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This study employed diverse genetic methodologies, including Transcriptome-Wide Association Studies (TWAS), Mendelian Randomization (MR), FOCUS, and colocalization analysis to investigate the genetic landscape of Primary Sclerosing Cholangitis (PSC) and its association with Inflammatory Bowel Disease (IBD),. We identified seven genes that are potentially causative of PSC and four among seven demonstrate significant links to IBD and the gut-liver axis. Our research revealed a notable causal relationship between PSC and IBD, specifically Ulcerative Colitis (UC). Additionally, we explored the influence of gut microbiota and metabolites on PSC to uncover the potential intermediary roles. These findings have deepened our understanding of PSC's pathogenesis and suggested novel therapeutic targets, addressing a crucial need for effective treatment of this complicated disease.