Gehlen, Jan, Giel, Ann-Sophie ORCID: 0000-0003-2973-2099, Koellges, Ricarda, Haas, Stephan L. ORCID: 0000-0003-4329-8751, Zhang, Rong, Trcka, Jiri, Sungur, Ayse O., Renziehausen, Florian, Bornholdt, Dorothea, Jung, Daphne, Hoyer, Paul D., Nordenskjold, Agneta, Tibboel, Dick, Vlot, John, Spaander, Manon C. W., Smigiel, Robert, Patkowski, Dariusz ORCID: 0000-0002-4583-5517, Roeleveld, Nel ORCID: 0000-0002-3390-4466, van Rooij, Iris Alm, de Blaauw, Ivo, Hoelscher, Alice, Pauly, Marcus, Leutner, Andreas, Fuchs, Joerg, Niethammer, Joel, Melissari, Maria-Theodora, Jenetzky, Ekkehart, Zwink, Nadine, Thiele, Holger, Hilger, Alina Christine, Hess, Timo ORCID: 0000-0003-2778-4274, Trautmann, Jessica, Marks, Matthias, Baumgarten, Martin, Blaess, Gaby, Landen, Mikael, Fundin, Bengt, Bulik, Cynthia M., Pennimpede, Tracie, Ludwig, Michael, Ludwig, Kerstin U., Mangold, Elisabeth, Heilmann-Heimbach, Stefanie, Moebus, Susanne ORCID: 0000-0002-0072-5410, Herrmann, Bernhard G., Alsabeah, Kristina, Burgos, Carmen M., Lilja, Helene E., Azodi, Sahar, Stenstrom, Pernilla, Arnbjornsson, Einar, Frybova, Barbora, Lebensztejn, Dariusz M., Debek, Wojciech ORCID: 0000-0001-6023-8510, Kolodziejczyk, Elwira, Kozera, Katarzyna, Kierkus, Jaroslaw, Kalicinski, Piotr ORCID: 0000-0003-0555-2229, Stefanowicz, Marek, Socha-Banasiak, Anna, Kolejwa, Michal, Piaseczna-Piotrowska, Anna, Czkwianianc, Elzbieta, Noethen, Markus M., Grote, Phillip, Rygl, Michal, Reinshagen, Konrad, Spychalski, Nicole, Ludwikowski, Barbara, Hubertus, Jochen ORCID: 0000-0003-3206-6170, Heydweiller, Andreas, Ure, Benno, Muensterer, Oliver J., Aubert, Ophelia, Gosemann, Jan-Hendrik, Lacher, Martin, Degenhardt, Petra ORCID: 0000-0001-7506-9457, Boemers, Thomas M., Mokrowiecka, Anna, Malecka-Panas, Ewa, Woehr, Markus, Knapp, Michael, Seitz, Guido, de Klein, Annelies, Oracz, Grzegorz, Brosens, Erwin ORCID: 0000-0001-8235-4010, Reutter, Heiko and Schumacher, Johannes (2022). First genome-wide association study of esophageal atresia identifies three genetic risk loci at CTNNA3, FOXF1/FOXC2/FOXL1, and HNF1B. Hum. Genet. Genom. Adv., 3 (2). AMSTERDAM: ELSEVIER. ISSN 2666-2477

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Abstract

Esophageal atresia with or without tracheoesophageal fistula (EA/TEF) is the most common congenital malformation of the upper digestive tract. This study represents the first genome-wide association study (GWAS) to identify risk loci for EA/TEF. We used a European case-control sample comprising 764 EA/TEF patients and 5,778 controls and observed genome-wide significant associations at three loci. On chromosome 10q21 within the gene CTNNA3 (p = 2.11 x 10(-8); odds ratio [OR] = 3.94; 95% confidence interval [CI], 3.10-5.00), on chromosome 16q24 next to the FOX gene cluster (p = 2.25 x 10(-10); OR = 1.47; 95% CI, 1.38-1.55) and on chromosome 17q12 next to the gene HNF1B (p = 3.35 x 10(-16); OR = 1.75; 95% CI, 1.64-1.87). We next carried out an esophageal/tracheal transcriptome profiling in rat embryos at four selected embryonic time points. Based on these data and on already published data, the implicated genes at all three GWAS loci are promising candidates for EA/TEF development. We also analyzed the genetic EA/TEF architecture beyond the single marker level, which revealed an estimated single-nucleotide polymorphism (SNP)-based heritability of around 37% +/- 14% standard deviation. In addition, we examined the polygenicity of EA/TEF and found that EA/TEF is less polygenic than other complex genetic diseases. In conclusion, the results of our study contribute to a better understanding on the underlying genetic architecture of ET/TEF with the identification of three risk loci and candidate genes.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Gehlen, JanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Giel, Ann-SophieUNSPECIFIEDorcid.org/0000-0003-2973-2099UNSPECIFIED
Koellges, RicardaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Haas, Stephan L.UNSPECIFIEDorcid.org/0000-0003-4329-8751UNSPECIFIED
Zhang, RongUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Trcka, JiriUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Sungur, Ayse O.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Renziehausen, FlorianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bornholdt, DorotheaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Jung, DaphneUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hoyer, Paul D.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Nordenskjold, AgnetaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Tibboel, DickUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Vlot, JohnUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Spaander, Manon C. W.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Smigiel, RobertUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Patkowski, DariuszUNSPECIFIEDorcid.org/0000-0002-4583-5517UNSPECIFIED
Roeleveld, NelUNSPECIFIEDorcid.org/0000-0002-3390-4466UNSPECIFIED
van Rooij, Iris AlmUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
de Blaauw, IvoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hoelscher, AliceUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Pauly, MarcusUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Leutner, AndreasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Fuchs, JoergUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Niethammer, JoelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Melissari, Maria-TheodoraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Jenetzky, EkkehartUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Zwink, NadineUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Thiele, HolgerUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hilger, Alina ChristineUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hess, TimoUNSPECIFIEDorcid.org/0000-0003-2778-4274UNSPECIFIED
Trautmann, JessicaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Marks, MatthiasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Baumgarten, MartinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Blaess, GabyUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Landen, MikaelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Fundin, BengtUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bulik, Cynthia M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Pennimpede, TracieUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ludwig, MichaelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ludwig, Kerstin U.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mangold, ElisabethUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Heilmann-Heimbach, StefanieUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Moebus, SusanneUNSPECIFIEDorcid.org/0000-0002-0072-5410UNSPECIFIED
Herrmann, Bernhard G.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Alsabeah, KristinaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Burgos, Carmen M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lilja, Helene E.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Azodi, SaharUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Stenstrom, PernillaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Arnbjornsson, EinarUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Frybova, BarboraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lebensztejn, Dariusz M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Debek, WojciechUNSPECIFIEDorcid.org/0000-0001-6023-8510UNSPECIFIED
Kolodziejczyk, ElwiraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kozera, KatarzynaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kierkus, JaroslawUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kalicinski, PiotrUNSPECIFIEDorcid.org/0000-0003-0555-2229UNSPECIFIED
Stefanowicz, MarekUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Socha-Banasiak, AnnaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kolejwa, MichalUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Piaseczna-Piotrowska, AnnaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Czkwianianc, ElzbietaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Noethen, Markus M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Grote, PhillipUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Rygl, MichalUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Reinshagen, KonradUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Spychalski, NicoleUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ludwikowski, BarbaraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hubertus, JochenUNSPECIFIEDorcid.org/0000-0003-3206-6170UNSPECIFIED
Heydweiller, AndreasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ure, BennoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Muensterer, Oliver J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Aubert, OpheliaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gosemann, Jan-HendrikUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lacher, MartinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Degenhardt, PetraUNSPECIFIEDorcid.org/0000-0001-7506-9457UNSPECIFIED
Boemers, Thomas M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mokrowiecka, AnnaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Malecka-Panas, EwaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Woehr, MarkusUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Knapp, MichaelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Seitz, GuidoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
de Klein, AnneliesUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Oracz, GrzegorzUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Brosens, ErwinUNSPECIFIEDorcid.org/0000-0001-8235-4010UNSPECIFIED
Reutter, HeikoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schumacher, JohannesUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-699137
DOI: 10.1016/j.xhgg.2022.100093
Journal or Publication Title: Hum. Genet. Genom. Adv.
Volume: 3
Number: 2
Date: 2022
Publisher: ELSEVIER
Place of Publication: AMSTERDAM
ISSN: 2666-2477
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
TRACHEOESOPHAGEAL FISTULA; VACTERL ASSOCIATION; EPIDEMIOLOGY; MUTATIONS; TRACHEAMultiple languages
Genetics & HeredityMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/69913

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