Objective: In this study, we used genome-wide association study (GWAS) data to explore whether WNT pathway genes were associated with non-syndromic oral clefts (NSOC) considering gene-gene interaction and gene-environment interaction.
Methods: We conducted the analysis using 806 non-syndromic cleft lip with or without cleft palate (NSCL/P) case-parent trios and 202 non-syndromic cleft palate (NSCP) case-parent trios among Chinese populations selected from an international consortium established for a GWAS of non-syndromic oral clefts. Genotype data and maternal environmental exposures were collected through DNA samples and questionnaires. Conditional Logistic regression models were adopted to explore gene-gene interaction and gene-environment in teraction using trio package in R software. The threshold of significance level was set as 3.47×10-4 using Bonferroni correction.
Results: A total of 144 single nucleotide polymorphisms (SNPs) in seven genes passed the quality control process in NSCL/P trios and NSCP trios, respectively. Totally six pairs of SNPs interactions showed statistically significant SNP-SNP interaction (P < 3.47×10-4) after Bonferroni correction, which were rs7618735 (WNT5A) and rs10848543 (WNT5B), rs631948 (WNT11) and rs556874 (WNT5A), and rs631948 (WNT11) and rs472631 (WNT5A) among NSCL/P trios; rs589149 (WNT11) and rs4765834 (WNT5B), rs1402704 (WNT11) and rs358792 (WNT5A), and rs1402704 (WNT11) and rs358793 (WNT5A) among NSCP trios, respectively. In addition, no significant result was found for gene-environment interaction analysis in both of the NSCL/P trios and NSCP trios.
Conclusion: Though this study failed to detect significant association based on gene-environment interactions of seven WNT pathway genes and the risk of NSOC, WNT pathway genes may influence the risk of NSOC through potential gene-gene interaction.
目的: 利用全基因组关联研究(genome-wide association study，GWAS)数据，从基因-基因交互作用和基因-环境交互作用方面探索WNT代谢通路相关基因在中国人群非综合征型唇腭裂(non-syndromic oral clefts，NSOC)发生风险中的作用。
方法: 本研究样本来自“唇腭裂基因和交互作用的国际合作研究”项目在中国地区募集的806个非综合征型唇裂合并或不合并腭裂(non-syndromic cleft lip with or without cleft palate，NSCL/P)核心家系和202个非综合征型单纯腭裂(non-syndromic cleft palate，NSCP)核心家系。通过收集研究对象的DNA样本和问卷调查获得基因型数据和母亲孕期环境暴露信息, 利用此GWAS数据，采用条件Logistic回归模型探讨基因-基因交互作用和基因-环境交互作用，由R软件中的trio软件包完成。经过Bonferroni多重检验校正后，统计学检验的显著性阈值均设为P < 3.47×10-4。
结果: 经过数据质量控制后，NSCL/P核心家系和NSCP核心家系各纳入7个基因上的144个单核苷酸多态性(single nucleotide polymorphisms, SNPs)位点进入分析。在NSCL/P和NSCP家系中，分别有三对SNPs交互作用达到统计学显著性水平(P < 3.47×10-4)：rs7618735(WNT5A)与rs10848543(WNT5B)，rs631948(WNT11)与rs556874(WNT5A)以及rs631948(WNT11)与rs472631(WNT5A)；rs589149(WNT11)与rs4765834(WNT5B)，rs1402704(WNT11)与rs358792(WNT5A)以及rs1402704(WNT11)与rs358793(WNT5A)。此外，基因-环境交互作用分析未发现显著结果。
结论: 未发现WNT代谢通路相关基因-环境交互作用在NSCL/P和NSCP发病风险中的作用，但WNT代谢通路相关基因可能通过基因-基因交互作用影响NSOC的发病风险。
Keywords: Genome-wide association studies; Non-syndromic oral clefts; WNT signaling pathway.