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BackgroundOver 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.MethodsUsing 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.ResultsAlthough 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).ConclusionsThis study identified novel genetic susceptibility loci for EAC and BE using an eQTL set-based genetic association approach.ImpactThis 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.

Original publication

DOI

10.1158/1055-9965.epi-22-0096

Type

Journal article

Journal

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

Publication Date

09/2022

Volume

31

Pages

1735 - 1745

Addresses

Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington.

Keywords

Humans, Adenocarcinoma, Esophageal Neoplasms, Barrett Esophagus, Genetic Predisposition to Disease, Quantitative Trait Loci