Patel PJ, Beaty TH, Ruczinski I, Murray JC, Marazita ML, Munger RG, Hetmanski JB, Wu T, Murray T, Rose M, Redett RJ, Jin SC, Lie RT, Wu-Chou Y-H, Wang H, Ye X, Yeow V, Chong S, Jee SH, Shi B, Scott AF. X-linked markers in the Duchenne muscular dystrophy gene associated with oral clefts. Eur J Oral Sci 2013; 121: 63-68. © 2013 Eur J Oral Sci
As part of an international consortium, case–parent trios were collected for a genome-wide association study of isolated, non-syndromic oral clefts, including cleft lip (CL), cleft palate (CP), and cleft lip and palate (CLP). Non-syndromic oral clefts have a complex and heterogeneous etiology. Risk is influenced by genes and environmental factors, and differs markedly by gender. Family-based association tests (FBAT) were used on 14,486 single nucleotide polymorphisms (SNPs) spanning the X chromosome, stratified by type of cleft and racial group. Significant results, even after multiple-comparisons correction, were obtained for the Duchenne muscular dystrophy (DMD) gene, the largest single gene in the human genome, among CL/P (i.e. both CL and CLP combined) trios. When stratified into groups of European and Asian ancestry, stronger signals were obtained for Asian subjects. Although conventional sliding-window haplotype analysis showed no increase in significance, selected combinations of the 25 most significant SNPs in the DMD gene identified four SNPs together that attained genome-wide significance among Asian CL/P trios, raising the possibility of interaction between distant SNPs within the DMD gene.