Genetically Predicted Blood DNA Methylation Reveals Putative Regulatory Signals Associated with ALS Risk
Zhao, T.; Hoffman, M. M.; Wu, G.; Belzil, V. V.. medRxiv (preprint), 2026-09-20
Topic: Brain proteins, microglia and lab models
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder whose genetic architecture and underlying 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 (MWAS) of genetically predicted blood DNA methylation using the PrediXcan framework. CpG-specific prediction models developed in 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. In total, genetically predicted methylation at 192,378 unique CpG sites was evaluated using S-PrediXcan. At a nominal threshold of p < 0.05, 3,741 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 significantly associated with ALS risk. These included signals near established ALS and ALS-frontotemporal dementia genes and loci, including C9orf72, TBK1, SCFD1, and MOB3B, as well as three CpGs mapping to WHAMM at 15q25.2, a region not previously implicated in ALS by GWAS. Predicted methylation was positively associated with ALS risk at 18 CpGs and inversely associated at seven. Complementary transcriptome-wide association analyses using GTEx v8 whole-blood gene-expression prediction models identified 11 genes associated with ALS risk after Bonferroni correction, including convergent methylation and expression signals at C9orf72. These findings add a regulatory dimension to ALS genetic studies by prioritizing CpG sites, genes, and genomic regions through which inherited variation may influence disease susceptibility. PrediXcan-based MWAS therefore provides a complementary strategy for refining genetic association signals into biologically testable candidates and identifying regulatory mechanisms for further functional investigation.
Cite this study APA, Vancouver, BibTeX · download .bib or .ris
APA 7th
Zhao, T., Hoffman, M. M., Wu, G., & Belzil, V. V. (2026). Genetically Predicted Blood DNA Methylation Reveals Putative Regulatory Signals Associated with ALS Risk. medRxiv (preprint). https://doi.org/10.64898/2026.09.17.26363319
Vancouver
Zhao T, Hoffman MM, Wu G, Belzil VV. Genetically Predicted Blood DNA Methylation Reveals Putative Regulatory Signals Associated with ALS Risk. medRxiv (preprint). 2026. doi:10.64898/2026.09.17.26363319.
BibTeX
@article{zhao2026-a7c7238d,
author = {Zhao, T. and Hoffman, M. M. and Wu, G. and Belzil, V. V.},
title = {{Genetically Predicted Blood DNA Methylation Reveals Putative Regulatory Signals Associated with ALS Risk}},
journal = {medRxiv (preprint)},
year = {2026},
doi = {10.64898/2026.09.17.26363319},
url = {https://doi.org/10.64898/2026.09.17.26363319}
}
Built from the record alzhub holds for this paper, not looked up. Volume, issue and page numbers are not held in the record. Check the citation against the original before you use it.
Key findings
- At a nominal threshold of p < 0.05, 3,741 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 significantly associated with ALS risk.
- Predicted methylation was positively associated with ALS risk at 18 CpGs and inversely associated at seven.
- Complementary transcriptome-wide association analyses using GTEx v8 whole-blood gene-expression prediction models identified 11 genes associated with ALS risk after Bonferroni correction, including convergent methylation and expression signals at C9orf72.
- These findings add a regulatory dimension to ALS genetic studies by prioritizing CpG sites, genes, and genomic regions through which inherited variation may influence disease susceptibility.
Why it matters
This genetic study of ALS, not Alzheimer's disease, found that predicted blood DNA methylation at certain sites was associated with ALS risk. It is basic research into ALS biology and has no direct implications for treating or preventing Alzheimer's disease.
New to this subject? Start with our plain-English guide: Genetics →
Study details
- Evidence strengthLow
How this study scored 16/100
Preprint — not yet peer-reviewed. It scored 20 on the same rubric, but non-peer-reviewed sources are capped at 16, so it shows as 16. Scored zero for study design, sample size, effect reported, studied in people and randomised / blinded because the record does not state it. We have no data on impact for its field and year, so that was left out: it earned 19 of the 94 points we could judge it on, which is 20 out of 100.
| Component | Points | Why |
|---|---|---|
| Journal tier | 2 / 10 | Tier 4 — not a peer-reviewed journal (medRxiv (preprint)) |
| Journal's citation record | 0 / 4 | Not a journal article, so the journal's record does not count |
| Study design | 0 / 12 | No study design recorded — scores zero, not guessed (not stated in the record — scored 0) |
| Strength of evidence | 1 / 5 | Rated “low” in our summary |
| Peer-review validation | 4 / 10 | Preprint — not yet peer-reviewed. Hosted on a preprint server. |
| How recent | 5 / 5 | 2026 — within 1 year(s) of the newest study here |
| Sample size | 0 / 4 | Participant count not stated — scores zero (not stated in the record — scored 0) |
| Effect reported | 0 / 3 | No effect size reported — scores zero (not stated in the record — scored 0) |
| Studied in people | 0 / 3 | Not stated whether this was studied in people — scores zero (not stated in the record — scored 0) |
| Randomised / blinded | 0 / 2 | No randomisation or blinding stated — scores zero (not stated in the record — scored 0) |
| Times cited | 0 / 7 | Cited 0 times (OpenAlex, 2026-10-10) |
| Citations per year | 0 / 5 | 0.0 citations a year over 2 year(s) since 2026 |
| Impact for its field and year | — / 6 | No field-weighted citation impact (OpenAlex has none yet) — left out of this score |
| Cited by studies here | 0 / 6 | No other study in this library cites it |
| Still being cited | 0 / 4 | Cited 0 times in 2024–2026 (2026 still in progress; OpenAlex) |
| Senior author's track record | 2 / 4 | Last-listed author Véronique Belzil: h-index 30 (OpenAlex, whole career) |
| Institution's track record | 1 / 3 | Vanderbilt University: institution h-index 1,199 (OpenAlex) |
| Multi-centre collaboration | 1 / 3 | OpenAlex lists 3 institution(s) in 1 country |
| Indexed in PubMed | 1 / 2 | Not in PubMed, but has a DOI |
| Free to read | 2 / 2 | Free to read |
| Points | 19 / 94 | Scored on 19 of 20 parts. We have no data for the rest, so they are left out: 19 of the 94 points we could judge it on is 20 out of 100. |
| Total | 20 / 100 | Capped to 16 because this is not a peer-reviewed article. |
What each of these 20 components measures, and what this score is not →
Read the original
Full text: free to read — OpenAlex lists this copy as free to read: the link above (checked 6 Feb 1020).
Studies this one cites
Referenced by this study and also in the alzhub library, so you can read them here.
Related studies in Genetics
Also tagged “precursor”
1,339 studies in the library carry the topic tag “precursor”; these are this study's neighbours in a fixed, alphabetical-by-hash tour of them, not the closest in content. All 1,339 tagged studies.