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DOI 10.1016/j.xhgg.2022.100093

Медицинская библиотека · HGG advances · 2022

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

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

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Аннотация

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.

Для цитирования: Gehlen Jan, Giel Ann-Sophie, Köllges Ricarda, Haas Stephan L, Zhang Rong, Trcka Jiri, Sungur Ayse Ö, Renziehausen Florian, Bornholdt Dorothea, Jung Daphne, Hoyer Paul D, Nordenskjöld Agneta, Tibboel Dick, Vlot John, Spaander Manon C W, Smigiel Robert, Patkowski Dariusz, Roeleveld Nel, van Rooij Iris Alm, de Blaauw Ivo, Hölscher Alice, Pauly Marcus, Leutner Andreas, Fuchs Joerg, Niethammer Joel, Melissari Maria-Theodora, Jenetzky Ekkehart, Zwink Nadine, Thiele Holger, Hilger Alina Christine, Hess Timo, Trautmann Jessica, Marks Matthias, Baumgarten Martin, Bläss Gaby, Landén Mikael, Fundin Bengt, Bulik Cynthia M, Pennimpede Tracie, Ludwig Michael, Ludwig Kerstin U, Mangold Elisabeth, Heilmann-Heimbach Stefanie, Moebus Susanne, Herrmann Bernhard G, Alsabeah Kristina, Burgos Carmen M, Lilja Helene E, Azodi Sahar, Stenström Pernilla, Arnbjörnsson Einar, Frybova Barbora, Lebensztejn Dariusz M, Debek Wojciech, Kolodziejczyk Elwira, Kozera Katarzyna, Kierkus Jaroslaw, Kaliciński Piotr, Stefanowicz Marek, Socha-Banasiak Anna, Kolejwa Michal, Piaseczna-Piotrowska Anna, Czkwianianc Elzbieta, Nöthen Markus M, Grote Phillip, Rygl Michal, Reinshagen Konrad, Spychalski Nicole, Ludwikowski Barbara, Hubertus Jochen, Heydweiller Andreas, Ure Benno, Muensterer Oliver J, Aubert Ophelia, Gosemann Jan-Hendrik, Lacher Martin, Degenhardt Petra, Boemers Thomas M, Mokrowiecka Anna, Małecka-Panas Ewa, Wöhr Markus, Knapp Michael, Seitz Guido, de Klein Annelies, Oracz Grzegorz, Brosens Erwin, Reutter Heiko, Schumacher Johannes. First genome-wide association study of esophageal atresia identifies three genetic risk loci at CTNNA3, FOXF1/FOXC2/FOXL1, and HNF1B.. HGG advances. 2022. DOI: 10.1016/j.xhgg.2022.100093.
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