Genome-Wide Pleiotropic Analyses Characterize the Genetic Etiology Shared between Cardiovascular and Gastrointestinal Tract Diseases

Background This study aimed to investigate the shared genetic etiology between gastrointestinal tract and cardiovascular diseases, and to identify shared genomic loci, genes, and pathways.​ Methods Using aggregated genome-wide association statistics from public data sources, a genome-wide pleiotropic association study was conducted. Multiple statistical genetic approaches were applied to sequentially explore pleiotropic associations across genome-wide single-nucleotide variations, genes, biological pathways, and gut microbiota. The potential shared genetic causes among 7 gastrointestinal tract diseases and 11 cardiovascular diseases were analyzed.​ Results A total of 350 pleiotropic loci were identified. Colocalization analysis detected 95 shared causal loci across disease pairs. Multiple gene pathways were found to be closely associated with these diseases, and key biological processes—including cell signal transduction and T-cell activation—exhibited significant correlations across the studied diseases. A robust pleiotropic association was observed between gastrointestinal tract and cardiovascular diseases, suggesting that these diseases may cross-influence each other in the context of different immune cells and tissues, while sharing common immune response mechanisms. Several immune cell populations, such as CD103⁺ CD11b⁺ dendritic cells, CD8⁺ splenic lymph node DCs, and γδ T cells, showed cross-disease correlations, highlighting the critical role of the immune system in the pathogenesis of both gastrointestinal tract and cardiovascular diseases. Multitrait colocalization analysis via HyPrColoc identified 6 pleiotropic loci harboring shared microbiota, underscoring the significant involvement of gut microbiota in disease pleiotropy.​ Conclusions This study establishes a genetic and mechanistic framework for the shared etiology of gastrointestinal tract and cardiovascular diseases, with pleiotropic variants, inflammatory pathways, and gut microbiota interactions as key drivers. These insights not only deepen our understanding of cardiovascular-gastrointestinal comorbidities but also lay the groundwork for precision medicine strategies targeting shared biological mechanisms.