An integrative, genomic, transcriptomic and network-assisted study to identify genes associated with human cleft lip with or without cleft palate

Abstract

Background: 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. Results: 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. Conclusions: 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 multiomics integrative analyses revealed nine novel candidate genes involved in CL/P.

Transcriptomics unravels molecular players shaping dorsal lip hypertrophy in the vacuum cleaner cichlid, Gnathochromis permaxillaris

“…These processes involve cell motility, adhesion and developmental growth, as well as regulation of GTPase mediated signals, particularly, the Ras signalling pathway. A recent integrated genomic and transcriptomic study in humans has revealed that cell adhesion, cell junction and extracellular structure organizations are among the major biological processes involved in lip and cleft development and morphogenesis [ 47 ]. Furthermore, as studies on human and mouse have shown, biological processes involving developmental growth and cell proliferation are known to be the key mechanisms in upper lip development and morphogenesis [ 48 ].…”

Excessive All-Trans Retinoic Acid Inhibits Cell Proliferation Through Upregulated MicroRNA-4680-3p in Cultured Human Palate Cells

“…The binding of ligands to receptors induces the homo- or hetero-dimerization of receptors and activates the kinase domain that induces downstream signaling cascades such as MAPK/ERK and PI3K/AKT/mTOR pathways, known to be crucial for cell proliferation, migration, and differentiation (Avraham and Yarden, 2011 ; Arteaga and Engelman, 2014 ). Our previous bioinformatic study suggests that ERBB signaling pathway may play a substantial role in palate formation (Yan et al, 2020 ). In fact, the activation of the ERBB2 pathway upregulates CCND1 expression, decreases CDKN1B stability (Lee et al, 2000 ; Yang et al, 2000 ; Lenferink et al, 2001 ), and promotes cell proliferation and angiogenesis in tumors (Le et al, 2005 ).…”

Transcriptomics Unravels Molecular Players Shaping Dorsal Lip Hypertrophy in the Vacuum Cleaner Cichlid, Gnathochromis Permaxillaris

“…These processes involve cell motility, adhesion and developmental growth, as well as regulation of GTPase mediated signals, particularly, the RAS signalling pathway. A recent integrated genomic and transcriptomic study in humans has revealed that cell adhesion, cell junction and extracellular structure organizations are among the major biological processes involving lip and cleft development and morphogenesis [25]. Furthermore, as studies on human and mouse have shown, biological processes involving developmental growth and cell proliferation are known to be the key mechanisms in upper lip development and morphogenesis [26].…”