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Journal of Peking University (Health Sciences) ›› 2022, Vol. 54 ›› Issue (3): 394-399. doi: 10.19723/j.issn.1671-167X.2022.03.002

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Association study between haplotypes of WNT signaling pathway genes and nonsyndromic oral clefts among Chinese Han populations

Meng-ying WANG1,Wen-yong LI1,Ren ZHOU1,Si-yue WANG1,Dong-jing LIU1,Hong-chen ZHENG1,Zhi-bo ZHOU2,Hong-ping ZHU2,Tao WU1,*(),Yong-hua HU1   

  1. 1. Department of Epidemiology and Biostatistics, Peking University School of Public Health, Beijing 100191, China
    2. Department of Oral and Maxillofacial Surgery, Peking University School and Hospital of Stomatology & National Center of Stomatology & National Clinical Research Center for Oral Diseases & National Engineering Research Center of Oral Biomaterials and Digital Medical Devices & Beijing Key Laboratory of Digital Stomatology & NHC Research Center of Engineering and Technology for Computerized Dentistry & NMPA Key Laboratory for Dental Materials, Beijing 100081, China
  • Received:2020-10-28 Online:2022-06-18 Published:2022-06-14
  • Contact: Tao WU E-mail:twu@bjmu.edu.cn
  • Supported by:
    the National Natural Science Foundation of China(81102178);the National Natural Science Foundation of China(81573225);the Beijing Natural Science Foundation(7172115)

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Abstract:

Objective: To explore whether WNT signaling pathway genes were associated with non-syndromic oral clefts (NSOC) based on haplotypes analyses among 1 008 Chinese NSOC case-parent trios. Methods: The genome-wide association study (GWAS) data of 806 Chinese non-syndromic cleft lip with or without cleft palate (NSCL/P) trios and 202 Chinese non-syndromic cleft palate (NSCP) case-parent trios were drawn from the International Consortium to Identify Genes and Interactions Controlling Oral Clefts (ICOCs) study GWAS data set, whose Chinese study population were recruited from four provinces in China, namely Taiwan, Shandong, Hubei, and Sichuan provinces. The process of DNA genotyping was conducted by the Center for Inherited Disease Research in the Johns Hopkins University, using Illumina Human610-Quad v.1_B Bead Chip. The method of sliding windows was used to determine the haplotypes for analyses, including 2 SNPs haplotypes and 3 SNPs haplotypes. Haplotypes with a frequency lower than 1% were excluded for further analyses. To further assess the association between haplotypes and NSOC risks, and the transmission disequilibrium test (TDT) was performed. The Bonferroni method was adopted to correct multiple tests in the study, with which the threshold of statistical significance level was set as P < 0.05 divided by the number of tests, e.g P < 3.47×10-4 in the current stu-dy. All the statistical analyses were performed by using plink (v1.07). Results: After quality control, a total of 144 single nucleotide polymorphisms (SNPs) mapped in seven genes in WNT signaling pathway were included for the analyses among the 806 Chinese NSCL/P trios and 202 Chinese NSCP trios. A total of 1 042 haplotypes with frequency higher than 1% were included for NSCL/P analyses and another 1 057 haplotypes with frequency higher than 1% were included for NSCP analyses. Results from the TDT analyses showed that a total of 69 haplotypes were nominally associated with the NSCL/P risk among Chinese (P < 0.05). Another 34 haplotypes showed nominal significant association with the NSCP risk among Chinese (P < 0.05). However, none of these haplotypes reached pre-defined statistical significance level after Bonferroni correction (P>3.47×10-4). Conclusion: This study failed to observe any statistically significant associations between haplotypes of seven WNT signaling pathway genes and the risk of NSOC among Chinese. Further studies are warranted to replicate the findings here.

Key words: Non-syndromic oral clefts, WNT signaling pathway genes, Haplotypes, Case-parent trios

CLC Number: 

  • R181.2

Table 1

Information of WNT signaling pathway genes"

Genes Chromosome Number of SNPs in NSCL/P Number of SNPs in NSCP
WNT3 17 7 7
WNT3A 1 8 7
WNT5A 3 45 46
WNT5B 12 28 28
WNT9A 1 13 13
WNT9B 17 9 9
WNT11 11 34 34

Table 2

Results of haplotype analyses in NSCL/P trios"

Genes SNPs Haplotype Frequency P
2 SNPs in haplotype
    WNT5A rs4968282_rs197932 GC 0.238 0.006
    WNT5A rs11079737_rs3916033 GT 0.081 0.010
    WNT9B rs1530364_rs4968282 GA 0.715 0.012
    WNT5A rs10848539_rs2270038 AC 0.013 0.013
    WNT5A rs1444866_rs4580514 GA 0.016 0.015
    WNT9B rs6504591_rs1530364 TG 0.623 0.017
    WNT5A rs4580514_rs753449 AT 0.017 0.018
    WNT5A rs4580514_rs753449 CC 0.984 0.018
    WNT9B rs753449_rs3846035 TG 0.017 0.018
    WNT9B rs9863290_rs1829555 CA 0.016 0.018
3 SNPs in haplotype
    WNT9A rs4074668_rs1573059_rs945699 CTA 0.331 0.005
    WNT5A rs7207916_rs11079737_rs391603 GGT 0.076 0.008
    WNT9B rs1530364_rs4968282_rs197932 AGC 0.232 0.009
    WNT9B rs6504591_rs1530364_rs4968282 TGA 0.617 0.014
    WNT5A rs1444866_rs4580514_rs753449 GAT 0.016 0.015
    WNT5A rs17055216_rs1444866_rs458051 AGA 0.016 0.015
    WNT5B rs753449_rs3846035_rs9683127 TGG 0.016 0.018
    WNT3 rs4580514_rs753449_rs3846035 ATG 0.017 0.018
    WNT9B rs9863290_rs1829555_rs3846037 CAC 0.016 0.018
    WNT9B rs4766401_rs10848539_rs227003 TAC 0.013 0.019

Table 3

Results of haplotype analyses in NSCP trios"

Genes SNPs Haplotype Frequency P
2 SNPs in haplotype
    WNT9A rs1009658_rs12748472 TG 0.385 < 0.001
    WNT9A rs3820623_rs10127943 AG 0.264 0.001
    WNT9A rs12725747_rs3820623 GA 0.330 0.002
    WNT9A rs12748472_rs12725747 GG 0.624 0.011
    WNT3 rs11079737_rs3916033 GT 0.086 0.018
    WNT5A rs3856709_rs358783 TA 0.179 0.023
    WNT5A rs358783_rs358817 AC 0.176 0.024
    WNT9A rs1009658_rs12748472 TA 0.290 0.031
    WNT11 rs10899188_rs603232 AC 0.171 0.031
    WNT9A rs4518905_rs1009658 CC 0.273 0.035
3 SNPs in haplotype
    WNT9A rs1009658_rs12748472_rs127257 TGG 0.385 < 0.001
    WNT9A rs12725747_rs3820623_rs101279 GAG 0.261 0.001
    WNT9A rs12748472_rs12725747_rs38206 GGA 0.330 0.002
    WNT9A rs3820623_rs10127943_rs634106 AGC 0.150 0.008
    WNT3 rs7207916_rs11079737_rs391603 GGT 0.086 0.012
    WNT9A rs4518905_rs1009658_rs1274847 CTG 0.181 0.016
    WNT9A rs4518905_rs1009658_rs1274847 CCG 0.255 0.018
    WNT5B rs735890_rs3803163_rs2010851 AGC 0.033 0.019
    WNT5A rs3856709_rs358783_rs358817 TAC 0.177 0.024
    WNT5A rs358783_rs358817_rs6774673 ACC 0.177 0.024
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