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

Area of Science:

• Genetics
• Developmental Biology
• Birth Defects Research

Background:

• Nonsyndromic cleft lip with or without cleft palate (NSCL/P) is a common congenital anomaly with a complex genetic basis.
• Gene-gene interactions are increasingly recognized as significant contributors to the etiology of NSCL/P.
• A prior genome-wide association study identified a single-nucleotide polymorphism in SPRY1 associated with NSCL/P.

Purpose of the Study:

• To investigate the role of gene-gene interactions among SPRY family genes (SPRY1, SPRY2, SPRY4) in the development of NSCL/P.
• To analyze interactions using a large dataset of international case-parent trios.
• To identify specific SPRY gene interaction patterns in different ancestral populations.

Main Methods:

• Utilized 1,908 case-parent trios from an international consortium for genome-wide association studies.
• Applied Cordell's method with conditional logistic regression models to detect gene-gene interactions.
• Conducted subgroup analyses for European and Asian populations and employed permutation tests for validation.

Main Results:

• Identified significant gene-gene interactions among SPRY genes in both European (10 SNP pairs) and Asian (6 SNP pairs) populations after Bonferroni correction.
• The most significant interaction was robustly confirmed through 10,000-permutation tests (empirical P = 0.003).
• These findings underscore the importance of SPRY gene interactions in NSCL/P etiology.

Conclusions:

• Gene-gene interactions among SPRY genes play a significant role in the genetic architecture of nonsyndromic cleft lip with or without cleft palate.
• The identified interactions provide valuable insights for future research into the molecular mechanisms underlying NSCL/P.
• This study highlights the complexity of NSCL/P genetics and the contribution of epistatic effects.