Combining multi-omics approaches to prioritize the variant-regulated functional long non-coding RNAs in autism spectrum disorder

Objective: Rising evidence has indicated that long non-coding RNA (lncRNA) may play an essential role in the development of autism spectrum disorder (ASD). However, identifying the lncRNAs associated with ASD and the risk loci on them remains a major challenge. This study aims to identify potential causative variants and explore the related mechanisms.Methods: By leveraging differential expression analysis, WGCNA analysis and cis-expression quantitative analysis, our study mined functional SNPs with the regulated long non-coding RNA genes in brain tissues. We recruited 611 ASD children and 645 healthy children in the case-control study.Results: Total 68 different expressed lncRNAs were validated by calculating the brain tissue-specific expression using RNA-seq data. By the WGCNA method, 9 functional lncRNAs classified as e-lncRNA were found to interact with 976 ASD risk genes. Furthermore, we mined functional SNPs regulated long non-coding RNAs in brain tissues. We analyzed the association between candidate SNPs and ASD risks in Chinese children, which showed BDNF-AS rs1565228 allele G to C reduced the risk of ASD (OR = 0.81, 95%CI: 0.66-0.98). Further bioinformatics analysis showed that the variant rs1565228 C>G with the low binding affinity of transcription factor SRF caused the decreased expression of lncRNA BDNF-AS. Our study revealed that rs2295412 in the non-coding sequence of the lncRNA gene region was significantly associated with the risk of ASD.Discussion: These findings suggested that the SNPs in the non-coding region of lncRNA may play important roles in the genetic susceptibility of ASD, which may facilitate the early screening of ASD.

Automated summary

This study aims to identify potential causative variants of autism spectrum disorder (ASD) by analyzing the differential expression of long non-coding RNA genes in brain tissues. By utilizing different analytic methods, functional SNPs and their association with ASD risk were identified. A specific SNP (rs1565228) was found to reduce the risk of ASD, and further analysis indicated its role in regulating the expression of a specific long non-coding RNA.