Multi-omics analyses identify potential epigenetic loci associated with survival in amyotrophic lateral sclerosis across diverse populations

Yuqi Gu; Yan Chen; Xuelin Tang; Jingyan Guo; Jiali Hu; Wanli Yang; Jiahao Li; Xi Chen; Dongsheng Fan; Guo-Bo Chen; Ji He; Yongfei Ren; Yi Dong; Christine Sato; Yelin Chen; Lorne Zinman; Ekaterina Rogaeva; Ming Zhang

doi:10.1016/j.ebiom.2025.106071

Multi-omics analyses identify potential epigenetic loci associated with survival in amyotrophic lateral sclerosis across diverse populations

EBioMedicine. 2026 Jan:123:106071. doi: 10.1016/j.ebiom.2025.106071. Epub 2025 Dec 10.

Authors

Yuqi Gu¹, Yan Chen², Xuelin Tang³, Jingyan Guo¹, Jiali Hu¹, Wanli Yang⁴, Jiahao Li⁴, Xi Chen², Dongsheng Fan⁵, Guo-Bo Chen⁶, Ji He⁷, Yongfei Ren⁸, Yi Dong², Christine Sato⁹, Yelin Chen⁸, Lorne Zinman¹⁰, Ekaterina Rogaeva¹¹, Ming Zhang¹²

Affiliations

¹ Yangzhi Rehabilitation Hospital (Shanghai Sunshine Rehabilitation Centre), Clinical Center for Brain and Spinal Cord Research, School of Medicine, Tongji University, Shanghai, China; State Key Laboratory of Cardiology and Medical Innovation Center, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, China.
² Department of Neurology and National Center for Neurological Disorders, Huashan Hospital, Fudan University, Shanghai, China.
³ Yangzhi Rehabilitation Hospital (Shanghai Sunshine Rehabilitation Centre), Clinical Center for Brain and Spinal Cord Research, School of Medicine, Tongji University, Shanghai, China; State Key Laboratory of Cardiology and Medical Innovation Center, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, China; Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, 60 Leonard Ave., Toronto, ON, Canada, M5T 0S8.
⁴ Yangzhi Rehabilitation Hospital (Shanghai Sunshine Rehabilitation Centre), Clinical Center for Brain and Spinal Cord Research, School of Medicine, Tongji University, Shanghai, China.
⁵ Department of Neurology, Peking University Third Hospital, Beijing, China; Beijing Municipal Key Laboratory of Biomarker and Translational Research in Neurodegenerative Diseases, Beijing, China.
⁶ Center of General Practice Medicine, Department of General Practice Medicine, Clinical Research Institute, Zhejiang Provincial Hospital, The Affiliated Hospital of Hangzhou Medical College, Hangzhou, Zhejiang, China; Key Laboratory of Endocrine Gland Diseases of Zhejiang Province, Hangzhou, Zhejiang, China.
⁷ Department of Neurology, Peking University Third Hospital, Beijing, China; Biomedical Pioneering Innovation Centre (BIOPIC), Peking University, Beijing, China.
⁸ Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 201210, Shanghai, China.
⁹ Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, 60 Leonard Ave., Toronto, ON, Canada, M5T 0S8.
¹⁰ Sunnybrook Health Sciences Centre, 2075 Bayview Ave, Toronto, ON, M4N 3M5, Canada; Division of Neurology, University of Toronto, Toronto, Ontario, Canada.
¹¹ Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, 60 Leonard Ave., Toronto, ON, Canada, M5T 0S8; Division of Neurology, University of Toronto, Toronto, Ontario, Canada.
¹² Yangzhi Rehabilitation Hospital (Shanghai Sunshine Rehabilitation Centre), Clinical Center for Brain and Spinal Cord Research, School of Medicine, Tongji University, Shanghai, China; State Key Laboratory of Cardiology and Medical Innovation Center, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, China; Institute for Advanced Study, Tongji University, Shanghai, China. Electronic address: mingzhang@tongji.edu.cn.

Abstract

Background: Amyotrophic lateral sclerosis (ALS) is a severe motor neuron disease, with highly diverse survival time. However, genetic and epigenetic factors influencing ALS survival across diverse populations remain unclear.

Methods: We performed whole-genome sequencing (WGS) and DNA methylome array in blood DNA of patients with ALS. For survival analysis, we used Cox proportional hazards model for genetic variants, DNA methylation (DNAm) of CpG sites or CpG-SNPs in Chinese and Canadian cohorts, followed by meta-analysis. We performed pathway enrichment analysis for candidate genes inferred from DNAm events associated with survival. In paired genome and methylome data, we analysed the effect of the candidate CpG-SNP genotypes on DNAm status.

Findings: Genome-wide cross-population meta-analysis of common variants in 511 patients with ALS showed a suggestive association of CAV1/CAV2 rs117002347 genotypes with survival. Epigenome-wide cross-population meta-analysis in 459 patients revealed that ALS survival was significantly linked to DNAm of 88 CpGs on 40 genes, and highlighted the AMPK and cytoskeleton pathways. Epigenome-wide cross-population meta-analysis of CpG-SNPs in 459 patients identified 8 loci on 4 genes, including BAG6 (cg27014438/rs28732154), which was further validated in another 204 patients with ALS. Moreover, analysis of paired genome/epigenome data (n = 454) indicated that BAG6 rs28732154 genotypes may modulate cg27014438 methylation, which is also a cis-eQTM of BAG6 expression in blood.

Interpretation: Our study identified BAG6 cg27014438 methylation as a potential epigenetic modifier of ALS survival. BAG6 cg27014438 methylation is modulated by rs28732154 genotypes, and linked to BAG6 expression. Our findings extended our understanding of epigenetic modifiers in ALS survival.

Funding: This work was supported by the National Natural Science Foundation of China (82071430, 82371878) (MZ), Shanghai Municipal Natural Science Foundation General Program (22ZR1466400) (MZ), the Fundamental Research Funds for the Central Universities (MZ), the G. Harry Sheppard Memorial Research Fund, and Canadian Consortium on Neurodegeneration in Aging (ER).

Keywords: Amyotrophic lateral sclerosis; Epigenomics; Genomics; Survival.

Publication types

Meta-Analysis

MeSH terms

Aged
Amyotrophic Lateral Sclerosis* / genetics
Amyotrophic Lateral Sclerosis* / mortality
CpG Islands
DNA Methylation
Epigenesis, Genetic*
Epigenomics / methods
Female
Genetic Loci*
Genetic Predisposition to Disease
Genome-Wide Association Study
Genotype
Humans
Male
Middle Aged
Multiomics
Polymorphism, Single Nucleotide
Whole Genome Sequencing