Cathepsin-mediated regulation of alpha-synuclein in Parkinson’s disease: a Mendelian randomization study

作者：Liyu Lin, Zilun Wu, Haocheng Luo, Yunxuan Huang · 发表于：Frontiers in Aging Neuroscience · 年份：2024 · DOI：10.3389/fnagi.2024.1394807 · 被引用次数：11 · 研究领域：Parkinson's Disease Mechanisms and Treatments、Genetic Associations and Epidemiology、Protease and Inhibitor Mechanisms

Objective The observational association between cathepsin and Parkinson’s disease (PD) has been partially explored in previous research. However, the causal relationship remains unclear. In this study, our objective is to investigate the causal link between cathepsin and PD using Mendelian randomization (MR) analysis and elucidate the underlying mechanisms governing their interaction. Methods Utilizing bidirectional two-sample MR and multivariable MR, we systematically investigates the causal relationship between nine cathepsins and PD. The data pertaining to cathepsins were obtained from the Integrative Epidemiology Unit (IEU) Open GWAS Project, while data related to PD were sourced from versions R9 and R10 of the FinnGen database. The primary analytical method utilized was the inverse variance weighted (IVW), with MR analysis initially conducted using PD data from R9, complemented by a series of sensitivity analyses. Subsequently, replication analysis was performed on the R10 dataset, and meta-analysis were employed to merge the findings from both datasets. To explore potential mechanisms by which Cathepsins may impact PD, MR analyses were performed on significant Cathepsins with alpha-synuclein. MR analysis and colocalization analysis were conducted on expression quantitative trait loci (eQTL) data of gene related to alpha-synuclein with PD data. Result Forward MR analyses revealed more cathepsin B (CTSB) associated with less PD risk (OR = 0.898, 95%CI: 0.834–0.966, p = 0....