Abstract
Attention Deficit Hyperactivity Disorder (ADHD) is a childhood-onset neurodevelopmental disorder, whose etiology and pathogenesis are still largely unknown. In order to uncover novel regulatory networks and molecular pathways possibly related to ADHD, we performed an integrated miRNA and mRNA expression profiling analysis in peripheral blood samples of children with ADHD and age-matched typically developing (TD) children. The expression levels of 13 miRNAs were evaluated with microfluidic qPCR, and differentially expressed (DE) mRNAs were detected on an Illumina HiSeq 2500 genome analyzer. The miRNA targetome was identified using an integrated approach of validated and predicted interaction data extracted from seven different bioinformatic tools. Gene Ontology (GO) and pathway enrichment analyses were carried out. Results showed that six miRNAs (miR-652-3p, miR-942-5p, let-7b-5p, miR-181a-5p, miR-320a, and miR-148b-3p) and 560 genes were significantly DE in children with ADHD compared to TD subjects. After correction for multiple testing, only three miRNAs (miR-652-3p, miR-148b-3p, and miR-942-5p) remained significant. Genes known to be associated with ADHD (e.g., B4GALT2, SLC6A9 TLE1, ANK3, TRIO, TAF1, and SYNE1) were confirmed to be significantly DE in our study. Integrated miRNA and mRNA expression data identified critical key hubs involved in ADHD. Finally, the GO and pathway enrichment analyses of all DE genes showed their deep involvement in immune functions, reinforcing the hypothesis that an immune imbalance might contribute to the ADHD etiology. Despite the relatively small sample size, in this study we were able to build a complex miRNA-target interaction network in children with ADHD that might help in deciphering the disease pathogenesis. Validation in larger samples should be performed in order to possibly suggest novel therapeutic strategies for treating this complex disease.
Highlights
Attention Deficit Hyperactivity Disorder (ADHD) is a childhood-onset neurodevelopmental disorder characterized by inappropriate and impairing inattention, impulsivity, and hyperactivity [1].The disease occurs in 2%–10% of school-age children [2], more frequently identified in young males [3].Persistence rates of ADHD in adulthood range from 40% to 75%, with a worldwide prevalence of 3.4% [4,5].ADHD is considered a complex disorder caused by environmental [6], epigenetic [7], and genetic factors [8,9]
A gender-related discrepancy was registered, since the ADHD patients were all males compared to 14 males and 6 females in the typically developing (TD) group (p = 0.0316); to avoid any biases due to gender differences, all the comparisons were performed between the ADHD patients and both the 20
As in our approach, most of the studies preselected Micro-ribonucleic acids (miRNAs) involved in other neurological disorders and/or in neurobiology mechanisms investigated preselected miRNAs involved in other neurological disorders and/or in neurobiology based on literature reviews or miRNA databases [15,17,21]; we may have omitted some mechanisms based on literature reviews or miRNA databases [15,17,21]; we may have potential miRNAs associated with ADHD, as they are involved in unknown biological mechanisms
Summary
Persistence rates of ADHD in adulthood range from 40% to 75%, with a worldwide prevalence of 3.4% [4,5]. ADHD is considered a complex disorder caused by environmental [6], epigenetic [7], and genetic factors [8,9]. The risk of ADHD is estimated to be around 20% in the first-degree relatives of probands [2]. Several candidate genes [10,11,12,13] have been implicated in ADHD susceptibility, and a recent genome-wide association study (GWAS) identified significant risk loci located within or nearby genes involved in neurodevelopment processes [8]
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