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Analysis of candidate genes on chromosome 2 in oral cleft case-parent trios from three populations

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Abstract

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.

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Acknowledgments

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.

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Authors and Affiliations

  1. Johns Hopkins University, 615 N. Wolfe St., Baltimore, MD, USA

    T. H. Beaty, J. B. Hetmanski, M. D. Fallin, J. W. Park, J. W. Sull & K. Y. Liang

  2. Institute of Genetic Medicine, Johns Hopkins University, Baltimore, MD, USA

    I. McIntosh, S. A. Boyadjiev, E. W. Jabs, R. Ingersoll & A. F. Scott

  3. American University of the Caribbean, St. Maarten, Netherlands Antilles

    I. McIntosh

  4. School of Medicine, Johns Hopkins University, Baltimore, MD, USA

    C. A. VanderKolk & R. J. Redett

  5. Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore

    S. S. Chong & F. S. H. Cheah

  6. Chang Gung Memorial Hospital, Taipei, Taiwan

    Y. H. Wu-Chou & P. K. Chen

  7. National Health Research Institute, Taipei, Taiwan

    K. Y. Liang & Y. F. Chiu

  8. KK Women’s and Children’s Hospital, Singapore, Singapore

    V. Yeow, I. S. L. Ng & J. Cheng

  9. Chinese Academy of Medical Sciences, Beijing, People’s Republic of China

    S. Huang

  10. WuHan University, WuHan, People’s Republic of China

    X. Ye

  11. Peking University Health Science Center, Beijing, People’s Republic of China

    H. Wang

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  1. T. H. Beaty
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  18. I. S. L. Ng
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  22. H. Wang
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  23. R. Ingersoll
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  24. A. F. Scott
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Correspondence to T. H. Beaty.

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Beaty, T.H., Hetmanski, J.B., Fallin, M.D. et al. Analysis of candidate genes on chromosome 2 in oral cleft case-parent trios from three populations. Hum Genet 120, 501–518 (2006). https://doi.org/10.1007/s00439-006-0235-9

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