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. 2018 Nov;6(6):1157-1167.
doi: 10.1002/mgg3.497. Epub 2018 Nov 8.

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

Bing Li  1   2 , Lan Ma  3 , Chi Zhang  4 , Zhixuan Zhou  5 , Hua Yuan  2   3 , Hongbing Jiang  2   3 , Yongchu Pan  3   4   6 , Qian Tan  1   7
Affiliations

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

Bing Li et al. Mol Genet Genomic Med. 2018 Nov.

Abstract

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 < 0.5) with the reported SNPs except g.117037960A>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.

Keywords: endocytosis; epidermal growth factor receptor; genome-wide association study; nonsyndromic cleft lip with or without cleft palate; pathway; single-nucleotide polymorphism.

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Figures

Figure 1
Figure 1
Manhattan plot of the associations of the SNPs of the super pathway genes with risk of nonsyndromic cleft lip with or without cleft palate. The X‐axis presented different chromosome loci, and the Y‐axis presented −log10 p values of SNPs. Eighty‐two SNPs attained a statistical association with the risk of NSCL/P after an adjustment for multiple testing (Benjamini–Hochberg FDR procedure, p ≤ 0.05)
Figure 2
Figure 2
Regional plots of associations of three susceptibility loci with risk of NSCL/p. Figures showed association results of SNPs and recombination rates in three susceptibility loci (10q25.3, 17q12, and 1q23.1), and four lead SNPs were identified shown in a–d. For each plot, the −log10P values of the SNPs were presented according to the chromosomal positions of the SNPs. Estimated recombination rates were shown as light‐blue lines. The lead SNPs were presented in purple, and each of them was more significant than SNPs in moderate to high LD with it (r 2 ≥ 0.5). Other SNPs were colored according to their LD (r 2) with the lead SNP. The genes within or near the susceptibility region were annotated at the bottom, and their transcript direction was shown by arrows
Figure 3
Figure 3
Information of four lead SNPs in 127 reference human epigenomes. (a) Two lead SNPs at 10q25.3 (b) One lead SNP at17q12 (c) one lead SNP at 1q23.1. Four lead SNPs were presented in 127 consolidated human epigenomes based on uniformly processed data sets of Roadmap Epigenomics Project. Annotation for configuring colors was listed in the bottom (d)
Figure 4
Figure 4
Three genes expressions in proximal and distal positions of the maxilla and mandible in mouse embryonic stage. Man.Dis: Mandibular distal location; Man.Pro: Mandibular proximal location; Max.Dis: Maxillary distal location; Max.Pro: Maxillary proximal location. Figures showed median levels of SHTN1, AP2B1, and NTRK1 expressions in proximal and distal locations of maxilla and mandible during the 10.5th day to 14.5th day of mouse embryonic stage based on Geo data (GSE67985)
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