Evidence for genetic causality between iron metabolism and depression: a two-sample Mendelian randomization study

Abstract

Abstract BACKGROUND AND PURPOSE: Depressive disorder (DD) is a is a common clinical affective disorder whose specific etiology is still unclear. Although many previous studies have suggested that iron metabolism is involved in the development of DD, there is a lack of validated genetic evidence on whether iron metabolism-related indices (total iron binding capacity, transferrin saturation, ferritin, and serum iron) are causally related to DD. METHODS: This study was based on the largest genome-wide association study (GWAS) data to date. Mendelian randomization (MR) analysis was used to investigate the causal relationship between iron metabolism indices and DD, controlling for confounders and using genetic instrumental variables that were randomly assigned and not subject to any causal effects. RESULTS: By coordinated analysis of 86 iron metabolism marker-associated SNPs and 16,380,457 DD-associated SNPs, 65 iron homeostasis and DD-associated SNPs with genome-wide significance were finally screened out.The results of the IVW analyses suggested that total iron binding capacity (TIBC) ( β = 0.021; β = -0.059 to 0.101; P-value = 0.6104069), transferrin saturation (TSAT) ( 95%Cl = -0.059 to 0.101; P-value = 0.6104069), Transferrin saturation (TSAT) ( β = -0.038; 95%Cl = -0,146 to 0.070; P-value = 0.4886324), Ferritin (FER) ( β =0.002 ; 95%Cl = -0.139 to 0.143; P value = 0.9818161 ) had no genetic causality with DD. Serum iron (SI) ( β =-0.100; 95%Cl = -0.194 to -0.006; P-value = 0.03996619) was found to be genetically causally associated with DD.Mr-ivw's Cochran's Q test suggested that TSAT ( P-value = 0.1250508), FER ( P-value = 0.08852702), and SI ( P-value= 0.6674221) were not heterogeneous with the results of Mr-analysis of DD, and the MR-PRESSO global test showed that the presence of horizontal pleiotropy was not detected for TIBC ( P-value= 0.404), TSAT ( P-value= 0.192), and SI ( P-value= 0.628). CONCLUSIONS: The iron metabolism markers TIBC, TSAT and FER are not genetically causally associated with DD, whereas SI is genetically causally associated with DD, and higher levels of SI may reduce the risk of DD.