Gene–gene Interaction among Cell Adhesion Genes and Risk of Nonsyndromic Cleft Lip with or Without Cleft Palate in Chinese Case‐parent Trios

Abstract 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.