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The circles Part II: investigating causal relationship between genetic variants and circular RNA expression in autism

Autism spectrum disorder (ASD) is a pervasive neurodevelopmental and heritable complex disorder characterized by limited social communication, restricted and ritualized interests, and repetitive behavior [Mendelian Inheritance in Man (MIM) 209850]. In the US, an estimation of prevalence of ASDs was about 1 in 68 (14.6 per 1,000) children aged 8 years, suggesting that there are more than 2 million ASD individuals in the US. In Taiwan, ASD afflicts more than 18,000 people (the 2022’s report from Ministry of Health and Welfare, Taiwan); and its prevalence is increasing.

After successfully constructing autism-associated circular RNA regulatory network (Academai Sinica research news: The Circles Part I), Prof. Trees-Juen Chuang’s group (Genomics Research center, Academia Sinica) further integrated RNA-sequencing with genotype data from autistic brains to assess expression quantitative trait loci of circRNAs (circQTLs) that cis-regulate expression of nearby circRNAs and trans-regulate expression of distant genes (trans-eGenes) simultaneously (Fig. 1). We conducted two different types of approaches to determine the axes with mediation effects of circQTLs on trans-eGene expression through circRNA expression and showed that the mediation effects of the circQTLs on circRNA expression were positively correlated with the magnitude of circRNA-trans-eGene correlation of expression profile. We provided the first framework for systematically investigating trans-genetic effects of circQTLs and inferring the corresponding causal relations in ASD. The identified circQTL-circRNA-trans-eGene regulatory interactions, particularly the internal modules that were previously implicated in the examined disorders, also provided a helpful dataset for further investigating causative biology and cryptic regulatory mechanisms underlying the neuropsychiatric diseases.

 

 2022ASD F1 EN
Figure 1. Identification of expression quantitative trait loci of circRNAs (circQTLs) that cis-regulate expression of nearby circRNAs and trans-regulate expression of distant genes (trans-eGenes) simultaneously. (A) Schematic diagram representing direct (blue bold line with arrow) and mediation (red bold line with arrow) effects of circQTLs (trans-eQTLs) on the expression of trans-eGenes. (B) The identified circQTL-circRNA-miRNA-trans-eGene propagation networks plotted by the Cytoscape package.

 

CircRNAs are an emerging class of RNAs, which are formed by pre-mRNA back-splicing with a structure of covalently closed loops and endogenously expressed as single-strand, non-polyadenylated circular molecules. Although circRNAs are generally expressed at a much lower level compared with their corresponding co-linear mRNA isoforms, they are more stable than other types of RNAs. CircRNAs were observed to be especially abundant in mammalian brain tissue and often play important roles in development of nervous system. As for the layer of gene regulatory networks, circRNAs often serve as an upstream regulator of mRNAs. They may regulate genes in trans through mediating the activities of miRNAs or RNA binding proteins (RBPs), with the common miRNA/RBP target sites of circRNAs and the target genes. Hence, we are curious about whether SNPs that influence expression of nearby circRNAs (referred to as circQTLs) may also affect expression of remote genes, whereby circRNAs serve as an intermediate regulator bridging circQTLs and trans-eGenes. If this is possible, we may generate circQTL-circRNA-trans-eGene propagation paths in autistic brains and shed light on the functional consequences of the genetic loci and the etiology of this complex disease.

The manuscript has been published in Molecular Psychiatry (27: 4695-4706, 2022). The authors include three co-first authors (Te-Lun Mai (assistant professor, Department of Life Science, National Taiwan University; Big Data Analysis), Chia-Ying Chen (Biostatistics), Yu-Chen Chen (Molecular Biology), Tai-Wei Chiang (Programmer), and corresponding author Trees-Juen Chuang. We sincerely appreciate any related funding supports for our studies.

The paper titled “Trans-genetic effects of circular RNA expression quantitative trait loci and potential causal mechanisms in autism” can be read online at: https://www.nature.com/articles/s41380-022-01714-4

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