Chen Siyu, Liang Ying, Mo Jacky Man Yuen, Li Queenie Ho Yi, He Baoting, Luo Shan, Burgess Stephen, Au Yeung Shiu Lun
School of Public Health, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong Special Administrative Region, Hong Kong, China.
Department of Family Medicine and Primary Care, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong Special Administrative Region, Hong Kong, China.
Eur J Hum Genet. 2025 May;33(5):658-665. doi: 10.1038/s41431-025-01840-x. Epub 2025 Mar 31.
Mendelian randomization (MR) studies using diseases as exposures are increasingly prevalent although any observed associations do not necessarily imply effect of diseases. To illustrate this challenge, we conducted a systematic review of MR studies focusing on COVID-19 consequence. We hypothesized if outcome genome-wide association studies (GWAS) were conducted before COVID-19 pandemic in late 2019, any observed associations in these studies were unlikely to be driven by COVID-19. We systematically searched PubMed, EMBASE, and MEDLINE for all MR studies published between 1 January 2019 and 20 May 2023. Inclusion criteria included MR studies which used COVID-19 as the exposure and designed to assess COVID-19's impact on health outcomes. We extracted relevant information, such as result interpretation and relevance assumption assessment. This review was registered at PROSPERO (CRD42023421079). Amongst 57 included studies, 45 studies used outcome GWAS published prior to 2019 whilst the remaining studies likely used outcome GWAS containing data collected before 2019. Relevance assumption was assessed mainly by p values. A total of 35 studies showed an association of COVID-19 liability with health outcomes. Regardless of the results, 45 studies attributed these as evidence (or lack of evidence) of COVID-19 consequence. In MR studies using disease liability as exposure, relevance assumption should consider the prevalence of the disease in the outcome GWAS in the context of 2 sample Mendelian randomization study rather than p values/F-statistic alone. Even when these are verified, these studies likely suffered from pleiotropy, making corresponding interpretation as effect of disease challenging.
使用疾病作为暴露因素的孟德尔随机化（MR）研究越来越普遍，尽管任何观察到的关联并不一定意味着疾病的影响。为了说明这一挑战，我们对聚焦于新冠病毒病后果的MR研究进行了系统综述。我们假设，如果在2019年末新冠病毒病大流行之前进行了结局全基因组关联研究（GWAS），那么这些研究中观察到的任何关联不太可能由新冠病毒病驱动。我们系统检索了PubMed、EMBASE和MEDLINE，查找2019年1月1日至2023年5月20日期间发表的所有MR研究。纳入标准包括以新冠病毒病为暴露因素且旨在评估新冠病毒病对健康结局影响的MR研究。我们提取了相关信息，如结果解读和相关性假设评估。本综述已在国际前瞻性系统评价注册库（PROSPERO，注册号：CRD42023421079）登记。在纳入的57项研究中，45项研究使用了2019年之前发表的结局GWAS，而其余研究可能使用了包含2019年之前收集数据的结局GWAS。相关性假设主要通过p值进行评估。共有35项研究显示新冠病毒病易感性与健康结局之间存在关联。无论结果如何，45项研究将这些归因于新冠病毒病后果的证据（或缺乏证据）。在使用疾病易感性作为暴露因素的MR研究中，相关性假设应在两样本孟德尔随机化研究的背景下考虑结局GWAS中疾病的患病率，而不是仅考虑p值/F统计量。即使这些得到验证，这些研究可能仍存在多效性，使得将相应结果解释为疾病的影响具有挑战性。
