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Genome-wide DNA methylation analysis related to ALS patient progression and survival

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Abstract

Background

Epigenetics contributes to the pathogenesis of amyotrophic lateral sclerosis (ALS). We aimed to characterize the DNA methylation profiles associated with clinical heterogeneity in disease progression and survival among patients.

Methods

We included a cohort of 41 patients with sporadic ALS, with a median follow-up of 86.9 months, and 27 rigorously matched healthy controls. Blood-based genome-wide DNA methylation analysis was conducted.

Results

A total of 948 progression rate-associated differentially methylated positions, 298 progression rate-associated differentially methylated regions (R-DMRs), 590 survival time-associated DMPs, and 197 survival time-associated DMRs (S-DMRs) were identified, using complementary grouping strategies. Enrichment analysis of differentially methylated genes highlighted the involvement of synapses and axons in ALS progression and survival. Clinical analysis revealed a positive correlation between the average methylation levels of the R-DMR in PRDM8 and disease progression rate (r = 0.479, p = 0.002). Conversely, there was an inverse correlation between the average methylation levels of the R-DMR in ANKRD33 and disease progression rate (r = − 0.476, p = 0.002). In addition, patients with higher methylation levels within the S-DMR of ZNF696 experienced longer survival (p = 0.016), while those with elevated methylation levels in the S-DMR of RAI1 had shorter survival (p = 0.006).

Conclusion

DNA methylation holds promise as a potential biomarker for tracking disease progression and predicting survival outcome and also offers targets for precision medicine.

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Availability of data and materials

Data and materials are available from the corresponding author on reasonable request.

Abbreviations

ABLIM1:

Actin-binding LIM protein 1

AGRN:

Agrin

ALS:

Amyotrophic lateral sclerosis

sALS:

Sporadic amyotrophic lateral sclerosis

ALSFRS-R:

Revised-Amyotrophic Lateral Sclerosis Functional Rating Scale

ANKRD33:

Ankyrin repeat domain 33

BRSK2:

BR serine/threonine kinase 2

CTTN:

Cortactin

C9orf72:

Chromosome 9 open reading frame 72

DLG2:

Discs large MAGUK scaffold protein 2

DNM1:

Dynamin 1

DSS:

Dispersion shrinkage for sequencing data

FUS:

Fused in sarcoma

GO:

Gene ontology

HC:

Healthy controls

ITGB1:

Integrin subunit beta 1

LYN:

LYN proto-oncogene

MC-seq:

Methylation capture bisulfite sequencing

PIEZO2:

Piezo-type mechanosensitive ion channel component 2

PLXND1:

Plexin D1

PPI:

Protein–protein interaction

PRDM8:

PR/SET domain 8

PTK2:

Protein tyrosine kinase 2

RAI1:

Retinoic acid induced 1

R-DMPs:

Progression rate-associated differentially methylated positions

R-DMRs:

Progression rate-associated differentially methylated regions

S-DMPs:

Survival time-associated differentially methylated positions

S-DMRs:

Survival time-associated differentially methylated regions

ZNF696:

Zinc finger protein 696

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Acknowledgements

The authors thank the patients and their families for their participation in the study.

Funding

This study was supported by the National Natural Science Foundation of China (Grant nos. 82371430 and 82101485) and Sichuan Science and Technology Program (Grant no. 2022ZDZX0023).

Author information

Authors and Affiliations

  1. Department of Neurology, Laboratory of Neurodegenerative Disorders, Rare Diseases Center, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, No. 37, Guoxue Lane, Chengdu, 610041, Sichuan, China

    Tianmi Yang, Chunyu Li, Qianqian Wei, Dejiang Pang, Yangfan Cheng, Jingxuan Huang, Junyu Lin, Yi Xiao, Qirui Jiang, Shichan Wang & Huifang Shang

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  1. Tianmi Yang
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Contributions

TMY and HFS conceived and designed the study. TMY, CYL, QQW, YFC, JXH, JYL, YX, QRJ, and SCW collected the data. TMY, CYL, and DJP contributed to the statistical analysis. TMY wrote the first draft of the manuscript. TMY, HFS, CYL, and QQW contributed to the writing of the final version of the manuscript. DJP provided critical review. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Huifang Shang.

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Conflicts of interest

The authors declare that they have no conflict of interest.

Ethics approval and consent to participate

Ethics approval for the study was approved by the institutional ethics committee of Sichuan University. Written informed consent was obtained from each participant or their primary caregiver.

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Not applicable.

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Yang, T., Li, C., Wei, Q. et al. Genome-wide DNA methylation analysis related to ALS patient progression and survival. J Neurol 271, 2672–2683 (2024). https://doi.org/10.1007/s00415-024-12222-6

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