Genetic variants affecting RNA stability influence complex traits and disease risk

Gene expression is jointly modulated by transcriptional regulation and mRNA stability, yet the latter is often overlooked in studies on genetic variants. Leveraging metabolic labeling data (Bru/BruChase-seq) and a new computational pipeline, RNAtracker, we distinguished allele-specific RNA stability (asRS) from allele-specific RNA transcription (asRT) events. Our analysis identified >5,000 asRS variants, revealing comparable impact of stability on allelic imbalance as transcriptional regulation. This study highlights RNA stability as a critical, yet understudied mechanism linking genetic variation and disease. Overall design: To validate asRS genes identified by RNAtracker, we performed RNA-seq for GM12878, MCF-7, and HCT116 cells before treatment with 10 ug/ml (GM12878, HCT116) or 5 ug/ml (MCF-7) of the transcriptional inhibitor Actionomycin D, as well as 2h, 8h, and 24h post-treatment (3 replicates per timepoint).