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Journal of Peking University(Health Sciences) ›› 2019, Vol. 51 ›› Issue (3): 564-570. doi: 10.19723/j.issn.1671-167X.2019.03.028

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Exploring the association between SPRY gene family and non-syndromic oral clefts among Chinese populations using data of a next-generation sequencing study

Ren ZHOU1,Hong-chen ZHENG1,Wen-yong LI1,Meng-ying WANG1,Si-yue WANG1,Nan LI2,Jing LI3,Zhi-bo ZHOU2,Tao WU1,Hong-ping ZHU2△()   

  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 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. Department of Pediatric Dentistry, Peking University School and Hospital of Stomatology, Beijing 100081, China
  • Received:2019-03-18 Online:2019-06-18 Published:2019-06-26
  • Supported by:
    Supported by the National Natural Science Foundation of China (81573225) and the Fundamental Research Funds for the Central Universities: Peking University Medicine Seed Fund for Interdisciplinary Research (BMU2017MX018)

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Abstract: Objective: To explore the association between SPRY gene family and the risk of non-syndromic oral clefts among Chinese populations, in respect of single nucleotide polymorphisms (SNPs) association and parent-of-origin effects.Methods: Based on case-parent design, this study used the data of SPRY gene family in a next generation sequencing study of 183 non-syndromic cleft lip with or without cleft palate (NSCL/P) case-parent trios (549 participants) recruited from 2016 to 2018, to analyze the effects of SNP association and parent-of-origin. The sequencing study adopted a two-stage design. In the first stage, whole exome sequencing was conducted among 24 NSCL/P trios with family history to explore potential signals. Then in the second stage, another 159 NSCL/P trios were used as validation samples to verify the signals found in the first stage. The data of general information, disease features and parental environmental exposures for participants were collected through questionnaires. Blood samples were collected from each participant for DNA extraction and sequencing. Transmission disequilibrium tests (TDT) were conducted to test for the association between SNPs and NSCL/P, while Z score tests were applied to analyze parent-of-origin effects. The analyses were performed using Plink (v1.07). TRIO package in R (v3.5.1). Besides, famSKAT analyses were conducted in the first stage to combine the effect of SNPs located on the same gene, using famSKAT package in R(V3.5.1). Bonferroni method was adopted to correct multiple tests in the second stage. Results: Twenty-two SNPs in SPRY gene family were included for analyses after the quality control process in the first stage. Based on the variants annotation, functional prediction and statistical analysis, rs1298215244 (SPRY1) and rs504122 (SPRY2) were included in the second verification stage. TDTs in the verification stage revealed that rs1298215244: T>C, rs504122: G>C and rs504122: G>T were associated with the risk of NSCL/P after Bonferroni corrections, where rs504122: G>T was a rare variation. Although the test for parent-of-origin effect of rs1298215244: T>C reached nominal significance level, no SNP showed significant association with NSCL/P through parent-of-origin effect after Bonferroni corrections.Conclusion: This study found that SNPs (including both common and rare variants) among the SPRY gene family were associated with the risk of NSCL/P among Chinese populations. This study failed to detect parent-of-origin effects among the SPRY gene family.

Key words: Non-syndromic oral clefts, Association study, Case-parent trios, Next generation sequencing, SPRY gene family

CLC Number: 

  • R782.2

Table 1

The sex distribution of 183 NSCL/P cases in Chinese populations"

Stage Male Female Total
Stage 1 15 9 24
Stage 2 99 60 159
Total 114 69 183

Table 2

Transmission disequilibrium tests of SNPs in the SPRY gene family among 24 Chinese NSCL/P trios"

SNP Gene Chromosome Position Number of transmittedallele Number of non-transmitted allele P value
rs300574 SPRY1 4 124323738 18 9 0.083 3
rs4912844 SPRY4 5 141691371 1 5 0.102 5
rs4728 SPRY2 13 80910786 4 8 0.248 2
chr4: 124322600 SPRY1 4 124322600 1 0 0.317 3
rs1440299404 SPRY1 4 124322722 1 0 0.317 3

Table 3

The famSKAT analysis of SPRY genes among 24 Chinese NSCL/P trios"

phi Gene Number of alleles P value
0 SPRY1 5 1
SPRY2 5 0.533 2
SPRY4 12 0.754 2
0.2 SPRY1 5 1
SPRY2 5 0.587 5
SPRY4 12 0.918 3
0.5 SPRY1 5 1
SPRY2 5 0.662 8
SPRY4 12 0.964 0
0.8 SPRY1 5 1
SPRY2 5 0.676 8
SPRY4 12 0.962 2
1 SPRY1 5 1
SPRY2 5 1
SPRY4 12 0.943 6

Table 4

Transmission disequilibrium tests of potential signals in the SPRY gene family among 159 Chinese NSCL/P trios"

Allele Gene Variation MAF OR P value
rs1298215244 SPRY1 T>C 0.114 3.53 4.06×10-6
rs504122 SPRY2 G>C 0.116 2.45 4.81×10-4
rs504122 SPRY2 G>T 0.017 10.00 0.006 7

Table 5

Analyses of parent-of-origin effects for potential signals in the SPRY gene family among 159 Chinese NSCL/P trios"

Allele Gene Variation Paternal transmitted ∶untransmitted counts Maternal transmitted ∶untransmitted counts P value
rs1298215244 SPRY1 T>C 2.5 ∶25.5 12.5 ∶27.5 0.039 6
rs504122 SPRY2 G>C 11 ∶28 9 ∶21 0.870 6
rs504122 SPRY2 G>T 1 ∶3 0 ∶7 -
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