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

Nature Genetics 2019

ADHD Working Group of the Psychiatric Genomics Consortium (PGC)} and Demontis, Ditte and {Early Lifecourse & Genetic Epidemiology (EAGLE) Consortium} and {23andMe Research Team} and Walters, Raymond K. and Martin, Joanna and Mattheisen, Manuel and Als, Thomas D. and Agerbo, Esben and Baldursson, G{\'i}sli and Belliveau, Rich and Bybjerg-Grauholm, Jonas and B{\ae}kvad-Hansen, Marie and Cerrato, Felecia and Chambert, Kimberly and Churchhouse, Claire and Dumont, Ashley and Eriksson, Nicholas and Gandal, Michael and Goldstein, Jacqueline I. and Grasby, Katrina L. and Grove, Jakob and Gudmundsson, Olafur O. and Hansen, Christine S. and Hauberg, Mads Engel and Hollegaard, Mads V. and Howrigan, Daniel P. and Huang, Hailiang and Maller, Julian B. and Martin, Alicia R. and Martin, Nicholas G. and Moran, Jennifer and Pallesen, Jonatan and Palmer, Duncan S. and Pedersen, Carsten B{\o}cker and Pedersen, Marianne Gi{\o}rtz and Poterba, Timothy and Poulsen, Jesper Buchhave and Ripke, Stephan and Robinson, Elise B. and Satterstrom, F. Kyle and Stefansson, Hreinn and Stevens, Christine and Turley, Patrick and Walters, G. Bragi and Won, Hyejung and Wright, Margaret J. and Andreassen, Ole A. and Asherson, Philip and Burton, Christie L. and Boomsma, Dorret I. and Cormand, Bru and Dalsgaard, S{\o}ren and Franke, Barbara and Gelernter, Joel and Geschwind, Daniel and Hakonarson, Hakon and Haavik, Jan and Kranzler, Henry R. and Kuntsi, Jonna and Langley, Kate and Lesch, Klaus-Peter and Middeldorp, Christel and Reif, Andreas and Rohde, Luis Augusto and Roussos, Panos and Schachar, Russell and Sklar, Pamela and Sonuga-Barke, Edmund J. S. and Sullivan, Patrick F. and Thapar, Anita and Tung, Joyce Y. and Waldman, Irwin D. and Medland, Sarah E. and Stefansson, Kari and Nordentoft, Merete and Hougaard, David M. and Werge, Thomas and Mors, Ole and Mortensen, Preben Bo and Daly, Mark J. and Faraone, Stephen V. and B{\o}rglum, Anders D. and Neale, Benjamin M.

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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