Inherited genetics represents an important contributor to risk of esophageal adenocarcinoma (EAC), and its precursor Barrett's esophagus (BE). Genome-wide association studies have identified ~30 susceptibility variants for BE/EAC, yet genetic interactions remain unexamined. To address challenges in large-scale G×G scans, we combined knowledge-guided filtering and machine learning approaches, focusing on genes with (1) known/plausible links to BE/EAC pathogenesis (n = 493) or (2) prior evidence of biological interactions (n = 4,196). Approximately 75 × 106 SNP×SNP interactions were screened via hierarchical group lasso (glinternet) using BEACON GWAS data. The top ~2,000 interactions retained in each scan were prioritized using p values from single logistic models. Identical scans were repeated among males only (78%), with two independent GWAS datasets used for replication. In overall and male-specific primary replications, 11 of 187 and 20 of 191 interactions satisfied p < 0.05, respect...
| Authors | Yan, L; He, Q; Verma, SP; Zhang, X; Giel, AS; Maj, C; Graz, K; Naderi, E; Chen, J; Ali, MW; Gharahkhani, P; Shu, X; Offit, K; Shah, PM; Gerdes, H; Molena, D; Srivastava, A; MacGregor, S; BEACON Consortium; OCCAMS Consortium; Esophageal Cancer Consortium; Palles, C; Thieme, R; Vieth, M; Gockel, I; Vaughan, TL; Schumacher, J; Buas, MF |
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| Journal | HGG advances |
| Pages | 100399 |
| Volume | 6 |
| Date | 3/02/2025 |
| Grant ID | R01 CA266386 | NCI NIH HHS [CA] (United States); R01 DK128615 | NIDDK NIH HHS [DK] (United States); R03 CA223731 | NCI NIH HHS [CA] (United States) |
| Funding Body | |
| URL | http://www.ncbi.nlm.nih.gov/pubmed/?term=10.1016/j.xhgg.2025.100399 |