Integrated analysis of transcriptome and DNA sequence variation identifies genetic variants associated with circular RNA expression and their potential to contribute to disease risk

Expression quantitative trait loci (eQTL) are genomic regions that influence RNA transcript expression levels and have potential to contribute at all major stages of gene regulation cascade. Circular RNAs (circRNAs), an... [ view full abstract ]

Expression quantitative trait loci (eQTL) are genomic regions that influence RNA transcript expression levels and have potential to contribute at all major stages of gene regulation cascade. Circular RNAs (circRNAs), an emerging area of much research activity, with abundant presence in eukaryotic transcriptomes are linked to various human disorders and have not yet been studied for their association with genetic polymorphisms. We present an integrated analysis of circRNAs and genome sequence variation and show that circRNA expression is influenced by local single nucleotide polymorphic sites, referred to as circQTLs. These 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. Finally, circQTLs and eQTLs exist in separate linkage disequilibrium (LD) blocks with differential enrichments for functionally annotated features. The circQTL SNPs are highly enriched for human diseases and GWAS phenotypes and could potentially contribute to disease risk. This study reveals a previously uncharacterized role of the DNA sequence variation in human gene regulation and greatly improves our understanding of the mechanisms linking genetic variation to gene expression.