No Genetic Evidence for an Effect of Erythrocyte Zinc on Major Depression: Multivariable MR with GBD-2021 Triangulation
Description
Objectives: To systematically evaluate the causal effect of erythrocyte zinc levels on major depressive disorder (MDD) using multiple Mendelian randomization (MR) approaches. Methods: Two-sample MR was conducted using GWAS data for erythrocyte zinc (QIMR; n=2,603; ieu-a-1079) and MDD (PGC + UK Biobank; n=500,199; ieu-b-102). Four independent SNPs passed quality control and showed strong instrument strength. The primary analysis was inverse-variance weighted (IVW), complemented by MR-Egger, weighted median, MR-PRESSO, and robust adjusted profile score (RAPS). Multivariable MR (MVMR) adjusted for copper and iron. Sensitivity analyses included Steiger directionality and instrument diagnostics. We also performed a post hoc power analysis to evaluate detection thresholds for modest causal effects. To contextualize genetic findings, we conducted a brief ecological triangulation using GBD 2021 (1990–2021; DALY ASR): global trends, 2021 cross-sectional associations with SDI, and cross-correlations (raw vs first-differenced). Results: No significant causal effect of zinc on MDD was observed (IVW OR=0.997, 95% CI 0.959, 1.037, P=0.99), with consistent null findings across all MR methods. No evidence of pleiotropy or outlier variants was detected. MVMR estimates remained non-significant after adjusting for copper and iron (β=0.053, 95% CI –0.037, 0.143, P=0.23). Power analysis indicated >80% ability to detect ORs<0.97 or >1.03, reinforcing the robustness of null findings. Cross-platform validation using an independent zinc GWAS was attempted but infeasible due to non-overlapping SNPs. A brief GBD 2021 check indicated asynchronous population trends and weak, SDI-dependent associations, with no stable lead–lag after detrending. Findings were consistent with Steiger testing and detrended CCF, showing no stable lead–lag structure. Conclusions: Genetic evidence does not support a causal effect of zinc on MDD; estimates were consistently null across MR and MVMR with adequate power. A brief ecological triangulation using GBD 2021 showed asynchronous population trends and weak, SDI-dependent associations, aligning with the genetic null and suggesting that improving zinc status alone is unlikely to reduce depression burden at scale. Observational links may reflect residual confounding, reverse causation, or context-dependent biology. Future work should expand and diversify zinc GWAS, develop tissue- and time-specific instruments, and test nonlinearity, subgroup susceptibility, and gene–environment interactions. Keywords: Erythrocyte zinc；Major depressive disorder；Mendelian randomization；Causal inference；Multivariable MR；Genetic epidemiology；GBD