Relationship between major depressive disorder and venous thromboembolism: a five-ancestry genetic analysis

Major depressive disorder (MDD) and venous thromboembolism (VTE) frequently co-occur and impose substantial public health burdens. Previous Mendelian randomization (MR) studies examined their causal association but were limited to European (EUR) ancestry. This study utilizes trans-ethnic MR (TEMR) to address this limitation.

MDD data for EUR, African (AFR), Hispanic (HIS), East Asian (EAS), and South Asian (SAS) ancestries were obtained from the Psychiatric Genomics Consortium (PGC). VTE discovery and replication datasets were provided by the Global Biobank Meta-analysis Initiative and Million Veteran Program. Independent genome-wide significant variants (P < 5 × 10^-8) served as instrumental variables. The Nelder-Mead simplex algorithm was the primary optimizer in the TEMR framework, with EUR ancestry as auxiliary population. Validation included BFGS, CG, L-BFGS-B, and SANN. Sensitivity analyses comprised MRLap, the Steiger test, and assessments of heterogeneity and pleiotropy.

Validation confirmed bidirectional causal associations between MDD and VTE in EUR ancestry (OR > 1, P < 0.05). Forward TEMR showed genetically predicted MDD increased VTE risk in AFR ancestry (OR: 1.241, 95% CI: 1.149-1.340, P = 0.019). 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 robustness.

This TEMR study enhanced detection power by identifying increased MDD risk in EUR and AFR ancestries. It established a causal link from VTE to elevated MDD risk across all five ancestries, underscoring ancestry heterogeneity and improving generalizability.