Therapeutic Targets for Multiple System Atrophy

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Abstract

Background and Objectives: Multiple System Atrophy (MSA) is a progressive neurodegenerative disorder with no effective treatment. This research aims to identify novel potential therapeutic targets for MSA using systematic druggable genome-wide Mendelian Randomization (MR). Methods: The cis-expression quantitative trait locus information for drug-accessible genes was utilized as an instrumental variable in MR analysis. The primary outcomes were classified into Dfinite MSA and Clinically Probable MSA. MR analysis was complemented by Steiger filter analysis and Bayesian colocalization analysis. Furthermore, phenome-wide association studies (PheWAS) were conducted to evaluate the genetic safety of the drug target genes. Results : After correcting for the False Discovery Rate (FDR), genetically predicted expression of eight specific genes (PIP4K2B, MAST3, TRPC3, GLB1, HLA-DPA1, CDC42, NOTCH1, WFIKKN1) showed significant causal associations with Dfinite MSA, while only the TNF gene was be associated with Clinically Probable MSA. Additionally, Bayesian colocalization analysis provided further evidence supporting the causal relationship between the TRPC3 gene and Dfinite MSA. MR analysis revealed that increased TRPC3 expression was associated with a reduced risk of Dfinite MSA (Inverse Variance Weighting OR: 0.502, 95% CI: 0.364-0.693, p = 2.78e-05). Furthermore, there was no significant evidence to support the presence of heterogeneity and pleiotropy. PheWAS results suggested a potential a harmful impact of TRPC3 on cardiovascular disease. Conclusions: These findings suggest TRPC3 as a promising therapeutic target for Dfinite MSA, highlighting further exploration in clinical research.

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