. 2022 Sep 2;31(9):1735-1745.

doi: 10.1158/1055-9965.EPI-22-0096.

eQTL Set-Based Association Analysis Identifies Novel Susceptibility Loci for Barrett Esophagus and Esophageal Adenocarcinoma

Xiaoyu Wang¹, Puya Gharahkhani², David M Levine³, Rebecca C Fitzgerald⁴, Ines Gockel⁵, Douglas A Corley^{6

7}, Harvey A Risch⁸, Leslie Bernstein⁹, Wong-Ho Chow¹⁰, Lynn Onstad¹, Nicholas J Shaheen¹¹, Jesper Lagergren^{12

13}, Laura J Hardie¹⁴, Anna H Wu¹⁵, Paul D P Pharoah^{16

17}, Geoffrey Liu¹⁸, Lesley A Anderson¹⁹, Prasad G Iyer²⁰, Marilie D Gammon²¹, Carlos Caldas²², Weimin Ye¹², Hugh Barr²³, Paul Moayyedi²⁴, Rebecca Harrison²⁵, R G Peter Watson²⁶, Stephen Attwood²⁷, Laura Chegwidden²⁸, Sharon B Love²⁹, David MacDonald³⁰, John deCaestecker³¹, Hans Prenen³², Katja Ott^{33

34}, Susanne Moebus³⁵, Marino Venerito³⁶, Hauke Lang³⁷, Rupert Mayershofer³⁸, Michael Knapp³⁹, Lothar Veits⁴⁰, Christian Gerges⁴¹, Josef Weismüller⁴², Matthias Reeh⁴³, Markus M Nöthen⁴⁴, Jakob R Izbicki⁴⁵, Hendrik Manner⁴⁶, Horst Neuhaus⁴¹, Thomas Rösch⁴⁷, Anne C Böhmer⁴⁴, Arnulf H Hölscher⁴⁸, Mario Anders^{47

49}, Oliver Pech⁵⁰, Brigitte Schumacher^{41

51}, Claudia Schmidt⁵², Thomas Schmidt³³, Tania Noder⁴⁷, Dietmar Lorenz⁵³, Michael Vieth⁴⁰, Andrea May⁵⁴, Timo Hess⁵⁵, Nicole Kreuser⁵, Jessica Becker⁴⁴, Christian Ell⁵⁶, Ian Tomlinson⁵⁷, Claire Palles⁵⁸, Janusz A Jankowski⁵⁹, David C Whiteman⁶⁰, Stuart MacGregor², Johannes Schumacher⁵⁵, Thomas L Vaughan^{1

61}, Matthew F Buas⁶², James Y Dai^{1

3}

Affiliations

¹ Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington.
² QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
³ Department of Biostatistics, University of Washington, School of Public Health, Seattle, Washington.
⁴ Medical Research Council (MRC) Cancer Unit, Hutchison-MRC Research, Centre, University of Cambridge, Cambridge, UK.
⁵ Department of Visceral, Transplant, Thoracic and Vascular Surgery, University Hospital of Leipzig, Leipzig, Germany.
⁶ Division of Research, Kaiser Permanente Northern California, Oakland, California.
⁷ San Francisco Medical Center, Kaiser Permanente Northern California, San Francisco, California.
⁸ Department of Chronic Disease Epidemiology, Yale School of Public Health, New Haven, Connecticut.
⁹ Department of Population Sciences, Beckman Research Institute and City of Hope Comprehensive Cancer Center, Duarte, California.
¹⁰ Department of Epidemiology, MD Anderson Cancer Center, Houston, Texas.
¹¹ Division of Gastroenterology and Hepatology, University of North Carolina School of Medicine, University of North Carolina, Chapel Hill, North Carolina.
¹² Department of Molecular Medicine and Surgery, Karolinska Institute, Stockholm, Sweden.
¹³ School of Cancer and Pharmaceutical Sciences, King's College London, London, UK.
¹⁴ Division of Epidemiology, University of Leeds, Leeds, UK.
¹⁵ Department of Population and Public Health Sciences, University of Southern California/Norris Comprehensive Cancer Center, Los Angeles, California.
¹⁶ Department of Oncology, University of Cambridge, Cambridge, UK.
¹⁷ Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
¹⁸ Pharmacogenomic Epidemiology, Ontario Cancer Institute, Toronto, Ontario, Canada.
¹⁹ Department of Epidemiology and Public Health, Queen's University of Belfast, Royal Group of Hospitals, Northern Ireland.
²⁰ Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota.
²¹ Department of Epidemiology, University of North Carolina, Chapel Hill, North Carolina.
²² Cancer Research UK, Cambridge Institute, Cambridge, UK.
²³ Department of Upper GI Surgery, Gloucestershire Royal Hospital, Gloucester, UK.
²⁴ Farncombe Family Digestive Health Research Institute, Department of Medicine, McMaster University, Hamilton, Ontario, Canada.
²⁵ Department of Pathology, Leicester Royal Infirmary, Leicester, UK.
²⁶ Department of Medicine, Institute of Clinical Science, Royal Victoria Hospital, Belfast, UK.
²⁷ Department of General Surgery, North Tyneside General Hospital, North Shields, UK.
²⁸ University of Cambridge Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, UK.
²⁹ Centre for Statistics in Medicine and Oxford Clinical Trials Research Unit, Oxford, UK.
³⁰ Department of Oral Biological and Medical Sciences, University of British Columbia, Vancouver, British Columbia, Canada.
³¹ Digestive Diseases Centre, University Hospitals of Leicester, Leicester, UK.
³² Oncology Department, University Hospital Antwerp, Edegem, Belgium.
³³ Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Heidelberg, Germany.
³⁴ Department of General, Visceral and Thorax Surgery, RoMed Klinikum Rosenheim, Rosenheim, Germany.
³⁵ Institute for Urban Public Health, University Hospitals, University of Duisburg-Essen, Essen, Germany.
³⁶ Department of Gastroenterology, Hepatology and Infectious Diseases, Otto-von-Guericke University Hospital, Magdeburg, Germany.
³⁷ Department of General, Visceral and Transplant Surgery, University Medical Center, University of Mainz, Mainz, Germany.
³⁸ Gastroenterologie am Burgweiher, Bonn, Germany.
³⁹ Institute for Medical Biometry, Informatics, and Epidemiology, University of Bonn, Bonn, Germany.
⁴⁰ Institute of Pathology, Friedrich-Alexander-University Erlangen-Nuremberg, Klinikum Bayreuth, Bayreuth, Germany.
⁴¹ Department of Internal Medicine, Evangelisches Krankenhaus, Düsseldorf, Germany.
⁴² Gastroenterologische Gemeinschaftspraxis, Koblenz, Germany.
⁴³ Department of General, Visceral and Thoracic Surgery, Asklepios Harzklinik Goslar, Goslar, Germany.
⁴⁴ Institute of Human Genetics, Medical Faculty, University of Bonn, Bonn, Germany.
⁴⁵ General, Visceral and Thoracic Surgery Department and Clinic, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
⁴⁶ Department of Internal Medicine II, Frankfurt Hoechst Hospital, Frankfurt, Germany.
⁴⁷ Department of Interdisciplinary Endoscopy, University Hospital Hamburg-Eppendorf, Hamburg, Germany.
⁴⁸ Clinic for General, Visceral and Trauma Surgery, Contilia Center for Esophageal Diseases, Elisabeth Hospital Essen, Germany.
⁴⁹ Department of Gastroenterology and Interdisciplinary Endoscopy, Vivantes Wenckebach-Klinikum, Berlin, Germany.
⁵⁰ Department of Gastroenterology and Interventional Endoscopy, St. John of God Hospital, Regensburg, Germany.
⁵¹ Department of Internal Medicine and Gastroenterology, Elisabeth Hospital, Essen, Germany.
⁵² Department of General, Visceral and Cancer Surgery, University of Cologne, Cologne, Germany.
⁵³ Department of General and Visceral Surgery, Sana Klinikum, Offenbach, Germany.
⁵⁴ Department of Gastroenterology, Oncology and Pneumology, Asklepios Paulinen Klinik, Wiesbaden, Germany.
⁵⁵ Center for Human Genetics, University Hospital of Marburg, Marburg, Germany.
⁵⁶ Department of Medicine II, Sana Klinikum, Offenbach, Germany.
⁵⁷ Edinburgh Cancer Research Centre, IGMM, University of Edinburgh, Edinburgh, UK.
⁵⁸ Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, UK.
⁵⁹ Comprehensive Clinical Trials Unit, University College London, London, UK.
⁶⁰ Cancer Control, QIMR Berghofer Medical Research Institute, Brisbane, Australia.
⁶¹ Department of Epidemiology, University of Washington, School of Public Health, Seattle, Washington.
⁶² Department of Cancer Prevention and Control, Roswell Park Comprehensive Cancer Center, Buffalo, New York.

PMID: 35709760
PMCID: PMC9444939
DOI: 10.1158/1055-9965.EPI-22-0096

eQTL Set-Based Association Analysis Identifies Novel Susceptibility Loci for Barrett Esophagus and Esophageal Adenocarcinoma

Xiaoyu Wang et al. Cancer Epidemiol Biomarkers Prev. 2022.

. 2022 Sep 2;31(9):1735-1745.

doi: 10.1158/1055-9965.EPI-22-0096.

Authors

Affiliations

¹ Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington.
² QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
³ Department of Biostatistics, University of Washington, School of Public Health, Seattle, Washington.
⁴ Medical Research Council (MRC) Cancer Unit, Hutchison-MRC Research, Centre, University of Cambridge, Cambridge, UK.
⁵ Department of Visceral, Transplant, Thoracic and Vascular Surgery, University Hospital of Leipzig, Leipzig, Germany.
⁶ Division of Research, Kaiser Permanente Northern California, Oakland, California.
⁷ San Francisco Medical Center, Kaiser Permanente Northern California, San Francisco, California.
⁸ Department of Chronic Disease Epidemiology, Yale School of Public Health, New Haven, Connecticut.
⁹ Department of Population Sciences, Beckman Research Institute and City of Hope Comprehensive Cancer Center, Duarte, California.
¹⁰ Department of Epidemiology, MD Anderson Cancer Center, Houston, Texas.
¹¹ Division of Gastroenterology and Hepatology, University of North Carolina School of Medicine, University of North Carolina, Chapel Hill, North Carolina.
¹² Department of Molecular Medicine and Surgery, Karolinska Institute, Stockholm, Sweden.
¹³ School of Cancer and Pharmaceutical Sciences, King's College London, London, UK.
¹⁴ Division of Epidemiology, University of Leeds, Leeds, UK.
¹⁵ Department of Population and Public Health Sciences, University of Southern California/Norris Comprehensive Cancer Center, Los Angeles, California.
¹⁶ Department of Oncology, University of Cambridge, Cambridge, UK.
¹⁷ Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
¹⁸ Pharmacogenomic Epidemiology, Ontario Cancer Institute, Toronto, Ontario, Canada.
¹⁹ Department of Epidemiology and Public Health, Queen's University of Belfast, Royal Group of Hospitals, Northern Ireland.
²⁰ Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota.
²¹ Department of Epidemiology, University of North Carolina, Chapel Hill, North Carolina.
²² Cancer Research UK, Cambridge Institute, Cambridge, UK.
²³ Department of Upper GI Surgery, Gloucestershire Royal Hospital, Gloucester, UK.
²⁴ Farncombe Family Digestive Health Research Institute, Department of Medicine, McMaster University, Hamilton, Ontario, Canada.
²⁵ Department of Pathology, Leicester Royal Infirmary, Leicester, UK.
²⁶ Department of Medicine, Institute of Clinical Science, Royal Victoria Hospital, Belfast, UK.
²⁷ Department of General Surgery, North Tyneside General Hospital, North Shields, UK.
²⁸ University of Cambridge Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, UK.
²⁹ Centre for Statistics in Medicine and Oxford Clinical Trials Research Unit, Oxford, UK.
³⁰ Department of Oral Biological and Medical Sciences, University of British Columbia, Vancouver, British Columbia, Canada.
³¹ Digestive Diseases Centre, University Hospitals of Leicester, Leicester, UK.
³² Oncology Department, University Hospital Antwerp, Edegem, Belgium.
³³ Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Heidelberg, Germany.
³⁴ Department of General, Visceral and Thorax Surgery, RoMed Klinikum Rosenheim, Rosenheim, Germany.
³⁵ Institute for Urban Public Health, University Hospitals, University of Duisburg-Essen, Essen, Germany.
³⁶ Department of Gastroenterology, Hepatology and Infectious Diseases, Otto-von-Guericke University Hospital, Magdeburg, Germany.
³⁷ Department of General, Visceral and Transplant Surgery, University Medical Center, University of Mainz, Mainz, Germany.
³⁸ Gastroenterologie am Burgweiher, Bonn, Germany.
³⁹ Institute for Medical Biometry, Informatics, and Epidemiology, University of Bonn, Bonn, Germany.
⁴⁰ Institute of Pathology, Friedrich-Alexander-University Erlangen-Nuremberg, Klinikum Bayreuth, Bayreuth, Germany.
⁴¹ Department of Internal Medicine, Evangelisches Krankenhaus, Düsseldorf, Germany.
⁴² Gastroenterologische Gemeinschaftspraxis, Koblenz, Germany.
⁴³ Department of General, Visceral and Thoracic Surgery, Asklepios Harzklinik Goslar, Goslar, Germany.
⁴⁴ Institute of Human Genetics, Medical Faculty, University of Bonn, Bonn, Germany.
⁴⁵ General, Visceral and Thoracic Surgery Department and Clinic, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
⁴⁶ Department of Internal Medicine II, Frankfurt Hoechst Hospital, Frankfurt, Germany.
⁴⁷ Department of Interdisciplinary Endoscopy, University Hospital Hamburg-Eppendorf, Hamburg, Germany.
⁴⁸ Clinic for General, Visceral and Trauma Surgery, Contilia Center for Esophageal Diseases, Elisabeth Hospital Essen, Germany.
⁴⁹ Department of Gastroenterology and Interdisciplinary Endoscopy, Vivantes Wenckebach-Klinikum, Berlin, Germany.
⁵⁰ Department of Gastroenterology and Interventional Endoscopy, St. John of God Hospital, Regensburg, Germany.
⁵¹ Department of Internal Medicine and Gastroenterology, Elisabeth Hospital, Essen, Germany.
⁵² Department of General, Visceral and Cancer Surgery, University of Cologne, Cologne, Germany.
⁵³ Department of General and Visceral Surgery, Sana Klinikum, Offenbach, Germany.
⁵⁴ Department of Gastroenterology, Oncology and Pneumology, Asklepios Paulinen Klinik, Wiesbaden, Germany.
⁵⁵ Center for Human Genetics, University Hospital of Marburg, Marburg, Germany.
⁵⁶ Department of Medicine II, Sana Klinikum, Offenbach, Germany.
⁵⁷ Edinburgh Cancer Research Centre, IGMM, University of Edinburgh, Edinburgh, UK.
⁵⁸ Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, UK.
⁵⁹ Comprehensive Clinical Trials Unit, University College London, London, UK.
⁶⁰ Cancer Control, QIMR Berghofer Medical Research Institute, Brisbane, Australia.
⁶¹ Department of Epidemiology, University of Washington, School of Public Health, Seattle, Washington.
⁶² Department of Cancer Prevention and Control, Roswell Park Comprehensive Cancer Center, Buffalo, New York.

PMID: 35709760
PMCID: PMC9444939
DOI: 10.1158/1055-9965.EPI-22-0096

Abstract

Background: Over 20 susceptibility single-nucleotide polymorphisms (SNP) have been identified for esophageal adenocarcinoma (EAC) and its precursor, Barrett esophagus (BE), explaining a small portion of heritability.

Methods: Using genetic data from 4,323 BE and 4,116 EAC patients aggregated by international consortia including the Barrett's and Esophageal Adenocarcinoma Consortium (BEACON), we conducted a comprehensive transcriptome-wide association study (TWAS) for BE/EAC, leveraging Genotype Tissue Expression (GTEx) gene-expression data from six tissue types of plausible relevance to EAC etiology: mucosa and muscularis from the esophagus, gastroesophageal (GE) junction, stomach, whole blood, and visceral adipose. Two analytical approaches were taken: standard TWAS using the predicted gene expression from local expression quantitative trait loci (eQTL), and set-based SKAT association using selected eQTLs that predict the gene expression.

Results: Although the standard approach did not identify significant signals, the eQTL set-based approach identified eight novel associations, three of which were validated in independent external data (eQTL SNP sets for EXOC3, ZNF641, and HSP90AA1).

Conclusions: This study identified novel genetic susceptibility loci for EAC and BE using an eQTL set-based genetic association approach.

Impact: This study expanded the pool of genetic susceptibility loci for EAC and BE, suggesting the potential of the eQTL set-based genetic association approach as an alternative method for TWAS analysis.

PubMed Disclaimer

Conflict of interest statement

Disclosure of Interest: The authors report no conflict of interest.

Figures

**Figure 1.**
Predictive eQTL models for gene expression across 6 tissues in GTEx. (a) Violin plots for R² estimates for genes with R²≥0.01. (b) Venn diagram of genes with R²≥0.01 in three esophageal tissues in GTEx.

**Figure 2.**
Manhattan plots for p-values derived from two methods: eQTL set-based association by SKAT (top); standard TWAS using predicted gene expression (bottom). (a) BE versus control. (b) EA versus control. (c) BE/EA vs control. The line for FDR=0.05 is based on all three trait associations.

**Figure 3.**
Regional plots for novel loci that were discovered in Beacon/Cambridge discovery set and validated in Bonn data. (a) eQTLs of *EXOC3* in discovery. (b) eQTLs of *EXOC3* in validation. (c) eQTLs of *ZNF641* in discovery. (d) eQTLs of *ZNF641* in validation. (e) eQTLs of *HSP90AA1* in discovery. (f) eQTLs of *HSP90AA1* in validation.

See this image and copyright information in PMC

References

1. Thrift AP, Whiteman DC. The incidence of esophageal adenocarcinoma continues to rise: analysis of period and birth cohort effects on recent trends. Ann Oncol 2012;23(12):3155–62 doi 10.1093/annonc/mds181. - DOI - PubMed
1. Holmes RS, Vaughan TL. Epidemiology and pathogenesis of esophageal cancer. Semin Radiat Oncol 2007;17(1):2–9 doi 10.1016/j.semradonc.2006.09.003. - DOI - PubMed
1. Steevens J, Botterweck AA, Dirx MJ, van den Brandt PA, Schouten LJ. Trends in incidence of oesophageal and stomach cancer subtypes in Europe. Eur J Gastroenterol Hepatol 2010;22(6):669–78 doi 10.1097/MEG.0b013e32832ca091. - DOI - PubMed
1. Coleman HG, Xie SH, Lagergren J. The Epidemiology of Esophageal Adenocarcinoma. Gastroenterology 2018;154(2):390–405 doi 10.1053/j.gastro.2017.07.046. - DOI - PubMed
1. Njei B, McCarty TR, Birk JW. Trends in esophageal cancer survival in United States adults from 1973 to 2009: A SEER database analysis. J Gastroenterol Hepatol 2016;31(6):1141–6 doi 10.1111/jgh.13289. - DOI - PMC - PubMed

Publication types

Actions

MeSH terms

Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions

Save citation to file

Email citation

Add to Collections

Add to My Bibliography

Your saved search

Create a file for external citation management software

Your RSS Feed

eQTL Set-Based Association Analysis Identifies Novel Susceptibility Loci for Barrett Esophagus and Esophageal Adenocarcinoma

Affiliations

eQTL Set-Based Association Analysis Identifies Novel Susceptibility Loci for Barrett Esophagus and Esophageal Adenocarcinoma

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

References

Publication types

MeSH terms

Supplementary concepts

Grants and funding

LinkOut - more resources

Full Text Sources

Medical

Miscellaneous