Genotype-driven variations in lncRNA expression underlie predisposition to high-grade serous ovarian cancer

INTRODUCTION: New effective early diagnosis strategies and therapeutic targets are desperately needed for high-grade serous ovarian cancer (HGSOC). Previous functional interpretation of HGSOC genome-wide association studies (GWAS) have largely overlooked the role of long non-coding RNAs (lncRNAs). OBJECTIVES: Our study aims to identify novel causal genes, particularly lncRNAs, that contribute to HGSOC susceptibility and to explore whether their may provide preliminary insights relevant to early detection or therapeutic development. METHODS: We mapped genotype effects on the expression of both protein-coding genes (PCGs) and lncRNAs in 348 HGSOC tumor samples. By performing Bayesian colocalization analysis, we prioritized causal genes in HGSOC tumors and whole blood, respectively. Next, we generated a single-nucleus full-length transcriptome map of HGSOC tumor using snRandom-seq. Furthermore, we conducted in vitro assays to validate the functional role of lncRNA CRHR1-IT1 in HGSOC. RESULTS: Our findings reveal that genetic variants significantly drive expression changes in both PCGs and lncRNAs. Notably, lncRNAs contribute a greater proportion of HGSOC heritability than PCGs. Using Bayesian colocalization analysis, we prioritized 22 high-fidelity causal genes in HGSOC tumors and whole blood, including ARL17A and CRHR1-IT1. Through snRandom-seq, we characterized the single-cell expression patterns of candidate susceptibility PCGs and lncRNAs in HGSOC tumors. Furthermore, we showed that elevated CRHR1-IT1 expression promotes apoptosis and inhibits the growth of HGSOC cells in vitro. CONCLUSION: Our study highlights the significant regulatory role of genetic variants on both protein-coding genes and lncRNAs in HGSOC. While these findings enhance our understanding of HGSOC susceptibility and may inform future efforts toward biomarker discovery or immune-related therapeutic exploration.