title: Replication of genome wide association identified candidate genes confirm the role of common and rare variants in PAX7 and VAX1 in the etiology of nonsyndromic CL(P).
abstract: Following recent genome wide association studies (GWAS), significant genetic associations have been identified for several genes with nonsyndromic cleft lip with or without cleft palate (CL(P)). To replicate two of these GWAS signals, we investigated the role of common and rare variants in the PAX7 and VAX1 genes. TaqMan genotyping was carried out for SNPs in VAX1 and PAX7 and transmission disequilibrium test (TDT) was performed to test for linkage and association in each population. Direct sequencing in and around the PAX7 and VAX1 genes in 1,326 individuals of European and Asian ancestry was done. The TDT analysis showed strong associations with markers in VAX1 (rs7078160, P = 2.7E-06 and rs475202, P = 0.0002) in a combined sample of Mongolian and Japanese CL(P) case-parent triads. Analyses using parent-of-origin effects showed significant excess transmission of the minor allele from both parents with the effect in the mothers (P = 6.5E-05, OR (transmission) = 1.91) more striking than in the fathers (P = 0.004, OR (transmission) = 1.67) for VAX1 marker rs7078160 in the combined Mongolian and Japanese samples when all cleft types were combined. The rs6659735 trinucleotide marker in PAX7 was significantly associated with all the US cleft groups combined (P = 0.007 in all clefts and P = 0.02 in CL(P)). Eight rare missense mutations found in PAX7 and two rare missense mutations in VAX1. Our study replicated previous GWAS findings for markers in VAX1 in the Asian population, and identified rare variants in PAX7 and VAX1 that may contribute to the etiology of CL(P). Determining the role of rare variants clearly warrants further investigation.
authors: Department of Pediatrics, University of Iowa, Iowa City, IA 52242-1181, USA.
authors: Azeez
authors: A
authors: Butali
authors: Satoshi
authors: S
authors: Suzuki
authors: Margaret E
authors: ME
authors: Cooper
authors: Adela M
authors: AM
authors: Mansilla
authors: Karen
authors: K
authors: Cuenco
authors: Elizabeth J
authors: EJ
authors: Leslie
authors: Yasushi
authors: Y
authors: Suzuki
authors: Teruyuki
authors: T
authors: Niimi
authors: Masahiko
authors: M
authors: Yamamoto
authors: Gongorjav
authors: G
authors: Ayanga
authors: Tudevdorj
authors: T
authors: Erkhembaatar
authors: Hiroo
authors: H
authors: Furukawa
authors: Kumiko
authors: K
authors: Fujiwawa
authors: Hideto
authors: H
authors: Imura
authors: Aline L
authors: AL
authors: Petrin
authors: Nagato
authors: N
authors: Natsume
authors: Terri H
authors: TH
authors: Beaty
authors: Mary L
authors: ML
authors: Marazita
authors: Jeffery C
authors: JC
authors: Murray
mesh_terms: D000328:Adult; D044466:Asian People; D002971:Cleft Lip / Q000235:genetics*; D002972:Cleft Palate / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D005838:Genotype; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D008297:Male; D009154:Mutation; D051763:PAX7 Transcription Factor / Q000235:genetics*; D017422:Sequence Analysis, DNA; D014157:Transcription Factors / Q000235:genetics*; D014481:United States
chemical_list: D018398:Homeodomain Proteins; D051763:PAX7 Transcription Factor; C497321:PAX7 protein, human; D014157:Transcription Factors; C572055:VAX1 protein, human