Abstract
Attention-deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder with high heritability. At least 30% of patients diagnosed in childhood continue to suffer from ADHD during adulthood and genetic risk factors may play an essential role in the persistence of the disorder throughout lifespan. To date, genome-wide association studies (GWAS) of ADHD have been completed in seven independent datasets, six of which were pediatric samples and one on persistent ADHD using a DNA-pooling strategy, but none of them reported genome-wide significant associations. In an attempt to unravel novel genes for the persistence of ADHD into adulthood, we conducted the first two-stage GWAS in adults with ADHD. The discovery sample included 607 ADHD cases and 584 controls. Top signals were subsequently tested for replication in three independent follow-up samples of 2104 ADHD patients and 1901 controls. None of the findings exceeded the genome-wide threshold for significance (PGC<5e−08), but we found evidence for the involvement of the FBXO33 (F-box only protein 33) gene in combined ADHD in the discovery sample (P=9.02e−07) and in the joint analysis of both stages (P=9.7e−03). Additional evidence for a FBXO33 role in ADHD was found through gene-wise and pathway enrichment analyses in our genomic study. Risk alleles were associated with lower FBXO33 expression in lymphoblastoid cell lines and with reduced frontal gray matter volume in a sample of 1300 adult subjects. Our findings point for the first time at the ubiquitination machinery as a new disease mechanism for adult ADHD and establish a rationale for searching for additional risk variants in ubiquitination-related genes.
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Acknowledgements
We thank all persons who kindly participated in this research. Part of the DNA extractions and genotyping was performed at the Spanish National Genotyping Centre (CEGEN-Barcelona). Principal investigators of the Nijmegen Biomedical Study are L.A.L.M. Kiemeney, J. de Graaf, A.L.M. Verbeek, D.W. Swinkels, and B. Franke. Principal investigators of the Cognomics Initiative are B. Franke, S. Fisher, G. Fernandez, H. Brunner, P. Hagoort, J. Buitelaar, H. van Bokhoven, and D. Norris. We are grateful to Silvia Fochs, Anna Sànchez, Maribel López, Nuria Pey, and Muriel Ferrer for their assistance in contacting the families and administering the questionnaires. Marta Ribasés is a recipient of a Miguel de Servet contract from the ‘Instituto de Salud Carlos III, Ministerio de Ciencia e Innovación’, Spain. Financial support was received from ‘Fundació La Marató de TV3’ (ref. 092330/31), ‘Instituto de Salud Carlos III-FIS’ (PI11/00571, PI11/01629, PI12/01139, PI041436, PI081151, Red INMA G03/176, and CB06/02/0041), ‘Plan Nacional Sobre Drogas’ (PNSD#2011-0080), ‘Agència de Gestió d’Ajuts Universitaris i de Recerca-AGAUR, Generalitat de Catalunya ‘(2014SGR1357, 2014SGR0932, and 1999SGR00241), Ministerio de Economía y Competitividad, Spain’ (SAF2012-33484), and ‘Departament de Salut’, Government of Catalonia, Spain. The Dutch part of the project was supported by the Hersenstichting Nederland and by a Vici grant of The Netherlands Organisation for Scientific Research (NWO) to Barbara Franke. The Dutch controls were derived from the Nijmegen Biomedical Study (www.nijmegenbiomedischestudie.nl); European Commission (ENGAGE project and grant agreement HEALTH-F4-2007-201413). This work made use of the BIG (Brain Imaging Genetics) database, first established in Nijmegen, The Netherlands, in 2007. This resource is now part of Cognomics (www.cognomics.nl), a joint initiative by researchers of the Donders Centre for Cognitive Neuroimaging, the Human Genetics and Cognitive Neuroscience departments of the Radboud University Medical Centre and the Max Planck Institute for Psycholinguistics in Nijmegen. The Cognomics Initiative is supported by the participating departments and centers and by external grants, ie, the Biobanking and Biomolecular Resources Research Infrastructure (The Netherlands; BBMRI-NL), the Hersenstichting Nederland and The Netherlands Organisation for Scientific Research (NWO). Funding for the Norwegian cohort was provided by the K.G. Jebsen Foundation, the Norwegian Research Council, and Regional Health Authority of Western Norway. The sample used in this study is part of the international multicentre persistent ADHD collaboration (IMpACT). IMpACT unites major research centres working on the genetics of ADHD persistence across the lifespan and has participants in the Netherlands, Germany, Spain, Norway, the United Kingdom, the United States, Brazil and Sweden. Principal investigators of IMpACT are: Barbara Franke (chair), Andreas Reif, Stephen V. Faraone, Jan Haavik, Bru Cormand, Antoni Ramos Quiroga, Philip Asherson, Klaus-Peter Lesch, Jonna Kuntsi, Claiton Bau, Jan Buitelaar, Stefan Johansson, Henrik Larsson, Alysa Doyle, and Eugenio Grevet.
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Sánchez-Mora, C., Ramos-Quiroga, J., Bosch, R. et al. Case–Control Genome-Wide Association Study of Persistent Attention-Deficit Hyperactivity Disorder Identifies FBXO33 as a Novel Susceptibility Gene for the Disorder. Neuropsychopharmacol 40, 915–926 (2015). https://doi.org/10.1038/npp.2014.267
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DOI: https://doi.org/10.1038/npp.2014.267
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