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

Autor: Demontis D; The Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Aarhus, Denmark.; Centre for Integrative Sequencing, iSEQ, Aarhus University, Aarhus, Denmark.; Department of Biomedicine - Human Genetics, Aarhus University, Aarhus, Denmark., Walters RK; Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA., Martin J; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA.; Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.; MRC Centre for Neuropsychiatric Genetics & Genomics, School of Medicine, Cardiff University, Cardiff, UK., Mattheisen M; The Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Aarhus, Denmark.; Centre for Integrative Sequencing, iSEQ, Aarhus University, Aarhus, Denmark.; Department of Biomedicine - Human Genetics, Aarhus University, Aarhus, Denmark.; Centre for Psychiatry Research, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.; Stockholm Health Care Services, Stockholm County Council, Stockholm, Sweden.; Department of Psychiatry, Psychosomatics and Psychotherapy, University of Wuerzburg, Wuerzburg, Germany., Als TD; The Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Aarhus, Denmark.; Centre for Integrative Sequencing, iSEQ, Aarhus University, Aarhus, Denmark.; Department of Biomedicine - Human Genetics, Aarhus University, Aarhus, Denmark., Agerbo E; The Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Aarhus, Denmark.; National Centre for Register-Based Research, Aarhus University, Aarhus, Denmark.; Centre for Integrated Register-based Research, Aarhus University, Aarhus, Denmark., Baldursson G; Department of Child and Adolescent Psychiatry, National University Hospital, Reykjavik, Iceland., Belliveau R; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA., Bybjerg-Grauholm J; The Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Aarhus, Denmark.; Center for Neonatal Screening, Department for Congenital Disorders, Statens Serum Institut, Copenhagen, Denmark., Bækvad-Hansen M; The Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Aarhus, Denmark.; Center for Neonatal Screening, Department for Congenital Disorders, Statens Serum Institut, Copenhagen, Denmark., Cerrato F; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA., Chambert K; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA., Churchhouse C; Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA.; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA., Dumont A; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA., Eriksson N; 23andMe, Inc, Mountain View, CA, USA., Gandal M; Program in Neurogenetics, Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.; 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.; Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.; Department of Psychiatry, Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, Los Angeles, CA, USA., Goldstein JI; Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA.; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA., Grasby KL; QIMR Berghofer Medical Research Institute, Brisbane, Australia., Grove J; The Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Aarhus, Denmark.; Centre for Integrative Sequencing, iSEQ, Aarhus University, Aarhus, Denmark.; Department of Biomedicine - Human Genetics, Aarhus University, Aarhus, Denmark.; Bioinformatics Research Centre, Aarhus University, Aarhus, Denmark., Gudmundsson OO; Department of Child and Adolescent Psychiatry, National University Hospital, Reykjavik, Iceland.; deCODE genetics/Amgen, Reykjavík, Iceland.; Faculty of Medicine, University of Iceland, Reykjavík, Iceland., Hansen CS; The Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Aarhus, Denmark.; Center for Neonatal Screening, Department for Congenital Disorders, Statens Serum Institut, Copenhagen, Denmark.; Institute of Biological Psychiatry, MHC Sct. Hans, Mental Health Services Copenhagen, Roskilde, Denmark., Hauberg ME; The Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Aarhus, Denmark.; Centre for Integrative Sequencing, iSEQ, Aarhus University, Aarhus, Denmark.; Department of Biomedicine - Human Genetics, Aarhus University, Aarhus, Denmark., Hollegaard MV; The Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Aarhus, Denmark.; Center for Neonatal Screening, Department for Congenital Disorders, Statens Serum Institut, Copenhagen, Denmark., Howrigan DP; Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA., Huang H; Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA., Maller JB; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA.; Genomics plc, Oxford, UK., Martin AR; Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA.; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA., Martin NG; QIMR Berghofer Medical Research Institute, Brisbane, Australia., Moran J; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA., Pallesen J; The Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Aarhus, Denmark.; Centre for Integrative Sequencing, iSEQ, Aarhus University, Aarhus, Denmark.; Department of Biomedicine - Human Genetics, Aarhus University, Aarhus, Denmark., Palmer DS; Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA., Pedersen CB; The Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Aarhus, Denmark.; National Centre for Register-Based Research, Aarhus University, Aarhus, Denmark.; Centre for Integrated Register-based Research, Aarhus University, Aarhus, Denmark., Pedersen MG; The Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Aarhus, Denmark.; National Centre for Register-Based Research, Aarhus University, Aarhus, Denmark.; Centre for Integrated Register-based Research, Aarhus University, Aarhus, Denmark., Poterba T; Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA.; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA., Poulsen JB; The Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Aarhus, Denmark.; Center for Neonatal Screening, Department for Congenital Disorders, Statens Serum Institut, Copenhagen, Denmark., Ripke S; Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA.; Department of Psychiatry and Psychotherapy, Charité - Universitätsmedizin, Berlin, Germany., Robinson EB; Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.; Department of Epidemiology, Harvard Chan School of Public Health, Boston, MA, USA., Satterstrom FK; Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA.; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA., Stefansson H; deCODE genetics/Amgen, Reykjavík, Iceland., Stevens C; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA., Turley P; Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA., Walters GB; deCODE genetics/Amgen, Reykjavík, Iceland.; Faculty of Medicine, University of Iceland, Reykjavík, Iceland., Won H; Program in Neurogenetics, Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.; 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., Wright MJ; Queensland Brain Institute, University of Queensland, Brisbane, Australia., Andreassen OA; NORMENT KG Jebsen Centre for Psychosis Research, Division of Mental Health and Addiction, University of Oslo and Oslo University Hospital, Oslo, Norway., Asherson P; Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK., Burton CL; Psychiatry, Neurosciences and Mental Health, The Hospital for Sick Children, University of Toronto, Toronto, Canada., Boomsma DI; Department of Biological Psychology, Neuroscience Campus Amsterdam, VU University, Amsterdam, The Netherlands.; EMGO Institute for Health and Care Research, Amsterdam, The Netherlands., Cormand B; Departament de Genètica, Microbiologia i Estadística, Facultat de Biologia, Universitat de Barcelona, Barcelona, Catalonia, Spain.; Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III, Madrid, Spain.; Institut de Biomedicina de la Universitat de Barcelona (IBUB), Barcelona, Catalonia, Spain.; Institut de Recerca Sant Joan de Déu (IRSJD), Esplugues de Llobregat, Barcelona, Catalonia, Spain., Dalsgaard S; National Centre for Register-Based Research, Aarhus University, Aarhus, Denmark., Franke B; Departments of Human Genetics (855) and Psychiatry, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Centre, Nijmegen, The Netherlands., Gelernter J; Department of Psychiatry, Genetics, and Neuroscience, Yale University School of Medicine, New Haven, CT, USA.; Veterans Affairs Connecticut Healthcare Center, West Haven, CT, USA., Geschwind D; Program in Neurogenetics, Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.; 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.; Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA., Hakonarson H; The Center for Applied Genomics, The Children´s Hospital of Philadelphia, The Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA., Haavik J; K.G. Jebsen Centre for Neuropsychiatric Disorders, Department of Biomedicine, University of Bergen, Bergen, Norway.; Haukeland University Hospital, Bergen, Norway., Kranzler HR; Department of Psychiatry, The Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.; Veterans Integrated Service Network (VISN4) Mental Illness Research, Education, and Clinical Center (MIRECC), Crescenz VA Medical Center, Philadephia, PA, USA., Kuntsi J; Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK., Langley K; MRC Centre for Neuropsychiatric Genetics & Genomics, School of Medicine, Cardiff University, Cardiff, UK.; School of Psychology, Cardiff University, Cardiff, UK., Lesch KP; Division of Molecular Psychiatry, Center of Mental Health, University of Wuerzburg, Wuerzburg, Germany.; Department of Neuroscience, School for Mental Health and Neuroscience (MHENS), Maastricht University, Maastricht, The Netherlands.; Laboratory of Psychiatric Neurobiology, Institute of Molecular Medicine, I.M. Sechenov First Moscow State Medical University, Moscow, Russia., Middeldorp C; Department of Biological Psychology, Neuroscience Campus Amsterdam, VU University, Amsterdam, The Netherlands.; Child Health Research Centre, University of Queensland, Brisbane, Australia.; Child and Youth Mental Health Service, Children's Health Queensland Hospital and Health Service, Brisbane, Australia., Reif A; Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, University Hospital Frankfurt, Frankfurt am Main, Germany., Rohde LA; Department of Psychiatry, Faculty of Medicine, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil.; ADHD Outpatient Clinic, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil., Roussos P; Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA.; Institute for Genomics and Multiscale Biology, Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.; Friedman Brain Institute, Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA.; Mental Illness Research Education and Clinical Center (MIRECC), James J. Peters VA Medical Center, Bronx, New York, USA., Schachar R; Psychiatry, Neurosciences and Mental Health, The Hospital for Sick Children, University of Toronto, Toronto, Canada., Sklar P; Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA.; Institute for Genomics and Multiscale Biology, Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.; Friedman Brain Institute, Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA., Sonuga-Barke EJS; Institute of Psychiatry, Psychology & Neuroscience, Kings College, London, UK., Sullivan PF; Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.; Departments of Genetics and Psychiatry, University of North Carolina, Chapel Hill, NC, USA., Thapar A; MRC Centre for Neuropsychiatric Genetics & Genomics, School of Medicine, Cardiff University, Cardiff, UK., Tung JY; 23andMe, Inc, Mountain View, CA, USA., Waldman ID; Department of Psychology, Emory University, Atlanta, GA, USA., Medland SE; QIMR Berghofer Medical Research Institute, Brisbane, Australia., Stefansson K; deCODE genetics/Amgen, Reykjavík, Iceland.; Faculty of Medicine, University of Iceland, Reykjavík, Iceland., Nordentoft M; The Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Aarhus, Denmark.; Mental Health Services in the Capital Region of Denmark, Mental Health Center Copenhagen, University of Copenhagen, Copenhagen, Denmark., Hougaard DM; The Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Aarhus, Denmark.; Center for Neonatal Screening, Department for Congenital Disorders, Statens Serum Institut, Copenhagen, Denmark., Werge T; The Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Aarhus, Denmark.; Institute of Biological Psychiatry, MHC Sct. Hans, Mental Health Services Copenhagen, Roskilde, Denmark.; Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark., Mors O; The Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Aarhus, Denmark.; Psychosis Research Unit, Aarhus University Hospital, Risskov, Denmark., Mortensen PB; The Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Aarhus, Denmark.; Centre for Integrative Sequencing, iSEQ, Aarhus University, Aarhus, Denmark.; National Centre for Register-Based Research, Aarhus University, Aarhus, Denmark.; Centre for Integrated Register-based Research, Aarhus University, Aarhus, Denmark., Daly MJ; Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA.; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.; Institute for Molecular Medicine Finland (FIMM), Helsinki, Finland., Faraone SV; Departments of Psychiatry and Neuroscience and Physiology, SUNY Upstate Medical University, Syracuse, NY, USA. sfaraone@childpsychresearch.org., Børglum AD; The Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Aarhus, Denmark. anders@biomed.au.dk.; Centre for Integrative Sequencing, iSEQ, Aarhus University, Aarhus, Denmark. anders@biomed.au.dk.; Department of Biomedicine - Human Genetics, Aarhus University, Aarhus, Denmark. anders@biomed.au.dk., Neale BM; Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA. bneale@broadinstitute.org.; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA. bneale@broadinstitute.org.; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA. bneale@broadinstitute.org.
Jazyk: angličtina
Zdroj: Nature genetics [Nat Genet] 2019 Jan; Vol. 51 (1), pp. 63-75. Date of Electronic Publication: 2018 Nov 26.
DOI: 10.1038/s41588-018-0269-7
Abstrakt: 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.
Databáze: MEDLINE