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

• Published in: Nature genetics Vol. 55; no. 2; pp. 198 - 208
• Main Authors: Demontis, Ditte, Walters, G. Bragi, Athanasiadis, Georgios, Walters, Raymond, Therrien, Karen, Nielsen, Trine Tollerup, Farajzadeh, Leila, Voloudakis, Georgios, Bendl, Jaroslav, Zeng, Biau, Zhang, Wen, Grove, Jakob, Als, Thomas D., Duan, Jinjie, Satterstrom, F. Kyle, Bybjerg-Grauholm, Jonas, Bækved-Hansen, Marie, Gudmundsson, Olafur O., Magnusson, Sigurdur H., Baldursson, Gisli, Davidsdottir, Katrin, Haraldsdottir, Gyda S., Agerbo, Esben, Hoffman, Gabriel E., Dalsgaard, Søren, Martin, Joanna, Ribasés, Marta, Boomsma, Dorret I., Soler Artigas, Maria, Roth Mota, Nina, Howrigan, Daniel, Medland, Sarah E., Zayats, Tetyana, Rajagopal, Veera M., Nordentoft, Merete, Mors, Ole, Hougaard, David M., Mortensen, Preben Bo, Daly, Mark J., Faraone, Stephen V., Stefansson, Hreinn, Roussos, Panos, Franke, Barbara, Werge, Thomas, Neale, Benjamin M., Stefansson, Kari, Børglum, Anders D.
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.02.2023; Nature Publishing Group
• Subjects: 45/23; 45/43; 631/208/205/2138; 692/699/476/1311; Agriculture; Animal Genetics and Genomics; Attention Deficit Disorder with Hyperactivity - genetics; Attention deficit hyperactivity disorder; Biomedical and Life Sciences; Biomedicine; Bivariate analysis; Brain; Cancer Research; Chromosomes; Cognition; Cognition & reasoning; Cognitive ability; Dopamine receptors; Gene expression; Gene Function; Genes; Genetic Predisposition to Disease; Genome-wide association studies; Genome-Wide Association Study; Genomes; Genomics; Human Genetics; Humans; Hyperactivity; Mental disorders; Mesencephalon; Meta-analysis; Neurodevelopmental disorders; Risk
• ISSN: 1061-4036; 1546-1718; 1546-1718
• DOI: 10.1038/s41588-022-01285-8

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. Genome-wide analyses identify 27 loci associated with attention-deficit hyperactivity disorder and provide insights into its genetic architecture in relation to other psychiatric disorders and cognitive traits.