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

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Xiaoyu Wang, Puya Gharahkhani, David M. Levine, Rebecca C. Fitzgerald, Ines Gockel, Douglas A. Corley, Harvey A. Risch, Leslie Bernstein, Wong Ho Chow, Lynn Onstad, Nicholas J. Shaheen, Jesper Lagergren, Laura J. Hardie, Anna H. Wu, Paul D.P. Pharoah, Geoffrey Liu, Lesley A. Anderson, Prasad G. Iyer, Marilie D. Gammon, Carlos Caldas & 50 more Weimin Ye, Hugh Barr, Paul Moayyedi, Rebecca Harrison, R. G.Peter Watson, Stephen Attwood, Laura Chegwidden, Sharon B. Love, David MacDonald, John deCaestecker, Hans Prenen, Katja Ott, Susanne Moebus, Marino Venerito, Hauke Lang, Rupert Mayershofer, Michael Knapp, Lothar Veits, Christian Gerges, Josef Weismüller, Matthias Reeh, Markus M. Nöthen, Jakob R. Izbicki, Hendrik Manner, Horst Neuhaus, Thomas Rösch, Anne C. Böhmer, Arnulf H. Hölscher, Mario Anders, Oliver Pech, Brigitte Schumacher, Claudia Schmidt, Thomas Schmidt, Tania Noder, Dietmar Lorenz, Michael Vieth, Andrea May, Timo Hess, Nicole Kreuser, Jessica Becker, Christian Ell, Ian Tomlinson, Claire Palles, Janusz A. Jankowski, David C. Whiteman, Stuart MacGregor, Johannes Schumacher, Thomas L. Vaughan, Matthew F. Buas, James Y. Dai

Bibliographical note

Funding Information: conduct of the study. N.J. Shaheen reports grants from NIH during the conduct of the study; grants from Lucid, Steris, Medtronic, Pentax, CDx Medical, Interpace Diagnostics, and Phathom, personal fees from Aqua, Cook Medical, Castle, Exact outside the submitted work. P.D. Pharoah reports grants from Cancer Research UK during the conduct of the study. P.G. Iyer reports grants from Exact Sciences, Pentax Medical, Cernostics, other support from Exact Sciences, CDx Medical, Ambu, and Cernostics outside the submitted work. M. Venerito reports personal fees from Nordic Pharma, Merck Serono, Bayer Vital, Lilly, grants and personal fees from Sirtex, Ipsen, BMS, MSD, Eisai, Amgen, and AstraZeneca outside the submitted work. M.M. Nothen reports grants from Deutsche Forschungsgemeinschaft during the conduct of the study; personal fees from Life&Brain GmbH outside the submitted work. H. Manner reports grants from Erbe Elektromedizin, Germany outside the submitted work. D.C. Whiteman reports grants from the National Health and Medical Research Council of Australia during the conduct of the study. S. MacGregor reports grants from the Australian National Health and Medical Research Council during the conduct of the study. T.L. Vaughan reports grants from the Fred Hutch Cancer Center during the conduct of the study. No disclosures were reported by the other authors. Funding Information: J.Y. Dai and X. Wang were supported by the NCI grant R01 CA222833. M.F. Buas was supported by NCI grant R03CA223731. Computation is in part supported by NIH grant S10OD028685 to Fred Hutch Cancer Research Center. A full list of acknowledgments for consortia data used for this study is provided in the Supplementary Data. Publisher Copyright: © 2022 American Association for Cancer Research.

King's Authors

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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