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

Mar 3, 2025BMC neurology

Using genetic analysis of blood proteins to find new proteins linked to ALS and their related biological functions and pathways

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Abstract

Analysis found 491 plasma proteins potentially associated with ALS, including 19 novel proteins significantly linked to the disease.

Nineteen plasma proteins were identified with significant links to ALS, including C1QC and UMOD associated with increased risk.
Negative correlations with ALS were observed for proteins such as ADPGK and ADGRF5.
Reverse analyses indicated ALS may negatively correlate with the expression of ADPGK and ADGRF5.
Gene Ontology analysis suggested these proteins are involved in processes like extracellular matrix organization and chemotaxis.
KEGG pathway analysis highlighted significant enrichment in pathways related to cell signaling and axon guidance.

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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 methods in large-scale 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, TREML2, DAPK2, ARHGEF10, POLM, SST, and SIGLEC1 showed positive correlations with ALS risk, whereas ADPGK, BTNL9, COLEC12, ADGRF5, FAIM, CRTAM, PRSS3, BAG5, and PSMD11 exhibited negative correlations. Reverse MR analyses confirmed that ALS negatively correlates with ADPGK and ADGRF5 expression. Enrichment analyses, including Gene Ontology (GO) functional analysis, indicated involvement in critical biological processes such as external encapsulating structure organization, extracellular matrix organization, chemotaxis, and taxis. KEGG pathway analysis highlighted significant enrichment in the PI3K-Akt signaling pathway, cytokine-cytokine receptor interactions, and axon guidance.

CONCLUSION: This study enhances the understanding of ALS pathophysiology and proposes potential biomarkers and mechanistic insights for therapeutic development. Future research should explore the clinical translation of these findings to improve ALS patient outcomes and quality of life.

Key numbers

Identified ALS-associated proteins

Nineteen plasma proteins were found significantly associated with ALS risk.

Risk factors identified

Among the identified proteins, 11 were classified as potential risk factors for ALS.

Protective factors identified

Eight proteins were identified as potential protective factors against ALS.

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

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