A transcriptome-wide association study of high-grade serous epithelial ovarian cancer identifies new 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 of gene expression and splice junction usage in HGSOC-relevant tissue types ( N = 2,169) and the largest genome-wide association study available for HGSOC ( N = 13,037 cases and 40,941 controls). We identified 25 transcriptome-wide association study 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 that 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 new genes we identified: HAUS6 , KANSL1 and PRC1 , with the latter comparable to MYC . Our study implicates at least one target gene for 6 out of 13 distinct genome-wide association study regions, identifying 23 new candidate susceptibility genes for HGSOC.