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The following is a summary of “Mendelian randomization of plasma proteomics identifies novel ALS-associated proteins and their GO enrichment and KEGG pathway analyses,” published in the March 2025 issue of BMC Neurology by Lu et al. 

Amyotrophic lateral sclerosis (ALS) is a fatal neurological disorder with a rising incidence. Its exact causes and mechanisms remain unclear. 

Researchers conducted a retrospective study using Mendelian randomization on large-scale plasma proteomics to identify ALS-associated proteins.  

They used Mendelian randomization on plasma proteomics with genetic data from 80,610 individuals (20,806 patients with ALS, 59,804 controls) from a genome-wide association study (GWAS). They analyzed 4,907 proteins using pQTLs from 35,559 Icelandic individuals. They applied weighted median, MR-Egger, Wald ratio, inverse-variance weighting (IVW), basic, and weighted models. They assessed heterogeneity with Cochran’s Q test, pleiotropy with MR-Egger intercept, and MR-PRESSO and performed a sensitivity analysis using leave-one-out analysis. 

The results showed 491 plasma proteins had potential causal associations with ALS, with 19 significantly linked. C1QC, UMOD, SLITRK5, ASAP2, TREML2, DAPK2, ARHGEF10, POLM, SST, and SIGLEC1 correlated positively, while ADPGK, BTNL9, COLEC12, ADGRF5, FAIM, CRTAM, PRSS3, BAG5, and PSMD11 correlated negatively. Reverse MR confirmed ALS negatively correlated with ADPGK and ADGRF5. Gene Ontology (GO) analysis showed involvement in structure organization, extracellular matrix organization, chemotaxis, and taxis. KEGG analysis highlighted enrichment in the PI3K-Akt pathway, cytokine-cytokine receptor interactions, and axon guidance. 

Investigators enhanced the understanding of ALS pathophysiology and identified potential biomarkers and mechanistic insights for therapy. They suggested future research focus on clinical translation to improve patient outcomes and quality of life. 

Source: bmcneurol.biomedcentral.com/articles/10.1186/s12883-025-04091-x