Skip to main content

Thank you for visiting 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.

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


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).

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Figure 1: Manhattan plots for meta-analyses.

Accession codes

Primary accessions

NCBI Reference Sequence


  1. Mangold, E., Ludwig, K.U. & Nöthen, M.M. Trends Mol. Med. 17, 725–733 (2011).

    Article  CAS  Google Scholar 

  2. Rahimov, F. et al. Nat. Genet. 40, 1341–1347 (2008).

    Article  CAS  Google Scholar 

  3. Beaty, T.H. et al. Nat. Genet. 42, 525–529 (2010).

    Article  CAS  Google Scholar 

  4. Mangold, E. et al. Nat. Genet. 42, 24–26 (2010).

    Article  CAS  Google Scholar 

  5. Mansouri, A., Stoykova, A., Torres, M. & Gruss, P. Development 122, 831–838 (1996).

    Article  CAS  Google Scholar 

  6. Sull, J.W. et al. Eur. J. Hum. Genet. 17, 831–839 (2009).

    Article  CAS  Google Scholar 

  7. Himanen, J.P., Saha, N. & Nikolov, D.B. Curr. Opin. Cell Biol. 19, 534–542 (2007).

    Article  CAS  Google Scholar 

  8. Maunakea, A.K. et al. Nature 466, 253–257 (2010).

    Article  CAS  Google Scholar 

  9. Drieschner, N. et al. Gene 403, 110–117 (2007).

    Article  CAS  Google Scholar 

  10. Goodnough, L.H., Brugmann, S.A., Hu, D. & Helms, J.A. Dev. Dyn. 236, 1918–1928 (2007).

    Article  CAS  Google Scholar 

  11. Welsh, I.C., Hagge-Greenberg, A. & O'Brien, T.P. Mech. Dev. 124, 746–761 (2007).

    Article  CAS  Google Scholar 

  12. Jugessur, A., Farlie, P.G. & Kilpatrick, N. Oral Dis. 15, 437–453 (2009).

    Article  CAS  Google Scholar 

  13. Grosen, D. et al. J. Med. Genet. 47, 162–168 (2010).

    Article  Google Scholar 

  14. Matsumura, K. et al. Biochem. Biophys. Res. Commun. 404, 1076–1082 (2011).

    Article  CAS  Google Scholar 

  15. Vieira, A.R. et al. PLoS Genet. 1, e64 (2005).

    Article  Google Scholar 

Download references


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

Authors and Affiliations



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.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary Information

Rights and permissions

Reprints and Permissions

About this article

Cite this article

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).

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI:

This article is cited by


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