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Genetic Determinants of Leukocyte Count in Nonsyndromic Cleft Lip With or Without Cleft Palate Among Asians

Changyue Xing¹, Shu Lou¹, Yue Gao¹

¹Department of Orthodontics, Affiliated Hospital of Stomatology, Nanjing Medical University, Nanjing, China; State Key Laboratory of Cultivation Base of Research, Prevention and Treatment for Oral Diseases, Nanjing Medical University, Nanjing, China; Jiangsu Province Engineering Research Center of Stomatological Translational Medicine, Nanjing Medical University, Nanjing, China.

International Dental Journal

|July 4, 2025

Abstract

Objectives:

Previous studies have shown that maternal proinflammatory status could increase the risk of nonsyndromic cleft lip with or without cleft palate (NSCL/P) in offspring. This study aimed to assess the relationship between leukocyte counts and NSCL/P.

Methods:

The NSCL/P genome-wide association study (GWAS) data with a total of 1069 cases and 1724 controls were included. Summary statistics for 6 leukocyte counts GWASs (white blood cell count (WBC), neutrophil count (NC), monocyte count (MONO), lymphocyte count (LYM), eosinophil count (EOS), and basophil count (BASO)) in large-scale East Asian populations were obtained from the IEU OpenGWAS database. Genetic association analyses include genetic correlations and genetic overlaps of traits. Multi-trait analysis was used to identify pleiotropic loci, followed by enrichment analysis for pleiotropic genes. Mendelian Randomization (MR) analysis was performed to infer causality between exposure factors and NSCL/P.

Results:

We observed a significant global genetic correlation between WBC and NSCL/P (r_g = 0.14, P = 6.90E-03), as well as genetic overlap in 5 trait pairs of NSCL/P and WBC, NC, MONO, LYM, and BASO. Subsequently, we found 24 pleiotropic loci across these pairs, with the strongest pleiotropy in the genetic region 17q21.1 mapped to GSDMA. Notably, pleiotropic genes were enriched in the MHC protein complex, antigen processing and presentation, and bone cell development. In addition, MR analysis demonstrated that higher neutrophil counts significantly increased the risk of NSCL/P (odds ratio = 2.48, P = 5.41E-3), an effect that persisted in multivariable MR analyses (P = 1.33E-3) after adjusting for other inflammatory cell types.

Conclusion:

Our study revealed genetic correlations and shared pleiotropic loci between leukocyte counts and NSCL/P, with further evidence suggesting a potential causal relationship between neutrophil counts and NSCL/P.

Clinical Relevance:

High neutrophil cell counts showed a potential causal association with NSCL/P pathogenesis, suggesting an increased risk of disease development.

Keywords:

Genetic association studies Genetics Inflammation Mendelian randomization analysis Orofacial cleft

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