{"title":"[全现象范围的孟德尔随机化确定非综合征性唇裂伴或不伴腭裂的因果暴露]。","authors":"S Lou, C Y Xing, Y C Pan","doi":"10.3760/cma.j.cn112144-20250430-00165","DOIUrl":null,"url":null,"abstract":"<p><p><b>Objective:</b> To systematically investigate the causal effects of exposure factors on nonsyndromic cleft lip with or without cleft palate (NSCL/P) using a phenome-wide mendelian randomization (MR-PheWAS) framework and identify pleiotropic loci. <b>Methods:</b> This study integrated genome-wide association study (GWAS) data for NSCL/P, including 1 069 cases and 1 724 controls, and systematically evaluated causal associations between exposures and NSCL/P using the MR-PheWAS framework. GWAS summary data for 2 106 Asian population-exposure phenotypes were obtained from the IEU OpenGWAS database. The inverse-variance weighted (IVW) method served as the core causal inference model, supplemented by weighted median and MR-Egger regression to verify the robustness of causal associations. Additionally, multivariable MR analysis was conducted to adjust for confounding effects, alongside sensitivity tests (Cochran's Q and MR-PRESSO). Genetic correlations were analyzed using LD Score regression, and cross-phenotype pleiotropy analysis (PLACO/CPASSOC) was employed to identify shared genetic loci. Pathway enrichment and gene annotation data were integrated to explore potential biological mechanisms. <b>Results:</b> MR analysis identified serum calcium (<i>OR</i>=0.12, <i>P</i>=0.019), high-density lipoprotein (HDL, <i>OR</i>=0.61, <i>P</i>=0.039), and mean corpuscular hemoglobin concentration (MCHC, <i>OR</i>=0.39, <i>P</i>=0.032) as protective factors, whereas serum sodium (<i>OR</i>=21.41, <i>P</i>=0.013) was a risk factor. Furthermore, in subsequent analyses of genetic correlation and genetic overlap, a strong association was observed between serum calcium and NSCL/P. Cross-trait analysis localized pleiotropic loci to 16q24.2 and 3q21.1, involving CASR and CSTA, with significant enrichment in vitamin D response pathways. <b>Conclusions:</b> Numerous environmental exposure factors may have a causal impact on the outcomes of NSCL/P, and metabolic homeostasis (especially calcium signaling) plays a significant role in the pathogenesis of NSCL/P. Further genetic analyses identified potential pleiotropic loci primarily located at 16q24.2 and 3q21.1, involving key genes such as CASR and CSTA, and enriched in vitamin D response pathways. This study highlights the crucial position of genetic-environmental factors in the development of cleft lip and palate.</p>","PeriodicalId":23965,"journal":{"name":"中华口腔医学杂志","volume":"60 9","pages":"971-979"},"PeriodicalIF":0.0000,"publicationDate":"2025-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"[Phenome-wide mendelian randomization identifies causal exposures for nonsyndromic cleft lip with or without cleft palate].\",\"authors\":\"S Lou, C Y Xing, Y C Pan\",\"doi\":\"10.3760/cma.j.cn112144-20250430-00165\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p><b>Objective:</b> To systematically investigate the causal effects of exposure factors on nonsyndromic cleft lip with or without cleft palate (NSCL/P) using a phenome-wide mendelian randomization (MR-PheWAS) framework and identify pleiotropic loci. <b>Methods:</b> This study integrated genome-wide association study (GWAS) data for NSCL/P, including 1 069 cases and 1 724 controls, and systematically evaluated causal associations between exposures and NSCL/P using the MR-PheWAS framework. GWAS summary data for 2 106 Asian population-exposure phenotypes were obtained from the IEU OpenGWAS database. The inverse-variance weighted (IVW) method served as the core causal inference model, supplemented by weighted median and MR-Egger regression to verify the robustness of causal associations. Additionally, multivariable MR analysis was conducted to adjust for confounding effects, alongside sensitivity tests (Cochran's Q and MR-PRESSO). Genetic correlations were analyzed using LD Score regression, and cross-phenotype pleiotropy analysis (PLACO/CPASSOC) was employed to identify shared genetic loci. Pathway enrichment and gene annotation data were integrated to explore potential biological mechanisms. <b>Results:</b> MR analysis identified serum calcium (<i>OR</i>=0.12, <i>P</i>=0.019), high-density lipoprotein (HDL, <i>OR</i>=0.61, <i>P</i>=0.039), and mean corpuscular hemoglobin concentration (MCHC, <i>OR</i>=0.39, <i>P</i>=0.032) as protective factors, whereas serum sodium (<i>OR</i>=21.41, <i>P</i>=0.013) was a risk factor. Furthermore, in subsequent analyses of genetic correlation and genetic overlap, a strong association was observed between serum calcium and NSCL/P. Cross-trait analysis localized pleiotropic loci to 16q24.2 and 3q21.1, involving CASR and CSTA, with significant enrichment in vitamin D response pathways. <b>Conclusions:</b> Numerous environmental exposure factors may have a causal impact on the outcomes of NSCL/P, and metabolic homeostasis (especially calcium signaling) plays a significant role in the pathogenesis of NSCL/P. Further genetic analyses identified potential pleiotropic loci primarily located at 16q24.2 and 3q21.1, involving key genes such as CASR and CSTA, and enriched in vitamin D response pathways. This study highlights the crucial position of genetic-environmental factors in the development of cleft lip and palate.</p>\",\"PeriodicalId\":23965,\"journal\":{\"name\":\"中华口腔医学杂志\",\"volume\":\"60 9\",\"pages\":\"971-979\"},\"PeriodicalIF\":0.0000,\"publicationDate\":\"2025-09-09\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"中华口腔医学杂志\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.3760/cma.j.cn112144-20250430-00165\",\"RegionNum\":0,\"RegionCategory\":null,\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q4\",\"JCRName\":\"Medicine\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"中华口腔医学杂志","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.3760/cma.j.cn112144-20250430-00165","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q4","JCRName":"Medicine","Score":null,"Total":0}
[Phenome-wide mendelian randomization identifies causal exposures for nonsyndromic cleft lip with or without cleft palate].
Objective: To systematically investigate the causal effects of exposure factors on nonsyndromic cleft lip with or without cleft palate (NSCL/P) using a phenome-wide mendelian randomization (MR-PheWAS) framework and identify pleiotropic loci. Methods: This study integrated genome-wide association study (GWAS) data for NSCL/P, including 1 069 cases and 1 724 controls, and systematically evaluated causal associations between exposures and NSCL/P using the MR-PheWAS framework. GWAS summary data for 2 106 Asian population-exposure phenotypes were obtained from the IEU OpenGWAS database. The inverse-variance weighted (IVW) method served as the core causal inference model, supplemented by weighted median and MR-Egger regression to verify the robustness of causal associations. Additionally, multivariable MR analysis was conducted to adjust for confounding effects, alongside sensitivity tests (Cochran's Q and MR-PRESSO). Genetic correlations were analyzed using LD Score regression, and cross-phenotype pleiotropy analysis (PLACO/CPASSOC) was employed to identify shared genetic loci. Pathway enrichment and gene annotation data were integrated to explore potential biological mechanisms. Results: MR analysis identified serum calcium (OR=0.12, P=0.019), high-density lipoprotein (HDL, OR=0.61, P=0.039), and mean corpuscular hemoglobin concentration (MCHC, OR=0.39, P=0.032) as protective factors, whereas serum sodium (OR=21.41, P=0.013) was a risk factor. Furthermore, in subsequent analyses of genetic correlation and genetic overlap, a strong association was observed between serum calcium and NSCL/P. Cross-trait analysis localized pleiotropic loci to 16q24.2 and 3q21.1, involving CASR and CSTA, with significant enrichment in vitamin D response pathways. Conclusions: Numerous environmental exposure factors may have a causal impact on the outcomes of NSCL/P, and metabolic homeostasis (especially calcium signaling) plays a significant role in the pathogenesis of NSCL/P. Further genetic analyses identified potential pleiotropic loci primarily located at 16q24.2 and 3q21.1, involving key genes such as CASR and CSTA, and enriched in vitamin D response pathways. This study highlights the crucial position of genetic-environmental factors in the development of cleft lip and palate.
期刊介绍:
Founded in August 1953, Chinese Journal of Stomatology is a monthly academic journal of stomatology published publicly at home and abroad, sponsored by the Chinese Medical Association and co-sponsored by the Chinese Stomatology Association. It mainly reports the leading scientific research results and clinical diagnosis and treatment experience in the field of oral medicine, as well as the basic theoretical research that has a guiding role in oral clinical practice and is closely combined with oral clinical practice.
Chinese Journal of Over the years, Stomatology has been published in Medline, Scopus database, Toxicology Abstracts Database, Chemical Abstracts Database, American Cancer database, Russian Abstracts database, China Core Journal of Science and Technology, Peking University Core Journal, CSCD and other more than 20 important journals at home and abroad Physical medicine database and retrieval system included.