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Journal of Peking University (Health Sciences) ›› 2020, Vol. 52 ›› Issue (5): 809-814. doi: 10.19723/j.issn.1671-167X.2020.05.003

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Exploring parent-of-origin effects for non-syndromic cleft lip with or without cleft palate on PTCH1, PTCH2, SHH, SMO genes in Chinese case-parent trios

Wen-yong LI1,Meng-ying WANG1,Ren ZHOU1,Si-yue WANG1,Hong-chen ZHENG1,Hong-ping ZHU2,Zhi-bo ZHOU2,Tao WU1,3,∆(),Hong WANG1,Bing SHI4   

  1. 1. Department of Epidemiology and Biostatistics, School of Public Health, Peking University, Beijing 100191, China
    2. Department of Oral and Maxillofacial Surgery, Peking University School and Hospital of Stomatology & National Clinical Research Center for Oral Diseases & National Engineering Laboratory for Digital and Material Technology of Stomatology & Beijing Key Laboratory of Digital Stomatology, Beijing 100081, China
    3. Key Laboratory of Reproductive Health, Ministry of Health, Beijing 100191, China
    4. Department of Oral and Maxillofacial Surgery, State Key Laboratory of Oral Disease, West China College of Stomatology, Sichuan University, Chengdu 610041, China
  • Received:2018-04-26 Online:2020-10-18 Published:2020-10-15
  • Contact: Tao WU E-mail:twu@bjmu.edu.cn
  • Supported by:
    National Natural Science Foundation of China(81102178);National Natural Science Foundation of China(81573225);Beijing Municipal Natural Science Foundation(7172115);Peking University Health Science Center Interdisciplinary Research Fund(BMU2017MX018)

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Abstract:

Objective: Non-syndromic cleft lip with or without cleft palate (NSCL/P) is a common birth defect, affecting 1.4 per 1 000 live births, and multiple genetic and environmental risk factors influencing its risk. All the known genetic risk factors accounted for a small proportion of the heritability. Several authors have suggested parent-of-origin effects (PoO) may play an important role in the etiology of this complex and heterogeneous malformation. To clarify the genetic association between PTCH1, PTCH2, SHH and SMO in hedgehog (HH) pathway and NSCL/P, as well as testing for potential PoO effects in Chinese case-parent trios. Methods: We tested for transmission disequilibrium tests (TDT) and PoO effects using 83 common single nucleotide polymorphic (SNP) markers of HH pathway genes from 806 NSCL/P case-parent trios. These trios were drawn from an international consortium established for a genome-wide association studies (GWAS) of non-syndromic oral clefts of multiple ethnicities. DNA samples were collected from each trio. Single marker and haplotype based analysis were performed both in TDT tests and PoO effects. SNPs were excluded if they (i) had a call rate of < 95%, (ii) had a minor allele frequency (MAF) of < 0.05, (iii) had Mendelian errors over all trios of >5%, (iv) had a genotype distribution in the parents that deviated from the Hardy-Weinberg equilibrium (HWE) (P < 0.000 1). The process was done using Plink (version 1.07, http://pngu.mgh.harvard.edu/~purcell/plink/data.shtml). TDT test was performed in Plink v1.07. A log-linear model was used to explore PoO effects using Haplin v6.2.1 as implemented in R package v3.4.2. Significance level was assessed using the Bonferroni correction. Results: A total of 18 SNPs were dropped due to low MAF, thus leaving 65 SNPs available for the analysis. Thus the Bonferroni threshold was 7.7×10 -4 (0.05/65). Nominal significant association with NSCL/P was found at a SNP (rs4448343 in PTCH1, P=0.023) and six haplotypes (rs10512249-rs4448343, rs1461208-rs7786445, rs10512249-rs4448343, rs16909865-rs10512249-rs4448343, rs1461208-rs7786445-rs12698335, and rs288756-rs288758-rs1151790, P<0.05). A total of six haplotypes (rs288765-rs1233563, rs12537550-rs11765352, rs872723-rs288765-rs1233563, rs288765-rs1233563-rs288756, rs6459952-rs12537550-rs11765352, and rs12537550-rs11765352-rs6971211) showed PoO effect (P<0.05). None of the results remained significant after the Bonferroni correction (P>7.7×10 -4). Conclusion: Neither significant association between SNPs within HH pathway and the risk of NSCL/P nor PoO effects was seen in this study.

Key words: Parent-of-origin effects, Non-syndromic cleft lip with or without cleft palate, Hedgehog pathway

CLC Number: 

  • R394

Figure 1

The hedgehog pathway genes"

Table 1

The distribution of 806 NSCL/P case-parent trios in China"

Site Male Female Total
Taiwan 139 94 233
Shandong 193 81 274
Hubei 132 55 187
Sichuan 75 37 112
Total 539 267 806

Table 2

The selected single SNP and haplotype association results with nominal significance based on TDT in 806 Chinese case-parents trios"

Type Gene Haplotype SNP ID P value
SNP PTCH1 - rs4448343 0.023
Haplotype PTCH1 AG rs10512249-rs4448343 0.025
Haplotype SHH GC rs1461208-rs7786445 0.026
Haplotype PTCH1 GA rs10512249-rs4448343 0.031
Haplotype PTCH1 CGA rs16909865-rs10512249-rs4448343 0.036
Haplotype SHH GCG rs1461208-rs7786445-rs12698335 0.036
Haplotype SHH GGC rs288756-rs288758-rs1151790 0.047

Table 3

The results of PoO effects in 806 Chinese case-parents trios"

Gene SNP ID RRm
(95%CI)		 RRm
P value		 RRf
(95%CI)		 RRf P value RRR
(95%CI)		 RRR
P value
SHH rs288765-rs1233563 0.43
(0.15-1.29)		 0.134 1.04
(0.41-2.75)		 0.919 0.41
(0.20-0.86)		 0.018
SHH rs12537550-rs11765352 1.22
(0.87-1.71)		 0.239 0.90
(0.64-0.24)		 0.518 1.36
(1.01-1.82)		 0.036
SHH rs872723-rs288765-rs1233563 0.54
(0.23-1.29)		 0.161 1.33
(0.66-2.69)		 0.427 0.41
(0.20-0.86)		 0.017
SHH rs288765-rs1233563-rs288756 0.58
(0.28-1.20)		 0.153 1.29
(0.72-2.31)		 0.386 0.45
(0.21-0.95)		 0.035
SHH rs6459952-rs12537550-rs11765352 1.16
(0.84-1.61)		 0.366 0.81
(0.59-1.11)		 0.192 1.44
(1.06-1.95)		 0.021
SHH rs12537550-rs11765352-rs6971211 1.13
(0.83-1.56)		 0.433 0.81
(0.59-1.11)		 0.180 1.40
(1.04-1.90)		 0.025
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