Identification of the relationship between 1400 blood metabolites and urolithiasis: A bidirectional Mendelian randomization study

Relationships between blood metabolites and urolithiasis have been identified in few previous observational studies, and causality remains uncertain. We tried to examine whether blood metabolites were causally associated with upper and lower urinary stones in this bidirectional Mendelian randomization (MR) study. The causal relationship between 1400 blood metabolites and upper and lower urinary stones was investigated using genome-wide association study data. The primary analysis for causality analysis was the inverse variance weighted method, with 4 other methods used as complementary analyses. Intersection was then conducted to show the shared metabolites between upper and lower urinary tract stones, followed by the MR-Egger intercept test, Cochran Q test, leave-one-out analysis, MR-PRESSO and the linkage disequilibrium score regressions. The metabolic pathway analysis was conducted to identify potential metabolic pathways. Lastly, reverse MR analyses were also performed. We identified 15 metabolites as potential causal predictors of urinary stones in forward MR analyses. These metabolites consisted of 1 azole, 2 carbohydrates, 6 lipids, 1 nucleotide, 1 peptide, 1 urea, and 3 metabolites with unknown chemical properties. Additionally, urinary stones were found to be significantly associated with some of the above metabolites in reverse MR analyses. Metabolic pathway analysis identified several pathways that may be implicated in the development of urolithiasis. This MR study has established a causal relationship between 12 blood metabolites and the risk of upper and lower urinary tract stones. The identification of these blood metabolites provides valuable insights into early screening, prevention, and treatment of urolithiasis.