Cleft lip with or without cleft palate (CL/P) is one of the most common congenital human birth defects. A combination of genetic and epidemiology studies has contributed to a better knowledge of CL/P-associated candidate genes and environmental risk factors. However, the etiology of CL/P remains not fully understood. In this study, to identify new CL/P-associated genes, we conducted an integrative analysis using our in-house network tools, dmGWAS [dense module search for Genome-Wide Association Studies (GWAS)] and EW_dmGWAS (Edge-Weighted dmGWAS), in a combination with GWAS data, the human protein-protein interaction (PPI) network, and differential gene expression profiles. A total of 87 genes were consistently detected in both European and Asian ancestries in dmGWAS. There were 31.0% (27/87) showed nominal significance with CL/P (gene-based p < 0.05), with three genes showing strong association signals, including KIAA1598, GPR183, and ZMYND11 (p < 1 × 10− 3). In EW_dmGWAS, we identified 253 and 245 module genes associated with CL/P for European ancestry and the Asian ancestry, respectively. Functional enrichment analysis demonstrated that these genes were involved in cell adhesion, protein localization to the plasma membrane, the regulation of the apoptotic signaling pathway, and other pathological conditions. A small proportion of genes (5.1% for European ancestry; 2.4% for Asian ancestry) had prior evidence in CL/P as annotated in CleftGeneDB database. Our analysis highlighted nine novel CL/P candidate genes (BRD1, CREBBP, CSK, DNM1L, LOR, PTPN18, SND1, TGS1, and VIM) and 17 previously reported genes in the top modules. The genes identified through superimposing GWAS signals and differential gene expression profiles onto human PPI network, as well as their functional features, helped our understanding of the etiology of CL/P. Our multi-omics integrative analyses revealed nine novel candidate genes involved in CL/P.

中文翻译：

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一项综合，基因组，转录组和网络辅助研究，以鉴定与人or裂或不with裂相关的基因。

有或没有c裂（CL / P）的唇裂是最常见的先天性人类先天性缺陷之一。遗传和流行病学研究相结合，有助于更好地了解CL / P相关的候选基因和环境危险因素。但是，CL / P的病因仍未完全了解。在这项研究中，为了鉴定新的与CL / P相关的基因，我们使用内部网络工具dmGWAS [基因组全关联研究（GWAS）的密集模块搜索]和EW_dmGWAS（边缘加权dmGWAS）进行了整合分析，与GWAS数据，人类蛋白质间相互作用（PPI）网络和差异基因表达谱相结合。在dmGWAS的欧洲和亚洲祖先中共检测到87个基因。有31.0％（27/87）的CL / P表现为名义意义（基于基因的p < 0.05），三个具有强关联信号的基因包括KIAA1598，GPR183和ZMYND11（p <1×10-3）。在EW_dmGWAS中，我们分别为欧洲血统和亚洲血统确定了与CL / P相关的253和245个模块基因。功能富集分析表明，这些基因参与细胞粘附，蛋白质定位于质膜，凋亡信号通路的调控以及其他病理状况。如CleftGeneDB数据库中所注释的那样，一小部分基因（欧洲血统为5.1％；亚洲血统为2.4％）具有CL / P的先验证据。我们的分析突出显示了顶部模块中的9个新颖的CL / P候选基因（BRD1，CREBBP，CSK，DNM1L，LOR，PTPN18，SND1，TGS1和VIM）和17个先前报道的基因。通过将GWAS信号和差异基因表达谱叠加到人PPI网络上而鉴定出的基因及其功能特征，有助于我们了解CL / P的病因。我们的多组学综合分析揭示了参与CL / P的9个新候选基因。