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Journal of Peking University(Health Sciences) >

2020 , Vol. 52 >Issue 5: 809 - 814

DOI: https://doi.org/10.19723/j.issn.1671-167X.2020.05.003

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 LI ,
  • Meng-ying WANG ,
  • Ren ZHOU ,
  • Si-yue WANG ,
  • Hong-chen ZHENG ,
  • Hong-ping ZHU ,
  • Zhi-bo ZHOU ,
  • Tao WU ,
  • Hong WANG ,
  • Bing SHI
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  • 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 date: 2018-04-26

  Online published: 2020-10-15

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

Cite this article

Wen-yong LI , Meng-ying WANG , Ren ZHOU , Si-yue WANG , Hong-chen ZHENG , Hong-ping ZHU , Zhi-bo ZHOU , Tao WU , Hong WANG , Bing SHI . 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[J]. Journal of Peking University(Health Sciences), 2020 , 52(5) : 809 -814 . DOI: 10.19723/j.issn.1671-167X.2020.05.003

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