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.

Behavioural Neuroscience Experimental and Biological Psychology University of Marburg Marburg Germany

Center for Mind Brain and Behavior Philipps University Marburg Marburg Germany

Center of Pediatric Surgery Hannover Hannover Medical School Hannover Germany

Clinic for Neurology Section Neurobiological Research RWTH Aachen University Clinic Aachen Germany

Cologne Center for Genomics University of Cologne Cologne Germany

Department for Health Evidence Radboud Institute for Health Sciences Radboudumc Nijmegen the Netherlands

Department of Child and Adolescent Psychiatry and Psychotherapy University Medical Center of the Johannes Gutenberg University Mainz Mainz Germany

Department of Clinical Chemistry and Clinical Pharmacology University of Bonn Bonn Germany

Department of Clinical Genetics Erasmus Medical Centre Rotterdam the Netherlands

Department of Developmental Genetics Max Planck Institute for Molecular Genetics Berlin Germany

Department of Digestive Tract Diseases Medical University of Lodz Lodz Poland

Department of Gastroenterology and Hepatology Erasmus University Medical Center Rotterdam the Netherlands

Department of Gastroenterology Hepatology Feeding Disorders and Pediatrics The Children's Memorial Health Institute Warsaw Poland

Department of Genomics Life and Brain Center University of Bonn Bonn Germany

Department of Medical Epidemiology and Biostatistics Karolinska Institutet Stockholm Sweden

Department of Nutrition University of North Carolina at Chapel Hill Chapel Hill NC USA

Department of Paediatric Surgery 2nd Faculty of Medicine Charles University and Motol University Hospital Prague Czech Republic

Department of Paediatric Surgery Karolinska University Hospital Stockholm Sweden

Department of Pediatric Surgery and Intensive Care Erasmus Medical Centre Sophia Children's Hospital Rotterdam the Netherlands

Department of Pediatric Surgery and Pediatric Urology Medical Center for Children and Adolescents 8AUF DER BULT Hannover Germany

Department of Pediatric Surgery and Urology Cnopf'sche Kinderklinik Nürnberg Germany

Department of Pediatric Surgery and Urology Medical University of Bialystok Poland

Department of Pediatric Surgery and Urology University Hospital Cologne Cologne Germany

Department of Pediatric Surgery and Urology Wroclaw Medical University Wroclaw Poland

Department of Pediatric Surgery Asklepios Children's Hospital St Augustin St Augustin Germany

Department of Pediatric Surgery Children's Hospital University of Tübingen Tübingen Germany

Department of Pediatric Surgery Dr von Haunersches Kinderspital Ludwig Maximilians University Munich Munich Germany

Department of Pediatric Surgery Ernst von Bergmann Hospital Potsdam Germany

Department of Pediatric Surgery Marien Hospital Witten Ruhr University Bochum Germany

Department of Pediatric Surgery Medical Center Dortmund Dortmund Germany

Department of Pediatric Surgery Skåne University Hospital Lund Sweden

Department of Pediatric Surgery University Children's Hospital Marburg Germany

Department of Pediatric Surgery University Hospital Bonn Bonn Germany

Department of Pediatric Surgery University Medical Center Hamburg Eppendorf Hamburg Germany

Department of Pediatric Surgery University Medicine Mainz Mainz Germany

Department of Pediatric Surgery University of Leipzig Leipzig Germany

Department of Pediatric Surgery Urology and Transplantology The Children's Memorial Health Institute Warsaw Poland

Department of Pediatrics Children's Hospital University Hospital Bonn Bonn Germany

Department of Pediatrics Division of Pediatrics and Rare Disorders Wroclaw Medical University Wroclaw Poland

Department of Pediatrics Gastroenterology Hepatology Nutrition and Allergology Medical University of Bialystok Bialystok Poland

Department of Psychiatry and Neurochemistry Institute of Neuroscience and Physiology Sahlgrenska Academy at the University of Gothenburg Gothenburg Sweden

Department of Psychiatry University of North Carolina at Chapel Hill Chapel Hill NC USA

Department of Surgery Pediatric Surgery Radboudumc Amalia Children's Hospital Nijmegen the Netherlands

Department of Upper GI Diseases Karolinska University Hospital and Unit of Gastroenterology and Rheumatology Karolinska Institutet Stockholm Sweden

Department of Women's and Children's Health Karolinska Institutet Stockholm Sweden

Department of Women's and Children's Health Section of Pediatric Surgery Uppsala University Uppsala Sweden

Division of Cancer Biology and Genetics Queen's University Kingston Canada

Division of Neonatology and Pediatric Intensive Care Department of Pediatrics and Adolescent Medicine University Hospital Erlangen Germany

Faculty of Psychology and Educational Sciences Research Unit Brain and Cognition Laboratory of Biological Psychology Social and Affective Neuroscience Research Group Leuven Belgium

Gastroenterology Allergology and Pediatric Department Polish Mother's Memorial Hospital Research Institute Lodz Poland

Institute for Biology 2 Department for Neurobiological Research RWTH Aachen University Aachen Germany

Institute of Cardiovascular Regeneration Center for Molecular Medicine University of Frankfurt Frankfurt am Main Germany

Institute of Human Genetics University Hospital of Marburg Marburg Germany

Institute of Human Genetics University of Bonn School of Medicine and University Hospital Bonn Bonn Germany

Institute of Medical Biometry Informatics and Epidemiology University of Bonn Bonn Germany

Institute of Urban Public Health University Hospital of Essen University Duisburg Essen Essen Germany

KU Leuven Leuven Brain Institute Leuven Belgium

Perioperative Medicine and Intensive Care Karolinska University Stockholm Sweden

School of Medicine Faculty of Health University of Witten Herdecke Witten Germany

Zobrazit více v PubMed

Torfs C.P., Curry C.J., Bateson T.F. Population-based study of tracheoesophageal fistula and esophageal atresia. Teratology. 1995;52:220–232. PubMed

Spitz L. Oesophageal atresia. Orphanet J. Rare Dis. 2007;2:24. PubMed PMC

David T.J., O'Callaghan S.E. Oesophageal atresia in the South West of England. J. Med. Genet. 1975;12:1–11. PubMed PMC

Geneviève D., de Pontual L., Amiel J., Sarnacki S., Lyonnet S. An overview of isolated and syndromic oesophageal atresia. Clin. Genet. 2007;71:392–399. PubMed

Brown A.K., Roddam A.W., Spitz L., Ward S.J. Oesophageal atresia, related malformations, and medical problems: a family study. Am. J. Med. Genet. 1999;85:31–37. PubMed

Shaw-Smith C. Oesophageal atresia, tracheo-oesophageal fistula, and the VACTERL association: review of genetics and epidemiology. J. Med. Genet. 2006;43:545–554. PubMed PMC

Nassar N., Leoncini E., Amar E., Arteaga-Vázquez J., Bakker M.K., Bower C., Canfield M.A., Castilla E.E., Cocchi G., Correa A., et al. Prevalence of esophageal atresia among 18 international birth defects surveillance programs. Birth Defects Res. Part A Clin. Mol. Teratol. 2012;94:893–899. PubMed PMC

Depaepe A., Dolk H., Lechat M.F. The epidemiology of tracheo-oesophageal fistula and oesophageal atresia in Europe. EUROCAT Working Group. Arch. Dis. Child. 1993;68:743–748. PubMed PMC

McMullen K.P., Karnes P.S., Moir C.R., Michels V.V. Familial recurrence of tracheoesophageal fistula and associated malformations. Am. J. Med. Genet. 1996;63:525–528. PubMed

Robert E., Mutchinick O., Mastroiacovo P., Knudsen L.B., Daltveit A.K., Castilla E.E., Lancaster P., Källén B., Cocchi G. An international collaborative study of the epidemiology of esophageal atresia or stenosis. Reprod. Toxicol. 1993;7:405–421. PubMed

Van Staey M., De Bie S., Matton M.T., De Roose J. Familial congenital esophageal atresia. Personal case report and review of the literature. Hum. Genet. 1984;66:260–266. PubMed

Warren J., Evans K., Carter C.O. Offspring of patients with tracheo-oesophageal fistula. J. Med. Genet. 1979;16:338–340. PubMed PMC

de Jong E.M., Felix J.F., de Klein A., Tibboel D. Etiology of esophageal atresia and tracheoesophageal fistula: "mind the gap". Curr. Gastroenterol. Rep. 2010;12:215–222. PubMed PMC

Klar J., Engstrand-Lilja H., Maqbool K., Mattisson J., Feuk L., Dahl N. Whole genome sequencing of familial isolated oesophagus atresia uncover shared structural variants. BMC Med. Genomics. 2020;13:85. PubMed PMC

van Bokhoven H., Celli J., van Reeuwijk J., Rinne T., Glaudemans B., van Beusekom E., Rieu P., Newbury-Ecob R.A., Chiang C., Brunner H.G. MYCN haploinsufficiency is associated with reduced brain size and intestinal atresias in Feingold syndrome. Nat. Genet. 2005;37:465–467. PubMed

Motoyama J., Liu J., Mo R., Ding Q., Post M., Hui C.C. Essential function of Gli2 and Gli3 in the formation of lung, trachea and oesophagus. Nat. Genet. 1998;20:54–57. PubMed

Vissers L.E., van Ravenswaaij C.M., Admiraal R., Hurst J.A., de Vries B.B., Janssen I.M., van der Vliet W.A., Huys E.H., de Jong P.J., Hamel B.C., et al. Mutations in a new member of the chromodomain gene family cause CHARGE syndrome. Nat. Genet. 2004;36:955–957. PubMed

Das S., Forer L., Schönherr S., Sidore C., Locke A.E., Kwong A., Vrieze S.I., Chew E.Y., Levy S., McGue M., et al. Next-generation genotype imputation service and methods. Nat. Genet. 2016;48:1284–1287. PubMed PMC

Taliun D., Harris D.N., Kessler M.D., Carlson J., Szpiech Z.A., Torres R., Taliun S.A.G., Corvelo A., Gogarten S.M., Kang H.M., et al. Sequencing of 53,831 diverse genomes from the NHLBI TOPMed program. Nature. 2021;590:290–299. PubMed PMC

Fuchsberger C., Abecasis G.R., Hinds D.A. minimac2: faster genotype imputation. Bioinformatics. 2015;31:782–784. PubMed PMC

Chang C.C., Chow C.C., Tellier L.C., Vattikuti S., Purcell S.M., Lee J.J. Second-generation PLINK: rising to the challenge of larger and richer datasets. Gigascience. 2015;4:7. PubMed PMC

Willer C.J., Li Y., Abecasis G.R. METAL: fast and efficient meta-analysis of genomewide association scans. Bioinformatics. 2010;26:2190–2191. PubMed PMC

Chiarella S.E., Rabin E.E., Ostilla L.A., Flozak A.S., Gottardi C.J. alphaT-catenin: a developmentally dispensable, disease-linked member of the alpha-catenin family. Tissue Barriers. 2018;6:e1463896. PubMed PMC

Spence J.R., Lauf R., Shroyer N.F. Vertebrate intestinal endoderm development. Dev. Dyn. 2011;240:501–520. PubMed PMC

Billmyre K.K., Hutson M., Klingensmith J. One shall become two: separation of the esophagus and trachea from the common foregut tube. Dev. Dyn. 2015;244:277–288. PubMed PMC

Karczewski K.J., Francioli L.C., Tiao G., Cummings B.B., Alföldi J., Wang Q., Collins R.L., Laricchia K.M., Ganna A., Birnbaum D.P., et al. The mutational constraint spectrum quantified from variation in 141,456 humans. Nature. 2020;581:434–443. PubMed PMC

Pruim R.J., Welch R.P., Sanna S., Teslovich T.M., Chines P.S., Gliedt T.P., Boehnke M., Abecasis G.R., Willer C.J. LocusZoom: regional visualization of genome-wide association scan results. Bioinformatics. 2010;26:2336–2337. PubMed PMC

Han L., Chaturvedi P., Kishimoto K., Koike H., Nasr T., Iwasawa K., Giesbrecht K., Witcher P.C., Eicher A., Haines L., et al. Single cell transcriptomics identifies a signaling network coordinating endoderm and mesoderm diversification during foregut organogenesis. Nat. Commun. 2020;11:4158. PubMed PMC

Stankiewicz P., Sen P., Bhatt S.S., Storer M., Xia Z., Bejjani B.A., Ou Z., Wiszniewska J., Driscoll D.J., Maisenbacher M.K., et al. Genomic and genic deletions of the FOX gene cluster on 16q24.1 and inactivating mutations of FOXF1 cause alveolar capillary dysplasia and other malformations. Am. J. Hum. Genet. 2009;84:780–791. PubMed PMC

Ward L.D., Kellis M. HaploReg: a resource for exploring chromatin states, conservation, and regulatory motif alterations within sets of genetically linked variants. Nucleic Acids Res. 2012;40:D930–D934. PubMed PMC

Shaw-Smith C. Genetic factors in esophageal atresia, tracheo-esophageal fistula and the VACTERL association: roles for FOXF1 and the 16q24.1 FOX transcription factor gene cluster, and review of the literature. Eur. J. Med. Genet. 2010;53:6–13. PubMed PMC

Clissold R.L., Hamilton A.J., Hattersley A.T., Ellard S., Bingham C. HNF1B-associated renal and extra-renal disease-an expanding clinical spectrum. Nat. Rev. Nephrol. 2015;11:102–112. PubMed

Faguer S., Chassaing N., Bandin F., Prouheze C., Arveiler B., Rooryck C., Nogier M.B., Chauveau D., Calvas P., Decramer S. A 17q12 chromosomal duplication associated with renal disease and esophageal atresia. Eur. J. Med. Genet. 2011;54:e437–e440. PubMed

Hoskins B.E., Cramer C.H., 2nd, Tasic V., Kehinde E.O., Ashraf S., Bogdanovic R., Hoefele J., Pohl M., Hildebrandt F. Missense mutations in EYA1 and TCF2 are a rare cause of urinary tract malformations. Nephrol. Dial. Transpl. 2008;23:777–779. PubMed

Kotalova R., Dusatkova P., Cinek O., Dusatkova L., Dedic T., Seeman T., Lebl J., Pruhova S. Hepatic phenotypes of HNF1B gene mutations: a case of neonatal cholestasis requiring portoenterostomy and literature review. World J. Gastroenterol. 2015;21:2550–2557. PubMed PMC

Quintero-Rivera F., Woo J.S., Bomberg E.M., Wallace W.D., Peredo J., Dipple K.M. Duodenal atresia in 17q12 microdeletion including HNF1B: a new associated malformation in this syndrome. Am. J. Med. Genet. A. 2014;164A:3076–3082. PubMed

Rentzsch P., Witten D., Cooper G.M., Shendure J., Kircher M. CADD: predicting the deleteriousness of variants throughout the human genome. Nucleic Acids Res. 2019;47:D886–D894. PubMed PMC

Moll P., Ante M., Seitz A., Reda T. QuantSeq 3′ mRNA sequencing for RNA quantification. Nat. Methods. 2014;11:972. PubMed

Durinck S., Spellman P.T., Birney E., Huber W. Mapping identifiers for the integration of genomic datasets with the R/Bioconductor package biomaRt. Nat. Protoc. 2009;4:1184–1191. PubMed PMC

Bulik-Sullivan B., Finucane H.K., Anttila V., Gusev A., Day F.R., Loh P.R., ReproGen Consortium. Psychiatric Genomics Consortium. Genetic Consortium for Anorexia Nervosa of the Wellcome Trust Case Control Consortium 3. Duncan L., Perry J.R., Patterson N., Robinson E.B., et al. An atlas of genetic correlations across human diseases and traits. Nat. Genet. 2015;47:1236–1241. PubMed PMC

Watanabe K., Taskesen E., van Bochoven A., Posthuma D. Functional mapping and annotation of genetic associations with FUMA. Nat. Commun. 2017;8:1826. PubMed PMC

Mangold E., Ludwig K.U., Birnbaum S., Baluardo C., Ferrian M., Herms S., Reutter H., de Assis N.A., Chawa T.A., Mattheisen M., et al. Genome-wide association study identifies two susceptibility loci for nonsyndromic cleft lip with or without cleft palate. Nat. Genet. 2010;42:24–26. PubMed

Zhang Y., Qi G., Park J.H., Chatterjee N. Estimation of complex effect-size distributions using summary-level statistics from genome-wide association studies across 32 complex traits. Nat. Genet. 2018;50:1318–1326. PubMed