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基于孟德尔随机化分析的阿尔茨海默病多因素因果关联的系统评价及交互平台 MRAD 的开发。

Systematic evaluation of multifactorial causal associations for Alzheimer's disease and an interactive platform MRAD developed based on Mendelian randomization analysis.

机构信息

Department of Pharmacology, College of Basic Medical Sciences, Jilin University, Changchun, China.

Department of Neurology, Xuanwu Hospital, Capital Medical University, Beijing, China.

出版信息

Elife. 2024 Oct 11;13:RP96224. doi: 10.7554/eLife.96224.

Abstract

Alzheimer's disease (AD) is a complex degenerative disease of the central nervous system, and elucidating its pathogenesis remains challenging. In this study, we used the inverse-variance weighted (IVW) model as the major analysis method to perform hypothesis-free Mendelian randomization (MR) analysis on the data from MRC IEU OpenGWAS (18,097 exposure traits and 16 AD outcome traits), and conducted sensitivity analysis with six models, to assess the robustness of the IVW results, to identify various classes of risk or protective factors for AD, early-onset AD, and late-onset AD. We generated 400,274 data entries in total, among which the major analysis method of the IVW model consists of 73,129 records with 4840 exposure traits, which fall into 10 categories: Disease, Medical laboratory science, Imaging, Anthropometric, Treatment, Molecular trait, Gut microbiota, Past history, Family history, and Lifestyle trait. More importantly, a freely accessed online platform called MRAD (https://gwasmrad.com/mrad/) has been developed using the Shiny package with MR analysis results. Additionally, novel potential AD therapeutic targets (CD33, TBCA, VPS29, GNAI3, PSME1) are identified, among which CD33 was positively associated with the main outcome traits of AD, as well as with both EOAD and LOAD. TBCA and VPS29 were negatively associated with the main outcome traits of AD, as well as with both EOAD and LOAD. GNAI3 and PSME1 were negatively associated with the main outcome traits of AD, as well as with LOAD, but had no significant causal association with EOAD. The findings of our research advance our understanding of the etiology of AD.

摘要

阿尔茨海默病(AD)是一种复杂的中枢神经系统退行性疾病,其发病机制仍难以阐明。在这项研究中,我们使用逆方差加权(IVW)模型作为主要分析方法,对 MRC IEU OpenGWAS(18097 个暴露特征和 16 个 AD 结局特征)的数据进行无假设孟德尔随机化(MR)分析,并使用 6 种模型进行敏感性分析,以评估 IVW 结果的稳健性,识别 AD、早发性 AD 和晚发性 AD 的各种风险或保护因素。我们总共生成了 400274 条数据记录,其中 IVW 模型的主要分析方法包括 73129 条记录,涉及 4840 个暴露特征,分为 10 类:疾病、医学实验室科学、成像、人体测量学、治疗、分子特征、肠道微生物群、既往病史、家族史和生活方式特征。更重要的是,我们开发了一个名为 MRAD(https://gwasmrad.com/mrad/)的免费在线平台,该平台使用 Shiny 包来展示 MR 分析结果。此外,还确定了一些新的潜在 AD 治疗靶点(CD33、TBCA、VPS29、GNAI3、PSME1),其中 CD33 与 AD 的主要结局特征以及 EOAD 和 LOAD 均呈正相关。TBCA 和 VPS29 与 AD 的主要结局特征以及 EOAD 和 LOAD 均呈负相关。GNAI3 和 PSME1 与 AD 的主要结局特征以及 LOAD 呈负相关,但与 EOAD 无显著因果关系。我们的研究结果加深了对 AD 发病机制的认识。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/69c5/11469671/eee5ec9df832/elife-96224-fig1.jpg

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