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

Julia Schröder; Laura Chegwidden; Carlo Maj; Jan Gehlen; Jan Speller; Anne C. Böhmer; Oleg Borisov; Timo Hess; Nicole Kreuser; Marino Venerito; Hakan Alakus; Andrea May; Christian Gerges; Thomas Schmidt; Rene Thieme; Dominik Heider; Axel M. Hillmer; Julian Reingruber; Orestis Lyros; Arne Dietrich; Albrecht Hoffmeister; Matthias Mehdorn; Florian Lordick; Gertraud Stocker; Michael Hohaus; Daniel Reim; Jennis Kandler; Michaela Müller; Alanna Ebigbo; Claudia Fuchs; Christiane J. Bruns; Arnulf H. Hölscher; Hauke Lang; Peter P. Grimminger; Dani Dakkak; Yogesh Vashist; Sandra May; Siegfried Görg; Andre Franke; David Ellinghaus; Sara Galavotti; Lothar Veits; Josef Weismüller; Jens Dommermuth; Udo Benner; Thomas Rösch; Helmut Messmann; Brigitte Schumacher; Horst Neuhaus; Carsten Schmidt; Thaddäus T. Wissinowski; Markus M. Nöthen; Jing Dong; Jue Sheng Ong; Matthew F. Buas; Aaron P. Thrift; Thomas L. Vaughan; Ian Tomlinson; David C. Whiteman; Rebecca Claire Fitzgerald; Janusz Jankowski; Michael Vieth; Andreas Mayr; Puya Gharahkhani; Stuart MacGregor; Ines Gockel; Claire Palles; Johannes Schumacher

doi:10.1136/gutjnl-2021-326698

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

Julia Schröder, Laura Chegwidden, Carlo Maj, Jan Gehlen, Jan Speller, Anne C. Böhmer, Oleg Borisov, Timo Hess, Nicole Kreuser, Marino Venerito, Hakan Alakus, Andrea May, Christian Gerges, Thomas Schmidt, Rene Thieme, Dominik Heider, Axel M. Hillmer, Julian Reingruber, Orestis Lyros, Arne DietrichAlbrecht Hoffmeister, Matthias Mehdorn, Florian Lordick, Gertraud Stocker, Michael Hohaus, Daniel Reim, Jennis Kandler, Michaela Müller, Alanna Ebigbo, Claudia Fuchs, Christiane J. Bruns, Arnulf H. Hölscher, Hauke Lang, Peter P. Grimminger, Dani Dakkak, Yogesh Vashist, Sandra May, Siegfried Görg, Andre Franke, David Ellinghaus, Sara Galavotti, Lothar Veits, Josef Weismüller, Jens Dommermuth, Udo Benner, Thomas Rösch, Helmut Messmann, Brigitte Schumacher, Horst Neuhaus, Carsten Schmidt, Thaddäus T. Wissinowski, Markus M. Nöthen, Jing Dong, Jue Sheng Ong, Matthew F. Buas, Aaron P. Thrift, Thomas L. Vaughan, Ian Tomlinson, David C. Whiteman, Rebecca Claire Fitzgerald, Janusz Jankowski, Michael Vieth, Andreas Mayr, Puya Gharahkhani, Stuart MacGregor, Ines Gockel, Claire Palles, Johannes Schumacher^*

^*Korrespondierende/r Autor/-in für diese Arbeit

2 Zitate (Scopus)

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.

Originalsprache	Englisch
Zeitschrift	Gut
Jahrgang	72
Ausgabenummer	4
Seiten (von - bis)	612-623
Seitenumfang	12
ISSN	0017-5749
DOIs	https://doi.org/10.1136/gutjnl-2021-326698
Publikationsstatus	Veröffentlicht - 04.2023

Strategische Forschungsbereiche und Zentren

Querschnittsbereich: Medizinische Genetik
Profilbereich: Lübeck Integrated Oncology Network (LION)
Zentren: Universitäres Cancer Center Schleswig-Holstein (UCCSH)

DFG-Fachsystematik

2.22-14 Hämatologie, Onkologie

UN SDGs

Dieser Output leistet einen Beitrag zu folgendem(n) Ziel(en) für nachhaltige Entwicklung

Dokumente

10.1136/gutjnl-2021-326698

Weitere Links

Link to publication in Scopus

Fingerprint

Untersuchen Sie die Forschungsthemen von „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“. Zusammen bilden sie einen einzigartigen Fingerprint.

Zitieren

Schröder, J., Chegwidden, L., Maj, C., Gehlen, J., Speller, J., Böhmer, A. C., Borisov, O., Hess, T., Kreuser, N., Venerito, M., Alakus, H., May, A., Gerges, C., Schmidt, T., Thieme, R., Heider, D., Hillmer, A. M., Reingruber, J., Lyros, O., ... Schumacher, J. (2023). 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, 72(4), 612-623. https://doi.org/10.1136/gutjnl-2021-326698

@article{72cd0062a6bd43b7bd3ab34b6e18221b,

title = "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",

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.",

author = "Julia Schr{\"o}der and Laura Chegwidden and Carlo Maj and Jan Gehlen and Jan Speller and B{\"o}hmer, {Anne C.} and Oleg Borisov and Timo Hess and Nicole Kreuser and Marino Venerito and Hakan Alakus and Andrea May and Christian Gerges and Thomas Schmidt and Rene Thieme and Dominik Heider and Hillmer, {Axel M.} and Julian Reingruber and Orestis Lyros and Arne Dietrich and Albrecht Hoffmeister and Matthias Mehdorn and Florian Lordick and Gertraud Stocker and Michael Hohaus and Daniel Reim and Jennis Kandler and Michaela M{\"u}ller and Alanna Ebigbo and Claudia Fuchs and Bruns, {Christiane J.} and H{\"o}lscher, {Arnulf H.} and Hauke Lang and Grimminger, {Peter P.} and Dani Dakkak and Yogesh Vashist and Sandra May and Siegfried G{\"o}rg and Andre Franke and David Ellinghaus and Sara Galavotti and Lothar Veits and Josef Weism{\"u}ller and Jens Dommermuth and Udo Benner and Thomas R{\"o}sch and Helmut Messmann and Brigitte Schumacher and Horst Neuhaus and Carsten Schmidt and Wissinowski, {Thadd{\"a}us T.} and N{\"o}then, {Markus M.} and Jing Dong and Ong, {Jue Sheng} and Buas, {Matthew F.} and Thrift, {Aaron P.} and Vaughan, {Thomas L.} and Ian Tomlinson and Whiteman, {David C.} and Fitzgerald, {Rebecca Claire} and Janusz Jankowski and Michael Vieth and Andreas Mayr and Puya Gharahkhani and Stuart MacGregor and Ines Gockel and Claire Palles and Johannes Schumacher",

note = "Publisher Copyright: {\textcopyright} Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.",

year = "2023",

month = apr,

doi = "10.1136/gutjnl-2021-326698",

language = "English",

volume = "72",

pages = "612--623",

journal = "Gut",

issn = "0017-5749",

number = "4",

}

Schröder, J, Chegwidden, L, Maj, C, Gehlen, J, Speller, J, Böhmer, AC, Borisov, O, Hess, T, Kreuser, N, Venerito, M, Alakus, H, May, A, Gerges, C, Schmidt, T, Thieme, R, Heider, D, Hillmer, AM, Reingruber, J, Lyros, O, Dietrich, A, Hoffmeister, A, Mehdorn, M, Lordick, F, Stocker, G, Hohaus, M, Reim, D, Kandler, J, Müller, M, Ebigbo, A, Fuchs, C, Bruns, CJ, Hölscher, AH, Lang, H, Grimminger, PP, Dakkak, D, Vashist, Y, May, S , Görg, S, Franke, A, Ellinghaus, D, Galavotti, S, Veits, L, Weismüller, J, Dommermuth, J, Benner, U, Rösch, T, Messmann, H, Schumacher, B, Neuhaus, H, Schmidt, C, Wissinowski, TT, Nöthen, MM, Dong, J, Ong, JS, Buas, MF, Thrift, AP, Vaughan, TL, Tomlinson, I, Whiteman, DC, Fitzgerald, RC, Jankowski, J, Vieth, M, Mayr, A, Gharahkhani, P, MacGregor, S, Gockel, I, Palles, C & Schumacher, J 2023, '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, Jg. 72, Nr. 4, S. 612-623. https://doi.org/10.1136/gutjnl-2021-326698

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. / Schröder, Julia; Chegwidden, Laura; Maj, Carlo et al.
in: Gut, Jahrgang 72, Nr. 4, 04.2023, S. 612-623.

Publikation: Beiträge in Fachzeitschriften › Zeitschriftenaufsätze › Forschung › Begutachtung

TY - JOUR

T1 - 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

AU - Schröder, Julia

AU - Chegwidden, Laura

AU - Maj, Carlo

AU - Gehlen, Jan

AU - Speller, Jan

AU - Böhmer, Anne C.

AU - Borisov, Oleg

AU - Hess, Timo

AU - Kreuser, Nicole

AU - Venerito, Marino

AU - Alakus, Hakan

AU - May, Andrea

AU - Gerges, Christian

AU - Schmidt, Thomas

AU - Thieme, Rene

AU - Heider, Dominik

AU - Hillmer, Axel M.

AU - Reingruber, Julian

AU - Lyros, Orestis

AU - Dietrich, Arne

AU - Hoffmeister, Albrecht

AU - Mehdorn, Matthias

AU - Lordick, Florian

AU - Stocker, Gertraud

AU - Hohaus, Michael

AU - Reim, Daniel

AU - Kandler, Jennis

AU - Müller, Michaela

AU - Ebigbo, Alanna

AU - Fuchs, Claudia

AU - Bruns, Christiane J.

AU - Hölscher, Arnulf H.

AU - Lang, Hauke

AU - Grimminger, Peter P.

AU - Dakkak, Dani

AU - Vashist, Yogesh

AU - May, Sandra

AU - Görg, Siegfried

AU - Franke, Andre

AU - Ellinghaus, David

AU - Galavotti, Sara

AU - Veits, Lothar

AU - Weismüller, Josef

AU - Dommermuth, Jens

AU - Benner, Udo

AU - Rösch, Thomas

AU - Messmann, Helmut

AU - Schumacher, Brigitte

AU - Neuhaus, Horst

AU - Schmidt, Carsten

AU - Wissinowski, Thaddäus T.

AU - Nöthen, Markus M.

AU - Dong, Jing

AU - Ong, Jue Sheng

AU - Buas, Matthew F.

AU - Thrift, Aaron P.

AU - Vaughan, Thomas L.

AU - Tomlinson, Ian

AU - Whiteman, David C.

AU - Fitzgerald, Rebecca Claire

AU - Jankowski, Janusz

AU - Vieth, Michael

AU - Mayr, Andreas

AU - Gharahkhani, Puya

AU - MacGregor, Stuart

AU - Gockel, Ines

AU - Palles, Claire

AU - Schumacher, Johannes

PY - 2023/4

Y1 - 2023/4

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85135474475&partnerID=8YFLogxK

U2 - 10.1136/gutjnl-2021-326698

DO - 10.1136/gutjnl-2021-326698

M3 - Journal articles

C2 - 35882562

AN - SCOPUS:85135474475

SN - 0017-5749

VL - 72

SP - 612

EP - 623

JO - Gut

JF - Gut

IS - 4

ER -