A two-sample bidirectional Mendelian randomized study on the causal relationship between iron status and post-traumatic stress disorder

Chen Xiaohua; Yang Hui; Xing Bai

doi:10.3969/j.issn.1002-1949.2025.03.001

Abstract：Objective To explore the causal relationship between iron status and the risk of post-traumatic stress disorder(PTSD)based on a Mendelian randomization(MR)study.Methods Two-sample bidirectional MR analysis was performed by using publicly available genome-wide association study(GWAS)summary data.Summary data for four iron status-related indicators,including serum iron,ferritin,total iron-binding capacity(TIBC)and transferrin saturation(TSAT),were obtained from the UK Biobank,and summary data for PTSD were obtained from the FinnGen database.MR analysis were conducted by using inverse variance weighted(IVW)as the primary method,and two regression models including MR-Egger and weighted median as supplementary methods to assess the causal relationship between exposure factors and outcome variables.Additionally,the MR-Egger intercept test and MR-pleiotropy residual sum and outliers(MR-PRESSO)test were employed to assess the horizontal pleiotropy and outlier single nucleotide polymorphism(SNP),Cochran's Q test in MR-Egger and IVW methods was performed to evaluate the heterogeneity among the SNPs,and sensitivity analysis was performed by using the"leave-one-out"method.Finally,reverse MR analysis was used to verify the robustness of the results.Results The results of IVW method showed that elevated serum ferritin(OR=0.741,95％CI 0.586-0.937,P＜0.001)were causally associated with reduced risk of PTSD.However,there was no potential genetic causal relationship of serum iron,TIBC and TSAT with PTSD(P＞0.05).In the reverse MR analyses,none of the three methods supported a reverse causal relationship.The screened SNPs did not have horizontal pleiotropy or heterogeneity because the MR-Egger regression model intercept term test,MR-PRESSO Global test and Cochran's Q test were not statistically significant(P＞0.05).Sensitivity analysis based on the"leave-one-out"method showed that a single SNP did not affect the robustness of the causal association effect values.Conclusions The serum ferritin level predicted genetically is causally associated with the risk of PTSD,indicating that high levels of serum ferritin may be a protective factor for PTSD,which may provide new ideas for the genetic research and clinical intervention of PTSD.