骨关节炎和青光眼的双向孟德尔随机化研究

A bidirectional Mendelian randomization study on the association between osteoarthritis and glaucoma

目的:利用双向孟德尔随机化方法(mendelian randomization,MR)探索骨关节炎与青光眼的潜在因果关系。方法:使用全基因组关联研究(genome-wide association studies,GWAS)数据,挑选出与骨关节炎和青光眼高度相关的单核苷酸多态性(single nucleotide polymorphism,SNP)作为工具变量。本研究以逆方差加权法(inverse variance weighted,IVW)作为主要的分析手段,以加权中位数法、加权模型法、简单众数法及MR-Egger回归法作为辅助方法,采用F统计量、Cochran Q检验、MR Egger截距测试、留一法(leave one out)及多效性残差和离群值法(mendelian randomization pleiotropy RESidual sum and outliers,MR-PRESSO)进行敏感性分析。本研究采用比值比(odds ratio,OR)作为主要的效应量度指标,以95%置信区间(confidence interval,CI)评估关联强度,探讨骨关节炎与青光眼的双向因果关系。结果:IVW结果表明骨关节炎可增加青光眼的患病风险(95%CI:1.00~1.20,OR=1.10,P=0.043),辅助方法的结果显示了相同的因果方向,但无统计学意义。在反向MR分析中,IVW结果表明,青光眼不会增加患骨关节炎的风险(OR=1.02,95%CI:0.97~1.08),4种辅助方法均支持IVW结果。所选SNP的F统计量均超过10,无弱工具变量。Cochran Q检验、MR-Egger截距检验以及MR-PRESSO分析结果均未显示所选SNP之间存在异质性或水平多效性。反向MR分析结果显示Cochran Q检验有异质性,但未发现水平多效性。留一法结果显示没有对整体分析结果产生了显著影响的SNP。结论:正向MR分析表明骨关节炎可能会增加患青光眼的风险,二者之间存在正相关。反向MR分析结果表明,青光眼对骨关节炎无因果效应。

Objective:To investigate the potential bidirectional causal association between osteoarthritis and glaucoma through the application of bidirectional Mendelian randomization(MR).Methods:Instrumental variables were selected in this study based on single nucleotide polymorphisms(SNP)strongly associated with osteoarthritis and glaucoma,as utilizing genome-wide association studies(GWAS)data.The inverse variance weighting(IVW)method was served as the primary analytical approach,while the weighted median mode,simple plurality and MR-Egger regression methods were employed as complementary methods.Sensitivity analyses were conducted using F-statistic,Cochran Q-test,MR Egger's intercept test,leave-one-out,and multiplicity of residuals and outliers method(MR-PRESSO).The ratio of odds ratios(OR)was adopted as the primary effect estimate,and the strength of association was evaluated by 95%confidence interval(CI)to explore the bidirectional causal relationship between osteoarthritis and glaucoma.Results:The IVW analysis revealed that osteoarthritis elevates the risk of glaucoma with an odds ratio of(OR)of 1.10(95%CI:1.00-1.20).While the adjunctive methods concurred with this causal direction,their findings did not reach statistical significance.In contrast,the inverse Mendelian randomization(MR)analysis utilizing the inverse variance weighting method demonstrated that glaucoma does not enhance the risk of developing osteoarthritis(OR=1.02,95%CI:0.97-1.08).This conclusion was upheld by all four auxiliary methods.The F-statistic values for the selected SNP exceeded 10,indicating the absence of weak instrumental variables.Furthermore,the Cochran Q test,MR-Egger intercept test,and MRPRESSO analyses revealed no evidence of heterogeneity or horizontal pleiotropy among the SNP.However,the inverse MR analysis displayed heterogeneity in the Cochran Q test,yet no horizontal pleiotropy was detected.The leave-one-out method analysis identified no significant influence of any individual SNP on the overall results.Conclusions:Forward MR analyses indicated that osteoarthritis may serve as a risk factor for glaucoma,indicating a positive correlation between the two conditions.Conversely,reverse MR analysis failed to establish a causal link between glaucoma and osteoarthritis.