Systematic druggable genome-wide Mendelian randomization identifies therapeutic targets for gout

Gout is a prevalent and debilitating form of inflammatory arthritis caused by the deposition of monosodium urate crystals resulting from sustained hyperuricemia. Despite the availability of urate-lowering therapies, a substantial proportion of patients continue to experience recurrent flares or face treatment limitations, underscoring the urgent need for alternative therapeutic strategies. Recent advances in human genetics, particularly the application of genome-wide Mendelian randomization, enable systematic evaluation of druggable targets and provide a powerful approach to accelerate the discovery of novel therapeutic interventions for gout. We performed two-sample Mendelian randomization (MR) integrating druggable genes with cis-eQTL data from human blood to evaluate their causal effects on gout. Replication analysis was conducted in an independent gout GWAS cohort, and significant signals were further examined via SMR, HEIDI, and Bayesian colocalization to strengthen causal inference. To investigate potential mechanisms, mediation MR was applied to relevant biomarkers, and phenome-wide MR was employed to assess side effects and pleiotropic effects. Finally, the candidate genes were cross-referenced with pharmacological databases to identify actionable drugs. Using genome-wide druggable Mendelian randomization analysis combined with replication, SMR with HEIDI testing, and Bayesian colocalization, we identified three high-confidence druggable genes with potential causal roles in gout: KAT5, THBS3, and MAP3K11. Two-step MR suggested that KAT5 may influence gout risk indirectly via uric acid levels. Phe-MR indicated minimal potential adverse effects for KAT5, whereas MAP3K11 and THBS3 may be associated with altered risks of certain diseases. Drug target evaluation revealed that MAP3K11 is already addressed by approved therapeutics, suggesting strong repurposing potential, whereas THBS3 and KAT5 may serve as early leads for the development of therapeutics with novel mechanisms in gout. This study provides genetic evidence supporting KAT5, THBS3, and MAP3K11 as priority therapeutic targets in gout, offering valuable guidance for subsequent targeted drug development and repurposing.