GWAS meta-analysis of 16 790 patients with Barrett’s oesophagus and oesophageal adenocarcinoma identifies 16 novel genetic risk loci and provides insights into disease aetiology beyond the single marker level
Authors: Schröder Julia , Chegwidden Laura , Maj Carlo , Gehlen Jan , Speller Jan , Böhmer Anne C , Borisov Oleg , Hess Timo , Kreuser Nicole , Venerito Marino , Alakus Hakan , May Andrea , Gerges Christian , Schmidt Thomas , Thieme Rene , Heider Dominik , Hillmer Axel M , Reingruber Julian , Lyros Orestis , Dietrich Arne , Hoffmeister Albrecht , Mehdorn Matthias , Lordick Florian , Stocker Gertraud , Hohaus Michael , Reim Daniel , Kandler Jennis , Müller Michaela , Ebigbo Alanna , Fuchs Claudia , Bruns Christiane J , Hölscher Arnulf H , Lang Hauke , Grimminger Peter P , Dakkak Dani , Vashist Yogesh , May Sandra , Görg Siegfried , Franke Andre , Ellinghaus David , Galavotti Sara , Veits Lothar , Weismüller Josef , Dommermuth Jens , Benner Udo , Rösch Thomas , Messmann Helmut , Schumacher Brigitte , Neuhaus Horst , Schmidt Carsten , Wissinowski Thaddäus T , Nöthen Markus M ,   Wellcome Trust Case Control Consortium 2 (WTCCC2),   Esophageal Adenocarcinoma Genetics Consortium (EAGLE),   Barrett's and Esophageal Adenocarcinoma Consortium (BEACON), Dong Jing , Ong Jue-Sheng , Buas Matthew F , Thrift Aaron P , Vaughan Thomas L , Tomlinson Ian , Whiteman David C , Fitzgerald Rebecca Claire , Jankowski Janusz , Vieth Michael , Mayr Andreas , Gharahkhani Puya , MacGregor Stuart , Gockel Ines , Palles Claire , Schumacher Johannes 
Published: July 2022

Objective

Oesophageal cancer (EC) is the sixth leading cause of cancer-related deaths. Oesophageal adenocarcinoma (EA), with Barrett’s oesophagus (BE) as a precursor lesion, is the most prevalent EC subtype in the Western world. This study aims to contribute to better understand the genetic causes of BE/EA by leveraging genome wide association studies (GWAS), genetic correlation analyses and polygenic risk modelling.

Design

We combined data from previous GWAS with new cohorts, increasing the sample size to 16 790 BE/EA cases and 32 476 controls. We also carried out a transcriptome wide association study (TWAS) using expression data from disease-relevant tissues to identify BE/EA candidate genes. To investigate the relationship with reported BE/EA risk factors, a linkage disequilibrium score regression (LDSR) analysis was performed. BE/EA risk models were developed combining clinical/lifestyle risk factors with polygenic risk scores (PRS) derived from the GWAS meta-analysis.

Results

The GWAS meta-analysis identified 27 BE and/or EA risk loci, 11 of which were novel. The TWAS identified promising BE/EA candidate genes at seven GWAS loci and at five additional risk loci. The LDSR analysis led to the identification of novel genetic correlations and pointed to differences in BE and EA aetiology. Gastro-oesophageal reflux disease appeared to contribute stronger to the metaplastic BE transformation than to EA development. Finally, combining PRS with BE/EA risk factors improved the performance of the risk models.

Conclusion

Our findings provide further insights into BE/EA aetiology and its relationship to risk factors. The results lay the foundation for future follow-up studies to identify underlying disease mechanisms and improving risk prediction.