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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
[1] Wang M, Yuan Y, Wang Z, et al. Prevalence of orofacial clefts among live births in China: a systematic review and meta-analysis[J]. Birth Defects Res, 2017,109(13):1011-1019.
doi: 10.1002/bdr2.1043 pmid: 28635078
[2] Harville EW, Wilcox AJ, Lie RT, et al. Cleft lip and palate versus cleft lip only: are they distinct defects[J]. Am J Epidemiol, 2005,162(5):448-453.
doi: 10.1093/aje/kwi214 pmid: 16076837
[3] Leslie EJ, Marazita ML. Genetics of cleft lip and cleft palate[J]. Am J Med Genet C Semin Med Genet, 2013,163c(4):246-258.
doi: 10.1002/ajmg.c.31381 pmid: 24124047
[4] Jiang R, Bush JO, Lidral AC. Development of the upper lip: morphogenetic and molecular mechanisms[J]. Dev Dyn, 2006,235(5):1152-1166.
doi: 10.1002/dvdy.20646 pmid: 16292776
[5] Mossey PA, Little J, Munger RG, et al. Cleft lip and palate[J]. Lancet, 2009,374(9703):1773-1785.
doi: 10.1016/S0140-6736(09)60695-4 pmid: 19747722
[6] Grant SF, Wang K, Zhang H, et al. A genome-wide association study identifies a locus for nonsyndromic cleft lip with or without cleft palate on 8q24[J]. J Pediatr, 2009,155(6):909-913.
doi: 10.1016/j.jpeds.2009.06.020 pmid: 19656524
[7] Beaty TH, Marazita ML, Leslie EJ. Genetic factors influencing risk to orofacial clefts: today’s challenges and tomorrow's opportunities[J]. F1000Res, 2016,5:2800.
doi: 10.12688/f1000research.9503.1 pmid: 27990279
[8] Manolio TA, Collins FS, Cox NJ, et al. Finding the missing heritability of complex diseases[J]. Nature, 2009,461(7265):747-753.
doi: 10.1038/nature08494 pmid: 19812666
[9] Guilmatre A, Sharp AJ. Parent of origin effects[J]. Clin Genet, 2012,81(3):201-209.
doi: 10.1111/j.1399-0004.2011.01790.x
[10] Yu Y, Zuo X, He M, et al. Genome-wide analyses of non-syndromic cleft lip with palate identify 14 novel loci and genetic heterogeneity[J]. Nat Commun, 2017,8:14364.
doi: 10.1038/ncomms14364 pmid: 28232668
[11] Beaty TH, Murray JC, Marazita ML, et al. A genome-wide association study of cleft lip with and without cleft palate identifies risk variants near MAFB and ABCA4[J]. Nat Genet, 2010,42(6):525-529.
doi: 10.1038/ng.580 pmid: 20436469
[12] Gjessing HK, Lie RT. Case-parent triads: estimating single- and double-dose effects of fetal and maternal disease gene haplotypes[J]. Ann Hum Genet, 2006,70(Pt 3):382-396.
doi: 10.1111/j.1529-8817.2005.00218.x pmid: 16674560
[13] Gjerdevik M, Haaland OA, Romanowska J, et al. Parent-of-origin-environment interactions in case-parent triads with or without independent controls[J]. Ann Hum Genet, 2018,82(2):60-73.
doi: 10.1111/ahg.12224 pmid: 29094765
[14] Weinberg CR. Methods for detection of parent-of-origin effects in genetic studies of case-parents triads[J]. Am J Hum Genet, 1999,65(1):229-235.
doi: 10.1086/302466 pmid: 10364536
[15] Briscoe J, Therond PP. The mechanisms of Hedgehog signalling and its roles in development and disease[J]. Nat Rev Mol Cell Biol, 2013,14(7):416-429.
doi: 10.1038/nrm3598
[16] Taipale J, Cooper MK, Maiti T, et al. Patched acts catalytically to suppress the activity of Smoothened[J]. Nature, 2002,418(6900):892-897.
doi: 10.1038/nature00989 pmid: 12192414
[17] Wantia N, Rettinger G. The current understanding of cleft lip malformations[J]. Facial Plast Surg, 2002,18(3):147-153.
doi: 10.1055/s-2002-33061 pmid: 12152133
[18] Grosen D, Bille C, Petersen I, et al. Risk of oral clefts in twins[J]. Epidemiology, 2011,22(3):313-319.
doi: 10.1097/EDE.0b013e3182125f9c
[19] Mangold E, Ludwig KU, Birnbaum S, et al. Genome-wide association study identifies two susceptibility loci for nonsyndromic cleft lip with or without cleft palate[J]. Nat Genet, 2010,42(1):24-26.
doi: 10.1038/ng.506 pmid: 20023658
[20] Sun Y, Huang Y, Yin A, et al. Genome-wide association study identifies a new susceptibility locus for cleft lip with or without a cleft palate[J]. Nat Commun, 2015,6:6414.
pmid: 25775280
[21] Lo Muzio L. Nevoid basal cell carcinoma syndrome (Gorlin syndrome)[J]. Orphanet J Rare Dis, 2008,3(1):32.
doi: 10.1186/1750-1172-3-32
[22] Metzis V, Courtney AD, Kerr MC, et al. Patched1 is required in neural crest cells for the prevention of orofacial clefts[J]. Hum Mol Genet, 2013,22(24):5026-5035.
doi: 10.1093/hmg/ddt353
[23] Xiao Y, Taub MA, Ruczinski I, et al. Evidence for SNP-SNP interaction identified through targeted sequencing of cleft case-parent trios[J]. Genet Epidemiol, 2017,41(3):244-250.
pmid: 28019042
[24] de Araujo TK, Secolin R, Felix TM, et al. A multicentric association study between 39 genes and nonsyndromic cleft lip and palate in a Brazilian population[J]. J Craniomaxillofac Surg, 2016,44(1):16-20.
pmid: 26602496
[25] Rubini M, Brusati R, Garattini G, et al. Cystathionine beta-synthase c.844ins68 gene variant and non-syndromic cleft lip and palate[J]. Am J Med Genet A, 2005,136a(4):368-372.
pmid: 16007597
[26] Reutter H, Birnbaum S, Mende M, et al. TGFB3 displays parent-of-origin effects among central Europeans with nonsyndromic cleft lip and palate[J]. J Hum Genet, 2008,53(7):656-661.
doi: 10.1007/s10038-008-0296-9
[27] Sull JW, Liang KY, Hetmanski JB, et al. Differential parental transmission of markers in RUNX2 among cleft case-parent trios from four populations[J]. Genet Epidemiol, 2008,32(6):505-512.
pmid: 18357615
[28] Sull JW, Liang KY, Hetmanski JB, et al. Maternal transmission effects of the PAX genes among cleft case-parent trios from four populations[J]. Eur J Hum Genet, 2009,17(6):831-839.
pmid: 19142206
[29] Sull JW, Liang KY, Hetmanski JB, et al. Evidence that TGFA influences risk to cleft lip with/without cleft palate through unconventional genetic mechanisms[J]. Hum Genet, 2009,126(3):385-394.
pmid: 19444471
[30] Suazo J, Santos JL, Jara L, et al. Parent-of-origin effects for MSX1 in a Chilean population with nonsyndromic cleft lip/palate[J]. Am J Med Genet A, 2010,152a(8):2011-2016.
pmid: 20635363
[31] Shi M, Murray JC, Marazita ML, et al. Genome wide study of maternal and parent-of-origin effects on the etiology of orofacial clefts[J]. Am J Med Genet A, 2012,158a(4):784-794.
doi: 10.1002/ajmg.a.35257
[32] Garg P, Ludwig KU, Bohmer AC, et al. Genome-wide analysis of parent-of-origin effects in non-syndromic orofacial clefts[J]. Eur J Hum Genet, 2014,22(6):822-830.
doi: 10.1038/ejhg.2013.235
[33] Morris RW, Kaplan NL. On the advantage of haplotype analysis in the presence of multiple disease susceptibility alleles[J]. Genet Epidemiol, 2002,23(3):221-233.
pmid: 12384975
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