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.
目的: 探索非综合征型唇裂伴或不伴腭裂(non-syndromic cleft lip with or without cleft palate, NSCL/P)全基因组常见遗传变异对NSCL/P风险的影响。
方法: 利用全基因组关联研究(genome-wide association study, GWAS)数据，以全基因组单核苷酸多态性(single nucleotide polymorphism, SNP)遗传度和基因组不同分区SNP遗传度评估基因组上常见变异的效应。对GWAS汇总数据进行质量控制，标准包括数据中无缺失值、弱势等位基因频率≥1%、P值在0~1、SNP正负链明确等。利用连锁不平衡得分回归计算NSCL/P的SNP遗传度，采用分层的连锁不平衡得分回归计算基因组编码区、启动子区、内含子区、增强子区和超级增强子区的分区SNP遗传度，并评估不同分区内的富集度，分析工具为LDSC (v1.0.1)软件。
结果: 纳入中国人群806个NSCL/P核心家系(2 418人)的GWAS数据，490 593个SNP通过质量控制，被纳入到SNP遗传度的计算中。观测样本中NSCL/P的SNP遗传度为0.55(95%CI: 0.28~0.82), 由于观测样本患病率较高，按中国人群患病率转换为一般人群后SNP遗传度为0.37(95%CI: 0.19~0.55)。SNP遗传度在增强子区的富集度为15.70(P=0.04)，在超级增强子区的富集度为3.18(P=0.03)。
结论: 基因组常见变异有助于解释一部分中国人群NSCL/P目前未被解释的遗传度，同时中国人群NSCL/P的SNP遗传度在增强子分区和超级增强子分区中显著富集，提示该区域中可能存在未被发现的遗传致病因素。
Keywords: Case-parent trios; Non-syndromic cleft lip with or without cleft palate; Single nucleotide polymorphism heritability.