Bidirectional and Multivariable Mendelian Randomization Study of PCOS and VTE

Background: We used bidirectional and multivariable Mendelian randomization (MR) to test whether polycystic ovary syndrome (PCOS) is causally related to venous thromboembolism (VTE). Methods: Using European-ancestry GWAS summary statistics, we performed bidirectional two-sample univariable MR and multivariable MR adjusting for diabetes, body mass index (BMI), hormone replacement therapy, and oral contraceptive use. Robustness was assessed with Cochran’s Q, MR-Egger intercept, MR-PRESSO, and leave-one-out analyses. Results: Univariable MR showed no causal effect of PCOS on VTE (IVW OR 1.008, 95% CI 0.974– 1.042; p = 0.653), and reverse-direction MR provided no evidence that VTE causally influences PCOS. In multivariable MR, PCOS remained not associated with VTE (IVW OR 1.016, 95% CI 0.987– 1.045; p = 0.285), whereas BMI had a clear independent positive effect on VTE risk (IVW OR 1.358, 95% CI 1.262– 1.461; p < 0.001). Conclusion: Genetic evidence does not support a causal relationship between PCOS and VTE. BMI is independently associated with VTE risk and appears to be a key determinant of VTE risk. Keywords: polycystic ovary syndrome, venous thromboembolism, mendelian randomization, body mass index, genetic epidemiology, multivariable analysis