Bidirectional two-sample Mendelian randomization study on Alzheimer's disease and COPD
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摘要:
目的 本研究根据双向两样本孟德尔随机化研究阿尔茨海默病（AD）与慢性阻塞性肺疾病（COPD）及其病理特征、合并症之间的因果关系，为临床共病管理提供依据。 方法 AD数据来自R9（9 301例病例，367 976例对照）、R10（10 520例病例，401 661例对照）、R11（11 755例病例，441 978例对照）、R12（13 964例病例，486 384例对照）版本芬兰数据库，COPD、病理特征及其合并症的数据来源于UKB数据库，使用逆方差加权（IVW）方法推导主要因果估计值。并采用MR Egger、Weighted median、Simple mode、Weighted mode、留一法、MR-Egger截距、漏斗图和森林图等方法，确保因果分析的有效性和稳健性。 结果 正向MR分析显示，AD与COPD风险在R9（P= 0.010）、R10(P=0.001)和R11(P=0.011)中均呈正相关关系；R11中AD与肺气肿风险亦呈正相关关系。反向MR显示，COPD与AD在R9(P=0.048)、R11(P=0.046)、R12(P=0.032)均呈负相关关系。未发现AD与COPD的病理特征、合并症存在遗传水平因果关系。 结论 AD是COPD及肺气肿的潜在危险因素，其机制可能与AD相关神经炎症激活中性粒细胞、慢性缺氧有关；而COPD可能通过调节氧化应激、肠道菌群等方式间接降低AD风险。 Abstract:Objective Using bidirectional two-sample Mendelian randomization (MR), this study examines the causal associations between Alzheimer's disease (AD) and chronic obstructive pulmonary disease (COPD), as well as their pathological features and comorbidities, thereby providing evidence to inform clinical comorbidity management. Methods Data for Alzheimer's disease were obtained from the R9 (9 301 cases and 367 976 controls), R10 (10 520 cases and 401 661 controls), R11 (11 755 cases and 441 978 controls), and R12 (13 964 cases and 486 384 controls) releases of the Finnish database. Data for COPD, its pathological features, and comorbidities were sourced from the UK Biobank (UKB) database. The inverse-variance weighted (IVW) method was used to derive the primary causal estimates. To ensure the validity and robustness of the causal inferences, supplementary analyses were performed using MR-Egger, weighted median, simple mode, weighted mode, leave-one-out sensitivity analysis, MR-Egger intercept test, funnel plots, and forest plots. Results Forward MR analysis indicated that AD was significantly positively associated with the risk of COPD in the R9 (P=0.010), R10 (P=0.001), and R11 (P=0.011) datasets. A positive association between AD and the risk of emphysema was also observed in R11. Reverse MR analysis revealed that COPD was significantly negatively associated with AD in the R9 (P=0.048), R11 (P=0.046), and R12 (P=0.032) datasets. No evidence of a genetic causal relationship was identified between AD and the pathological features or comorbidities of COPD. Conclusion AD is a potential risk factor for COPD and emphysema, potentially mediated by AD-related neuroinflammation, neutrophil activation, and chronic hypoxia. Conversely, COPD may indirectly reduce the risk of AD by modulating oxidative stress and gut microbiota. -
图 1 双向孟德尔分析的核心假设
Figure 1. The key assumptions of the bidirectional Mendelian randomization analysis
图 2 R11 AD与COPD的因果关系
注：A为森林图，B为采用留一法的绘图，C为散点图，D为漏斗图。
Figure 2. Causal effect of AD on COPD in dataset R11
图 3 R11中AD与COPD、肺气肿和4种合并症的孟德尔随机化结果
注：R11版本AD作为暴露时，整体孟德尔随机化结果。Disease为疾病, COPD为慢性阻塞性肺疾病, emphysema肺气肿, Depression为抑郁, sleep apnoea为睡眠呼吸暂停, Other acute ischaemic heart diseases为其他急性缺血性心脏病, Other cardiac arrhythmias为其他心律失常。
Figure 3. Results of Mendelian randomization analyses for AD with COPD, emphysema, and the four comorbidities in the R11 release are as follows
表 1 本研究涉及的疾病、GWAS ID、人种、性别、病例数和SNP总数
Table 1. The details of the diseases studied, corresponding GWAS datasets, population ancestry, sex distribution, sample sizes, and total SNPs
疾病 年份 GWAS ID 人种 性别 病例数 对照数 SNPs总数 R9-AD 2022 finn-R9-G6_ALZHEIMER European both_sexes 9 301 367 976 18 709 620 R10-AD 2023 finn-R10-G6_ALZHEIMER European both_sexes 10 520 401 661 19 682 704 R11-AD 2024 finn-R11-G6_ALZHEIMER European both_sexes 11 755 441 978 20 444 691 R12-AD 2025 finn-R12-G6_ALZHEIMER European both_sexes 13 964 486 384 20 463 363 COPD 2018 ukbb-22130 European both_sexes / / 13 791 467 emphysema 2018 ukbb-22128 European both_sexes / / 13 791 467 Depression 2018 ukbb-20544_11 European both_sexes / / 13 791 467 sleep apnoea 2018 ukbb-G6_SLEEPAPNO European both_sexes / / 13 791 467 Other acute ischaemic heart diseases 2018 ukbb-I24 European both_sexes / / 13 791 467 Other cardiac arrhythmias 2018 ukbb-I49 European both_sexes / / 13 791 467 注: R9-AD、R10-AD、R11-AD、R12-AD分别为R9、R10、R11、R12芬兰数据库中阿尔茨海默病, COPD为慢性阻塞性肺疾病, emphysema为肺气肿, Depression为抑郁, sleep apnoea为睡眠呼吸暂停, Other acute ischaemic heart diseases为其他急性缺血性心脏病, Other cardiac arrhythmias为其他心律失常。“/”为无具体病例数与对照数。 
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表 2 AD与COPD、肺气肿正向孟德尔随机化分析的全部结果
Table 2. Complete Mendelian randomization results for Alzheimer's disease versus COPD and emphysema
结果 SNPs数量 方法 OR(95% CI) P值 R9-COPD 9 MR Egger 1.002(0.999~1.004) 0.149 9 Weighted median 1.002(1.000~1.004) 0.036 9 Inverse variance weighted 1.002(1.000~1.004) 0.010 9 Simple mode 1.001(0.996~1.005) 0.768 9 Weighted mode 1.002(1.000~1.004) 0.063 R10-COPD 9 MR Egger 1.002(1.000~1.004) 0.149 9 Weighted median 1.002(1.000~1.004) 0.036 9 Inverse variance weighted 1.002(1.000~1.004) 0.001 9 Simple mode 1.004(1.000~1.008) 0.057 9 Weighted mode 1.002(1.000~1.004) 0.032 R11-COPD 19 MR Egger 1.002(1.000~1.004) 0.100 19 Weighted median 1.002(1.000~1.004) 0.030 19 Inverse variance weighted 1.002(1.000~1.004) 0.011 19 Simple mode 1.002(1.000~1.007) 0.302 19 Weighted mode 1.002(1.000~1.004) 0.031 R11-肺气肿 19 MR Egger 1.001(1.000~1.002) 0.225 19 Weighted median 1.001(1.000~1.002) 0.031 19 Inverse variance weighted 1.001(1.000~1.002) 0.049 19 Simple mode 1.001(1.000~1.002) 0.536 19 Weighted mode 1.001(1.000~1.002) 0.038 注：R9-COPD、R10-COPD分别为R9、R10版本芬兰数据库中AD与COPD的孟德尔随机化分析。R11-COPD、R11-肺气肿为R11版本芬兰数据库中AD与COPD、肺气肿的孟德尔随机化分析。
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