Identification and Functional Analysis of Long Non-coding RNAs in Autism Spectrum Disorders

Abstract

Genetic and environmental factors, alone or in combination, contribute to the pathogenesis of autism spectrum disorder (ASD). Although many protein-coding genes have now been identified as disease risk genes for ASD, a detailed illustration of long non-coding RNAs (lncRNAs) associated with ASD remains elusive. In this study, we first identified ASD-related lncRNAs based on genomic variant data of individuals with ASD from a twin study. In total, 532 ASD-related lncRNAs were identified, and 86.7% of these ASD-related lncRNAs were further validated by an independent copy number variant (CNV) dataset. Then, the functions and associated biological pathways of ASD-related lncRNAs were explored by enrichment analysis of their three different types of functional neighbor genes (i.e., genomic neighbors, competing endogenous RNA (ceRNA) neighbors, and gene co-expression neighbors in the cortex). The results have shown that most of the functional neighbor genes of ASD-related lncRNAs were enriched in nervous system development, inflammatory responses, and transcriptional regulation. Moreover, we explored the differential functions of ASD-related lncRNAs in distinct brain regions by using gene co-expression network analysis based on tissue-specific gene expression profiles. As a set, ASD-related lncRNAs were mainly associated with nervous system development and dopaminergic synapse in the cortex, but associated with transcriptional regulation in the cerebellum. In addition, a functional network analysis was conducted for the highly reliable functional neighbor genes of ASD-related lncRNAs. We found that all the highly reliable functional neighbor genes were connected in a single functional network, which provided additional clues for the action mechanisms of ASD-related lncRNAs. Finally, we predicted several potential drugs based on the enrichment of drug-induced pathway sets in the ASD-altered biological pathway list. Among these drugs, several (e.g., amoxapine, piperine, and diflunisal) were partly supported by the previous reports. In conclusion, ASD-related lncRNAs participated in the pathogenesis of ASD through various known biological pathways, which may be differential in distinct brain regions. Detailed investigation into ASD-related lncRNAs can provide clues for developing potential ASD diagnosis biomarkers and therapy.

Brain Long Noncoding RNAs: Multitask Regulators of Neuronal Differentiation and Function

“…Considering the importance of lncRNAs in neuronal physiology it is not surprising that dysregulation of lncRNAs in the brain might be linked to neurodevelopmental disorders [ 160 , 161 ], autism spectrum disorders [ 162 , 163 , 164 ], substance use [ 165 ], intellectual disability [ 166 ], neurodegenerative diseases and neurological disorders [ 167 , 168 ]. A growing number of studies report that lncRNAs are associated with the pathology and development of neurodegenerative diseases [ 80 , 114 , 169 , 170 ].…”

Impact of MicroRNAs in Interaction With Environmental Factors on Autism Spectrum Disorder: An Exploratory Pilot Study

“…It is reported that the annual incidence of ASD is between 1 and 3% ( 3 ). The prevalence of ASD is sex imbalance with a distribution of three males to one female ( 4 , 5 ). ASD often impairs social skills and autonomy, causing ASD children with difficulty in social, speech, and behavioral skill development.…”

“…Approximately 10% of ASD patients are reported to have an identifiable genetic cause ( 8 ). The characteristics of highly genetic heterogeneity made the pathophysiology of ASD really elusive ( 4 ). MicroRNAs (miRNAs) are short noncoding RNAs with 18–25 nucleotides, playing an important role in regulating gene expression of ASD patients ( 9 ).…”

Impact of microRNAs in Interaction with Environmental Factors on Autism Spectrum Disorder: An Exploratory Pilot Study

“…It has been reported that the worldwide prevalence of ASD is between 1% and 3% of the general population [3] . The prevalence of ASD is sex imbalance, with a distribution of three males to one female [4] . In most cases, ASD symptoms are rst recognized in early childhood, with an average diagnosis age of 4 years [5] .…”

“…Approximately 10% of ASD patients were reported to have an identi able genetic cause [8] , with estimated genetic contributions accounting for > 50-60% of ASD risk [5] . The characteristics of highly genetic and phenotypic heterogeneity made the pathophysiology of ASD really elusive [9] . Noncoding RNA is a crucial player involved in regulating chromatin structure and gene expression of ASD patients [10] .…”