Detalhes do Documento

Background: Autism spectrum disorder (ASD) is a neurodevelopmental disorder with a strong genetic component. Many risk genes are associated with ASD, however most of the genetic determinants are still unknown and a role for gene regulatory mechanisms is likely. MicroRNAs (miRNAs) regulate gene expression, playing key roles in neural development and function, and have been implicated in ASD onset and progression. Methods: To identify miRNA potentially associated with ASD, we conducted a comprehensive analysis of Single Nucleotide Variants (SNVs) and Copy Number Variants (CNVs) from ASD patients (N = 4300 and N = 3570, respectively) and control subjects (N = 67442 and N = 9649, respectively). We further performed functional enrichment analysis to understand the functional impact of these miRNAs variants. Results: Our results identified 28 miRNAs significantly enriched for putative disrupted SNVs and 31 miRNAs exclusively or more frequently targeted by CNVs in ASD cases, when compared to controls (α=0.05). These genes encode 70 mature miRNAs, including some novel and others previously implicated in ASD, that are predicted to target 2745 brain-expressed genes. Functional analysis indicates they are enriched in processes such as cellular signaling, gene regulation, protein metabolism, and chromatin structure, all of which are critical for ASD development. Interestingly, 44 of the identified miRNAs are predicted to regulate 71 genes strongly associated with increased ASD risk. Conclusion: This comprehensive gene-based analysis highlights miRNAs that regulate gene networks and cellular pathways essential for brain function and plasticity, which are often disrupted in ASD patients.