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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 and Jung, Daphne , et al. (2022) In Human Genetics and Genomics Advances 3(2). p.1-8
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... (More)

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.

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publishing date
type
Contribution to journal
publication status
published
in
Human Genetics and Genomics Advances
volume
3
issue
2
article number
100093
pages
1 - 8
publisher
Elsevier
external identifiers
  • pmid:35199045
  • scopus:85124251722
ISSN
2666-2477
DOI
10.1016/j.xhgg.2022.100093
language
English
LU publication?
no
additional info
© 2022 The Authors.
id
08a84872-eb68-4f3b-b3e7-f7ef3007c534
date added to LUP
2022-02-26 20:02:44
date last changed
2024-06-20 07:53:00
@article{08a84872-eb68-4f3b-b3e7-f7ef3007c534,
  abstract     = {{<p>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.</p>}},
  author       = {{Gehlen, Jan and Giel, Ann-Sophie and Köllges, Ricarda and Haas, Stephan L and Zhang, Rong and Trcka, Jiri and Sungur, Ayse Ö and Renziehausen, Florian and Bornholdt, Dorothea and Jung, Daphne and Hoyer, Paul D and Nordenskjöld, Agneta and Tibboel, Dick and Vlot, John and Spaander, Manon C W and Smigiel, Robert and Patkowski, Dariusz and Roeleveld, Nel and van Rooij, Iris Alm and de Blaauw, Ivo and Hölscher, Alice and Pauly, Marcus and Leutner, Andreas and Fuchs, Joerg and Niethammer, Joel and Melissari, Maria-Theodora and Jenetzky, Ekkehart and Zwink, Nadine and Thiele, Holger and Hilger, Alina Christine and Hess, Timo and Trautmann, Jessica and Marks, Matthias and Baumgarten, Martin and Bläss, Gaby and Landén, Mikael and Fundin, Bengt and Bulik, Cynthia M and Pennimpede, Tracie and Ludwig, Michael and Ludwig, Kerstin U and Mangold, Elisabeth and Heilmann-Heimbach, Stefanie and Moebus, Susanne and Herrmann, Bernhard G and Alsabeah, Kristina and Burgos, Carmen M and Lilja, Helene E and Azodi, Sahar and Stenström, Pernilla and Arnbjörnsson, Einar and Frybova, Barbora and Lebensztejn, Dariusz M and Debek, Wojciech and Kolodziejczyk, Elwira and Kozera, Katarzyna and Kierkus, Jaroslaw and Kaliciński, Piotr and Stefanowicz, Marek and Socha-Banasiak, Anna and Kolejwa, Michal and Piaseczna-Piotrowska, Anna and Czkwianianc, Elzbieta and Nöthen, Markus M and Grote, Phillip and Rygl, Michal and Reinshagen, Konrad and Spychalski, Nicole and Ludwikowski, Barbara and Hubertus, Jochen and Heydweiller, Andreas and Ure, Benno and Muensterer, Oliver J and Aubert, Ophelia and Gosemann, Jan-Hendrik and Lacher, Martin and Degenhardt, Petra and Boemers, Thomas M and Mokrowiecka, Anna and Małecka-Panas, Ewa and Wöhr, Markus and Knapp, Michael and Seitz, Guido and de Klein, Annelies and Oracz, Grzegorz and Brosens, Erwin and Reutter, Heiko and Schumacher, Johannes}},
  issn         = {{2666-2477}},
  language     = {{eng}},
  month        = {{04}},
  number       = {{2}},
  pages        = {{1--8}},
  publisher    = {{Elsevier}},
  series       = {{Human Genetics and Genomics Advances}},
  title        = {{First genome-wide association study of esophageal atresia identifies three genetic risk loci at CTNNA3, FOXF1/FOXC2/FOXL1, and HNF1B}},
  url          = {{http://dx.doi.org/10.1016/j.xhgg.2022.100093}},
  doi          = {{10.1016/j.xhgg.2022.100093}},
  volume       = {{3}},
  year         = {{2022}},
}