Relationship between Major Depressive Disorder and Venous Thromboembolism: A Five-Ancestry Genetic Analysis

Objectives: Major depressive disorder (MDD) and venous thromboembolism (VTE) frequently co-occur and pose substantial public health burdens. Previous Mendelian randomization (MR) studies have explored the causal association between MDD and VTE but were limited to European (EUR) ancestry. This study employs Trans-ethnic MR (TEMR) to address this limitation.Methods: MDD data for EUR, African (AFR), Hispanic (HIS), East Asian (EAS), and South Asian (SAS) ancestries were obtained from the Psychiatric Genomics Consortium (PGC). The Global Biobank Meta-analysis Initiative and Million Veteran Program provided discovery and replication datasets for VTE. Independent genome-wide significant variants (P < 5 × 10⁻⁸) served as instrumental variables, were validated using the Nelder-Mead simplex algorithm as the primary optimizer in the TEMR framework, with EUR ancestry as the auxiliary population. Validation included Broyden–Fletcher–Goldfarb–Shanno (BFGS), Conjugate Gradient (CG), Limited-memory BFGS with Box Constraints (L-BFGS-B), and Simulated Annealing (SANN). Sensitivity analyses comprised MRLap, the Steiger test, and assessments of heterogeneity and pleiotropy.Results: Validation analyses confirmed a bidirectional causal association between MDD and VTE risk in EUR ancestry (OR > 1, P < 0.05). Forward TEMR analysis showed genetically predicted MDD in AFR ancestry increased VTE risk (OR: 1.241, 95% CI: 1.149-1.340, P = 0.019), while reverse analysis indicated genetically predicted VTE increased MDD risk in EAS (OR: 1.014, 95% CI: 1.013-1.015, P = 8.74×10-16), SAS (OR: 1.078, 95% CI: 1.044-1.113, P = 0.028), AFR (OR: 1.076, 95% CI: 1.074-1.078, P = 2.51×10-109), and HIS (OR: 1.123, 95% CI: 1.111-1.134, P = 8.41×10-6) ancestries. Sensitivity and validation analyses supported the robustness of these findings.Conclusion: This TEMR study enhanced detection power, identifying increased MDD risk in EUR and AFR ancestries. It also established a causal link between VTE and elevated MDD risk across all five ancestries, underscoring ancestry heterogeneity and enhancing generalizability.