Gene–gene interaction among cell adhesion genes and risk of nonsyndromic cleft lip with or without cleft palate in Chinese case‐parent trios

BACKGROUND: Nonsyndromic cleft lip with or without cleft palate (NSCL/P) is a common birth defect with complex etiology. One strategy for studying the genetic risk factors of NSCL/P is to consider gene–gene interaction (G × G) among gene pathways having a role in craniofacial development. The present study aimed to investigate the G × G among cell adhesion gene pathway. METHODS: We carried out an interaction analysis of eight genes involved in cell adherens junctions among 806 NSCL/P Chinese case‐parent trios originally recruited for a genome‐wide association study (GWAS). Regression‐based approach was used to test for two‐way G × G interaction, while machine learning algorithm was run for exploring both two‐way and multi‐way interaction that may affect the risk of NSCL/P. RESULTS: A two‐way ACTN1 × CTNNB1 interaction reached the adjusted significance level. The single nucleotide polymorphisms pair composed of rs17252114 (CTNNB1) and rs1274944 (ACTN1) yielded a p value of .0002, and this interaction was also supported by the logic regression algorithm. Higher order interactions involving ACTN1, CTNNB1, and CDH1 were picked out by logic regression, suggesting a potential role in NSCL/P risk. CONCLUSION: This study suggests for the first time evidence of both two‐way and multi‐way G × G interactions among cell adhesion genes contributing to the NSCL/P risk.