Center for Precision Health, School of Biomedical Informatics, The University of Texas Health Science Center at Houston, 7000 Fannin St. Suite 600, Houston, TX, 77030, USA.
Department of Diagnostic and Biomedical Sciences, School of Dentistry, The University of Texas Health Science Center at Houston, Houston, TX, 77054, USA.
BMC Med Genomics. 2020 Apr 3;13(Suppl 5):39. doi: 10.1186/s12920-020-0675-4.
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). 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.
唇裂伴或不伴腭裂（CL/P）是最常见的人类先天性出生缺陷之一。遗传和流行病学研究的结合有助于更好地了解与 CL/P 相关的候选基因和环境风险因素。然而，CL/P 的病因仍不完全清楚。在这项研究中，为了确定新的与 CL/P 相关的基因，我们使用内部网络工具 dmGWAS（全基因组关联研究的密集模块搜索）和 EW_dmGWAS（边缘加权 dmGWAS）进行了综合分析，结合 GWAS 数据、人类蛋白质-蛋白质相互作用（PPI）网络和差异基因表达谱。
在 dmGWAS 中，共检测到 87 个在欧洲和亚洲血统中一致存在的基因。其中 31.0%（27/87）与 CL/P 具有名义显著性（基于基因的 p<0.05），有三个基因显示出强烈的关联信号，包括 KIAA1598、GPR183 和 ZMYND11（p<1×10）。在 EW_dmGWAS 中，我们分别鉴定出与欧洲血统和亚洲血统的 CL/P 相关的 253 个和 245 个模块基因。功能富集分析表明，这些基因参与细胞黏附、质膜蛋白定位、凋亡信号通路的调节和其他病理状况。一小部分基因（欧洲血统为 5.1%；亚洲血统为 2.4%）在 CleftGeneDB 数据库中有 CL/P 相关的注释。我们的分析突出了九个新的 CL/P 候选基因（BRD1、CREBBP、CSK、DNM1L、LOR、PTPN18、SND1、TGS1 和 VIM）和前 17 个报告的基因在顶级模块中。
通过将 GWAS 信号和差异基因表达谱叠加到人类 PPI 网络上，并结合其功能特征，确定的基因有助于我们理解 CL/P 的病因。我们的多组学综合分析揭示了九个新的候选基因与 CL/P 有关。
