title: 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 European ancestry than among trios of Asian ancestry. We examined marker information content and haplotype diversity across 13 recruitment sites (from Europe, United States, and Asia) separately, and conducted principal components analysis (PCA) on parents. As expected, PCA revealed large genetic distances between Europeans and Asians, and a north-south cline from Korea to Singapore in Asia, with Filipino parents forming a somewhat distinct Southeast Asian cluster. Hierarchical clustering of SNP heterozygosity revealed two major clades consistent with PCA results. All genotyped SNPs giving P < 10(-6) in the allelic transmission disequilibrium test (TDT) showed higher heterozygosity in Europeans than Asians. On average, European ancestry parents had higher haplotype diversity than Asians. Imputing additional variants across chr8q24 increased the strength of statistical evidence among Europeans and also revealed a significant signal among Asians (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 Asian ancestry was not due to any distinct genetic effect, but could simply reflect low power due to lower allele frequencies in Asians.
authors.affiliation: Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland 21205, USA.
authors.forename: Tanda
authors.initials: T
authors.lastname: Murray
authors.forename: Margaret A
authors.initials: MA
authors.lastname: Taub
authors.forename: Ingo
authors.initials: I
authors.lastname: Ruczinski
authors.forename: Alan F
authors.initials: AF
authors.lastname: Scott
authors.forename: Jacqueline B
authors.initials: JB
authors.lastname: Hetmanski
authors.forename: Holger
authors.initials: H
authors.lastname: Schwender
authors.forename: Poorav
authors.initials: P
authors.lastname: Patel
authors.forename: Tian Xiao
authors.initials: TX
authors.lastname: Zhang
authors.forename: Ronald G
authors.initials: RG
authors.lastname: Munger
authors.forename: Allen J
authors.initials: AJ
authors.lastname: Wilcox
authors.forename: Xiaoqian
authors.initials: X
authors.lastname: Ye
authors.forename: Hong
authors.initials: H
authors.lastname: Wang
authors.forename: Tao
authors.initials: T
authors.lastname: Wu
authors.forename: Yah Huei
authors.initials: YH
authors.lastname: Wu-Chou
authors.forename: Bing
authors.initials: B
authors.lastname: Shi
authors.forename: Sun Ha
authors.initials: SH
authors.lastname: Jee
authors.forename: Samuel
authors.initials: S
authors.lastname: Chong
authors.forename: Vincent
authors.initials: V
authors.lastname: Yeow
authors.forename: Jeffrey C
authors.initials: JC
authors.lastname: Murray
authors.forename: Mary L
authors.initials: ML
authors.lastname: Marazita
authors.forename: Terri H
authors.initials: TH
authors.lastname: Beaty
mesh_terms: D000483:Alleles; D044466:Asian People; D002898:Chromosomes, Human, Pair 8; D002971:Cleft Lip / Q000150:complications / Q000208:ethnology / Q000235:genetics*; D002972:Cleft Palate / Q000150:complications / Q000208:ethnology / Q000235:genetics*; D016000:Cluster Analysis; D020022:Genetic Predisposition to Disease; D016678:Genome; D005838:Genotype; D006239:Haplotypes; D006579:Heterozygote; D006801:Humans; D015810:Linkage Disequilibrium; D008957:Models, Genetic; D025341:Principal Component Analysis; D044465:White People