4.6 Article

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

Journal

ASIAN JOURNAL OF PSYCHIATRY
Volume 80, Issue -, Pages -

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ELSEVIER
DOI: 10.1016/j.ajp.2022.103357

Keywords

Autism spectrum disorder; School children; Molecular genetics; LncRNA

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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.
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.

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