Gene–gene interaction between MSX1 and TP63 in Asian case-parent trios with nonsyndromic cleft lip with or without cleft palate

Dongjing Liu, Holger Schwender, Mengying Wang, Hong Wang, Ping Wang, Hongping Zhu, Zhibo Zhou, Jing Li, Tao Wu, Terri H. Beaty

Research output: Contribution to journalArticlepeer-review

5 Scopus citations


Background: Small ubiquitin-like modification, also known as sumoylation, is a crucial post-translational regulatory mechanisms involved in development of the lip and palate. Recent studies reported two sumoylation target genes, MSX1 and TP63, to have achieved genome-wide level significance in tests of association with nonsyndromic clefts. Here, we performed a candidate gene analysis considering gene–gene and gene–environment interaction for SUMO1, MSX1, and TP63 to further explore the etiology of nonsyndromic cleft lip with or without cleft palate (NSCL/P). Methods: A total of 130 single-nucleotide polymorphisms (SNPs) in or near SUMO1, MSX1, and TP63 was analyzed among 1,038 Asian NSCL/P trios ascertained through an international consortium. Conditional logistic regression models were used to explore gene–gene (G × G) and gene–environment (G × E) interaction involving maternal environmental tobacco smoke and multivitamin supplementation. Bonferroni correction was used for G × E analysis and permutation tests were used for G × G analysis. Results: While transmission disequilibrium tests and gene–environment interaction analysis showed no significant results, we did find signals of gene–gene interaction between SNPs near MSX1 and TP63. Three pairwise interactions yielded significant p values in permutation tests (rs884690 and rs9290890 with p = 9.34 × 10−5 and empirical p = 1.00 × 10−4, rs1022136 and rs4687098 with p = 2.41 × 10−4 and empirical p = 2.95 × 10−4, rs6819546 and rs9681004 with p = 5.15 × 10−4 and empirical p = 3.02 × 10−4). Conclusion: Gene–gene interaction between MSX1 and TP63 may influence the risk of NSCL/P in Asian populations. Our study provided additional understanding of the genetic etiology of NSCL/P and underlined the importance of considering gene–gene interaction in the etiology of this common craniofacial malformation.

Original languageEnglish (US)
Pages (from-to)317-324
Number of pages8
JournalBirth Defects Research
Issue number4
StatePublished - Mar 1 2018


  • association study
  • case-parent trio
  • gene–gene interaction
  • nonsyndromic cleft lip with or without cleft palate
  • sumoylation

ASJC Scopus subject areas

  • Pediatrics, Perinatology, and Child Health
  • Embryology
  • Toxicology
  • Developmental Biology
  • Health, Toxicology and Mutagenesis


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