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

• Type of Material: Article
• Authors: Ditte Demontis, Aarhus University; Raymond K. Walters, Harvard University; Joanna Martin, Broad Institute of Harvard and MIT; Manuel Mattheisen, Aarhus University; Thomas D. Als, Aarhus University; Esben Agerbo, Aarhus University; Gisli Baldursson, National University Hospital; Rich Belliveau, Broad Institute of Harvard and MIT; Jonas Bybjerg-Grauholm, Statens Serum Institut; Marie Baekvad-Hansen, Statens Serum Institut; Felecia Cerrato, Broad Institute of Harvard and MIT; Kimberly Chambert, Broad Institute of Harvard and MIT; Claire Churchhouse, Harvard University; Ashley Dumont, Broad Institute of Harvard and MIT; Nicholas Eriksson, 23andMe, Inc.; Michael Gandal, University of California Los Angeles; Jacqueline I. Goldstein, Harvard University; Katrina L. Grasby, QIMR Berghofer Medical Research Institute; Jakob Grove, Aarhus University; Olafur O. Gudmundsson, National University Hospital; Christine S. Hansen, Statens Serum Institut; Mads Engel Hauberg, Aarhus University; Mads V. Hollegaard, Statens Serum Institut; Daniel P. Howrigan, Harvard University; Hailiang Huang, Harvard University; Julian B. Maller, Broad Institute of Harvard and MIT; Alicia R. Martin, Harvard University; Nicholas G. Martin, QIMR Berghofer Medical Research Institute; Jennifer Moran, Broad Institute of Harvard and MIT; Irwin Waldman, Emory University
• Language: English
• Date: 2019-01-01
• Publisher: Nature Research (part of Springer Nature)
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2018, The Author(s), under exclusive licence to Springer Nature America, Inc.
• Final Published Version (URL): http://dx.doi.org/10.1038/s41588-018-0269-7
• Title of Journal or Parent Work: Nature Genetics
• ISSN: 1061-4036
• Volume: 51
• Issue: 1
• Start Page: 63
• End Page: +
• Grant/Funding Information: See publication for full funding statement.
• Keywords: DEFICIT HYPERACTIVITY DISORDER; PROVIDES INSIGHTS; GENETIC ARCHITECTURE; ASSOCIATION METAANALYSIS; MAJOR DEPRESSION; SEXUAL-BEHAVIOR; POLYGENIC RISK; Genetics & Heredity; US CHILDREN; Life Sciences & Biomedicine; LD SCORE REGRESSION; Science & Technology; IDENTIFIES 11
• Research Categories: Psychology, General; Biology, Genetics; Biology, Neuroscience

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.