Genetic alternative splicing regulation mapping of cartilage and synovium reveals tissue-specific mechanisms of joint-related traits

Abstract Cartilage and synovium are essential tissues involved in joint-related diseases and traits, including osteoarthritis (OA), rheumatoid arthritis (RA), and human height. Although genome-wide association studies (GWAS) identify numerous risk loci for these traits, the molecular mechanisms underlying these associations, particularly those involving alternative splicing, remain poorly understood due to the lack of splicing-related genetic data in relevant tissues. To address this limitation, we generate a splicing quantitative trait loci (sQTL) resource for cartilage and synovium. We identify 2,796 independent cis-sQTLs and six trans-sGenes across the two tissues, including 179 tissue-specific cis-sQTLs. Fine-mapping analysis identifies 116 high-confidence functional sVariants predicted to affect splicing through splice site gain or loss, with approximately half located outside canonical splice site motifs. Integration of sQTL data with GWAS summary statistics reveals 12 osteoarthritis, 6 rheumatoid arthritis, and 183 height effector genes in joint tissues. Notably, seven of the 12 osteoarthritis effector genes show joint tissue-specific colocalization. Together with the finding that tissue-specific sGenes play crucial roles in tissue-related biological processes and diseases, our work highlights the significant impact of tissue-specific alternative splicing regulation on disease etiology and provides a valuable resource for further mechanistic validation.