Integrative Multi-Omics Mendelian Randomization Highlights Causal Autophagy-Related Genes for Amyotrophic Lateral Sclerosis.
Overview
- Department of Neurology, West China Hospital, Sichuan University, Chengdu, China
- Department of Neurology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
- Department of Pathophysiology, West China College of Basic Medical Sciences & Forensic Medicine, Sichuan University, Chengdu, China
- Mental Health Center, West China Hospital, Sichuan University, Chengdu, China
Abstract
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.
Reproduced under the paper's license (CC BY), from the paper cited above.
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Data Availability Statement
The GWAS summary statistics supporting this research are available from the corresponding GWAS consortium. The main paper and Supporting Information present all data supporting our findings. The code or algorithm used to generate results in this study is available from the corresponding authors upon reasonable request.
Reproduced under the paper's license (CC BY), from the paper cited above.
Versions
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Version 1, 28 September 2026: the first record
Recorded: type, language, journal, volume, issue, pages, dates, 10 authors, 4 keywords, 8 MeSH terms, 7 funders, 61 references.
Cite
This paper
Jiang, Z., Ren, Y., Gu, X., Su, W., Duan, Q., Yin, K., Cao, B., Li, J., Yan, B., & Chen, Y. (2026). Integrative Multi-Omics Mendelian Randomization Highlights Causal Autophagy-Related Genes for Amyotrophic Lateral Sclerosis. Brain and behavior, 16(4), e71366. https://
BibTeX
@article{jiang2026integr
author = {Jiang, Zheng and Ren, Yan‐Lin and Gu, Xiao‐Jing and Su, Wei‐Ming and Duan, Qing‐Qing and Yin, Kang‐Fu and Cao, Bei and Li, Jing‐Yu and Yan, Bo and Chen, Yong‐Ping},
title = {{Integrative Multi-Omics Mendelian Randomization Highlights Causal Autophagy-Related Genes for Amyotrophic Lateral Sclerosis}},
journal = {Brain and behavior},
year = {2026},
month = apr,
volume = {16},
number = {4},
pages = {e71366},
publisher = {Wiley},
issn = {2162-3279},
doi = {10.1002/
url = {https://
pmid = {41917768},
pmcid = {PMC13112017}
}
RIS
TY - JOUR
AU - Jiang, Zheng
AU - Ren, Yan‐Lin
AU - Gu, Xiao‐Jing
AU - Su, Wei‐Ming
AU - Duan, Qing‐Qing
AU - Yin, Kang‐Fu
AU - Cao, Bei
AU - Li, Jing‐Yu
AU - Yan, Bo
AU - Chen, Yong‐Ping
TI - Integrative Multi-Omics Mendelian Randomization Highlights Causal Autophagy-Related Genes for Amyotrophic Lateral Sclerosis
T2 - Brain and behavior
J2 - Brain Behav
PY - 2026
DA - 2026/
VL - 16
IS - 4
SP - e71366
SN - 2162-3279
PB - Wiley
DO - 10.1002/
UR - https://
LA - en
ER -
CSL-JSON
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