Examining Markers in 8q24 to Explain Differences in Evidence for Association With Cleft Lip With/Without Cleft Palate Between Asians and Europeans

Abstract

In a recent genome‐wide association study (GWAS ) from an international consortium, evidence of linkage and association in chr8q24 was much stronger among nonsyndromic cleft lip/palate (CL /P ) case‐parent trios of E uropean ancestry than among trios of A sian ancestry. We examined marker information content and haplotype diversity across 13 recruitment sites (from E urope, U nited S tates, and A sia) separately, and conducted principal components analysis (PCA ) on parents. As expected, PCA revealed large genetic distances between E uropeans and A sians, and a north‐south cline from K orea to S ingapore in A sia, with F ilipino parents forming a somewhat distinct S outheast A sian cluster. Hierarchical clustering of SNP heterozygosity revealed two major clades consistent with PCA results. All genotyped SNP s giving P < 10⁻⁶ in the allelic transmission disequilibrium test (TDT ) showed higher heterozygosity in E uropeans than A sians. On average, E uropean ancestry parents had higher haplotype diversity than A sians. Imputing additional variants across chr8q24 increased the strength of statistical evidence among E uropeans and also revealed a significant signal among A sians (although it did not reach genome‐wide significance). Tests for SNP ‐population interaction were negative, indicating the lack of strong signal for 8q24 in families of A sian ancestry was not due to any distinct genetic effect, but could simply reflect low power due to lower allele frequencies in A sians. Genet. Epidemiol. 36:392–399, 2012.