银屑病与阿尔茨海默病:一项两样本双向孟德尔随机化研究

Psoriasis and Alzheimer disease:a two-sample two-way Mendelian randomization study

目的采用两样本双向孟德尔随机化(Mendelian randomization,MR)方法分析银屑病与阿尔茨海默病(Alzheimer disease,AD)之间是否存在因果关联。方法正向研究从全基因组关联研究数据库综合统计数据中获取与银屑病相关的单核苷酸多态性(single nucleotide polymorphism,SNP)作为工具变量,AD作为结局;反向研究则获取与AD相关的SNP作为工具变量,银屑病作为结局。使用两样本双向MR分析,通过逆方差加权法(inverse variance weighted,IVW)、MR-Egger回归法、加权中位数、简单模式和加权模式等回归模型的比值比(odds ratio,OR)和95%置信区间(confidence interval,CI)评估银屑病与AD的因果关系。使用Cochran Q检验评估遗传工具变量异质性,使用MR-Egger截距法检验评估水平多效性,使用“留一法”评估单个SNP对因果关系影响的敏感性,观察漏斗图是否对称评估是否存在偏倚。结果正向研究共纳入19个与银屑病相关的SNP作为工具变量。正向研究的IVW分析结果表明银屑病与AD存在因果关联[OR=1.032,95%CI(1.014,1.051),P<0.001],且MR-Egger回归法[OR=1.042,95%CI(1.012,1.073),P=0.013]、加权中位数[OR=1.048,95%CI(1.023,1.074),P<0.001]、加权模式[OR=1.046,95%CI(1.020,1.073),P=0.002]均支持该结果;异质性检验(IVW结果:Q=13.752,P=0.745;MR-Egger回归法结果:Q=13.134,P=0.727)、MR-Egger截距法(Egger截距=–0.004,P=0.442)、“留一法”分析结果、漏斗图结果均显示MR分析结果可靠。反向研究共纳入127个与AD相关的SNP作为工具变量。反向研究中没有证据支持AD会增加银屑病的发病风险(P>0.05);异质性检验提示存在异质性(IVW结果:Q=232.496,P<0.001;MR-Egger回归法结果:Q=232.119,P<0.001),MR-Egger截距法(Egger截距=0.003,P=0.652)、“留一法”分析结果和漏斗图结果均显示MR分析结果可靠。结论银屑病与AD存在因果关联,银屑病可能会增加AD的发病风险。

Objective To analyze whether there is a causal association between psoriasis and Alzheimer disease(AD)by a two-sample two-way Mendelian randomization(MR)method.Methods In the forward study,the single nucleotide polymorphisms(SNPs)associated with psoriasis were obtained from the comprehensive statistical data of the genome-wide association study database as the instrumental variables,and AD as the outcome;in the reverse study,the SNPs associated with AD were taken as instrumental variables,and psoriasis as the outcome.Using two-sample two-way MR analysis,the odds ratio(OR)value and 95%confidence interval(CI)of regression models,namely inverse variance weighted(IVW)method,MR-Egger regression method,weighted median method,simple pattern method,and weighted pattern method,were used to evaluate the causal relationship between psoriasis and AD.Cochran’s Q test was used to assess the heterogeneity of genetic instrumental variables,MR-Egger intercept method was used to test the horizontal pleiotropy of the assessment,“leave-one-out”method was used to assess the sensitivity of a SNP to the effect of causality,and the symmetry of funnel plot was observed to assess bias.Results A total of 19 SNPs associated with psoriasis were included as instrumental variables in the forward study.The IVW analysis of the forward study showed that there was a causal correlation between psoriasis and AD[OR=1.032,95%CI(1.014,1.051),P<0.001],and MR-Egger regression method[OR=1.042,95%CI(1.012,1.073),P=0.013],weighted median[OR=1.048,95%CI(1.023,1.074),P<0.001],and weighted model[OR=1.046,95%CI(1.020,1.073),P=0.002]all supported this result.Heterogeneity test(IVW result:Q=13.752,P=0.745;MR-Egger regression result:Q=13.134,P=0.727),MR-Egger intercept method(Egger intercept=–0.004,P=0.442),the results of“leave-one-out”method and funnel plot showed that the results of MR analysis were reliable.A total of 127 AD-related SNPs were included as instrumental variables in the reverse study.In reverse research,there was no evidence to support the AD could increase the risk of psoriasis(P>0.05).Heterogeneity test(IVW result:Q=232.496,P<0.001;MR-Egger regression result:Q=232.119,P<0.001)suggested heterogeneity,but MR-Egger intercept method(Egger intercept=0.003,P=0.652),the results of“leave-one-out”method and funnel plot showed that the results of MR analysis were reliable.Conclusion There is a causal association between psoriasis and AD,and psoriasis may increase the risk of AD.