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

Ditte Demontis(Aarhus University), Raymond K. Walters(Broad Institute), Joanna Martin(Broad Institute), Manuel Mattheisen(Aarhus University), Thomas D. Als(Aarhus University), Esben Agerbo(Aarhus University), Gísli Baldursson(National University Hospital of Iceland), Rich Belliveau(Broad Institute), Jonas Bybjerg‐Grauholm(Statens Serum Institut), Marie Bækvad‐Hansen(Statens Serum Institut), Felecia Cerrato(Broad Institute), Kimberly Chambert(Broad Institute), Claire Churchhouse(Broad Institute), Ashley Dumont(Broad Institute), Nicholas Eriksson(23andMe (United States)), Michael J. Gandal(University of California, Los Angeles), Jacqueline I. Goldstein(Broad Institute), Katrina L. Grasby(QIMR Berghofer Medical Research Institute), Jakob Grove(Aarhus University), Ólafur Ó. Guðmundsson(deCODE Genetics (Iceland)), Christine Søholm Hansen(Statens Serum Institut), Mads E. Hauberg(Aarhus University), Mads V. Hollegaard(Statens Serum Institut), Daniel P. Howrigan(Broad Institute), Hailiang Huang(Broad Institute), Julian Maller(Broad Institute), Alicia R. Martin(Broad Institute), Nicholas G. Martin(QIMR Berghofer Medical Research Institute), Jennifer L. Moran(Broad Institute), Jonatan Pallesen(Aarhus University), Duncan S. Palmer(Broad Institute), Carsten Bøcker Pedersen(Aarhus University), Marianne Giørtz Pedersen(Aarhus University), Timothy Poterba(Broad Institute), Jesper Buchhave Poulsen(Statens Serum Institut), Stephan Ripke(Broad Institute), Elise Robinson(Harvard University), F. Kyle Satterstrom(Broad Institute), Hreinn Stefánsson(deCODE Genetics (Iceland)), Christine Stevens(Broad Institute), Patrick Turley(Broad Institute), G. Bragi Walters(deCODE Genetics (Iceland)), Hyejung Won(University of California, Los Angeles), Margaret J. Wright(The University of Queensland), Ole A. Andreassen(Oslo University Hospital), Philip Asherson(King's College London), Christie L. Burton(University of Toronto), Dorret I. Boomsma(Amsterdam Neuroscience), Bru Cormand(Instituto de Salud Carlos III), Søren Dalsgaard(Aarhus University), Barbara Franke(Radboud University Nijmegen), Joel Gelernter(Yale University), Daniel H. Geschwind(University of California, Los Angeles), Håkon Håkonarson(Children's Hospital of Philadelphia), Jan Haavik(Haukeland University Hospital), Henry R. Kranzler(Mental Illness Research, Education and Clinical Centers), Jonna Kuntsi(King's College London), K. Langley(Cardiff University), Klaus‐Peter Lesch(Sechenov University), Christel M. Middeldorp(The University of Queensland), Andreas Reif(Goethe University Frankfurt), Luís Augusto Rohde(Universidade Federal do Rio Grande do Sul), Panos Roussos(Allen Institute for Brain Science), Russell Schachar(University of Toronto), Pamela Sklar(Allen Institute for Brain Science), Edmund Sonuga‐Barke(King's College London), Patrick F. Sullivan(University of North Carolina at Chapel Hill), Anita Thapar(Cardiff University), Joyce Y. Tung(23andMe (United States)), Irwin D. Waldman(Emory University), Sarah E. Medland(QIMR Berghofer Medical Research Institute), Kāri Stefánsson(deCODE Genetics (Iceland)), Merete Nordentoft(University of Copenhagen), David M. Hougaard(Statens Serum Institut), Thomas Werge(University of Copenhagen), Ole Mors(Aarhus University Hospital), Preben Bo Mortensen(Aarhus University), Mark J. Daly(Broad Institute), Stephen V. Faraone(SUNY Upstate Medical University), Anders D. Børglum(Aarhus University), Benjamin M. Neale(Broad Institute)
Nature Genetics
November 23, 2018
10.1038/s41588-018-0269-7
Cited by 2,307Open Access
Full Text

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.

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