Genome-wide analyses of ADHD identify 27 risk loci, refine the genetic architecture and implicate several cognitive domains

Ditte Demontis, G. Bragi Walters, Georgios Athanasiadis, Raymond Walters, Karen Therrien, Trine Tollerup Nielsen, Leila Farajzadeh, Georgios Voloudakis, Jaroslav Bendl, Biau Zeng, Wen Zhang, Jakob Grove, Thomas D. Als, Jinjie Duan, F. Kyle Satterstrom, Jonas Bybjerg-Grauholm, Marie Bækved-Hansen, Olafur O. Gudmundsson, Sigurdur H. Magnusson, Gisli BaldurssonKatrin Davidsdottir, Gyda S. Haraldsdottir, Esben Agerbo, Gabriel E. Hoffman, Søren Dalsgaard, Joanna Martin, Marta Ribasés, Dorret I. Boomsma, Maria Soler Artigas, Nina Roth Mota, Daniel Howrigan, Sarah E. Medland, Tetyana Zayats, Veera M. Rajagopal, Merete Nordentoft, Ole Mors, David M. Hougaard, Stephen V. Faraone, Hreinn Stefansson, Panos Roussos, Barbara Franke, Thomas Werge, Benjamin M. Neale, Kari Stefansson, Anders D. Børglum, ADHD Working Group of the Psychiatric Genomics Consortium, iPSYCH-Broad Consortium

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Attention-deficit hyperactivity disorder (ADHD) is a prevalent neurodevelopmental disorder with a major genetic component. Here, we present a genome-wide association study meta-analysis of ADHD comprising 38,691 individuals with ADHD and 186,843 controls. We identified 27 genome-wide significant loci, highlighting 76 potential risk genes enriched among genes expressed particularly in early brain development. Overall, ADHD genetic risk was associated with several brain-specific neuronal subtypes and midbrain dopaminergic neurons. In exome-sequencing data from 17,896 individuals, we identified an increased load of rare protein-truncating variants in ADHD for a set of risk genes enriched with probable causal common variants, potentially implicating SORCS3 in ADHD by both common and rare variants. Bivariate Gaussian mixture modeling estimated that 84–98% of ADHD-influencing variants are shared with other psychiatric disorders. In addition, common-variant ADHD risk was associated with impaired complex cognition such as verbal reasoning and a range of executive functions, including attention.

Original languageEnglish
Pages (from-to)198-208
Number of pages11
JournalNature Genetics
Issue number2
Publication statusPublished - Feb 2023

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