Associations of genetic variants in endocytic trafficking of epidermal growth factor receptor super pathway with risk of nonsyndromic cleft lip with or without cleft palate

• Published in: Molecular genetics & genomic medicine 2018-11, Vol.6 (6), p.1157-1167
• Main Authors: Li, Bing, Ma, Lan, Zhang, Chi, Zhou, Zhixuan, Yuan, Hua, Jiang, Hongbing, Pan, Yongchu, Tan, Qian
• Format: Article
• Language: English
• Subjects: Adaptor Protein Complex beta Subunits - genetics; Carrier Proteins - genetics; Case-Control Studies; Cell adhesion & migration; Cell migration; Cleft Lip - genetics; Cleft Lip - pathology; Cleft lip/palate; Cleft Palate - genetics; Cleft Palate - pathology; Craniofacial growth; Cytoskeletal Proteins; Developmental stages; Embryogenesis; endocytosis; Epidermal growth factor; epidermal growth factor receptor; Epidermal growth factor receptors; Etiology; Genes; Genetic diversity; Genetic variance; Genome-wide association studies; Genomes; genome‐wide association study; Growth factors; Humans; Linkage Disequilibrium; nonsyndromic cleft lip with or without cleft palate; Original; pathway; Polymorphism, Single Nucleotide; Receptor, trkA - genetics; Regression analysis; Risk; Single-nucleotide polymorphism; Statistical analysis
• ISSN: 2324-9269; 2324-9269
• DOI: 10.1002/mgg3.497

Background The genetic etiology of nonsyndromic cleft lip with or without cleft palate (NSCL/P) has not been fully clarified to date. Epidermal growth factor receptor (EGFR) was reportedly involved in its biological establishment and regulation of cell migration during the embryonic stage. Methods We selected a super pathway of endocytic trafficking of EGFR and investigated the associations of single‐nucleotide polymorphisms (SNPs) in the super pathway with the risk of NSCL/P by analyzing our published genome‐wide association study (GWAS) data from 504 NSCL/P individuals and 455 controls. After the false discovery rate (FDR) control, we conducted linkage disequilibrium (LD) analyses and conditional regression analyses to obtain independent lead SNPs. We performed LD analyses between the lead SNPs and the reported SNPs to find novel ones from our study. We annotated the lead SNPs and investigated their mapped genes in silico. Results A total of 82 SNPs showed a statistical association with the risk of NSCL/P after FDR control. They contained three reported SNPs which were g.117068049G>A (rs7078160), g.117086783C>G (rs10886040), and g.117101266G>T (rs17095681). Four independent lead SNPs were obtained, including g.116979803 T>C (rs1905539) and g.117037960A>G (rs7902502) at 10q25.3, g.35720163G>C (rs75656820) at 17q12, and g.156864512G>A (rs1800877) at 1q23.1. Three of them were in low LD (r2 G (rs7902502), so these three were newly identified. Lead SNPs were mapped to three genes: SHTN1, AP2B1, and NTRK1. The three genes were relatively more highly expressed in the human craniofacial region and in the proximal maxillary location during the craniofacial development stage of the embryonic mouse. Conclusion Our results suggested that SHTN1, AP2B1, and NTRK1 might be associated with the development of NSCL/P. We selected a super pathway of endocytic trafficking of EGFR and investigated the associations of SNPs of genes in the super pathway with the risk of NSCL/P by analyzing our GWAS data. We found three newly identified susceptible SNPs (rs1905539, rs75656820, and rs1800877) and obtained three risk genes: SHTN1, AP2B1, and NTRK1.