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Genome-wide association study identifies two susceptibility loci for nonsyndromic cleft lip with or without cleft palate

Abstract

We conducted a genome-wide association study for nonsyndromic cleft lip with or without cleft palate (NSCL/P) in 401 affected individuals and 1,323 controls, with replication in an independent sample of 793 NSCL/P triads. We report two new loci associated with NSCL/P at 17q22 (rs227731, combined P = 1.07 × 10−8, relative risk in homozygotes = 1.84, 95% CI 1.34–2.53) and 10q25.3 (rs7078160, combined P = 1.92 × 10−8, relative risk in homozygotes = 2.17, 95% CI 1.32–3.56).

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Figure 1: Details of the loci showing genome-wide significant association with NSCL/P in the combined sample.

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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.). We acknowledge our collaborating clinical partners, all colleagues who contributed to the European Collaboration on Craniofacial Anomalies (EUROCRAN) project, our laboratory technicians and colleagues responsible for database management (for a complete list of all individuals see Supplementary Note). 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). The Heinz Nixdorf Recall cohort was established with the generous support of the Heinz Nixdorf Foundation, Germany (Chairman: G. Schmidt). POPGEN biobank is financed by the local Ministry of Science, Economy and Transport of Schleswig-Holstein, Germany. The Kooperative Gesundheitforschung in der Region Augsburg (KORA) research platform was initiated and financed by the Helmholtz Center Munich, German Research Center for Environmental Health, which is funded by the German Federal Ministry of Education and Research and by the state of Bavaria. The work of KORA is supported by the German Federal Ministry of Education and Research (BMBF) in the context of the German National Genome Research Network (NGFN-2 and NGFN-plus). The EUROCRAN study was supported by the European Commission FP5 (contract no. QLG1-CT-2000-01019), and the ITALCLEFT study was supported by a FAR-2008 grant from the University of Ferrara, Italy. N.A.d.A. is supported by the Conselho Nacional de Pesquisa (CNPq), Brasil. T.A.C. is supported by a grant from the Ministry of Higher Education, Syrian Arab Republic. Additional acknowledgments are found in the Supplementary Note.

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

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Correspondence to Elisabeth Mangold.

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Supplementary Figures 1–3, Supplementary Tables 1–4, Supplementary Methods and Supplementary Note (PDF 602 kb)

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Mangold, E., Ludwig, K., Birnbaum, S. et al. Genome-wide association study identifies two susceptibility loci for nonsyndromic cleft lip with or without cleft palate. Nat Genet 42, 24–26 (2010). https://doi.org/10.1038/ng.506

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