Multi-omics Mendelian randomization identified adaptive immune response-related drug targets in psoriatic arthritis

Psoriatic arthritis is a chronically progressive, inflammatory disease mediated by immunity, accompanied by severe disability, which seriously affects the patient's physical and mental health. Despite considerable advances in the treatment of psoriatic arthritis, there remains a subset of patients for whom none of the available treatments is effective. Consequently, we identified novel drug targets for psoriatic arthritis by integrating adaptive immune-related genes. We combined Mendelian randomization (MR) and summary data-based MR (SMR) analyses to explore potential drug targets of psoriatic arthritis. Cis-expressed quantitative trait loci (cis-eQTL) data as exposure factors were obtained from the eQTLGen consortium. Genome-wide association study (GWAS) summary data for psoriatic arthritis were obtained from the FinnGen database and the IEU database. Additional analyses included Bayesian colocalization, bidirectional MR, and multivariate MR (MVMR) to further strengthen the reliability of the results. Drug prediction and phenome-wide association studies (PheWAS) were employed to assess the potential of drug targets for clinical practice. Finally, protein-protein interaction (PPI) network analysis and enrichment analysis were performed to probe the functional characteristics and biological implications of potential therapeutic targets. In the discovery phase, we identified 13 adaptive immune-related genes with significant Mendelian randomization evidence for association with psoriatic arthritis, with genetically predicted higher IL6ST expression associated with increased disease risk. In the replication phase, IL6ST retained consistent direction and effect sizes across outcome, method, and exposure validation analyses. Colocalization and reverse MR provided further support for IL6ST as a genetically prioritized candidate therapeutic target for psoriatic arthritis. PheWAS and compound-gene signature enrichment analyses did not reveal strong pleiotropic associations and suggested exploratory translational context for IL6ST, whereas PPI network and enrichment analyses indicated that IL6ST and its interacting proteins are embedded in immune and inflammatory pathways implicated in psoriatic arthritis. This study identified IL6ST as a genetically supported candidate therapeutic target for psoriatic arthritis, providing certain insights into drug development for psoriatic arthritis.