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. 2025 Apr 29;16(5):523.
doi: 10.3390/genes16050523.

Genetic Analysis Reveals a Protective Effect of Sphingomyelin on Cholelithiasis

Kun Mao  1   2 , Ang Li  1   2 , Haochen Liu  1 , Yuntong Gao  1 , Ziyan Wang  1 , Xisu Wang  1 , Shixuan Liu  1 , Ziyuan Gao  1 , Jiaqi Quan  1 , Moyan Shao  1 , Yunxi Liu  1 , Liang Shi  1 , Bo Zhang  3   4   5 , Tianxiao Zhang  1   6
Affiliations

Genetic Analysis Reveals a Protective Effect of Sphingomyelin on Cholelithiasis

Kun Mao et al. Genes (Basel). .

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.

Keywords: Mendelian randomization; cholelithiasis; choline metabolites; colocalization analysis; low-density lipoprotein.

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Conflict of interest statement

All authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript; or in the decision to publish the results.

Figures

Figure 1
Figure 1
Conceptual framework of this study.
Figure 2
Figure 2
Mendelian randomization analysis of the relationship between choline metabolites and cholelithiasis (results corresponding to five different methods).
Figure 3
Figure 3
Forest plots of mediated Mendelian randomization analysis. (A) MR-estimated effects of sphingomyelin on LDL and HDL, presented as β1 with 95% CI. (B) MR-estimated effects of LDL and HDL on cholelithiasis, presented as β2 with 95% CI. (C) Indirect effects and proportions mediated of each mediator separately, by product of coefficients method with delta method estimated 95% CIs.
Figure 4
Figure 4
Manhattan plots for colocalization analysis. (A) Manhattan plot of selected SNPs associations with PPH4 at the genome-wide scale, the vertical coordinate indicates PPH4. Yellow and purple dots are used to distinguish between different chromosomes. (B–H) Locus comparison plot for the colocalization regions (PPH4 > 0.9) that were identified through the implementation of the COLOC analysis. The purple dot is used to denote the independent SNPs associated with genetic liability. The corresponding “selected SNPs” are rs1260326, rs4665972, 1s56266464, 1s3802548, 1s35106244, 1575003668 and rs2649999 in order.
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