From genetic causality to druggable targets: A multiomics framework identifies ZSCAN16 in gout pathogenesis

ObjectiveGout is a prevalent form of inflammatory arthritis in which many patients respond suboptimally to current therapies. Drug development is hampered by a lack of genetically validated targets, leading to high clinical trial attrition. This study aimed to systematically identify and prioritize novel, druggable targets for gout via a multilayered genetic and functional genomics approach.MethodsWe performed two-sample Mendelian randomization (MR) using cis-expression quantitative trait locus (cis-eQTL) data and dual independent gout genome-wide association study (GWAS) cohorts (openGWAS and FinnGen). The candidate genes were subjected to a rigorous validation pipeline including Bayesian colocalization, phenome-wide association studies (PheWASs) to assess pleiotropy and on-target safety, and single-cell RNA sequencing (scRNA-seq) to delineate the cellular context. Molecular docking was used to evaluate the structural druggability of prioritized targets.ResultsMR analysis revealed 15 genes causally associated with gout. Colocalization analysis (PPH4 > 0.8) prioritized two targets: ZSCAN16 (risk-increasing, OR = 1.04, 95% CI [1.02-1.06]) and TRIM10 (protective, OR = 0.96, 95% CI [0.94-0.98]). Crucially, PheWAS revealed that ZSCAN16 is highly specific to gout, whereas TRIM10 exhibited extensive pleiotropy with hematological and cardiometabolic traits, indicating significant safety risks. Single-cell analysis provided orthogonal validation, demonstrating flare-specific upregulation of ZSCAN16 in cytotoxic T/NK cells. Molecular docking confirmed ZSCAN16 as a structurally druggable target, showing high-affinity binding with known compounds (e.g. digoxin, binding energy = -9.6 kcal/mol).ConclusionsOur study identifies ZSCAN16 as a high-potential, druggable therapeutic target for gout, highlighting its genetic influence on specific immune cell activities during acute flares. Conversely, TRIM10 was deprioritized owing to substantial pleiotropic liabilities and poor chemical tractability. These findings suggest that ZSCAN16 could play a crucial role in the pathogenesis of gout and may provide a valuable lead for future drug discovery efforts.