铁状态与创伤后应激障碍因果关联的两样本双向孟德尔随机化研究  

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

作　　者：陈小花 杨慧 邢柏 Chen Xiaohua;Yang Hui;Xing Bai(Department of Emergency,the Second Affiliated Hospital of Hainan Medical University,Haikou 570311,China)

机构地区：[1]海南医科大学第二附属医院急诊科,海南海口570311

出　　处：《中国急救医学》2025年第3期185-191,共7页Chinese Journal of Critical Care Medicine

摘　　要：目的采用孟德尔随机化(Mendelian randomization,MR)方法探究铁状态与创伤后应激障碍(post-traumatic stress disorder,PTSD)风险的因果关联。方法使用公开的全基因组关联研究(genome-wide association study,GWAS)汇总数据进行两样本双向MR分析。血清铁、铁蛋白、总铁结合能力(total iron-binding capacity,TIBC)和转铁蛋白饱和度(transferrin saturation,TSAT)等四项铁状态相关指标的汇总数据来自英国生物银行,PTSD的汇总数据来自芬兰数据库。采用逆方差加权(inverse variance weighted,IVW)作为MR分析的主要方法,同时采用MR-Egger和加权中位数两种回归模型作为补充方法,以评估暴露因素与结局变量之间的因果关系。此外,采用MR-Egger截距项检验和MR-多效性残差和异常值(MR-PRESSO)检验评估水平多效性及离群的单核苷酸多态性(single nucleotide polymorphism,SNP),应用MR-Egger和IVW方法中的Cochran′s Q检验评估SNPs的异质性,并采用留一法进行敏感性分析。最后,采用反向MR分析验证结果的稳健性。结果IVW法分析结果显示,血清铁蛋白(OR=0.741,95%CI 0.586~0.937,P<0.001)水平升高与PTSD风险降低之间存在因果关联。然而,血清铁、TIBC和TSAT与PTSD之间没有潜在的遗传因果关系(P>0.05)。在反向MR分析中,三种方法均不支持反向因果关系。MR-Egger回归模型截距项检验、MR-PRESSO检验和Cochran′s Q检验的P值均>0.05,即筛选出的SNPs不存在水平多效性和异质性。此外,基于留一法的敏感度分析显示,单一SNP并不影响因果关联效应值的稳健性。结论遗传学预测的血清铁蛋白水平与PTSD风险之间存在因果关系,即高水平的血清铁蛋白可能是PTSD的保护因素,这可能为PTSD的基因研究和临床干预提供了新思路。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

关 键 词：铁 铁蛋白 创伤后应激障碍 孟德尔随机化 因果推断 

分 类 号：R749.5[医药卫生—神经病学与精神病学]