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

Nature Genetics volume 41, pages 473–477 (2009)Cite this article

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.

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

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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

Author notes

  1. Stefanie Birnbaum, Kerstin U Ludwig, Markus M Nöthen and Elisabeth Mangold: These authors contributed equally to this work.

Authors and Affiliations

  1. Institute of Human Genetics, University of Bonn, Bonn, Germany

    Stefanie Birnbaum, Heiko Reutter, Nilma Almeida de Assis, Peter Propping, Sven Cichon, Per Hoffmann, Markus M Nöthen & Elisabeth Mangold

  2. Department of Oral and Maxillofacial Surgery, University of Göttingen, Göttingen, Germany

    Stefanie Birnbaum & Franz-Josef Kramer

  3. Department of Genomics, Life and Brain Center, University of Bonn, Bonn, Germany

    Kerstin U Ludwig, Stefan Herms, Margrieta A Alblas, Sandra Barth, Sven Cichon, Per Hoffmann & Markus M Nöthen

  4. Institute of Medical Biometry, Informatics and Epidemiology, University of Bonn, Bonn, Germany

    Michael Steffens, Thomas F Wienker & Michael Knapp

  5. Department of Experimental and Diagnostic Medicine, Medical Genetics Unit, University of Ferrara, Ferrara, Italy

    Michele Rubini, Carlotta Baluardo & Melissa Ferrian

  6. Center for Genomics & Human Genetics, Feinstein Institute for Medical Research, Northshore-LIJ University Hospital, New York, USA

    Jan Freudenberg

  7. Department of Cleft Lip and Cleft Palate Surgery, Humboldt University of Berlin, Berlin, Germany

    Carola Lauster & Gül Schmidt

  8. Department of Oral and Maxillo-Facial Surgery, University of Cologne, Cologne, Germany

    Martin Scheer

  9. Department of Orthodontics, University of Cologne, Cologne, Germany

    Bert Braumann

  10. Department of Oral and Maxillo-Facial Surgery, Radboud University Nijmegen, Nijmegen, The Netherlands

    Stefaan J Bergé

  11. Department of Oral and Maxillo-Facial-Plastic Surgery, University of Bonn, Bonn, Germany

    Rudolf H Reich

  12. Department of Oral and Maxillo-Facial Surgery, University of Leipzig, Leipzig, Germany

    Franziska Schiefke & Alexander Hemprich

  13. Monitoring of Congenital Malformations Saxony Anhalt, University of Magdeburg, Magdeburg, Germany

    Simone Pötzsch

  14. University Medical Center, Rotterdam, The Netherlands

    Regine P Steegers-Theunissen

  15. Institute of Experimental Hematology and Transfusion Medicine, University of Bonn, Bonn, Germany

    Bernd Pötzsch

  16. Institute for Medical Informatics, Biometry and Epidemiology, University Hospital of Essen, University Duisburg-Essen, Germany

    Susanne Moebus

  17. Institute of Human Genetics, University Hospital of Essen, University Duisburg-Essen, Germany

    Bernhard Horsthemke

  18. Orthodontic Unit, Dental Hospital & School, University of Dundee, Dundee, UK

    Peter A Mossey

Authors
  1. Stefanie Birnbaum
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  33. Markus M Nöthen
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  34. Elisabeth Mangold
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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.

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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

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