# Genetic Analysis Reveals a Protective Effect of Sphingomyelin on Cholelithiasis

## TL;DR

This study finds that sphingomyelin has a protective effect against gallstones, with LDL playing a key role in this relationship.

## Contribution

The novel contribution is identifying a protective causal effect of sphingomyelin on cholelithiasis mediated by LDL, supported by genetic evidence.

## Key findings

- Sphingomyelin has a significant protective causal effect on cholelithiasis (p-value = 0.0002).
- LDL mediates 59.18% of the causal relationship between sphingomyelin and cholelithiasis.
- Seven genes (e.g., GCKR, ABCG8) are colocalized with the causal signal between sphingomyelin and cholelithiasis.

## Abstract

Background: Cholelithiasis is the most common disorder affecting the biliary system. Choline is an essential nutrient in the human diet and is crucial for the synthesis of neurotransmitters. Previous studies have suggested an association between choline metabolites and cholelithiasis. However, the underlying mechanisms remain unclear. This research aims to fill the knowledge gap regarding the role of choline metabolites in cholelithiasis. Methods: Genetic data related to choline metabolites and other covariates were retrieved from the U.K. Biobank and IEU OpenGWAS database. Two-sample (TSMR) and multivariate Mendelian randomization (MVMR) analyses, mediation analysis, linkage disequilibrium score regression (LDSC), colocalization analysis, and enrichment analysis were performed. Results: A significant causal relationship was identified between serum level of sphingomyelin and cholelithiasis (p-value = 0.0002). A protective causal effect was identified in MVMR analysis. The following mediated MR analysis indicated that only LDL mediated a large part of the causal relationship (59.18%). Seven genes, including GCKR, SNX17, ABCG8, MARCH8, FUT2, APOH, and HNF1A, were revealed to be colocalized with the causal signal between sphingomyelin and cholelithiasis. Conclusion: The present study has identified a protective effect between sphingomyelin and cholelithiasis. This effect is largely mediated by LDL. The findings of this study offer valuable information for further exploration of the molecular mechanisms of cholelithiasis.