Meta-analysis Reveals Genome-Wide Significance at 15q13 for Nonsyndromic Clefting of Both the Lip and the Palate, and Functional Analyses Implicate GREM1 As a Plausible Causative Gene
Nonsyndromic orofacial clefts are common birth defects with multifactorial etiology. The most common type is cleft lip, which occurs with or without cleft palate (nsCLP and nsCLO, respectively). Although genetic components play an important role in nsCLP, the genetic factors that predispose to pala...
| Autores principales: | , , , , , , , , , , , , , , , , , , , |
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| Formato: | Artículo |
| Lenguaje: | inglés |
| Publicado: |
Public Library of Science
2016
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| Acceso en línea: | http://eprints.uanl.mx/14839/1/54.PDF |
| _version_ | 1824414158733443072 |
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| author | Ludwig, Kerstin U. Ahmed, Syeda Tasnim Böhmer, Anne C. Sangani, Nasim Bahram Varghese, Sheryil Klamt, Johanna Schuenke, Hannah Gültepe, Pinar Hofmann, Andrea Rubini, Michele Aldhorae, Khalid Ahmed Steegers Theunissen, Regine P. Rojas Martínez, Augusto Reiter, Rudolf Borck, Guntram Knapp, Michael Nakatomi, Mitsushiro Graf, Daniel Mangold, Elisabeth Peters, Heiko |
| author_facet | Ludwig, Kerstin U. Ahmed, Syeda Tasnim Böhmer, Anne C. Sangani, Nasim Bahram Varghese, Sheryil Klamt, Johanna Schuenke, Hannah Gültepe, Pinar Hofmann, Andrea Rubini, Michele Aldhorae, Khalid Ahmed Steegers Theunissen, Regine P. Rojas Martínez, Augusto Reiter, Rudolf Borck, Guntram Knapp, Michael Nakatomi, Mitsushiro Graf, Daniel Mangold, Elisabeth Peters, Heiko |
| author_sort | Ludwig, Kerstin U. |
| collection | Repositorio Institucional |
| description | Nonsyndromic orofacial clefts are common birth defects with multifactorial etiology. The most common type is cleft lip, which occurs with or without cleft palate (nsCLP and nsCLO, respectively). Although genetic components play an important role in nsCLP, the genetic
factors that predispose to palate involvement are largely unknown. In this study, we carried out a meta-analysis on genetic and clinical data from three large cohorts and identified strong association between a region on chromosome 15q13 and nsCLP (P = 8.13×10−14 for
rs1258763; relative risk (RR): 1.46, 95% confidence interval (CI): 1.32–1.61)) but not nsCLO (P = 0.27; RR: 1.09 (0.94–1.27)). The 5 kb region of strongest association maps downstream of Gremlin-1 (GREM1), which encodes a secreted antagonist of the BMP4 pathway. We show during mouse embryogenesis, Grem1 is expressed in the developing lip and soft palate but not in the hard palate. This is consistent with genotype-phenotype correlations between rs1258763 and a specific nsCLP subphenotype, since a more than two-fold increase in risk was observed in patients displaying clefts of both the lip and soft palate but who had an intact hard palate (RR: 3.76, CI: 1.47–9.61, Pdiff<0.05). While we did not find lip or palate defects in Grem1-deficient mice, wild type embryonic palatal shelves developed divergent shapes when cultured in the presence of ectopic Grem1 protein (P = 0.0014). The present study identified a non-coding region at 15q13 as the second, genome-wide significant
locus specific for nsCLP, after 13q31. Moreover, our data suggest that the closely located GREM1 gene contributes to a rare clinical nsCLP entity. This entity specifically
involves abnormalities of the lip and soft palate, which develop at different time-points and in separate anatomical regions. |
| format | Article |
| id | eprints-14839 |
| institution | UANL |
| language | English |
| publishDate | 2016 |
| publisher | Public Library of Science |
| record_format | eprints |
| spelling | eprints-148392020-03-06T21:47:08Z http://eprints.uanl.mx/14839/ Meta-analysis Reveals Genome-Wide Significance at 15q13 for Nonsyndromic Clefting of Both the Lip and the Palate, and Functional Analyses Implicate GREM1 As a Plausible Causative Gene Ludwig, Kerstin U. Ahmed, Syeda Tasnim Böhmer, Anne C. Sangani, Nasim Bahram Varghese, Sheryil Klamt, Johanna Schuenke, Hannah Gültepe, Pinar Hofmann, Andrea Rubini, Michele Aldhorae, Khalid Ahmed Steegers Theunissen, Regine P. Rojas Martínez, Augusto Reiter, Rudolf Borck, Guntram Knapp, Michael Nakatomi, Mitsushiro Graf, Daniel Mangold, Elisabeth Peters, Heiko Nonsyndromic orofacial clefts are common birth defects with multifactorial etiology. The most common type is cleft lip, which occurs with or without cleft palate (nsCLP and nsCLO, respectively). Although genetic components play an important role in nsCLP, the genetic factors that predispose to palate involvement are largely unknown. In this study, we carried out a meta-analysis on genetic and clinical data from three large cohorts and identified strong association between a region on chromosome 15q13 and nsCLP (P = 8.13×10−14 for rs1258763; relative risk (RR): 1.46, 95% confidence interval (CI): 1.32–1.61)) but not nsCLO (P = 0.27; RR: 1.09 (0.94–1.27)). The 5 kb region of strongest association maps downstream of Gremlin-1 (GREM1), which encodes a secreted antagonist of the BMP4 pathway. We show during mouse embryogenesis, Grem1 is expressed in the developing lip and soft palate but not in the hard palate. This is consistent with genotype-phenotype correlations between rs1258763 and a specific nsCLP subphenotype, since a more than two-fold increase in risk was observed in patients displaying clefts of both the lip and soft palate but who had an intact hard palate (RR: 3.76, CI: 1.47–9.61, Pdiff<0.05). While we did not find lip or palate defects in Grem1-deficient mice, wild type embryonic palatal shelves developed divergent shapes when cultured in the presence of ectopic Grem1 protein (P = 0.0014). The present study identified a non-coding region at 15q13 as the second, genome-wide significant locus specific for nsCLP, after 13q31. Moreover, our data suggest that the closely located GREM1 gene contributes to a rare clinical nsCLP entity. This entity specifically involves abnormalities of the lip and soft palate, which develop at different time-points and in separate anatomical regions. Public Library of Science 2016 Article PeerReviewed text en cc_by_nc_nd http://eprints.uanl.mx/14839/1/54.PDF http://eprints.uanl.mx/14839/1.haspreviewThumbnailVersion/54.PDF Ludwig, Kerstin U. y Ahmed, Syeda Tasnim y Böhmer, Anne C. y Sangani, Nasim Bahram y Varghese, Sheryil y Klamt, Johanna y Schuenke, Hannah y Gültepe, Pinar y Hofmann, Andrea y Rubini, Michele y Aldhorae, Khalid Ahmed y Steegers Theunissen, Regine P. y Rojas Martínez, Augusto y Reiter, Rudolf y Borck, Guntram y Knapp, Michael y Nakatomi, Mitsushiro y Graf, Daniel y Mangold, Elisabeth y Peters, Heiko (2016) Meta-analysis Reveals Genome-Wide Significance at 15q13 for Nonsyndromic Clefting of Both the Lip and the Palate, and Functional Analyses Implicate GREM1 As a Plausible Causative Gene. PLoS Genetics, 12 (3). e1005914. ISSN 1553-7404 http://doi.org/10.1371/journal.pgen.1005914 doi:10.1371/journal.pgen.1005914 |
| spellingShingle | Ludwig, Kerstin U. Ahmed, Syeda Tasnim Böhmer, Anne C. Sangani, Nasim Bahram Varghese, Sheryil Klamt, Johanna Schuenke, Hannah Gültepe, Pinar Hofmann, Andrea Rubini, Michele Aldhorae, Khalid Ahmed Steegers Theunissen, Regine P. Rojas Martínez, Augusto Reiter, Rudolf Borck, Guntram Knapp, Michael Nakatomi, Mitsushiro Graf, Daniel Mangold, Elisabeth Peters, Heiko Meta-analysis Reveals Genome-Wide Significance at 15q13 for Nonsyndromic Clefting of Both the Lip and the Palate, and Functional Analyses Implicate GREM1 As a Plausible Causative Gene |
| thumbnail | https://rediab.uanl.mx/themes/sandal5/images/online.png |
| title | Meta-analysis Reveals Genome-Wide Significance at 15q13 for Nonsyndromic Clefting of Both the Lip and the Palate, and Functional Analyses Implicate GREM1 As a Plausible Causative Gene |
| title_full | Meta-analysis Reveals Genome-Wide Significance at 15q13 for Nonsyndromic Clefting of Both the Lip and the Palate, and Functional Analyses Implicate GREM1 As a Plausible Causative Gene |
| title_fullStr | Meta-analysis Reveals Genome-Wide Significance at 15q13 for Nonsyndromic Clefting of Both the Lip and the Palate, and Functional Analyses Implicate GREM1 As a Plausible Causative Gene |
| title_full_unstemmed | Meta-analysis Reveals Genome-Wide Significance at 15q13 for Nonsyndromic Clefting of Both the Lip and the Palate, and Functional Analyses Implicate GREM1 As a Plausible Causative Gene |
| title_short | Meta-analysis Reveals Genome-Wide Significance at 15q13 for Nonsyndromic Clefting of Both the Lip and the Palate, and Functional Analyses Implicate GREM1 As a Plausible Causative Gene |
| title_sort | meta analysis reveals genome wide significance at 15q13 for nonsyndromic clefting of both the lip and the palate and functional analyses implicate grem1 as a plausible causative gene |
| url | http://eprints.uanl.mx/14839/1/54.PDF |
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