Skip to main content

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

Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology

Authors: 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, 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

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.

©2022 American Association for Cancer Research.

PMID: 35709760

Participating cluster members