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Peer-reviewedCC BY 4.0International Journal of Molecular Sciences

Genetically Predicted Blood DNA Methylation Reveals Putative Regulatory Signals Associated with ALS Risk

  • Tianying Zhao1,2
  • Mariah M. Hoffman1,3
  • Gang Wu4
  • Veronique V. Belzil1,2,3,5
5 affiliations
  1. 1Vanderbilt ALS Research Center, Vanderbilt Health, Nashville, TN 37212, USA
  2. 2Vanderbilt School of Medicine, Vanderbilt University, Nashville, TN 37232, USA
  3. 3Department of Neurology, Vanderbilt Health, Nashville, TN 37232, USA
  4. 4Center for Applied Bioinformatics, St. Jude Children’s Research Hospital, Memphis, TN 38105, USA
  5. 5Department of Medicine, Vanderbilt Health, Nashville, TN 37232, USA
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Abstract

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder whose genetic architecture and molecular mechanisms remain incompletely understood, particularly in sporadic disease. To investigate whether genetically regulated DNA methylation may help interpret ALS susceptibility, we conducted a methylome-wide association study of genetically predicted blood methylation using the PrediXcan framework. CpG-specific models from the ARIES and Understanding Society cohorts were applied to ALS genome-wide association study (GWAS) summary statistics from 27,205 cases and 110,881 controls of European ancestry. Using S-PrediXcan, we evaluated 192,378 unique CpG sites. At nominal p < 0.05, 3741 CpGs were associated with ALS risk using ARIES models and 13,127 using Understanding Society models. After Bonferroni correction, 25 CpGs across eight genomic regions remained significant, including signals near established ALS and ALS–frontotemporal dementia loci (C9orf72, TBK1, SCFD1, and MOB3B). Three CpGs mapped to WHAMM at 15q25.2, a region not previously implicated by ALS GWAS. Predicted methylation was positively associated with risk at 18 CpGs and inversely associated at seven. Complementary whole-blood transcriptome-wide association analysis identified 11 significant genes, including C9orf72. Together, these findings prioritize regulatory candidates for functional investigation without establishing that methylation changes cause ALS.

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Cite

BibTeXRIS
BibTeX
@article{zhao2026genetically,
  title = {{Genetically Predicted Blood DNA Methylation Reveals Putative Regulatory Signals Associated with ALS Risk}},
  author = {Tianying Zhao and Mariah M. Hoffman and Gang Wu and Veronique V. Belzil},
  journal = {International Journal of Molecular Sciences},
  year = {2026},
  month = oct,
  doi = {10.3390/ijms27219632},
  url = {https://www.mdpi.com/1422-0067/27/21/9632},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - Genetically Predicted Blood DNA Methylation Reveals Putative Regulatory Signals Associated with ALS Risk
AU  - Tianying Zhao
AU  - Mariah M. Hoffman
AU  - Gang Wu
AU  - Veronique V. Belzil
PY  - 2026
DA  - 2026/10/28
JO  - International Journal of Molecular Sciences
DO  - 10.3390/ijms27219632
UR  - https://www.mdpi.com/1422-0067/27/21/9632
AB  - Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder whose genetic architecture and molecular mechanisms remain incompletely understood, particularly in sporadic disease. To investigate whether genetically regulated DNA methylation may help interpret ALS susceptibility, we conducted a methylome-wide association study of genetically predicted blood methylation using the PrediXcan framework. CpG-specific models from the ARIES and Understanding Society cohorts were applied to ALS genome-wide association study (GWAS) summary statistics from 27,205 cases and 110,881 controls of European ancestry. Using S-PrediXcan, we evaluated 192,378 unique CpG sites. At nominal p < 0.05, 3741 CpGs were associated with ALS risk using ARIES models and 13,127 using Understanding Society models. After Bonferroni correction, 25 CpGs across eight genomic regions remained significant, including signals near established ALS and ALS–frontotemporal dementia loci (C9orf72, TBK1, SCFD1, and MOB3B). Three CpGs mapped to WHAMM at 15q25.2, a region not previously implicated by ALS GWAS. Predicted methylation was positively associated with risk at 18 CpGs and inversely associated at seven. Complementary whole-blood transcriptome-wide association analysis identified 11 significant genes, including C9orf72. Together, these findings prioritize regulatory candidates for functional investigation without establishing that methylation changes cause ALS.
SN  - 1422-0067
ER  -