19种凝血因子表型与神经退行性疾病关联的双向孟德尔随机化研究及表达数量性状位点共定位分析OA

Objective To explore the potential causal relationships between 19 coagulation factor phenotypes and 3 common neurodegenerative diseases(NDDs)using a bidirectional two-sample Mendelian randomization(MR)approach.Methods Genome-wide association study(GWAS)data for 19 plasma coagulation factor phenotypes were obtained from the GWAS Catalog database,and genetic data for Alzheimer's disease(AD),Parkinson's disease(PD),and amyotrophic lateral sclerosis(ALS)were retrieved from the IEU Open GWAS database.The inverse-variance weighted(IVW)method was used for causal inference,and Cochran's Q test was employed to assess the heterogeneity of single nucleotide polymorphisms(SNPs).To exclude the interference of horizontal pleiotropy,the MR-Egger intercept test was conducted,together with leave-one-out sensitivity analysis and reverse MR validation,to systematically evaluate SNP-specific effects and the stability of the causal direction.Colocalization analysis was subsequently performed to examine the positive SNPs identified in the MR results.Results Plasma coagulation factor ⅩⅢ(F Ⅹ Ⅲ)level(OR=0.951,95%CI 0.925-0.978,P=0.0004),factor Ⅺ(F Ⅺ)level(OR=0.972,95%CI 0.950-0.994,P=0.016),and factor Ⅶ(FⅦ)level(OR=1.024,95%CI 1.001-1.048,P=0.035)were associated with AD.Plasma coagulation factor Ⅴ(FⅤ)level(OR=1.188,95%CI 1.013-1.393,P=0.033)was associated with PD.Plasma vitamin K-dependent protein C level(OR=1.108,95%CI 1.104-1.178,P=0.00084),and activated protein C level(OR=1.149,95%CI 1.034-1.276,P=0.009)were associated with ALS.No horizontal pleiotropy or heterogeneity was detected in any of the above positive results.Colocalization analysis provided moderate evidence for two SNPs(rs11904888,rs8119351),supporting their role as shared genetic factors for the corresponding coagulation factors and NDDs.Reverse MR analysis showed no significant reverse effects of the three NDDs on the respective coagulation factors.Conclusions Higher FⅩⅢ and FⅪ are protective factors for AD,while higher FⅦ is a risk factor for AD;higher FⅤ is a risk factor for PD;higher plasma vitamin K-dependent protein C and activated protein C are risk factors for ALS.