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Genome-wide meta-analyses of nonsyndromic cleft lip with or without cleft palate identify six new risk loci

Nature Genetics volume 44, pages 968–971 (2012)Cite this article

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Abstract

We have conducted the first meta-analyses for nonsyndromic cleft lip with or without cleft palate (NSCL/P) using data from the two largest genome-wide association studies published to date. We confirmed associations with all previously identified loci and identified six additional susceptibility regions (1p36, 2p21, 3p11.1, 8q21.3, 13q31.1 and 15q22). Analysis of phenotypic variability identified the first specific genetic risk factor for NSCLP (nonsyndromic cleft lip plus palate) (rs8001641; PNSCLP = 6.51 × 10−11; homozygote relative risk = 2.41, 95% confidence interval (CI) 1.84–3.16).

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Figure 1: Manhattan plots for meta-analyses.

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Acknowledgements

We thank all affected individuals and their families for their participation in this study, as well as the German support group for people with cleft lip and/or palate (Deutsche Selbsthilfevereinigung für Lippen-Gaumen-Fehlbildungen e.V.). 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 and WI 1555/5-1) and the Austrian Cleft Palate Craniofacial Association (ACPCA). T.A. and E.N. are supported by grants from the Ministry of Higher Education, Syrian Arab Republic. The data sets used for the analyses described in this manuscript were obtained from dbGaP under accession phs000094.v1.p1. Additional acknowledgments are provided in the Supplementary Note.

Author information

Author notes

  1. Kerstin U Ludwig and Elisabeth Mangold: These authors contributed equally to this work.

  2. Michael Knapp and Markus M Nöthen: These authors jointly directed this work.

Authors and Affiliations

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

    Kerstin U Ludwig, Elisabeth Mangold, Stefan Herms, Stefanie Nowak, Heiko Reutter, Jessica Becker, Ruth Herberz, Taofik AlChawa, Entessar Nasser, Anne C Böhmer, Manuel Mattheisen, Margrieta A Alblas, Sandra Barth, Nadine Kluck, Per Hoffmann, Sven Cichon, Peter Propping & Markus M Nöthen

  2. Department of Genomics, Life & Brain Center, University of Bonn, Bonn, Germany

    Kerstin U Ludwig, Stefan Herms, Jessica Becker, Ruth Herberz, Taofik AlChawa, Entessar Nasser, Anne C Böhmer, Margrieta A Alblas, Sandra Barth, Nadine Kluck, Per Hoffmann, Sven Cichon & Markus M Nöthen

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

    Stefanie Nowak & Franz-Josef Kramer

  4. Department of Neonatology, Children's Hospital, University of Bonn, Bonn, Germany

    Heiko Reutter

  5. Department of Otolaryngology, Asklepios Klinik Altona, Hamburg, Germany

    Anna Paul

  6. Department for Otolaryngology, Addenbrooke's Hospital, Cambridge University Hospitals National Health Service (NHS) Foundation Trust, Cambridge, UK

    Anna Paul

  7. Department of Biostatistics, Harvard School of Public Health, Boston, Massachusetts, USA

    Manuel Mattheisen & Christoph Lange

  8. Institute for Genomic Mathematics, University of Bonn, Bonn, Germany

    Manuel Mattheisen & Christoph Lange

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

    Carola Lauster

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

    Bert Braumann

  11. Department of Oral and Maxillofacial Plastic Surgery, University of Bonn, Bonn, Germany

    Rudolf H Reich

  12. Department of Oral and Maxillofacial Surgery, University of Leipzig, Leipzig, Germany

    Alexander Hemprich

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

    Simone Pötzsch

  14. Department of Medical Genetics, University Hospital and University of Antwerp, Antwerp, Belgium

    Bettina Blaumeiser

  15. Department of Orthodontics, University of Bonn, Bonn, Germany

    Nikolaos Daratsianos

  16. Department of Oral and Maxillofacial Surgery, Head and Neck Centre, Asklepios Klinik Nord, Heidberg, Hamburg, Germany

    Thomas Kreusch

  17. Department of Pediatrics, University of Iowa, Iowa City, Iowa, USA

    Jeffrey C Murray

  18. Center for Craniofacial and Dental Genetics, School of Dental Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA

    Mary L Marazita

  19. Department of Biostatistics, Johns Hopkins University School of Public Health, Baltimore, Maryland, USA

    Ingo Ruczinski

  20. Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA

    Alan F Scott

  21. Department of Epidemiology, Johns Hopkins University School of Public Health, Baltimore, Maryland, USA

    Terri H Beaty

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

    Thomas F Wienker & Michael Knapp

  23. Department of Obstetrics and Gynecology, Erasmus Medical Center, University Medical Center, Rotterdam, The Netherlands

    Regine P Steegers-Theunissen

  24. Department of Epidemiology, Erasmus Medical Center, University Medical Center, Rotterdam, The Netherlands

    Regine P Steegers-Theunissen

  25. Department of Clinical Genetics, Erasmus Medical Center, University Medical Center, Rotterdam, The Netherlands

    Regine P Steegers-Theunissen

  26. Department of Epidemiology, Radboud University Medical Center, Nijmegen, The Netherlands

    Regine P Steegers-Theunissen

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

    Michele Rubini

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

    Peter A Mossey

  29. Institute of Neuroscience and Medicine (INM-1), Structural and Functional Organization of the Brain, Genomic Imaging, Research Center Jülich, Jülich, Germany

    Sven Cichon

Authors
  1. Kerstin U Ludwig
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  2. Elisabeth Mangold
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  7. Jessica Becker
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  23. Thomas Kreusch
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  30. Thomas F Wienker
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  31. Regine P Steegers-Theunissen
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  32. Michele Rubini
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  33. Peter A Mossey
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  34. Per Hoffmann
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  36. Sven Cichon
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  37. Peter Propping
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Contributions

E.M., F.-J.K., T.F.W., P.P. and M.M.N. initiated the study. E.M., S.N., K.U.L., P.H., M.K., M.R., P.A.M. and M.M.N. contributed to the study design. M.M.N., E.M., S.C., P.H. and K.U.L. coordinated the work. K.U.L., E.M., M.K. and M.M.N. prepared the manuscript, with feedback from the other authors. S.N., H.R., A.P., C. Lauster, B. Braumann, R.H.R., A.H., S.P., B. Blaumeiser, N.D., T.K., R.P.S.-T., F.-J.K., M.R. and P.A.M. clinically characterized the families with cleft lip and collected the blood samples. K.U.L., R.H., E.N., T.A., S.B., A.C.B., N.K., M.A.A. and J.B. prepared the DNA and performed the molecular genetic analyses in the Bonn-II study. J.C.M., M.L.M., I.R., A.F.S. and T.H.B. contributed data from the Baltimore study. M.K., S.H., C. Lange and M.M. conducted the statistical analyses. M.M.N., E.M., M.K., K.U.L., M.R. and P.P. analyzed and interpreted the data.

Corresponding author

Correspondence to Elisabeth Mangold.

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The authors declare no competing financial interests.

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Ludwig, K., Mangold, E., Herms, S. et al. Genome-wide meta-analyses of nonsyndromic cleft lip with or without cleft palate identify six new risk loci. Nat Genet 44, 968–971 (2012). https://doi.org/10.1038/ng.2360

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