{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T01:13:20Z","timestamp":1760058800998,"version":"build-2065373602"},"reference-count":40,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2025,4,29]],"date-time":"2025-04-29T00:00:00Z","timestamp":1745884800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Hygiene and Health Care Scientific Research Program of Shaanxi Province","award":["2022D010","HXDSH20232686"],"award-info":[{"award-number":["2022D010","HXDSH20232686"]}]},{"name":"Scientific Research Program of Shaanxi Provincial Centre for Disease Control and Prevention","award":["2022D010","HXDSH20232686"],"award-info":[{"award-number":["2022D010","HXDSH20232686"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>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.<\/jats:p>","DOI":"10.3390\/genes16050523","type":"journal-article","created":{"date-parts":[[2025,5,1]],"date-time":"2025-05-01T03:50:43Z","timestamp":1746071443000},"page":"523","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Genetic Analysis Reveals a Protective Effect of Sphingomyelin on Cholelithiasis"],"prefix":"10.3390","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0009-0008-1778-0169","authenticated-orcid":false,"given":"Kun","family":"Mao","sequence":"first","affiliation":[{"name":"Department of Epidemiology and Biostatistics, School of Public Health, Xi\u2019an Jiaotong University Health Science Center, Xi\u2019an 710061, China"},{"name":"Xi\u2019an Jiaotong University Health Science Center, Xi\u2019an 710061, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ang","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Epidemiology and Biostatistics, School of Public Health, Xi\u2019an Jiaotong University Health Science Center, Xi\u2019an 710061, China"},{"name":"Xi\u2019an Jiaotong University Health Science Center, Xi\u2019an 710061, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Haochen","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Epidemiology and Biostatistics, School of Public Health, Xi\u2019an Jiaotong University Health Science Center, Xi\u2019an 710061, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yuntong","family":"Gao","sequence":"additional","affiliation":[{"name":"Department of Epidemiology and Biostatistics, School of Public Health, Xi\u2019an Jiaotong University Health Science Center, Xi\u2019an 710061, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ziyan","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Epidemiology and Biostatistics, School of Public Health, Xi\u2019an Jiaotong University Health Science Center, Xi\u2019an 710061, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xisu","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Epidemiology and Biostatistics, School of Public Health, Xi\u2019an Jiaotong University Health Science Center, Xi\u2019an 710061, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shixuan","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Epidemiology and Biostatistics, School of Public Health, Xi\u2019an Jiaotong University Health Science Center, Xi\u2019an 710061, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ziyuan","family":"Gao","sequence":"additional","affiliation":[{"name":"Department of Epidemiology and Biostatistics, School of Public Health, Xi\u2019an Jiaotong University Health Science Center, Xi\u2019an 710061, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jiaqi","family":"Quan","sequence":"additional","affiliation":[{"name":"Department of Epidemiology and Biostatistics, School of Public Health, Xi\u2019an Jiaotong University Health Science Center, Xi\u2019an 710061, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Moyan","family":"Shao","sequence":"additional","affiliation":[{"name":"Department of Epidemiology and Biostatistics, School of Public Health, Xi\u2019an Jiaotong University Health Science Center, Xi\u2019an 710061, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yunxi","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Epidemiology and Biostatistics, School of Public Health, Xi\u2019an Jiaotong University Health Science Center, Xi\u2019an 710061, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Liang","family":"Shi","sequence":"additional","affiliation":[{"name":"Department of Epidemiology and Biostatistics, School of Public Health, Xi\u2019an Jiaotong University Health Science Center, Xi\u2019an 710061, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bo","family":"Zhang","sequence":"additional","affiliation":[{"name":"School of Life Science and Technology, Xi\u2019an Jiaotong University, Xi\u2019an 710049, China"},{"name":"The Key Laboratory of Biomedical Information Engineering of Ministry of Education, Xi\u2019an Jiaotong University, Xi\u2019an 710049, China"},{"name":"The School of Mathematics and Statistics, Xi\u2019an Jiaotong University, Xi\u2019an 710049, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5835-8625","authenticated-orcid":false,"given":"Tianxiao","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Epidemiology and Biostatistics, School of Public Health, Xi\u2019an Jiaotong University Health Science Center, Xi\u2019an 710061, China"},{"name":"Department of Geriatric Endocrinology Metabolism, The Second Affiliated Hospital of Xi\u2019an Jiaotong University, Xi\u2019an 710004, China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,4,29]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"16024","DOI":"10.1038\/nrdp.2016.24","article-title":"Gallstones","volume":"2","author":"Lammert","year":"2016","journal-title":"Nat. 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