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 Blaauw; Alice 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

doi:10.1016/j.xhgg.2022.100093

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

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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 × 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 language	English
Article number	100093
Journal	Human Genetics and Genomics Advances
Volume	3
Issue number	2
DOIs	https://doi.org/10.1016/j.xhgg.2022.100093
Publication status	Published - 14 Apr 2022

Bibliographical note

Acknowledgments:
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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10.1016/j.xhgg.2022.100093

1-s2.0-S2666247722000094-mainFinal published version, 559 KBLicence: CC BY-NC-ND

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Gehlen, J., Giel, A. S., Köllges, R., Haas, S. L., Zhang, R., Trcka, J., Sungur, A., Renziehausen, F., Bornholdt, D., Jung, D., Hoyer, P. D., Nordenskjöld, A., Tibboel, D., Vlot, J., Spaander, M. C. W., Smigiel, R., Patkowski, D., Roeleveld, N., van Rooij, I. ALM., ... 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), Article 100093. https://doi.org/10.1016/j.xhgg.2022.100093

@article{04de304afe414486933e29d308cad106,

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

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.",

author = "Jan Gehlen and Giel, {Ann Sophie} and Ricarda K{\"o}llges and Haas, {Stephan L.} and Rong Zhang and Jiri Trcka and Ayse Sungur and Florian Renziehausen and Dorothea Bornholdt and Daphne Jung and Hoyer, {Paul D.} and Agneta Nordenskj{\"o}ld and Dick Tibboel and John Vlot and Spaander, {Manon C.W.} and Robert Smigiel and Dariusz Patkowski and Nel Roeleveld and {van Rooij}, {Iris ALM} and {de Blaauw}, Ivo and Alice H{\"o}lscher and Marcus Pauly and Andreas Leutner and Joerg Fuchs and Joel Niethammer and Melissari, {Maria Theodora} and Ekkehart Jenetzky and Nadine Zwink and Holger Thiele and Hilger, {Alina Christine} and Timo Hess and Jessica Trautmann and Matthias Marks and Martin Baumgarten and Gaby Bl{\"a}ss and Mikael Land{\'e}n and Bengt Fundin and Bulik, {Cynthia M.} and Tracie Pennimpede and Michael Ludwig and Ludwig, {Kerstin U.} and Elisabeth Mangold and Stefanie Heilmann-Heimbach and Susanne Moebus and Herrmann, {Bernhard G.} and Kristina Alsabeah and Burgos, {Carmen M.} and Lilja, {Helene E.} and Sahar Azodi and Pernilla Stenstr{\"o}m and Einar Arnbj{\"o}rnsson and Barbora Frybova and Lebensztejn, {Dariusz M.} and Wojciech Debek and Elwira Kolodziejczyk and Katarzyna Kozera and Jaroslaw Kierkus and Piotr Kalici{\'n}ski and Marek Stefanowicz and Anna Socha-Banasiak and Michal Kolejwa and Anna Piaseczna-Piotrowska and Elzbieta Czkwianianc and N{\"o}then, {Markus M.} and Phillip Grote and Michal Rygl and Konrad Reinshagen and Nicole Spychalski and Barbara Ludwikowski and Jochen Hubertus and Andreas Heydweiller and Benno Ure and Muensterer, {Oliver J.} and Ophelia Aubert and Gosemann, {Jan Hendrik} and Martin Lacher and Petra Degenhardt and Boemers, {Thomas M.} and Anna Mokrowiecka and Ewa Ma{\l}ecka-Panas and Markus W{\"o}hr and Michael Knapp and Guido Seitz and {de Klein}, Annelies and Grzegorz Oracz and Erwin Brosens and Heiko Reutter and Johannes Schumacher",

note = "Acknowledgments: The authors thank all study participants and the German self-help organization KEKS e.V. (Kinder und Erwachsene mit Erkrankungen der Speiser{\"o}hre) 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 Kr{\"o}ner-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: {\textcopyright} 2022 The Authors",

year = "2022",

month = apr,

day = "14",

doi = "10.1016/j.xhgg.2022.100093",

language = "English",

volume = "3",

journal = "Human Genetics and Genomics Advances",

issn = "2666-2477",

publisher = "Cell Press",

number = "2",

}

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, MCW, Smigiel, R, Patkowski, D, Roeleveld, N, van Rooij, IALM, 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, '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, vol. 3, no. 2, 100093. https://doi.org/10.1016/j.xhgg.2022.100093

TY - JOUR

T1 - First genome-wide association study of esophageal atresia identifies three genetic risk loci at CTNNA3, FOXF1/FOXC2/FOXL1, and HNF1B

AU - Gehlen, Jan

AU - Giel, Ann Sophie

AU - Köllges, Ricarda

AU - Haas, Stephan L.

AU - Zhang, Rong

AU - Trcka, Jiri

AU - Sungur, Ayse

AU - Renziehausen, Florian

AU - Bornholdt, Dorothea

AU - Jung, Daphne

AU - Hoyer, Paul D.

AU - Nordenskjöld, Agneta

AU - Tibboel, Dick

AU - Vlot, John

AU - Spaander, Manon C.W.

AU - Smigiel, Robert

AU - Patkowski, Dariusz

AU - Roeleveld, Nel

AU - van Rooij, Iris ALM

AU - de Blaauw, Ivo

AU - Hölscher, Alice

AU - Pauly, Marcus

AU - Leutner, Andreas

AU - Fuchs, Joerg

AU - Niethammer, Joel

AU - Melissari, Maria Theodora

AU - Jenetzky, Ekkehart

AU - Zwink, Nadine

AU - Thiele, Holger

AU - Hilger, Alina Christine

AU - Hess, Timo

AU - Trautmann, Jessica

AU - Marks, Matthias

AU - Baumgarten, Martin

AU - Bläss, Gaby

AU - Landén, Mikael

AU - Fundin, Bengt

AU - Bulik, Cynthia M.

AU - Pennimpede, Tracie

AU - Ludwig, Michael

AU - Ludwig, Kerstin U.

AU - Mangold, Elisabeth

AU - Heilmann-Heimbach, Stefanie

AU - Moebus, Susanne

AU - Herrmann, Bernhard G.

AU - Alsabeah, Kristina

AU - Burgos, Carmen M.

AU - Lilja, Helene E.

AU - Azodi, Sahar

AU - Stenström, Pernilla

AU - Arnbjörnsson, Einar

AU - Frybova, Barbora

AU - Lebensztejn, Dariusz M.

AU - Debek, Wojciech

AU - Kolodziejczyk, Elwira

AU - Kozera, Katarzyna

AU - Kierkus, Jaroslaw

AU - Kaliciński, Piotr

AU - Stefanowicz, Marek

AU - Socha-Banasiak, Anna

AU - Kolejwa, Michal

AU - Piaseczna-Piotrowska, Anna

AU - Czkwianianc, Elzbieta

AU - Nöthen, Markus M.

AU - Grote, Phillip

AU - Rygl, Michal

AU - Reinshagen, Konrad

AU - Spychalski, Nicole

AU - Ludwikowski, Barbara

AU - Hubertus, Jochen

AU - Heydweiller, Andreas

AU - Ure, Benno

AU - Muensterer, Oliver J.

AU - Aubert, Ophelia

AU - Gosemann, Jan Hendrik

AU - Lacher, Martin

AU - Degenhardt, Petra

AU - Boemers, Thomas M.

AU - Mokrowiecka, Anna

AU - Małecka-Panas, Ewa

AU - Wöhr, Markus

AU - Knapp, Michael

AU - Seitz, Guido

AU - de Klein, Annelies

AU - Oracz, Grzegorz

AU - Brosens, Erwin

AU - Reutter, Heiko

AU - Schumacher, Johannes

N1 - Acknowledgments: 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

PY - 2022/4/14

Y1 - 2022/4/14

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85124251722&partnerID=8YFLogxK

U2 - 10.1016/j.xhgg.2022.100093

DO - 10.1016/j.xhgg.2022.100093

M3 - Article

AN - SCOPUS:85124251722

SN - 2666-2477

VL - 3

JO - Human Genetics and Genomics Advances

JF - Human Genetics and Genomics Advances

IS - 2

M1 - 100093

ER -

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

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