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Title:	Gene-wide association study reveals RNF122 ubiquitin ligase as a novel susceptibility gene for attention deficit hyperactivity disorder
Author:	Garcia Martínez, Iris; Sánchez-Mora, Cristina; Soler Artigas, María; Rovira, Paula; Pagerols, Mireia; Corrales, Montse; Calvo Sánchez, Eva; Richarte, Vanesa; Bustamante Pineda, Mariona; Sunyer Deu, Jordi; Cormand, Bru; Casas, Miguel; Ramos Quiroga, Josep Antoni; Ribasés, Marta
Abstract:	Attention Deficit Hyperactivity Disorder (ADHD) is a common childhood-onset neurodevelopmental condition characterized by pervasive impairment of attention, hyperactivity, and/or impulsivity that can persist into adulthood. The aetiology of ADHD is complex and multifactorial and, despite the wealth of evidence for its high heritability, genetic studies have provided modest evidence for the involvement of specific genes and have failed to identify consistent and replicable results. Due to the lack of robust findings, we performed gene-wide and pathway enrichment analyses using pre-existing GWAS data from 607 persistent ADHD subjects and 584 controls, produced by our group. Subsequently, expression profiles of genes surpassing a follow-up threshold of P-value < 1e-03 in the gene-wide analyses were tested in peripheral blood mononucleated cells (PBMCs) of 45 medication-naive adults with ADHD and 39 healthy unrelated controls. We found preliminary evidence for genetic association between RNF122 and ADHD and for its overexpression in adults with ADHD. RNF122 encodes for an E3 ubiquitin ligase involved in the proteasome-mediated processing, trafficking, and degradation of proteins that acts as an essential mediator of the substrate specificity of ubiquitin ligation. Thus, our findings support previous data that place the ubiquitin-proteasome system as a promising candidate for its involvement in the aetiology of ADHD.
Abstract:	Over the course of this investigation, I.G. M. has been a recipient of a predoctoral fellowship from the Vall d’Hebron Research Institute (PRED-VHIR-2012), Barcelona, Spain, and currently she is a recipient of a contract from the 7th Framework Programme for Research, Technological Development and Demonstration, European Commission (AGGRESSOTYPE_FP7HEALTH2013/602805). C.S. M. is a recipient of a Sara Borrell contract from the Instituto de Salud Carlos III, Ministerio de Economía, Industria y Competitividad, Spain (CD15/00199) and a mobility grant from the Instituto de Salud Carlos III, Ministerio de Economía, Industria y Competitividad, Spain (MV16/00039). M.S. A. is a recipient of a contract from the Biomedical Research Networking Centre in Mental Health (CIBERSAM), Madrid, Spain. P.R. is a recipient of a predoctoral fellowship from the Agència de Gestió d’Ajuts Universitaris i de Recerca (AGAUR), Generalitat de Catalunya, Spain (2016FI_B 00899). M.P. is recipient of a predoctoral fellowship from the Vall d’Hebron Research Institute, Barcelona, Spain (PRED-VHIR-2013) and a research grant from the Deutscher Akademischer Austauschdienst (DAAD), Germany (Research Grants - Short-Term Grants, 2017). E.C. S. is a recipient of a predoctoral fellowship from the Collaborative Research Training Programme for Medical Doctors (PhD4MD), Centre for Genomic Regulation (CRG) and Vall d’Hebron Research Institute (VHIR), Barcelona, Spain (II14/00018). M.R. is a recipient of a Miguel de Servet contract from the Instituto de Salud Carlos III, Ministerio de Economía, Industria y Competitividad, Spain (CP09/00119 and CPII15/00023). This investigation was supported by Instituto de Salud Carlos III (PI12/01139, PI14/01700, PI15/01789, PI16/01505), and cofinanced by the European Regional Development Fund (ERDF), Agència de Gestió d’Ajuts Universitaris i de Recerca-AGAUR, Generalitat de Catalunya (2014SGR1357, 2014SGR0932), Ministerio de Economía, Industria y Competitividad, Spain (SAF2012-33484, SAF2015-68341-R), the European College of Neuropsychopharmacology (ECNP network: ‘ADHD across the lifespan’), Departament de Salut, Generalitat de Catalunya, Spain, and a NARSAD Young Investigator Grant from the Brain & Behavior Research Foundation. This project has also received funding from the European Union’s Horizon 2020 Research and Innovation Programme under the grant agreements No 667302 and 643051.
Subject(s):	-Behavioural genetics -Genome-wide association studies
Rights:	© Open Access. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. http://creativecommons.org/licenses/by/4.0/
Document type:	Article Article - Published version
Published by:	Nature Publishing Group
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