Imputation of Orofacial Clefting Data Identifies Novel Risk Loci and Sheds Light on the Genetic Background of Cleft Lip ± Cleft Palate and Cleft Palate Only.

Ludwig, Kerstin U. y Böhmer, Anne C. y Bowes, John y Nikolić, Miloš y Ishorst, Nina y Wyatt, Niki y Hammond, Nigel L. y Gölz, Lina y Thieme, Frederic y Barth, Sandra y Schuenke, Hannah y Klamt, Johanna y Spielmann, Malte y Aldhorae, Khalid Ahmed y Rojas Martínez, Augusto y Nöthen, Markus M. y Rada Iglesias, Alvaro y Dixon, Michael J. y Knapp, Michael y Mangold, Elisabeth (2017) Imputation of Orofacial Clefting Data Identifies Novel Risk Loci and Sheds Light on the Genetic Background of Cleft Lip ± Cleft Palate and Cleft Palate Only. Human Molecular Genetics, 26 (4). pp. 829-842. ISSN 0964-6906

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URL o página oficial: http://doi.org/10.1093/hmg/ddx012

Resumen

Abstract Nonsyndromic cleft lip with or without cleft palate (nsCL/P) is among the most common human birth defects with multifactorial etiology. Here, we present results from a genome-wide imputation study of nsCL/P in which, after adding replication cohort data, four novel risk loci for nsCL/P are identified (at chromosomal regions 2p21, 14q22, 15q24 and 19p13). On a systematic level, we show that the association signalswithin this high-density datasetare enriched in functionally-relevant genomic regions that are active in both human neural crest cells (hNCC) and mouse embryonic craniofacial tissue. This enrichment is also detectable in hNCC regions primed for later activity. Using GCTA analyses, we suggest that 30% of the estimated variance in risk for nsCL/P in the European population can be attributed to common variants, with 25.5% contributed to by the 24 risk loci known to date. For each of these, we identify credible SNPs using a Bayesian refinementapproach, with two loci harbouring only one probable causal variant. Finally, we demonstrate that there is no polygenic component of nsCL/P detectable that is shared with nonsyndromic cleft palate only (nsCPO). Our data suggest that, while common variants are strongly contributing to risk for nsCL/P, they do not seem to be involved in nsCPO which might be more often caused by rare deleterious variants. Our study generates novel insights into both nsCL/P and nsCPO etiology and provides a systematic framework for research into craniofacial development and malformation.

Tipo de elemento: Article
Materias: R Medicina > RA Aspectos Públicos de la Medicina
Divisiones: Centro de Investigación y Desarrollo en Ciencias de la Salud
Usuario depositante: Editor Repositorio
Creadores:
CreadorEmailORCID
Ludwig, Kerstin U.NO ESPECIFICADONO ESPECIFICADO
Böhmer, Anne C.NO ESPECIFICADONO ESPECIFICADO
Bowes, JohnNO ESPECIFICADONO ESPECIFICADO
Nikolić, MilošNO ESPECIFICADONO ESPECIFICADO
Ishorst, NinaNO ESPECIFICADONO ESPECIFICADO
Wyatt, NikiNO ESPECIFICADONO ESPECIFICADO
Hammond, Nigel L.NO ESPECIFICADONO ESPECIFICADO
Gölz, LinaNO ESPECIFICADONO ESPECIFICADO
Thieme, FredericNO ESPECIFICADONO ESPECIFICADO
Barth, SandraNO ESPECIFICADONO ESPECIFICADO
Schuenke, HannahNO ESPECIFICADONO ESPECIFICADO
Klamt, JohannaNO ESPECIFICADONO ESPECIFICADO
Spielmann, MalteNO ESPECIFICADONO ESPECIFICADO
Aldhorae, Khalid AhmedNO ESPECIFICADONO ESPECIFICADO
Rojas Martínez, AugustoNO ESPECIFICADONO ESPECIFICADO
Nöthen, Markus M.NO ESPECIFICADONO ESPECIFICADO
Rada Iglesias, AlvaroNO ESPECIFICADONO ESPECIFICADO
Dixon, Michael J.NO ESPECIFICADONO ESPECIFICADO
Knapp, MichaelNO ESPECIFICADONO ESPECIFICADO
Mangold, ElisabethNO ESPECIFICADONO ESPECIFICADO
Fecha del depósito: 18 Mar 2020 18:33
Última modificación: 29 Abr 2020 16:12
URI: http://eprints.uanl.mx/id/eprint/18139

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