A transcriptome-wide association study of high grade serous epithelial ovarian cancer identifies novel susceptibility genes and splice variants

We sought to identify susceptibility genes for high-grade serous ovarian cancer (HGSOC) by performing a transcriptome-wide association study (TWAS) of gene expression and splice junction usage in HGSOC-relevant tissue types (N = 2,169) and the largest GWAS available for HGSOC (N = 13,037 cases/40,941 controls). We identified 25 TWAS significant genes, 7 at the junction level only, including LRRC46 at 19q21.32, (P = 1 × 10(−9)), CHMP4C at 8q21 (P = 2 × 10(−11)), and a PRC1 junction at 15q26 (P = 7 × 10(−9)). In vitro assays for CHMP4C showed the associated variant induces allele specific exon inclusion (P = 0.0024). Functional screens in HGSOC cell lines found evidence of essentiality for three of the novel genes we identified: HAUS6, KANSL1 and PRC1, with the latter comparable to CMYC. Our study implicated at least one target gene for 6/13 distinct GWAS regions, identifying 23 novel candidate susceptibility genes for HGSOC.