Multiancestry Transcriptome-Wide Association Study Identifies Candidate Genes Associated with Hepatoblastoma

Abstract Background: Hepatoblastoma (HB) is a rare embryonal liver tumor, with an increasing global incidence that underscores the need to understand its genetic etiology. Methods: Utilizing the ancestry-matched expression quantitative loci data, we performed a HB transcriptome-wide association study (TWAS) on 4,539 Europeans, 1,047 Latinos, and 378 African Americans (∼1:10 case–control ratio). We conducted a meta-analysis of multiancestry transcriptome-wide analysis (METRO), followed by METRO-Egger sensitivity analysis and ancestry-specific gene set enrichment analyses. We further explored genes with additional evidence gathered from independent cohorts and databases. Results: Across the three ancestries, the discovered genes shared the same effect direction across ancestries. A meta-analysis of the three ancestries identified 28 genes significantly associated with HB risk, and 15 were nominally significant for at least two ancestries. Our post-TWAS analyses highlighted 8 genes among these 28, including OXER1 (meta-analysis P value = 7.34 × 10−6), FADS1 (P value = 4.01 × 10−6), and UGDH (P value = 5.29 × 10−8), which were expressed in fetal liver hepatoblast cells and were differentially expressed in tumor and normal tissues in an independent Japanese HB study (P values = 2.61 × 10−13, 3.62 × 10−3, and 1.95 × 10−9, respectively). Conclusions: We pinpointed eight potential genes associated with HB using data from an ongoing multiancestry genome-wide association study. Impact: We conducted the largest HB TWAS to date, prompting further exploration of genes.