Schroeder, Julia, Chegwidden, Laura, Maj, Carlo, Gehlen, Jan, Speller, Jan ORCID: 0000-0003-1106-8177, Boehmer, 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, Mueller, Michaela, Ebigbo, Alanna, Fuchs, Claudia, Bruns, Christiane J., Holscher, Arnulf H., Lang, Hauke, Grimminger, Peter P., Dakkak, Dani, Vashist, Yogesh, May, Sandra, Gorg, Siegfried, Franke, Andre, Ellinghaus, David, Galavotti, Sara, Veits, Lothar, Weismuller, Josef, Dommermuth, Jens, Benner, Udo, Roesch, Thomas, Messmann, Helmut, Schumacher, Brigitte, Neuhaus, Horst, Schmidt, Carsten, Wissinowski, Thaddaus T., Noethen, Markus M., 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 ORCID: 0000-0001-7106-9732, Gharahkhani, Puya, MacGregor, Stuart, Gockel, Ines, Palles, Claire and Schumacher, Johannes . 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. Gut. LONDON: BMJ PUBLISHING GROUP. ISSN 1468-3288

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Abstract

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.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Schroeder, JuliaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Chegwidden, LauraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Maj, CarloUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gehlen, JanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Speller, JanUNSPECIFIEDorcid.org/0000-0003-1106-8177UNSPECIFIED
Boehmer, Anne C.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Borisov, OlegUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hess, TimoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kreuser, NicoleUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Venerito, MarinoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Alakus, HakanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
May, AndreaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gerges, ChristianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schmidt, ThomasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Thieme, ReneUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Heider, DominikUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hillmer, Axel M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Reingruber, JulianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lyros, OrestisUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Dietrich, ArneUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hoffmeister, AlbrechtUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mehdorn, MatthiasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lordick, FlorianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Stocker, GertraudUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hohaus, MichaelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Reim, DanielUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kandler, JennisUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mueller, MichaelaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ebigbo, AlannaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Fuchs, ClaudiaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bruns, Christiane J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Holscher, Arnulf H.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lang, HaukeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Grimminger, Peter P.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Dakkak, DaniUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Vashist, YogeshUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
May, SandraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gorg, SiegfriedUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Franke, AndreUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ellinghaus, DavidUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Galavotti, SaraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Veits, LotharUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Weismuller, JosefUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Dommermuth, JensUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Benner, UdoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Roesch, ThomasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Messmann, HelmutUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schumacher, BrigitteUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Neuhaus, HorstUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schmidt, CarstenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wissinowski, Thaddaus T.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Noethen, Markus M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Dong, JingUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ong, Jue-ShengUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Buas, Matthew F.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Thrift, Aaron P.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Vaughan, Thomas L.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Tomlinson, IanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Whiteman, David C.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Fitzgerald, Rebecca ClaireUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Jankowski, JanuszUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Vieth, MichaelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mayr, AndreasUNSPECIFIEDorcid.org/0000-0001-7106-9732UNSPECIFIED
Gharahkhani, PuyaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
MacGregor, StuartUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gockel, InesUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Palles, ClaireUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schumacher, JohannesUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-698433
DOI: 10.1136/gutjnl-2021-326698
Journal or Publication Title: Gut
Publisher: BMJ PUBLISHING GROUP
Place of Publication: LONDON
ISSN: 1468-3288
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
GENOME-WIDE ASSOCIATION; GASTROESOPHAGEAL-REFLUX DISEASE; VARIANTS; ALCOHOL; HERNIAMultiple languages
Gastroenterology & HepatologyMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/69843

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