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Genome-Wide Meta-Analyses of Nonsyndromic Cleft Lip With or Without Cleft Palate Identify Six New Risk Loci

September 2012

Background: Nonsyndromic cleft lip with or without cleft palate (NSCL/P) is one of the most common birth defects. Genetic studies have identified several genomic regions (e.g., chromosome 8q24) or genes (e.g., IRF6) that affect susceptibility. This study combines data from two large GWAS (from Beaty et al., and Mangold et al.) to advance understanding of genetic factors contributing to susceptibility to NSCL/P. The Beaty et al. study includes parent-offspring trios, primarily of Asian (795 complete trios) or European (666 complete trios) heritage from a number of countries. The Mangold et al. study includes 399 cases and 1,318 controls of central European origin.

Advance: In the meta-analysis of data from European heritage participants, genome-wide significant results were found for six genomic regions, three of which had been identified in previous reports (8q24, 10q25, 17q22); the three other regions had been implicated in the Mangold et al. study (2p21, 13q31, 15q22). Data from the European and Asian heritage groups were then analyzed together to identify genomic regions that may affect susceptibility in both groups, but did not reach statistical significance in the European ancestry analyses. Five of the six significant findings for the European heritage group were also found in the combined analyses (the one exception: 15q22). Six additional genomic regions reached statistical significance, three of which were previously reported regions (1p22.1, 1q32.3 (IRF6), 20q12). One region was implicated in the Beaty et al. study (1p36), and two regions were not previously reported (3p11.1, 8q21.3). For some of these genomic regions, biologic evidence supports the idea that the genetic variants in these regions affect susceptibility to NSCL/P. For example, the significant result in the 1p36 region is located in an intron in PAX7, which has been functionally implicated in craniofacial development. The investigators also analyzed the data separately for individuals who had cleft lip only (NSCLO) versus cleft lip with cleft palate (NSCLP). One region, 13q31, appeared to contribute only to NSCLP.

Public Impact/Significance: This study provides evidence of additional genomic regions that may contribute to development of NSCL/P. Future studies are needed to identify the specific genes and variants involved, and to understand the ways in which these genes affect craniofacial development and development of NSCL/P.

Publication Citation and Link to Publication:
Ludwig KU, Mangold E, Herms S, et. al. (2012). Genome-wide meta-analyses of nonsyndromic cleft lip with or without cleft palate identify six new risk loci. Nat Genet, 10:1038/ng.2360. Link to PDF Article

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This page last updated: February 26, 2014