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

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.

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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.

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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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