KEY POINTS: Positive genetic links and shared genetic architecture exist between gastrointestinal disorders and kidney stone disease. Ion homeostasis and response to vitamin D bridge two types of disorders. Genetically predicted irritable bowel syndrome, gastroesophageal reflux, and Crohn's disease were associated with higher risk of kidney stone disease. BACKGROUND: Epidemiological associations between kidney stone disease (KSD) and gastrointestinal disorders have been reported, and intestinal homeostasis plays a critical role in stone formation. However, the underlying intrinsic link is not adequately understood. This study aims to investigate the genetic associations between these two types of diseases. METHODS: We obtained summary statistics from large-scale genome-wide association studies of KSD and gastrointestinal diseases, including gastroesophageal reflux disease, peptic ulcer disease, inflammatory bowel disease and its subtypes, irritable bowel syndrome, and diverticular disease (=311,254–720,199). Their overall genetic correlations were first estimated. We then detected the shared genetic architecture, including pleiotropic single nucleotide polymorphisms, loci, genes, and biological processes, through cross-trait analyses. In addition, bidirectional Mendelian randomization analysis was performed to look for their causal relationships. RESULTS: We found significantly positive genetic correlations between KSD and all five gastrointestinal diseases. The cross-trait analysis identified 3184 potential pleiotropic single nucleotide polymorphisms, and 33 of which were pleiotropic loci shared by the two disorders. Gene-level analyses revealed eight pleiotropic causal genes, primarily enriched in biological pathways involving ion homeostasis and response to vitamin D. In the Mendelian randomization analysis, we detected causal effects from gastroesophageal reflux disease, irritable bowel syndrome, and Crohn's disease to KSD, while no reverse causality was observed. CONCLUSIONS: Our study demonstrated the positive genetic links between KSD and gastrointestinal diseases and reported pleiotropic variants, loci, and genes, implicating potential biological mechanisms in the pathogenesis of stone disease. These findings further support the role of the gut-kidney axis and provide a genetic basis for the prevention, coregulation, and treatment of these diseases.