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

Ditte Demontis(Aarhus University), G. Bragi Walters(deCODE Genetics (Iceland)), Georgios Athanasiadis(Copenhagen University Hospital), Raymond K. Walters(Broad Institute), Karen Therrien(Allen Institute for Brain Science), Trine Tollerup Nielsen(Aarhus University), Leila Farajzadeh(Aarhus University), Georgios Voloudakis(Allen Institute for Brain Science), Jaroslav Bendl(Allen Institute for Brain Science), Biau Zeng(Allen Institute for Brain Science), Wen Zhang(Allen Institute for Brain Science), Jakob Grove(Aarhus University), Thomas D. Als(Aarhus University), Jinjie Duan(Aarhus University), F. Kyle Satterstrom(Broad Institute), Jonas Bybjerg‐Grauholm(Statens Serum Institut), Marie Bækved-Hansen(Statens Serum Institut), Ólafur Ó. Guðmundsson(deCODE Genetics (Iceland)), Sigurður H. Magnússon(deCODE Genetics (Iceland)), Gísli Baldursson(National University Hospital of Iceland), Katrín Davíðsdóttir(Administration of Occupational Safety and Health), Gyða S. Haraldsdóttir(Administration of Occupational Safety and Health), Esben Agerbo(Aarhus University), Gabriel E. Hoffman(Allen Institute for Brain Science), Søren Dalsgaard(University of Copenhagen), Joanna Martin(Cardiff University), Marta Ribasès(Universitat Autònoma de Barcelona), Dorret I. Boomsma(Vrije Universiteit Amsterdam), María Soler Artigas(Universitat Autònoma de Barcelona), Nina Roth Mota(Radboud University Nijmegen), Daniel P. Howrigan(Broad Institute), Sarah E. Medland(QIMR Berghofer Medical Research Institute), Tetyana Zayats(Broad Institute), Veera M. Rajagopal(Aarhus University), Alexandra Havdahl(Norwegian Institute of Public Health), Alysa E. Doyle(Harvard University), Andreas Reif(Goethe University Frankfurt), Anita Thapar(Cardiff University), Bru Cormand(Centre for Biomedical Network Research on Rare Diseases), Calwing Liao(McGill University), Christie L. Burton(Hospital for Sick Children), Claiton H.D. Bau(Universidade Federal do Rio Grande do Sul), Diego Luiz Rovaris(Universidade de São Paulo), Edmund Sonuga‐Barke(King's College London), Elizabeth C. Corfield(Norwegian Institute of Public Health), Eugênio H. Grevet(Universidade Federal do Rio Grande do Sul), Henrik Larsson(Örebro University), Ian R. Gizer(University of Missouri), Irwin D. Waldman(Emory University), Isabell Brikell(Aarhus University), Jan Haavik(Haukeland University Hospital), Jennifer Crosbie(Hospital for Sick Children), James J. McGough, Jonna Kuntsi(King's College London), Joseph Glessner(Children's Hospital of Philadelphia), K. Langley(Cardiff University), Klaus‐Peter Lesch(Sechenov University), Luís Augusto Rohde(Universidade Federal do Rio Grande do Sul), Mara Helena Hutz(Universidade Federal do Rio Grande do Sul), Marieke Klein(Radboud University Nijmegen), Mark A. Bellgrove(Monash University), Martin Tesli(Oslo University Hospital), Michael O’Donovan(Cardiff University), Ole A. Andreassen(Oslo University Hospital), Patrick W. L. Leung(Chinese University of Hong Kong), Pedro Mário Pan(Universidade Federal de São Paulo), Ridha Joober(Douglas Mental Health University Institute), Russell Schachar(Hospital for Sick Children), Sandra K. Loo, Stephanie H. Witt(Heidelberg University), Ted Reichborn‐Kjennerud(Norwegian Institute of Public Health), Tobias Banaschewski(Heidelberg University), Ziarih Hawi(Monash University), Mark J. Daly(Broad Institute), Ole Mors(Aarhus University Hospital), Merete Nordentoft(Copenhagen University Hospital), Ole Mors(Aarhus University Hospital), David M. Hougaard(Statens Serum Institut), Preben Bo Mortensen(Aarhus University), Mark J. Daly(Broad Institute), Stephen V. Faraone(SUNY Upstate Medical University), Hreinn Stefánsson(deCODE Genetics (Iceland)), Panos Roussos(Allen Institute for Brain Science), Barbara Franke(Radboud University Nijmegen), Thomas Werge(Copenhagen University Hospital), Benjamin M. Neale(Broad Institute), Kāri Stefánsson(deCODE Genetics (Iceland)), Anders D. Børglum(Aarhus University)
Nature Genetics
January 26, 2023
10.1038/s41588-022-01285-8
Cited by 741Open Access
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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.

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