| Resumo: | Introduction: Autism Spectrum Disorder (ASD) is a highly heterogeneous neurodevelopmental disorder with an unclear etiology. Genetic factors are estimated to account for ~50-80% of the familial ASD risk but most of the genetic determinants are still not known. Several copy number variants (CNVs) targeting ASD candidate genes explain some ASD cases. Still, further exploration of noncoding RNAs targeted by CNVs is necessary. MicroRNA (miRNA) and long noncoding RNA (lncRNA) are regulatory molecules, abundantly expressed in the brain, that play an important role during early stages of neural development. Thus, they are strong candidates for ASD. The goal of this work is to identify miRNA and lncRNA genes targeted by CNVs in a cohort of ASD patients and examine their target genes and biological pathways. Methods: We compared the frequency of miRNA and lncRNA genes targeted by CNVs in a cohort of 2446 ASD subjects and 9649 ancestry-matched control subjects. Genetic data from ASD patients was obtained from the Autism Genome Project and the control group from the Database of Genomic Variant (DGV). Both cases and controls were quantified using the same detection method. AGP data was transformed to hg19 annotation followed by functional annotation using the most recent dataset from MIRBASE. Statistical analysis was performed using Fisher’s exact test followed by Bonferroni correction (p-value<0.05). Results: We found 9 miRNAs exclusively targeted by CNVs in ASD subjects and 7 miRNAs more frequently targeted by CNVs in ASD subjects, when compared to controls. From these, only 2 were already known to be associated with ASD. Interestingly, we identified 4 novel miRNAs associated with ASD that were previously described to be associated with Schizophrenia, a disorder that presents some phenotypic overlap with ASD. Putative targets of these 16 miRNAs were enriched for ASD risk genes described in SFARI database. Gene enrichment analysis indicates that these genes are involved in neurodevelopmental processes, which is consistent with literature. In addition, we also found 102 novel lncRNAs more frequently targeted by CNVs in ASD. Discussion: These results support our hypothesis that genetic variants targeting noncoding regulatory RNAs are involved in ASD pathophysiology. This innovative approach will allow the identification of novel biomarkers and drug targets in ASD, which can contribute to a better diagnosis and treatment.
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