Detection of circular RNA expression and related quantitative trait loci in the human dorsolateral prefrontal cortex

Zelin Liu,Yuan Ran,Changyu Tao,Jian Chen,Ence Yang,Sichen Li

doi:10.1186/s13059-019-1701-8

Zelin Liu, Yuan Ran + Show 4 more

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https://doi.org/10.1186/s13059-019-1701-8

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Abstract

BackgroundCircular RNAs (circRNAs) are implicated in various biological processes. As a layer of the gene regulatory network, circRNA expression is also an intermediate phenotype bridging genetic variation and phenotypic changes. Thus, analyzing circRNA expression variation will shed light on molecular fundamentals of complex traits and diseases.ResultsWe systematically characterize 10,559 high-quality circRNAs in 589 human dorsolateral prefrontal cortex samples. We identify biological and technical factors contributing to expression heterogeneity associated with the expression levels of many circRNAs, including the well-known circRNA CDR1as. Combining the expression levels of circRNAs with genetic cis-acting SNPs, we detect 196,255 circRNA quantitative trait loci (circQTLs). By characterizing circQTL SNPs, we find that partial circQTL SNPs might influence circRNA formation by altering the canonical splicing site or the reverse complementary sequence match. Additionally, we find that a subset of these circQTL SNPs is highly linked to genome-wide association study signals of complex diseases, especially schizophrenia, inflammatory bowel disease, and type II diabetes mellitus.ConclusionsOur results reveal technical, biological, and genetic factors affecting circRNA expression variation among individuals, which lead to further understanding of circRNA regulation and thus of the genetic architecture of complex traits or diseases.

Highlights

Circular RNAs are implicated in various biological processes
Identification of Circular RNA (circRNA) in the human brain We systemically identified circRNAs by analyzing Ribo-Zero RNA-seq data from postmortem dorsolateral prefrontal cortex (DLPFC) samples collected from 258 schizophrenia (SCZ) patients, 54 affective/mood disorder (AFF) patients, and 277 controls (Table 1) downloaded from the CommonMind Consortium (CMC) database [11]
By testing all Circular RNA quantitative trait loci (circQTL) SNPs in high linkage disequilibrium (r2 > 0.8) with Genome-wide association studies (GWAS) SNPs (Additional file 9: Table S8), we further identified 157 circRNAs associated with 122 diseases

Summary

Introduction

Circular RNAs (circRNAs) are implicated in various biological processes. As a layer of the gene regulatory network, circRNA expression is an intermediate phenotype bridging genetic variation and phenotypic changes. Analyzing circRNA expression variation will shed light on molecular fundamentals of complex traits and diseases. Circular RNAs (circRNAs) are a class of recently identified long noncoding RNAs with a covalently closed continuous loop structure formed via back-splicing that have neither a 5′ cap nor a 3′ polyadenylated tail [1]. Several studies have identified circRNAs and quantified their abundance at the transcript level [9, 10], but small sample sizes limited their efforts to systemically dissect changes in circRNA expression. Data from the CommonMind Consortium (CMC) provide an opportunity to decipher circRNA expression variation. The CMC comprises nearly 600 brain samples obtained from the autopsies of individuals

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