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.
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.
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