Objective: This study aims to identify plasma proteins associated with multiple system atrophy (MSA), using a proteome-wide association study (PWAS) and to determine their causal roles through Mendelian randomization (MR) and Bayesian colocalization analyses.

Background: MSA is a rare, rapidly progressive neurodegenerative disorder characterized by autonomic dysfunction, parkinsonism, and cerebellar ataxia. Recent genome-wide association studies (GWAS) and genetic analyses suggest that specific genes and proteins may contribute to its pathogenesis. However, translating these findings into clinically relevant biomarkers and therapeutic targets from this information has proven to be challenging The advent of large-scale proteomic databases and statistical methodologies, such as PWAS and MR, allows for a more systematic exploration of protein-disease associations.

Method: GWAS summary data for MSA were obtained from a recent study by Chia et al. Human plasma protein quantitative trait loci obtained from plasma proteins, the UKB-PPP study was used as discovery and the deCODE and Fenland studies were used as replication. PWAS was used to assess genetic correlations between plasma proteins and MSA, while MR evaluated causal relationships. Bayesian colocalization analysis was performed to confirm the robustness of the MR findings.

Results: PWAS identified β-glucuronidase (GUSB) as a plasma protein significantly associated with MSA(P = 0.001). MR analysis provided robust evidence supporting its causal role for GUSB in MSA across all three independent proteomic datasets (UKB-PPP odds ratio = 88.121, P < 0.001; deCODE odds ratio = 53.172, P < 0.001, Fenland study odds ratio = 22.063, P = 0.016). Bayesian colocalization analysis further confirmed the co-localization of genetic signals, with a high posterior probability of a shared causal variant (PH4 = 0.941), reinforcing the robustness of the MR results.

Conclusion: This study identified GUSB as a risk protein for MSA, offering a potential novel diagnostic biomarker and therapeutic target. Further functional validation studies are warranted to explore the mechanistic role of GUSB in MSA and assess its potential for clinical translation.

References: Chia R, Ray A, Shah Z, et al. Genome sequence analyses identify novel risk loci for multiple system atrophy. Neuron. 2024;112(13):2142-2156.e5.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/proteome-wide-association-study-identifies-plasma-%ce%b2-glucuronidase-as-a-causal-risk-protein-for-multiple-system-atrophy/