sQTLs

Splicing quantitative trait loci (sQTLs) are genetic variants that influence RNA splicing patterns. They are identified by linking genotype with splicing phenotypes derived from RNA sequencing across individuals, tissues, or conditions. The most common splicing phenotype is percent spliced in (PSI), representing the fraction of transcripts in which a particular exon is included or a splice site is utilized. sQTLs can affect exon skipping, intron retention, or the choice of alternative 5' or 3' splice sites, and may alter regulatory elements or splice factor binding sites.

Most sQTL studies focus on cis effects, where the variant is near the affected splicing event, typically within about 1 Mb, though trans-sQTLs have also been reported. Data come from RNA-seq and genotype data; splicing events are quantified with PSI-based methods or intron cluster approaches. Statistical models, often linear or linear mixed models, test associations between genotype and splicing traits, with covariates for population structure, technical factors, and hidden confounders. Multiple testing correction and tissue-specific analyses are common challenges.

Interpreting sQTLs helps connect genetic variation to transcript diversity and complex traits. Colocalization with disease GWAS signals suggests that splicing changes mediate disease risk. Functional validation, such as minigene assays or genome editing, can confirm regulatory effects. sQTLs complement expression QTLs by revealing regulatory variation that shapes isoform usage rather than overall transcript abundance.