First genome-wide association study of esophageal atresia identifies three genetic risk loci at CTNNA3, FOXF1/FOXC2/FOXL1, and HNF1B

Jan Gehlen, Ann Sophie Giel, Ricarda Köllges, Stephan L. Haas, Rong Zhang, Jiri Trcka, Ayse Sungur, Florian Renziehausen, Dorothea Bornholdt, Daphne Jung, Paul D. Hoyer, Agneta Nordenskjöld, Dick Tibboel, John Vlot, Manon C.W. Spaander, Robert Smigiel, Dariusz Patkowski, Nel Roeleveld, Iris ALM van Rooij, Ivo de BlaauwAlice Hölscher, Marcus Pauly, Andreas Leutner, Joerg Fuchs, Joel Niethammer, Maria Theodora Melissari, Ekkehart Jenetzky, Nadine Zwink, Holger Thiele, Alina Christine Hilger, Timo Hess, Jessica Trautmann, Matthias Marks, Martin Baumgarten, Gaby Bläss, Mikael Landén, Bengt Fundin, Cynthia M. Bulik, Tracie Pennimpede, Michael Ludwig, Kerstin U. Ludwig, Elisabeth Mangold, Stefanie Heilmann-Heimbach, Susanne Moebus, Bernhard G. Herrmann, Kristina Alsabeah, Carmen M. Burgos, Helene E. Lilja, Sahar Azodi, Pernilla Stenström, Einar Arnbjörnsson, Barbora Frybova, Dariusz M. Lebensztejn, Wojciech Debek, Elwira Kolodziejczyk, Katarzyna Kozera, Jaroslaw Kierkus, Piotr Kaliciński, Marek Stefanowicz, Anna Socha-Banasiak, Michal Kolejwa, Anna Piaseczna-Piotrowska, Elzbieta Czkwianianc, Markus M. Nöthen, Phillip Grote, Michal Rygl, Konrad Reinshagen, Nicole Spychalski, Barbara Ludwikowski, Jochen Hubertus, Andreas Heydweiller, Benno Ure, Oliver J. Muensterer, Ophelia Aubert, Jan Hendrik Gosemann, Martin Lacher, Petra Degenhardt, Thomas M. Boemers, Anna Mokrowiecka, Ewa Małecka-Panas, Markus Wöhr, Michael Knapp, Guido Seitz, Annelies de Klein, Grzegorz Oracz, Erwin Brosens, Heiko Reutter*, Johannes Schumacher

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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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 × 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 × 10−10; OR = 1.47; 95% CI, 1.38–1.55) and on chromosome 17q12 next to the gene HNF1B (p = 3.35 × 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.

Original languageEnglish
Article number100093
JournalHuman Genetics and Genomics Advances
Issue number2
Publication statusPublished - 14 Apr 2022

Bibliographical note

The authors thank all study participants and the German self-help organization KEKS e.V. (Kinder und Erwachsene mit Erkrankungen der Speiseröhre) for their assistance with recruitment. The authors also thank the Heinz Nixdorf Foundation for access to control subjects from the cohort of the Heinz Nixdorf Recall Study (HNR). In addition, the authors thank the following research funding organizations: Else Kröner-Fresenius Foundation (grant 2014_A14 ), Deutsche Forschungsgemeinschaft (DFG) (grants LU 731/3-1 , LU 1944/3-1 , RE 1723/1-1 , RE 1723/2-1 , RE 1723/1-3 , TH 1327/1-1 , WO 1732/4-2 , Exc147-2 ), the LOEWE Center for Cell and Gene Therapy Frankfurt (LOEWE-CGT), the German Cancer Aid (Deutsche Krebshilfe) (grant 70113577 ), and the Sophia Foundations for Scientific Research (grant SWOO13-09 ). Swedish controls were collected as part of the Anorexia Nervosa Genetics Initiative (ANGI), which is an initiative of the Klarman Family Foundation.

Publisher Copyright: © 2022 The Authors


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