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.
Highlights
Twenty additional genes were found associated with persistent Attention Deficit Hyperactivity Disorder (ADHD) when we considered the 10% most significant SNPs of each gene locus, with KCNG4 (P-value = 1.0e-04) and TAF1C (P-value = 1.9e-04) as top signals (Table 1)
We did not find evidence for rs3735951 acting as cis-eQTL in preexisting datasets of cortical gene expression (GSE8919 and GSE30272)[35, 36], that could explain the RNF122 expression differences identified in ADHD (See Supplementary Table S3), functional prediction revealed that rs3735951 may lie within a partially overlapped exonic splicing enhancer (ESE) site and an exonic splicing silencer (ESS) site (See Supplementary Table S4)
With the aim of uncovering new underlying genes involved in persistent ADHD and providing additional evidence for the contribution of previously identified genes, we performed gene-wide and pathway enrichment analyses in a pre-existing genome-wide association studies (GWAS) dataset of adult ADHD followed by gene expression profiling
Summary
Considering the absence of genome-wide significant associations and the limited overlap between top hits from SNP-based GWAS on ADHD, analyses focusing on gene-set enrichment or pathway-based approaches raise as promising strategies to address the genetic complexity of the disorder[9]. These strategies allow combining effects of multiple SNPs (gene-wide studies) or multiple genes (gene-set analyses), while reducing multiple testing comparisons and providing insights into the involvement of specific biological functions or pathways[9]. Expression profiles of genes surpassing a follow-up significance 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
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