Background:　Sepsis,　a　life-threatening　condition　driven　by　dysregulated　immune　responses,　imposes　a　substantial　global　health　burden.　Despite　advancements,　its　complex　pathophysiology　and　urgent　need　for　timely　intervention　underscore　the　necessity　to　identify　novel　genetic　risk　factors.　This　study　aimed　to　systematically　investigate　causal　genetic　determinants　of　sepsis　and　its　severe　subtypes.　Methods:　Leveraging　genome-wide　association　study　data　from　the　UK　Biobank,　two-sample　Mendelian　randomization　analysis　was　performed　on　72　candidate　genes.　Complementary　methods　included　protein-protein　interaction　network　mapping,　heatmap　visualization,　Bayesian　colocalization,　regional　association　analysis,　and　transcriptomic　sequencing.　Results:　A　series　of　genes　was　identified　to　be　causally　associated　with　severe　sepsis　subtypes.　The　PSMA4　gene　emerged　as　the　most　robust　causal　gene　across　all　sepsis　phenotypes　(sepsis:　beta　=　0.23,　P　=　4.07　x　10(-36);　sepsis　in　critical　care:　beta　=　0.22,　P　=　3.49　x　10(-4);　sepsis　with　28-day　death　in　critical　care:　beta　=　0.43,　P　=　5.94　x　10(-19)).　Colocalization　confirmed　a　shared　causal　variant　between　PSMA4　expression　and　sepsis　risk　(PP.H4.abf　=　96.5%).　In　the　transcriptomic　data,　we　found　that　the　expression　of　PSMA4　was　significantly　elevated　in　sepsis　and　septic　shock　patients　(P　=　0.003　for　sepsis　patients　and　P　＜　0.001　for　septic　shock　patients,　respectively).　Conclusion:　By　employing　a　comprehensive　multidimensional　approach,　we　identified　key　genetic　contributors　to　sepsis,　with　PSMA4　emerging　as　the　most　significant　genetic　risk　factor　underlying　both　susceptibility　and　disease　severity.　These　findings　highlighted　PSMA4　as　a　therapeutic　target,　offering　the　potential　for　sepsis　management.