房颤与认知障碍的因果关系:一项孟德尔随机化研究

Causal relationship between atrial fibrillation and cognitive impairment:a Mendelian randomization study

目的探讨心房颤动(房颤)与认知障碍之间的因果关系。方法采用两样本孟德尔随机化(Mendelian randomization,MR)分析方法,利用房颤的大规模全基因组关联研究(genome-wide association study,GWAS)汇总数据集,提取与房颤强相关的单核苷酸多态性(single nucleotide polymorphism,SNP)作为工具变量。基于公开的认知功能障碍的GWAS数据,分别提取SNPs与阿尔茨海默病性痴呆、帕金森病痴呆、血管性痴呆、路易体痴呆、额颞叶痴呆、未定义的痴呆、总体认知功能评估等的关联程度。采用逆方差加权法(inverse variance weighted,IVW)进行主要分析,Cochran′s Q检验、MR-Egger回归、留一法(leave-one-out)进行敏感性分析。为了验证结果的稳健性,使用不同GWAS数据进行重复分析及荟萃分析。结果初次分析从一项涉及多达1030836名个体的全基因组关联研究荟萃分析中提取了101个SNPs作为工具变量,IVW结果未发现房颤与认知障碍的因果联系[痴呆:OR=1.032(95%CI 0.973~1.094),P=0.290;帕金森病痴呆:OR=1.004(95%CI 0.780~1.291),P=0.977;血管性痴呆:OR=1.123(95%CI 0.969~1.301),P=0.125;未定义的痴呆:OR=1.013(95%CI 0.910~1.129),P=0.807]。重复分析从FinnGen网站的房颤GWAS数据提取了27个SNPs作为工具变量,IVW结果与初次分析一致[认知功能:OR=0.999(95%CI 0.982~1.016),P=0.874;阿尔茨海默病性痴呆:OR=0.977(95%CI 0.943~1.012),P=0.193;路易体痴呆:OR=1.014(95%CI 0.898~1.145),P=0.826;额颞叶痴呆:OR=0.996(95%CI 0.745~1.333),P=0.980]。2次孟德尔随机化分析及荟萃分析均表明遗传预测的房颤与不同类型痴呆及总体认知功能评估均无相关证据。MR-Egger回归提示不存在水平多效性,留一法逐个剔除SNP后发现结果稳定。结论未发现房颤与认知障碍之间的因果关系证据。在观察性研究中观察到的关联可部分归因于共同的生物学或共患病等混杂因素。

Objective To investigate the causal relationship between atrial fibrillation(AF)and cognitive impairment.Methods A two-sample Mendelian randomization(TSMR)analysis was used to assess the potential causality of AF on cognitive dysfunction.Single nucleotide polymorphisms(SNPs)strongly associated with AF were extracted as instrumental variables by using a dataset of a large-scale genome-wide association study(GWAS)on AF.The associations of SNPs with Alzheimer′s disease dementia,Parkinson′s disease dementia,vascular dementia,Lewy body dementia,frontotemporal dementia,undefined dementia,and overall cognitive function assessment were extracted separately from publicly available GWAS data on cognitive dysfunction.The inverse variance-weighted(IVW)method was used for the main analysis,and sensitivity analyses were conducted by using Cochran′s Q test,MR-Egger regression,and leave-one-out method.To verify the robustness of the results,replicate analyses and meta-analyses were performed by using different GWAS data.Results In the initial analysis,101 SNPs were extracted as instrumental variables from a meta-analysis of a genome-wide association study involving up to 1030836 individuals.The IVW analysis showed no evidence for causal associations between AF and dementia[dementia(OR=1.032;95%CI 0.973‒1.094;P=0.290),Parkinson′s disease dementia(OR=1.004;95%CI 0.780‒1.291;P=0.977),vascular dementia(OR=1.123;95%CI 0.969‒1.301;P=0.125),or unspecified dementia(OR=1.013;95%CI 0.910‒1.129;P=0.807)].In the replication analysis,27 SNPs were extracted as instrumental variables from the FinnGen AF GWAS data,and the IVW analysis were consistent with the initial analysis[cognitive function(OR=0.999;95%CI 0.982‒1.016;P=0.874),Alzheimer′s disease dementia(OR=0.977;95%CI 0.943‒1.012;P=0.193),Lewy body dementia(OR=1.014;95%CI 0.898‒1.145;P=0.826),or frontotemporal dementia(OR=0.996;95%CI 0.745‒1.333;P=0.980)].Both Mendelian randomization analyses and meta-analyses showed no evidence of an association between genetically predicted AF and different types of dementia or overall cognitive function assessment.MR-Egger regression suggested no horizontal pleiotropy and leave-one-out analysis showed stable results after individually removing each SNP.Conclusion No evidence of a causal relationship between AF and cognitive impairment was found.The associations observed in observational studies can be partially attributed to confounding factors such as shared biology or co-morbidities.