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Replication of Genome Wide Association Identified Candidate Genes Confirm the Role of Common and Rare Variants in PAX 7 and VAX 1 in the Etiology of Nonsyndromic CL(P)
Author(s) -
Butali Azeez,
Suzuki Satoshi,
Cooper Margaret E.,
Mansilla Adela M.,
Cuenco Karen,
Leslie Elizabeth J.,
Suzuki Yasushi,
Niimi Teruyuki,
Yamamoto Masahiko,
Ayanga Gongorjav,
Erkhembaatar Tudevdorj,
Furukawa Hiroo,
Fujiwawa Kumiko,
Imura Hideto,
Petrin Aline L.,
Natsume Nagato,
Beaty Terri H.,
Marazita Mary L.,
Murray Jeffery C.
Publication year - 2013
Publication title -
american journal of medical genetics part a
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.064
H-Index - 112
eISSN - 1552-4833
pISSN - 1552-4825
DOI - 10.1002/ajmg.a.35749
Subject(s) - genetics , replication (statistics) , gene , biology , genome , computational biology , virology
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. © 2013 Wiley Periodicals, Inc.