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Sci Rep. 2017 Jul 14;7(1):5407. doi: 10.1038/s41598-017-05514-7.

Gene-wide Association Study Reveals RNF122 Ubiquitin Ligase as a Novel Susceptibility Gene for Attention Deficit Hyperactivity Disorder.

Author information

1
Psychiatric Genetics Unit, Group of Psychiatry, Mental Health and Addiction, Vall d'Hebron Research Institute (VHIR), Universitat Autònoma de Barcelona, Barcelona, Catalonia, Spain.
2
Department of Psychiatry, Hospital Universitari Vall d'Hebron, Barcelona, Catalonia, Spain.
3
Biomedical Network Research Centre on Mental Health (CIBERSAM), Instituto de Salud Carlos III, Madrid, Spain.
4
Department of Psychiatry and Legal Medicine, Universitat Autònoma de Barcelona, Barcelona, Catalonia, Spain.
5
ISGlobal, Centre for Research in Environmental Epidemiology (CREAL), Barcelona, Spain.
6
Genomics and Disease Group, Bioinformatics and Genomics Program, Centre for Genomic Regulation (CRG), Barcelona, Spain.
7
Universitat Pompeu Fabra (UPF), Barcelona, Spain.
8
CIBER Epidemiología y Salud Pública (CIBERESP), Madrid, Spain.
9
IMIM (Hospital del Mar Medical Research Institute), Barcelona, Spain.
10
Departament de Genètica, Microbiologia i Estadística, Facultat de Biologia, Universitat de Barcelona, Barcelona, Catalonia, Spain.
11
Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III, Madrid, Spain.
12
Institut de Biomedicina de la Universitat de Barcelona (IBUB), Barcelona, Catalonia, Spain.
13
Institut de Recerca Sant Joan de Déu (IR-SJD), Esplugues, Catalonia, Spain.
14
Psychiatric Genetics Unit, Group of Psychiatry, Mental Health and Addiction, Vall d'Hebron Research Institute (VHIR), Universitat Autònoma de Barcelona, Barcelona, Catalonia, Spain. marta.ribases@vhir.org.
15
Department of Psychiatry, Hospital Universitari Vall d'Hebron, Barcelona, Catalonia, Spain. marta.ribases@vhir.org.
16
Biomedical Network Research Centre on Mental Health (CIBERSAM), Instituto de Salud Carlos III, Madrid, Spain. marta.ribases@vhir.org.

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.

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