Identification of human genetic variants controlling circular RNA expression

Abstract

Circular RNAs (circRNAs) are abundant in eukaryotic transcriptomes and have been linked to various human disorders. However, understanding genetic control of circular RNA expression is in early stages.Here we present the first integrated analysis of circRNAs and genome sequence variation from lymphoblastoid cell lines of the 1000 genomes project. We identified thousands of circRNAs in the RNAseq data and show their association with local single nucleotide polymorphic sites, referred to as circQTLs, which influence the circRNA transcript abundance. Strikingly, we found that circQTLs exist independently of eQTLs with most circQTLs having no effect on mRNA expression. Only a fraction of the polymorphic sites are shared and linked to both circRNA and mRNA expression with mostly similar effects on circular and linear RNA. A shared intronic QTL, rs55928920, of HMSD gene drives the circular and linear expression in opposite directions, potentially modulating circRNA levels at the expense of mRNA. Finally, circQTLs and eQTLs are largely independent and exist in separate linkage disequilibrium (LD) blocks with circQTLs highly enriched for functional genomic elements and regulatory regions. This study reveals a previously uncharacterized role of DNA sequence variation in human circular RNA regulation.

Trans-genetic effects of circular RNA expression quantitative trait loci and potential causal mechanisms in autism

“…The majority of circQTLs (90.5%; 603 out of 666; Supplementary Table 2) were located in the anking sequences of back-splice sites. These observations were consistent with previous studies for distance distribution analysis of circQTLs in other human samples 33,34 . Next, backsplicing was reported to be facilitated by reverse complementary sequences (RCSs) residing in the introns anking circularized exons 27,35,36 .…”

Inflammation Related circRNAs Polymorphism and Ischemic Stroke Prognosis

“…Recent studies have provided evidence on single nucleotide polymorphisms (SNPs) associated with circRNA expression. Ahmed et al [9] integrated circular RNA expression from RNA-seq data of lymphoblastoid cell lines with genome sequence variation from the 1000 Genomes Project and identi ed thousands of cis-acting genetic variants at the circRNA in uencing its expression, referred to as circRNA quantitative trait loci (circQTLs). Additionally, circQTLs existed independently of eQTLs and exerted no effect on mRNA expression.…”