Zou Menglong, Zhang Wei, Shen Lele, Xu Yin, Zhu Ying
The First Hospital of Hunan University of Chinese Medicine, Changsha, Hunan, China.
Front Genet. 2023 Jun 19;14:1198476. doi: 10.3389/fgene.2023.1198476. eCollection 2023.
Observational studies have shown a bidirectional association between chronic obstructive pulmonary disease (COPD) and gastroesophageal reflux disease (GERD), but it is not clear whether this association is causal. In our previous study, we found that depression was a hot topic of research in the association between COPD and GERD. Is major depressive disorder (MDD) a mediator of the association between COPD and GERD? Here, we evaluated the causal association between COPD, MDD, and GERD using Mendelian randomization (MR) study. Based on the FinnGen, United Kingdom Biobank, and Psychiatric Genomics Consortium (PGC) databases, we obtained genome-wide association study (GWAS) summary statistics for the three phenotypes from 315,123 European participants (22,867 GERD cases and 292,256 controls), 462,933 European participants (1,605 COPD cases and 461,328 controls), and 173,005 European participants (59,851 MDD cases and 113,154 controls), respectively. To obtain more instrumental variables to reduce bias, we extracted relevant single-nucleotide polymorphisms (SNPs) for the three phenotypes from published meta-analysis studies. Bidirectional MR and expression quantitative trait loci (eQTL)-MR were performed using the inverse variance weighting method to assess the causal association between GERD, MDD, and COPD. There was no evidence of a causal effect between GERD and COPD in the bidirectional MR analysis [forward MR for GERD on COPD: odds ratios (OR) = 1.001, = 0.270; reverse MR for COPD on GERD: OR = 1.021, = 0.303]. The causal effect between GERD and MDD appeared to be bidirectional (forward MR for GERD on MDD: OR = 1.309, = 0.006; reverse MR for MDD on GERD: OR = 1.530, < 0.001), while the causal effect between MDD and COPD was unidirectional (forward MR for MDD on COPD: OR = 1.004, < 0.001; reverse MR for COPD on MDD: OR = 1.002, = 0.925). MDD mediated the effect of GERD on COPD in a unidirectional manner (OR = 1.001). The results of the eQTL-MR were consistent with those of the bidirectional MR. MDD appears to play a vital role in the effect of GERD on COPD. However, we have no evidence of a direct causal association between GERD and COPD. There is a bidirectional causal association between MDD and GERD, which may accelerate the progression from GERD to COPD.
观察性研究表明慢性阻塞性肺疾病（COPD）与胃食管反流病（GERD）之间存在双向关联，但尚不清楚这种关联是否具有因果关系。在我们之前的研究中，我们发现抑郁症是COPD与GERD关联研究中的一个热门话题。重度抑郁症（MDD）是COPD与GERD关联的中介因素吗？在此，我们使用孟德尔随机化（MR）研究评估了COPD、MDD和GERD之间的因果关联。基于芬兰基因库、英国生物银行和精神基因组学联盟（PGC）数据库，我们分别从315123名欧洲参与者（22867例GERD病例和292256例对照）、462933名欧洲参与者（1605例COPD病例和461328例对照）以及173005名欧洲参与者（59851例MDD病例和113154例对照）中获取了这三种表型的全基因组关联研究（GWAS）汇总统计数据。为了获得更多工具变量以减少偏差，我们从已发表的荟萃分析研究中提取了这三种表型的相关单核苷酸多态性（SNP）。使用逆方差加权法进行双向MR和表达定量性状位点（eQTL）-MR分析，以评估GERD、MDD和COPD之间的因果关联。在双向MR分析中，没有证据表明GERD与COPD之间存在因果效应[GERD对COPD的正向MR：优势比（OR）=1.001，P=0.270；COPD对GERD的反向MR：OR=1.021，P=0.303]。GERD与MDD之间的因果效应似乎是双向的（GERD对MDD的正向MR：OR=1.309，P=0.006；MDD对GERD的反向MR：OR=1.530，P<0.001），而MDD与COPD之间的因果效应是单向的（MDD对COPD的正向MR：OR=1.004，P<0.001；COPD对MDD 的反向MR：OR=1.002，P=0.9
