1. eQTL Set-Based Association Analysis Identifies Novel Susceptibility Loci for Barrett Esophagus and Esophageal Adenocarcinoma.
- Author
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Wang, Xiaoyu, Gharahkhani, P., Levine, D.M., Fitzgerald, R.C., Gockel, I., Corley, D.A., Risch, H.A., Bernstein, L., Chow, W.H., Onstad, L., Shaheen, N.J., Lagergren, J., Hardie, L.J., Wu, A.H., Pharoah, P.D., Liu, G., Anderson, L.A., Iyer, P.G., Gammon, M.D., Caldas, C., Ye, W., Barr, H., Moayyedi, P., Harrison, R., Watson, R.G.P., Attwood, S., Chegwidden, L., Love, S.B., 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, M.M., Izbicki, J.R., Manner, H., Neuhaus, H., Rösch, T., Böhmer, A.C., Hölscher, A.H., 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, J.A., Whiteman, D.C., MacGregor, S., Schumacher, J., Vaughan, T.L., Buas, M.F., Dai, J.Y., Wang, Xiaoyu, Gharahkhani, P., Levine, D.M., Fitzgerald, R.C., Gockel, I., Corley, D.A., Risch, H.A., Bernstein, L., Chow, W.H., Onstad, L., Shaheen, N.J., Lagergren, J., Hardie, L.J., Wu, A.H., Pharoah, P.D., Liu, G., Anderson, L.A., Iyer, P.G., Gammon, M.D., Caldas, C., Ye, W., Barr, H., Moayyedi, P., Harrison, R., Watson, R.G.P., Attwood, S., Chegwidden, L., Love, S.B., 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, M.M., Izbicki, J.R., Manner, H., Neuhaus, H., Rösch, T., Böhmer, A.C., Hölscher, A.H., 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, J.A., Whiteman, D.C., MacGregor, S., Schumacher, J., Vaughan, T.L., Buas, M.F., and Dai, J.Y.
- Abstract
Item does not contain fulltext, 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.
- Published
- 2022