Identification and functional analysis of long non-coding RNAs in autism spectrum disorders

Abstract

BackgroundGenetic 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, our aim was to identify ASD-related lncRNAs and explore their functions and associated biological pathways in autism. MethodsASD-related lncRNAs were identified based on genomic variant data of individuals with ASD from a twin study, and further validated using an independent copy number variant (CNV) dataset.The functions and associated biological pathways of ASD-related lncRNAs were explored by enrichment analysis of 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 differential functions of ASD-related lncRNAs in distinct brain regions were demonstrated by using gene co-expression network analysis based on tissue-specific gene expression profiles.Moreover, a functional network analysis were conducted for highly reliable functional neighbor genes of ASD-related lncRNAs. Finally, several potential drugs were predicted based on the enrichment of drug-induced pathway sets in ASD-altered biological pathway list. ResultsIn total, 532 ASD-related lncRNAs were identified, and 86.7% of these ASD-related lncRNAs 2 were further validated by a copy number variant (CNV) dataset. Most of functional neighbor genes of ASD-related lncRNAs were enriched in several functions and biological pathways, including nervous system development, inflammatory response and transcriptional regulation. 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. Moreover, all highly reliable functional neighbor genes were connected in a single functional network. Finally, several potential drugs were predicted and partly supported by the previous reports. ConclusionsWe concluded that ASD-related lncRNAs participate in the pathogenesis of ASD through various known biological pathways, which may be differential in distinct brain regions. And detailed investigation of ASD-related lncRNAs also provided clues for developing potential ASD diagnosis biomarker and therapy.

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

“…We would like to thank Huang et al (2019) for kindly sharing their genomic variant data, which made our identification and further analysis of ASD-related lncRNAs possible. This manuscript has been released as a pre-print at bioRxiv (Tong et al, 2020).…”

Alteration of long non-coding RNAs and mRNAs expression profiles by compound heterozygous ASXL3 mutations in the mouse brain

“…Recent studies revealed that many lncRNAs are prevalently expressed in both the developing and adult central nervous systems, especially in the brain [12]. More importantly, accumulating evidence shows that an abnormal lncRNAs expression in neural tissues are closely associated with the initiation and progression of various severe neurological diseases such as glioma, autism, Alzheimer's disease, Parkinson's disease, and schizophrenia [13][14][15][16][17]. Transcriptomic analysis showed that a group of lncRNAs are acutely and dynamically expressed during neuronal activation processes [17].…”