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

Wang X, Gharahkhani P, Levine DM, Fitzgerald RC, Gockel I, Corley DA, Risch HA, Bernstein L, Chow WH, Onstad L, Shaheen NJ, Lagergren J, Hardie LJ, Wu AH, Pharoah PD, Liu G, Anderson LA, Iyer PG, Gammon MD, Caldas C, Ye W, Barr H, Moayyedi P, Harrison R, Watson RG, Attwood S, Chegwidden L, Love SB, MacDonald D, deCaestecker J, Prenen H, Ott K, Moebus S, Venerito M, Lang H, Mayershofer R, Knapp M, Veits L, Gerges C, Weismüller J, Reeh M, Nöthen MM, Izbicki JR, Manner H, Neuhaus H, Rösch T, Böhmer AC, Hölscher AH, Anders M, Pech O, Schumacher B, Schmidt C, Schmidt T, Noder T, Lorenz D, Vieth M, May A, Hess T, Kreuser N, Becker J, Ell C, Tomlinson I, Palles C, Jankowski JA, Whiteman DC, MacGregor S, Schumacher J, Vaughan TL, Buas MF, Dai JY (2022)

Publication Type: Journal article

Publication year: 2022

Journal

Book Volume: 31

Pages Range: 1735-1745

Journal Issue: 9

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.

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Additional Organisation(s)

Involved external institutions

QIMR Berghofer Medical Research Institute (früher: the Queensland Institute of Medical Research) Australia (AU) University of Washington United States (USA) (US) Ruprecht-Karls-Universität Heidelberg Germany (DE) Rheinische Friedrich-Wilhelms-Universität Bonn Germany (DE) Elisabeth-Krankenhaus Essen Germany (DE) Universitätsklinikum Hamburg-Eppendorf (UKE) Germany (DE) Krankenhaus Barmherzige Brüder Germany (DE) Evangelisches Krankenhaus Düsseldorf Germany (DE) Universität zu Köln Germany (DE) University College London (UCL) United Kingdom (GB) Universitätsklinikum Gießen und Marburg (UKGM) Germany (DE) Roswell Park Cancer Institute United States (USA) (US) Fred Hutchinson Cancer Research Center United States (USA) (US) Karolinska Institute Sweden (SE) University of Cambridge United Kingdom (GB) Sana Kliniken AG Germany (DE) Leicester Royal Infirmary United Kingdom (GB) Universitätsklinikum Leipzig Germany (DE) Queen's University United Kingdom (GB) University of North Carolina at Chapel Hill United States (USA) (US) University of Edinburgh United Kingdom (GB) City of Hope Medical Center United States (USA) (US) Gloucestershire Hospitals United Kingdom (GB) Royal Victoria Hospital United Kingdom (GB) University Hospitals of Leicester NHS Trust United Kingdom (GB) Hospital Network Antwerp / Ziekenhuis Netwerk Antwerpen (ZNA) Belgium (BE) Universitätsklinikum Essen Germany (DE) University of Leeds United Kingdom (GB) Sanofi-Aventis Groupe France (FR) Yale University United States (USA) (US) University of Birmingham United Kingdom (GB) University of British Columbia Canada (CA) Otto-von-Guericke-Universität Magdeburg Germany (DE) Keck School of Medicine of USC United States (USA) (US) Kaiser Permanente United States (USA) (US) Asklepios Klinik Wiesbaden Germany (DE) University of Toronto Canada (CA) Mayo Clinic United States (USA) (US) McMaster University Canada (CA) North Tyneside General Hospital United Kingdom (GB) University of Texas MD Anderson Cancer Center United States (USA) (US) University of Oxford United Kingdom (GB) Universitätsmedizin der Johannes Gutenberg-Universität Mainz Germany (DE)

How to cite

APA:

Wang, X., Gharahkhani, P., Levine, D.M., Fitzgerald, R.C., Gockel, I., Corley, D.A.,... Dai, J.Y. (2022). eQTL Set-Based Association Analysis Identifies Novel Susceptibility Loci for Barrett Esophagus and Esophageal Adenocarcinoma. Cancer Epidemiology Biomarkers & Prevention, 31(9), 1735-1745. https://doi.org/10.1158/1055-9965.EPI-22-0096

MLA:

Wang, Xiaoyu, et al. "eQTL Set-Based Association Analysis Identifies Novel Susceptibility Loci for Barrett Esophagus and Esophageal Adenocarcinoma." Cancer Epidemiology Biomarkers & Prevention 31.9 (2022): 1735-1745.

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