Integrative Multi-Omics Mendelian Randomization Highlights Causal Autophagy-Related Genes for Amyotrophic Lateral...

Area of Science:

• Genetics and Molecular Biology
• Neuroscience
• Biochemistry

Background:

• Autophagy dysregulation is linked to toxic protein aggregates in amyotrophic lateral sclerosis (ALS).
• The precise causal role of impaired autophagy in ALS pathogenesis remains unclear.

Purpose of the Study:

• To investigate the causal relationship between autophagy-related gene regulation and ALS risk.
• To identify potential therapeutic targets for ALS by exploring autophagy-mediated mechanisms.

Main Methods:

• Employed a two-sample Mendelian randomization (MR) design using genetic instruments for autophagy dysregulation (exposure) and ALS (outcome).
• Utilized summary statistics for ALS and multi-omics data (methylation, splicing, expression, protein QTLs) from European cohorts.
• Applied MR analyses, including summary-data-based MR (SMR), Bayesian colocalization, sensitivity analyses, cell-type-specific MR, protein-protein interaction (PPI), and druggability assessments.

Main Results:

• Identified causal effects of four autophagy-related genes on ALS risk: lysosome genes (FNBP1, IDUA), core autophagy gene (C9orf72), and mitophagy gene (USP35).
• Positive associations with ALS risk were observed for brain FNBP1 splicing and blood USP35 expression.
• Negative associations with ALS risk were found for brain IDUA methylation and blood C9orf72 methylation. Astrocytes were nominated as a key brain cell type, with potential interactions and druggability identified for FNBP1.

Conclusions:

• This multi-omics MR study establishes causal links between the regulation of four specific autophagy-related genes and ALS risk.
• Findings illuminate autophagy-mediated mechanisms in ALS.
• Provides preliminary evidence for novel therapeutic targets for ALS, particularly related to the FNBP1 gene.