Analysis of candidate genes on chromosome 2 in oral cleft case-parent trios from three populations
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Isolated oral clefts, including cleft lip with/without cleft palate (CL/P) and cleft palate (CP), have a complex and heterogeneous etiology. Case-parent trios from three populations were used to study genes spanning chromosome 2, where single nucleotide polymorphic (SNP) markers were analyzed individually and as haplotypes. Case-parent trios from three populations (74 from Maryland, 64 from Singapore and 95 from Taiwan) were genotyped for 962 SNPs in 104 genes on chromosome 2, including two well-recognized candidate genes: TGFA and SATB2. Individual SNPs and haplotypes (in sliding windows of 2–5 SNPs) were used to test for linkage and disequilibrium separately in CL/P and CP trios. A novel candidate gene (ZNF533) showed consistent evidence of linkage and disequilibrium in all three populations for both CL/P and CP. SNPs in key regions of ZNF533 showed considerable variability in estimated genotypic odds ratios and their significance, suggesting allelic heterogeneity. Haplotype frequencies for regions of ZNF533 were estimated and used to partition genetic variance into among-and within-population components. Wright’s fixation index, a measure of genetic diversity, showed little difference between Singapore and Taiwan compared with Maryland. The tensin-1 gene (TNS1) also showed evidence of linkage and disequilibrium among both CL/P and CP trios in all three populations, albeit at a lower level of significance. Additional genes (VAX2, GLI2, ZHFX1B on 2p; WNT6–WNT10A and COL4A3–COL4A4 on 2q) showed consistent evidence of linkage and disequilibrium only among CL/P trios in all three populations, and TGFA showed significant evidence in two of three populations.
KeywordsLinkage Disequilibrium Single Nucleotide Polymorphic Cleft Palate Individual SNPs Multiplex Family
This research was supported by R01-DE-10293, R21-DE-13707, R01-DE-13939 and R01-DE-14581 from the National Institute of Dental & Craniofacial Research. Information from the COGENE consortium was collected with support from N01-DE-92630. We thank all participants who donated samples from the Maryland oral cleft study, participants recruited from Chang Gung Memorial Hospital in Taipei, as well as those from KK Women’s & Children’s Hospital in Singapore. The hard work of staff at all three institutions is gratefully acknowledged and deeply appreciated. We are grateful to the Smile Train Foundation for supporting research on oral clefts in China, and we acknowledge support from D43-TW-06176 which fostered collaborations in China.
- Cooper ME, Ratay J, Marazita ML (2006) Asian oral-facial cleft birth prevalence. Cleft-Palate Craniofac J (e-pub)Google Scholar
- Excoffier L (2003) Analysis of population subdivision. In: Balding DJ, Bishop M, Cannings C (eds) Handbook of statistical genetics, 2nd edn. Wiley, West Sussex, England, pp 713–745Google Scholar
- Fan JB, Oliphant A, Shen R, Kermani BG, Garcia F, Gunderson KL, Hansen M, Steemers F, Butler SL, Deloukas P, Galver L, Hunt S, McBride C, Bibikova M, Rubano T, Chen J, Wickham E, Doucet D, Chang W, Campbell D, Zhang B, Kruglyak S, Bentley D, Haas J, Rigault P, Zhou L, Steulpnagel J, Chee MS (2003) Highly parallel SNP genotyping. Cold Spring Harb Symp Quant Biol 68:69–78PubMedCrossRefGoogle Scholar
- Maestri NE, Beaty TH, Hetmanski J, Smith EA, McIntosh I, Wyszynski DF, Liang K-Y, Duffy DL, VanderKolk C (1997) Application of transmission disequilibrium tests to nonsyndromic oral clefts: including candidate genes and environmental exposures in the models. Am J Med Genet 73:337–344PubMedCrossRefGoogle Scholar
- Mitchell LE. (2002) Twin studies in oral cleft research. In: Wyszynski DF (ed) Cleft lip and palate, Oxford University Press, Oxford, pp 214–221Google Scholar
- Mossey PA, Little J (2002) Epidemiology of oral clefts: an international perspective. In: Wyszynksi DF (ed) Cleft lip and palate, Oxford University Press, Oxford, pp 127–158Google Scholar
- Oliphant A, Barker DL, Stuelpnagel JR, Chee MS (2002) BeadArray™ technology: enabling an accurate, cost-efficient approach to high-throughput genotyping. Biotechniques 32:S56–S61Google Scholar
- Strausberg RL, Feingold EA, Grouse LH, Derge JG, Klausner RD, Collins FS, Wagner L et al, Mammalian Gene Collection Program Team (2002) Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. Proc Natl Acad Sci USA 99:16899–16903Google Scholar
- Vieira AR, Avila JR, Daack-Hirsch S, Dragan E, Félix TM, Rahimov F, Harrington J, Schultz RR, Watanabe Y, Johnson M, Fang J, O’Brien SE, Orioli IM, Castilla EE, FitzPatrick DR, Jiang R, Marazita ML, Murray JC (2005) Medical sequencing of candidate genes for nonsyndromic cleft lip and palate. Plos Genet 1:e64Google Scholar
- Zweier C, Albrecht B, Mitulla B, Behrens R, Beese M, Gillessen-Kaesbach G, Rott H.-D, Rauch A (2002) ‘Mowat-Wilson’ syndrome with and without Hirschsprung disease is a distinct, recognizable multiple congenital anomalies-mental retardation syndrome caused by mutations in the zinc finger homeo box 1B gene. Am J Med Genet 108: 177–181PubMedCrossRefGoogle Scholar