Genetic control of RNA splicing and its distinctive role in complex trait variation

Abstract Most genetic variants identified from genome-wide association studies (GWAS) in humans are noncoding, indicating their role in gene regulation. Prior studies have shown considerable links of GWAS signals to expression quantitative trait loci (eQTLs), but the links to other genetic regulatory mechanisms such as splicing QTLs (sQTLs) are underexplored. Here, we introduce a transcript-based sQTL method (named THISTLE) with improved power for sQTL detection. Applying THISTLE along with LeafCutter, an event-based sQTL method, to brain transcriptomic data (n=1,073), we identified 7,491 genes with sQTLs with P<5×10^(-8) (the largest brain cis-sQTL collection to date), ~68% of which were distinct from eQTLs. Integrating the sQTL data into GWAS for ten brain-related complex traits (including diseases), we identified 107 genes associated with the traits through the sQTLs, ~68% of which could not be discovered using eQTL data. Our study demonstrates the distinctive role of most sQTLs in genetic regulation of transcription and complex trait variation.