Phenome-wide mendelian randomization identifies causal exposures for nonsyndromic cleft lip with or without cleft palate
10.3760/cma.j.cn112144-20250430-00165
- VernacularTitle:基于表型组孟德尔随机化探究非综合征型唇腭裂因果暴露因素的研究
- Author:
Shu LOU
1
;
Changyue XING
1
;
Yongchu PAN
1
Author Information
1. 南京医科大学附属口腔医院正畸科 口腔疾病研究与防治国家级重点实验室培育建设点（南京医科大学）江苏省口腔转化医学工程研究中心，南京210029
- Publication Type:Journal Article
- Keywords:
Cleft lip;
Cleft Palate;
Mendelian randomization analysis;
Genetic;
Phenotype
- From:
Chinese Journal of Stomatology
2025;60(9):971-979
- CountryChina
- Language:Chinese
-
Abstract:
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.
