Identification of disease genes for esophageal atresia with or without tracheoesophageal fistula (EA/TEF)

• Applicants: Professor Dr. Markus M. Nöthen, since 7/2018; Professor Dr. Heiko Reutter
• Subject Area: Human Genetics
• Term: from 2018 to 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 398459291

Esophageal atresia with or without tracheoesophageal fistula (EA/TEF) represents the most common congenital malformation of the upper digestive tract. In the majority of cases EA/TEF is non-syndromic with an underlying multifactorial mode of inheritance, involving genetic and environmental risk factors. In multifactorial diseases genetic risk variants can be identified through genome-wide association studies (GWAS) using large case-control cohorts. The number of identified variants thereby depends on the size of GWAS samples. Identified risk variants and corresponding genes can be further used for system biological studies in order to identify cellular networks in which GWAS risk genes are enriched and which are of etiological relevance. The applicants have established an international research network called great (Genetic Risk for Esophageal ATresia; www.great-konsortium.de) with the purpose of deciphering the genetic and cell biological causes of EA/TEF. Therefore, a biobank has been set up with EA/TEF patients of European descent.In an initial GWAS on 387 patients and 1,308 ethnically matched controls, the applicants identified two genome-wide significant EA/TEF risk loci (P < 5 x 10-08), which are located on chromosome 16q24 and 17q12 respectively. To the best of our knowledge, this study represents the first GWAS performed on EA/TEF to date. The aim of the proposed project is the extension of this GWAS through the inclusion of additional patient and control samples from Central Europe (Germany and The Netherlands), Poland, and Sweden. In total, we plan to include 1,000 patients in the extended GWAS representing the largest EA/TEF cohort for genetic studies worldwide. Thus, 613 additional EA/TEF patients are awaiting genotyping. The planned study will also include a total of 4,322 ethnically-matched controls that have been already GWAS-genotyped. In addition to standard GWAS analysis, we will perform conditional analyses at each identified risk locus using the most associated EA/TEF risk variant. This analysis should lead to identification of further risk variants at each locus. The GWAS data will also be used to investigate the contribution of copy number variants (CNVs) to EA/TEF development. These studies will be followed by in silico functional analyses for all implicated EA/TEF loci. This will reveal potential EA/TEF cellular networks and disease mechanisms, which are of particular interest in terms of future in vivo functional studies. The identified risk variants, corresponding genes and cellular pathways will make an important contribution in the elucidation of the pathophysiology of EA/TEF. Knowledge about the cellular causes of EA/TEF might ultimately lead to the identification of gene-environmental interactions that might allow preventing these interactions during the embryonic EA/TEF vulnerable time-period in the future.

• DFG Programme: Research Grants
• Ehemaliger Antragsteller: Professor Dr. Johannes Schumacher, until 6/2018