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

Nature Genetics 2023

Demontis, Ditte and Walters, G. Bragi and Athanasiadis, Georgios and Walters, Raymond and Therrien, Karen and Nielsen, Trine Tollerup and Farajzadeh, Leila and Voloudakis, Georgios and Bendl, Jaroslav and Zeng, Biau and Zhang, Wen and Grove, Jakob and Als, Thomas D. and Duan, Jinjie and Satterstrom, F. Kyle and Bybjerg-Grauholm, Jonas and B{\ae}kved-Hansen, Marie and Gudmundsson, Olafur O. and Magnusson, Sigurdur H. and Baldursson, Gisli and Davidsdottir, Katrin and Haraldsdottir, Gyda S. and Agerbo, Esben and Hoffman, Gabriel E. and Dalsgaard, S{\o}ren and Martin, Joanna and Ribas{\'e}s, Marta and Boomsma, Dorret I. and Soler Artigas, Maria and Roth Mota, Nina and Howrigan, Daniel and Medland, Sarah E. and Zayats, Tetyana and Rajagopal, Veera M. and {ADHD Working Group of the Psychiatric Genomics Consortium} and Havdahl, Alexandra and Doyle, Alysa and Reif, Andreas and Thapar, Anita and Cormand, Bru and Liao, Calwing and Burton, Christie and Bau, Claiton H. D. and Rovaris, Diego Luiz and Sonuga-Barke, Edmund and Corfield, Elizabeth and Grevet, Eugenio Horacio and Larsson, Henrik and Gizer, Ian R. and Waldman, Irwin and Brikell, Isabell and Haavik, Jan and Crosbie, Jennifer and McGough, James and Kuntsi, Jonna and Glessner, Joseph and Langley, Kate and Lesch, Klaus-Peter and Rohde, Luis Augusto and Hutz, Mara H. and Klein, Marieke and Bellgrove, Mark and Tesli, Martin and O'Donovan, Michael C. and Andreassen, Ole Andreas and Leung, Patrick W. L. and Pan, Pedro M. and Joober, Ridha and Schachar, Russel and Loo, Sandra and Witt, Stephanie H. and Reichborn-Kjennerud, Ted and Banaschewski, Tobias and Hawi, Ziarih and {iPSYCH-Broad Consortium} and Daly, Mark J. and Mors, Ole and Nordentoft, Merete and Mors, Ole and Hougaard, David M. and Mortensen, Preben Bo and Daly, Mark J. and Faraone, Stephen V. and Stefansson, Hreinn and Roussos, Panos and Franke, Barbara and Werge, Thomas and Neale, Benjamin M. and Stefansson, Kari and B{\o}rglum, Anders D.

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.

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