An integrative pipeline for circular RNA quantitative trait locus discovery with application in human T cells

Molecular quantitative trait locus (QTL) mapping has proven to be a powerful approach for prioritizing genetic regulatory variants and causal genes identified by genome-wide association studies. Recently, this success has been extended to circular RNA (circRNA), a potential group of RNAs that can serve as markers for the diagnosis, prognosis, or therapeutic targets of various human diseases. However, a well-developed computational pipeline for circRNA QTL (circQTL) discovery is still lacking.

We introduce an integrative method for circQTL mapping and implement it as an automated pipeline based on Nextflow, named cscQTL. The proposed method has two main advantages. Firstly, cscQTL improves the specificity by systematically combining outputs of multiple circRNA calling algorithms to obtain highly confident circRNA annotations. Secondly, cscQTL improves the sensitivity by accurately quantifying circRNA expression with the help of pseudo references. Compared to the single method approach, cscQTL effectively identifies circQTLs with an increase of 20%-100% circQTLs detected and recovered all circQTLs that are highly supported by the single method approach. We apply cscQTL to a dataset of human T cells and discover genetic variants that control the expression of 55 circRNAs. By colocalization tests, we further identify circBACH2 and circYY1AP1 as potential candidates for immune disease regulation.

cscQTL is freely available at: https://github.com/datngu/cscQTL and https://doi.org/10.5281/zenodo.7851982.