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. 2013 May;161A(5):965-72.
doi: 10.1002/ajmg.a.35749. Epub 2013 Mar 5.

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)

Azeez Butali  1 , Satoshi Suzuki, Margaret E Cooper, Adela M Mansilla, Karen Cuenco, Elizabeth J Leslie, Yasushi Suzuki, Teruyuki Niimi, Masahiko Yamamoto, Gongorjav Ayanga, Tudevdorj Erkhembaatar, Hiroo Furukawa, Kumiko Fujiwawa, Hideto Imura, Aline L Petrin, Nagato Natsume, Terri H Beaty, Mary L Marazita, Jeffery C Murray
Affiliations

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)

Azeez Butali et al. Am J Med Genet A. 2013 May.

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.

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References

    1. Avila JR, Jezewski PA, Vieira AR, Orioli IM, Castilla EE, Christensen K, Daack-Hirsch S, Romitti PA, Murray JC. PVRL1 variants contribute to non-syndromic cleft lip and palate in multiple populations. Am J Med Genet A. 2006;140:2562–2570. - PMC - PubMed
    1. Beaty TH, Murray JC, Marazita ML, Munger RG, Ruczinski I, Hetmanski JB, Liang KY, Wu T, Murray T, Fallin MD, Redett RA, Raymond G, Schwender H, Jin SC, Cooper ME, Dunnwald M, Mansilla MA, Leslie E, Bullard S, Lidral AC, Moreno LM, Menezes R, Vieira AR, Petrin A, Wilcox AJ, Lie RT, Jabs EW, Wu-Chou YH, Chen PK, Wang H, Ye X, Huang S, Yeow V, Chong SS, Jee SH, Shi B, Christensen K, Melbye M, Doheny KF, Pugh EW, Ling H, Castilla EE, Czeizel AE, Ma L, Field LL, Brody L, Pangilinan F, Mills JL, Molloy AM, Kirke PN, Scott JM, Arcos-Burgos M, Scott AF. A genome wide association study of cleft lip with / without cleft palate using case-parent trios of European and Asian ancestry identifies MAFB and ABCA4 as novel candidate genes. Nat Genet. 2010;42:525–529. - PMC - PubMed
    1. Birnbaum S, Ludwig KU, Reutter H, Herms S, Steffens M, Rubini M, Baluardo C, Ferrian M, Almeida de Assis N, Alblas MA, Barth S, Freudenberg J, Lauster C, Schmidt G, Scheer M, Braumann B, Bergé SJ, Reich RH, Schiefke F, Hemprich A, Pötzsch S, Steegers-Theunissen RP, Pötzsch B, Moebus S, Horsthemke B, Kramer FJ, Wienker TF, Mossey PA, Propping P, Cichon S, Hoffmann P, Knapp M, Nöthen MM, Mangold E. Key susceptibility locus for nonsyndromic cleft lip with or withgout cleft palate on chromosome 8q24. Nature Genet. 2009;41:473–477. - PubMed
    1. Chiquet BT, Lidral AC, Stal S, Mulliken JB, Moreno LM, Arcos-Burgos M, Valencia-Ramirez C, Blanton SH, Hecht JT. CRISPLD2: a novel NSCLP candidate gene. Hum Mol Genet. 2007;16:2241–2248. - PMC - PubMed
    1. Cordell HJ. Epistasis: what it means, what it doesn’t mean, and statistical methods to detect it in humans. Hum Molec Genet. 2002;11:2463–2468. - PubMed

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