Response splicing quantitative trait loci in primary human chondrocytes identify putative osteoarthritis risk genes

Osteoarthritis affects millions worldwide, yet effective treatments remain elusive due to poorly understood molecular mechanisms. While genome-wide association studies (GWAS) have identified hundreds of osteoarthritis-associated loci, identifying the genes impacted at each locus remains challenging. We investigate alternative splicing using RNA-sequencing data from 101 human chondrocyte samples treated with phosphate-buffered saline or fibronectin fragment, an osteoarthritis trigger. We identified 590 differentially spliced genes between conditions, with FN-f inducing splicing events similar to those in primary osteoarthritis tissue. CRISPR/Cas9 mimicking of an SNRNP70 splicing event observed in osteoarthritis induced an osteoarthritis-like expression pattern. Integration with genotyping data revealed 7188 splicing quantitative trait loci (sQTL) affecting 3056 genes, including 738 and 343 condition-specific sQTLs for resting and fibronectin fragment, respectively. Colocalization with osteoarthritis GWAS identified 6 putative risk genes. Our study highlights the significant impact of alternative splicing in osteoarthritis and provides potential therapeutic targets. The authors identify thousands of genetic variants affecting RNA splicing in primary human chondrocytes and link several of them to osteoarthritis risk using genome editing and computational approaches.