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

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 ORCID: https://orcid.org/0000-0002-8911-3479, Ribasés, Marta, Boomsma, Dorret I., Soler Artigas, Maria, Roth Mota, Nina, Howrigan, Daniel, Medland, Sarah E., Zayats, Tetyana, Rajagopal, Veera M., Havdahl, Alexandra, Doyle, Alysa, Reif, Andreas, Thapar, Anita ORCID: https://orcid.org/0000-0002-3689-737X, Cormand, Bru, Liao, Calwing, Burton, Christie, Bau, Claiton H. D., Rovaris, Diego Luiz, Sonuga-Barke, Edmund, Corfield, Elizabeth, Grevet, Eugenio Horacio, Larsson, Henrik, Gizer, Ian R., Waldman, Irwin, Brikell, Isabell, Haavik, Jan, Crosbie, Jennifer, McGough, James, Kuntsi, Joanna, Glessner, Joseph, Langley, Kate, Lesch, Klaus-Peter, Rohde, Luis Augusto, Hutz, Mara H., Klein, Marieke, Bellgrove, Mark, Tesli, Martin, O'Donovan, Michael C. ORCID: https://orcid.org/0000-0001-7073-2379, Andreassen, Ole Andreas, Leung, Patrick W. L., Pan, Pedro M., Joober, Ridha, Schachar, Russel, Loo, Sandra, Witt, Stephanie H., Reichborn-Kjennerud, Ted, Banaschewski, Tobias, Hawi, Ziarih, Daly, Mark J., Mors, Ole, 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 and Børglum, Anders D. 2023. Genome-wide analyses of ADHD identify 27 risk loci, refine the genetic architecture and implicate several cognitive domains. Nature Genetics 55 , pp. 198-208. 10.1038/s41588-022-01285-8

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Abstract

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.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Medicine MRC Centre for Neuropsychiatric Genetics and Genomics (CNGG)
Publisher:	Nature Research
ISSN:	1061-4036
Date of First Compliant Deposit:	31 January 2023
Date of Acceptance:	9 December 2022
Last Modified:	22 Nov 2023 16:47
URI:	https://orca.cardiff.ac.uk/id/eprint/156384

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