The Potential Role of Serum Iron in Depression: Further Exploration of Future Research Directions

Depressive disorder (DD) is a common affective disorder with an unclear specific etiology. Although many previous studies have suggested that iron metabolism is involved in the development of DD, there is a lack of validated genetic evidence regarding whether iron metabolism-related indices (i.e., total iron binding capacity, transferrin saturation, ferritin, and serum iron) are causally related to DD.

This study conducted a bidirectional Mendelian randomization (MR) analysis based on the largest existing genome-wide association study (GWAS) dataset. We used MR to investigate the causal relationship between iron metabolism indicators and DD by controlling for confounding factors and utilizing randomly assigned genetic instrumental variables that are not affected by any causal effects.

Through coordinated analysis of 86 iron metabolism-related SNPs and 16,380,457 DD-related SNPs, 65 SNPs with genome-wide significance that were found to be related to DD iron homeostasis were screened. The IVW analysis results suggest that total iron binding capacity (TIBC) (β = 0.021; 95% Cl = -0.059 to 0.101; p value = 0.610), transferrin saturation (TSAT) (β = -0.038; 95% Cl = -0.146 to 0.070; p value = 0.489), and ferritin (FER) (β = 0.002; 95% Cl = -0.139 to 0.143; p value = 0.982) have no genetic causal relationship with DD, and serum iron (SI) (β = -0.100; 95% Cl = -0.194 to -0.006; p value = 0.040) is considered to have a genetic causal relationship with DD. The Cochran test of MR-IVW suggests that TSAT (p value = 0.125), FER (p value = 0.089), SI (p value = 0.667), and DD have no heterogeneity in the MR analysis results. The MR Egger level multieffect test results show that TIBC (p value = 0.875), TSAT (p value = 0.585), FER (p value = 0.990), and SI (p value = 0.352) all have no level multieffect. In addition, the IVW analysis results of the effect of DD on iron metabolism indicators suggest that there is no causal relationship between DD and TIBC (β = -0.009; 95% Cl = -0.024 to 0.007; p value = 0.218), TSAT (β = -0.008; 95% Cl = -0.024 to 0.008; p value = 0.277), FER (β = -0.002; 95% Cl = -0.016 to 0.012; p value = 0.761), and SI (β = -0.008; 95% Cl = -0.024 to 0.008; p value = 0.263). The results of the sensitivity analysis indicate that no heterogeneity or horizontal pleiotropy was present in the observed results (p > 0.05).

The iron metabolism markers TIBC, TSAT, and FER have no genetic causal relationship with DD, while SI has a genetic causal relationship with DD. Decreased SI levels may increase the risk of DD. In addition, DD has no clear genetic association with the four indicators of iron metabolism.