Gene-based analysis identifies novel microRNA candidates for Autism Spectrum Disorder

Abstract

BackgroundAutism Spectrum Disorder (ASD) is a complex neurodevelopmental condition with unclear physiopathology. Biomarker-based diagnostic tools for early detection and targeted treatments have yet to be developed. MicroRNAs (miRNAs), which are critical regulators of genes involved in brain development and function, are emerging as promising candidates as molecular mechanisms, biomarkers, and therapeutic targets for ASD. This study aimed to identify miRNAs involved in ASD and evaluate their potential functions through in silico analysis. MethodsA comprehensive analysis was performed to find genomic variants with a predicted functional impact on miRNA activity. Using large datasets of Single Nucleotide Variants (SNVs, N = 4300) and Copy Number Variants (CNVs, N = 3570) from ASD cases, we identified miRNAs targeted by CNVs or containing SNVs predicted to disrupt their function in ASD subjects, and compared their frequencies with controls. Selected regulatory miRNA-mRNA networks and their associated biological functions were characterized. ResultsSeventy mature miRNAs were identified, including both previously reported and novel ASD candidates, predicted to regulate 2742 brain-expressed genes. Enrichment analysis revealed their involvement in cellular signaling, transcription regulation, protein metabolism, and chromatin organization - biological processes strongly related to ASD. Notably, 63% of these miRNAs are predicted to target 71 known ASD risk genes and the KCNB1, MECP2, NCKAP1 and ZBTB20 genes are each regulated by at least four miRNAs. ConclusionsThis gene-based analysis identified miRNAs regulating gene networks and biological pathways implicated in brain function and plasticity, frequently disrupted in ASD. These findings strengthen the evidence for miRNA involvement in ASD, paving the way for novel diagnostic and therapeutic strategies.