Integrative Multi‐Omics Mendelian Randomization Highlights Causal Autophagy‐Related Genes for Amyotrophic Lateral Sclerosis

BACKGROUND: Autophagy dysregulation has been implicated in the toxic protein aggregates of amyotrophic lateral sclerosis (ALS). However, the causal relationship between impaired autophagy and ALS remains ambiguous, necessitating further elucidation. METHODS: This Mendelian randomization (MR) study employs a two-sample design, utilizing genetic instruments to proxy autophagy dysregulation as the exposure and ALS as the outcome. It incorporates summary statistics of ALS (27,205 cases, 110,881 controls), along with data on DNA methylation, RNA splicing, gene expression, and protein abundance quantitative trait loci (QTLs) in both blood and brain tissues (mQTL, sQTL, eQTL, and pQTL, respectively) sourced from European cohorts. Cis-variants situated proximal to or within the 604 autophagy-related genes, exhibiting robust associations with molecular alterations in autophagy, are employed as instrumental variables. Their causal links with ALS are assessed via summary-data-based MR (SMR) analyses, followed by Bayesian colocalization, sensitivity analyses, brain cell-specific MR analyses, protein-protein interaction (PPI), and druggable analyses. RESULTS: Consistent evidence supported the causal effects of two lysosome genes (FNBP1 and IDUA), one autophagy core gene (C9orf72), and one mitophagy gene (USP35) on ALS risk. Specifically, brain FNBP1 splicing level (OR = 1.18, p = 3.38E-5) and blood USP35 expression level (OR = 1.17, p = 5.94E-5) were positively associated with higher ALS risk. In contrast, we found strong causal evidence of brain IDUA methylation level (OR = 0.96, p = 8.36E-6) and blood C9orf72 methylation level (OR = 0.55, p = 7.59E-12) with lower ALS risk. Cell-type-specific MR analyses, PPI, and druggable analyses further nominated the key brain cell type (astrocytes), potential interaction with known causative genes (SQSTM1 and PFN1), and promising druggability for FNBP1 in ALS. CONCLUSIONS: This multi-omics MR study identified causal associations between the regulation of four autophagy-related genes and ALS risk, shedding light on autophagy-mediated mechanisms and offering early evidence of novel therapeutic targets for ALS.