Family-based analysis of MSX1 haplotypes for association with oral clefts

Oral clefts, one of the most common forms of birth defects, are considered to be of complex etiology, including both genetic and environmental causes. To date, however, no particular genetic cause has been confirmed for isolated, nonsyndromic oral clefts. Previous case-control and family-based association studies reported an association between an intronic CA repeat of the MSX1 gene and risk for oral clefts. In this study, we identify eight single-nucleotide polymorphisms (SNPs) in the MSX1 gene, and present genotype results for these SNPs in a set of 206 oral cleft cases and their parents. We performed single-marker and haplotype-based transmission disequilibrium tests (TDTs), and tested for evidence of interaction between MSX1 haplotypes and exposure to maternal smoking in the first trimester, using a case-only approach. The haplotype TDT analyses further implicate this gene, or region, in controlling the risk for oral clefts, particularly for cleft palate. In addition, case-only haplotype analyses suggest an interaction between variation in the MSX1 gene and exposure to maternal smoking. This study encourages further focus on the MSX1 gene region to ultimately determine specific variants predisposing to oral clefts.