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Journal of Peking University (Health Sciences) ›› 2024, Vol. 56 ›› Issue (5): 775-780. doi: 10.19723/j.issn.1671-167X.2024.05.004

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Single nucleotide polymorphism heritability of non-syndromic cleft lip with or without cleft palate in Chinese population

Enci XUE1, Xi CHEN1, Xueheng WANG1, Siyue WANG1, Mengying WANG1, Jin LI1, Xueying QIN1, Yiqun WU1, Nan LI2, Jing LI3, Zhibo ZHOU2, Hongping ZHU2, Tao WU1,*(), Dafang CHEN1, Yonghua HU1   

  1. 1. Department of Epidemiology and Biostatistics, Peking University School of Public Health, Beijing 100191, China
    2. Department of Oral and Maxillofacial Surgery, Peking University School of Stomatology, Beijing 100081, China
    3. Department of Pediatric Dentistry, Peking University School of Stomatology, Beijing 100081, China
  • Received:2021-03-18 Online:2024-10-18 Published:2024-10-16
  • Contact: Tao WU E-mail:twu@bjmu.edu.cn
  • Supported by:
    the National Natural Science Foundation of China(81102178)

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Abstract:

Objective: To delve into the intricate relationship between common genetic variations across the entire genome and the risk of non-syndromic cleft lip with or without cleft palate (NSCL/P). Methods: Utilizing summary statistics data from genome-wide association studies (GWAS), a thorough investigation to evaluate the impact of common variations on the genome were undertook. This involved assessing single nucleotide polymorphism (SNP) heritability across the entire genome, as well as within specific genomic regions. To ensure the robustness of our analysis, stringent quality control measures were applied to the GWAS summary statistics data. Criteria for inclusion encompassed the absence of missing values, a minor allele frequency ≥1%, P-values falling within the range of 0 to 1, and clear SNP strand orientation. SNP meeting these stringent criteria were then meticulously included in our analysis. The SNP heritability of NSCL/P was calculated using linkage disequilibrium score regression. Additionally, hierarchical linkage disequilibrium score regression to partition SNP heritability within coding regions, promoters, introns, enhancers, and super enhancers were employed, and the enrichment levels within different genomic regions using LDSC (v1.0.1) software were further elucidated. Results: Our study drew upon GWAS summary statistics data obtained from 806 NSCL/P trios, comprising a total of 2 418 individuals from the Chinese population. Following rigorous quality control procedures, 490 593 out of 492 993 SNP were deemed suitable for inclusion in SNP heritability calculations. The observed SNP heritability of NSCL/P was 0.55 (95%CI: 0.28-0.82). Adjusting for the elevated disease pre-valence within our sample, the SNP heritability scaled down to 0.37 (95%CI: 0.19-0.55) based on the prevalence observed in the general Chinese population. Notably, our enrichment analysis unveiled significant enrichment of SNP heritability within enhancer regions (15.70, P=0.04) and super enhancer regions (3.18, P=0.03). Conclusion: Our study sheds light on the intricate interplay between common genetic variations and the risk of NSCL/P in the Chinese population. By elucidating the SNP heritability landscape across different genomic regions, we contribute valuable insights into the genetic basis of NSCL/P. The significant enrichment of SNP heritability within enhancer and super enhancer regions underscores the potential role of these regulatory elements in shaping the genetic susceptibility to NSCL/P. This paves the way for further research aimed at uncovering novel genetic pathogenic factors underlying NSCL/P pathogenesis.

Key words: Non-syndromic cleft lip with or without cleft palate, Single nucleotide polymorphism heritability, Case-parent trios

CLC Number: 

  • R394.1

Table 1

Regional and gender distribution of 806 NSCL/P trios in China"

Site Male Female Total
China Taiwan, n 139 94 233
Shandong, n 193 81 274
Hubei, n 132 55 187
Sichuan, n 75 37 112
Total, n 539 267 806

Table 2

Partitioning SNP heritability results of NSCL/P"

Annotation Proportion of SNP Proportion of SNP heritability Enrichment P for enrichment
Coding 0.014 0.035 2.44 0.91
Promoter 0.046 0.144 3.12 0.70
Intron 0.388 0.289 0.74 0.63
Enhancer 0.042 0.654 15.70 0.04
Super-enhancer 0.167 0.532 3.18 0.03
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