HGG Advances (Apr 2022)
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 Ö. 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
Affiliations
- Jan Gehlen
- Institute of Human Genetics, University Hospital of Marburg, Marburg, Germany
- Ann-Sophie Giel
- Institute of Human Genetics, University Hospital of Marburg, Marburg, Germany
- Ricarda Köllges
- Institute of Human Genetics, University of Bonn, School of Medicine & University Hospital Bonn, Bonn, Germany; Department of Genomics, Life & Brain Center, University of Bonn, Bonn, Germany
- Stephan L. Haas
- Department of Upper GI Diseases, Karolinska University Hospital and Unit of Gastroenterology and Rheumatology, Karolinska Institutet, Stockholm, Sweden
- Rong Zhang
- Institute of Human Genetics, University of Bonn, School of Medicine & University Hospital Bonn, Bonn, Germany; Department of Genomics, Life & Brain Center, University of Bonn, Bonn, Germany
- Jiri Trcka
- Department of Paediatric Surgery, 2nd Faculty of Medicine Charles University and Motol University Hospital, Prague, Czech Republic
- Ayse Ö. Sungur
- Behavioural Neuroscience, Experimental and Biological Psychology, University of Marburg, Marburg, Germany
- Florian Renziehausen
- Institute of Human Genetics, University of Bonn, School of Medicine & University Hospital Bonn, Bonn, Germany; Department of Genomics, Life & Brain Center, University of Bonn, Bonn, Germany
- Dorothea Bornholdt
- Institute of Human Genetics, University Hospital of Marburg, Marburg, Germany
- Daphne Jung
- Institute of Human Genetics, University Hospital of Marburg, Marburg, Germany; Department of Pediatric Surgery, University Children's Hospital, Marburg, Germany
- Paul D. Hoyer
- Department of Pediatric Surgery, University Children's Hospital, Marburg, Germany
- Agneta Nordenskjöld
- Department of Women′s and Children′s Health, Karolinska Institutet, Stockholm, Sweden; Department of Paediatric Surgery, Karolinska University Hospital, Stockholm, Sweden
- Dick Tibboel
- Department of Pediatric Surgery and Intensive Care, Erasmus Medical Centre - Sophia Children's Hospital, Rotterdam, the Netherlands
- John Vlot
- Department of Pediatric Surgery and Intensive Care, Erasmus Medical Centre - Sophia Children's Hospital, Rotterdam, the Netherlands
- Manon C.W. Spaander
- Department of Gastroenterology and Hepatology, Erasmus University Medical Center, Rotterdam, the Netherlands
- Robert Smigiel
- Department of Pediatrics, Division of Pediatrics and Rare Disorders, Wroclaw Medical University, Wroclaw, Poland
- Dariusz Patkowski
- Department of Pediatric Surgery and Urology, Wroclaw Medical University, Wroclaw, Poland
- Nel Roeleveld
- Department for Health Evidence, Radboud Institute for Health Sciences, Radboudumc, Nijmegen, the Netherlands
- Iris ALM. van Rooij
- Department for Health Evidence, Radboud Institute for Health Sciences, Radboudumc, Nijmegen, the Netherlands
- Ivo de Blaauw
- Department of Surgery, Pediatric Surgery, Radboudumc Amalia Children's Hospital, Nijmegen, the Netherlands
- Alice Hölscher
- Department of Pediatric Surgery and Urology, University Hospital Cologne, Cologne, Germany
- Marcus Pauly
- Department of Pediatric Surgery, Asklepios Children's Hospital St. Augustin, St. Augustin, Germany
- Andreas Leutner
- Department of Pediatric Surgery, Medical Center Dortmund, Dortmund, Germany
- Joerg Fuchs
- Department of Pediatric Surgery Children's Hospital, University of Tübingen, Tübingen, Germany
- Joel Niethammer
- Department of Pediatric Surgery Children's Hospital, University of Tübingen, Tübingen, Germany
- Maria-Theodora Melissari
- Institute of Cardiovascular Regeneration, Center for Molecular Medicine, University of Frankfurt, Frankfurt am Main, Germany
- Ekkehart Jenetzky
- School of Medicine, Faculty of Health, University of Witten/Herdecke, Witten, Germany; Department of Child and Adolescent Psychiatry and Psychotherapy, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany
- Nadine Zwink
- Department of Child and Adolescent Psychiatry and Psychotherapy, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany
- Holger Thiele
- Cologne Center for Genomics, University of Cologne, Cologne, Germany
- Alina Christine Hilger
- Institute of Human Genetics, University of Bonn, School of Medicine & University Hospital Bonn, Bonn, Germany; Department of Pediatrics, Children's Hospital, University Hospital Bonn, Bonn, Germany
- Timo Hess
- Institute of Human Genetics, University Hospital of Marburg, Marburg, Germany
- Jessica Trautmann
- Institute of Human Genetics, University of Bonn, School of Medicine & University Hospital Bonn, Bonn, Germany; Department of Genomics, Life & Brain Center, University of Bonn, Bonn, Germany
- Matthias Marks
- Clinic for Neurology, Section Neurobiological Research, RWTH Aachen University Clinic, Aachen, Germany; Institute for Biology II, Department for Neurobiological Research, RWTH Aachen University, Aachen, Germany
- Martin Baumgarten
- Institute of Human Genetics, University Hospital of Marburg, Marburg, Germany
- Gaby Bläss
- Department of Developmental Genetics, Max-Planck-Institute for Molecular Genetics, Berlin, Germany
- Mikael Landén
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden; Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden
- Bengt Fundin
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
- Cynthia M. Bulik
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden; Department of Psychiatry, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; Department of Nutrition, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
- Tracie Pennimpede
- Department of Developmental Genetics, Max-Planck-Institute for Molecular Genetics, Berlin, Germany; Division of Cancer Biology and Genetics, Queen's University, Kingston, Canada
- Michael Ludwig
- Department of Clinical Chemistry and Clinical Pharmacology, University of Bonn, Bonn, Germany
- Kerstin U. Ludwig
- Institute of Human Genetics, University of Bonn, School of Medicine & University Hospital Bonn, Bonn, Germany; Department of Genomics, Life & Brain Center, University of Bonn, Bonn, Germany
- Elisabeth Mangold
- Institute of Human Genetics, University of Bonn, School of Medicine & University Hospital Bonn, Bonn, Germany
- Stefanie Heilmann-Heimbach
- Institute of Human Genetics, University of Bonn, School of Medicine & University Hospital Bonn, Bonn, Germany; Department of Genomics, Life & Brain Center, University of Bonn, Bonn, Germany
- Susanne Moebus
- Institute of Urban Public Health, University Hospital of Essen, University Duisburg-Essen, Essen, Germany
- Bernhard G. Herrmann
- Department of Developmental Genetics, Max-Planck-Institute for Molecular Genetics, Berlin, Germany
- Kristina Alsabeah
- Department of Upper GI Diseases, Karolinska University Hospital and Unit of Gastroenterology and Rheumatology, Karolinska Institutet, Stockholm, Sweden
- Carmen M. Burgos
- Department of Women′s and Children′s Health, Karolinska Institutet, Stockholm, Sweden; Department of Paediatric Surgery, Karolinska University Hospital, Stockholm, Sweden
- Helene E. Lilja
- Department of Women's and Children's Health, Section of Pediatric Surgery, Uppsala University, Uppsala, Sweden
- Sahar Azodi
- Perioperative Medicine and Intensive Care, Karolinska University, Stockholm, Sweden
- Pernilla Stenström
- Department of Pediatric Surgery, Skåne University Hospital, Lund, Sweden
- Einar Arnbjörnsson
- Department of Pediatric Surgery, Skåne University Hospital, Lund, Sweden
- Barbora Frybova
- Department of Paediatric Surgery, 2nd Faculty of Medicine Charles University and Motol University Hospital, Prague, Czech Republic
- Dariusz M. Lebensztejn
- Department of Pediatrics, Gastroenterology, Hepatology, Nutrition and Allergology, Medical University of Bialystok, Bialystok, Poland
- Wojciech Debek
- Department of Pediatric Surgery and Urology, Medical University of Bialystok, Poland
- Elwira Kolodziejczyk
- Department of Gastroenterology, Hepatology, Feeding Disorders and Pediatrics, The Children's Memorial Health Institute, Warsaw, Poland
- Katarzyna Kozera
- Department of Gastroenterology, Hepatology, Feeding Disorders and Pediatrics, The Children's Memorial Health Institute, Warsaw, Poland
- Jaroslaw Kierkus
- Department of Gastroenterology, Hepatology, Feeding Disorders and Pediatrics, The Children's Memorial Health Institute, Warsaw, Poland
- Piotr Kaliciński
- Gastroenterology, Allergology and Pediatric Department, Polish-Mother's Memorial Hospital. Research Institute, Lodz, Poland
- Marek Stefanowicz
- Gastroenterology, Allergology and Pediatric Department, Polish-Mother's Memorial Hospital. Research Institute, Lodz, Poland
- Anna Socha-Banasiak
- Gastroenterology, Allergology and Pediatric Department, Polish-Mother's Memorial Hospital. Research Institute, Lodz, Poland
- Michal Kolejwa
- Gastroenterology, Allergology and Pediatric Department, Polish-Mother's Memorial Hospital. Research Institute, Lodz, Poland
- Anna Piaseczna-Piotrowska
- Department of Pediatric Surgery, Urology and Transplantology, The Children's Memorial Health Institute, Warsaw, Poland
- Elzbieta Czkwianianc
- Gastroenterology, Allergology and Pediatric Department, Polish-Mother's Memorial Hospital. Research Institute, Lodz, Poland
- Markus M. Nöthen
- Institute of Human Genetics, University of Bonn, School of Medicine & University Hospital Bonn, Bonn, Germany; Department of Genomics, Life & Brain Center, University of Bonn, Bonn, Germany
- Phillip Grote
- Institute of Cardiovascular Regeneration, Center for Molecular Medicine, University of Frankfurt, Frankfurt am Main, Germany
- Michal Rygl
- Department of Paediatric Surgery, 2nd Faculty of Medicine Charles University and Motol University Hospital, Prague, Czech Republic
- Konrad Reinshagen
- Department of Pediatric Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
- Nicole Spychalski
- Department of Pediatric Surgery and Urology, Cnopf'sche Kinderklinik, Nürnberg, Germany
- Barbara Ludwikowski
- Department of Pediatric Surgery and Pediatric Urology, Medical Center for Children and Adolescents 8AUF DER BULT, Hannover, Germany
- Jochen Hubertus
- Department of Pediatric Surgery, Marien Hospital Witten, Ruhr-University Bochum, Germany
- Andreas Heydweiller
- Department of Pediatric Surgery, University Hospital Bonn, Bonn, Germany
- Benno Ure
- Center of Pediatric Surgery Hannover, Hannover Medical School, Hannover, Germany
- Oliver J. Muensterer
- Department of Pediatric Surgery, University Medicine Mainz, Mainz, Germany; Department of Pediatric Surgery, Dr. von Haunersches Kinderspital, Ludwig-Maximilians-University (LMU) Munich, Munich, Germany
- Ophelia Aubert
- Department of Pediatric Surgery, University of Leipzig, Leipzig, Germany
- Jan-Hendrik Gosemann
- Department of Pediatric Surgery, University of Leipzig, Leipzig, Germany
- Martin Lacher
- Department of Pediatric Surgery, University of Leipzig, Leipzig, Germany
- Petra Degenhardt
- Department of Pediatric Surgery, Ernst von Bergmann Hospital, Potsdam, Germany
- Thomas M. Boemers
- Department of Pediatric Surgery and Urology, University Hospital Cologne, Cologne, Germany
- Anna Mokrowiecka
- Department of Digestive Tract Diseases, Medical University of Lodz, Lodz, Poland
- Ewa Małecka-Panas
- Department of Digestive Tract Diseases, Medical University of Lodz, Lodz, Poland
- Markus Wöhr
- Behavioural Neuroscience, Experimental and Biological Psychology, University of Marburg, Marburg, Germany; Center for Mind, Brain and Behavior, Philipps-University Marburg, Marburg, Germany; Faculty of Psychology and Educational Sciences, Research Unit Brain and Cognition, Laboratory of Biological Psychology, Social and Affective Neuroscience Research Group, Leuven, Belgium; KU Leuven, Leuven Brain Institute, Leuven, Belgium
- Michael Knapp
- Institute of Medical Biometry, Informatics, and Epidemiology, University of Bonn, Bonn, Germany
- Guido Seitz
- Department of Pediatric Surgery, University Children's Hospital, Marburg, Germany
- Annelies de Klein
- Department of Clinical Genetics, Erasmus Medical Centre, Rotterdam, the Netherlands
- Grzegorz Oracz
- Department of Gastroenterology, Hepatology, Feeding Disorders and Pediatrics, The Children's Memorial Health Institute, Warsaw, Poland
- Erwin Brosens
- Department of Clinical Genetics, Erasmus Medical Centre, Rotterdam, the Netherlands
- Heiko Reutter
- Institute of Human Genetics, University of Bonn, School of Medicine & University Hospital Bonn, Bonn, Germany; Division of Neonatology and Pediatric Intensive Care, Department of Pediatrics and Adolescent Medicine, University Hospital, Erlangen, Germany; Corresponding author
- Johannes Schumacher
- Institute of Human Genetics, University Hospital of Marburg, Marburg, Germany; Institute of Human Genetics, University of Bonn, School of Medicine & University Hospital Bonn, Bonn, Germany; Corresponding author
- Journal volume & issue
-
Vol. 3,
no. 2
p. 100093
Abstract
Summary: 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.
