Genome-wide association studies (GWASs) have identified about 30 different susceptibility loci associated with high grade serous ovarian cancer (HGSOC) risk. We hypothesized that risk variants at these loci may impact the expression and splicing of nearby genes in independent cohorts, thus identifying potential susceptibility genes. We compiled gene expression and genotyping data from 2,169 samples for 6 different HGSOC-relevant tissue types. We integrated these data with GWAS data from 13,037 HGSOC cases and 40,941 controls, and performed a transcriptome-wide association study (TWAS) across >70,000 significantly heritable gene/exon features. We identified 32 transcriptome-wide significant associations for 21 unique genes, plus 98 significant exon-level associations in 25 unique genes. We implicated multiple novel genes at risk loci, e.g. LRRC46 at 19q21.32 (TWAS P=1x10-8) and a PRC1 splicing event (TWAS P=1x10-6) which was splice-variant specific and exhibited no eQTL signal. Overall, gene expression and splicing events explained 35% of SNP-heritability for HGSOC (s.e. 11%, P=9x10-4) and implicated a target gene for 8/13 distinct genome-wide significant regions.

Multi-Tissue Transcriptome-Wide Association Studies Identify 21 Novel Candidate Susceptibility Genes for High Grade Serous Epithelial Ovarian Cancer