Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Key susceptibility locus for nonsyndromic cleft lip with or without cleft palate on chromosome 8q24

Abstract

We conducted a genome-wide association study involving 224 cases and 383 controls of Central European origin to identify susceptibility loci for nonsyndromic cleft lip with or without cleft palate (NSCL/P). A 640-kb region at chromosome 8q24.21 was found to contain multiple markers with highly significant evidence for association with the cleft phenotype, including three markers that reached genome-wide significance. The 640-kb cleft-associated region was saturated with 146 SNP markers and then analyzed in our entire NSCL/P sample of 462 unrelated cases and 954 controls. In the entire sample, the most significant SNP (rs987525) had a P value of 3.34 × 10−24. The odds ratio was 2.57 (95% CI = 2.02–3.26) for the heterozygous genotype and 6.05 (95% CI = 3.88–9.43) for the homozygous genotype. The calculated population attributable risk for this marker is 0.41, suggesting that this study has identified a major susceptibility locus for NSCL/P.

This is a preview of subscription content

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

Figure 1: Genome-wide association scan for NSCL/P.
Figure 2: Details of the region 129,700,000–130,340,000 on chromosome 8q24.

Accession codes

Accessions

NCBI Reference Sequence

References

  1. Marazita, M.L. et al. Meta-analysis of 13 genome scans reveals multiple cleft lip/palate genes with novel loci on 9q21 and 2q32–35. Am. J. Hum. Genet. 75, 161–173 (2004).

    CAS  Article  Google Scholar 

  2. Jugessur, A. et al. Genetic variants in IRF6 and the risk of facial clefts: single-marker and haplotype-based analyses in a population-based case-control study of facial clefts in Norway. Genet. Epidemiol. 32, 413–424 (2008).

    Article  Google Scholar 

  3. Rahimov, F. et al. Disruption of an AP-2α binding site in an IRF6 enhancer is associated with cleft lip. Nat. Genet. 40, 1341–1347 (2008).

    CAS  Article  Google Scholar 

  4. Patterson, N., Price, A.L. & Reich, D. Population structure and eigenanalysis. PLoS Genet. 2, e190 (2006).

    Article  Google Scholar 

  5. Reich, D., Price, A.L. & Patterson, N. Principal component analysis of genetic data. Nat. Genet. 40, 491–492 (2008).

    CAS  Article  Google Scholar 

  6. International HapMap Consortium. A haplotype map of the human genome. Nature 437, 1299–1320 (2005).

  7. Lohmueller, K.E., Pearce, C.L., Pike, M., Lander, E.S. & Hirschhorn, J.N. Meta-analysis of genetic association studies supports a contribution of common variants to susceptibility to common disease. Nat. Genet. 33, 177–182 (2003).

    CAS  Article  Google Scholar 

  8. Becker, T. & Knapp, M. A powerful strategy to account for multiple testing in the context of haplotype analysis. Am. J. Hum. Genet. 75, 561–570 (2004).

    CAS  Article  Google Scholar 

  9. Weinberg, C.R. Methods for detection of parent-of-origin effects in genetic studies of case-parents triads. Am. J. Hum. Genet. 65, 229–235 (1999).

    CAS  Article  Google Scholar 

  10. Cann, H.M. et al. A human genome diversity cell line panel. Science 296, 261–262 (2002).

    CAS  Article  Google Scholar 

  11. Sivertsen, A. et al. Familial risk of oral clefts by morphological type and severity: population based cohort study of first degree relatives. Br. Med. J. 336, 432–434 (2008).

    Article  Google Scholar 

  12. Kondo, S. et al. Mutations in IRF6 cause Van der Woude and popliteal pterygium syndromes. Nat. Genet. 32, 285–289 (2002).

    CAS  Article  Google Scholar 

  13. Hirano, T. et al. Genes encoded within 8q24 on the amplicon of a large extrachromosomal element are selectively repressed during the terminal differentiation of HL-60 cells. Mutat. Res. 640, 97–106 (2008).

    CAS  Article  Google Scholar 

  14. Stanke, M., Steinkamp, R., Waack, S. & Morgenstern, B. AUGUSTUS: a web server for gene finding in eukaryotes. Nucleic Acids Res. 32, W309–W312 (2004).

    CAS  Article  Google Scholar 

  15. Dixon, A.L. et al. A whole-genome association study of global gene expression. Nat. Genet. 39, 1202–1207 (2007).

    CAS  Article  Google Scholar 

  16. Moffatt, M.F. et al. Genetic variants regulating ORMDL3 expression are determinants of susceptibility to childhood asthma. Nature 448, 470–473 (2007).

    CAS  Article  Google Scholar 

  17. Stranger, B.E. et al. Relative impact of nucleotide and copy number variation on gene expression phenotypes. Science 315, 848–853 (2007).

    CAS  Article  Google Scholar 

  18. Tomlinson, I. et al. A genome-wide association scan of tag SNPs identifies a susceptibility variant for colorectal cancer at 8q24.21. Nat. Genet. 39, 984–988 (2007).

    CAS  Article  Google Scholar 

  19. Ghoussaini, M. et al. Multiple loci with different cancer specificities within the 8q24 gene desert. J. Natl. Cancer Inst. 100, 962–966 (2008).

    CAS  Article  Google Scholar 

  20. Prescott, N.J., Lees, M.M., Winter, R.M. & Malcolm, S. Identification of susceptibility loci for nonsyndromic cleft lip with or without cleft palate in a two stage genome scan of affected sib-pairs. Hum. Genet. 106, 345–350 (2000).

    CAS  Article  Google Scholar 

  21. Risch, N. & Merikangas, K. The future of genetic studies of complex human diseases. Science 273, 1516–1517 (1996).

    CAS  Article  Google Scholar 

  22. Murray, J.C. Gene/environment causes of cleft lip and/or palate. Clin. Genet. 61, 248–256 (2002).

    CAS  Article  Google Scholar 

  23. Mossey, P.A. & Little, J. Epidemiology of oral clefts: an international perspective. in Cleft Lip and Palate: From Origin to Treatment (ed. Wyszynski, D.) 127–144 (Oxford University Press, New York, 2002).

    Google Scholar 

  24. Moskvina, V., Holmans, P., Schmidt, K.M. & Craddock, N. Design of case-controls studies with unscreened controls. Ann. Hum. Genet. 69, 566–576 (2005).

    CAS  Article  Google Scholar 

  25. Stefansson, H. et al. Large recurrent microdeletions associated with schizophrenia. Nature 455, 232–236 (2008).

    CAS  Article  Google Scholar 

  26. Jackson, M.R., Genin, E., Knapp, M. & Escary, J.L. Accurate power approximations for χ2-tests in case-control association studies of complex disease genes. Ann. Hum. Genet. 66, 307–321 (2002).

    CAS  Article  Google Scholar 

  27. Schaid, D.J. & Sommer, S.S. Genotype relative risks: methods for design and analysis of candidate-gene association studies. Am. J. Hum. Genet. 53, 1114–1126 (1993).

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Abecasis, G.R. & Cookson, W.O. GOLD–graphical overview of linkage disequilibrium. Bioinformatics 16, 182–183 (2000).

    CAS  Article  Google Scholar 

  29. Barrett, J.C., Fry, B., Maller, J. & Daly, M.J. Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics 21, 263–265 (2005).

    CAS  Article  Google Scholar 

Download references

Acknowledgements

We thank the subjects and their families for their participation in the study as well as the German support group for people with cleft lip and/or palate (Deutsche Selbsthilfevereinigung für Lippen-Gaumen-Fehlbildungen e.V.). We acknowledge M. Saffar, H. Koch, C. Opitz, M. Krimmel, K. Gundlach, K. Lohrer and B. Blaumeiser for their kind support in contacting subjects. The EUROCRAN project included contributions from R. Brusati, G. Garattini, E. Calzolari, M. Accordi and A. Franchella (Italy), W.C. Shaw, P. Nelson and P. Houston (UK), S. de Weerd and I. Krapels (Netherlands), V. Kozelj and B. Peterlin (Slovenia), Y. Anastassov (Bulgaria), S. Hanstein (Estonia), A. Czeizel (Hungary), I. Klimova (Slovak Republic) and J. Little (Canada). We also thank S. Raeder, S. Uhlhaas, N. Kluck, A. Flosdorff and M. Arbustini for their laboratory work; H. Henschke and A. Diaz Lacava for their database management; and S. Boehringer for discussions. The study was supported by the Deutsche Forschungsgemeinschaft (FOR 423 and individual grants MA 2546/3-1, KR 1912/7-1, NO 246/6-1, WI 1555/5-1). The Heinz Nixdorf Recall cohort was established with the generous support of the Heinz Nixdorf Foundation, Germany (Chairman: Dr. jur. G. Schmidt). The EUROCRAN study was supported by the European Comission FP5 (contract no. QLG1-CT-2000-01019) and the ITALCLEFT study by a FAR-2008 grant from the University of Ferrara. N.A. is supported by the CNPq/Brazil.

Author information

Authors and Affiliations

Authors

Contributions

E.M., F.-J.K., T.F.W., P.P. and M.M.N. initiated the study; S. Birnbaum, K.U.L., E.M. and M.M.N. contributed to the study design; M.M.N., E.M., S.C., P.H. and S. Birnbaum coordinated the work and prepared the manuscript, with feedback from the other authors; S. Birnbaum, H.R., C.L., G.S., M. Scheer, B.B., S.J.B., R.H.R., F.S., A.H., F.-J.K., R.P.S.-T., S.P and P.A.M. clinically characterized the cleft families and collected blood samples; S.M., B.H. and B.P. characterized and recruited controls; K.U.L., N.A., M.A.A., C.B., M.F. and S. Barth prepared DNA and performed molecular genetic experiments; M.K., S.H. and M. Steffens performed statistical analysis; K.U.L. performed expression analysis. M.M.N., E.M., M.K., T.F.W., J.F., S. Birnbaum, M.R. and P.P. analyzed and interpreted data.

Corresponding author

Correspondence to Elisabeth Mangold.

Supplementary information

Supplementary Text and Figures

Supplementary Methods, Supplementary Tables 1–3 and Supplementary Figures 1 and 2 (PDF 525 kb)

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Birnbaum, S., Ludwig, K., Reutter, H. et al. Key susceptibility locus for nonsyndromic cleft lip with or without cleft palate on chromosome 8q24. Nat Genet 41, 473–477 (2009). https://doi.org/10.1038/ng.333

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ng.333

Further reading

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing