Genome-wide analyses of attention deficit hyperactivity disorder 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 Baldursson, Katrin 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, ADHD Working Group of the Psychiatric Genomics Consortium, iPSYCH-Broad Consortium, Merete Nordentoft, Ole Mors, David M Hougaard, Preben Bo Mortensen, Mark J Daly, Stephen V Faraone, Hreinn Stefansson, Panos Roussos, Barbara Franke, Thomas Werge, Benjamin M Neale, Kari Stefansson, Anders D Børglum (2023)
Nature Genetics 55(2), 198-208
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 sub-types and midbrain dopaminergic neurons. In exomesequencing 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 likely 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. Additionally, common variant ADHD risk was associated with impaired complex cognition such as verbal reasoning and a range of executive functions, including attention.
Categories: ADHS Allgemein
Keywords: attention deficit hyperactivity disorder, genome-wide association study, risk loci, genetics, cognitive domains