TY - JOUR
T1 - Non-Syndromic Cleft Lip with or without Cleft Palate
T2 - Genome-Wide Association Study in Europeans Identifies a Suggestive Risk Locus at 16p12.1 and Supports SH3PXD2A as a Clefting Susceptibility Gene
AU - van Rooij, Iris A. L. M.
AU - Ludwig, Kerstin U.
AU - Welzenbach, Julia
AU - Ishorst, Nina
AU - Thonissen, Michelle
AU - Galesloot, Tessel E.
AU - Ongkosuwito, Edwin
AU - Berge, Stefaan J.
AU - Aldhorae, Khalid
AU - Rojas-Martinez, Augusto
AU - Kiemeney, Lambertus A. L. M.
AU - Vermeesch, Joris Robert
AU - Brunner, Han
AU - Roeleveld, Nel
AU - Devriendt, Koen
AU - Dormaar, Titiaan
AU - Hens, Greet
AU - Knapp, Michael
AU - Carels, Carine
AU - Mangold, Elisabeth
N1 - Funding Information:
Acknowledgments: The authors thank all patients, relatives, and control individuals for their participation. We thank Marjan Kloen, the social nurse of the Cleft lip/palate team of the Radboudumc for her help in the recruitment of patients and acknowledge the invaluable assistance of all other clinical, laboratory, and bioinformatic personnel. This study makes use of data generated by the DECIPHER community. A full list of centres who contributed to the generation of the data is available from http://decipher.sanger.ac.uk and via email from [email protected]. Funding for the project was provided by the Wellcome Trust.
Funding Information:
Funding: This study was sponsored by the EOS Research Grant 2015, (EOS: European Orthodontic Society, London; Title of the study: Genome-wide association study for orofacial clefts and subphenotypes); by The European Science Foundation (09-RNP-023, Title of the network grant: ESF Network for Orofacial Clefts Research, Prevention and Treatment (EuroCleftNet)); and by the German Research Foundation (Grant LU1944-3/1, Title of the study: Integrative craniofacial genomics).
Funding Information:
This study was sponsored by the EOS Research Grant 2015, (EOS: European Orthodontic Society, London; Title of the study: Genome-wide association study for orofacial clefts and subphenotypes); by The European Science Foundation (09-RNP-023, Title of the network grant: ESF Network for Orofacial Clefts Research, Prevention and Treatment (EuroCleftNet)); and by the German Research Foundation (Grant LU1944-3/1, Title of the study: Integrative craniofacial genomics). The authors thank all patients, relatives, and control individuals for their participation. We thank Marjan Kloen, the social nurse of the Cleft lip/palate team of the Radboudumc for her help in the recruitment of patients and acknowledge the invaluable assistance of all other clinical, laboratory, and bioinformatic personnel. This study makes use of data generated by the DECIPHER community. A full list of centres who contributed to the generation of the data is available from http://decipher.sanger.ac.uk and via email from [email protected]. Funding for the project was provided by the Wellcome Trust.
Publisher Copyright:
© 2019 by the authors. Licensee MDPI, Basel, Switzerland.
PY - 2019/12/7
Y1 - 2019/12/7
N2 - Non-syndromic cleft lip with or without cleft palate (nsCL/P) ranks among the most common human congenital malformations, and has a multifactorial background in which both exogenous and genetic risk factors act in concert. The present report describes a genome-wide association study (GWAS) involving a total of 285 nsCL/P patients and 1212 controls from the Netherlands and Belgium. Twenty of the 40 previously reported nsC/LP susceptibility loci were replicated, which underlined the validity of this sample. SNV-based analysis of the data identified an as yet unreported suggestive locus at chromosome 16p12.1 (p-value of the lead SNV: 4.17 x 10( -7)). This association was replicated in two of three patient/control replication series (Central European and Yemeni). Gene analysis of the GWAS data prioritized SH3PXD2A at chromosome 10824.33 as a candidate gene for nsCL/P. To date, support for this gene as a cleft gene has been restricted to data from zebrafish and a knockout mouse model. The present GWAS was the first to implicate SH3PXD2A in non-syndromic cleft formation in humans. In summary, although performed in a relatively small sample, the present GWAS generated novel insights into nsCL/P etiology.
AB - Non-syndromic cleft lip with or without cleft palate (nsCL/P) ranks among the most common human congenital malformations, and has a multifactorial background in which both exogenous and genetic risk factors act in concert. The present report describes a genome-wide association study (GWAS) involving a total of 285 nsCL/P patients and 1212 controls from the Netherlands and Belgium. Twenty of the 40 previously reported nsC/LP susceptibility loci were replicated, which underlined the validity of this sample. SNV-based analysis of the data identified an as yet unreported suggestive locus at chromosome 16p12.1 (p-value of the lead SNV: 4.17 x 10( -7)). This association was replicated in two of three patient/control replication series (Central European and Yemeni). Gene analysis of the GWAS data prioritized SH3PXD2A at chromosome 10824.33 as a candidate gene for nsCL/P. To date, support for this gene as a cleft gene has been restricted to data from zebrafish and a knockout mouse model. The present GWAS was the first to implicate SH3PXD2A in non-syndromic cleft formation in humans. In summary, although performed in a relatively small sample, the present GWAS generated novel insights into nsCL/P etiology.
KW - congenital malformation
KW - orofacial cleft
KW - cleft lip with or without cleft palate
KW - genome-wide association study
KW - NONSYNDROMIC OROFACIAL CLEFTS
KW - GENOTYPE IMPUTATION
KW - CANDIDATE GENES
KW - VARIANTS
KW - IRF6
KW - METAANALYSES
KW - FOXE1
U2 - 10.3390/genes10121023
DO - 10.3390/genes10121023
M3 - Article
C2 - 31817908
SN - 2073-4425
VL - 10
JO - Genes
JF - Genes
IS - 12
M1 - 1023
ER -