Risk variants and polygenic architecture of disruptive behavior disorders in the context of attention-deficit/hyperactivity disorder
Year: 2021
Type: review
Study design: Observational Study
Abstract: Attention-Deficit/Hyperactivity Disorder (ADHD) is a childhood psychiatric disorder often comorbid with disruptive behavior disorders (DBDs). ADHD comorbid with DBDs (ADHD+DBDs) is a complex phenotype with a risk component that can be attributed to common genetic variants. Here we report a large GWAS meta-analysis of ADHD+DBDs based on seven cohorts in total including 3,802 cases and 31,305 controls. Three genome-wide significant loci were identified on chromosomes 1, 7, and 11. A GWAS meta-analysis including a Chinese cohort supported the locus on chromosome 11 to be a strong risk locus for ADHD+DBDs across European and Chinese ancestries (rs7118422, P=3.15×10 -10 , OR=1.17). This locus was not associated with ADHD without DBDs in a secondary GWAS of 13,583 ADHD cases and 22,314 controls, suggesting that the locus is a specific risk locus for the comorbid phenotype. We found a higher SNP heritability for ADHD+DBDs (h 2 SNP =0.34) when compared to ADHD without DBDs (h 2 SNP =0.20). Genetic correlations of ADHD+DBDs with aggressive (r g =0.81) and anti-social behaviors (r g =0.82) were high, and polygenic risk score analyses revealed a significant increased burden of variants associated with ADHD and aggression in individuals with ADHD+DBDs compared to ADHD without DBDs. Our results suggests that ADHD+DBDs represent a more severe phenotype with respect to the genetic risk load than ADHD without DBDs, in line with previous studies, and that the risk load to some extent can be explained by variants associated with aggressive behavior.
Source: Nature Communications
Authors: Ditte Demontis, Raymond K. Walters, Veera M. Rajagopal, Irwin D. Waldman, Jakob Grove, Thomas D. Als, Søren Dalsgaard, Marta Ribasés, Jonas Bybjerg-Grauholm, Maria Bækvad-Hansen, Thomas Werge, Merete Nordentoft, Ole Mors, Preben Bo Mortensen, Ole A. Andreassen, Maria Jesús Arranz, Tobias Banaschewski, Claiton Bau, Mark Bellgrove, Joseph Biederman, Isabell Brikell, Jan K. Buitelaar, Christie L. Burton, Miguel Casas, Jennifer Crosbie, Alysa E. Doyle, Richard P. Ebstein, Josephine Elia, Corfield C. Elizabeth, Eugenio Grevet, Natalie Grizenko, Alexandra Havdahl, Ziarih Hawi, Johannes Hebebrand, Amaia Hervas, Sarah Hohmann, Jan Haavik, Ridha Joober, Lindsey Kent, Jonna Kuntsi, Kate Langley, Henrik Larsson, Klaus-Peter Lesch, Patrick W. L. Leung, Calwing Liao, Sandra K. Loo, Joanna Martin, Nicholas G. Martin, Sarah E. Medland, Ana Miranda, Nina Roth Mota, Robert D. Oades, Josep Antoni Ramos-Quiroga, Andreas Reif, Marcella Rietschel, Herbert Roeyers, Luis Augusto Rohde, Aribert Rothenberger, Paula Rovira, Cristina Sánchez-Mora, Russell James Schachar, Sarojini Sengupta, Maria Soler Artigas, Hans-Christoph Steinhausen, Anita Thapar, Stephanie H. Witt, Li Yang, Tetyana Zayats, Yanli Zhang-James, Bru Cormand, David M. Hougaard, Benjamin M. Neale, Barbara Franke, Stephen V. Faraone, Anders D. Børglum
Institutions: Aarhus University, Lundbeck Foundation, Broad Institute, Harvard University, Massachusetts General Hospital, Stanley Center for Psychiatric Research, Emory University, Universitat Autònoma de Barcelona, Instituto de Salud Carlos III, Centro de Investigación Biomédica en Red de Salud Mental, Vall d'Hebron Institut de Recerca, Vall d'Hebron Hospital Universitari, Universitat de Barcelona, Statens Serum Institut, University of Copenhagen, Sankt Hans Hospital, Mental Health Services, Copenhagen University Hospital, Aarhus University Hospital, Oslo University Hospital, University of Oslo, University Hospital Mútua de Terrassa, Mútua Terrassa, Heidelberg University, Central Institute of Mental Health, Medizinische Fakultät Mannheim, Universidade Federal do Rio Grande do Sul, Hospital de Clínicas de Porto Alegre, Monash University, Karolinska Institutet, Radboud University Medical Center, Donders Institute for Brain, Cognition and Behaviour, University of Toronto, Hospital for Sick Children, Southwestern University of Finance and Economics, Alfred I. duPont Hospital for Children, Thomas Jefferson University, Norwegian Institute of Public Health, Douglas Mental Health University Institute, McGill University, Essen University Hospital, University of Duisburg-Essen, Haukeland University Hospital, University of Bergen, University of St Andrews, King's College London, Cardiff University, Örebro University, Sechenov University, University of Würzburg, Maastricht University, Chinese University of Hong Kong, University of California, Los Angeles, QIMR Berghofer Medical Research Institute, Universitat de València, University Hospital Frankfurt, Ghent University, Universitätsmedizin Göttingen, University of Southern Denmark, University of Basel, University of Zurich, Peking University Sixth Hospital, SUNY Upstate Medical University, Centre for Biomedical Network Research on Rare Diseases, Institut de Recerca Sant Joan de Déu, Institut de Biomedicina de la Universitat de Barcelona, Radboud University Nijmegen
Language: English
Subfield: Psychiatry and Mental health
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $5,560
Funders: Eli Lilly and Company, Pfizer, American Academy of Child and Adolescent Psychiatry, Sunovion, National Alliance for Research on Schizophrenia and Depression, University of St Andrews, European Commission, Generalitat de Catalunya, Ministerio de Economía y Competitividad, Lundbeckfonden, Novo Nordisk, Shire, Helsefonden, TrygFonden, European College of Neuropsychopharmacology, Novo Nordisk Fonden, H. Lundbeck A/S, National Institutes of Health, Genentech, Horizon 2020 Framework Programme, Pfizer Pharmaceuticals, Agència de Gestió d'Ajuts Universitaris i de Recerca, Instituto de Salud Carlos III, European Regional Development Fund, National Institute of Mental Health, National Institute on Drug Abuse, National Institute of Environmental Health Sciences
Awards: G1075404386, G1124005961, 2/7 Psychiatric Genomics Consortium: Finding Actionable Variation, 5/7 Psychiatric Genomics Consortium: Finding actionable variation, G1482489452, G1613426579, G1888088267, G1953887145, G2017605187, Estudio de asociación a escala metagenómica (MGWAS) en adultos con TDAH a través de secuenciación masiva de ADN de muestras fecales, G214445032, G2191771826, G2325242462, G2558956044, G2654049849, G2682322565, G2708544407, G2713162615, G2719215791, G2783655308, Impacto del Riesgo Genético Acumulado para el Trastorno por Déficit de Atención con Hiperactividad en las Drogodependencias e Identificación de la Base Genética Compartida, G3246699782, G3288897321, G3327970292, G3425560458, G3552952322, G363525713, Trastorno por déficit de Atención con Hiperactividad, Puntuación de Riesgo Poligénico para alteraciones neurocognitivas, trastornos del aprendizaje y bajo rendimiento escolar, G3987400284, G4025991980, G4077098235, G4304466693, G4318859775, G434337789, G4376102721, G4420342495, G4937468798, G5234783520, G5346812449, G5497799976, G564446902, Effects of Nutrition and Lifestyle on Impulsive, Compulsive, and Externalizing behaviours, G570796765, G5808246334, G6057383737, G6079324567, Comorbid Conditions of Attention deficit / hyperactivity disorder, G6260285634, G6268823086, G6298273575, G6305174853, G6332337720, G6742998398, Air-pollution risk for Autism and ADHD - cross-disorder insights and genetic liability, G697019932, G7186216202, G7320609940, G7612806523, G7714368294, G837377678, G8401089885, G84716273, Aggression subtyping for improved insight and treatment innovation in psychiatric disorders, G8824911526, G9458626
OpenAlex ID: W3122992840