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Nat Genet. 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.

Collaborators (140)

Albayrak Ö, Anney RJL, Arranz MJ, Banaschewski TJ, Bau C, Biederman J, Buitelaar JK, Casas M, Charach A, Crosbie J, Dempfle A, Doyle AE, Ebstein RP, Elia J, Freitag C, Föcker M, Gill M, Grevet E, Hawi Z, Hebebrand J, Herpertz-Dahlmann B, Hervas A, Hinney A, Hohmann S, Holmans P, Hutz M, Ickowitz A, Johansson S, Kent L, Kittel-Schneider S, Lambregts-Rommelse N, Lehmkuhl G, Loo SK, McGough JJ, Meyer J, Mick E, Middletion F, Miranda A, Mota NR, Mulas F, Mulligan A, Nelson F, Nguyen TT, Oades RD, O'Donovan MC, Owen MJ, Palmason H, Ramos-Quiroga JA, Renner TJ, Ribasés M, Rietschel M, Rivero O, Romanos J, Romanos M, Rothenberger A, Royers H, Sánchez-Mora C, Scherag A, Schimmelmann BG, Schäfer H, Sergeant J, Sinzig J, Smalley SL, Steinhausen HC, Thompson M, Todorov A, Vasquez AA, Walitza S, Wang Y, Warnke A, Williams N, Witt SH, Yang L, Zayats T, Zhang-James Y, Smith GD, Davies GE, Ehli EA, Evans DM, Fedko IO, Greven CU, Groen-Blokhuis MM, Guxens M, Hammerschlag AR, Hartman CA, Heinrich J, Jan Hottenga J, Hudziak J, Jugessur A, Kemp JP, Krapohl E, Murcia M, Myhre R, Nolte IM, Nyholt DR, Ormel J, Ouwens KG, Pappa I, Pennell CE, Plomin R, Ring S, Standl M, Stergiakouli E, Pourcain BS, Stoltenberg C, Sunyer J, Thiering E, Tiemeier H, Tiesler CMT, Timpson NJ, Trzaskowski M, van der Most PJ, Vilor-Tejedor N, Wang CA, Whitehouse AJO, Zhao H, Agee M, Alipanahi B, Auton A, Bell RK, Bryc K, Elson SL, Fontanillas P, Furlotte NA, Hinds DA, Hromatka BS, Huber KE, Kleinman A, Litterman NK, McIntyre MH, Mountain JL, Northover CAM, Pitts SJ, Sathirapongsasuti JF, Sazonova OV, Shelton JF, Shringarpure S, Tian C, Vacic V, Wilson CH.

Author information

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.

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.

Comment in

PMID:
30478444
PMCID:
PMC6481311
DOI:
10.1038/s41588-018-0269-7
[Indexed for MEDLINE]
Free PMC Article

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