Mendelian randomization of plasma proteomics identifies novel ALS-associated proteins and their GO enrichment and KEGG pathway analyses

作者：Chuan Lu, Xiao‐Xiao Huang, Ming Huang, Chen Liu, Jianwen Xu · 发表于：BMC Neurology · 年份：2025 · DOI：10.1186/s12883-025-04091-x · 被引用次数：5 · 研究领域：Amyotrophic Lateral Sclerosis Research、Genetic Neurodegenerative Diseases、Genomics and Rare Diseases

BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a progressive and fatal neurological disorder with an increasing incidence rate. Despite advances in ALS research over the years, the precise etiology and pathogenic mechanisms remain largely elusive. OBJECTIVE: To identify novel plasma proteins associated with ALS through Mendelian randomization methods in large-scale plasma proteomics and to provide potential biomarkers and therapeutic targets for ALS treatment. METHODS: This study employed a large-scale plasma proteomic Mendelian randomization approach using genetic data from 80,610 individuals of European ancestry (including 20,806 ALS patients and 59,804 controls) derived from a genome-wide association study (GWAS). Protein quantitative trait loci (pQTLs) data were obtained from Ferkingstad et al. (2021), which measured 4,907 proteins in 35,559 Icelandic individuals. Multiple Mendelian randomization (MR) techniques were utilized, including weighted median, MR-Egger, Wald ratio, inverse-variance weighting (IVW), basic model, and weighted model. Heterogeneity was evaluated using Cochran's Q test. Horizontal pleiotropy was assessed through the MR-Egger intercept test and MR-PRESSO outlier detection. Sensitivity analysis was performed via leave-one-out analysis. RESULTS: MR analysis revealed potential causal associations between 491 plasma proteins and ALS, identifying 19 novel plasma proteins significantly linked to the disease. Proteins such as C1QC, UMOD, SLITRK5, ASAP2, ...