Meta-Analysis

. 2019 Jan;51(1):63-75.

doi: 10.1038/s41588-018-0269-7. Epub 2018 Nov 26.

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

Ditte Demontis^#^{1

2

3}, Raymond K Walters^#^{4

5}, Joanna Martin^{5

6

7}, Manuel Mattheisen^{1

2

3

8

9

10}, Thomas D Als^{1

2

3}, Esben Agerbo^{1

11

12}, Gísli Baldursson¹³, Rich Belliveau⁵, Jonas Bybjerg-Grauholm^{1

14}, Marie Bækvad-Hansen^{1

14}, Felecia Cerrato⁵, Kimberly Chambert⁵, Claire Churchhouse^{4

5

15}, Ashley Dumont⁵, Nicholas Eriksson¹⁶, Michael Gandal^{17

18

19

20}, Jacqueline I Goldstein^{4

5

15}, Katrina L Grasby²¹, Jakob Grove^{1

2

3

22}, Olafur O Gudmundsson^{13

23

24}, Christine S Hansen^{1

14

25}, Mads Engel Hauberg^{1

2

3}, Mads V Hollegaard^{1

14}, Daniel P Howrigan^{4

5}, Hailiang Huang^{4

5}, Julian B Maller^{5

26}, Alicia R Martin^{4

5

15}, Nicholas G Martin²¹, Jennifer Moran⁵, Jonatan Pallesen^{1

2

3}, Duncan S Palmer^{4

5}, Carsten Bøcker Pedersen^{1

11

12}, Marianne Giørtz Pedersen^{1

11

12}, Timothy Poterba^{4

5

15}, Jesper Buchhave Poulsen^{1

14}, Stephan Ripke^{4

5

27}, Elise B Robinson^{4

28}, F Kyle Satterstrom^{4

5

15}, Hreinn Stefansson²³, Christine Stevens⁵, Patrick Turley^{4

5}, G Bragi Walters^{23

24}, Hyejung Won^{17

18}, Margaret J Wright²⁹; ADHD Working Group of the Psychiatric Genomics Consortium (PGC); Early Lifecourse & Genetic Epidemiology (EAGLE) Consortium; 23andMe Research Team; Ole A Andreassen³⁰, Philip Asherson³¹, Christie L Burton³², Dorret I Boomsma^{33

34}, Bru Cormand^{35

36

37

38}, Søren Dalsgaard¹¹, Barbara Franke³⁹, Joel Gelernter^{40

41}, Daniel Geschwind^{17

18

19}, Hakon Hakonarson⁴², Jan Haavik^{43

44}, Henry R Kranzler^{45

46}, Jonna Kuntsi³¹, Kate Langley^{7

47}, Klaus-Peter Lesch^{48

49

50}, Christel Middeldorp^{33

51

52}, Andreas Reif⁵³, Luis Augusto Rohde^{54

55}, Panos Roussos^{56

57

58

59}, Russell Schachar³², Pamela Sklar^{56

57

58}, Edmund J S Sonuga-Barke⁶⁰, Patrick F Sullivan^{6

61}, Anita Thapar⁷, Joyce Y Tung¹⁶, Irwin D Waldman⁶², Sarah E Medland²¹, Kari Stefansson^{23

24}, Merete Nordentoft^{1

63}, David M Hougaard^{1

14}, Thomas Werge^{1

25

64}, Ole Mors^{1

65}, Preben Bo Mortensen^{1

2

11

12}, Mark J Daly^{4

5

15

66}, Stephen V Faraone⁶⁷, Anders D Børglum^{68

69

70}, Benjamin M Neale^{71

72

73}

Collaborators, Affiliations

Collaborators

Özgür Albayrak, Richard J L Anney, Maria Jesús Arranz, Tobias J Banaschewski, Claiton Bau, Joseph Biederman, Jan K Buitelaar, Miguel Casas, Alice Charach, Jennifer Crosbie, Astrid Dempfle, Alysa E Doyle, Richard P Ebstein, Josephine Elia, Christine Freitag, Manuel Föcker, Michael Gill, Eugenio Grevet, Ziarih Hawi, Johannes Hebebrand, Beate Herpertz-Dahlmann, Amaia Hervas, Anke Hinney, Sarah Hohmann, Peter Holmans, Mara Hutz, Abel Ickowitz, Stefan Johansson, Lindsey Kent, Sarah Kittel-Schneider, Nanda Lambregts-Rommelse, Gerd Lehmkuhl, Sandra K Loo, James J McGough, Jobst Meyer, Eric Mick, Frank Middletion, Ana Miranda, Nina Roth Mota, Fernando Mulas, Aisling Mulligan, Freimer Nelson, T Trang Nguyen, Robert D Oades, Michael C O'Donovan, Michael J Owen, Haukur Palmason, Josep Antoni Ramos-Quiroga, Tobias J Renner, Marta Ribasés, Marcella Rietschel, Olga Rivero, Jasmin Romanos, Marcel Romanos, Aribert Rothenberger, Herbert Royers, Christina Sánchez-Mora, André Scherag, Benno G Schimmelmann, Helmut Schäfer, Joseph Sergeant, Judith Sinzig, Susan L Smalley, Hans-Christoph Steinhausen, Margaret Thompson, Alexandre Todorov, Alejandro Arias Vasquez, Susanne Walitza, Yufeng Wang, Andreas Warnke, Nigel Williams, Stephanie H Witt, Li Yang, Tetyana Zayats, Yanli Zhang-James, George Davey Smith, Gareth E Davies, Erik A Ehli, David M Evans, Iryna O Fedko, Corina U Greven, Maria M Groen-Blokhuis, Monica Guxens, Anke R Hammerschlag, Catharina A Hartman, Joachim Heinrich, Jouke Jan Hottenga, James Hudziak, Astanand Jugessur, John P Kemp, Eva Krapohl, Mario Murcia, Ronny Myhre, Ilja M Nolte, Dale R Nyholt, Johan Ormel, Klaasjan G Ouwens, Irene Pappa, Craig E Pennell, Robert Plomin, Susan Ring, Marie Standl, Evie Stergiakouli, Beate St Pourcain, Camilla Stoltenberg, Jordi Sunyer, Elisabeth Thiering, Henning Tiemeier, Carla M T Tiesler, Nicholas J Timpson, Maciej Trzaskowski, Peter Johannes van der Most, Natalia Vilor-Tejedor, Carol A Wang, Andrew J O Whitehouse, Huiying Zhao, 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

Affiliations

¹ The Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Aarhus, Denmark.
² Centre for Integrative Sequencing, iSEQ, Aarhus University, Aarhus, Denmark.
³ Department of Biomedicine - Human Genetics, Aarhus University, Aarhus, Denmark.
⁴ Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
⁵ Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
⁶ Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
⁷ MRC Centre for Neuropsychiatric Genetics & Genomics, School of Medicine, Cardiff University, Cardiff, UK.
⁸ Centre for Psychiatry Research, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
⁹ Stockholm Health Care Services, Stockholm County Council, Stockholm, Sweden.
¹⁰ Department of Psychiatry, Psychosomatics and Psychotherapy, University of Wuerzburg, Wuerzburg, Germany.
¹¹ National Centre for Register-Based Research, Aarhus University, Aarhus, Denmark.
¹² Centre for Integrated Register-based Research, Aarhus University, Aarhus, Denmark.
¹³ Department of Child and Adolescent Psychiatry, National University Hospital, Reykjavik, Iceland.
¹⁴ Center for Neonatal Screening, Department for Congenital Disorders, Statens Serum Institut, Copenhagen, Denmark.
¹⁵ Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
¹⁶ 23andMe, Inc, Mountain View, CA, USA.
¹⁷ Program in Neurogenetics, Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
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.
¹⁹ Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
²⁰ Department of Psychiatry, Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, Los Angeles, CA, USA.
²¹ QIMR Berghofer Medical Research Institute, Brisbane, Australia.
²² Bioinformatics Research Centre, Aarhus University, Aarhus, Denmark.
²³ deCODE genetics/Amgen, Reykjavík, Iceland.
²⁴ Faculty of Medicine, University of Iceland, Reykjavík, Iceland.
²⁵ Institute of Biological Psychiatry, MHC Sct. Hans, Mental Health Services Copenhagen, Roskilde, Denmark.
²⁶ Genomics plc, Oxford, UK.
²⁷ Department of Psychiatry and Psychotherapy, Charité - Universitätsmedizin, Berlin, Germany.
²⁸ Department of Epidemiology, Harvard Chan School of Public Health, Boston, MA, USA.
²⁹ Queensland Brain Institute, University of Queensland, Brisbane, Australia.
³⁰ NORMENT KG Jebsen Centre for Psychosis Research, Division of Mental Health and Addiction, University of Oslo and Oslo University Hospital, Oslo, Norway.
³¹ Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.
³² Psychiatry, Neurosciences and Mental Health, The Hospital for Sick Children, University of Toronto, Toronto, Canada.
³³ Department of Biological Psychology, Neuroscience Campus Amsterdam, VU University, Amsterdam, The Netherlands.
³⁴ EMGO Institute for Health and Care Research, Amsterdam, The Netherlands.
³⁵ Departament de Genètica, Microbiologia i Estadística, Facultat de Biologia, Universitat de Barcelona, Barcelona, Catalonia, Spain.
³⁶ Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III, Madrid, Spain.
³⁷ Institut de Biomedicina de la Universitat de Barcelona (IBUB), Barcelona, Catalonia, Spain.
³⁸ Institut de Recerca Sant Joan de Déu (IRSJD), Esplugues de Llobregat, Barcelona, Catalonia, Spain.
³⁹ Departments of Human Genetics (855) and Psychiatry, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Centre, Nijmegen, The Netherlands.
⁴⁰ Department of Psychiatry, Genetics, and Neuroscience, Yale University School of Medicine, New Haven, CT, USA.
⁴¹ Veterans Affairs Connecticut Healthcare Center, West Haven, CT, USA.
⁴² The Center for Applied Genomics, The Children´s Hospital of Philadelphia, The Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
⁴³ K.G. Jebsen Centre for Neuropsychiatric Disorders, Department of Biomedicine, University of Bergen, Bergen, Norway.
⁴⁴ Haukeland University Hospital, Bergen, Norway.
⁴⁵ Department of Psychiatry, The Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
⁴⁶ Veterans Integrated Service Network (VISN4) Mental Illness Research, Education, and Clinical Center (MIRECC), Crescenz VA Medical Center, Philadephia, PA, USA.
⁴⁷ School of Psychology, Cardiff University, Cardiff, UK.
⁴⁸ Division of Molecular Psychiatry, Center of Mental Health, University of Wuerzburg, Wuerzburg, Germany.
⁴⁹ Department of Neuroscience, School for Mental Health and Neuroscience (MHENS), Maastricht University, Maastricht, The Netherlands.
⁵⁰ Laboratory of Psychiatric Neurobiology, Institute of Molecular Medicine, I.M. Sechenov First Moscow State Medical University, Moscow, Russia.
⁵¹ Child Health Research Centre, University of Queensland, Brisbane, Australia.
⁵² Child and Youth Mental Health Service, Children's Health Queensland Hospital and Health Service, Brisbane, Australia.
⁵³ Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, University Hospital Frankfurt, Frankfurt am Main, Germany.
⁵⁴ Department of Psychiatry, Faculty of Medicine, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil.
⁵⁵ ADHD Outpatient Clinic, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil.
⁵⁶ Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
⁵⁷ Institute for Genomics and Multiscale Biology, Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
⁵⁸ Friedman Brain Institute, Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
⁵⁹ Mental Illness Research Education and Clinical Center (MIRECC), James J. Peters VA Medical Center, Bronx, New York, USA.
⁶⁰ Institute of Psychiatry, Psychology & Neuroscience, Kings College, London, UK.
⁶¹ Departments of Genetics and Psychiatry, University of North Carolina, Chapel Hill, NC, USA.
⁶² Department of Psychology, Emory University, Atlanta, GA, USA.
⁶³ Mental Health Services in the Capital Region of Denmark, Mental Health Center Copenhagen, University of Copenhagen, Copenhagen, Denmark.
⁶⁴ Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark.
⁶⁵ Psychosis Research Unit, Aarhus University Hospital, Risskov, Denmark.
⁶⁶ Institute for Molecular Medicine Finland (FIMM), Helsinki, Finland.
⁶⁷ Departments of Psychiatry and Neuroscience and Physiology, SUNY Upstate Medical University, Syracuse, NY, USA. sfaraone@childpsychresearch.org.
⁶⁸ The Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Aarhus, Denmark. anders@biomed.au.dk.
⁶⁹ Centre for Integrative Sequencing, iSEQ, Aarhus University, Aarhus, Denmark. anders@biomed.au.dk.
⁷⁰ Department of Biomedicine - Human Genetics, Aarhus University, Aarhus, Denmark. anders@biomed.au.dk.
⁷¹ Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA. bneale@broadinstitute.org.
⁷² Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA. bneale@broadinstitute.org.
⁷³ Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA. bneale@broadinstitute.org.

^# Contributed equally.

PMID: 30478444
PMCID: PMC6481311
DOI: 10.1038/s41588-018-0269-7

Meta-Analysis

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

Ditte Demontis et al. Nat Genet. 2019 Jan.

. 2019 Jan;51(1):63-75.

doi: 10.1038/s41588-018-0269-7. Epub 2018 Nov 26.

Authors

Collaborators

Özgür Albayrak, Richard J L Anney, Maria Jesús Arranz, Tobias J Banaschewski, Claiton Bau, Joseph Biederman, Jan K Buitelaar, Miguel Casas, Alice Charach, Jennifer Crosbie, Astrid Dempfle, Alysa E Doyle, Richard P Ebstein, Josephine Elia, Christine Freitag, Manuel Föcker, Michael Gill, Eugenio Grevet, Ziarih Hawi, Johannes Hebebrand, Beate Herpertz-Dahlmann, Amaia Hervas, Anke Hinney, Sarah Hohmann, Peter Holmans, Mara Hutz, Abel Ickowitz, Stefan Johansson, Lindsey Kent, Sarah Kittel-Schneider, Nanda Lambregts-Rommelse, Gerd Lehmkuhl, Sandra K Loo, James J McGough, Jobst Meyer, Eric Mick, Frank Middletion, Ana Miranda, Nina Roth Mota, Fernando Mulas, Aisling Mulligan, Freimer Nelson, T Trang Nguyen, Robert D Oades, Michael C O'Donovan, Michael J Owen, Haukur Palmason, Josep Antoni Ramos-Quiroga, Tobias J Renner, Marta Ribasés, Marcella Rietschel, Olga Rivero, Jasmin Romanos, Marcel Romanos, Aribert Rothenberger, Herbert Royers, Christina Sánchez-Mora, André Scherag, Benno G Schimmelmann, Helmut Schäfer, Joseph Sergeant, Judith Sinzig, Susan L Smalley, Hans-Christoph Steinhausen, Margaret Thompson, Alexandre Todorov, Alejandro Arias Vasquez, Susanne Walitza, Yufeng Wang, Andreas Warnke, Nigel Williams, Stephanie H Witt, Li Yang, Tetyana Zayats, Yanli Zhang-James, George Davey Smith, Gareth E Davies, Erik A Ehli, David M Evans, Iryna O Fedko, Corina U Greven, Maria M Groen-Blokhuis, Monica Guxens, Anke R Hammerschlag, Catharina A Hartman, Joachim Heinrich, Jouke Jan Hottenga, James Hudziak, Astanand Jugessur, John P Kemp, Eva Krapohl, Mario Murcia, Ronny Myhre, Ilja M Nolte, Dale R Nyholt, Johan Ormel, Klaasjan G Ouwens, Irene Pappa, Craig E Pennell, Robert Plomin, Susan Ring, Marie Standl, Evie Stergiakouli, Beate St Pourcain, Camilla Stoltenberg, Jordi Sunyer, Elisabeth Thiering, Henning Tiemeier, Carla M T Tiesler, Nicholas J Timpson, Maciej Trzaskowski, Peter Johannes van der Most, Natalia Vilor-Tejedor, Carol A Wang, Andrew J O Whitehouse, Huiying Zhao, 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

Affiliations

¹ The Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Aarhus, Denmark.
² Centre for Integrative Sequencing, iSEQ, Aarhus University, Aarhus, Denmark.
³ Department of Biomedicine - Human Genetics, Aarhus University, Aarhus, Denmark.
⁴ Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
⁵ Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
⁶ Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
⁷ MRC Centre for Neuropsychiatric Genetics & Genomics, School of Medicine, Cardiff University, Cardiff, UK.
⁸ Centre for Psychiatry Research, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
⁹ Stockholm Health Care Services, Stockholm County Council, Stockholm, Sweden.
¹⁰ Department of Psychiatry, Psychosomatics and Psychotherapy, University of Wuerzburg, Wuerzburg, Germany.
¹¹ National Centre for Register-Based Research, Aarhus University, Aarhus, Denmark.
¹² Centre for Integrated Register-based Research, Aarhus University, Aarhus, Denmark.
¹³ Department of Child and Adolescent Psychiatry, National University Hospital, Reykjavik, Iceland.
¹⁴ Center for Neonatal Screening, Department for Congenital Disorders, Statens Serum Institut, Copenhagen, Denmark.
¹⁵ Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
¹⁶ 23andMe, Inc, Mountain View, CA, USA.
¹⁷ Program in Neurogenetics, Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
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.
¹⁹ Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
²⁰ Department of Psychiatry, Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, Los Angeles, CA, USA.
²¹ QIMR Berghofer Medical Research Institute, Brisbane, Australia.
²² Bioinformatics Research Centre, Aarhus University, Aarhus, Denmark.
²³ deCODE genetics/Amgen, Reykjavík, Iceland.
²⁴ Faculty of Medicine, University of Iceland, Reykjavík, Iceland.
²⁵ Institute of Biological Psychiatry, MHC Sct. Hans, Mental Health Services Copenhagen, Roskilde, Denmark.
²⁶ Genomics plc, Oxford, UK.
²⁷ Department of Psychiatry and Psychotherapy, Charité - Universitätsmedizin, Berlin, Germany.
²⁸ Department of Epidemiology, Harvard Chan School of Public Health, Boston, MA, USA.
²⁹ Queensland Brain Institute, University of Queensland, Brisbane, Australia.
³⁰ NORMENT KG Jebsen Centre for Psychosis Research, Division of Mental Health and Addiction, University of Oslo and Oslo University Hospital, Oslo, Norway.
³¹ Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.
³² Psychiatry, Neurosciences and Mental Health, The Hospital for Sick Children, University of Toronto, Toronto, Canada.
³³ Department of Biological Psychology, Neuroscience Campus Amsterdam, VU University, Amsterdam, The Netherlands.
³⁴ EMGO Institute for Health and Care Research, Amsterdam, The Netherlands.
³⁵ Departament de Genètica, Microbiologia i Estadística, Facultat de Biologia, Universitat de Barcelona, Barcelona, Catalonia, Spain.
³⁶ Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III, Madrid, Spain.
³⁷ Institut de Biomedicina de la Universitat de Barcelona (IBUB), Barcelona, Catalonia, Spain.
³⁸ Institut de Recerca Sant Joan de Déu (IRSJD), Esplugues de Llobregat, Barcelona, Catalonia, Spain.
³⁹ Departments of Human Genetics (855) and Psychiatry, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Centre, Nijmegen, The Netherlands.
⁴⁰ Department of Psychiatry, Genetics, and Neuroscience, Yale University School of Medicine, New Haven, CT, USA.
⁴¹ Veterans Affairs Connecticut Healthcare Center, West Haven, CT, USA.
⁴² The Center for Applied Genomics, The Children´s Hospital of Philadelphia, The Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
⁴³ K.G. Jebsen Centre for Neuropsychiatric Disorders, Department of Biomedicine, University of Bergen, Bergen, Norway.
⁴⁴ Haukeland University Hospital, Bergen, Norway.
⁴⁵ Department of Psychiatry, The Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
⁴⁶ Veterans Integrated Service Network (VISN4) Mental Illness Research, Education, and Clinical Center (MIRECC), Crescenz VA Medical Center, Philadephia, PA, USA.
⁴⁷ School of Psychology, Cardiff University, Cardiff, UK.
⁴⁸ Division of Molecular Psychiatry, Center of Mental Health, University of Wuerzburg, Wuerzburg, Germany.
⁴⁹ Department of Neuroscience, School for Mental Health and Neuroscience (MHENS), Maastricht University, Maastricht, The Netherlands.
⁵⁰ Laboratory of Psychiatric Neurobiology, Institute of Molecular Medicine, I.M. Sechenov First Moscow State Medical University, Moscow, Russia.
⁵¹ Child Health Research Centre, University of Queensland, Brisbane, Australia.
⁵² Child and Youth Mental Health Service, Children's Health Queensland Hospital and Health Service, Brisbane, Australia.
⁵³ Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, University Hospital Frankfurt, Frankfurt am Main, Germany.
⁵⁴ Department of Psychiatry, Faculty of Medicine, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil.
⁵⁵ ADHD Outpatient Clinic, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil.
⁵⁶ Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
⁵⁷ Institute for Genomics and Multiscale Biology, Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
⁵⁸ Friedman Brain Institute, Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
⁵⁹ Mental Illness Research Education and Clinical Center (MIRECC), James J. Peters VA Medical Center, Bronx, New York, USA.
⁶⁰ Institute of Psychiatry, Psychology & Neuroscience, Kings College, London, UK.
⁶¹ Departments of Genetics and Psychiatry, University of North Carolina, Chapel Hill, NC, USA.
⁶² Department of Psychology, Emory University, Atlanta, GA, USA.
⁶³ Mental Health Services in the Capital Region of Denmark, Mental Health Center Copenhagen, University of Copenhagen, Copenhagen, Denmark.
⁶⁴ Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark.
⁶⁵ Psychosis Research Unit, Aarhus University Hospital, Risskov, Denmark.
⁶⁶ Institute for Molecular Medicine Finland (FIMM), Helsinki, Finland.
⁶⁷ Departments of Psychiatry and Neuroscience and Physiology, SUNY Upstate Medical University, Syracuse, NY, USA. sfaraone@childpsychresearch.org.
⁶⁸ The Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Aarhus, Denmark. anders@biomed.au.dk.
⁶⁹ Centre for Integrative Sequencing, iSEQ, Aarhus University, Aarhus, Denmark. anders@biomed.au.dk.
⁷⁰ Department of Biomedicine - Human Genetics, Aarhus University, Aarhus, Denmark. anders@biomed.au.dk.
⁷¹ Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA. bneale@broadinstitute.org.
⁷² Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA. bneale@broadinstitute.org.
⁷³ Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA. bneale@broadinstitute.org.

^# Contributed equally.

PMID: 30478444
PMCID: PMC6481311
DOI: 10.1038/s41588-018-0269-7

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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Conflict of interest statement

Competing Interests

In the past year, Dr. Faraone 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. Dr. Faraone 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.

Dr. Neale 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.

Olafur O. Gudmundsson, G. Bragi Walters, Hreinn Stefansson and Kari Stefansson are employees of deCODE genetics/Amgen.

Nicholas Eriksson, Joyce Y Tung, and the 23andMe Research Team are employees of 23andMe, Inc., and hold stock or stock options in 23andMe.

Dr. Rohde 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 last three years. He receives authorship royalties from Oxford Press and ArtMed. He also received travel award for taking part of 2015 WFADHD meeting from Shire. The ADHD and Juvenile Bipolar Disorder Outpatient Programs chaired by him received unrestricted educational and research support from the following pharmaceutical companies in the last three years: Eli-Lilly, Janssen-Cilag, Novartis, and Shire.

Over the last three years Dr. Sonuga-Barke 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. 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.

Dr. Franke has received educational speaking fees from Merz and Shire.

Dr. Schachar’s disclosures: ehave equity and advisory board, Ironshore Pharmaceuticals Advisory Board.

Dr. Reif has received a research grant from Medice, and speaker’s honorarium from Medice and Servier.

Dr. Haavik has received speaker fees from Shire, Lilly and Novartis.

Dr. Kranzler 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.

Drs. Kranzler and Gelernter are named as inventors on PCT patent application #15/878,640 entitled: "Genotype-guided dosing of opioid agonists," filed January 24, 2018.

Dr Asherson 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.

Dr. Andreassen has received speaker fees from Lundbeck and Sunovion. Dr Kuntsi has received speaker’s honorarium from Medice; all funds are received by King’s College London and used for studies of ADHD.

Thomas Werge has acted as lecturer and scientific advisor to H. Lundbeck A/S

Figures

**Figure 1.. Manhattan plot of the results from the GWAS meta-analysis of ADHD.**
The index variants in the 12 genome-wide significant loci are highlighted as a green diamond. Index variants located with a distance less than 400kb are considered as one locus. The y-axis represents –log(two-sided P-values) for association of variants with ADHD, from meta-analysis using an inverse-variance weighted fixed effects model, and a total sample size of 20,183 ADHD cases and 35,191 controls. The vertical red line represents the threshold for genome-wide significance.

**Figure 2.. Odds Ratio by PRS for ADHD**
Odds Ratio (OR) by PRS within each decile estimated for n = 18,298 biological independent individuals in the PGC samples (red dots) and in n = 37,076 biological independent individuals in the iPSYCH sample (blue dots). PRSs in the iPSYCH sample were obtained by five leave-one-out analyses, using 4 of 5 groups as training datasets for estimation of SNP weights, while estimating Polygenic Risk Scores (PRS) for the remaining target group. Odds ratios and 95% confidence limits (error bars) were estimated using logistic regression on the continuous scores.

**Figure 3.. Genetic correlations of ADHD with other phenotypes**
Significant genetic correlations between ADHD (results from Europena GWAS meta-analysis of 19,099 cases, 34,194 controls) and other traits reveal overlap of genetic risk factors for ADHD across several groups of traits (grouping indicated by a horizontal line): educational, psychiatric/personality, weight (and possible weight related traits), smoking behaviour/smoking-related cancer, reproductive traits and parental longevity (Sample size of the external GWASs are presented in Supplementary Table 5). In total 219 traits were tested and only traits significant after Bonferroni correction are presented in the figure. Two significant educational phenotypes are omitted due to substantial overlap with years of schooling. Genetic correlation is presented as a dot and error bars indicate 95% confidence limits.

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Comment in

First genetic risk loci for ADHD identified.
Ridler C. Ridler C. Nat Rev Neurol. 2019 Jan;15(1):4. doi: 10.1038/s41582-018-0117-5. Nat Rev Neurol. 2019. PMID: 30531819 No abstract available.
Risk loci for ADHD.
Clyde D. Clyde D. Nat Rev Genet. 2019 Feb;20(2):69. doi: 10.1038/s41576-018-0084-0. Nat Rev Genet. 2019. PMID: 30532079 No abstract available.

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

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

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