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


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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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.

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Authors and Affiliations



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.

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Correspondence to Elisabeth Mangold.

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

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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).

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