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

Gehlen J, Giel AS, Köllges R, Haas SL, Zhang R, Trcka J, Sungur A, Renziehausen F, Bornholdt D, Jung D, Hoyer PD, Nordenskjöld A, Tibboel D, Vlot J, Spaander MC, Smigiel R, Patkowski D, Roeleveld N, van Rooij IA, de Blaauw I, Hölscher A, Pauly M, Leutner A, Fuchs J, Niethammer J, Melissari MT, Jenetzky E, Zwink N, Thiele H, Hilger AC, Hess T, Trautmann J, Marks M, Baumgarten M, Bläss G, Landén M, Fundin B, Bulik CM, Pennimpede T, Ludwig M, Ludwig KU, Mangold E, Heilmann-Heimbach S, Moebus S, Herrmann BG, Alsabeah K, Burgos CM, Lilja HE, Azodi S, Stenström P, Arnbjörnsson E, Frybova B, Lebensztejn DM, Debek W, Kolodziejczyk E, Kozera K, Kierkus J, Kaliciński P, Stefanowicz M, Socha-Banasiak A, Kolejwa M, Piaseczna-Piotrowska A, Czkwianianc E, Nöthen MM, Grote P, Rygl M, Reinshagen K, Spychalski N, Ludwikowski B, Hubertus J, Heydweiller A, Ure B, Muensterer OJ, Aubert O, Gosemann JH, Lacher M, Degenhardt P, Boemers TM, Mokrowiecka A, Małecka-Panas E, Wöhr M, Knapp M, Seitz G, de Klein A, Oracz G, Brosens E, Reutter H, Schumacher J (2022)

Publication Type: Journal article

Publication year: 2022

Journal

Book Volume: 3

Article Number: 100093

Journal Issue: 2

DOI: 10.1016/j.xhgg.2022.100093

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 × 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.

Involved external institutions

Universitätsklinikum Bonn Germany (DE) Karolinska Institute Sweden (SE) Universitätsklinikum Gießen und Marburg (UKGM) Germany (DE) Karolinska University Hospital / Karolinska Universitetssjukhuset Sweden (SE) Motol University Hospital / Fakultní nemocnice v Motole Czech Republic (CZ) Philipps-Universität Marburg Germany (DE) Erasmus University Medical Center (MC) Netherlands (NL) Wrocław Medical University / Uniwersytet Medyczny we Wrocławiu Poland (PL) Radboud University Nijmegen Medical Centre / Radboudumc of voluit Radboud Universitair Medisch Centrum (UMC) Netherlands (NL) Universitätsklinikum Köln Germany (DE) Asklepios Kliniken Germany (DE) Dortmunder Centrum für Medizin & Gesundheit (DOC) Germany (DE) Eberhard Karls Universität Tübingen Germany (DE) Goethe-Universität Frankfurt am Main Germany (DE) Universität Witten/Herdecke Germany (DE) Universitätsmedizin der Johannes Gutenberg-Universität Mainz Germany (DE) Universität zu Köln Germany (DE) Universitätsklinikum Aachen (UKA) Germany (DE) Max-Planck-Institut für molekulare Genetik / Max Planck Institute for Molecular Genetics Germany (DE) Rheinische Friedrich-Wilhelms-Universität Bonn Germany (DE) Universitätsklinikum Essen Germany (DE) Uppsala University Sweden (SE) Skåne University Hospital / Skånes universitetssjukhus Sweden (SE) Medical University of Bialystok Poland (PL) Children's Memorial Health Institute / Instytut "Pomnik - Centrum Zdrowia Dziecka" Poland (PL) Instytut Centrum Zdrowia Matki Polki w Łodzi (ICZMP) / Polish Mother’s Memorial Hospital Research Institute Poland (PL) Universitätsklinikum Hamburg-Eppendorf (UKE) Germany (DE) Cnopf'sche Kinderklinik Germany (DE) Kinder- und Jugendkrankenhaus "Auf der Bult" Germany (DE) Ruhr-Universität Bochum (RUB) Germany (DE) Medizinische Hochschule Hannover (MHH) / Hannover Medical School Germany (DE) Universität Leipzig Germany (DE) Klinikum Ernst von Bergmann Germany (DE) Medical University of Łódź / Uniwersytet Medyczny w Łodzi Poland (PL)

How to cite

APA:

Gehlen, J., Giel, A.S., Köllges, R., Haas, S.L., Zhang, R., Trcka, J.,... Schumacher, J. (2022). First genome-wide association study of esophageal atresia identifies three genetic risk loci at CTNNA3, FOXF1/FOXC2/FOXL1, and HNF1B. Human Genetics and Genomics Advances, 3(2). https://doi.org/10.1016/j.xhgg.2022.100093

MLA:

Gehlen, Jan, et al. "First genome-wide association study of esophageal atresia identifies three genetic risk loci at CTNNA3, FOXF1/FOXC2/FOXL1, and HNF1B." Human Genetics and Genomics Advances 3.2 (2022).

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