GWAS Reveals Distinct Genetic Architecture of Schistosomiasis-Induced Hepatic Fibrosis with <i>DGKG</i> as a Key Mediator

Abstract Background &amp; Aims Schistosomiasis is a major cause of hepatic fibrosis in endemic regions, yet the host genetic determinants of disease progression remain poorly defined. We aimed to identify genetic drivers and underlying mechanisms of schistosomiasis-induced hepatic fibrosis. Methods We performed a genome-wide association study (GWAS) of 984 Schistosoma japonicum -infected individuals from hyperendemic areas in China followed by multi-omics integration and experimental validation to identify causal genes and fibrogenic pathways. Results Schistosomiasis-associated fibrosis exhibited a genetic architecture distinct from metabolic and viral liver fibrosis, supporting pathogen-specific mechanisms. Eight novel susceptibility loci were identified, including a genome-wide significant signal at 16p13 (rs73575170, P = 3.9 × 10⁻⁸). Integrative mapping linked these loci to 262 genes enriched in liver sinusoidal endothelial cells ( P = 5.84 × 10⁻⁵) and sphingolipid metabolism pathways ( P = 4.19 × 10⁻⁵). Notably, Diacylglycerol kinase gamma ( DGKG , rs6762330, P = 4.37 × 10⁻⁶) emerged as a key candidate, with its expression in peri-granuloma and periportal hepatocytes strongly correlating with fibrosis severity ( r = 0.816). In vivo , Dgkg knockout attenuated hepatic fibrosis and immunopathology while restoring cholesterol homeostasis, whereas Dgkg overexpression exacerbated fibrogenesis and increased TNF-α levels tenfold. Conclusions This study identifies DGKG as a key mediator linking lipid metabolism and immune signaling in schistosomiasis-induced fibrosis, uncovering a pathogen-specific genetic mechanism and providing a potential therapeutic target for infection-associated liver fibrosis. Impact and Implications This study defines a pathogen-specific genetic architecture underlying schistosomiasis-associated hepatic fibrosis, distinguishing it from metabolic and viral fibrotic liver diseases. By integrating GWAS analysis and in vivo functional validation, DGKG is identified as a key regulator linking lipid metabolism and immune-driven fibrogenesis. These findings highlight liver sinusoidal endothelial cells and sphingolipid signaling as critical cellular and molecular contexts for schistosomiasis-associated hepatic fibrosis. Beyond advancing mechanistic understanding of schistosomiasis, this work provides a genetic and functional framework for targeting DGKG -mediated pathways, with potential implications for precision therapies in parasitically mediated liver fibrotic disorders.