Azeez Butali and Satoshi Suzuki equally contributed to this work.
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)
Article first published online: 5 MAR 2013
Copyright © 2012 Wiley Periodicals, Inc.
American Journal of Medical Genetics Part A
Volume 161, Issue 5, pages 965–972, May 2013
How to Cite
2012. 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). Am J Med Genet Part A 161A:965–972., , , , , , , , , , , , , , , , , , .
- Issue published online: 22 APR 2013
- Article first published online: 5 MAR 2013
- Manuscript Accepted: 11 OCT 2012
- Manuscript Received: 11 JUN 2012
- National Institute for Dental and Craniofacial Research (NIH), Face Base Grant. Grant Numbers: K99-DE022378-01, R37-DE08559 R01-DE016148, U01-DE-018993, U01 DE-20057
- Aichi-Gakuin. Grant Number: 20791560
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.