Abstract

Attention-Deficit/Hyperactivity Disorder (ADHD) is a childhood psychiatric disorder often comorbid with disruptive behavior disorders (DBDs). Here, we report a GWAS meta-analysis of ADHD comorbid with DBDs (ADHD + DBDs) including 3802 cases and 31,305 controls. We identify three genome-wide significant loci on chromosomes 1, 7, and 11. A meta-analysis including a Chinese cohort supports that the locus on chromosome 11 is a strong risk locus for ADHD + DBDs across European and Chinese ancestries (rs7118422, P = 3.15×10−10, OR = 1.17). We find a higher SNP heritability for ADHD + DBDs (h2SNP = 0.34) when compared to ADHD without DBDs (h2SNP = 0.20), high genetic correlations between ADHD + DBDs and aggressive (rg = 0.81) and anti-social behaviors (rg = 0.82), and an increased burden (polygenic score) of variants associated with ADHD and aggression in ADHD + DBDs compared to ADHD without DBDs. Our results suggest an increased load of common risk variants in ADHD + DBDs compared to ADHD without DBDs, which in part can be explained by variants associated with aggressive behavior.

ADHD is often found to be comorbid with disruptive behavior disorders, but the genetic loci underlying this comorbidity are unknown. Here, the authors have performed a GWAS meta-analysis of ADHD with disruptive behavior disorders, finding three genome-wide significant loci in Europeans, and replicating one in a Chinese cohort.

Details

Title
Risk variants and polygenic architecture of disruptive behavior disorders in the context of attention-deficit/hyperactivity disorder
Author
Demontis Ditte 1   VIAFID ORCID Logo  ; Walters, Raymond K 2   VIAFID ORCID Logo  ; Rajagopal, Veera M 1   VIAFID ORCID Logo  ; Waldman, Irwin D 3   VIAFID ORCID Logo  ; Grove Jakob 4   VIAFID ORCID Logo  ; Als, Thomas D 1   VIAFID ORCID Logo  ; Dalsgaard Søren 5   VIAFID ORCID Logo  ; Ribasés Marta 6   VIAFID ORCID Logo  ; Jonas, Bybjerg-Grauholm 7   VIAFID ORCID Logo  ; Bækvad-Hansen, Maria 7 ; Werge, Thomas 8   VIAFID ORCID Logo  ; Nordentoft Merete 9 ; Mors Ole 10 ; Mortensen, Preben Bo 11 ; Andreassen, Ole A 12 ; Arranz, Maria Jesús 13 ; Banaschewski Tobias 14 ; Bau Claiton 15 ; Bellgrove, Mark 16 ; Biederman, Joseph 17 ; Brikell Isabell 18 ; Buitelaar, Jan K 19 ; Burton, Christie L 20 ; Casas, Miguel 21 ; Crosbie, Jennifer 20 ; Doyle, Alysa E 22 ; Ebstein, Richard P 23 ; Elia, Josephine 24 ; Corfield, Elizabeth, C 25 ; Grevet Eugenio 26 ; Grizenko Natalie 27 ; Havdahl Alexandra 25 ; Hawi Ziarih 16 ; Hebebrand Johannes 28 ; Hervas Amaia 29 ; Hohmann, Sarah 14 ; Haavik, Jan 30 ; Joober Ridha 27 ; Lindsey, Kent 31 ; Kuntsi Jonna 32 ; Langley, Kate 33 ; Larsson Henrik 34 ; Lesch Klaus-Peter 35 ; Leung Patrick W L 36 ; Liao Calwing 37 ; Loo, Sandra K 38 ; Martin, Joanna 39 ; Martin, Nicholas G 40 ; Medland, Sarah E 40 ; Miranda, Ana 41 ; Mota, Nina Roth 42 ; Oades, Robert D 43 ; Ramos-Quiroga, Josep Antoni 21 ; Reif, Andreas 44 ; Rietschel Marcella 45 ; Roeyers Herbert 46 ; Rohde, Luis Augusto 47 ; Rothenberger Aribert 48 ; Rovira, Paula 49 ; Sánchez-Mora, Cristina 49 ; Schachar Russell James 20 ; Sengupta Sarojini 27 ; Artigas, Maria Soler 49 ; Hans-Christoph, Steinhausen 50 ; Thapar, Anita 39 ; Witt, Stephanie H 45 ; Yang, Li 51 ; Zayats Tetyana 52 ; Zhang-James, Yanli 53 ; Cormand Bru 54 ; Hougaard, David M 7   VIAFID ORCID Logo  ; Neale, Benjamin M 55   VIAFID ORCID Logo  ; Franke, Barbara 56   VIAFID ORCID Logo  ; Faraone, Stephen V 57 ; Børglum, Anders D 1   VIAFID ORCID Logo 

1  The Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Aarhus, Denmark (GRID:grid.452548.a) (ISNI:0000 0000 9817 5300); Center for Genomics and Personalized Medicine, Aarhus, Denmark (GRID:grid.452548.a); Aarhus University, Department of Biomedicine - Human Genetics, Aarhus, Denmark (GRID:grid.7048.b) (ISNI:0000 0001 1956 2722) 
2  Massachusetts General Hospital and Harvard Medical School, Analytic and Translational Genetics Unit, Department of Medicine, Boston, USA (GRID:grid.32224.35) (ISNI:0000 0004 0386 9924); Broad Institute of MIT and Harvard, Stanley Center for Psychiatric Research, Cambridge, USA (GRID:grid.66859.34) 
3  Emory University, Department of Psychology, Atlanta, USA (GRID:grid.189967.8) (ISNI:0000 0001 0941 6502) 
4  The Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Aarhus, Denmark (GRID:grid.452548.a) (ISNI:0000 0000 9817 5300); Center for Genomics and Personalized Medicine, Aarhus, Denmark (GRID:grid.452548.a); Aarhus University, Department of Biomedicine - Human Genetics, Aarhus, Denmark (GRID:grid.7048.b) (ISNI:0000 0001 1956 2722); Aarhus University, Bioinformatics Research Centre, Aarhus, Denmark (GRID:grid.7048.b) (ISNI:0000 0001 1956 2722) 
5  Aarhus University, National Centre for Register-Based Research, Aarhus, Denmark (GRID:grid.7048.b) (ISNI:0000 0001 1956 2722) 
6  Universitat Autònoma de Barcelona, Psychiatric Genetics Unit, Group of Psychiatry, Mental Health and Addiction, Vall d’Hebron Research Institute (VHIR), Barcelona, Spain (GRID:grid.7080.f); Hospital Universitari Vall d’Hebron, Department of Psychiatry, Barcelona, Spain (GRID:grid.411083.f) (ISNI:0000 0001 0675 8654); Instituto de Salud Carlos III, Biomedical Network Research Center on Mental Health (CIBERSAM), Madrid, Spain (GRID:grid.413448.e) (ISNI:0000 0000 9314 1427); Universitat de Barcelona, Departament de Genètica, Microbiologia i Estadística, Facultat de Biologia, Barcelona, Spain (GRID:grid.5841.8) (ISNI:0000 0004 1937 0247) 
7  The Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Aarhus, Denmark (GRID:grid.452548.a) (ISNI:0000 0000 9817 5300); Statens Serum Institut, Center for Neonatal Screening, Department for Congenital Disorders, Copenhagen, Denmark (GRID:grid.6203.7) (ISNI:0000 0004 0417 4147) 
8  The Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Aarhus, Denmark (GRID:grid.452548.a) (ISNI:0000 0000 9817 5300); University of Copenhagen, GLOBE Institute, Center for GeoGenetics, Copenhagen, Denmark (GRID:grid.5254.6) (ISNI:0000 0001 0674 042X); Mental Health Services Copenhagen, Institute of Biological Psychiatry, MHC Sct. Hans, Roskilde, Denmark (GRID:grid.466916.a) (ISNI:0000 0004 0631 4836); University of Copenhagen, Department of Clinical Medicine, Copenhagen, Denmark (GRID:grid.5254.6) (ISNI:0000 0001 0674 042X) 
9  The Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Aarhus, Denmark (GRID:grid.452548.a) (ISNI:0000 0000 9817 5300); Mental Health Centre Copenhagen Mental Health Services in the Capital Region of Denmark, Copenhagen University Hospital, Hellerup, Denmark (GRID:grid.452548.a); University of Copenhagen, Department of Clinical Medicine, Faculty of Health and Medical Sciences, Copenhagen, Denmark (GRID:grid.5254.6) (ISNI:0000 0001 0674 042X) 
10  The Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Aarhus, Denmark (GRID:grid.452548.a) (ISNI:0000 0000 9817 5300); Aarhus University Hospital, Psychosis Research Unit, Aarhus, Denmark (GRID:grid.154185.c) (ISNI:0000 0004 0512 597X) 
11  The Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Aarhus, Denmark (GRID:grid.452548.a) (ISNI:0000 0000 9817 5300); Center for Genomics and Personalized Medicine, Aarhus, Denmark (GRID:grid.452548.a); Aarhus University, National Centre for Register-Based Research, Aarhus, Denmark (GRID:grid.7048.b) (ISNI:0000 0001 1956 2722); Aarhus University, Centre for Integrated Register-Based Research, Aarhus, Denmark (GRID:grid.7048.b) (ISNI:0000 0001 1956 2722) 
12  Oslo University Hospital and University of Oslo, NORMENT Centre, Division of Mental Health and Addiction, Oslo, Norway (GRID:grid.55325.34) (ISNI:0000 0004 0389 8485); Oslo University Hospital and University of Oslo, KG Jebsen Centre for Neurodevelopment, Division of Mental Health and Addiction, Oslo, Norway (GRID:grid.55325.34) (ISNI:0000 0004 0389 8485) 
13  University Hospital Mutua Terrassa, Fundacio Docencia i Recerca Mutua Terrassa, Barcelona, Spain (GRID:grid.414875.b) (ISNI:0000 0004 1794 4956) 
14  Medical Faculty Mannheim and University of Heidelberg, Department of Child and Adolescent Psychiatry, Central Institute of Mental Health, Mannheim, Germany (GRID:grid.7700.0) (ISNI:0000 0001 2190 4373) 
15  Universidade Federal do Rio Grande do Sul, Department of Genetics, Instituto de Biociências, Porto Alegre, Brazil (GRID:grid.8532.c) (ISNI:0000 0001 2200 7498); Hospital de Clínicas de Porto Alegre, Adulthood ADHD Outpatient Program (ProDAH), Clinical Research Center, Porto Alegre, Brazil (GRID:grid.414449.8) (ISNI:0000 0001 0125 3761); Hospital de Clínicas de Porto Alegre, Developmental Psychiatry Program, Experimental Research Center, Porto Alegre, Brazil (GRID:grid.414449.8) (ISNI:0000 0001 0125 3761) 
16  Monash University, School of Psychological Sciences and Turner Institute for Brain and Mental Health, Melbourne, Australia (GRID:grid.1002.3) (ISNI:0000 0004 1936 7857) 
17  Massachusetts General Hospital, Department of Psychiatry, Boston, USA (GRID:grid.32224.35) (ISNI:0000 0004 0386 9924); Harvard Medical School, Department of Psychiatry, Boston, USA (GRID:grid.38142.3c) (ISNI:000000041936754X) 
18  Karolinska Instituttet, Department of Medical Epidemiology and Biostatistics, Stockholm, Sweden (GRID:grid.38142.3c) 
19  Radboud University Medical Center, Department of Cognitive Neuroscience, Donders Institute for Brain, Cognition and Behavior, Nijmegen, The Netherlands (GRID:grid.10417.33) (ISNI:0000 0004 0444 9382); Karakter Child and Adolescent Psychiatry University Center, Nijmegen, The Netherlands (GRID:grid.10417.33) 
20  University of Toronto, Psychiatry, Neurosciences and Mental Health, The Hospital for Sick Children, Toronto, Canada (GRID:grid.17063.33) (ISNI:0000 0001 2157 2938) 
21  Universitat Autònoma de Barcelona, Department of Psychiatry and Forensic Medicine, Barcelona, Spain (GRID:grid.7080.f); University Hospital Vall d’Hebron, Department of Psychiatry, Barcelona, Spain (GRID:grid.411083.f) (ISNI:0000 0001 0675 8654) 
22  Massachusetts General Hospital and Harvard Medical School, Center for Genomic Medicine and Department of Psychiatry, Boston, USA (GRID:grid.32224.35) (ISNI:0000 0004 0386 9924) 
23  Southwestern University of Finance and Economics, (SWUFE), China Center for Behavior Economics and Finance, Chengdu, China (GRID:grid.443347.3) (ISNI:0000 0004 1761 2353) 
24  Nemours A.I. duPont Hospital for Children, Department of Pediatrics, Wilmington, USA (GRID:grid.239281.3) (ISNI:0000 0004 0458 9676); Thomas Jefferson University, Department of Psychiatry, Sidney Kimmel Medical College, Philadelphia, USA (GRID:grid.265008.9) (ISNI:0000 0001 2166 5843) 
25  Norwegian Institute of Public Health, Department of Mental Disorders, Oslo, Norway (GRID:grid.418193.6) (ISNI:0000 0001 1541 4204) 
26  Hospital de Clínicas de Porto Alegre, Adulthood ADHD Outpatient Program (ProDAH), Clinical Research Center, Porto Alegre, Brazil (GRID:grid.414449.8) (ISNI:0000 0001 0125 3761); Hospital de Clínicas de Porto Alegre, Developmental Psychiatry Program, Experimental Research Center, Porto Alegre, Brazil (GRID:grid.414449.8) (ISNI:0000 0001 0125 3761); Universidade Federal do Rio Grande do Sul, Department of Psychiatry, Faculty of Medicine, Porto Alegre, Brazil (GRID:grid.8532.c) (ISNI:0000 0001 2200 7498) 
27  McGill University, Department of Psychiatry and Douglas Hospital Research Centre, Douglas Mental Health Univerity Institute, Montreal, Canada (GRID:grid.14709.3b) (ISNI:0000 0004 1936 8649) 
28  University of Duisburg-Essen, Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, University Hospital Essen, Essen, Germany (GRID:grid.5718.b) (ISNI:0000 0001 2187 5445) 
29  University Hospital Mutua Terrassa &Institute of global comprehensive attention to neurodevelopment (IGAIN), Child and Adolescent Service, Barcelona, Spain (GRID:grid.5718.b) 
30  University of Bergen, Centre for Neuropsychiatric Disorders, Department of Biomedicine, Bergen, Norway (GRID:grid.7914.b) (ISNI:0000 0004 1936 7443); Haukeland University Hospital, Bergen Centre of Brain Plasticity, Division of Psychiatry, Bergen, Norway (GRID:grid.412008.f) (ISNI:0000 0000 9753 1393) 
31  University of St Andrews, St. Andrews, UK (GRID:grid.11914.3c) (ISNI:0000 0001 0721 1626) 
32  King’s College London, Social, Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology and Neuroscience, London, UK (GRID:grid.13097.3c) (ISNI:0000 0001 2322 6764) 
33  Cardiff University, MRC Centre for Neuropsychiatric Genetics & Genomics, School of Medicine, Cardiff, UK (GRID:grid.5600.3) (ISNI:0000 0001 0807 5670); Cardiff University, School of Psychology, Cardiff, UK (GRID:grid.5600.3) (ISNI:0000 0001 0807 5670) 
34  Karolinska Instituttet, Department of Medical Epidemiology and Biostatistics, Stockholm, Sweden (GRID:grid.5600.3); Örebro University, School of Medical Sciences, Örebro, Sweden (GRID:grid.15895.30) (ISNI:0000 0001 0738 8966) 
35  University of Wuerzburg, Division of Molecular Psychiatry, Center of Mental Health, Wuerzburg, Germany (GRID:grid.8379.5) (ISNI:0000 0001 1958 8658); Maastricht University, Department of Neuroscience, School for Mental Health and Neuroscience (MHENS), Maastricht, The Netherlands (GRID:grid.5012.6) (ISNI:0000 0001 0481 6099); I.M. Sechenov First Moscow State Medical University, Laboratory of Psychiatric Neurobiology, Institute of Molecular Medicine, Moscow, Russia (GRID:grid.448878.f) (ISNI:0000 0001 2288 8774) 
36  The Chinese University of Hong Kong, Department of Psychology, Hong Kong, China (GRID:grid.10784.3a) (ISNI:0000 0004 1937 0482) 
37  McGill University, Department of Human Genetics, Montreal, Canada (GRID:grid.14709.3b) (ISNI:0000 0004 1936 8649) 
38  University of California, Semel Institute for Neuroscience and Human Behavior, UCLA David Geffen School of Medicine, Los Angeles, USA (GRID:grid.19006.3e) (ISNI:0000 0000 9632 6718) 
39  Cardiff University, MRC Centre for Neuropsychiatric Genetics & Genomics, School of Medicine, Cardiff, UK (GRID:grid.5600.3) (ISNI:0000 0001 0807 5670) 
40  QIMR Berghofer Medical Research Institute, Brisbane, Australia (GRID:grid.1049.c) (ISNI:0000 0001 2294 1395) 
41  University of Valencia, Department of Developmental and Educational Psychology, Valencia, Spain (GRID:grid.5338.d) (ISNI:0000 0001 2173 938X) 
42  Radboud University Medical Center, Department of Human Genetics, Nijmegen, The Netherlands (GRID:grid.10417.33) (ISNI:0000 0004 0444 9382); ADHD Outpatient Clinic, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil (GRID:grid.414449.8) (ISNI:0000 0001 0125 3761) 
43  University of Duisburg-Essen, Clinic for Child and Adolescent Psychiatry and Psychotherapy, Essen, Germany (GRID:grid.5718.b) (ISNI:0000 0001 2187 5445) 
44  University Hospital Frankfurt, Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, Frankfurt am Main, Germany (GRID:grid.411088.4) (ISNI:0000 0004 0578 8220) 
45  Medical Faculty Mannheim and University of Heidelberg, Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Mannheim, Germany (GRID:grid.7700.0) (ISNI:0000 0001 2190 4373) 
46  Ghent University, Department of Experimental Clinical and Health Psychology, Ghent, Belgium (GRID:grid.5342.0) (ISNI:0000 0001 2069 7798) 
47  Universidade Federal do Rio Grande do Sul, Department of Psychiatry, Porto Alegre, Brazil (GRID:grid.8532.c) (ISNI:0000 0001 2200 7498); ADHD Outpatient & Development Psychiatry Program, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil (GRID:grid.414449.8) (ISNI:0000 0001 0125 3761) 
48  University Medical Center Göttingen, Child and Adolescent Psychiatry, Göttingen, Germany (GRID:grid.411984.1) (ISNI:0000 0001 0482 5331) 
49  University Hospital Vall d’Hebron, Department of Psychiatry, Barcelona, Spain (GRID:grid.411083.f) (ISNI:0000 0001 0675 8654) 
50  University of Southern Denmark, Department of Child and Adolescent Psychiatry, Odense, Denmark (GRID:grid.10825.3e) (ISNI:0000 0001 0728 0170); University of Basel, Clinical Psychology and Epidemiology, Institute of Psychology, Basel, Switzerland (GRID:grid.6612.3) (ISNI:0000 0004 1937 0642); University of Zurich, Department of Child and Adolescent Psychiatry, Zurich, Switzerland (GRID:grid.7400.3) (ISNI:0000 0004 1937 0650) 
51  Peking University Sixth Hospital/Institute of Mental Health, Child and Adolescent Mental Health Centre, Beijing, China (GRID:grid.11135.37) (ISNI:0000 0001 2256 9319) 
52  Oslo University, PROMENTA, Oslo, Norway (GRID:grid.5510.1) (ISNI:0000 0004 1936 8921) 
53  SUNY Upstate Medical University, Department of Psychiatry, Syracuse, USA (GRID:grid.411023.5) (ISNI:0000 0000 9159 4457) 
54  Universitat de Barcelona, Departament de Genètica, Microbiologia i Estadística, Facultat de Biologia, Barcelona, Spain (GRID:grid.5841.8) (ISNI:0000 0004 1937 0247); Instituto de Salud Carlos III, Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Madrid, Spain (GRID:grid.413448.e) (ISNI:0000 0000 9314 1427); Institut de Biomedicina de la Universitat de Barcelona (IBUB), Barcelona, Spain (GRID:grid.5841.8) (ISNI:0000 0004 1937 0247); Esplugues de Llobregat, Institut de Recerca Sant Joan de Déu (IRSJD), Barcelona, Spain (GRID:grid.5841.8) 
55  Massachusetts General Hospital and Harvard Medical School, Analytic and Translational Genetics Unit, Department of Medicine, Boston, USA (GRID:grid.32224.35) (ISNI:0000 0004 0386 9924); Broad Institute of MIT and Harvard, Stanley Center for Psychiatric Research, Cambridge, USA (GRID:grid.66859.34); Broad Institute of MIT and Harvard, Program in Medical and Population Genetics, Cambridge, USA (GRID:grid.66859.34) 
56  Radboud University Medical Center, Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Nijmegen, The Netherlands (GRID:grid.10417.33) (ISNI:0000 0004 0444 9382); Radboud University Medical Center, Department of Psychiatry, Donders Institute for Brain, Cognition and Behaviour, Nijmegen, The Netherlands (GRID:grid.10417.33) (ISNI:0000 0004 0444 9382) 
57  SUNY Upstate Medical University, Departments of Psychiatry and of Neuroscience and Physiology, Syracuse, USA (GRID:grid.411023.5) (ISNI:0000 0000 9159 4457) 
Publication year
2021
Publication date
2021
Publisher
Nature Publishing Group
e-ISSN
20411723
Source type
Scholarly Journal
Language of publication
English
DOI
https://doi.org/10.1038/s41467-020-20443-2
ProQuest document ID
2480546809
Copyright
© The Author(s) 2021. corrected publication 2021. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.