Gene-Gene Interactions among SPRYs for Nonsyndromic Cleft Lip/Palate

Nonsyndromic cleft lip with or without cleft palate (NSCL/P) is a common birth defect with a complex genetic architecture. Gene-gene interactions have been increasingly regarded as contributing to the etiology of NSCL/P. A recent genome-wide association study revealed that a novel single-nucleotide polymorphism at SPRY1 in 4q28.1 showed a significant association with NSCL/P. In the current study, we explored the role of 3 SPRY genes in the etiology of NSCL/P by detecting gene-gene interactions: SPRY1, SPRY2, and SPRY4-with SPRY3 excluded due to its special location on the X chromosome. We selected markers in 3 SPRY genes to test for gene-gene interactions using 1,908 case-parent trios recruited from an international consortium established for a genome-wide association study of nonsyndromic oral clefts. As the trios came from populations with different ancestries, subgroup analyses were conducted among Europeans and Asians. Cordell's method based on conditional logistic regression models was applied to test for potential gene-gene interactions via the statistical package TRIO in R software. Gene-gene interaction analyses yielded 10 pairs of SNPs in Europeans and 6 pairs in Asians that achieved significance after Bonferroni correction. The significant interactions were confirmed in the 10,000-permutation tests (empirical P = 0.003 for the most significant interaction). The study identified gene-gene interactions among SPRY genes among 1,908 NSCL/P trios, which revealed the importance of potential gene-gene interactions for understanding the genetic architecture of NSCL/P. The evidence of gene-gene interactions in this study also provided clues for future biological studies to further investigate the mechanism of how SPRY genes participate in the development of NSCL/P.