie Stergiakouli
  139. Radboud University Medical Center, Donders Institute for Brain, Cognition and Behaviour, Department of Cognitive Neuroscience, Nijmegen, The Netherlands

    • Corina U. Greven
  140. Medical Research Council Social, Genetic & Developmental Psychiatry Centre, Institute of Psychiatry, Psychology & Neuroscience, King’s College London, London, UK

    • Corina U. Greven
    • , Eva Krapohl
    •  & Robert Plomin
  141. GGZ inGeest, Amsterdam, The Netherlands

    • Maria M. Groen-Blokhuis
  142. ISGlobal - Centre for Research in Environmental Epidemiology (CREAL), Barcelona, Spain

    • Monica Guxens
    •  & Natalia Vilor-Tejedor
  143. Universitat Pompeu Fabra (UPF), Barcelona, Spain

    • Monica Guxens
    • , Jordi Sunyer
    •  & Natalia Vilor-Tejedor
  144. Department of Child and Adolescent Psychiatry/Psychology, Erasmus University Medical Centre–Sophia Children’s Hospital, Rotterdam, The Netherlands

    • Monica Guxens
    •  & Irene Pappa
  145. Department of Complex Trait Genetics, Center for Neurogenomics and Cognitive Research, Amsterdam Neuroscience, VU University Amsterdam, Amsterdam, The Netherlands

    • Anke R. Hammerschlag
  146. Department of Psychiatry, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands

    • Catharina A. Hartman
    •  & Johan Ormel
  147. Institute of Epidemiology I, Helmholtz Zentrum München – German Research Centre for Environmental Health, Neuherberg, Germany

    • Joachim Heinrich
    • , Marie Standl
    • , Elisabeth Thiering
    •  & Carla M.T. Tiesler
  148. Institute and Outpatient Clinic for Occupational, Social and Environmental Medicine, Inner City Clinic, University Hospital of Munich (LMU), Munich, Germany

    • Joachim Heinrich
  149. Biological Psychology, Faculty of Behavioural and Movement Sciences, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands

    • Jouke Jan Hottenga
  150. Vermont Center for Children Youth and Families and University of Vermont Medical Center, University of Vermont, Burlington, VT, USA

    • James Hudziak
  151. Child Psychiatry, School of Medicine, Washington University, St. Louis, MO, USA

    • James Hudziak
  152. Erasmus University Medical Centre–Sophia Children’s Hospital, Rotterdam, The Netherlands

    • James Hudziak
    •  & Henning Tiemeier
  153. Geisel School of Medicine, Dartmouth, Hanover, NH, USA

    • James Hudziak
  154. Department of Genetic Research and Bioinformatics, Norwegian Institute of Public Health, Oslo, Norway

    • Astanand Jugessur
  155. Department of Global Public Health and Primary Care, University of Bergen, Bergen, Norway

    • Astanand Jugessur
  156. Epidemiology and Environmental Health Joint Research Unit, FISABIO-Universitat Jaume I-Universitat de València, Valencia, Spain

    • Mario Murcia
  157. Department of Genes and Environment, Norwegian Institute of Public Health, Oslo, Norway

    • Ronny Myhre
  158. Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands

    • Ilja M. Nolte
    •  & Peter Johannes van der Most
  159. Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, Queensland, Australia

    • Dale R. Nyholt
    •  & Huiying Zhao
  160. Generation R Study Group, Erasmus Medical Center, Rotterdam, The Netherlands

    • Irene Pappa
  161. School of Women’s and Infants’ Health, The University of Western Australia, Crawley, Western Australia, Australia

    • Craig E. Pennell
    •  & Carol A. Wang
  162. School of Social and Community Medicine, University of Bristol, Bristol, UK

    • Susan Ring
  163. Max Planck Institute for Psycholinguistics, Nijmegen, The Netherlands

    • Beate St Pourcain
  164. Norwegian Institute of Public Health, Oslo, Norway

    • Camilla Stoltenberg
  165. CIBER Epidemiología y Salud Pública (CIBERESP), Barcelona, Spain

    • Jordi Sunyer
    •  & Natalia Vilor-Tejedor
  166. ISGlobal Barcelona Institute for Global Health, Barcelona, Spain

    • Jordi Sunyer
  167. Division of Metabolic Diseases and Nutritional Medicine, Dr. von Hauner Children’s Hospital, Ludwig-Maximilians-University of Munich, Munich, Germany

    • Elisabeth Thiering
    •  & Carla M.T. Tiesler
  168. Telethon Kids Institute, University of Western Australia, West Perth, Western Australia, Australia

    • Andrew J.O. Whitehouse

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Consortia

  1. ADHD Working Group of the Psychiatric Genomics Consortium (PGC)

  1. Early Lifecourse & Genetic Epidemiology (EAGLE) Consortium

  1. 23andMe Research Team

Contributions

Analysis: D.D., R.K.W., J. Martin, M.M., T.D.A., C.C., N.E., M.G., K.L.G., M.E.H., D.P.H., H. Huang, J.B.M., A.R.M., J.P., D.S.P., T.P., S.R., E.B.R., F.K.S., H.S., P.T., G.B.W., H.W., D.I.B., D.G., C.M., P.R., P.F.S., J.Y.T., S.E.M., K.S., A.D.B. and B.M.N. supervised and coordinated analyses. Sample and/or data provider and processing: D.D., R.K.W., J. Martin, M.M., E.A., G.B., R.B., J.B.-G., M.B.-H., F.C., K.C., A.D., N.E., J.I.G., J. Grove, O.O.G., C.S.H., M.V.H., J.B.M., N.G.M., J. Moran, C.B.P., M.G.P., J.B.P., S.R., C.S., M.J.W., O.A.A., P.A., C.L.B., D.I.B., B.C., S.D., B.F., J. Gelernter, H. Hakonarson, J.H., H.R.K., J.K., K.L., K.-P.L., C.M., A.R., L.A.R., R.S., P.S., E.J.S.S.-B., A.T., J.Y.T., I.D.W., S.E.M., D.M.H., O.M., P.B.M., A.D.B., ADHD Working Group of the Psychiatric Genomics Consortium, Early Lifecourse & Genetic Epidemiology (EAGLE) Consortium, 23andMe Research Team. Core PI group: S.E.M., K.S., M.N., D.M.H., T.W., O.M., P.B.M., M.J.D., S.V.F., A.D.B., B.M.N. Core writing group: D.D., R.K.W., J. Martin, S.V.F., A.D.B., B.M.N. Direction of study: A.D.B., S.V.F., B.M.N. All authors contributed with critical revision of the manuscript.

Competing interests

In the past year, S.V.F. received income, potential income, travel expenses, continuing education support and/or research support from Lundbeck, Rhodes, Arbor, KenPharm, Ironshore, Shire, Akili Interactive Labs, CogCubed, Alcobra, VAYA, Sunovion, Genomind and Neurolifesciences. With his institution, he has US patent US20130217707 A1 for the use of sodium–hydrogen exchange inhibitors in the treatment of ADHD. In previous years, he received support from: Shire, Neurovance, Alcobra, Otsuka, McNeil, Janssen, Novartis, Pfizer and Eli Lilly. S.V.F. receives royalties from books published by Guilford Press: Straight Talk about Your Child’s Mental Health; Oxford University Press: Schizophrenia: The Facts; and Elsevier: ADHD: Non-Pharmacologic Interventions. He is principal investigator of www.adhdinadults.com.

B.M.N. is a member of Deep Genomics Scientific Advisory Board and has received travel expenses from Illumina. He also serves as a consultant for Avanir and Trigeminal solutions.

O.O.G., G.B.W., H.S. and K.S. are employees of deCODE genetics/Amgen.

N.E., J.Y.T., and the 23andMe Research Team are employees of 23andMe, Inc. and hold stock or stock options in 23andMe.

L.A.R. has received honoraria, has been on the speakers’ bureau/advisory board and/or has acted as a consultant for Eli-Lilly, Janssen-Cilag, Novartis, Medice and Shire in the past three years. He receives authorship royalties from Oxford Press and ArtMed. He also received a travel award from Shire for taking part in the 2015 WFADHD meeting. The ADHD and Juvenile Bipolar Disorder Outpatient Programs unrestricted educational and research support from the following pharmaceutical companies in the past three years: Eli-Lilly, Janssen-Cilag, Novartis and Shire. Over the past three years E.J.S.-B. has received speaker fees, consultancy, research funding and conference support from Shire Pharma and speaker fees from Janssen-Cilag. He has received consultancy fees from Neurotech solutions, Aarhus University, Copenhagen University and Berhanderling, Skolerne, Copenhagen, KU Leuven and book royalties from OUP and Jessica Kingsley. He is the editor-in-chief of the Journal of Child Psychology and Psychiatry, for which his university receives financial support. B.F. has received educational speaking fees from Merz and Shire.

R.S. has equity in and is on the advisory board of Ironshore Pharmaceuticals. A.R. has received a research grant from Medice and speaker’s honorarium from Medice and Servier. J.H. has received speaker fees from Shire, Lilly and Novartis. H.R.K. has been an advisory board member, consultant, or CME speaker for Alkermes, Indivior, and Lundbeck. He is also a member of the American Society of Clinical Psychopharmacology’s Alcohol Clinical Trials Initiative, which was supported in the last three years by AbbVie, Alkermes, Ethypharm, Indivior, Lilly, Lundbeck, Otsuka, Pfizer, Arbor, and Amygdala Neurosciences. H.R.K. and J.G. are named as inventors on PCT patent application #15/878,640 entitled: “Genotype-guided dosing of opioid agonists,” filed January 24, 2018. P.A. received honoraria paid to King’s College London by Shire, Flynn Pharma, Lilly, Janssen, Novartis and Lunbeck for research, speaker fees, education events, advisory board membership or consultancy. O.A.A. has received speaker fees from Lundbeck and Sunovion. J.K. has received speaker’s honorarium from Medice; all funds are received by King’s College London and used for studies of ADHD. T.W. has acted as lecturer and scientific advisor to H. Lundbeck A/S.

Corresponding authors

Correspondence to Stephen V. Faraone or Anders D. Børglum or Benjamin M. Neale.

Supplementary information

  1. Supplementary Text and Figures

    Supplementary Figures 1–26, Supplementary Tables 1–14 and Supplementary Note

  2. Reporting Summary

  3. Supplementary Data 1

    Extended results from genetic correlation analyses of ADHD and 219 phenotypes

  4. Supplementary Data 2

    Bayesian credible sets of variants for each of the 12 genome-wide significant loci

  5. Supplementary Data 3

    Summary of the observed annotations for the credible set at each genome-wide significant locus

  6. Supplementary Data 4

    Variant-level annotations for the credible set at each genome-wide significant locus

  7. Supplementary Data 5

    Results of gene set analyses using sets from Gene Ontology

  8. Supplementary Data 6

    Genome-wide significant index variants in meta-analyses of iPSYCH, PGC, deCODE, 23andMe and EAGLE/QIMR

About this article

Publication history

Received

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Published

DOI

https://doi.org/10.1038/s41588-018-0269-7