Molecular Portrait of Potential Attention Deficit/ Hyperactivity Disorder Candidate Genes and Regulating Micrornas Expression in Normal Human Developing Brain Tissues

Abstract

Attention-deficit/hyperactivity disorder (ADHD) is the most common neuropsychiatric disorder in childhood affecting 5-6% of children, and is a major global health concern, which seems to increase in magnitude. The etiology of ADHD is still poorly understood, however; there are indications of genetic as well as environmental and epigenetic factors contributing to the development of the disorder. The objectives of this study was i) to identify potential ADHD candidate genes; ii) to explore spatial and temporal transcriptional fluctuation of the identified ADHD candidate genes in normal developing human brain tissues, and iii) to identify miRNAs regulating the identified ADHD candidate genes and explore how these miRNAs are expressed in normal developing human brain tissues. From search in literature and publicly available databases, we identified 103 shared potential ADHD candidate genes. These genes were expressed and enriched in several human brain regions and developmental stages. Clustering analysis of these genes based on their expression levels showed a clear difference between fetal stage and the other developmental stages. There was no clear gender or brain region differences between samples. Further, functional analysis of these genes revealed that they participate in a variety of different and widely distributed functional pathways implicated with ADHD. From miRNA-target prediction analysis, we identified twenty miRNAs regulating the identified 103 genes, and the expression pattern of these miRNAs was developmental stage dependent. These miRNAs were enriched in functional pathways and disease ontologies relevant to neurodevelopment. The knowledge of the expression pattern of potential ADHD candidate genes and miRNAs, which regulate these genes across different stages of brain development, is essential for understanding normal brain development and subsequent disease development of the brain. In addition, identification of miRNA-regulated ADHD candidate genes can be used to develop blood-based molecular markers to be investigated in future studies of ADHD patients.