Bidirectional Association between Atrial Fibrillation and Ovarian Cancer: Evidence from the UK Biobank and Mendelian Randomization.

BACKGROUND: Atrial fibrillation (AF) and ovarian cancer are leading causes of morbidity, with emerging evidence suggesting potential interplay. However, their temporal and genetic relationships remain unclear. METHODS: We analyzed 265,248 women from the UK Biobank using bidirectional Cox models to examine associations between AF and ovarian cancer. Two-sample Mendelian randomization (MR) assessed genetically proxied AF liability on ovarian cancer risk, complemented by summary data-based MR and functional genomic analyses to identify shared genes. Loss-of-function assays in SKOV3 ovarian cancer cells evaluated biological plausibility. RESULTS: During a median 17.8-year follow-up, both directions showed significant associations: AF increased ovarian cancer risk [HR, 1.30; 95% confidence interval (CI), 1.05-1.61], and ovarian cancer increased AF risk (HR, 1.75; 95% CI, 1.43-2.14), particularly for serous histotypes. MR analyses indicated a modest genetic association between AF liability and ovarian cancer (OR, 1.05; 95% CI, 1.00-1.11), with directionality confirmed by MR-Steiger tests. Summary data-based MR and integrative analyses identified nucleoporin 50 and synaptotagmin-like 2 as shared susceptibility genes, in which knockdown inhibited the proliferation of ovarian cancer cells. CONCLUSIONS: This study provides complementary observational and genetic evidence linking AF and ovarian cancer. Although bidirectional associations were observed in the UK Biobank cohort, MR analyses supported a genetic contribution of AF liability to ovarian cancer risk but not the reverse. Integrative genomic analyses further nominated nucleoporin 50 and synaptotagmin-like 2 as potential mediators of the AF-ovarian cancer connection. IMPACT: Women with AF may represent a high-risk group for ovarian cancer, highlighting the need for cardio-oncology surveillance and biomarker-guided screening strategies.